New derivatives of bisphosphonates acid and method of production thereof

 

(57) Abstract:

Usage: in medicine to treat diseases of the skeletal system. The inventive Products: derivatives bisphosphonates acid f-ly Q1Q2C[P(O)(OR1)(OR SIG2)] [P(O)(OR3)(OR4)], where one or two groups R1-R4are CH3C2H5or ISO-C3H7and the rest of the group R1-R4are hydrogen, Q1Is H or OH, Q2- straight or branched lower alkyl, cycloalkyl, 2-oxyethyl, 3-oksipropil, 2-amino-ethyl, 3-aminopropyl. Reagent 1: tetraeder methylenephosphonic acid. Reagent 2: acid or base. Efforts reactions: hydrolysis is carried out Paladino in the aquatic environment. 2 S. and 3 C.p. f-crystals, 14 PL.

The invention relates to new derivatives methylenephosphonic acid, in particular alkyl - or aminoalkylsilane esters methylenephosphonic acids and salts of esters, a process for the production of these new compounds, and to pharmaceutical compositions containing these new compounds.

Several publications describe methylenephosphonate acid, their salts and some therefire, but there are only a few descriptions of new acids have been described in the publications: EP 0221 611, J. Am. Chem. Soc. 78 (1956) 4450; J. Chem. Soc. (14959) 2266 and 2272; J. Am. Chem. Soc. 84 (1962) 1976; J. Org Chem. 35, (1970) 3149; J. Org. Chem. 36, (1971) 3843 and Phosphorus, Sulfur and Silicon 42, (1989) 73.

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

They are also well suited for the treatment of disorders related to calcium metabolism and others, especially ferrous metals. They can be used for the treatment of diseases of the skeletal system, especially the bony structures and disorders resorption, such as osteoporosis and disease Paget, as well as for the treatment of diseases of the soft tissues, such as the state of the complications and mineralization and bone formation.

On the other hand, being analogues of pyrophosphate, new derivatives of substituted methylenephosphonic acids are also suitable for treatment of disorders in /pyro/phosphating bodily functions, including functions, where active, but sancomplex metal or a combination of the latter.

New bisphosphonates regulate either directly or indirectly, the quality and level of cations and/or pyrophosphate compounds, freely present in the body fluids, as well as their binding, activation, and release of tissue. Therefore, they are able to regulate cellular metabolism, growth and destruction. They are therefore useful for treatment of, for example, bone cancer and metastasis in them, ectopic calcification, kidney stones, rheumatoid arthritis, bone infections and destruction of bone.

Typical of the new substituted methylenephosphonate is a selective targeted and controlled the action providing the best therapeutic index.

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, R22or OR', where R' is C1-C4-lower alkyl or acyl.

Q2is C1-C10the alkyl straight or branched chain, optionally unsaturated, oxyalkyl or aminoalkyl, and oxygen as the Deputy may contain one group or nitrogen as the Deputy may contain one or two groups that are C1-C4lower-alkyl or acyl, or two substituent at the nitrogen form together with the nitrogen atom a saturated, partially saturated or aromatic heterocycle, or Q2is optionally substituted and optionally a partially saturated C3-C10-cycloalkyl, which is not necessarily connected with the molecule straight or branched alkalinous group containing 1-4 carbon atoms, including stereoisomers such as geometrical isomers and optically active isomers of the compounds, as well as pharmacologically acceptable salts of the compounds.

Group R1, R2, R3and R4independently are straight or branched alkyl, alkenyl or quinil and they contain 1 to 10, 2 to 10 carbon atoms, preferably 1 7, 2 7, and particularly suitable 1 4, is whether cycloalkenyl with 3-10 carbon atoms, preferably, however, cyclopropyl-bootrom, -Pentium or-hexyl.

Aryl or aralkyl mean optional C1-C4-lower alkyl, -lower alkoxy or galijasevic monocyclic aryl or aralkyl, such as phenyl and benzyl, preferably, however, unsubstituted phenyl or benzyl.

In the silyl group SiR3the group R is lower alkyl containing 1 to 4 carbon atoms, and in particular, stands, ethyl, isopropyl, bootrom, tert-bootrom or he is phenyl, or R-substituted phenyl, as well as different combination of lower Akilov and fanilow, which were discussed, such as dimethyl-tert-butyl, methylisobutyl, dimetilfenil, diethylphenyl, methyl-tert-butylphenyl, aminobutiramida-/2,6-dimetilfenil/.

Group Q2contains as alkyl, alkenyl and quinil, hydroxy - or aminoalkyl-alkenyl or quinil group with 1 to 10, 2 to 10, preferably 1 to 4, respectively 2 to 4 carbon atoms. As Deputy to the oxygen of the hydroxyl group may be one, but as a substituent at the nitrogen of the amino group may have one or two C1-C4lower alkyl groups or acyl groups, or two Deputy can together with the nitrogen atom of the n, which is, for example, morpholinium, thiomorpholine, piperidinium, piperazinil, azetidinol, pyrrolidinium, and as aromatic or partially gidrirovannoe group, pirrallo, imidazolium, triazolium, oxazolium, thiazolium, or as partially gidrirovannoe pyridium, pirimidinom, pyrazinium, pyridazinyl or azepino. Preferably it contains 3 to 6 atoms in the ring, and especially he is pyrrolidino or piperidino, or phthalimidopropyl.

