Derivatives postnatural acids and their pharmacologically acceptable salts and compositions on their basis

 

(57) Abstract:

Use: medicine for the treatment of disorders of calcium metabolism. Products: derivatives postnatural acid of the formula R-alk-CH(CO2R4-CH(CO2R3)P(O)(OR5)2where R is an amino group NR1R2, R1and R2- H, C1- C6-alkyl; a nitrogen-containing five-membered heterocyclic ring which is selected from the group including caloried, imidazole, pyrrolidine, alk is a covalent bond, methylene or alkylene containing from 2 to 6 carbon atoms, R3, R4and R5-H, C1- C6-alkyl and their pharmaceutically acceptable salts, and in the case when R3, R4and R5- methyl and alk is a covalent bond, R can not mean dimethylaminopropyl. Reagent I: carboxylic acid derivative of formula R-alk-CH(y)-CO2R4where R, alk and R4have the above values, y is the group to delete. Reagent 2: compound of formula H2C(CO2R3)P(O)(OR5)2where R3and R5have the above values. Reaction conditions: in a medium of an organic solvent in the presence of a base. 2 S. and 1 C.p. f-crystals, 1 table.

The invention relates to new derivatives phosphono-antanov "Phosphorus and Sulfur 13, 85 /1982/, describes the synthesis of 3-dimethyl ether dimethylamino-2-dimethylphosphino-succinic acid, however, farmakologicheskoi action of this compound is unknown.

Currently, it is found that similar derivatives phosphono-succinic acid have a great influence on calcium metabolism and, thus, is suitable for treatment on a large scale disturbances of calcium metabolism. First of all, they can very well be used where the broken formation and resorption of bone tissue, i.e. they are suitable for treating diseases of bone/skeletal/ system, such as osteoporosis, Paget disease, Bechterew's disease, and others.

On the basis of these properties, however, they also find application in the treatment of urolithiasis and for prevention of heterotopic ossification. Due to its effect on calcium metabolism they, then, form the basis for the treatment of rheumatoid arthritis, osteoarthritis and degenerative arthrosis.

The object of the present invention is compounds of General formula I

< / BR>
in which

R - if necessary substituted amino group of General formula-NR1R2and R1and R2independently from one another, each is hydrogen, the bottom of the case ring, which if necessary can be single or twofold substituted by lower alkyl or halogen;

alk is a valence bond, methylene group, saturated or unsaturated, linear or branched Allenova chain with 2 to 6 C-atoms; and

R3, R4, R5each independently from each other hydrogen, lower alkyl or benzyl;

and their pharmacologically acceptable salts;

moreover, in the case when R3=R4=R5=CH3and alk is a valence bond, R can not be dimethylaminopropoxy.

Lower alkyl in all cases should represent a linear or branched C1-C6is an alkyl group, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or hexyl, in particular methyl, ethyl, propyl, isobutyl and pentyl.

Lower alkenyl denotes unsaturated residues with 3-6 C atoms, such as, for example, allyl, but-2-enyl, hexa-2,4-dienyl, especially allyl.

Lower quinil should be an unsaturated residues with 3-6 C atoms, such as, for example, propargyl, but-3-inyl, Gex-5-inyl, in particular, however, propargyl.

If the remainder R is a saturated heterocyclic ring, it is a 3-8-membered rings, which, azepino, morpholino or thiomorpholine ring, especially pyrolidine, azepino and morpholino ring.

If R is an unsaturated heterocyclic ring, it is usually about the imidazoline ring.

If R is a heteroaromatic ring, this is a five - or six-membered rings as pyridine, pyrimidine, pyrazinone, imidazole, especially pyridine and imidazole ring.

The heterocyclic ring can be substituted by one or twice C1-C6- alkyl groups, preferably methyl, ethyl or ISO-propyl group, as well as chlorine or bromine.

Alk, in case saturated or unsaturated, linear or branched alkalinous chain, represents the remains, as, for example, methylene, ethylene, propylene, butylene, 2-methylpropyl, pentile, 1,1-dimethylpropyl, 2,3-dimethyl-propylene, 2,2-dimethyl-propylene, 2-methyl-butylene, hexylen, 2,3-dimethyl-butylene, 2-methyl-pentile, 2-butylen, 2-Butylin, in particular methylene, ethylene, propylene, butylene, 2-methyl-propylene, pentile, hexylen and 2-butylen.

