Derivative guanidinate-1,1-bis-phosphonic acids and method of production thereof

 

(57) Abstract:

Usage: medicine to prevent bone resorbtive. The inventive derivative guanidinate-1,1-bis-phosphonic acids f-ly /1/ and their tautomeric forms, where R - disubstituted phenyl with the substituents R11and R12- R13SO2-, R14R15N-, pyridinyl, phenoxy, halogen, R13, R14, R15- C1-C6-alkyl/ N - substituted indolyl, R5-R8hydrogen or1-C6-alkyl. Reagent 1. Connection f-crystals /II/, where R5- R8have the specified values. Reagent 2: compound f-crystals /III/. Reaction conditions: inert solvent. 2 S. and 2 C.p. f-crystals, 1 table.

The invention relates to a derivative of guanidine-1,1-bis phosphonic acid, method for their production and to their use.

Treatment of diseases of the skeletal system becomes increasingly important. For example, a common bone disease is osteoporosis. In the various forms of osteoporosis is too strong bone loss, so in the end you lose mechanical stability of the bone. In healthy people the norm, with which the formation of osteoclasts and osteoplasty, the composition of the e, so this leads to bone resorption.

We already know that the derivative guanidinate-1,1-bis-phosphonic acid used for the prevention and/or treatment of osteoporosis (European patent 0546548).

In the desire to obtain other effective compounds for the treatment and prevention of osteoporosis with little side effects, it was found that guanidinate-1,1-bis phosphonic acid according to the invention reduces bone resorption.

The invention relates, therefore, connection of the tautomeric formulas 1A, 1B, or 1C

< / BR>
< / BR>
and/or physiologically tolerable salts of compounds of formula 1A, 1B or 1C;

if this

R has the following value:

1) residue of the formula V

;

if this

R11or R12have the following meanings:

,

if this

R13does

1) (C1- C6)-alkyl,

2) (C5- C7-cycloalkyl,

3) cyclopentylmethyl,

4) cyclohexylmethyl,

5) phenyl,

6) phenyl substituted once to three-fold through

6.1 fluorine atom,

6.2 chlorine atom,

6.3 methyl or

6.4 methoxy,

if this

n represents the integer 0, 1 or 2,

if this

R14and Ris and

2) (C1-C6) - alkyl,

3) phenyl,

4) phenyl substituted once or twice through

4.1 fluorine atom,

4.2 chlorine atom

4.3 methyl or

4.4 methoxy,

5) -(CH2)m- phenyl, and m represents an integer of 1 to 4 or

6) -(CH2)m- phenyl, and m represents an integer of 1 to 4 and the phenyl residue substituted once or twice stated in 4.1 - 4.4 remains,

7) R14and R15form together a straight or branched chain with 4-7 carbon atoms, the chain may optionally be interrupted through

7.1 O,

7.2 S or

7.3 NR10,

thus R10does

1) a hydrogen atom, or

2) methyl or

8) R14and R15together with the nitrogen atom to which they are bound, form

8.1 dihydroindolone,

8.2 tetrahydroquinoline or

8.3 tetrahydroisoquinoline ring,

and the other Deputy denotes R11or R12< / BR>
(a) a hydrogen atom,

b) a halogen atom as a fluorine atom, chlorine atom, bromine atom or iodine atom,

c) (C1- C4)-alkyl,

(d) (C1- C4)-alkoxy,

e) phenoxy,

f) phenoxy, one triple substituted through

1) a fluorine atom or a chlorine atom is23has the above value, or

< / BR>
if this

R14and R15have a specified value or

11) the rest of the formula VI

< / BR>
if this

R21, R22or R23have the following meanings:

(a) a hydrogen atom,

b) a halogen atom as a fluorine atom, chlorine atom, bromine atom, iodine atom, or

(C) (C1- C12)-alkyl,

and one of the substituents R21, R22or R23may denote also

1) N3,

2) CN,

3) OH,

4) (C1- C10)-alkoxy,

5) R24- CnH2n-Om,

if this

m denotes the number 0 or 1,

n denotes the number 0, 1, 2 or 3,

R24is

1) CpF2p+1< / BR>
while p denotes the number 1, 2 or 3, if n denotes the number 0 or 1,

2) (C3- C12-cycloalkyl,

3) phenyl,

4) peridot,

5) hinely or

6) ethanolic,

moreover, a cyclic system of residues 3) - 6) is not substituted or substituted by a residue from the group

3.1 fluorine atom,

3.2 chlorine atom,

3.3 CF3,

3,4 - methyl

3,5 - methoxy or

3.6 NR25R26< / BR>
thus R25and R26- same or different and independently of one another have the value of
R31, R32, R33or R34have the following meanings:

(a) a hydrogen atom,

b) a halogen atom as a fluorine atom, chlorine atom, bromine atom or iodine atom,

c) -CN,

d) -NO2,

(e) -N3,

f) - (C1- C6)-alkyl, straight or branched chain, or

g) R35- CnH2n-Z-,

while n denotes the number 0, 1, 2, 3, 4, 5 or 6, and Allenova chain-CnH2nis a straight or branched, and C-atom may be replaced through O-, S - or N-atom, R35is