Acyl may be alkyl-, aryl - or arylalkylamines, but also alkoxy, aryloxy or alcoxycarbenium, where alkyl contains 1 to 4 carbon atoms and the aryl has the values given above. Halogen means chlorine, bromine, fluorine or iodine. Cycloalkyl and alkenyl as the group Q2contains 3 to 10 carbon atoms, and preferably is cyclopropyl-bootrom, -Pentium, -hexyl, -heptyl, more preferably by cyclopentyl or cyclohexyl, and these groups may be unsubstituted or substituted C1-4-alkyl. They can be bicyclic, preferably bicyclo/3.2.0/ or/2.2.1/heptyl, -/4.2.0/ or/3.2.1/actiom, -/3.3.1/nonilon or appropriate spiropentane balance, and the corresponding cycloalkenyl group and compounds of the formula I are preferably their salts with pharmaceutically acceptable bases, such as metal salts, for example alkali metal salts, especially lithium, sodium and potassium, salts of alkaline earth metals such as calcium salts or magnesium salts of copper, aluminum or zinc, and also ammonium salts with ammonia or with primary, secondary or tertiary, as aliphatic and alicyclic, and aromatic amines, and Quaternary ammonium salts, such as halides, sulfates and hydroxides, with aminoalcohols, such as ethanol-, diethanol - and triethanolamine, Tris/oximeter/aminomethane, 1 - and 2-methyl - 1,1-, 1,2 - and 2,2-dimethylaminoethanol, N-mono and N,N-dialkylaminoalkyl, N/oximeter and ethyl/-N,N-atendimento and aminogroup ethers and cryptate, and heterocyclic ammonium salts, such as azetidine, pyrrolidine, piperidine, piperazine, morpholine, pyrrole, imidazole, pyridine, pyrimidine, chinoline, etc. salts.

Especially good results were obtained with the following mono - or dimethyl-, mono - or diethyl-, mono - or diisopropyl esters, or corresponding mixed diesters, where Q1is hydroxyl, and Q2is lower alkyl, such as stands, ethyl, propylene, isopropyl, 2,2-dimethylpropyl or scrap, /3-methyl/pencil/amino/propylene, 5-aminopentyl.

Examples of such compounds are:

methyl ether /1-occidentalize/bisphosphonates acid dimethyl and diethyl ether /1-oxoethylidene/bisphosphonates acid,

onomatology ether /2,2-dimethyl-1-oxopropylidene/bisphosphonates acid,

onomatology ether /hydroxy/cyclohexyl/Meriden/bisphosphonates acid,

dimethyl ether /1,2-dioxyethylene/bisphosphonates acid,

onomatology ether /1,3-dioxypurine/bisphosphonates acid,

onomatology and monotropy ether /3-amino-1-oxopropylidene/bisphosphonates acid,

onomatology and monotropy ether /4-amino-1-oxybutylene/bisphosphonates acid,

onomatology and monoisopropyl ether /6-amino-1-oxygenlimited/bisphosphonates acid,

P, P'-dimethyl and P, P'-diethyl ester and 3-amino-1-oxopropylidene/bisphosphonates acid,

P, P'-dimethyl and P, P'-diethyl ester of 4-amino-1-oxybutylene/bisphosphonates acid,

monotropy ether [/4-dimethylamino/-1-oxybutylene] bisphosphonates acid, and

onomatology ether [[3-methyl/pencil/amino]-1-oxopropylidene]bisphosphonates acid.

The invention also relates to a method of extortion is rmula II

< / BR>
in which Q1and Q2have the previously indicated meanings, and R1, R2, R3and R4have the previously indicated meanings, with the exception of hydrogen, selectively hydrolyzing

in the corresponding triavir formula I, where one of the groups R1, R2, R3and R4mean hydrogen or its salt, or

in the respective fluids of the formula I, where two groups of R1, R2, R3and R4are hydrogen, or its salt, or

in the corresponding monoether formula I, where three of the groups R1, R2, R3and R4are hydrogen, or its salt, or

b) bisphosphonic acid formula

< / BR>
or a metal or ammonium salt or corresponding tetrachlorinated, where Q1and Q2have the previously indicated meanings, selective etherification by interacting with etherification agent corresponding to the desired group R1, R2, R3and R4,

in the corresponding monoether formula I, where three of the groups R1, R2, R3and R4are hydrogen, or

in the respective fluids of the formula I, where two of the groups R1, R2, R3and R4are hydrogen, or

in the appropriate treerow these partial esters, or

C) phosphonate of the formula IX

< / BR>
enter into reaction with activated phosphate or acid phosphonate corresponding to the formula X

< / BR>
where in these formulas, Y is hydrogen, hydroxyl or halogen or other leaving group, Z is hydrogen, halogen, acyloxy, sulfonyloxy, alkoxy or aryloxy, and R1R4and Q1and Q2form a double-linked oxygen or aminogroup, or carry out the reaction with postitem corresponding to the formula X, or

d) a bisphosphonate of the formula I, in which instead of Q2there carbanionic plot, enter into reaction with tsepliaeva group, substituted Q2or a bisphosphonate, corresponding to the formula I, in which instead of Q2there tsepliaeva group, is introduced into reaction with w-carbanion corresponding to Q2or /Q2-C1/ w carbanion attached on the reactions of addition of Michael to alkalicarbonate, or

e) bisphosphonate compound of formula XI

< / BR>
in which R1, R2, R3and R4and Q1and Q2have the meanings specified for formula I, or a corresponding acid phosphonate compound oxidizes in the compound of formula I, and optionally, partial esters of acids obtained by the point the duty esters, and/or, if desired, the resulting compound of formula I is transformed into some other compound of formula I by hydrolysis, esterification or transesterification, and/or the compound of formula I is the group of Q1turn to another group of Q1within the scope of the definition.

