CS247198B2 - A method for producing methylenediphosphonic acid derivatives - Google Patents

Abstract

The invention relates to a process for the production of methylenediphosphonic acid derivatives of the general formula I, in which R1 represents an alkyl group with 1 to 6 carbon atoms, a cyclohexyl group, a phenyl group optionally substituted by halogen, an alkyl group with 1 to 6 carbon atoms or a trifluoromethyl group, and the group of the formula Alk represents a straight or branched alkylene group with 1 to 6 carbon atoms, R2 represents hydrogen and an alkyl group with 1 to 6 carbon atoms, R3 represents hydrogen, an alkyl group with 1 to 6 carbon atoms, a benzyl group or a phenyl group optionally substituted by chlorine or a methyl group or also R2 and R3 together represent the group (CH2)5 and n represents the integer 0, 1 or 2, provided that R1 does not represent a methyl group when Alk represents -CH2-CH2-, R2=R3=H and n=0, as well as salts of these derivatives with mineral or organic bases, the essence of which consists in heating phosphorous acid and phosphorus trichloride in a suitable solvent with an amide of the general formula, in which Ri, R2, R3, Alk and n have the above-mentioned meaning.

Description

The invention relates to a process for the production of novel methylenediphosphonic acid derivatives which exhibit therapeutic properties predisposing these derivatives to use in the treatment of rheumatic diseases.

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

in which

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

Alk means a straight or branched alkylene group with 1 to 6 carbon atoms,

R ₂ represents hydrogen and an alkyl group with 1 to 6 carbon atoms,

R^ represents hydrogen, an alkyl group with 1 to 6 carbon atoms, a benzyl group or a phenyl group optionally substituted by chlorine or methyl, or also

R ₂ and R 3 together represent a group (CH 2 ) and n represents an integer 0, 1 or 2, provided that R 3 does not represent a methyl group when Alk represents -CH ₂ -CH ₂ -, and n = 0.

The acids of the general 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 the general formula I has already been described, but in no case have the therapeutic properties of this compound been described.

Thus, patent DE 2 754 821 describes a compound of the general formula I in which R 1 represents a methyl group, n represents 0, Alk represents a group -CH ₂ -CH ₂ - and R 8 and R 1 represent hydrogen.

This patent also describes the corresponding salts derived from alkali metals and alkaline earth metals and the use of these products as additives in the treatment of wastewater in the textile and paper industries.

The other compounds of general formula X are novel compounds.

The subject of the invention is a process for the preparation of the above-mentioned compounds of general formula _I. If the meaning of the general substituents R ₂ and R 3 is arbitrary, the compounds of general formula I can be prepared from amide starting products of general formula R 4 .

in which , n, Alk, R ₂ and

These amides are obtained

R.-S-Alk-C-N ’

I II X <0) _n 0

Rg have the meanings given above.

in a known manner from acids of the general formula

R^-$-Alk-COOH in which R^, Alk and n have the above meaning, for example by the action of thionyl chloride or phosphorus trichloride on said acid and then by reaction with an amine of the general formula

The amide thus prepared is then heated with phosphorous acid and phosphorus trichloride in an inert solvent such as dimethyloxyethane at a temperature of 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 so that the salt crystallizes upon cooling after optionally adding a third of the solvent.

The method according to the invention is explained in the following part of the description in the form of specific examples of embodiments.

Example 1

Sodium salt of 1-methylamino-4-(4-chlorophenylthio)butylidene-1,1-aliphosphonic acid (SR 43 140 A)

General formula I:

^R<| “vv— ^Cl n =0 Alk = (CH ₂ ) ₃ R. = CH.

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

The mixture is then left at room temperature for 12 hours, after which the precipitated crystals are centrifuged. These crystals are washed with methanol and then with acetone.

Product weight: 25 g.

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

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

Product weight: 24.25g;

The melting point of the product is higher than 260 °C. Elemental analysis:

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

Examples 2 to 13

The procedure is the same as in Example 1, but the starting amide is changed, and the products of the general formula I, in which n = 0, are obtained; these products are listed in the following Table 1. If the acid does not crystallize upon cooling the reaction mixture, then the reaction mixture is evaporated to dryness under vacuum and the residue is taken up with water.