1) a hydrogen atom,

2) (C3- C6)-alkenyl,

3) (C5- C8-cycloalkyl,

4) (C5- C8-cycloalkyl substituted with a hydroxy-group or methylene group substituted through O, S or N atom, or

5) phenyl, unsubstituted or substituted by 1-3 residues from the group

5.1 halogen atom as a fluorine atom, chlorine atom, bromine atom or iodine atom,

5.2 CF3,

5.3 CH3-S(O)x,

while x denotes the number 0, 1 or 2,

5.4 R36- Wy< / BR>
thus R36denotes a hydrogen atom, methyl or ethyl, W denotes O-atom, NH or NCH3and y denotes 0 or 1,

5.5 CmF2m+1while m represents the number 1, 2 or 3,

5.6 pyridyl,

5.7 China is that q represents the number 1, 2 or 3,

4) -[C(CH3)(OH)]q-,

while q represents the number 1, 2 or 3,

5) -O-,

6) -NH-,

7) ,

8) -S(O)x-,

when X is 0, 1 or 2,

9) -SO2-NH - or

< / BR>
X has the following value

a) N or

b) C-R37,

thus R37denotes a hydrogen atom, (C1- C4-alkyl or (C2- C4)-alkenyl,

Y has the following meaning

a) NH,

b) N-(C1-C6)-alkyl,

s) -N-(C2-C4)-alkenyl or

d) R35- Cn-H2n-Z-,

thus R35, n and Z have the definition in paragraph (g), R5, R6, R7and R8the same or different in independence of each other have the following meanings

(a) a hydrogen atom,

b), (C1- C5)-alkyl, straight or branched chain, or

(C) phenyl.

If the substituents R11, R12, R21, R22, R23, R24, R25, R26, R31, R32, R33, R34or R35contain one or more centers of asymmetry, as connections with S-configuration, and the connection with the R-configuration belong to the invention. The compounds can exist as optical isomers, diesterase branched chain.

Preferred compound of formula 1A, 1B or 1C and/or a physiologically tolerable salt of the compounds of formula 1A, 1B or 1C, and R has the following value:

1) residue of the formula V; R11has the following value:

(a) fluorine atom,

b) a chlorine atom,

,

thus R14and R15have a named value,

d) R13- S(O)nwhile n denotes 0, 1 or 2, or

e) phenoxy, R12has the following value:

a) R13- S(O), n denotes 0, 1 or 2, or

while R14and R15have the above significance, or

II) a residue of formula VI; R21, R22or R23have the following meanings:

(a) a hydrogen atom,

b) a halogen atom as a fluorine atom, a chlorine atom or a bromine atom, or

c) (C1- C8)-alkyl,

and one of the substituents R21, R22or R23may denote also

1) OH,

2) (C1- C6)-alkoxy,

3) R24- CnH2n-Om,

while m denotes the number 0 or 1, n denotes the number 0, 1, 2 or 3,

R24does

1) CpF2p+1,

while p denotes the number 1, if n denotes the number 0 or 1,

2) (C5- C7-cycloalkyl, the Cove 3) - 6) is not substituted or substituted by a residue from the group

3.1 fluorine atom,

3.2 chlorine atom,

3.3 CF3,

3.4 CH3or

3.5 methoxy, or

III) a residue of formula VII; R31, R32, R33or R34have the following meaning: a) a hydrogen atom,

b) a halogen atom as a fluorine atom, chlorine atom, bromine atom or iodine atom,

c) (C1- C6)- alkyl, straight or branched chain,

or

d) R35- CnH2n-Z-,

in this case n represents the integer 0,1 or 2, and Allenova chain-CnH2nis a straight or branched C-atom may be replaced through O-, S-or N-atom,

R35is

1) a hydrogen atom,

2) (C5- C8-cycloalkyl,

3) (C5- C8-cycloalkyl, substituted hydroxy-group, or a methylene group substituted through O-, S-or N-atom, or

4) phenyl, unsubstituted or substituted by 1-3 residues from the group

4.1 halogen atom as a fluorine atom, chlorine atom, bromine atom or iodine atom,

4.2 CF3,

4.3 CH3-S(O)x< / BR>
thus x is 0,1 or 2,

4.4 R36-Wy,

thus R36denotes a hydrogen atom, methyl or ethyl, W is O-atom, NH or NCH3and y denotes 0 or 1/BR> 4.8 ethanolic,

Z represents

1) -CO-,

2) -CH2-,

3) -[CH(OH)]q-,

q thus represents the number 1, 2 or 3,

4) -[C(CH3)(OH)]q- while g denotes the number 1, 2 or 3,

5) -O - or

6) -S(O)x-,

when x is 0, 1 or 2,

X has the following value

a) N or

b) CH,

y has the following meaning

a) N-(C1- C6) -alkyl,

b) -N-(C2- C4) -alkenyl or

c) R35- Cn-H2n-Z-,

thus R35n and Z are defined as in paragraph

d) R5, R6, R7and R8the same or different and independently of one another have the following meanings

(a) a hydrogen atom, or

b), (C1- C5-alkyl, straight or branched chain, and the physiologically tolerated salts of compounds of formula 1a, 1b or 1C.

