Method of producing methylenediphosphonic acid and alkali salts thereof

专利摘要:
L'invention concerne des dérivés de l'acide méthylènediphosphonique de formule: dans laquelle: R1 représente: - un groupe alkyle en C1-C6 - un groupe cycloalkyle en C5-C7 - un groupe phényle éventuellement substitué une ou plusieurs fois par un halogène, un groupe alkyle en C1-C6, un groupe trifluorométhyle, - un hétérocycle à 5 ou 6 chaînons comportant 1 ou 2 hétéroatomes choisis parmi l'azote et le soufre, Alk désigne un groupe alkylène droit ou ramifié en C1-C6, R2 représente l'hydrogène, un groupe alkyle en C1-C6 ou un groupe -CONH2 R3 représente l'hydrogène, un groupe alkyle en C1-C6, un groupe benzyle ou un groupe phényle éventuellement substitué par un chlore ou un méthyle ou encore R et R3 pris ensemble représentent un groupe (CH2)m où m = 4 ou 5 enfin, n représente un nombre entier 0, 1 ou 2, ou un des sels dudit dérivé avec des bases organiques ou minérales. Ces dérivés sont doués de propriétés antirhumatis- males.
公开号:SU1419520A3
申请号:SU864027243
申请日:1986-04-18
公开日:1988-08-23
发明作者:Барбье Ален；Брельер Жан-Клод；Гарсиа Жорж
申请人:Санофи (Фирма)；
IPC主号:

专利说明:

This invention relates to the chemistry of organophosphorus compounds with a C — P bond, and specifically to a process for the preparation of new derivatives of methylenediphosphonic acid of the general formula
NHz)
(R20) 2P-C - PlOK2) 2
About A1K About I S-R,
where R, - C, -C-alkyl, cyclohexyl, phenyl, KOTopbrii may be substituted by one or two halogen atoms, C, -C (, - al Kilpm, trifluoromethyl, 2-pyridyl;
A1K - C, -C-alkylene g straight or branched chain, provided that R is different from CH, with A1K (CH,) ,; Rj is hydrogen or alkali metal
that l. T
These compounds can be used as anti-inflammatory and antirheumatic drugs.
The aim of the invention is to develop an accessible process for the preparation of methylenediphosphonic acid derivatives of formula (1), which have anti-inflammatory and anti-inflammatory activity.
Example 1. The 1-amino-4-1p1clohex1x-thio-1,1-β-butylidene diphosphonic acid caffeine sodium salt is monohydrated (SR 42684 L).
R
; n 0; A1K (CH); R. R N
4 Cyclohexyl-thio-butyronitrile, To a solution of 3.5 g of sodium in 75 ml of methanol, 18 g of cyclohexanethiol are added. Stir at 20 ° C for 1 hour, then add 14.2 ml of 4-chloro-butyronitrile and heat the mixture under reflux for 3 hours before concentrating in vacuo. R sediment was introduced with 300 ml of ether, the solution was washed with water, dried, concentrated and subjected to distillation in vacuum at 0.03 mm Hg. 20.8 g of a colorless oil are obtained, which are distilled between 120 and 125 ° C. The 4-cyclohexyl-thio-butonnitrile thus obtained is characterized by a K 0.70 coefficient in thin layer chromatography on silicon doproxide (silica gels 60 F 54 Merck); isopropyl ether is used as a solvent.
The 1-amino-4-cyclohexyl-thio-1,1-butylidene diphosphonic acid caustic sodium salt is monohydrated.
A mixture of 11 g of phosphorous acid and 10 g of 4-cyclohexyl-thio-butyronitrile is heated at 160 ° C for 3 hours. The precipitate is taken up in 40 ml of water, it crystallizes into a solid yellow substance, which is washed with water, then with acetone and ether. This compound is introduced into a solution of 1.5 g of sodium in 70 ml of distilled water. Heat the mixture at 50 ° C with stirring until complete dissolution, leave to cool, and add 250 ml of methanol. The resulting colorless precipitate is filtered off, washed with methanol, then dried at 80 ° C at 0.1 mm Hg. Melting point ZEP, Yield 89.4%.
Elemental analysis with one water molecule.
Calculated,%: C, 26.49; H 4.67; N 3.08.
Found,%: C 25.93; H 4.90; N 3.04.
Example 2. The disodium salt of 1-amino-5- (2-pyridyl-thio) -1,1-amylidene diphosphonic acid (SR 42709 A).
R 0; A1K (CHj);
5- (2-Pyridinyl-thio) valeriannitrile.
To a solution of 2.26 g of sodium in 200 ml of methanol was added gradually 10 g of 2-mercaptopyridine and 20 g of 6-bromovaleranonitrile. After heating for 3 hours under reflux, the reaction mixture is concentrated in vacuo. The precipitate is absorbed by 200 ml of ether. The solution is washed with water, then dried and concentrated, in this way 15 g of the target nitrile, characterized by an R coefficient, of 0.39 in thin-layer chromatography on silica (silica gel 60 F 54 Merck) with isopropyl ether as a solvent, are obtained.
Disodium salt of 1-a shno-5- (2-pyridyl-thio) -1, 1-amylidene diphosphonic acid.
The mixture is heated at 150 ° C for 1 hour, then at 170 ° C for 3 hours a mixture of 10.2 g of 5- (2-pyridyl-thio) valerianonitrile and 12 g of | 1yus (1-acid acid. After cooling, the mixture is absorbed by 100 ml of water and add 2.5 g of sodium acetate.
The mixture is then extracted twice with ether and the aqueous phase is separated, added to it} from 300 ml of methanol, the precipitate formed, filtered off, washed with methanol, then with ether and finally recrystallized from a mixture of water - methanol ( 60/40). In this way, 4.2 g of the expected product are obtained. Melting point 300 ° C. Yield 20.54%.
Elemental analysis.
Calculated,%: C 30.00; H 4.03; N 7.00.
Found,%: C 30.00; H 4.20; N 7.02.
Example 3. The disodium salt of 1-amino-6-propylthio-1,1-hexylidenediphosphonic acid (SR 42708A).
R, - (CH) g-CH3; p O, A1K I - (CHj) y-; , H
1-Cyano-5-propylthio-pent n ..
To a solution of 8 g of sodium in 600 ml of ethanol, 26 g of propanthiol are gradually added, followed by 45 g of 1-cyaio-5-bromo penta. After heating for 6 hours under reflux, the solvent is concentrated, then a precipitate is taken up in 500 ml
: Connection
R,
R,
SR 42710