According to one method of connection is obtained by selectinga hydrolysis of tetrapyrrol corresponding to the formula I. Thus, tetraethyl used as source material, where the group R1R4and Q1and Q2have these values, this tetraethyl hydrolyzing on stage in triavir III, IV fluids, and V and monoether VI. If necessary, a partial ester or its salt can be isolated and purified by extraction, fractional crystallization or chromatography, and, if desired, the free acid can be converted into a salt or a salt into the free acid.

This reaction is shown in scheme I (the reaction goes in the direction of the upper arrow).

< / BR>
Hydrolysis of tetrapyrrol II can be carried out in the processing of both acid and base, using thermal decomposition, and in certain cases also using water, alcohols or other neutral or non-neutral agents transacylase the P>o
C. Acid are the usual inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and Lewis acids, such as ether, boron TRIFLUORIDE, chetyrehhloristy titanium, etc. as well as a number of organic acids, such as oxalic acid, formic acid, acetic acid and other carboxylic acids, methansulfonate acid and other sulfonic acids, such as tajikista, other fluorine - and chlorine substituted acids, such as sulfonic and carboxylic, for example triperoxonane acid and triftormetilfullerenov acid, and their water solutions.

The grounds are mostly alkaline and ammonialike and ammonia and aqueous solutions, as well as a number of amines such as primary, secondary and tertiary amines, such as diethyl-, triethyl-, aminobutiramida and tributylamine, aniline, N - and N,N-dialkylamino anilines and heterocyclic amines such as pyridine, morpholine, piperidine, piperazine, etc., and hydrazines, such as N,N-dimethylhydrazine.

In addition, can be used acids and bases connected by a solid substrate, such as Amberlite, or in the presence of an organic solvent or water, or various smetacek sodium and lithium, or suitable inorganic salts such as sodium iodide, lithium bromide, ammonium chloride and NaBr/PTC, ester group can be converted to its corresponding salt, such as sodium, ammonium and lithium salt.

Thermal decomposition is usually carried out approx a temperature of about 100 - 400oC, typically at a temperature of not higher than 250oC. the Presence of a suitable catalyst, such as acid or acid solution, or a Quaternary ammonium salt, speeds up the passage of the reaction at lower temperatures. Some active substituents, such as benzyl and allyl, can be removed by catalytic regeneration or electrolytic.

To improve the solubility and control of the reaction temperature during the reaction can be used as co-solvents inert organic solvents, such as hydrocarbons, lower alcohols and stable ketones and esters, haloalkyl, such as chloroform, dichloromethane, lilim, acetonitrile etc.

When the group R1-R4in terrafire formula II are the same, the hydrolysis is conducted Paladino and is interrupted when the concentration of the target partial ester becomes the most is to tetraethyl formula II, in which the ester groups are not identical, and that the groups were different in terms of speed of hydrolysis. For example, it was found that the hydrolysis rate of alilovic and cyrilovich esters depends on the structure as follows:

silyl > tertiary > secondary > primary

It is possible to influence the rate of hydrolysis, changing the size and shape of the alkyl or silyl substituent, and e factors. It is often possible to carry out the transesterification, to change the order of hydrolysis of various ester centers. In particular, the methyl ester can be expedient to turn to the corresponding acid by silloway ether.

Pure partial esters may thus be advantageously obtained by selective hydrolysis of the mixed esters of the formula I, which were obtained using the ester groups, which are advantageous from the viewpoint of hydrolysis.

Can also use other selective hydrolysis reaction, especially from the chemistry of phosphate and monophosphates.

The passage of hydrolysis can be controlled, for example, by chromatography or by using31P-NMR spectroscopy. The reaction may be interrupted mixture or in the form of the free acid or as a salt deposition, extraction or chromatography, and the salt form can be converted into the free acid or the free acid in its salt.

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

So, tetraconata formula VII /R1-R4H/ can be used as a starting material, which can be either free acid or salt, such as a metal salt or ammonium salt, or may be used corresponding tetrachlorohydrex phosphonic acid, and depending on the desired result from 1 to 4 equivalents of the target aliphatic or aromatic alcohol, or the corresponding activated reagents alkylation, sililirovanie and arilirovaniya, such as orthoclone esters, catenateall and other reagents transferring alkyl-, silyl - and aryl groups, such as diazocompounds, active esters of carboxylic acids, sulfates, etc., the Reaction is usually carried out in anhydrous conditions, preferably in the temperature range from 0 to 150oC, or by using an inert co-solvent when tokido anion bisphosphonates, often ammonium salt, and an organic halide or sulfonate, or by the condensation reaction between the group of phosphonic acid and the appropriate alcohol or phenol, using the reagent for removal of water, such as carbodiimide.

Thus, the pure partial esters and mixed esters can be obtained by selective esterification, optionally Paladino, tetracyclo formula VII. Can also be used other selective esterification reaction, previously known in the chemistry of phosphates and phosphonates.

Over the course of the esterification reaction can be monitored, for example, chromatography or using31P-NMR, and interrupt the reaction, when the content of the target partial ester is the greatest and the product isolated from the reaction mixture by precipitation, extraction or chromatography, and optionally the obtained salt form is converted into the free acid or the free acid is converted into its salt.

Partial esters according to the invention can also be obtained by constructing the P-s-R framework of its parts

< / BR>
where in the formula Y is hydrogen, hydroxyl or halogen, or other tsepliaeva group, Z is a halogen, alkoxy, sulfonyloxy, al is 2 are double-linked oxygen or aminogroups. As the base can be used, for example, sodium hydride, utility or diisopropylamide lithium. The original material is not necessarily available sites free acid (one of the groups R1-R4=H) should be neutralized with a sufficient amount of the base before the reaction mix. Must also be neutralized active centers in the groups Q1and Q2or active site must be protected with a protecting group.