Compounds of General formula I contain at least two of this present application.

Compounds of General formula /I/ get itself known methods, preferably those that:

a/. derivatives of carboxylic acids of General formula (II)

< / BR>
in which

R, alk and R4have the above meanings and Y is a removable group, such as, for example, Gal-or-O-SO2-Z, and Gal should indicate the chloride, bromide or iodide, and Z must denote methyl, phenyl, p-were or p-nitrophenyl, enter into interaction with a complex ester phosphonooxy acid of General formula (III

< / BR>
in which

R3and R5have the above significance, in the case when R is a primary or secondary amino group, it should be in a protected form, for example, in the form of acylamino or palaeotopography; and, if necessary, the formed esters of partially or fully omelet to the corresponding acids of General formula /I/; or

b) compounds of General formula /IV/

< / BR>
in which

R, alk, R3and R4have the above values, enter into interaction with dialkylphosphites General formula: H-P/O/OR5/2/V/, in which R5have the above values, and, if necessary, the formed esters of partially or totally>/BR>in which

R3, R4and R5have the above meanings, in itself known manner enter into interaction with the compound of General formula /VIII/ R-alk-M /VIII/ in which R has the above meanings and M is hydrogen or alkali or alkaline earth metal, and, if necessary, the formed esters of partially or fully omelet to the corresponding acids of General formula /I/ and desirable in the case of translating a pharmacologically acceptable salt.

Compounds of General formula (II) receive the fact that, in the case when Y=Gal, the compound of General formula IX/: R-alk-CH2-CO2R4/IX/, in which R, alk and R4have the above values, halogenous according to known literature method; or when Y in the formula (II) denotes the O-SO2-Z - group, hydroxyl group, compounds of General formula /X/

< / BR>
in which

R, alk and R4have the above values are converted into the corresponding ester sulfonic acids

Compounds of General formula (III partially available on sale /Aldrich - Chemie GmbH u.Go.KG/ and in special cases are obtained by known methods by reacting a derivative halogenases acid of General formula /XI/

Gal-CH2is the General formula /XII/ P/OR5/3(XII)

in which R5have the above values.

Compounds of General formula /IV/ get the fact that

1. The compound of General formula /XIII/ R-H

in which R has the above significance, alkylate using compounds of General formula /XIV/

< / BR>
in which

Gal, alk, R3and R4have the above meanings; or

2. The compound of General formula /XV/.

< / BR>
in which

R, alk, R3and R4have the above values, dehydration by known methods.

Compounds of General formula /V/ available for sale /Aldrich Co/.

Compounds of General formula /VI/ get the fact that the compound of General formula /V/ enter into interaction with complex acetylenedicarbonic acid ester of General formula /XVI/

R4O2C-C-C-CO2R3(XVI)

W

R3and R4have the above values.

Compounds of General formula /VII/ get itself in a known manner, so that the compound of General formula /XVII/

< / BR>
in which

R3and R4have the above values, enter into interaction with the compound of General formula /XII/.

Compounds of General formula /VIII/ in the case when M is not oboznachaiut by known methods by alkylation of compounds of General formula /XIII/ using compounds of General formula Gal-alk-CH2-CO2R4/XVIII/ where Gal, "alk' and R4have the above values.

Compounds of General formula /X/, you can get well-known from the literature methods by oxidation of the corresponding compounds of General formula IX/.

Compounds of General formula /XIV/ you can get itself in a known manner, so that the compound of General formula /XIX/

< / BR>
in which

R3and R4have the above values, enter into interaction with the compound of General formula /XX/: Gal - l - Gal /XX/, in which Gal and alk have the above values.

Compounds of General formula /XV/ get itself in a known manner by reacting compounds of General formula /IX/ s in connection with the General formula /XXI/

< / BR>
in which

R3have the above values.

