Method of producing derivatives of methylenediphosphonic acid

专利摘要:
The invention relates to phosphonic acids, in particular, to the preparation of methylenediphosphonic acid derivatives (MDFC) of the general formula: (H; 0) P (0) 2 - C (OH) - (CHi) SRi, where R, H, C, - C-alkyl; R C, -C-alkyl of normal or iso-structure, phenyl, non- or substituted by halogen or methyl pyridyl group. CH CC1-CH CH-C C-S-CH N, p 1-10, used in medicine. The goal is to obtain active compounds of the specified class. MDFCs are synthesized from the acid chlorohydride of the general formula (CH) C (0) C1, where R and p are as indicated above, and trialkylphosphite at 30 - under nitrogen atmosphere, followed by treatment of the resulting carbonyl-containing phosphonate with dialkylphosphite at 0-50 ° C in the presence of dibutylamine. The desired product is obtained in the form of an ester, which is transferred by saponification to the corresponding acid. VDFC show anti-inflammatory and antirheumatic activity, their degree of inhibition of secretion of neutral proteases stimulated by chondrocytes in vitro is 22-50%. 3 tab. i O) so O) as ate with
公开号:SU1367859A3
申请号:SU843754451
申请日:1984-06-26
公开日:1988-01-15
发明作者:Клод Брельер Жан；Эмонд-Альт Ксавье；Гарсиа Жорж
申请人:Санофи (Фирма)；
IPC主号:

专利说明:


