Derivatives of anhydride methylenephosphonic acids, processes for their preparation, pharmaceutical composition

 

The invention relates to new derivatives of anhydride methylenephosphonic acid of the formula I, where Y1, Y2, Y3and Y4group OR1, NR2R3, OCOR1, OCNR2R3, O(CO)OR1, O(SO2R1or OP(O)R2(OR3), where R1, R2and R3- H, C1-22alkyl, aryl, possibly substituted, or SiR3where R3- C1-C4alkyl, provided that at least one of the groups Y1, Y2, Y3and Y4other than the group OR1or NR2R3, Q1and Q2Is H, F, Cl, Br, I, methods of obtaining these new compounds as well as pharmaceutical preparations containing these new compounds. Connections have a more controlled effect on metabolism and body functions. 4 C. and 7 C.p. f-crystals, 5 PL.

The subject of this invention is new derivatives of methylenephosphonic acid, especially new anhydrides halogen-substituted methylenephosphonic acid, anhydrides of ester, amide anhydrides and anhydrides complex affirmed, methods of obtaining these new compounds as well as pharmaceutical preparations containing these new Saeidi of ester, the amide anhydrides, anhydrides complex affirmed and partial anhydrides, and their salts, in some cases clearly show better properties than the corresponding bisphosphonic acids, their derivatives in incomplete form of ester, partial amide and incomplete complicated affirmed, thanks to better kinetics and the ability to use anhydrous derivatives, for this reason, they have a more controlled effect on metabolism and body functions.

The main problem with the well-known methylenephosphonate, which is used only in the form of salts tetracyclune forms, is their poor absorption when administered orally. Therefore, the required dose should be longer.

On the absorption and effectiveness can be influenced or by processing of the substituents on the intermediate carbon, or by replacing groups attached to phosphorus. Some examples of improvements to properties of bisphosphonates by replacing the substituents on the intermediate carbon found in the literature (Bisfosfonate on Bones, ed. Bijvoet, Fleisch and Russel, Elsevier, Amsterdam 1995). The absorption of bisphosphonates in the form of tetracycline or salt to the suitability of the patient tried to improve prescription medications (SA 2120538, EP 407345, EP 550385, EP 566535, US 5462932, WO one dose. However, phosphoric part used for the regulation of only a small number of cases. Typically, these regulators in phosphoric parts were incomplete esters, complex piramidy and amides. Anhydrite derivatives which are the subject of the invention are characterized by a desirable selective and controlled action, which means a better therapeutic index.

Methylenephosphonate acid, and their salts, complex therefire, complex amidoamine, partial esters and partial complex piramidy disclosed in some publications, but anhydrite derivatives which are the subject of the invention, not only not mentioned in the literature, but their properties were unknown.

Obtaining complex tetrapyrrol methylenephosphonic acid disclosed in the publications US 4447256, DE 2831578, EP 337706, EP 282320, EP 356866, J. Am. Chem. Soc. 78 (1956) 4450; J. Chem. Soc. 1959, 2272; J. Am. Chem. Soc. 84 (1962) 1876; J. Org. Chem. 35 (1970) 3149; J. Org. Chem. 36 (1971) 3843, Phosphorus, Sulfur and Silicon 42 (1989) 73, J. Chem. Soc. Perkin Trans. 2, (1992) 835 and Phosphorus, Sulfur and Silicon 70 (1992) 182 (mixed complex terrafire). Getting tetramolopium disclosed in the publications of J. were obtained. Chem. 304 (1986) 283; Tetrahedron Lett. 26 (1985) 4435 and Acta Chem. Scand. 51 (1997) 932.

Obtaining partial esters disclosed in the publications WO 9015806, WO 9211267, WO 9221169, Terov disclosed in patent publication WO 9211268.

Mono - or bisphosphonate parts can be added to the well-known medical substance is inseparable or as procacci and thus can enhance targeted delivery of the latter to the bone, when it is used to treat bone diseases or to improve the solubility in the aqueous phase of poorly soluble drugs. For this purpose there are known some mixed anhydrides, mainly phosphoric acid and carboxylic acid.

New molecules in accordance with the present invention, which contain a group of the acid anhydride as procast or are active as such, are very suitable for the treatment of disorders associated with calcium metabolism and other, especially ferrous metals. They can be used in the treatment and diseases of the bones, especially violations of the formation and bone resorption, such as osteoporosis and Paget's disease, and diseases of soft tissues, such as the status of deposits, mineralization and violations of ossification.

On the other hand, being analogues of pyrophosphate, new anhydrite derived methylenephosphonic acids are suitable for treating disorders pyrophosphate body functions, including the same is applied to the (pyro)phosphate or acts as a complex of the metal or as a combination of the latter.

New bisphosphonates regulate, either directly or through an indirect mechanism, quality and concentration of both cations and/or pyrophosphate compounds that are freely present in the body fluids or associated with tissues that are active in the tissues and are released from them, i.e., the formation, dissolution, education links and elimination. Therefore, they are able to regulate metabolism, growth and destruction of cells.

Based on the above, they can be used, for example, in the treatment of bone cancer and its metastasis, ectopic calcification, kidney stones, rheumatoid arthritis, osteitis and degenerations of bones.

The present invention relates to new derivatives methylenephosphonic acid of General formula Iwhere Y1, Y2, Y3and Y4indicate the group OR1, NR2R3, OCOR1, OCONR2R3, O(CO)OR1, O(SO2R1, O(SO2OR1or OP(O) R2(OR3), where R1, R2and R3denote, independently of one another, hydrogen, linear or branched, optionally substituted, optionally unsaturated C1-C22alkyl, optionally someseni the l SiR3where R represents C1-C4alkyl, phenyl, substituted phenyl, or a combination of C1-C4Akilov and/or fanilow, or group, R2and R3together with the neighboring nitrogen atom to form a 3 - to 10-membered saturated, partially saturated or aromatic ring, where in addition to the nitrogen atom may be one or two heteroatoms selected from the group N, O and S, or group, R2and R3together with the adjacent group O-RO-O form a 5 - or 6-membered ring, provided that in formula I at least one of the groups Y1, Y2, Y3and Y4is other than the group or SIG1or NR2R3; Q1and Q2denote, independently of one another, hydrogen, fluorine, chlorine, bromine or iodine, including stereoisomers such as geometrical isomers and optically active isomers, of the compounds, as well as pharmacologically acceptable salts of these compounds.