Compounds of General formula /XVII/ get known methods by the allyl synthesized compounds of General formula /XXII/

< / BR>
in which

R3and R4have the above values.

Halogenoalkane compounds of General formula IX/ is carried out by introducing its interaction with molecular halogen /as chlorine, bromine, iodine/ preferably bromine, without solvent is terepharmacy carbon, and with the addition of red phosphorus, trichloride phosphorus or tribromide phosphorus and at a temperature of from room temperature to 100oC, preferably at 90oC /K. Stoh, Chem. Pharm. Bull. 34. 2078/1986/; H. J. Ziegler, Synthesis, 1969, 39/. Further compounds of General formula IX can be halogenate the fact that, in an aprotic solvent as tetrahydrofuran, at low temperature, preferably at -78oC, metallinou using lithium amide, diisopropylaniline, and then metilirovannye compounds of General formula IX/ enter into interaction with bromine, iodine, tetrachloride or cetarehhloristam carbon /M. Hesse, Helv. Chim. Acta 72, 847/1989/; R. T Arnold J. Org. Chem. 43, 3687/1978 respectively, with N-chloro or N-bromo-succinimide /W. Oppolzer, Tetrahedron Lett. 26, 5037/1985/.

The transfer of the hydroxyl group of compounds of General formula /X/ into the corresponding ester sulfonic acids carried out by conventional means, as, for example, by condensation with a sulfonic acid chloride as the acid chloride methane-, benzene-, p-toluene - or p-nitrobenzene-sulfonic acids, preferably the acid chloride methane - or p-toluene-sulfonic acids, in an inert solvent as methylene chloride, tetrahydrofuran or diethyl ether, preferably methylene chloride, in the application helperC to room temperature.

On obtaining the compounds of General formula /XIX/ see R. Eyjolfsson, Acta, Chem, Scand, 3075/1970/.

The interaction of the compounds of formula (II) with a compound of General formula (III carried out, as a rule, in an aprotic solvent like toluene, tetrahydrofuran, diethyl ether or dimethylformamide, preferably dimethylformamide, or tetrahydrofuran, using a strong base like potassium hydride, sodium hydride, diisopropylamide lithium or hexamethyldisilane lithium, preferably sodium hydride or diisopropylamide lithium, and at temperatures of - 78oC 90oC, it is preferable, however, if -10oCoC room temperature.

The interaction of compounds of General formula IV with compound of General formula /V/ occurs when the conditions of accession to Michael, in a solvent like methanol, ethanol, toluene, tetrahydrofuran, diethyl ether or dimethylformamide, preferably methanol, tetrahydrofuran or dimethylformamide, without other additives, or when applying the Foundation, as methylate or sodium ethylate, or potassium, sodium hydride, potassium hydride or diisopropylamide lithium, preferably sodium methylate, sodium hydride or diisopropylamide lithium, and at temperatures about the connection between General formula /VI/, consequently, /V/, and the compound of General formula /VIII/ hold, as a rule, in conditions of joining Michael in a solvent like methanol, ethanol, toluene, tetrahydrofuran, diethyl ether or dimethylformamide, preferably methanol, tetrahydrofuran or dimethylformamide, with no other additives or when applying Foundation as sodium hydride, potassium hydride, diisopropylamide lithium utility, ethylaniline, and, if necessary, salts of copper, as the chloride or copper bromide to form the corresponding cuprate compounds of General formula /VIII/ /see G. H. Posner, Tetrahedron Letters 37, 3215 /1977//, and at temperatures from -78 to 90oC, preferably from -78 to room temperature.