s
This invention relates to the chemistry of organophosphorus phosphorus compounds with a C – P bond, namely the preparation method
by volume). Thus obtained target product in the form of a colorless oil (8.7 g). Chromatographic derivatives of methylenediphosphonic g graph on silica E 0.40
(ethyl acetate: ethanol, 95g5 by volume). In exactly the same way, but. acidic acid chloride used
total acid acids
OH about
Rio
p-e-k
O (SNg 5Kg
OR
f)
you and / or phosphite, crawl -products
ten
(l) presented in table. one.
Example 2. Di- (tert-butyl amine) -4- (4-chlorophenylthio) - -oxy-, 1- -butylidene diphosphonate (SR 41903),
Boil with reflux where B, is hydrogen, C, -C4-alkyl normal d in a nitrogen atmosphere for 12 h
leg structure;
K 'is C-Cj-alkyl of normal or iso-structure, phenyl, phenyl, substituted by halogen or methyl group, pyridyl or group
TO.
20
a mixture of 5 g of tetraethyl-4 (chlorophenylthio) 1-hydroxy-1, I-butylidene diphosphonate and 50 ml of 12 N hydrochloric acid. It is evaporated to dryness under vacuum, then the residue is taken up in 100 ml of distilled water and washed twice with 100 ml of ether. The aqueous phase is evaporated to dryness. A colorless solid remains, which is dissolved in 30 ml of isopropanol and treated with 3.6 ml of tert-butylamine. The precipitate is filtered off with suction and washed with isopropanolm, acetone and, finally, ether. After drying under vacuum, a colorless solid (4 g); m.p. .202-205 ° C (decomposition).
: p is an integer from 1 to 10. Compounds of formula (1) exhibit antirheumatic activity and can be used in medicine.
The aim of the invention is to develop a method for producing derivatives of methylene diphosphonic acid, which can be used as anti-inflammatory and antirheumatic agents.
Example 1. Tetraethyl 5- (4-fluoro-fensch 1: thio) -1-hydroxy 1, 1 pentyl ydenedifrsonat (SR 41906).
To 12.1 g of 5- (4-fluorophenylthio) valyl chloride, located in the atmosphere of nitrogen, 8.8 g of triethyl phosphite are added with stirring. The mixture is stirred for 3 hours at 35 ° C, then the reaction mixture is cooled to 0 ° C and a mixture of 0.45 ml of dibutylamine and 6.5 ml of phosphite diethyl ™ is introduced over 10 minutes. Continue stirring for 1 hour, then add 20 ml of 1N hydrochloric acid and 100 ml of diethyl ether. After stirring, the ether layer is separated and the aqueous phase is re-extracted with 100 ml of methylene chloride. The organic extracts are combined, dried over
you and / or phosphite, crawl -products
0
0
a mixture of 5 g of tetraethyl-4 (chlorophenylthio) 1-hydroxy-1, I-butylidene diphosphonate and 50 ml of 12 N hydrochloric acid. It is evaporated to dryness under vacuum, then the residue is taken up in 100 ml of distilled water and washed twice with 100 ml of ether. The aqueous phase is evaporated to dryness. A colorless solid remains, which is dissolved in 30 ml of isopropanol and treated with 3.6 ml of tert-butylamine. The precipitate is filtered off with suction and washed with isopropanolm, acetone and, finally, ether. After drying under vacuum, a colorless solid (4 g); m.p. .202-205 ° C (decomposition).
In the same way, starting from SR 42090 ester, 5- (2-pyridyl-thio) -1,1-pentylidene-phosphonic acid in the form of a free acid (SR 42099), t, pl. 194 197 ° C (isopropanol). The product yield is 90%.
Example 3. Di- (tert-butyl-amine) -5- (4-fluoro-phenylthio) -1-hydroxy -1 -1-pentylidene diphosphonate (SR 41909).
To a stirred and cooled to 0 ° C solution of ester SR 41906 (meter 1) in 15 ml of carbon tetrachloride is added 5 ml of trimethylbromosilane and left for 40 hours at 25 ° C. Added 40 and stirred for 1 hour The aqueous phase is decanted, which is washed twice in 30 ml of methylene chloride. The iodine phase is evaporated to dryness under vacuum. The residue is dissolved in 30 ml of water and again evaporated to dryness under vacuum. The syrupy residue is converted to the dibutalamine salt. Half-
five
0
0
sulphate, sodium and solvents precipitate a solid, colorless substance, evaporate under vacuum. mp 21–2115 p. Prodzgkt yield 89%.
In the same way, acids are obtained from various esters, representing
The residue is chromatographed on a silica column, eluting with a mixture of methylene chloride and ethanol (95-5
Table 2, 2.
Table 2, 2.
The novel compounds are used as anti-inflammatory and antirheumatic drugs and their pharmacological properties are emphasized as follows.
An in vitro study is based on the fact that cultured chondrocytes secrete neutral proteinases after stimulation with a factor synthesized by peritoneal macrophages and mononuclear blood cells.
This type of stimulation is applicable in rheumatic diseases.
 The principle of testa is to study the secretion of neutral proteinases stimulated by chondrocytes; treated products, compared with the secretion of untreated stimulated chondrocytes.
Used the next test move. Preparation of chondrocytes. Ho-drops were harvested from the cartilage of the calf's nasal septum or the inter-articular cartilage of the rabbit by enzymatic digestion and cultured in DMEM medium with 10% calf serum at a cell density of 10 cm per petri dish. The culture medium was refreshed all 48 hours.
After a week after cultivation, the cells were sub-cultured by trypsin EDTA, the cells were again placed for cultivation in DMEM medium with 10% fetal calf serum at a cell density of 2
 10 per thick Petri size 16 mm. The drain was sold after 3 days of washing.
Preparation of the medium that causes peritoneal macrophages. Rabbit peritoneal macrophages were obtained by a known technique.
Human blood mononuclear cells were prepared and cultured according to the DOWER method.
After cultivation, the chondrocyte-containing stimulating factor recuperates the medium, is filtered on a filter with a pore size of 0.22 microns, and frozen at -20 ° C.
Chondrocyte stimulation. During fusion, the culture medium of the chondrocytes is loaded with the medium DMEM from a 1% short germ calf containing 20% of the medium containing the activation factor of the chondrocytes.
The test products are introduced into the culture medium at the same time.
five
0
time as the activation medium, at a concentration at which the cytotoxicity of the product is avoided by its failure to make it unacceptable. After:; - t; ,, Wednesday Wednesday,:. . definitions in it with.; g, hp: 1n. n .-: 1; raral proteinases.
The results are presented in Table. 3. They are expressed as a percentage inhibition of secretion of neutral proteases stimulated by chondrocytes treated with the test products f compared to that of stimulated chondrocytes not treated with products. A reference is chosen as a comparison - sodium etidronate.
In vivo study: arthritis with an auxiliary agent.
Injection of r-cobacteritmi into a rat causes polyarthritis resembling human rheumatoid arthritis.
A suspension of Mycobacterium tubercu-5 losis (0.4 mg per 0.05 ml of paraffin oil) is injected intradermally into the tail of males.
Methylenediphosphonic acid derivatives have low toxicity.
thirty