Can also be used in the reaction Michaelis-Arbuzov, where the second reactive compound is postit, or reaction Michaelis-Becker, where Z is hydrogen.

In some cases, Q1may be imposed by the exchange reaction or oxidation reaction, or restore, where the hydroxyl can be obtained from hydrogen, halogen, or amino, the amino group can be obtained from halogen or hydroxyl, hydrogen can be obtained from the halogen and the halogen can be obtained from the hydrogen.

Q2can also be introduced into the molecule, or by reaction bisphosphonates of a carbanion or the corresponding reaction involving C-halogen or other tsepliaeva.

Compounds according to the invention can also be obtained by using attach for Michael to alkalicarbonate described in the EP patent application 0221611.

Esters according to the invention can also be obtained from the R-s-R-structures at a lower level of oxidation by oxidation.

< / BR>
where in the formula, R1-R4and Q1and Q2have these values, and where the structure of phosphonite can exist in equilibrium with the structure of the acidic phosphonate. All traditional oxidizing agents or their solutions, such as hydrogen peroxide, pergolide connection percolate, permanganate, etc. can be applied.

Partial esters bisphosphonates acid according to the invention can also be obtained from other partial esters when carrying out reactions intra - and intermolecular exchange.

Terrafire II and the corresponding tetracyclic IV used as starting compounds in the above reactions can be obtained by known methods, such as found in the literature for constructing R-s-R framework of its parts, for example when using the above-mentioned reactions Michaelis-Becker, Michaelis-o introduced as part of bisphosphonates, taking into account the structure of the desired partial ester, and by appropriate substitution in the frame or anion derived from it, such as alkylation or by reaction of the merger.

Whereas obtaining a target of ester, if necessary, the resulting terrafire can be converted into other suitable terrafire reactions of metabolism. In the group OR1-OR4can be exchanged directly or through the appropriate phosphono-chloride or other known methods.

Optically active partial esters can be better prepared when using the known optically active compounds such as optically active alcohols, when receiving the above-mentioned starting materials, intermediate products and final products or by exchange reactions.

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

First, were determined physico-chemical effects of the compounds according to the invention in respect to the education of their calcium phosphate crystals and activity of inhibiting the deposition Shinoda et al. [Calc. Tiss Int 1983, 35:87] and Jung et al. [Calc. Tiss Res 1973, 11:269] (table 1).

The tables indicate the superiority of the compounds of the invention, especially their higher protivorechivye activity in the test in vivo.

Partial esters of substituted biophosphonate acids of formula I can be used as pharmaceutical products as such or in the form of their pharmacologically acceptable salts, such as alkali or ammonium salts. Such salts can be obtained by the reaction of esters of the acids with the appropriate inorganic or organic bases. Depending on the reaction conditions, salts of esters can also be obtained directly in the above reactions.

The new compounds I of the present invention can be introduced interline or parenteral. Can be taken into account in every traditional forms of administration, such as tablets, capsules, granules, syrups, solutions, implants and suspensions. Can also be used any auxiliary substances for the production, dissolution and drug administration and stabilizator, tartrate and citrate buffers, alcohols, EDTA and other non-toxic complexing agents, solid and liquid polymers and other sterile substances-substances, starch, lactose, mannitol, methylcellulose, talc, silicic acid, fatty acids, gelatin, agaragar, calcium phosphate, magnesium stearate, animal and vegetable fats and, optionally, flavoring and sweetening agents.

Dosage depends on several factors such as route of administration, species, age and individual condition. The daily dose is about 0.1 to 1000 mg, typically 1 to 100 mg per person, they can be entered as a single dose and can be divided into several doses.

Below are examples of capsules and tablets.

The capsule mg/capsule:

Active ingredients 10,0

Starch 20,0

Magnesium stearate 1,0

Tablet, mg:

The active ingredient 40,0

Microcrystalline cellulose 20,0

Lactose 67,0

Starch 10,0

Talc 4,0

Magnesium stearate 1,0

For medical use, as well as for intramuscular or parenteral administration of the drug can be prepared, for example, by infusion concentrate, where the auxiliaries can be ispolzuetsa, suitable for this purpose.

Connection efiromaslichnij form according to the present invention are liquid or waxy substances, which are usually soluble in organic solvents and in some cases in water. Salts of esters are solid, crystalline or typical powdery substances, which are usually soluble in water, in some cases, in organic solvents, but only some types of structures are poorly soluble in all solvents. Compounds are very stable in neutral solutions at room temperature.

The structure of the compounds can be easily confirmed1H,13C and31P-AMP-spectroscopy and FAB-mass spectrometry, or in the case similarbank derivatives, EI-mass-spectroscopy. For preconcentration and determination of impurities is very suitable31P-AMP spectroscopy (85% H3PO40#). Can also be used for ion-exchange and exclusive HPLC for polar compounds as such and GC or GC/MS for tetrapyrrol and similarbank esters of the acids. For compounds of sodium and other metals were determined separately, as well as possible water content in the crystals. For the.

Obtaining raw materials.

Example A. Obtaining tetramethyl ether /1-oxoethylidene/bisphosphonates acid.

Dissolve 0,047 mol dimethylphosphite and 0,0026 mol of dibutylamine in diisopropyl ether and added to a solution 0,047 mol dimethylterephthalate at 0oC. the Solution was stirred at 0oC for 4 h and one day at room temperature. The product is filtered, washed with diisopropyl ether and dried. The output is 8.3 g (67%31P NMR 22, 95mm ppm; CDCl3).