Especially preferred compound of formula 1a, 1b or 1c, and R11has the following value:

< / BR>
thus R14or R15the same or different and independently of one another have the following meanings

1) a hydrogen atom, or

2) (C1- C4)-alkyl, or

R14and R15form together (C4- C7)-alkyl chain, or

b) R13- S-,
R12has the following value:

a) CH3-SO2-,

b) H2N - SO2-,

(c) phenoxy or

d) phenoxy substituted with chlorine in the para-position,

R5, R6, R7and R8the same or different and are independently of each of the following is

(a) a hydrogen atom, or

b), (C1- C4)-alkyl,

and physiologically tolerated salts of compounds of formula 1a, 1b or 1C.

Especially preferred:

complex tetraethyl ester 2-[(methyl-2-indolocarbazole)- (aminoiminomethyl)amino)] -ethane-1,1-bis-phosphonic acid, 2-[(1-methyl-2-indolocarbazole)-(aminoiminomethyl)amino)] -ethane - 1,1-bis-phosphonic acid, 2-[(3-methylsulphonyl-4-piperidinyl)- (aminoiminomethyl)amino)] -ethane-1,1-bis-phosphonic acid, complex tetraethyl ester 2-[(3-methylsulphonyl-4-piperidyl-benzoyl)- (aminoiminomethyl)amino)] -ethane-1,1-bis-phosphonic acid, complex tetraethyl ester 2-[(3,5-dichloro-benzene). (aminoiminomethyl)-amino)] -ethane-1,1-bis-phosphonic acid and 2-[(3,5-dichloro-benzene)-(aminoiminomethyl)-amino)]-ethane-1,1-bis-phosphonic acid.

Compounds according to the invention can be obtained, for example, as follows.

The compound of formula IV

< / BR>
and

R
< / BR>
in the presence of an inert solvent to a compound of formula Ia, Ib and Ic, and R11and R12are named in the formula Ia, Ib and Ic value, and, if necessary

B) ester bis-phosphonic acid compounds of formula Ia, Ib or 1c converted into the corresponding bis-phosphonic acid, or

the compound of formula IV, and R5, R6, R7and R8have a named formula 1a is, enters into interaction

C) with the compound of the formula VIII

< / BR>
in the presence of an inert solvent to a compound of formula Ia, Ib or Ic, and R21, R22and R23are named in the formula Ia, Ib or Ic value, and, if necessary

(D) ester bis-phosphonic acid compounds of formula Ia, Ib or Ic is transformed into the corresponding bis-phosphonic acid, or

the compound of formula IV, and R5, R6, R7and R8have a named formula 1a is, enters into interaction

E) with the compound of the formula IX

< / BR>
in the presence of an inert solvent to a compound of formula Ia, Ib or Ic, and R31, R32, R33and R34are named in the formula Ia, Ib or Ic value, and, if necessary

F) ester bis-phosphonic the version of the method (A) it is best to do so, the compound of the formula III in equimolar amounts or in an excess of up to three times the number of interacting, if necessary, in an inert solvent like dimethyl sulfoxide (DMSO), dimethylformamide (DMF), toluene, (C1- C4-alkanol, tetrahydrofuran (THF), dioxane or simple diethyl ether, with a compound of formula IV, with the addition of the base, like potassium carbonate, sodium carbonate, potassium hydroxide, triethylamine, diethylamine or also without the addition of base to the compound of formula Ia, Ib or Ic. The reaction temperature is about 25 - 100oC, mainly in the application of solvent at 25oC and the boiling point of the solvent, particularly when the 70oC. the reaction Time is 6 to 48 hours, preferably 12 to 24 hours of the End of the reaction can be determined, for example, using thin-layer chromatography.

For isolation and purification of the reaction products of the formula Ia, Ib or Ic, the reaction mixture can be cleaned on a column of silica gel with a mixture solvent of acetic ether and alcohol, the volume ratio is 6: 1. The compounds of formula Ia, Ib or Ic can be converted into the corresponding bis-phosphonic acid hydrolysis (method B), for example nagrevatelem in anhydrous solvent and subsequent hydrolysis. Anhydrous Hydrobromic acid in acetic acid can be used directly or after appropriate dilution, or apply trimethylsilylmethyl dissolved in a solvent like carbon tetrachloride, dimethylformamide. chloroform or toluene. The hydrolysis can be conducted under cooling or under heating, for example, you can turn ester with trimethylsilylethynyl when cooled at -10oC or below and receive a partially saponified product.

The source connection options method A) for compounds III and IV can be obtained in a simple manner from the literature (European patent 0 298 553; European patent 0 416 499).

