CS247198B2 - Method of methylendiphosphonium acid's derivatives production - Google Patents

Abstract

The invention relates to a process for the preparation of derivatives methylene diphosphonic acid of formula I wherein R 1 is alkyl C 1 -C 6 cyclohexyl I think, the phenyl group will fall substituted helogen, alkyl C 1 -C 6 or trifluoromethyl and a group of formulas Alk is straight or branched alkylene C 1 -C 6, R 2 is hydrogen and alkyl of 1 to 1 Is carbon, R3 is hydrogen, alkyl C 1 -C 6 benzyl or a phenyl group optionally chlorine or methyl substituted or also R2 and R3 together represents (CH2) 5 and n represents whole the number 0, 1 or 2, provided that R 1 is not methyl group when Alk is -CH 2 -CH 2 -, R 2 = R 3 = H and n = 0, as well and salts of these derivatives with mineral or organic bases, the essence of which lies in that phosphorous acid and chloride are present phosphorous in a suitable solvent with an amide of the formula wherein R1, R2, R3, Alk and n are as defined above.

Description

The present invention relates to a process for the preparation of novel methylenediphosphonic acid derivatives having therapeutic properties predetermined for use in the treatment of rheumatic diseases.

The compounds of the invention correspond to the following general formula (I)

in which

R 1 represents an alkyl group having 1 to 6 carbon atoms, a cyclohexyl group, a phenyl group optionally substituted by halogen, an alkyl group having 1 to 6 carbon atoms or a trifluoromethyl group, and a group of the formula

Alk represents a straight or branched alkylene group having 1 to 6 carbon atoms,

R ₂ represents hydrogen and alkyl having 1 to 6 carbon atoms,

R 6 represents hydrogen, C 1 -C 6 alkyl, benzyl or phenyl optionally substituted by chlorine or methyl, or else

R ₂ and R 2 together represent (CH 2) and n is an integer of 0, 1 or 2, provided that R 2 is not a methyl group when Alk is -CH ₂ -CH ₂ -, an = 0.

The acids of the formula I are capable of forming salts with mineral or organic bases. These salts also form part of the invention. One of the compounds of formula (I) has already been described, but the therapeutic properties of the compound have not been described in any way.

Thus, patent DE 2754821 describes a compound of formula I wherein R is methyl, n is 0, Alk is -CH ₂ -CH ₂ - and R and Rg are hydrogen.

This patent also discloses the corresponding alkali and alkaline earth metal salts and the use of these products as additives in wastewater treatment in the textile and paper industry.

Other compounds of formula X are novel compounds.

The present invention provides a process for the preparation of the aforementioned compounds of formula (I _). Wherein the meaning of the general substituents R ₂ and R 2 may be any of the compounds of formula I may be prepared from the amide starting products of formula R.

wherein, n, Alk, R ₂ and

These amides are obtained

R.-S-Alk-C-N '

I II X <0) _n0

R 8 are as defined above.

in a known manner from the acids of the general formula

R 6 - $ - Alk-COOH wherein R 6, Alk and n are as defined above, for example by treating thioyl chloride or phosphorus trichloride with said amine and then reacting with an amine of the formula

The amide thus prepared is then heated with phosphorous acid and phosphorous trichloride in an inert solvent such as dimethyoxyethane at 50 to 100 ° C for 2 to 6 hours.

The phosphoric acids thus obtained can be converted into salts in a manner known per se. This conversion is carried out in a warm solvent such that the salt crystallizes by cooling after the optional addition of a third of the solvent.

The process according to the invention is explained in the following part of the description by way of specific examples.

Example 1

1-Methylamino-4- (4-chlorophenylthio) butylidene-1,1-aphosphonic acid sodium salt (SR 43 140 A)

General formula I:

^{R <|} "Ethyl N- ^Cl, n = 0, Alk = _{(CH2) 3} R = CH.

A mixture of 20 g of N-methyl-4- (4-chlorophenylthio) butyramide, 10 ml of phosphorous trichloride, 13 g of phosphorous acid and 100 ml of dimethoxyethane is heated at reflux temperature for 3 hours.

The mixture was then allowed to stand at room temperature for 12 hours, after which time the precipitated crystals were centrifuged. The crystals were washed with methanol and then with acetone.

Product weight: 25 g.

The acid thus obtained is suspended in 250 ml of water, 15 g of sodium acetate are added thereto, and the mixture is heated to reflux temperature for 3 hours.

After cooling, the solid is centrifuged, washed with methanol and then ether, and then dried.

Product Weight: 24.25 g;

The melting point of the product is greater than 260 ° C. Elementary analysis:

C% H% N% calculated 32.09 4.16 3.40 found 32.09 3.85 3.46

Examples 2 to 13

The procedure was as in Example 1, except that the starting amide was varied to give the products of formula I wherein n = 0; these products are shown in Table 1. If the acid does not crystallize by cooling the reaction mixture, the reaction mixture is evaporated to dryness under vacuum and the residue is taken up in water.

For the preparation of sodium salts, sodium acetate can be replaced with sodium hydroxide.