Dimethylacetophenone used as source material, it can be obtained as follows.

Add 0.31 mol of acetylchloride at 0oC slowly to 0.3 mol trimethylphosphite. The mixture is stirred for 5 h at 0oC and left overnight at room temperature. The product is distilled under reduced pressure, so Kip. 96 - 100oC/9 mm RT.article Yield 39 g (86%).

Accordingly can be obtained:

P, P-dimethyl P',P'-diethyl ether /1-oxoethylidene/bisphosphonates acid from dimethylterephthalate and diethylphosphate /31P NMR 20,54/23,32 ppm, J 39,4 Hz, CDCl3/.

P,P-dimethyl P',P'-bis/(trimethylsilyl)/new ether /1-oxoethylidene/bisphosphonates acid from the Teal-P,P'-bis-trimethylsilyl)/new ether /1-oxoethylidene/bisphosphonates acid from methyl/(trimethylsilyl)/acetylacetonate and methyl/(trimethylsilyl)/phosphite /31P NMR of 0.50 ppm, CDCl3/.

P, P-dimethyl P', P'-diethyl ether /1-occidentalize/ bisphosphonates acid from dimethylmethylphosphonate and diethylphosphate /31P NMR 20,9/23,39 MRP, J37,0 Hz, CDCl3/.

P, P-dimethyl P', P'-diisopropyl ether /1-occidentalize/phosphonic acid from dimethylmethylphosphonate and diisopropylphenol /31P NMR 16,63/21,56 ppm, J=41,0 Hz, CDCl3/.

Tetramethyl ether /1-occidentalize/bisphosphonates acid from dimethylmethylphosphonate and dimethylphosphite /31P NMR vs. 20.62 ppm, CDCl3/.

Tetramethyl ether /1-hydroxy-2,2-dimethylpropylene/ bisphosphonates acid from dimethylmethylphosphonate and dimethylphosphite /31P NMR 23,80 ppm, CDCl3/.

P,P-dimethyl P',P'-diethyl ether /1-hydroxy-2,2-dimethylpropylene/bisphosphonates acid from dimethylmethylphosphonate and diethylphosphate /31P NMR 20,57/23,46 ppm, J=31,1 Hz, CDCl3/.

Tetramethyl ether /oxide/cyclohexyl/Meriden/bisphosphonates acid from dimethylcyclohexanone and dimethylphosphite /31P NMR 23,13 ppm, CDCl3.

In addition, can be obtained:

P, P-dimethyl P', P'-diisopropyl ether /1 - oxoethylidene/bisphosphonates acid from diisopropylate the new ether /I-oxoethylidene/bisphosphonates acid from diisopropylfluorophosphate and diethylphosphate /31P NMR 16,55/18,95 ppm, J=41.7 Hz, CDCl3/.

P, P-dimethyl P',P'-diisopropyl ether /I-occidentalize/bisphosphonates acid from diisopropylfluorophosphate and dimethylphosphite /31P NMR 16,63/21,56 ppm, J=41,0 Hz, CDCl3/.

P, P-dimethyl P', P'-disutility ether /I-oxoethylidene/ bisphosphonates acid from dibutylnitrosamine and dimethylphosphite /31P NMR 20,40/23,33 ppm, J= 40,1 Hz, CDCl3.

P, P-diethyl-P', P'-diisopropyl ether /I-occidentalize/bisphosphonates acid from diisopropylfluorophosphate and diethylphosphate.

P-ethyl/P, P', P'-Tris/trimethylsilyloxy/ether//4-dimethylamino/-I - oxybutylene/bisphosphonates acid from bis/(trimethylsilyl)// 4-dimethylamino/butanolate and ethyl/(trimethylsilyl)/ phosphite.

P-methyl-/P, P',P-Tris/(trimethylsilyl)/new ether //3-methyl/phenteramine/-I-oxopropylidene/ bisphosphonates acid from methyl/(trimethylsilyl)//3-methyl/pencil/amino/propenylboronic and bis/(trimethylsilyl)/phosphite.

Example B. Obtaining tetramethyl ether /I-occidentalize/bisphosphonates acid.

Heated 6 h at 100oC mixture of 0.1 mol /I-occidentalize/bisphosphonates acid and 0.5 mol of triethylorthoformate. Then distilled formed Myanmar 20,63 MRP, CDCl3.

In the same way get:

tetramethyl ether /I-oxoethylidene/bisphosphonates acid (31P NMR, 22, 95mm ppm, CDCl3)

tetramethyl ether /I-hydroxy-2,2-dimethylpropylene/ bisphosphonates acid (31P NMR 23,80 ppm, CDCl3)

tetramethyl ether of 4-amino-I-oxybutylene/biphosphonates acid,

tetramethyl ether /3-amino-I-oxopropylidene/bisphosphonates acid,

tetraethyl ester and 3-amino-I-oxopropylidene/bisphosphonates acid,

tetramethyl ether /3-/dimethylamino-I-oxopropylidene/bisphosphonates acid,

tetraethyl ether /6-amino-I-oxygenlimited/bisphosphonates acid (31P NMR of 23.1 ppm, CDCl3)

tetramethyl ether /6-amino-I-oxygenlimited/bisphosphonates acid,

tetraethyl ether /3-/dimethylamine/-I-oxopropylidene/bisphosphonates acid,

tetramethyl ether //3-benzyloxycarbonylamino/-I-oxopropylidene/bisphosphonates acid.

tetraethyl ether //4 benzyloxycarbonylamino/-I-oxybutylene/bisphosphonates acid.