In the case of method (C) it is best to act in such a way that the compound VIII and equimolar amounts or in an excess of up to three times the amount if necessary in an inert solvent like dimethyl sulfoxide (DMSO), dimethylformamide (DMF), toluene, (C1- C4-alkanol, tetrahydrofuran (THF), dioxane or simple diethyl ether, interacts with the compound of the formula IV, with the addition of the base, like potassium carbonate, sodium carbonate, potassium hydroxide, triethylamine, diethylamine or choice without additives grounds Danii solvent of between approximately 25oC and the boiling point of the solvent, particularly when the 70oC. the reaction Times are 6 to 48 h, preferably 12 to 24 hours of the End of the reaction can be determined, for example, using thin-layer chromatography.

For isolation and purification of the reaction products of the formula Ia, Ib and Ic, the reaction mixture can be cleaned on a column of silica gel with a mixture solvent of acetic ether and alcohol, the volume ratio is 6:1. The compounds of formula Ia, Ib or 1c can be converted into the corresponding bis-phosphonic acid hydrolysis (method D), for example, by heating with phlegm in concentrated hydrochloric acid or by treatment with strong acids or trimethylsilylethynyl in anhydrous solvent and subsequent hydrolysis. Anhydrous Hydrobromic acid in acetic acid can be used directly or after appropriate dilution, or apply trimethylsilylmethyl dissolved in a solvent like carbon tetrachloride, dimethylformamide, chloroform or toluene. The hydrolysis can be conducted under cooling or under heating, for example, you can turn ester with trimethylsilylethynyl when cooled at -10oC or below and receive castignoli simple manner known from the literature (European patent 0 298 553; European patent 0 416 499).

The compounds of formula VIII can be obtained due to the fact that the compound of formula II

< / BR>
interact with guanidine, where R1- R3have a specified value, and L denotes easily nucleophile substituted residual group.

Activated derivatives of the acid of formula II, where L denotes alkoxy, mainly, a methoxy group, fenoxaprop, phenylthio-, methylthio-, 2-pyridylthio, nitrogen heterocycle, predominantly 1-imidazolyl, it is advantageous to obtain a known manner based on an acid chlorides of carboxylic acids (formula II, L = Cl), which on its part can be obtained again in a known manner based on carboxylic acids (formula II, L = OH), for example, by using chloride tiomila. Along with anhydrides of carboxylic acids of the formula II (L = Cl) can be obtained also other activated acid derivatives of the formula II in a known manner directly based on derivatives of benzoic acid (formula II, L = OH), such as methyl ester of the formula II with L = OCH3treatment with gaseous HCl in methanol, imidazoline formula II by treatment carbonyl diimidazol (L = 1-imidazolyl, Staab, Angew. Chem. Int. Ed. Atom solvent, as the activation of benzoic acids with dicyclohexylcarbodiimide (DCC) or O-[(cyano(etoxycarbonyl)methylene)amino] -1,1,3,3 - tetramethylethylenediamine ("TOTU") (Weiss u. Krommer, Chemiker Zeitung 98, 817 (1974)). A number of suitable methods for obtaining activated derivatives of carboxylic acids of formula II are given when specifying a literary source J. March, Advanced Organic Chemistry, third edition (John Wiley & Sons, 1985), page 350.

The transformation of the activated carboxylic acid derivative of the formula II with guanidine is known in proton or aprotic polar but inert organic solvent. When the conversion of methyl esters of benzoic acids (II, L = OMe) with guanidine, methanol and tetrahydrofuran save between 20oC and the boiling point of these solvents. In most reactions of compounds II with salt-free guanidine was advantageous to work in an aprotic inert solvents, such as tetrahydrofuran, dimethoxyethane, dioxane. But when using a base, such as NaOH as solvent at transformation II also used the water.

If L = Cl, it is advantageous to work with the addition of traps acid, for example, in the form of excess guanidine for tying kaleidostone the literature. Unknown compounds of formula II can be obtained well-known from the literature methods.

Carboxylic acids or their esters of the formula II (e.g. = L-OH or-O - methyl) with R2in is halogen or R3the value of nitro can serve as a diverse source of connection for other carboxylic acids of the formula II, and a halogen at position R2very easy to replace in a known manner on numerous nucleophilic reagents as phenols or alcohols R4-CnH2n-OH, or their salts of the alkali metal with the formation of the corresponding derivatives of benzoic acid. Similarly nitro after recovery to the corresponding aminobenzoic acid in the reactions of Sandmeyer or Ullman can lead to the desired halogen-substituted derivatives of benzoic acid. Chlorine, bromine or iodine, in many cases, you can enter in the appropriate benzoic acid as a result of direct halogenation using the catalyst of the Friedel-known manner.

In option E) it is best to act in such a way that the compound of formula IX in equimolar amounts or in an excess of up to three times the number of turns, if necessary, in an inert furan (THF), dioxane or simple diethyl ether, with a compound of formula IV, with the addition of the base, like potassium carbonate, sodium carbonate, potassium hydroxide, triethylamine, diethylamine or also without the addition of base to the compounds of formula Ia, Ib or Ic. The reaction temperature is about 25-100oC, mainly in the application of the solvent the reaction temperature ranges from 25oC to the boiling point of the solvent, particularly about 70oC. the reaction Times are 6 to 48 h, preferably 12 to 24 hours of the End of the reaction can be determined, for example, using thin-layer chromatography.