Table 1

Example E. Code number R- ^ SR Alk ^R 2 r ₃ Acid or salt Melting point (° C) Analysis: (calculated value) 2 43 141 < ^CH 2> 3 ^CH 3 ^CH 3 Acid 202 % C 35.70 (35.63) ΐ H 4.99 (4.73) % N 3.47 (3.42)

3 43 162 A Dvousodná salt with 1 H ₂ O _C , -Q_ (CH ₂ ) ₃ η taller than % C 38.70 % H 3.94 260 (38,50) (4,19) % N 2.65 (2,63) 4 43 164 Acid 222 Cl—— (ch ₂ ) ₄ h - <ch ₂ ) ₅ ch ₃ % C, 41.42 % H, 6.37 (41,79) (6,14) % N 2.99 (3,04) 5 43 163 ^ci -O < ^CH 2> 3 - ^CH 2> 5 Acid 208

% C 40.61 (40.59)% H 5.68 (5.45)% N 3.11 (3.15)

43 175

Cl; ^(CH 2> -3. ^H

WHOSE

Disodium salt taller than 260 % C, 32.80 (32,95) % H 3.56 (3,94) % N 2.26 (2,40)

43 176 ci—— (ch ₂ ) ₃ h _ ₀ Η ₂ _θ

Acid with 2 H ₂ O

194 % C 41.64 (41,60) % H 4.53 (4,82) % N 2.76 l 2,79)

continuation of Table 1

Example Code number R ^

No. SR

Alk R ₂

Acid or salt Melting point (° C)

Analysis:

(calculated value)

8 43,299 B ^H 3 ^C_ O ^{- CH} 2 H ^ H ₃ 'Ύ Disodium salt with 2 H 10 greater than 260 % C 32.03 (32.07) % H 5.05 % N 3.09 (5,15) (3,11) 9 43 404 CH ₃ -CH ₂ - _{(CH2) 4} H -CH ₃ Sodium salt taller than % C, 28.34 % H 5.55 % N 4.26 300 (28,00) (5,87) (4.08) 10 43,376 A A cf ₃ (ch ₂ ) ₂ H ” ^CH 3 Potassium salt with 1 H ₂ O greater than 300% C 28,36 (28,39)% H 3,24 (3,68)

% N 2.99 (3.01)

43,368 (ch ₂ ) ₅ H

- CH 2 -Potassium salt with 2 H, 0 greater than 300% C 36.96 (36.61)% H 5.69 (5.48) i N 3.07 (3.06)

369 A ^H 3 ^{C 4} O -

_-CH-O - H

43,354 (ch _{2 4 4} h

-CH ₂ ~ CH ₂ -CH ₃ Disodium salt with 1 H ₂ O 260% C 36.96 (36.61)% H 5.69 (5.48)% N 3.07 (3.06)

-CHg Disodium salt with 1/3 I ^ O higher than 260% C 31,20 (31,38)% H 4,40 (4,45)

N N 6.62 (6.65)

Example 14

4- (4-chlorophenylsulfinyl) -1-methylaminobutylidene-1,1-diphosphonic acid (SR 43 264)

General formula

Cl

Alk = (CH ₂ ) ₃ R ₂ = H

A mixture of 8.5 g of N-methyl-4- (4-chlorophenylsulfinyl) butyramide, 4 ml of phosphorus trichloride, 8 g of phosphorous acid and 50 ml of 1,2-dimethoxyethane is heated to reflux temperature for 3 hours.

The solvent is evaporated to dryness under vacuum and the residue is taken up in boiling water. The solid is centrifuged, washed with water and then with ethanol. 6 g of solid are obtained, the melting point of which is higher than 260 ° C.

Elemental analysis of product with 1 water molecule:

C% H% N% calculated 31.27 4.76 3.30 found 31.28 4.78 3.32 Example 15 Dec

4- (4-chlorophenylsulfinyl) -1-benzylanino-1,1-diphosphonic acid (SR 43 462)

General formula I:

Cl

Alk = (CH ₂ ) ₃

The procedure is as in Example 14, except that N-methyl-4- (4-chlorophenylsulfinyl) butyramide is replaced by an equivalent amount of N-benzyl-4- (4-chlorophenylsulfinyl) butyramide.

The compound SR 43 462 is isolated

Melting point: 230 ° C

Elementary analysis:

^C 17 ^H 22 ^C1NO 7 ^P 2 ^{S <481 '82>}

c% H% N i calculated 43.83 4.76 3.00 found 43.87 4.68 2.97 Example 16

1-Methylamino-4- (4-methylphenylsulfonyl) -propylidene-1,1-diphosphonic acid sodium salt (SR 43 370 A)

General formula I:

^R 1 ^{= h} 3 ^C = n = 2

Alk = (CH ₂ ) ₂

A mixture of 9.5 g of N-methyl-3- (4-methylphenylsulfonyl) propionamide, 9 ml of phosphorous trichloride, 6 g of phosphorous acid and 50 ml of 1,2-dimethoxyethane is heated to reflux temperature for 3 hours. The reaction mixture is then concentrated to dryness under vacuum and the residue is taken up in 200 ml of boiling water.