Example C. Receiving tetramethyl ether /I-hydroxy-2,2-dimethyl-propylidene/bisphosphonates acid.

Dissolved in chloroform 0.1 mol trimethylphosphite and medlennaya the solvent under reduced pressure and the product precipitated diisopropyl ether. Yield 24 g (80%31P NMR 23,80 ppm, CDCl3).

In the same way get:

tetramethyl ether /4-/N-phthalimide/-I-oxybutylene/bisphosphonates acid 831P NMR 19,90 ppm, CDCl3)

tetramethyl ether/3-/N-phthalimide/-I-oxopropylidene/bisphosphonates acid,

tetramethyl ether /3-/benzyloxycarbonylamino/-I-oxopropylidene/bisphosphonates acid.

Example 1. Obtaining P', P'-diisopropyl ether /I-oxoethylidene/bisphosphonates acid and its disodium salt.

In a solution of 0.02 mol of P,P-dimethyl P',P' -diisopropyl ether /I-oxoethylidene/bisphosphonates acid in acetonitrile is slowly added to 0.04 mol of sodium iodide and 0,042 mole chloromethylstyrene at room temperature. The solution is stirred for 2 h, after which the solvent under reduced pressure. The residue from the distillation was dissolved in a small amount of warm water and alkalinized solution with dilute sodium hydroxide solution. The product is precipitated by adding ethanol /31P NMR Ls 16.80/23,24 ppm, J 37.6 Hz, D2O/(Conn.9)

Accordingly the following can be derived esters and their sodium salts:

P,P-dimethyl ether /I-oxoethylidene/bisphosphonates acid from the corresponding tetramethyl EF acid from the corresponding P,P-dimethyl-P',-P'-dibutylamino ether (31F NMR 27,95/28,97 ppm, J=31,2 Hz, D2O).

P',P'-diethyl ether /I-oxoethylidene/bisphosphonates acid from the corresponding P, P-dimethyl P', P'-diethyl ether /31P NMR 13,41/29,68 ppm, J= 29,9 Hz, D2/(Conn.8).

P, P-dimethyl ester of 4-amino-I-oxybutylene/bisphosphonates acid from the corresponding tetramethyl ester.

P, P-dimethyl ether /6-amino-1-oxygenlimited/bisphosphonates acid from the corresponding tetramethyl ester.

P,P-dimethyl ether /4-/N-phthalimide/-1-oxybutylene/bisphosphonates acid from the corresponding tetramethyl ester (31P NMR 15,76/23,8 ppm, J 23,7 Hz, D2O).

P, P-diethyl ether /3-amino-1-oxopropylidene/bisphosphonates acid from the corresponding tetraethyl ester.

P,P-dimethyl ether /3/-amino-1-oxopropylidene/bisphosphonates acid from the corresponding tetramethyl ester.

P', P'-diisopropyl ether /1-occidentalize/bisphosphonates acid from the corresponding P,P-dimethyl P',P'-diisopropyl ether (31P NMR 14,60/26,80 ppm, J=31.7 Hz, D2O) (connect.2).

P, P-dimethyl ether /1-occidentalize/bisphosphonates acid from the corresponding tetramethyl ester (31P NMR 15,72/27,62 MRP, J P, P-dimethyl P',P'-diethyl ether (31P NMR 12,30/increased by 28.70 ppm, J= 27,1 Hz, D2)

P,P-dimethyl ether /1-hydroxy-1-cyclohexylmethyl/bisphosphonates acid from the corresponding tetramethyl ester.

Example 2. Getting monoisopropyl ether /1-occidentalize/ bisphosphonates acid.

Dissolve 0.02 mol P,P-dimethyl P',P'-diisopropyl ether /1-occidentalize/biophosphonates acid in dichloromethane and slowly added to the solution at room temperature 0,062 mole bromotrimethylsilane. The solution is stirred for 3 h at room temperature, after which the solvent is distilled off under reduced pressure. The residue from the distillation was dissolved in a small amount of methanol and the solution is evaporated (31P NMR 17/22/22,76 ppm, J=27,1 Hz, D2O) (compound 10).

In the same way can be obtained:

monoisopropyl ether /1-oxoethylidene/bisphosphonates acid from the corresponding P,P-dimethyl P',P'-diisopropyl ether (31P NMR 18,36/23,04 ppm, J 28,8 Hz, D2O)(Conn.1),

monoisopropyl ether /1-oxoethylidene/ bisphosphonates acid from the corresponding tetraisopropyl ester,

monobutyl ether /1-oxoethylidene/ bisphosphonates acid from the corresponding P,P-dimethyl P',P'-n/bisphosphonates acid corresponding tetramethyl ester,

onomatology ether /4-/ N-phthalimide/-1-oxybutylene/ bisphosphonates acid from the corresponding tetramethyl ester,

onomatology ether /1-oxypiperidine/ bisphosphonates acid from the corresponding tetramethyl ester (31P NMR 16,36/24,0 ppm, J of 24.5 Hz, D2O) (Conn. 4),

onomatology ether /hydroxy/cyclohexyl/Meriden/bisphosphonates acid from the corresponding tetramethyl ester (31P NMR 15,84/23,40 ppm, J Hz to 27.0, D2O) (Conn. 5),

monotropy ether /1-occidentalize/bisphosphonates acid from the corresponding P, P-dimethyl P', P'-diethyl ether (31P NMR, 18,73/20,61 ppm, J 32,3 Hz, D2O)

onomatology ether /1-hydroxy-2,2-dimethylpropylene, bisphosphonates acid from the corresponding tetramethyl ester (31P NMR 16,55/24,18 ppm, J 23,3 Hz, D2O) (connect. 11),

monotropy ether /3-/benzyloxycarbonylamino/bisphosphonates acid from the corresponding tetraethyl ester,

onomatology ether /3-/ N-phtalimide/-1-oxopropylidene/phosphonic acid from the corresponding tetramethyl ester,

P, P'-dimethyl ether /1-occidentalize/bisphosphonates acid from the corresponding tetramethyl ester (31P NMR 20,70 ppm, D2O)

P, P'-dimethyl ether /4 -/ the 18,78 MRP, D2O)

P, P'-dimethyl ether /3-/benzyloxycarbonylamino/-1-oxopropylidene/bisphosphonates acid from the corresponding tetraethyl ester.