For isolation and purification of the reaction products of the formula Ia, Ib or Ic, the reaction mixture can be cleaned on a column of silica gel with a mixture solvent of acetic ether and/or alcohol, the volume ratio is 6: 1. The compounds of formula Ia, Ib or Ic can be converted into the corresponding bis-phosphonic acid hydrolysis (method F), for example by heating with phlegm in concentrated hydrochloric acid, or by treatment in a strong acid or trimethylsilylethynyl in anhydrous solvent and subsequent hydrolysis. Anhydrous Hydrobromic acid in acetic acid can note the output in the solvent, as carbon tetrachloride, dimethylformamide, chloroform or toluene. The hydrolysis can be conducted under cooling or under heating, for example, you can turn ester with trimethylsilylethynyl when cooled at -10oC or below, and to obtain a partially saponified product.

The source connection options method A) for compounds of formula IV can be obtained in a simple manner known from the literature (European patent 0298553; European patent 0416499).

The compounds of formula IX can be obtained in a known manner (patent Germany 4326005.5).

The invention relates also to medicines that contain at least an effective amount of at least compound of formula Ia, Ib or Ic and/or at least one physiologically-tolerated salts of the compounds of formula Ia, Ib or Ic, along with suitable in pharmacy and physiologically tolerated excipients and chemicals carriers, diluents and/or other active ingredients.

Further, the invention relates to the use of compounds of formula Ia, Ib or Ic and/or their physiologically-tolerated salts to obtain drugs for prevention and treatment of degenerative illness and Ic and/or their physiologically-tolerated salts to obtain drugs for the treatment of diseases with increased bone resorption, especially osteocarcinoma and metastasis, Paget's disease, hypercalcemia or osteoporosis.

Medicinal product according to the invention it is possible to assign surface, through the skin, in the room, intravenously, intramuscularly, intraperitoneally, subcutaneously, inside joints, periartikulyarno, rectally or orally.

Medicinal product according to the invention for the prevention and treatment of osteoporosis get in due to the fact that at least the compound of formula Ia, Ib or Ic and/or one of their physiologically-tolerated salts, in this case, auxiliary substances and/or substances-media lead into a suitable form of administration. Auxiliary substances and substances-carriers belong to the group of carriers, preserving drugs and other conventional auxiliary substances.

In this connection formulae Ia, Ib and Ic can be applied together with one or auxiliary galenovye drugs in veterinary medicine and in medicine.

The specialist knows what excipients suitable for the desired prescription drugs. Along with the solvent, means for gel formation, the basics for candles, auxiliary substances for tableta, emulsifiers, defoamers, substances that improve the taste, preservatives, agents, dissolution or dyes.

For oral use, the active compounds are mixed with appropriate additives, such as substances-carriers, stabilizers or inert solvents, and translated by customary methods into suitable forms of introduction, as tablets, coated tablets, push-fit capsules, aqueous, alcoholic or oily solutions. As inert carriers can be used, for example gum Arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, especially corn starch. You can do either dry or moist granules. As oily substances vehicles or solvents used, for example, vegetable or animal oils as sunflower oil or cod-liver oil.

For subcutaneous or intravenous administration, the active compounds, if desired with the usual substances as agents of dissolution, emulsifiers or other auxiliaries, dissolve, form a suspension or emulsion. As solvents take, for example into consideration: water, physiological sodium chloride solution or alcohols, for example ethanol, n is slichnih named solvents.

As a pharmaceutical composition for the destination in the form of aerosols when sprinklers are used, for example solutions, suspensions or emulsions of the active substances of the formula Ia, Ib or Ic in pharmaceutically navasivayam fear solvent, especially ethanol, or water, or in mixtures of such solvents. The composition as needed may also contain other pharmaceutical auxiliary substances, such as surfactants, emulsifiers and stabilizers, as well as working gas. This formulation contains the active substance is usually in a concentration of 0.1 to 10, especially from 0.3 to 3 wt.%.

The prescribed dosage of the active substance of the formula 1A, 1B or 1C and frequency assignments depend on the strength and duration of the applied compounds; in addition, on the type and extent of the disease being treated, as well as gender, age, weight and individual susceptibility of a mammal or human, which is being treated.

The applied dosage of medicines according to the invention depends on various factors, as a form of introduction of the drug and the condition, weight and severity of the disease of the patient. However, the daily dose of about 5000 mg should not be exceeded only by the s medicinal products according to the invention can be in the form of a single purpose or for multiple small doses. Prefer the appointment for 3 to 8 doses per day.

Below the invention is explained in detail on the basis of examples. The data in percent refer to volume percent, unless otherwise indicated.

Example 1. Obtaining complex tetraethyl ester 2-[(3-methylsulphonyl-4-piperidyl-benzoyl)-(aminoiminomethyl)amino] -ethane-1,1 - bisphosphonate acid.