In order to prepare sodium salts, sodium acetate can be replaced with sodium hydroxide.

Table 1

Example e. Code number R-^ SR Alcohol ^R 2 r ₃ Acid or salt Melting point (°C) Analysis: (calculated value) 2 43 141 C-θ— < ^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 Two-way salt with 1 H ₂ O _C ,-Q_ (CH ₂ ) ₃ η higher 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 ) ₃ hours -<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 higher 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 HjO greater than 260 % C 32.03 (32.07) % H 5.05 % N 3.09 ( 5.15) ( 3.11) 9 43,404 CH3 _{- CH2-} (ch ₂ ) ₄ H -CH ₃ Sodium salt higher than % C 28.34 % H 5.55 % N 4.26 300 (28.00) ( 5.87) ( 4.08) 10 43 376 A And 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

-CHj Dipotassium salt with 2 H.,0 higher than 300 % C 36.96 (36.61) % H 5.69 ( 5.48) i N 3.07 ( 3.06)

369 A ^H 3 ^C ^O~

-CH-CH _O - H

43 354 (ch ₂ í 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)

S N 6.62 ( 6.65)

Example 14

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

General formula I

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 a solid product are obtained, the melting point of which is higher than 260°C.

Elemental analysis of the product with 1 water molecule:

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

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

General formula I:

Cl

Alk = (CH ₂ ) ₃

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

Compound SR 43 462 is isolated

Melting point: 230 °C

Elemental analysis:

^C 17 ^H 22 ^{C 1 NO} 7 ^P 2 ^S < ⁴⁸¹ ' ⁸² >

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

Sodium salt of 1-methylamino-4-(4-methylphenylsulfonyl)-propylidene-1,1-diphosphonic acid (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 phosphorus 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 is removed for 12 hours, and then the solid is centrifuged and 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 to 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 is 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 agents and their pharmacological properties are proven to be anti-inflammatory and antirheumatic in the following way.

In vivo test: induced arthritis

If a rat is injected with mycobacterium, it will develop polyarthritis that resembles rheumatoid arthritis in humans in some aspects.

Protocol

A suspension of Mycobacterium Tuberculosis (0.4 mg) in paraffin oil (0.05 ml) is 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 pronounced symptoms of arthritis are sorted.

These are divided into two groups of 14 animals each.

The animals in the first group were given: for 3 weeks, 6 days a week:

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

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

The animals in the second group are given a placebo and this group serves as a comparison group.

After the three weeks mentioned, half of the animals in each group are killed; the animals in the other two halves are allowed to live for another two weeks and then they are also killed.

The hind limb of all sacrificed experimental animals is then separated at the level of the hock joint and this separated part of the limb is weighed. The average weight of said limb is determined for each of said halves of the experimental animal groups.

The efficacy of the test product is expressed as the percentage change in the average weight of the indicated limb of arthritic rats compared to the average weight of the indicated limb of arthritic rats of the control group.

The results thus obtained for some of the tested products prepared according to the method of the invention are shown in the following Table 2. For each tested product, the therapeutic efficacy of this product is expressed as the percentage inhibition of the weight of the rat hind right limb after three weeks of application of the tested product.

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

Table 2

Number Method Percentage of weight inhibition product application rat limbs SR after 3 weeks of application 2 weeks after application completion

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

The results presented demonstrate the significant antirheumatic efficacy of the products produced by the method according to the invention after their three-week application.

The products of the invention are only slightly toxic.

These products can be used in human therapy for the treatment of inflammatory diseases, in particular for the treatment of arthritic conditions. The compounds of the invention can be used in particular for the treatment of rheumatoid arthritis. The invention also relates to pharmaceutical preparations which contain as active ingredient a compound of the invention and a pharmaceutically acceptable vehicle.

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

The daily dose of these products can range from 100 mg to 5 g in adult patients; this dose can 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.