Optional unsaturated C1-C22alkyl as a group, R1, R2and R3denotes alkyl, alkenyl or alkynyl that contain independently from each other from 1 to 22, respectively from 2 to 22 carbon atoms, preferably from 1 to 8, respectively, from 2 to 8 carbon atoms and most preferably from 1 to 5, the fit is PI R1, R2and R3denotes cycloalkyl or alkenyl, which contain from 3 to 10 carbon atoms, preferably 5 or 6 carbon atoms and may be unsubstituted or substituted, for example, lower alkyl (1-4C). Preferably this cyclopropyl, -butyl, -pentyl or-heptyl or corresponding cycloalkenyl. Heterocyclyl contain in the ring one or more heteroatoms from the group N, O and s

Aryl or aralkyl as group R1, R2and R3denotes optional C1-C4-alkyl, -alkoxy or substituted with halogen monocyclic aryl or aralkyl, such as phenyl or benzyl, most preferably, however, unsubstituted phenyl or benzyl.

When cellgroup SiR3R denotes a lower alkyl containing from 1 to 4 C-atoms, it refers specifically methyl, ethyl, isopropyl, butyl or tert-butyl. When the group R in, cellgroup denotes a combination of C1-C4-Akilov or fanilow, then it is, for example, dimethyl-tert-butyl, maildisplay, dimetilfenil, diethylphenyl, methyl-tert-butylphenyl or aminobutiramida (2,6-dimetilfenil).

When R2and R3together with the nitrogen atom form a saturated heterocyclic ring, this stake is whether pyrrolidinyl, or, when they form a partially saturated or aromatic ring, the ring is, for example, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl or azepine. This group may be substituted as described above for cycloalkyl, but preferred, however, unsubstituted, such as, for example, pyrrolidinyl, morpholinyl or piperazinil.

When R2and R3together with the adjacent group O-RO-O form a 5 - or 6-membered ring, the specified ring is preferably dioxaphospholane or dioxaphospholane.

Most preferably when Q1and Q2are both chlorine atoms.

Salts of compounds of the formula I is, mainly, their salts with pharmaceutically acceptable bases, such as metal salts, for example alkali metal salts, especially salts of lithium, sodium and potassium, salts of alkaline earth metals such as calcium salts or magnesium salts of copper, aluminum or zinc, and ammonium salts derived from ammonia or primary, secondary or tertiary, as aliphatic and alicyclic, and aromatic amines, salts of aliphatic or aromatic Quaternary ammonium salts with amines dimetilaminoetanol, N-mono - and N,N-dialkylaminoalkyl, N-(hydroxymethyl and ethyl)-N, N-amandemen and aminocarnitine and cryptate and heterocyclic ammonium salt, such as salt azetidine, pyrrolidine, piperidine, piperazine, morpholine, pyrrole, imidazole, pyridinium and chinoline, various tetraalkyl-ammonium salts such as salts of Tetramethylammonium, methyltrioctylammonium and benzyldimethyl-top alkylamine.

Preferred compounds according to the invention are derived methylenephosphonic acid of the formula I, where two of the groups Y1, Y2, Y3and Y4are groups OCOR2where R1such as defined above. Especially preferred of these compounds are those where R1denotes a linear or branched C1-C22alkyl or phenyl.

Preferred compounds according to the invention are also derived methylenephosphonic acid of the formula I, where two of the groups Y1, Y2, Y3and Y4are groups OR1where R1such as defined above. Especially preferred of these compounds are those where R1denotes a linear or branched C1-C22alkyl or phenyl.

Y3and Y4are groups OCOR1or or1are the connections where the third Deputy of the Y1, Y2, Y3and Y4selected from the group consisting of alkylsulfonyl, low alkylcarboxylic, benzoyl, arylsulfonyl, mono - and di-lower alkyl-phosphoryla.

Examples of preferred compounds according to the invention are, for example: disodium P,P'-diacetyl(dihlormetilen)a bisphosphonate and a free acid, disodium P, P'-dibutyryl (dihlormetilen) a bisphosphonate and a free acid, disodium P,P'-di(pivaloyl) (dihlormetilen)a bisphosphonate and a free acid, disodium P, P'-di(benzoyl) (dihlormetilen)a bisphosphonate and a free acid, disodium P,P'-di(isobutyryl)(dihlormetilen)a bisphosphonate and a free acid, disodium P,P'-di(deletion) (dihlormetilen) a bisphosphonate and a free acid, disodium P, P'-di(octadecanoyl) (dihlormetilen) a bisphosphonate and a free acid.

Derivatives in accordance with the present invention can be obtained in many different ways depending on what anhydride methylenephosphonic acid it is advisable to get. Methylenephosphonate acid used as starting materials, and their salts, complex therefire, closable (see for example WO 92/11267 and WO 92/11268). Thus, partial esters can be obtained, for example, by selective hydrolysis of complex tetraeder methylenephosphonic acid by selective esterification bisphosphonates acid or other partial esters by intramolecular or intermolecular reactions. Incomplete complex amidoamine may be, on the other hand, obtained, for example, by selective hydrolysis of Tetra(Mediafire) bisphosphonates acid or other incomplete piramidal by intramolecular or intermolecular reactions.