权利要求:
Claims (1)
[1]
Invention Formula
A process for the preparation of methylene diphosphonic acid derivatives with general formonOH
ly
RlOv
R ,,
 O (cH, v
SP
where E is hydrogen, C, -C-alkyl of normal structure; EI C1-C5 alkyl of normal or iso-structure, phenyl, phenyl, substituted with halogen or methyl group, pyridyl or group
S
p is an integer from 1 to 10, consisting in the fact that the acid chloride of an organostio-substituted carboxylic acid of the general formula
R, S- (CH5,) n-COCl,
1367859
where RJ i.p have the indicated meanings, when in the presence of dibutylamine, they are reacted with trialkyl- and isolating the desired product as. phosphate at ZO-ZZ С followed by ether or saponification with a corresponding carbonyl-forming acid, which keeps phosphonate with dialkyl phosphite
Synthesis of the 4 eic characteristics of methylenediphosphonic acid derivatives of general formula.
 B (w, v. C
Connection, No. R, Characterization of TLC on silica; Yield,%
SR 41962-CH. . - (CHj) ,, - CHj3 Colorless oil, Rj. 0.40 (ethyl acetate: 25
ethanol 80:20 by volume)
SR 41963
2 Colorless oil, R: 0.3 {ethyl acetate: 23
ethanol 95: 5 by volume)
SR 42292
-C, Hj
/ sn
SNS
I Colorless oil, Rj: 0.3 (ethyl acetate: 14.5 ethanol 95: 5 by volume)
SR 41940
-cjHj rVcH,
SR 41876
-WITH,
y-C1 3 Oil; Rj: 0.34 (ethyl acetate; ethanol 95: 5 by volume)
SR 42295
-sn, 4 Colorless oil, R: 0.25 (ethyl acetate ethanol 95: 5 by volume)
SR 42014 SR 42089
CjHj (midrange If)
 CHj
5 Colorless oil, Rr: 0.30 (ethyl acetate: 36
ethanol 95: 5 by volume.)
10 Colorless oil, R: 0.25 (ethyl acetate: 37
ethanol 95: 5 by volume)
SR 42090-CjHj I W
 K sr Cl SR 42294 -CjRj L
S
Table t
Colorless oil, R: 0.5 (ethyl acetate: ethanol 90:10 by volume)
56,6
66
54
Pale yellow oil, Rj: 0.15 (ethyl-. 30
acetate: ethanol 95: 5 by volume)
Solid colorless substance, t.pp. 72 ° С58
(isopropyl ether)
table 2
Synthesis and Liquid Chemical Characteristics of Methyl Derivatives of Diphosphocid Acid
general formula
SR 42 U2
ten
Stert-butyl) salt "so pl. 242-24b With
SR 4209710 -CH,
SR 42304.5LAD
. S
Di-tert-butylamine salt, so p.85
195-200 C (decomposition).
The free acid crystallizes with 97
1 water molecule, so pl. 205-208 С
SR 42023
SR 42296
5-CHjCHjCHj
N - ,, 01
V-x
Salt with 2.5 molecules of tert-butyl a, 81.3
m.p. 202-205 С (decomposition)
Acid free, mp. 165-168 С
72
SR 42016
Disodium salt, so pl. 7ЗОО С
SR 42293
/ sn
-C-CH-j
sn
Tert-butylamine salt (, 75 mol), mp. 220-225 С (decomposition)
SR 4I96I
3- (СН) -СНз
Tert-butyl salt (1.5 mol, so pl. 175-178 C)
SR 42017
Acid free, mp. 145-148 С
SR 42099
s
Acid free, mp. 194-197 with (isopropanol)
41.4
72
35
74
52
47.3
90
Inhibition of arthritis,%

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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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FR8213250A|FR2531088B1|1982-07-29|1982-07-29|ANTI-INFLAMMATORY PRODUCTS DERIVED FROM METHYLENEDIPHOSPHONIC ACID AND THEIR PREPARATION METHOD|

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