After cooling, the solution is filtered and 20 g of sodium acetate are added. The reaction mixture was removed for 12 hours and then the solid was centrifuged, washed twice with water and then with acetone.

The crude sodium salt is suspended in 100 ml of distilled water. To this suspension is then added 1 ml of concentrated hydrochloric acid and the mixture is heated at reflux temperature for 30 minutes. After cooling, the precipitate is centrifuged and washed with water and methanol.

After drying above 300 ° C, 3.6 g of the desired product are obtained. the melting point of this product is

Elementary analysis: C% H% N% calculated 32.12 4.41 3.41 found 31.79 4.21 3.39 Compounds according to the invention are S '

The compositions and their pharmacological properties have been shown to be anti-inflammatory and anti-rheumatic in the following manner.

In vivo test: induced arthritis

When a rat is injected with mycobacterium, it induces polyarthritis, which in some aspects resembles rheumatoid arthritis in humans.

Protocol

A suspension of Mycobacterium Tuberculosis (0.4 mg) in paraffin oil (0.05 ml) was injected intradermally into the tails of male Sprague-Dawley rats with an average body weight of 150 g.

After 15 days, the animals showing the most severe symptoms of arthritis are sorted out.

These are divided into two groups of 14 animals each.

The animals of the first group are for 3 weeks, 6 days a week:

- administer doses of 0.32 to 32 µmol / kg / day subcutaneously,

or orally administer doses of 0.16 mmol / kg / day.

The animals of the second group are given a placebo and this group serves as a comparator group.

After the three weeks, half the animals of each group were sacrificed; the animals of the remaining two halves are allowed to live for a further 2 weeks and then sacrificed.

The hind limb at the level of the ankle joint is then separated from all sacrificed animals and weighed. For each of the halves of the groups of test animals, the average weight of said extremity is determined.

The efficacy of the test product is expressed as a percentage change in the average weight of said limb of arthritic rats relative to the average weight of said limb of arthritic rats of the comparative group.

The results so obtained are shown in Table 2 for some test products prepared by the method of the invention. For each test product, the therapeutic efficacy of this product is expressed as percent inhibition of rat hind limb weight after three weeks of test product administration.

This table also shows the results after five weeks for some of the products tested, i.e.. after three weeks of application of the test product and two consecutive weeks without application of the test product.

Table 2

Number Way Percentage weight inhibition product application rat roots SR after 3 weeks of application 2 weeks after stopping the application

43 140 AND subcutaneously 52 43 141 subcutaneously 36 43 162 AND subcutaneously 49 43 163 subcutaneously 35 43 164 subcutaneously 35 43 175 AND subcutaneously 22nd 43 176 subcutaneously 52 43 264 subcutaneously 29 43 299 (B) subcutaneously 25 43 304 AND subcutaneously 30 43 354 AND subcutaneously 44 43 368 AND subcutaneously 20 May 43 369 AND subcutaneously 38 43 370 AND subcutaneously 32 43 376 AND subcutaneously 38

These results demonstrate a significant anti-rheumatic efficacy of the products produced by the process of the invention after three weeks of application.

The products according to the invention are of low toxicity.

These products can be used in human therapy for the treatment of diseases of inflammatory origin, particularly for the treatment of arthritic conditions. In particular, the compounds of the invention may be used for the treatment of rheumatic polyarthritis. The invention also relates to pharmaceutical compositions comprising as active ingredient a compound of the invention and a pharmaceutically acceptable vehicle.

The pharmaceutical compositions may be in a suitable galenic form for oral, endorectal and parenteral administration. In particular, they are gelatin capsules or tablets containing the active ingredient in an amount of 10 to 500 mg / unit dose.

The daily dose of these products may range from 100 mg to 5 g in adult patients; this dose may be divided into several smaller doses.

Claims (1)

A process for the preparation of methylenediphosphonic acid derivatives of the general formula I wherein: R 1 represents an alkyl group having 1 to 6 carbon atoms, a cyclohexyl group, a phenyl group optionally substituted by halogen, an alkyl group having 1 to 6 carbon atoms or a trifluoromethyl group, and a group of the formula Alk represents a straight or branched alkylene group having 1 to 6 carbon atoms, R ₂ represents hydrogen or alkyl having 1 to 6 carbon atoms, R 6 represents hydrogen, C 1 -C 6 alkyl, benzyl or phenyl optionally substituted by chlorine or methyl, or else R ₂ and R together represent a group (CH ^^ represents an integer of 0, 1 or 2, provided that R ₁ is not methyl when Alk is -CH ₂ -CH _n -, ^R 2 ^{= R} 3 ^"H and n = 0 as well as the salts of said derivatives with mineral or organic bases, characterized by heating the amide of the formula S - Alk) '(ó c ti In which R @ ₁ , R @ ₂ , R @ 4, Alkane are as defined above, with phosphorous acid and phosphorus trichloride in an inert solvent at a temperature of 50 to 100 DEG C., whereupon the acid thus obtained is optionally converted into one of its salts.