3,24 g (10 mmol) (3-methylsulphonyl-4-piperidyl-benzoyl)-(aminoiminomethyl)amine and 3.0 g (10 mmol) of a compound tetraethyl ester vinyltetrazole acid are dissolved in 40 ml of absolute tetrahydrofuran. To do this, add 0.5 g (3.6 mmole) of dry potassium carbonate and heated for 3.5 h in a protective gas atmosphere to a boil. Then again added 0.33 g (2.4 mmol) of potassium carbonate and heated for another 2 hours to boil. Then the reaction mixture is stirred for another 16 h at room temperature. After filtration and separation of the solvent to obtain 4.5 g of crude material. The substance is subjected to chromatography on a column of silica gel. The solvent is acetic ether with 10% ethanol.

Yield: 3.2 g (52% of theory).

The melting point 148-152oC.

31P-NMR-spectroscopy (NMR - nuclear magnetic resonance) : (CDCl3) dP = to 21.77 MRP.

1.5 g (2.4 mmol) of a compound tetraethyl ester 2-[(3-methyl - sulfonyl-4-piperidyl-benzoyl)-(aminoiminomethyl)amino)] -ethane - 1,1-bis-phosphonic acid from example 1 are dissolved in 60 ml of absolute dioxane at 60oC. Then bring the reaction solution to room temperature and added 1.64 g (10,8 mmol) bratiotis-silane. Stirred for 16 h at room temperature and then heated for another 4 h to 60oC. and Then separating the solvent and low-boiling component at 0.1 Torr/40oC. To the residue then add 15 ml of water and the mixture is stirred for 4 h at room temperature. The resulting residue is filtered and washed several times with ethanol. Then boil the residue in 20 ml of methanol and 1 ml of water.

Yield: 460 mg (38% of theory).

The melting point 209oC.

31P-NMR-spectroscopy:

(NaOD/D2O) 19,13 WFP.

Example 3. Obtaining complex tetraethyl ester 2-[(3,5-dichloro-benzoyl-(aminoiminomethyl)amino]]-ethane-1,1-bis - phosphonic acid.

650 mg (2.4 mmol (3,5-dichloro-benzoyl)-(aminoiminomethyl)amine and 730 mg (2.4 mmol) of a compound tetraethyl ester vinyltetrazole acid are dissolved in 30 ml of toluene and 6 ml of dimethylformamide (DMF). There is added 0.17 g to obtain 1.8 g of crude product. The substance is purified on a column of silica gel. The solvent is acetone.

Yield: 450 mg (35% of theory).

The melting point 146-149oC.

31P-NMR-spectroscopy:

(CDCl3) 21,73 MRP.

Example 4. Getting 2-[(3,5-dichloro-benzoyl)- (aminoiminomethyl)amino)]-ethane-1,1-bis-phosphonic acid.

350 mg (of 0.62 mmol) of a compound tetraethyl ester 2-[(3,5-dichloro-benzoyl)-(aminoiminomethyl)amino)]-ethane-1,1-bis - phosphonic acid dissolved in 20 ml of acetonitrile. Add in an atmosphere of argon 0.3 g of sodium iodide and 0.41 ml (3.10 mmol) of bromotrimethylsilane. Stirred for 16 h at room temperature and then 1 h at 40oC. Then filtered the resulting sodium bromide, and separating the mother liquor from solvent and low-boiling components at 0.1 Torr/40oC. To the residue is added 20 ml of methylene chloride and again sucked off from the formed solids. Methylene chloride is separated at 0.1 Torr/40oC.

Then add 15 ml of water and stirred for 15 min at room temperature. Water is removed at 12 Torr/60oC. To the obtained residue, then add 10 ml of isopropanol and add about 1-2 ml of water. All this heat 5 min. After cooling otsenyv 267oC.

31P-NMR-spectroscopy:

(NaOD/D2O)31P=KZT 19.09 MRP.

1H-NMR-spectroscopy:

(NaOD/D2) = 1,90 (tt,2JPH=14 Hz3JPH=6 Hz, 1H); 3,48 (td, 3JPH=14 Hz3JHH=6 Hz, 2H; was 7.45 (S, 1H); 7,54 (S2H).

C13-NMR-spectroscopy:

(NaOD/D2O) = 43,8 (C-1); 44.1KHZ (C-2); 129, 9MM (C-3'); 133,0 (C-4); 136,7 (C-5, O-5'); 142,0 (C-6); 162,5 (C-Gua); 174,9 (C=0).

MS-spectroscopy:

m/e= 419

Example 5. Obtaining complex tetraethyl ester 2-[(1-methyl-2-indolocarbazole)-(aminoiminomethyl)amino)] - ethane-1,1-bisphosphonate acid.

1.0 g (3.9 mmol) of (1-methyl-2-indolocarbazole-guanidine-hydrochloride and 1.2 g (4 mmole) of a compound tetraethyl ester vinyltetrazole acid are dissolved in 40 ml of tetrahydrofuran (THF) and 15 ml of dimethylformamide (DMF). There is added 0.55 g (4 mmole) of dry potassium carbonate and heated for 21 hours before boiling. Then the reaction mixture is filtered and rotate. Obtain 2.0 g of a crude product. The substance is purified on a column of silica gel. The solvent is ethanol.

Yield: 1.4 g (70% of theory).