The reaction between the compound of General formula /XI/ and the compound of General formula /XII/ shall, as a rule, without solvent, at temperatures from room temperature up to 150oC, preferably at 130oC, when the reaction time from 30 minutes to 30 hours, preferably for 18 hours

Alkylation of compounds of General formula /XIII/ using compounds of General formula /XIV/ or compounds of the General formula /XVIII/ usually carried out in a solvent as methanol, ethanol, propanol, tetrahydrofuran, diethyl ether or dimethylformamide, prepact the Oia, as potassium carbonate, sodium methylate, sodium hydride or potassium diisopropylamide lithium utility or finality, preferably sodium hydride, potassium carbonate, utility or finality, and at a temperature of from -78oC to the boiling temperature under reflux solvent used, preferably at -78oC 50oC. Dehydration of compounds of General formula /XV/ usually proceeds in a solvent like benzene, toluene, xylene, chloroform or methylene chloride, preferably toluene or methylene chloride, with the addition of dehydrating as sulfuric acid, phosphoric acid, p-toluensulfonate, preferably p-toluensulfonate, and at a temperature from room temperature up to the boiling temperature under reflux solvent used, preferably at 100oC. About the interaction connections /V/ connection /XVI/ see R. Burgada, Phosphorusand Sulfur 13, 85/1982/.

The reaction of the compound /XII/ connection /XVII/ normally carried out by a solvent at temperatures 50-180oC, preferably at 150oC.

The interaction of the compounds of formula /XIX/ connection formula /XX/ carry out usually in an inert solvent like tetrahydrofuran, in the application justify the false ether carboxylic acids of General formula IX/ c aldehyde of the formula /XXI/ usually carried out in a solvent, as methanol, ethanol, tetrahydrofuran, diethyl ether or dimethylformamide, preferably methanol or tetrahydrofuran, in the presence of a basic condensing means as methylate or sodium ethylate, tert-butyl potassium, sodium hydride or diisopropylamide lithium, preferably sodium methylate, tert.-butyl potassium or diisopropylamide lithium, and at temperatures from -78 to 60oC, preferably from -78oC to room temperature.

About the allyl bromirovanii 2-metilfenidato or 2-methylmaleimide acids and their derivatives, see J. Org. Chem. 34, 1228 /1969/. Oxidation of compounds of General formula IX to compounds of General formula /X/ carry out usually in a solvent as tetrahydrofuran, by adding bases, as diisopropylamide lithium or N-isopropyl-N-cyclohexylamino lithium, in the application of the oxidizer, as derived oxaziridine, proximality or oxygen, at temperatures from -78oC to room temperature, preferably at 50oC /C. Tamm. Tetrahedron Lett. 26, 203 /1985/; F. A. Davis J. Org. Chem. 51, 2402/1986/; C. Winotai Synth. Commun. 18, 2141 /1988/.

The free phosphonic acid group in the compounds of General formula I by heating with trialkylamine esters of ortho-formic acid can translat the developments of General formula /I/ to the corresponding free phosphonic acid group exercise, as a rule, without solvent or in an inert solvent like methylene chloride, thanks to trimethylsilylethynyl as trimethylsilylpropyne or iodide, at temperatures between -50oC to room temperature, preferably at 0oC.

The esterification of the free carboxylic acid groups in the compounds of General formula /I/ carried out according to known literature methods by heating compounds of General formula I, in which R3and/or R4- hydrogen is contained as a residual alcohol) cooked in a complex ether carboxylic acid with an alcohol, with the addition of an acid catalyst as hydrochloric acid, sulfuric acid or p-toluensulfonate, preferably sulfuric acid. Saponification of the group of ester carboxylic acid compounds of the General formula /I/ exercise ordinary ways, the fact that an ester of carboxylic acid of General formula /I/ in the water, or in mixtures of water with tetrahydrofuran, dioxane, methanol or ethanol, preferably in a mixture of water with tetrahydrofuran, is treated with a hydroxide, like sodium hydroxide, potassium or lithium, preferably sodium hydroxide or lithium, and at temperatures from room temperature up to 80oC, preferably at room temperaturethe fact, according to conventional methods, the compound of General formula /I/, where R denotes acylamino or palaeotopography, treated with an aqueous inorganic acids, respectively, bases as hydrochloric acid or sulfuric acid, respectively, sodium hydroxide or potassium, or enter into interaction with hydrazine or hydroxylamine.

The group of esters of phosphonic and carboxylic acid compounds of the General formula /I/, then, can omelet by boiling with hydrochloric or Hydrobromic acid. If in the compounds of General formula /I/ are benzyl ester group, by hydrogenolysis can be translated into the corresponding free phosphonic group, respectively, carboxylic acids.