Compounds in accordance with the present invention, where the group Y1, Y2, Y3and Y4are either partially (from 1 to 3 groups), or all of the substituents mentioned above for these groups, but different from OR1or NR2R3can be obtained according to alternative (a) according to scheme 1 by sequential substitution reactions of the respective methylenephosphonic acids or their salts. Source material (II) where at least one of the groups X1-X4or are all independent from each other HE or OM, where M can mean a metal or ammonium group, is subjected to selective interaction with desirable proizvode b) according to scheme 1, when at least one of the groups X1-X4or they are all atoms of halogen or halogen counterparts, respectively, such as sulfonyloxy, the interaction of this compound with the selected acid (acids) (A-HE) or its salt with a metal (A-Ω) and finally removing the excess of the group's and possibly unnecessary group Y, for example, by hydrolysis with water. If these unnecessary, especially halogenated, group substituted by adding an alcohol, thiol or amine to the mixture, get the mixed anhydrides of ester, affirmed or amidoamine.

Scheme 1:

a) Xn(n = 1-4) HE or OM, where M denotes a metal or an ammonium group; Q1and Q2shall have the same meaning as above; Z represents a halogen atom, or equivalent; And refers to a group OCOR1, OCNR2R3, O(CO)OR1, O(SO2R1, O(SO2OR1or OP(O)R2(OR3), where the values of R1, R2and R3above, or
b) Xn(n = 1-4) - halogen or similar; Z indicates HE or OM, where M denotes a metal or an ammonium group; And Q1and Q2have the values specified above.

From tetraploidy I, obtained as described above, can then be obtained by polling �4.gif">
(C) Yn(n = 4) -- And --> Yn(n = 1-3) - A, where a has the same values as above in scheme 1.

During the hydrolysis can be tracked or chromatography, or by using31P-NMR spectroscopy. The reaction can be terminated when the concentration of the desired partial anhydride (at least one of the groups Y IS HE or OM) will be close to the highest, and the product can be isolated from the reaction mixture or as an acid or as a salt by precipitation, extraction or chromatography.

The mixed anhydrides of ester, affirmed or amidoamine can be obtained mainly on the basis of the molecule corresponding to the formula I where the group Y1, Y2, Y3and Y4present a selected number of the above mentioned groups or other groups specified for Y, different from OR1or NR2R3. The specified connection can react according to the method (a) with a suitable galogenangidridy acid or according to the method (b) with acid or its salt with the metal.

The new compounds according to the invention can be introduced interline or parenteral. Subject to the discussion of all conventional forms of administration, such as tablets, capsules, granules, syrups, solutions, implants and Suslina dosage forms, dissolution and injection, such as stabilizing agents, viscosity regulators, dispersing agents, and buffers.

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

The dosage depends on various factors, such as the method of administration, species, age and individual condition. The daily dose is from about 1 to 1000 mg, typically from 10 to 200 mg per person, and they can be entered as a single dose or can be divided into several doses.

The following is part of a regular capsules and tablets:
Capsule mg/capsule
Active substance - 100,0
Starch - 20,0
Magnesium stearate - 1,0
Tablet mg/tablet
Active substance - 400,0
Microcrystalline cellulose - 20,0
Lactose - 67,0
Starch - 10,0
Talc - 4,0
Magnesium stearate - 1,0
Compounds of the present invention can be prepared in the form of p is the quality assistive devices can be used, for example, sterile water, phosphate buffer, sodium chloride, sodium hydroxide, chloromethane acid or other suitable pharmaceutically acceptable additives.

The purpose of the following examples is to illustrate the invention, but without any of its limitations.

Example 1: P,P-Dimethyl-P'-methanesulfonyl(dihlormetilen) bisphosphonate methyltrioctylammonium salt and free acid
12.2 g (0,025 mol) methyltrioctylammonium salt trimethyl(dihlormetilen) bisphosphonates and 2.9 g (0,025 mol) of methylchloride dissolved in 150 ml of anhydrous acetonitrile and the solution is stirred for 20 minutes at the boiling flask with reflux condenser. The reaction course is monitored31P-NMR. The solvent is evaporated in vacuum and get around to 13.2 g (96% of theoretical) of a yellow oily methyltrioctylammonium salt of P, P-dimethyl-P' -methanesulfonyl (dihlormetilen) bisphosphonates (31P-NMR (CDCl3): 13,12 M. D. (R), -2,42 M. D. (R'),2JRR, = 20,3 Hz3JpH=to 10.7 Hz), the concentration of which is equal to 99.5%, and from which the corresponding acid can be isolated in the free state by treatment with acid.

For example, the following methylenephosphonate R,R-W-R'-monoamide and their Quaternary and armetale)bisphosphonates,31P-NMR (CDCl3): 15,13 M. D. (R), -0,63 M. D. (R'),2Jpp,=18,9 Hz3JpH=10,7 Hz.

Methyltrioctylammonium salt of P,P-dimethyl-P'-pentyl (dihlormetilen) bisphosphonates,31P-NMR (CDCl3): 15,12 M. D. (R), -1,04 m d(R'),2Jpp,=18.6 Hz,3JpH=10,6 Hz.

Methyltrioctylammonium salt of P,P-dimethyl-P'-benzoyl (dihlormetilen)bisphosphonates,31P-NMR (Dl3): 14,87 M. D. (R), -0,79 M. D. (R'),2JRR,=23,0 Hz3JpH=10,7 Hz.

Methyltrioctylammonium salt of P,P-dimethyl-P'-trichloroacetyl (dihlormetilen)bisphosphonates,31P-NMR (Dl3) 14,03 M. D. (P) 1,04 M. D. (R'),2JRR,=19.9 Hz,3JpH=10,8 Hz.

N-isopropylpyridine salt of R,R-aminobutiramida P'-pivaloyl (dihlormetilen) bisphosphonates,31P-NMR (CDCl3): 8,99 M. D. (R), 0,24, M. D. (R'),2JRR,=24.5 Hz,3JpH=6,6 Hz.