Further according to the method of the preceding example can be obtained the following compounds when used instead of chlorine-tert-butyl/dimethyl/silane, for example bromine/mid/silane (1 equivalent):

P-methyl-P', P'-disutility ether /1-oxoethylidene/bisphosphonates acid from the corresponding P, P-Dimethyl P',P'-dibutylamino ether (31P NMR 17,19/25,79 ppm, J 34,7 Hz, D2O)

P-methyl-P', P'-diethyl ether /1-oxoethylidene/bisphosphonates acid from the corresponding P, P-dimethyl P', P'-diethyl ether (31P NMR 17,47/26,01 ppm, J 35.1 Hz, D2O)

P-methyl-P',P'-diisopropyl ether /1-oxoethylidene/ bisphosphonates acid from the corresponding P, P-dimethyl P',P'-diisopropyl ether (31P NMR 19,10/of 22.44 ppm, J 37,3 Hz, D2O) (connect. 6),

P-methyl-P',P'-diethyl ether /1-occidentalize/bisphosphonates acid from the corresponding P,P-dimethyl P',P'-diethyl ester,

timetravel ether /4-/ N-phthalimide/-1-oxybutylene/ bisphosphonates acid from the corresponding tetramethyl ester (31P NMR 12,01/30,89 ppm, J is 25.3 Hz, D2O)

timetravel ether /6-amino-1-oaks nanometrology ether /1-oxoethylidene/bisphosphonates acid and its trinational salt.

Mixed toluene solution of 0.02 mol /1-oxoethylidene/bisphosphonates acid and 0.04 mol of triethylorthoformate under 100oC for 4 h Distilled off under reduced pressure, the solvent and unreacted triethylorthoformate. The residue from evaporation was dissolved in ethanol. When adding the calculated amount (0.06 mol) of 40% aqueous sodium hydroxide solution to the ethanol solution of the product precipitates in the form of trinational salt (31P NMR 17,25/24,86 ppm, J in 27.3 Hz, D2O) (connect. 7).

Accordingly can be obtained:

monotonically ether /3-amino-1-oxopropylidene/bisphosphonates acid,

onomatology ether /6-amino-1-oxoethylidene/bisphosphonates acid.

Example 5. Getting nanometrology ether /1-occidentalize/bisphosphonates acid and its trinational salt.

Dissolving 0.01 mol of tetramethyl ether /1-occidentalize/bisphosphonates acid in 70 ml of toluene and added to a solution of 0.06 mol methanesulfonic acid. The solution is stirred under heating and control hydrolysis with 31P-NMR spectroscopy. The mixture is cooled and the solvent is evaporated under reduced pressure. The residue from evaporation is dissolved in a dilute solution of hydroc throwaway and dried (yield 52%31P NMR 16,36/24,00 ppm, J of 24.5 Hz, D2O).

Example 6. Obtaining P,P'-dimethyl ether /1-oxoethylidene/ bisphosphonates acid.

Dissolving 0.01 mol of P, P'-dimethyl-P,P'-bis-trimethylsilyl ether /1-oxoethylidene/bisphosphonates acid in methanol and the solution stirred for 2 h at room temperature. The solvent is distilled off, the residue from the distillation is dissolved in dilute sodium hydroxide solution and precipitated disodium salt product by adding a double volume of ethanol (yield 72%31P NMR 21, 19 ppm, D2O) (connect. 12).

Example 7. Obtaining P, P'-dimethyl ether /1-occidentalize/bisphosphonates acid.

Dissolving 0.01 mol of tetramethyl ether /1-occidentalize/bisphosphonates acid in acetone and the solution added is 0.023 mol solution of sodium iodide. The solution is stirred at room temperature for 8 h, after which it is filtered. The solvent is evaporated. The product is recovered from the residue after evaporation in the form of datatrieve salt, as described in the previous example (yield 59%31P NMR 19,06 ppm, D2O).

Accordingly can be obtained:

P, P'-dimethyl ether /1-hydroxy-2,2-dimethylpropylene/ bisphosphonates acid from the corresponding bisphosphonate acid from the corresponding tetramethyl ester (31P NMR 18,79 ppm, D2O) (connect. 3),

P-methyl-P'-ethyl ether /1-occidentalize/bisphosphonates acid from the corresponding P,P-dimethyl-P,P'- diethyl ether (31P NMR 19,06 ppm, D2O)

P, P'-diethyl ether /4-/benzyloxycarbonylamino/-1-oxybutylene/bisphosphonates acid from the corresponding tetraethyl ester,

P, P'-dimethyl ether /4-/benzyloxycarbonylamino/-1-oxybutylene/bisphosphonates acid from the corresponding tetramethyl ester,

P, P'-diethyl ether /3-/benzyloxycarbonylamino/-1 lipropilen/bisphosphonates acid from the corresponding tetramethyl ester.

Example 8. Getting nanometrology ether /1-oxoethylidene/bisphosphonates acid.