As pharmacologically acceptable salts are used primarily mono-, respectively, disloca or ammonium salt, which receive the usual way, for example, by titration of the compounds with inorganic or organic bases, such as sodium bicarbonate or potassium hydroxide, sodium hydroxide, potassium hydroxide, aqueous ammonia or amines, such as trimethyl - or triethyl-amine.

Salt is cleaned, usually by resultant deposition rates from the be applied in liquid or solid form, intestinal or parenteral. While taking into account all the usual forms of administration, such as tablets, capsules, pills, syrups, solutions, suspensions, etc. as a medium for injection take into consideration preferably water, which contains customary in the case of solutions for injection of additives as stabilizers, agents, dissolution and buffers.

Such additives are, for example, tartrate and citrate buffers, ethanol, complex-forming agents like ethylenediaminetetraacetic acid and its non-toxic salts/ high-molecular polymers /as liquid polyethylene oxide/ to adjust the viscosity. Liquid carriers for solution for injections must be sterile and preferably, they poured into ampoules. Solid carriers are, for example, starch, lactose, mannitol, methylcellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids like stearic acid, gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high molecular weight polymers /as glycols/ suitable for oral administration of the composition in the desired case may contain sweetening and flavoring agents.

The dosage may depend on various Paterno 10-1000 mg/person, preferably 100-500 mg/person and can be entered at one time or divided into several times.

In the sense of the present invention, in addition to those specified in the examples, compounds and obtained by the combination of all specified in the claims, the values of the substituents of the compounds, preferred are the following derivatives of succinic acid, and their sodium and potassium salts, methyl, ethyl or benzyl esters:

a/. 3-amino-2-phosphono-succinic acid; so pl. 220oC /decomposition/;

b/. 3-dimethylamino-2-phosphono-succinic acid;

c/. 2-/N-methyl-N-propylamino/-2-phosphono-succinic acid;

d/. 3-/1-pyrrolidino/-2-phosphono-succinic acid;

e/. 3-/imidazol-1-yl/-2-phosphono-succinic acid;

f/. 3-aminomethyl-2-phosphono-succinic acid; so pl. 103oC /decomposition/;

g/. 3-dimethylaminomethyl-2-phosphono-succinic acid, so pl. 112oC /decomposition/;

h/. 3-/N-methyl-N-pentylamine/-methyl-2-phosphono-succinic acid; so pl. 110oC;

i/. 3-/2-dimethylamino-ethyl/-2-phosphono-succinic acid;

j/. 3-{2-/N-methyl-N-propylamino/ethyl}-2-phosphono-succinic acid;

k/. 2-phosphono-3-{2-/pyrrolidin-1-yl/-ethyl}-succinic acid;

l/. 3-/2-/imidazol-1-yl/ethyl/-2-phosphono-succinic acid is one-1-yl/propyl}-succinic acid;

o/. 3-/4-aminobutyl/-2-phosphono-succinic acid; so pl. 135oC /decomposition/;

p/. 2-phosphono-3-{4-/pyrrolidin-1-yl/butyl}-succinic acid;

g/. 3-/5-aminopentyl/-2-phosphono-succinic acid;

r/. 2-phosphono-3-{5-/pyrrolidin-1-yl/-pentyl}-succinic acid;

s/. 3-{5-/imidazol-1-yl/-pentyl}-2-phosphono-succinic acid;

t/. 3-/6-aminohexyl/-2-fasino-succinic acid;

u/. 2-phosphono-3-{6-/pyrrolidin-1-yl/hexyl}-succinic acid;

v/. 3-{6-/imidazol-1-yl/-hexyl}-2-phosphono-succinic acid;

w/. 2-phosphono-3-/pyrid-2-yl/-succinic acid;

x/. 2-phosphono-3-/pyrid-3-yl/-succinic acid;

y/. 2-phosphono-3-/pyrid-4-yl/-succinic acid;

z/. 3-/imidazol-2-yl/-2-phosphono-succinic acid;

aa/. 3-/imidazol-4-yl/-2-phosphono-succinic acid;