SR 42707 A
CP



water and extracted with ether. The concentrated organic phase after chromatography on a column of two
 silica (230-240 mesh) yields 28 g of the target nitrile, characterized by a coeff. of R, 0.60 in thin-layer chromatography on silica gel (silica gel 60 F 54 Merck) with isopropyl ether as a solvent (RI 0.10 in a mixture of acetone-hexane 1/9 as a solvent).
Disodium salt of 1-amino - 6-propyl-thio-1,1-hexylidenediphosphonic acid
15 lots.
A solution of 17.5 g of 1-cyano-5-propyl-β-thio-pentane and 20 g of phosphorous acid121 is heated at 150 ° C for 1 hour, then at 180 ° C for 2 hours.
20 After cooling, the precipitate is taken up with acetone, filtered, then dried. 40 g of sodium acetate are added to the solution in 400 ml of water. The mixture is stirred for 1 h, then filtered. 400 ml of methanol are added to the aqueous solution and the precipitate is filtered off. After drying, 11.4 g of the expected product are obtained. Melting point 300 C. Yield 53.3%.
30 Elemental analysis.
Calculated,%: C 28.6; H 5.57; - N 3.7.
Found,%: C 28.1; H 5.84; N3,46. According to the examples described, the following compounds were prepared:
35
I
A1K
(CHj), (OH 2) 2
ABOUT
about
M.p.
300 300
Output,%
51, 6 (salt)
16.8 (salt)
SR 42683
 H N (and about 260-261 56.1
 (acid)
C1
SR 42683 A O H N (CH,), O 300 48 (salt) C1
SR 42718 A SR 509 A
Compound SR 42710 - dhydrato-Found,%: C 23.67; H 3.28;
bath tetrasodium salt of acid. 55 3.04; S 6.83.
Elemental analysis with two water molecules. Compound SR 42 707 A - dihydra Calculated,%: C 23.95; H 3.35; ti-tetrated sodium salt, KisN 3.10; S 7,10. Lots.
H (CH2) j O 300 42 (salt) O 300 27 (salt)
Elemental analysis of p two water molecules.
Calculated,%: C 22.48; H 3.01; N 2.62.
Found,%: C 22.21; H 2.38; N 2.33.
Compound SR A2 683 is a monohydrated acid.
Elemental analysis with one water molecule.
Calculated,%: C 26.10; H 3.65; N 3.38.
Found,%: C 25.3; H 3.26; N 3.58.
Compound SR 42 683 A is a monohydrated tetrasodium acid salt.
Elemental analysis with one water molecule.
Calculated,%: C 21.52; H 2.21; N 2.79.
Found,%: C 21.00; H 2.41; N 2.51.
Compound SR 42 718 A is a trihydrated tetrasodium acid salt.
Elemental analysis with three water molecules.
Calculated,%: C 24.85; H 3.96; N 2.89.
Found,%: C 24.42; H 3.92; N 2.88.
Compound SR 42 509 A is an acid tetralate of the Riev salt.
Elemental analysis.
Calculated,%: C 25.90; N 3.02.
Found,%: C 26.25; N 3.10.
The compounds can be used as anti-inflammatory and antirheumatic drugs, and their pharmacological properties have been found in the following manner.
A study on vivo arthritis caused by an adjuvant.
The injection of mycobacteria in a rat causes polyarthritis, resembling human rheumatoid arthritis in some clinical pictures.
Suspension of Mycobacterium tuberculosis Mycobact. Tubercul (0.4 mg) in paraffin oil (0.05 ml) is injected intradermally into the tail of male rats of the Sprague Dawley breed with an average weight of 150 g.
After 15 days, animals with particularly severe symptoms are selected.
five
0
five
0
arthritis. These rats are divided into two batches of 14 animals.
Animals of the 1st group were treated for 6 days / week for 3 weeks, either subcutaneously with doses ranging from 0.32 mol to 32 CD / mol / kg / day, or oral administration with a dose of 0.16 (U mol / kg per day