31P-NMR-spectroscopy:

(CDCI3) = 21,98 MRP.

Example 6. Getting 2-[(1-methyl-2-indolocarbazole)- (aminoiminomethyl)amino)]-ethane-1,1-BS-phosphonic acid from example 5 are dissolved in 40 ml of acetonitrile. There is added in an argon atmosphere 0.6 g of sodium iodide and 1.2 ml (90 mmol) of bromotrimethylsilane. Stirred for 16 h at room temperature and then 1 h at 40oC. Then filtered the resulting sodium bromide, and separating the mother liquor from solvent and low-boiling components at 0.1 Torr/40oC. To the residue is added 20 ml of methylene chloride and again sucked off from the formed solids. Methylene chloride is separated at 0.1 Torr/40oC. Then add 15 ml of water and stirred for 15 min at room temperature. Water is removed at 12 Torr/60oC. To the obtained residue, then add 10 ml of isopropanol and add about 1-2 ml of water. All this heat 5 min. After cooling suck colorless crystals and dried at 12 Torr.

Yield: 300 mg (38%).

31P-NMR-spectroscopy:

(NaOD/D2O) P=18,07 MRP.

1H-NMR-spectroscopy:

(NaOD/D2O) = to 1.98 (tt,2JPH= 14 Hz3JHH= 6 Hz, IH); 3,65(td3JPH= 14 Hz 3JHH= 6 Hz, 2H); 7,08-8,56 (aromatics - H, 5).

13C-NMR-spectroscopy:

(NaOD/D2O) = 32,5 (C-1); For 41.8 (C-2); A 41.9 (C-3); 103,2 (C-4); Of 105.2 (C-5); 120,2 (C-6); 122,0 (C-7); Of 124.1 (C-8); 126,2 (C-9); 137,8 (C-10); 139,2 (C-11); 139,7 (C-12); 160,8 (C-Gua); 172,2 (C=0).

Neil-4-phenoxy-benzoyl)-(aminoiminomethyl)amino] - ethane-1,1-bis-phosphonic acid.

1.8 g (a 4.86 mmol) (3-methylsulphonyl-4-phenoxy-benzoyl)- (aminoiminomethyl)amine and of 1.46 g (a 4.86 mmole) of a compound tetraethyl ester vinyltetrazole acid turn, as described in example 1.

The substance is subjected to chromatography on a column of silica gel. The solvent is acetic ether: acetone = 1:1.

Yield: 800 mg (26%).

The melting point 145oC.

31P-NMR-spectroscopy:

(CDCl3) 31P= 22,10 MRP.

1H-NMR-spectroscopy:

(CDCl3) = 1,35 (t, 12H); AND 3.31 (S, 3H); 4.0 a (mc, 2H); 4,20 (mc, 9H); to 6.88 (d, 1H); 7,13 (mc, 2H); 7.24 to (mc, 1H); 7,42 (mc, 2H); 8,35 (d, 1H); 8,89 (S, 1H) ppm.

13C-NMR - spectroscopy:

(CDCl3) = 16,43; 29,30; 37,89; 43,36; 53,87; 63,14; 117,25; 120; 36; 125,33; 129,72; 130,25; 155,06; 157,82; 175,0 MRP.

Example 8. Obtaining complex tetraethyl ester 2-[(3-methylsulphonyl-4-N, N-diethylamino-benzoyl)-(aminoiminomethyl)amino] - ethane-1,1-bis-phosphonic acid.

1.0 g (2.9 mmol) of (3-methylsulphonyl-4-N-N-diethylaminobenzoic)- (aminoiminomethyl)amine and 0.9 g (2.9 mmol) of a compound tetraethyl ester vinyltetrazole acid turn, as described in example 1.

Substance exposes chromatography on a column of silica gel. As P>C.

31P-NMR-spectroscopy:

(CDCl3) 31P = 22,12 MRP.

1H-NMR-spectroscopy:

(CDCl3) =of 1.07 (t, 6H); to 1.35 (t, 12H); 3,18 (q, 4H); to 3.34 (S, 3H); 3,98 (mc, 2H); 4,20 (mc, 9H); to 7.32 (d, 1H); at 8.36 (d, 1H); of 8.92 (S, 1H) ppm.

13C-NMR-spectroscopy:

(CDCl3) 12,09; 16,38; 38,20; 42,59; 48,37; 63,34; 124,46; 137,21; 136,99; 153,34; 175,64 MRP.

Example 9. Getting 2-[(3-methylsulphonyl-4-phenoxy-benzoyl)- (aminoiminomethyl)amino]-ethane-1,1-bis-phosphonic acid.

350 mg (0.55 mmol) of a compound tetraethyl ester 2-[(3-methylsulphonyl-4-phenoxy-benzoyl)-(aminoiminomethyl)amino] - ethane-1,1-bis-phosphonic acid from example 7 transform, as described in example 2.

The product after hydrolysis sucked off 40 ml of water and washed with 30 ml of acetone.

Yield: 150 mg (52,4%).

The melting point of 242oC.

31P-NMR-spectroscopy:

(NaOD/D2O)31P = 17,65 MRP.