ab/. 2-phosphono-3-/pyrrolidin-2-yl/-succinic acid;

ac/. 2-phosphono-3-/pyrrolidin-3-yl/-succinic acid;

ad/. 2-phosphono-3-/pyrid-2-yl-methyl/-succinic acid;

ae/. 2-phosphono-3-/pyrid-3-yl-methyl/-succinic acid;

af/. 2-phosphono-3-/pyrid-4-yl-methyl/-succinic acid;

ag/. 3-/imidazol-2-yl-methyl/-2-phosphono-succinic acid;

ah/. 3-/imidazol-4-yl-methyl/-2-phosphono-succinic acid;

ai/. 2-phosphono-3-/pyrrolidin-2-yl-methyl/-succinic acid;

aj/. 2-phosphono-3-/pyrrolidin-3-yl/ethyl}-succinic acid;

am/. 2-phosphono-3-{2-/pyrid-4-yl/ethyl}-succinic acid;

an/. 3-{2-/imidazol-2-yl/-ethyl}-2-phosphono-succinic acid;

ao/. 3-{2-/imidazol-4-yl/-ethyl}-2-phosphono-succinic acid;

ap/. 2-phosphono-3-{/2-/pyrrolidin-2-yl/-ethyl}-succinic acid;

ag/. 2-phosphono-3-{2-/pyrrolidin-3-yl/ethyl}-succinic acid;

ar/. 3-{3-/imidazol-4-yl/propyl}-2-phosphono-succinic acid;

as/. 2-phosphono-3-{4-/pyrrolidin-2-yl/butyl}-succinic acid;

at/. 3-/N-allyl-N-methylamino/-2-phosphono-succinic acid;

au/. 3-/N-methyl-N-propargylamine/-2-phosphono-succinic acid;

av/. 3-{4-N-alkyl-N-methylamino/butyl}-2-phosphono-succinic acid;

aw/. 3-{4-/N-methyl-N-propargylamine/butyl}-2-phosphono-succinic acid;

ax/. 3-{4-N-ethyl-N-isobutylamino/butyl}-2-phosphono-succinic acid;

ay/. 3-azepin-1-yl-methyl/2-phosphono-succinic acid;

az/. 2-phosphono-3-{1-/pyrrolidin-1-yl/ethyl}-succinic acid;

ba/. 2-phosphono-3-{2-/pyrid-2-yl/propyl}-succinic acid;

bb/. 2-phosphono-3-{1-methyl-1-/pyrid-3-yl/ethyl}-succinic acid;

bc/. 3-{3-/imidazol-1-yl/2-2-methyl-Propyl}-2-phosphono-succinic acid;

bd/. 3-/3-amino-butyl/-2-phosphono-succinic acid;

be/. 3-{1,1-dimethyl-3-/N-methyl-N-pentylamine/-propyl}-2-phosphono-succinic acid;

bf/. 3-{ 3-/imidazol-4-yl/-2,3-dimethy the
bh/. 3-{2-methyl-4-/pyrrolidin-2-yl/butyl}-2-phosphono-succinic acid;

bi/. 3-{ 2,3-dimethyl-4-/pyrrolidin-2-yl/butyl} -2-phosphono-succinic acid;

bi/. 3-/5-amino-2-methyl-pentyl/-2-phosphono-succinic acid;

bk/. 2-phosphono-3-{4-/pyrid-2-yl/-buta-2-enyl}-succinic acid;

bl/. 2-phosphono-3-{4-pyrid-4-yl/-buta-2-inyl}-succinic acid.

The following examples show some ways how you can apply for the synthesis proposed according to the invention compounds. However, they should not represent limitations of the subject invention. The structure of the compounds guaranteed1H,31P - and, if necessary13C-NMR-spectroscopy. The purity of the substance is determined using C-, H-, N-, P-, if necessary Na-analysis, and by using thin-layer chromatography, respectively, of thin-layer electrophoresis cellulose, oxalate buffer with pH= 4,0/.

Example 1. Ethyl ester of 2-diethylphosphino-3-methoxycarbonyl-5-caloried-valerianic acid.