Ethyltrimethylammonium salt of P,P-diethyl-P'-methanesulfonyl (dihlormetilen)bisphosphonates,31P-NMR (CDCl3): 9,90 m D. (R), -1,29 M. D. (R'),2JRR,=22,8 Hz3JpH=7,9 Hz.

N-isopropylpyridine salt of R,R-aminobutiramida P'-methanesulfonyl(dihlormetilen)bisphosphonates,31P-NMR (CDCl3): 7,79 M. D. (P) of-1.45 M. D. (R'),2JRR,=23,3 Hz3JpH=6,4 Hz.

R (CDCl3): 10,80 m D. (R), -2,21 M. D. (R'),2Jpp,=21.2 Hz,3JpH=6,5 Hz,3JR,n=10.5 Hz.

Methyltrioctylammonium salt of P,P-dimethyl-P'-benzazolyl (dihlormetilen)bisphosphonates,31P-NMR (CDCl3): 13,07 M. D. (R), -2,28 M. D. (R'),2JRR,=21,0 Hz3JpH=10,7 Hz.

Methyltrioctylammonium salt of P,P-dimethyl-P'-p-toluensulfonyl(dihlormetilen)bisphosphonates,31P-NMR (CDCl3): of 13.27 M. D. (R), -2,54 M. D. (R'),2JRR,=20.2 Hz,3JpH=10,3 Hz.

Methyltrioctylammonium salt of P, P-dimethyl-P'-2,4,6-trimethylbenzenesulfonyl(dihlormetilen)bisphosphonates,31P-NMR (CDCl3): 13,53 M. D. (R), -2,81 M. D. (R'),2Jpp,=22,0 Hz3JpH=10,8 Hz.

Methyltrioctylammonium salt of P, P-dimethyl-P'-2,4,6-triisopropylbenzenesulfonyl(dihlormetilen)bisphosphonates,31P-NMR (Dl3): 13,54 M. D. (R), -2,83 M. D. (R'),2Jpp,=21,9 Hz3JpH=10,8 Hz.

Methyltrioctylammonium salt of P, P-dimethyl-P'-d-10-camphorsulfonic (dihlormetilen) bisphosphonates,31P-NMR (Dl3): 13,06 M. D. (R), -2,82 M. D. (R'),2JRR,=20.7 Hz,3JpH=10,7 Hz.

Methyltrioctylammonium salt of P,P-dimethyl-P'-pivaloyl (dibromomethyl) bisphosphonates,31P-NMR (CDCl3): 15,16 M. D. (R) is econsultancy (dibromomethyl)bisphosphonates,31P-NMR (CDCl3): 12,99 M. D. (R), -2,83 M. D. (R'),2JRR,=15.7 Hz,3JpH=10,6 Hz.

Methyltrioctylammonium salt of P, P-dimethyl-P'-trichlormethane sulfonyl(dibromomethyl)bisphosphonates,31P-NMR (Dl3): 13,12 M. D. (R), -2,98 M. D. (R'),2JRR,=15,4 Hz.

Methyltrioctylammonium salt of P,P-dimethyl-P'-p-toluensulfonyl(dihlormetilen)bisphosphonates,31P-NMR (CDCl3): 13,13 M. D. (R), -2,95 M. D. (R'),2JRR,=15.1 Hz,3JpH=10,8 Hz.

Methyltrioctylammonium salt of P,P-dimethyl-P'-pivaloyl (monobromomethane)bisphosphonates,31P-NMR (CDCl3): 20,51 M. D. (R) of 0.95 m d (R'),2JRR=6,0 Hz2JpH=16.5 Hz,3JpH=10,9 Hz.

Methyltrioctylammonium salt of P, P-dimethyl-P'-methanesulfonyl (monobromomethane)bisphosphonates,31P-NMR (CDCl3): 17,46 M. D. (R), 1,19 M. D. (R'),2JRR=7,3 Hz,3JpH=17.3 Hz,3JpH=11,0 Hz.

Methyltrioctylammonium salt of P,P-dimethyl-P'-acetyl (dihlormetilen)bisphosphonates,31P-NMR (CDCl3): 13,71 M. D. (P) -4,10 M. D. (R'),2JRR,=18,9 Hz.

Methyltrioctylammonium salt of P,P-dimethyl-P'-propionyl (dihlormetilen)bisphosphonates,31P-NMR (Dl3): of 14.57 M. D. (R), -1,61 M. D. (R'),2JRR,=19.1 Hz,3JpH=10,CDCl3): 14,17 M. D. (R), -1,18 M. D. (R'),2JRR,=18.3 Hz,3JpH=10,7 Hz.

Methyltrioctylammonium salt of P,P-dimethyl-P'-dimethylcarbamoyl(dihlormetilen)bisphosphonates,31P-NMR (CDCl3): 14,80 m D. (R), -1,62, M. D. (R'),2JRR,=18.2 Hz,3JpH=10,6 Hz.

Methyltrioctylammonium salt of P,P-dimethyl-P'-acetyl (dibromomethyl)bisphosphonates,31P-NMR (Dl3): 14,73 M. D. (R), -2,00 M. D. (R'),2JRR,=13,7 Hz3JpH=10,8 Hz.

Methyltrioctylammonium salt of P, P-dimethyl-P'-propionyl (dibromomethyl) bisphosphonates,31P-NMR (Dl3): 14,17 M. D. (R), -1,40 M. D. (R'),2JRR,=14,0 Hz3JpH=10,7 Hz.

Methyltrioctylammonium salt of P,P-dimethyl-P'-dimethylcarbamoyl(dibromomethyl)bisphosphonates,31P-NMR (CDCl3): 14,92 M. D. (R), -1,92 M. D. (R'),2JRR,=14,0 Hz.