Mix of 0.005 mol finely chopped /1-oxoethylidene/bisphosphonates acid with 100 ml of chloroform to the mixture and slowly add 25 ml of approximately 2% ether solution diazomethane at room temperature. After the addition, continue to stir for another 1 h, after which the solution is evaporated at reduced pressure (yield 42%31P NMR 17,25/24,85 ppm, J=27,3 Hz, J2O).

Accordingly can be obtained from other mono - and diesters, such as dimethyl, mono - and diethyl ethers, den/bisphosphonates acid and its trinational salt.

Suspended 0.01 mol of tetramethyl ether /1-occidentalize/bisphosphonates acid 10% hydrochloric acid and stirred the solution at 70oC. the reaction course is monitored according to the31P NMR spectroscopy. Upon termination of the reaction mixture is evaporated to dryness, the residue from evaporation is dissolved in sodium hydroxide solution and the precipitated product when adding the reference. The product is filtered and dried (yield 55%31P NMR 16,36/24,00 ppm, J= 24.5 Hz, D2O).

Accordingly can be obtained onomatology ether //3-dimethylamino/-1-oxopropylidene/bisphosphonates acid.

Example 10. Getting disodium salt of P,P-diethyl ester of 4-amino-1-oxybutylene/bisphosphonates acid.

Dissolve 1 g of P,P-diethyl ether /4-/benzyloxycarbonylamino/-1-oxybutylene/bisphosphonates acid in 30 ml of standard and hydronaut at a pressure of 35 lb/in2(2,461 kg/cm2using as catalyst 0.1 g of 5% palladium on coal. The catalyst is filtered off and set the pH of the filtrate 7-7,5 with dilute sodium hydroxide solution. The solution is evaporated and the residue from evaporation is treated with acetone. The product is filtered and dried (yield 65%).

In the same way mog ether /3-/benzyloxycarbonylamino/-1-oxopropylidene/bisphosphonates acid,

P, P'-diethyl ester and 3-amino-1-oxopropylidene/bisphosphonates acid from P,P'/diethyl ether /3-/benzyloxycarbonylamino/-1-oxopropylidene/bisphosphonates acid,

P, P'-dimethyl ester of 4-amino-1-oxybutylene/bisphosphonates acid from P,P'-dimethyl ester /4 benzyloxycarbonylamino/-1-oxybutylene/bisphosphonates acid.

Example 11. Getting monoethylene ether //4-dimethylamino/-1-oxybutylene/bisphosphonates acid and its trinational salt.

A mixture of 0.01 mol of P-ethyl-/P,P'-Tris/trimethylsilyl ether //4-dimethylamino/-1-oxybutylene/bisphosphonates acid and dilute hydrochloric acid was stirred at 0oC for 0.5 h To filtered solution add dilute sodium hydroxide (in excess of 0.02 mol) and the product precipitated by reference.

Accordingly can be obtained onomatology ether //3-methyl/pencil/amino/-1-oxopropylidene/bisphosphonates acid.

The NMR spectra for compounds 1-12 are shown in table. 3-14, respectively.

1. New derivatives of bisphosphonates acid of General formula I

< / BR>
where one or two groups R1, R2, R3and R4independently methyl, ethyl or isopropyl, and the rest of the group R1, Enen lower alkyl, cycloalkyl, 2-oxyethyl, 3-oksipropil, 2-amino-ethyl, 3-aminopropyl, (3-dimethylamino)propyl, 3-methyl(pentyl)aminopropyl 2-methyl(pentyl)amino-ethyl, or 5-aminopentyl, as well as their pharmaceutically acceptable salts.

2. Connection on p. 1, where Q1hydroxy.

3. Connection under item 1 or 2, where Q2methyl, ethyl, propyl, isopropyl, 2,2-dimethylpropyl or butyl.

4. Connection on p. 1, characterized in that they represent onomatology and monotropy ether /1-oxoethylidene/bisphosphonates acid, onomatology ether /1-occidentalize/bisphosphonates acid, dimethyl and diethyl ether /1-oxoethylidene/bisphosphonates acid, onomatology ether /2,2-dimethyl-1-oxopropylidene/bisphosphonates acid, onomatology ether /hydroxy/cyclohexyl/Meriden/bisphosphonates acid, monotropy ether /1,3-dioxypurine/bisphosphonates acid, onomatology and monotropy ether /3-amino-1-oxopropylidene/bisphosphonates acid, onomatology and monotropy ether /4-amino-1-oxybutylene/bostonboy acid, onomatology and monoisopropyl ether /6-amino-1-oxygenlimited/bisphosphonates acid, P, P'-dimethyl and P,P'-diethyl ester and 3-amino-1-oxopropylidene/bisphosphonates acid, P,P'-dimethyl and the ilidene/bisphosphonates acid, onomatology ether /3-methyl(pentyl)amino/-1-hydroxypropylamino/bisphosphonates acid.

5. The method of obtaining compounds of formula I on p. 1, characterized in that a) tetraethyl methylenephosphonic acid of General formula II.

< / BR>
where Q1and Q2have the same meaning as in paragraph 1 of the formula I, and R1, R2, R3and R4have the same meaning as in paragraph 1, or three of lower alkyl/silyl except hydrogen, selectively hydrolyzing triavir corresponding to the formula I, where one of the groups R1, R2, R3and R4is hydrogen, or its salt, or in fluids, corresponding to the formula I, where two of the groups R1, R2, R3and R4are hydrogen, or its salt, or monoether corresponding to the formula I, where three of the groups R1, R2, R3and R4are hydrogen, or its salt.

 

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