The second group receives a placebo and serves as a control group.
After 3 weeks of treatment, half of the animals in each group were killed: the other half were left without treatment for 2 weeks, then, in turn, were also killed.
After killing, the right hind paw was cut at the level of the ankle joint, then weighed. Dn of each semigroup determined the average mass and standard mass error.
The activity of the product is expressed as a change in% of the average mass of the paws of rats with arthritis formed by the test substance relative to the mass of the paws of rats with arthritis not treated (control animals).
The results obtained with the various compounds according to the invention are presented in the table. Dp of each of the studied substances therapeutic activity is expressed as a percentage of inhibition of the mass of the paw after three weeks of treatment.
These results show significant antirheumatic activity of the products after treatment for 3 weeks.
It should be noted that this activity is maintained at an elevated level and sometimes increases even 2 weeks after the end of the treatment.
As a comparative structural analog, sodium etidronate of the formula
Oh he
 V
) rr (in, he
BUT
The tests were carried out under the conditions described for the compound of formula (1) at a dose of this compound (0.32 amol / kg), administered subcutaneously, the inhibition of the mass of the paw is 0%.
The compounds commonly used to treat rheumatism are of two types; compounds that have a profound effect on the treatment of rheumatic diseases, such as sodium aurothio propanol sulfonate and D-penicil lamin; Compounds that have a symptomatic effect on a rheumatic disease, in particular, indomethacin.
The first two compounds at a dose of 10 mg / kg had no effect on the test animals.
Indomethacin at a dose of 1 mg / kg causes an effect of only about 20%, therefore, less effective than many new products.
Moreover, the compounds of formula (1) do not have side effects, often associated with the use of non-steroidal anti-inflammatory drugs, such as indomethations.
The new compounds are slightly toxic and very significant vines to cause death.
As an example, you can specify
that in rat compound SR 42 509A, administered orally at a dose of 1500 mg / kg, does not cause death.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining derivatives of methyl diphosphonic acid of the general formula
H2 (R20) 2P-C.- (OR2) 2
 II1V II
I
Alk
I
Sr,
ABOUT
where R, is C, -C-alkyl, cyclohexyl, phenyl, which may be substituted by one or two halogen atoms, C, -She-alkyl, trifluoromethyl, 2-pyridyl;
L1K - C, -C-alkylene with a straight or branched chain, provided that R differs from CH3 at A1K (CH); R is hydrogen or alkali metal, and its alkali salts, characterized in that the nitrile of the general formula
I
R, -S-A1K-CN
where R and A1K have the indicated meanings, they are reacted with phosphorous acid at 140-200 ° C, followed by separation of the gel product as an acid or its transfer to an alkaline salt.

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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FR8401214A|FR2558837B1|1984-01-26|1984-01-26|METHYLENEDIPHOSPHONIC ACID DERIVATIVES, PROCESS FOR OBTAINING SAME AND ANTIRHUMATISMAL DRUGS CONTAINING THEM|

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