N-isopropylpyridine salt of R,R-aminobutiramida P'-acetyl (monochloramine)bisphosphonates,31P-NMR (Dl3): 14,49 M. D. (P) 3,07 m DV (R'),2JRR=8,4 Hz2JpH=17,1 Hz3JpH=7,7 Hz.

N-isopropylpyridine salt of R,R-aminobutiramida P'-pivaloyl (monochloramine)bisphosphonates,31P-NMR (CDCl3): 15,02 M. D. (P) 3,02 m DV (R'),2JRR=9.8 Hz,2JpH=17,4 Hz3Jmisappropriating salt of R,R-aminobutiramida P'-methanesulfonyl(bromchlormethane)bisphosphonates.

Obtaining raw materials:
Quaternary monoammonium salt complex Trifonov monochloro-, dichloro-, monobromo or (dibromomethyl) bisphosphonates for use as starting materials can be obtained, for example, by treatment of the corresponding complex tetraeder one equivalent of a tertiary amine in a dry inert solvent at a temperature of about 25-100oWith the progress of the reaction can be monitored using31P-NMR.

The following example illustrates the receipt of raw materials:
to 30.1 g (0.1 mol) of tetramethyl(dihlormetilen)bisphosphonates are dissolved in 60 ml of anhydrous chloroform and added to 18.6 g (0.1 mol) of anhydrous tributylamine. The solution is stirred at reflux for 4 h and the solvent is evaporated in vacuum. The output is about 50 g (100% of theoretical) of a colorless methyltrioctylammonium salt trimethyl(dihlormetilen) bisphosphonates, the concentration of which 98%. (31P-NMR (CDCl3): 15,50 m D. (R), 4,25 m DV (R'),2JRR,=16.6 Hz.)
Example 2: P,P-Dimethyl-P'-dimethylphosphoric (dihlormetilen) bisphosphonate methyltrioctylammonium salt and free acid
a 4.86 g (0.01 mol) methyltrioctylammonium salt trimethyl(oshita and the solution stirred at reflux for 1 h (the reaction course is monitored31P-NMR). The solvent is evaporated in vacuo, resulting in a gain of about 5.6 g (96% of theoretical) of a brownish oily methyltrioctylammonium salt of P,P-dimethyl-P'-dimethylphosphoric (dihlormetilen) bisphosphonates31P-NMR (CDCl3): 13,90 M. D. (R), -4,84 M. D. (R'), -10,23 M. D. (R"),2JRR,= 20,3 Hz2Jp p= 27.7 Hz,3Jp n=10,7 Hz3JR"n=11.7 Hz), the concentration of which is equal to about 90%, and from which the corresponding acid can be isolated in the free state by treatment with acid.

For example, the following phosphoryl(dihlormetilen)bisphosphonates and their Quaternary ammonium salts can be obtained similarly:
Methyltrioctylammonium salt of P, P-dimethyl-P'-diisopropylphenyl (dihlormetilen) bisphosphonates,31P-NMR (CDCl3): 14,95 m D. (R), -4,84 M. D. (R'), -13,98 M. D. (R"),2JRR, =20.6 Hz,2Jp p=26,1 Hz3JpH=10,6 Hz3JR"n=7,8 Hz.

N-isopropylpyridine salt of R,R-aminobutiramida P'-dimethylphosphoric(dihlormetilen)bisphosphonates,31P-NMR (CDCl3): which 9.22 M. D. (R), -3,74 M. D. (R'), -9,25 M. D. (R"),2Jpp,=22,3 Hz2Jp p=27.4 Hz.

Methyltrioctylammonium salt of P,P-di(trimethylsilyl)-P'-di(trimethylsilyl) phosphoryl (dichloromethyl the R R
=22,6 Hz.

Example 3: P,P,P'-Trimethyl-R'-pivaloyl (dihlormetilen) bisphosphonate
2.9 g (0.01 mol) P,P,P'-trimethyl (dihlormetilen) bisphosphonates and 1.7 g (0.014 mol) of pualeilani dissolved in 50 ml of anhydrous acetonitrile and the solution is stirred at reflux for 1.5 h (the reaction course is monitored31P-NMR). The solvent and excess reagent is evaporated in vacuo, resulting in a gain of about 3.3 g (90% of theory) of a brownish oily P,P,P'-trimethyl-R'-pivaloyl (dihlormetilen) bisphosphonates (31P-NMR (CDCl3): 10,41 M. D. (R), 9,17 M. D. (R'),2JRR,=23,7 Hz3JpH=10,9 Hz3JR n=10,9 Hz)).

For example, the following P,P,P'-triavir-P-monoamide (dihlormetilen)bisphosphonates acid can be obtained similarly:
P, P, P' - Triisopropyl-R'-pivaloyl (dihlormetilen) bisphosphonate (31P-NMR (Dl3): 6,40 m D. (R), 4,71, M. D. (R'),2Jpp,=26,2 Hz3JpH=6,5 Hz,3JR n= 6,7 Hz).

P, P, P'-Triisopropyl-R'-methanesulfonyl (dihlormetilen) bisphosphonate (31P-NMR (CDCl3): 5,32 M. D. (R), 0,39 M. D. (R'),2Jpp,=24,8 Hz3JpH=6,4 Hz,3JR n=6,8 Hz).

P, P-Dimethyl-P'-(trimethylsilyl)-P'-pivaloyl(dichloromethylene>

Example 4: Mixed salt bipiperidine-methyltryptamine R-methyl-R'-monomethylester (dihlormetilen) bisphosphonates and free acid
2.9 g (0,005 mol) methyltrioctylammonium salt of P,P-dimethyl-P'-dimethylphosphoric(dihlormetilen)bisphosphonates and 12 ml of anhydrous piperidine is stirred for 1 h at about 80o(The reaction course is monitored31P-NMR) and excess piperidine is evaporated in vacuo, resulting in a gain of about 3.5 g (97% of theoretical) brownish mixed salt bipiperidine-methyltryptamine R-methyl-R'-methylphosphonyl(dihlormetilen)bisphosphonates (31P-NMR (CDCl3): 7,00 m D. (R), -0,89 M. D. (R'), -7,51 M. D. (R"),2JRR,= 16,7 Hz2Jp p=28,9 Hz3JpH=10,0 Hz3JR"n=11.5 Hz), the concentration of which is about 90%, and from which the corresponding acid can be isolated in the free state by treatment with acid.