To 240 mg /10 mg/ DL of sodium hydride in 10 ml of absolute toluene is added dropwise while cooling 2.24 g /10 mmol/ teeterboro ether phosphonooxy acid. After the evolution of hydrogen, was added dropwise a solution 3,26 g /10 mmol/ meilovegod 24 hours at room temperature. The solution is neutralized with about 1 ml of ether solution of hydrogen chloride, concentrated on a rotary evaporator, and the remaining oil purified on 200 g of silica gel /eluting agent: acetone/toluene 1:1 by volume/. Obtain 2.8 g = 60%, colorless oil, whose structure is confirmed by NMR-spectroscopy.

Example 2. 3-/2-Amino-ethyl/-2-phosphono-succinic acid.

1.5 g /3.2 mmol/ Described in example 1 complex tetraeder in 40 ml of 6N hydrochloric acid is refluxed for 8 hours the Solution is concentrated to about volume of 10 ml, the precipitate is sucked off, the filtrate is completely concentrated, the residue is stirred with 3 ml of water, sucked off and the filtrate concentrated. Get a brownish oil, which was dissolved in 2 ml of water and placed 25 g of ion exchanger /Amberlite IR 120; H+- form/. Column elute with water and the fractions with the target substance concentrate. Obtain 0.34 g = 40% white amorphous powder with so pl. 127-130oC with decomposition.

Example 3. Ethyl ester of 2-diethylphosphino-3-etoxycarbonyl-7-/imidazol-1-yl/-heptacosanoic acid.

To 48 mg /2 mg/ DL of sodium hydride in 2 ml of absolute toluene was added dropwise 552 mg /4 mmol/ diethylphosphate and after the next 5 minago toluene. After 20 h, neutralized with ethereal solution of hydrogen chloride, the solvent is removed and the oily residue is purified by using 200 g of silica gel /eluting agent: acetone/toluene 1:1 by volume/. Get 380 mg = 44%, yellowish oil.

Used as source material diethyl ether 4-/imidazol-1-yl/butyl fumaric acid was prepared as follows:

To 72 mg /3 mg/ DL of sodium hydride in 3 ml of absolute dimethylformamide added 204 mg /3 mmol/ imidazole. After 15 minutes into the clear yellowish solution was added 921 mg /3 mmol/ diethyl ether /4-bromo-butyl/-fumaric acid {Tetrahedron Letters 22, 381/1981/} Left to mix overnight, neutralized with ethereal solution of hydrogen chloride, concentrated and the remaining oil purified on 150 g of silica gel [eluting agent: acetone/toluene 1:1 by volume)]. Receive 750 mg = 41% of the target substance in the form of butter.

Example 4. 3-{4-/Imidazol-1-yl/butyl}-2-phosphono-succinic acid.

432 mg /1 mmol/ described in example 3 complex tetraeder in 15 ml of 6N hydrochloric acid is refluxed for 6 hours the Solution is then concentrated, the residue is dissolved in 2 ml of water and placed 20 g of the ion exchanger /Amberlite IR 120; H+oC with decomposition.

Example 5. Methyl ester 2-diethylphosphino-3-methoxycarbonyl-4-pyrrolidin-1-yl/-butyric acid.

To 1.1 g /3,74 mmol/ methyl ester 2-diethylphosphino-3-ethoxycarbonyl-but-3-EN-acid in 10 ml of absolute toluene add 265 mg /3.74 mmol/ fresh of pyrrolidine. The solution is left to stand for 24 h at room temperature, concentrated and the residue is purified on 100 g of silica gel /eluting agent: acetone/toluene 1:4 by volume/. Obtain 490 mg = 38% of the target substance in the form of butter.

The NMR spectrum confirms the structure.

Used as starting material methyl ether 2-diethylphosphino-3-ethoxycarbonyl-but-3-EN-acid was obtained as follows:

To 7,19 g /30 mmol/ dimethyl ester 2-methyl bromide-fumaric acid {J. Org. Chem. 34, 1228 /1996/} slowly added dropwise to 5.2 ml /30 mmol/ triethylphosphite. When the internal temperature rises to 90oC. then heated for 1 h at 150oC, cooled and the oil is purified on a column of silica gel {eluting agent: acetone/toluene 1:4 by volume}. Get 4.9g = 54% of the target substance in the form of oil. The structure is confirmed by NMR and mass spectroscopy.