1H-NMR-spectroscopy:

(NaOD/D2O) = 2,04 (tt, 1H); 3,50 (S, 1H); 3,65 (td, 2H); 7,06 (d, 1H); 7,26 (d, 2H); 7,38 (mc, 1H); 7,54 (mc, 2H); 8,20 (mc, 1H); 8,55 (m, 1H) ppm.

Example 10. Getting 2-[(3-methylsulphonyl-4-N,N-diethylamino - benzoyl)-(aminoiminomethyl)amino]-ethane-1,1-bis-phosphonic acid.

600 mg (0.92 m mmol) of a compound tetraethyl ester 2-[(3-methylsulphonyl-4-N is isano in example 2.

After hydrolysis with water (30 ml) products suck and then mixed with acetone.

Output: 483 mg (100%).

The melting point 181oC.

31P-NMR-spectroscopy.

(NaOD/D2O)31P = 17,70 MRP.2JPH= 20,9 Hz3JPH= 14,2 Hz).

1H-NMR-spectroscopy:

(NaOD/D2O) =of 1.03 (t, 6H); 2,11 (tt, 1H); 3,12 (q, 4H); of 3.53 (S, 3H); 3,65 (td, 2H); 7,58 (d, 1H); compared to 8.26 (mc, 1H); 8,58 (m, 1H) ppm.

Example 11. The effectiveness of the compounds according to the invention prove in vitro in the following experiments.

Bone resorption is determined on the basis of the analysis45Ca-allocation of the embryonic cranium rats, aged 20 days. Bones put the marks and pregnant rats injected 200 microcurie/kg45CaCl22 days before open cranial box germ.

1. Cultivation of bones.

Cranial box embryos divided into two halves. One half of the skull is used for control, the other half is incubated with the compounds according to the invention.

Each half of the skull is cultivated in a sterile plastic Cup. Nutrient medium (BGSb-medium, Gibco) containing 1 ml of 10% fetal calf serum, penicil the new atmosphere of 5% CO2and 95% O2. After 48 HR culture medium replaced with fresh, add compounds according to the invention and parathyroid hormone (10-7M) and incubated for another 48 hours To control add parathyroid. The hormone (10-7M Sigma).

At the end of the experiment determine the activity of the45Ca in the nutrient medium and in the bones.

The results in the table show the inhibition45Ca - allocation in a nutrient medium in percent. The results represent the average of 3 to 5 experiments.

1. Derivative guanidinate-1,1-bis-phosphonic acid tautomeric formulas Ia, Ib, Ic

< / BR>
< / BR>
where R - a) the remainder of the formula

< / BR>
where R11and R12have the following meanings: R13-SO2-,

< / BR>
phenoxy or halogen, where R13, R14and R15- C1- C6-alkyl, b) residue formula

< / BR>
where R16- C1- C6-alkyl;

R5, R6, R7and R8is hydrogen or C1- C6-alkyl.

2. Connection on p. 1, representing a complex tetraethyl ester 2-[(1-methyl-2-indolocarbazole)-(aminoiminomethyl)amino)] -ethane-1,1-bis-phosphonic acid, 2-[(1-methyl-2-indolocarbazole)-(aminoiminomethyl)amino)]ethane-1,1-bis-phosphonic acid, 2-[(3-MoEHE ester 2-[(3-methylsulphonyl-4-piperidyl-benzoyl)-(aminoiminomethyl)amino)] -ethane-1,1-bis-phosphonic acid, complex tetraethyl ester 2-[(3,5-dichloro-benzoyl)-(aminoiminomethyl)amino)]-ethane-1,1-bis-phosphonic acid, 2-[(3,5-dichloro-benzoyl)-(aminoiminomethyl)amino)]-ethane-1,1-bis-phosphonic acid.

3. The method of obtaining compounds of tautomeric formulae Ia, Ib and Ic under item 1, characterized in that the compound of formula IV

< / BR>
where R5, R6, R7and R8are named in the formula Ia according to p. 1 values

interacting with the compound of the formula

< / BR>
in the presence of an inert solvent to a compound of formula Ia, Ib or Ic, and R11and R12have called in formulas Ia, Ib, Ic values and, if necessary, ester bis-phosphonic acid compounds of the formulae Ia, Ib or Ic is transformed into the corresponding bis-phosphonic acid, or a compound of formula IV, where R5, R6, R7and R8have a named formula Ia values, interacting with the compound of the formula

< / BR>
where R16is mentioned in paragraph 1 values

in the presence of an inert solvent to a compound of formula Ia, Ib or Ic and, if necessary, ester bis-phosphonic acid compounds of the formulae Ia, Ib and Ic converted into the corresponding bis-phosphonic acid.

4. PR is orblue.

Priority signs:

02.12.92 - R is a

< / BR>
where R11and R12- R13-SO2, R14R15N or

< / BR>
R13, R14, R15- C1- C6-alkyl;

13.05.93 - R is a

< / BR>
where R11and R12- phenoxy or halogen;

23.09.93 - R - N-substituted indolyl.

 

Same patents:

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

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
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