Example 5: P,P-Dimethyl P',P'-bis(trichloroacetyl) (dihlormetilen) bisphosphonate
a 4.86 g (0.01 mol) methyltrioctylammonium salt P,P,P-trimethyl (dihlormetilen)bisphosphonates and of 3.64 g (0.02 mol) of trichloroacetaldehyde in 50 ml of anhydrous acetonitrile is stirred at reflux for 2 h and the solvent is evaporated Rosenii about 1:1 P,P-dimethyl - P',P' -di (trichloroacetyl) (dihlormetilen) bisphosphonate (31P-NMR (Dl3): 14,25 M. D. (R), 0,11 M. D. (R'),2JRR,=20,3 Hz3JpH=10,6 Hz) and methyltrioctylammonium salt of P,P-dimethyl-P'-trichloroacetyl (dihlormetilen)bisphosphonates (see example 1).

Example 6: Disodium P-methyl-P'-acetyl(dihlormetilen) bisphosphonate and the free acid
of 3.9 g (0.01 mol) of a mixed salt disodium-piperidine P-methyl(dihlormetilen)bisphosphonates and 40 ml of acetanhydride stirred at room temperature for about 2 days. The mixture is cooled in ice water and the precipitate is filtered and washed with acetone and dried, the result of 3.3 g (96% of theoretical) of colourless crystalline disodium P-methyl-P'-acetyl(dihlormetilen)bisphosphonates (31P-NMR (D2O): 9,03 M. D. (R), 4,01 m DV (R'),2Jpp, = 16.5 Hz,3JpH=10.4 Hz), the concentration of which is about 100%, and from which the corresponding acid can be isolated in the free state by treatment with acid.

For example, the following symmetric complex averagegrade (dihlormetilen) bisphosphonates and their salts can be obtained similarly:
salt of bis(diethylamine) P-methyl-P'-pivaloyl (dihlormetilen) bisphosphonates,31P-NMR (Dl3): 5,68 m D. (R), 1,78 m DV (R'), 6.7 g (0.02 mol) of Terentieva salt (dihlormetilen) bisphosphonates acid and 220 ml of acetanhydride stirred for 60 h at 60o(The reaction course is monitored31P-NMR) and cooled. The precipitate is filtered and washed with acetone and subjected to recrystallization from a mixture of ethanol/water. After drying receive about 7.1 g (95% of theory.) colorless crystalline disodium P, P'-diacetyl(dihlormetilen)bisphosphonates (31P-NMR (D2O): 2,84 m D. (R, R')), the concentration of which is about 100%, and from which the corresponding acid can be isolated in the free state by treatment with acid.

For example, the following symmetric dianhydride (dihlormetilen)bisphosphonates acid can be obtained similarly:
Disodium P, P'-dibutyryl (dihlormetilen) a bisphosphonate,31P-NMR (D2O): 2,90 m D. (R, R').

Disodium P, P'-dualrail (dihlormetilen) a bisphosphonate,31P-NMR (D2O): 3,13 M. D. (R, R').

Disodium P,P'- di (pivaloyl)(dihlormetilen) a bisphosphonate,31P-NMR (D2O): 3,74 m D. (R, R').

Disodium P, P'-di (benzoyl)(dihlormetilen) a bisphosphonate,31P-NMR (D2O): 3,85 m D. (R, R'),
Disodium P, P'-di (isobutyryl)(dihlormetilen) a bisphosphonate,31P-NMR (D2O): 2,75 m D. (R, R').

istributional salt of P,P-bis (diethylamido)- R'-etoxycarbonyl(dihlormetilen)bisphosphonates and free acid
1,895 g (of 0.003 mol) methyltrioctylammonium salt of P,P-bis (diethylamido)-R'- methyl (dihlormetilen) bisphosphonates are dissolved in 11 ml of dry acetonitrile. The mixture is heated jacket and stirred until the internal temperature reaches 80oC. To the mixture at 80oWith added dropwise over 15 minutes a solution which contains 355 mg (of 0.003 mol) ethylchloride in 11 ml of dry acetonitrile. The mixture is stirred for 3 hours and 45 minutes until the internal temperature 80-82oWith, and evaporated to dryness. The mixture is left to crystallize overnight, the result is 2.1 g methyltrioctylammonium salt of P, P-bis(diethylamido)-R'-etoxycarbonyl(dihlormetilen) bisphosphonates (31P-NMR (D2O): 27,11 M. D. (R), 0,73 m DV (R'),2Jpp=22,3 Hz), the concentration of which is about 90%, and from which the corresponding acid can be isolated in free form by treatment with acid.

Example 9: Di(methyltrioctylammonium) salt of P,P-di (etoxycarbonyl)(dihlormetilen)bisphosphonates and free acid
3,36 g (0,005 mol) di(methyltrioctylammonium) salt of P, P'- dimethyl(dihlormetilen)bisphosphonates dissolved in 20 ml of anhydrous acetonitrile, the solution was added 2.17 g (0.02 mol) of ethylchloride and stirred for 30 minutes at about 75o31P-NMR (CDCl3): 0,40 m D. (R, R')), the concentration of which about 85%, and from which the corresponding acid can be isolated in free form by treatment with acid.

For example, the following symmetric dianhydride (dihlormetilen) bisphosphonates can be obtained similarly:
disodium, P,P'-bis (dimethylcarbamyl) (dihlormetilen) a bisphosphonate.