Example 6. 2-Hospira together with 50 ml of 6N hydrochloric acid is refluxed for 6 hours The solution is then concentrated, the residue is dissolved in 20 ml of water and purified by using ion-exchanger /Amberlite IR 120; H+- shape/ Fraction with the target substance is concentrated and dried. Obtain 2.14 g = 74% white powder with 0.5 mol water of crystallization; so pl. 122-124oC with decomposition.

Example 7. Methyl ester 2-diethylphosphino-4-/imidazol-1-yl/-3-methoxy-carbonyl-butyric acid.

To 75 mg /3 mg/ DL of sodium hydride in 10 ml of absolute tetrahydrofuran was added dropwise 205 mg /3 mmol/ imidazole in 10 ml of absolute tetrahydrofuran. After the evolution of hydrogen added 1.18 g /4 mmol/ methyl ester 2-diethylphosphino-3-ethoxycarbonyl-but-3-EN-acid /see example 5/ in 20 ml of absolute tetrahydrofuran and allowed to mix within 72 hours the Mixture is concentrated, add 20 ml of water, using 2n hydrochloric acid to establish a pH=6 and extracted repeatedly with methylene chloride. The combined organic phases are dried and concentrated. The residue is purified on 100 g of silica gel /eluting agent: acetone/toluene 3:1 by volume/. Obtain 610 mg = 61% of the target substance in the form of an oil, the NMR spectrum confirms the structure.

Example 8. 3-/Imidazol-1-yl-methyl/-2-phosphono-succinic acid.

oC with decomposition.

Pharmacological comparative experience.

Example 9. Analysis of osteoclasts.

Material and method:

Implementation experience carried out by the method of P. Collin, H. Gun and Fleiseh/Endocrinol. 131, 1181-87, 1992/ when using freshly isolated osteoclasts.

Features.

The preparation of osteoclasts, suspended in medium 199 [Gibeo AG, Basel, Switzerland] at pH of 7.36, for 5 min before and during 25 min while sticking to Valentine, as well as during the 24 h duration analysis [MEM Earle's] is treated with a substance at a concentration of 10-8M

The calculation steps /% suppression resorbtive/ in this analysis is done according to the following formula:

.

(See table)

The Protocol of comparative tests.

Comparative tests carried out at conditions, it is succinic acid A and 3-ethyl-2-phosphono-succinic acid /B/.

Results

Connection - the Suppression of resorption

A - 43%

B - 45%

In the case of compounds A and B we are talking about the selected examples. The results are best achieved with the comparative substances. Compared with the results achieved with the stated in the application connections /see example 9/, show a significant improvement of the relevant pharmacological properties in the case stated in the application connections.

Example 10 a composition.

Mix 1 kg of active substance, 4 kg of lactose, and 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate and pressed in the usual way tablets so that they get 50,000 tablets with a content of active substance 10 mg

1. Derivatives postnatural acid of General formula

< / BR>
where R is an amino group NR1R2where R1and R2is hydrogen or C1- C6-alkyl; a nitrogen-containing five-membered heterocyclic ring which is selected from the group including caloried, imidazole, pyrrolidine;

alk is a covalent bond, methylene or alkylene containing 2 to 6 carbon atoms;

R3, R4and R5independently from each other hydrogen, C1- C6-alkyl,

Naya communication, R cannot denote dimethylaminopropyl.

2. Composition, inhibiting the resorption of bone tissue containing the active substance and conventional excipients and carriers, characterized in that the active substance it contains a compound of General formula under item 1, in the amount of 10-1000 mg

3. Connection on p. 1, inhibiting the resorption of bone tissue.

 

Same patents:

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 organic chemistry, particularly to a technology for higher esters alkylphosphonic acids of General formula

< / BR>
where

R is alkyl (C1-C2halogenated;

R', R" are alkyl (C4-C8

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

-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 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 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
Up!