Example 10: P,P-Dimethyl-P'-pivaloyl-P-trimethylsilyl (dihlormetilen)bisphosphonate
2.2 g (0,004 mol) methyltrioctylammonium salt of P,P-dimethyl-P'-pivaloyl(dihlormetilen)bisphosphonates dissolved in 20 ml of anhydrous acetonitrile and the solution is cooled to 0oWith and add 0.45 g (0,0042 mol) of chlorotrimethylsilane in 5 ml of anhydrous acetonitrile under stirring at 0-5oC. After the addition the mixture is stirred for 10 min at 0-5oC and 1 h without cooling, and the solvent is evaporated in vacuum, the result is the desired product as a brown oil with a purity of about 80%. (31P-NMR (CDCl3): 12,59 M. D.(P) -2,10 M. D. (R'),2JRR=22.7 Hz,3JpH=11,0 Hz.)
Example 11: Dipyridinium salt of P,P'-di(deletion) (dihlormetilen)bisphosphonates
1.0 g (4,08 mmol) (dihlormetilen) bisphosphonates acid and 10 ml of dry tetrahydrofuran, smeshivanie stirred at about 23oC for 3 h and evaporated to dryness in a vacuum. Yield 4.3 g (100% of theory. ), of which 3.4 g dipyridinium salt of P,P'-di(deletion) (dihlormetilen) bisphosphonates (31P-NMR (CDCl3): 1,65 M. D. (R, R')), the concentration of which is about 100% (31P-NMR), and 0.9 g of pyridinium hydrochloride.

Similarly also receive:
Dipyridinium salt of P,P'-di(octadecanoyl)(dihlormetilen) bisphosphonates, (31P-NMR (CDCl3): 1,60 M. D. (R, R')).

Example 12: Trinacria monoricinoleate (dihlormetilen)bisphosphonate
5.0 g (15.0 mmol) of tetranitro (dihlormetilen)bisphosphonates and 23.1 g (108.3 mmol) of anhydride kupreeva acid is mixed with about 85oC for 7 h and at room temperature for 18 h (the reaction course is monitored31P-NMR). The mixture is filtered and washed with 2 ml of acetone and dried in vacuum, the result is about 5.4 g (88% of theory.) crystal trinacria monoricinoleate(dihlormetilen)bisphosphonates (31P-NMR (D2O): EUR 7.57 M. D. (R), 4,59, M. D. (P)2Jpp=17.6 Hz) with a concentration of 81%, while the concentration of the source material is 16% and the concentration of disodium P,P'-dioxanonane (dihlormetilen)bisphosphonates - 3% (31P-NMR).

Example 13: in vitro Tests molecules prodrugs, HPLC, used zoé/ion pair (socrata program for clodronate; gradient program for the simultaneous analysis of clodronate and molecule prodrugs), where the definition of the compounds is based on measurement of light scattering caused not evaporated compounds.

Equipment:
HPLC Merck LaChrom (Merck Hitachi Ltd., Japan) Kromasil 100 RP-C8 (250 x 4.6 in diam., 5 µm) (Higgins Analytical Inc., USA)
Eluent:
Socrata program: buffer methanol/ammonium acetate (3:97, pH 4,6), which contains 2,25% butylamine as the reagent ion pairs, flow 1.2 ml/min

Gradient program: methanol (3%-->40-60% for 1 min to 6 min)/ammonium acetate (pH of 4.6), which contains 2,25% butylamine as the reagent ion pairs, flow 1.2 ml/min

Detector: the detector light scattering Sedex 55 (Sedere, France)
Setting: temperature detector 70oWith the pressure of the volatile gas (filtered air) of 2.2 bar.

Solubility in water molecules prodrugs
The water solubility of the prodrug molecules is determined in phosphate buffer (50 mm, pH 7.4) at room temperature.

An excess of compounds that must be tested, dissolved in about 5 ml of phosphate buffer. The suspension is stirred for 2 hours, the suspension is filtered and the concentration of the prodrug in the filtrate determined HPLC. Solubility in water cadrona the

The distribution coefficient of the molecules prodrugs
Solubility in fats compounds tested are examined by determining the distribution coefficients (R) of the compounds at pH 7.4 and 2.0. The analysis is performed in a mixture of octanol/buffer.

When applied analysis method using a mixture of octanol/buffer used 1-octanol and phosphate buffer (50 mm, pH 7,40,= 0,15) saturate each other by stirring a mixture thereof during the night. The phases are separated and prepare a standard solution of prodrugs with the desired concentration in the buffer phase. Appropriate amounts of 1-octanol and a standard solution of phosphate buffer are mixed and the mixture was thoroughly shaken for 60 minutes

After stirring, the phases are separated and analyze the concentration of tested compound in the buffer phase before and after the distribution according to the above-described HPLC method. The distribution coefficient R calculated by the following formula:

where Cithe concentration of tested compound before distribution;
Candthe concentration of tested compound after the distribution;
Va- volume-buffer phase;
Vovolume phase octanol.

The coefficients R is roles molecules prodrugs
Chemical hydrolysis of prodrug molecules analyzed in phosphate buffer (50 mm,=0,15) at pH 2.0 and 7.4 and at 37oC.

The connection that must be examined is dissolved in 10.0 ml of phosphate buffer. The solution is stirred 24-1000 h in a water bath with magnetic stirrer and take samples at regular intervals and analyzed HPLC. From the results of the build schedule pseudopelade 1, where the number of remaining connections are shown as a function of time. From the slope (kk) thus obtained is a line graph to calculate the dissociation constant k (k = 2,303 x-kk), which calculate the half-life of T1/2(T1/2= 0,693/k) molecule prodrugs in these circumstances.

The half-lives of the compounds under test, shown in table 3.

Enzymatic hydrolysis of prodrug molecules (plasma)
The rate of the enzymatic hydrolysis of prodrug molecules determined in a mixture of plasma/buffer (80%-20%) at pH 7,40 and at 37oC.

The connection that must be tested, dissolved in buffer and once dissolved, add the plasma with a temperature of 37oC. the Solution is stirred with a magnetic stirrer and a sample of 0.25 ml is withdrawn from the mixture at intervals of 1 is Rob centrifuged, transparent supernatant evaporated to dryness, the residue dissolved in eluent HPLC method and the residual concentration of the prodrugs and the number of the formed clodronate analyze HPLC. From the obtained concentrations build the graph of the first order (the residual quantity of prodrugs as a function of time), which determine the dissociation constant and half-life (T1/2).

The half-lives of the compounds under test, shown in table 3.

Example 14: Effect on PTH induced bone resorption in vitro and absorption and hydrolysis of compounds in vivo
Effect on PTH induced bone resorption on the cranial bones of the mouse.

Newborn mouse mark by subcutaneous injection45Sa for four days before the killing. Fragments of skull bones micropreparation of the occipital bone, is subjected to pre-incubation in culture medium with indomethacin, washed and then cultured for three days with bisphosphonates prodrug or without him. Bone resorption stimulated by parathyroid hormone (PTH, 10 nm) and measured the effect on this stimulated resorption. As shown in table 4, the inhibition of resorption connections obvious. Inhibition of bisphospho Absorption and hydrolysis of compounds in vivo study on the hungry rats. Determine the absorbance of the total number released with the urine within 72 hours after injection. To determine the oral bioavailability of the released amount after oral administration compared to those after intravenous administration. Urine samples will be analyzed by the original medicinal substance, by mass-selective or nitrogen posteromarginal gas chromatography. The results presented in table 5, show enhanced bioavailability bisphosphonate prodrugs compared to that of the parent drug.


Claims

1. Derivatives of anhydride methylenephosphonic acid having a General formula I

where Y1, Y2, Y3and Y4indicate the group OR1, NR2R3, OCOR1, OCONR2R3, O(CO) OR1, O(SO2R1or OP(O)R2(OR3), where R1, R2and R3denote, independently of one another, hydrogen, linear or branched, optionally substituted, optionally unsaturated C1-C22alkyl, optionally substituted aryl or silyl SiR3where R3represents C1-C4alkyl, useppa OR1or NR2R3;
Q1and Q2denote, independently of one another, hydrogen, fluorine, chlorine, bromine or iodine,
including stereoisomers such as geometrical isomers and optically active isomers, of the compounds and pharmacologically acceptable salts of these compounds.

2. Derivatives of anhydride methylenephosphonic acid on p. 1, characterized in that Q1and Q2in the formula I are both chlorine atoms.

3. Derivatives of anhydride methylenephosphonic acid under item 1 or 2, characterized in that two of the groups Y1, Y2, Y3and Y4in the formula I are OCOR groups1where R1such, as defined in paragraph 1.

4. Derivatives of anhydride methylenephosphonic acid on p. 3, wherein R1denotes a linear or branched C1-C22alkyl or phenyl.

5. Derivatives of anhydride methylenephosphonic acid under item 1 or 2, characterized in that two of the groups Y1, Y2, Y3and Y4in the formula I are groups OR1where R1such, as defined in paragraph 1.

6. Derivatives of anhydride methylenephosphonic acid on p. 5, wherein R1denotes a linear or branched C1-C22 is the third of the groups Y1, Y2, Y3and Y4in the formula I is selected from the group consisting of alkylsulfonyl, low alkylcarboxylic, benzoyl, arylsulfonyl, mono - and di-lower alkyl-phosphoryla.

8. Derivatives of anhydride methylenephosphonic acid on p. 1, characterized in that represent a compound selected from the group including
disodium P,P'-diacetyl(dihlormetilen)a bisphosphonate or a free acid,
disodium P,P'-dibutyryl (dihlormetilen) a bisphosphonate or a free acid,
disodium P, P'-di (pivaloyl) (dihlormetilen)a bisphosphonate or a free acid,
disodium P, P'-di (benzoyl) (dihlormetilen)a bisphosphonate or a free acid,
disodium P, P'-di (isobutyryl)(dihlormetilen)a bisphosphonate or a free acid,
disodium P,P'-di (deletion) (dihlormetilen) a bisphosphonate or a free acid,
disodium P, P'-di (octadecanoyl) (dihlormetilen) a bisphosphonate or free acid.

9. The method of obtaining derivatives of anhydride methylenephosphonic acid according to p. 1, characterized in that the starting compound corresponding to the formula II

where at least one of the groups X1-X4or are all independent from each other and HE is>subjected to selective interaction with the desired acid derivative Z-A, where a denotes the group OCOR1, OCONR2R3, O(CO)OR1, O(SO2R1or OP(O)R2(OR3and Z denotes a halogen or similar, and to obtain the derivatives of I three-, di - and maneepong anhydride obtained tetrahydride subjected to selective hydrolysis.

10. The method of obtaining derivatives of anhydride methylenephosphonic acid according to p. 1, characterized in that the starting material corresponding to the formula II, where at least one of the groups X1-X4or are independently of each other by halogen atoms or halogen counterparts, is subjected to the interaction with the selected acid or acids selected (A-OH) (Z=OH) or its salt with a metal (A-OM) (Z= OM), where a and M have the same meaning as in paragraph 9, and, finally, remove the excess of the group's and optional extra group Y, for example, by hydrolysis with water and to obtain the derivatives of I three, di - and maneepong anhydride obtained above tetrahydride subjected to selective hydrolysis.

11. Pharmaceutical composition for the treatment of bone diseases, in particular violations of the formation and bone resorption, as well as diseases of the soft tissues in Cartagena it contains a derivative of the anhydride methylenephosphonic acid of the formula I on p. 1.

 

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