Strontium salts of sulphonic acids, a process for their preparation and pharmaceutical compositions containing them

Abstract

Strontium salts of the sulphonic acids of formula (I):

Description

EXAMPLE 1

Strontium 1,3-propanedisulphonate

A mixture of 222 g of 70% 1,3-propanedisulphonic acid in water (0.76 mol) and 200.4 g of strontium hydroxide octahydrate (0.75 mol) in 200 ml of water is heated at reflux for 3 hours. The reaction mixture is filtered hot and then cooled to 4° C. The precipitate formed is removed by filtration and 500 ml of 96% ethanol are added to the filtrate. The precipitate is filtered off, rinsed with 250 ml of a 70/30 ethanol/water mixture and dried to obtain 139 g of a white crystalline product of 1,3-propanedisulphonic acid strontium salt (yield 63%).

Melting point: >250° C.

Elemental Microanalysis:

	% C	% H	% S	% Sr
	Calculated	12.43	2.09	22.13	30.23
	Found	12.56	3.44	22.76	26.88

EXAMPLE 2

Strontium bis(3-amino-1-propanesulphonate)

The expected product is obtained by reaction of 3-amino-1-propanesulphonic acid with strontium hydroxide octahydrate in accordance with the procedure of Example 1.

EXAMPLE 3

Strontium Sulphonatoacetate

The expected product is obtained by reaction of sulphoacetic acid with strontium hydroxide octahydrate in accordance with the procedure of Example 1.

Melting point: >270° C.

Elemental Microanalysis:

	% C	% H	% S
	Calculated	10.64	0.89	14.21
	Found	9.77	1.20	14.18

EXAMPLE 4

Strontium bis(2-amino-1-ethanesulphonate)

The expected product is obtained by reaction of 2-amino-1-ethanesulphonic acid with strontium hydroxide octahydrate in accordance with the procedure of Example 1.

EXAMPLE 5

Strontium 1,4-butanedisulphonate

0.75 mol of strontium chloride hexahydrate and 0.75 mol of disodium 1,4-butane-disulphonate are dissolved in 600 ml of water. After stirring for 1 hour, 1 litre of 96% ethanol is added. The precipitate formed is filtered off, rinsed with 500 ml of a 70/30 ethanol/water mixture and dried to yield the expected product.

EXAMPLE 6

Strontium 1,2-benzenedisulphonate

The expected product is obtained by reaction of dipotassium 1,2-benzenedisulphonate with strontium chloride hexahydrate in accordance with the procedure of Example 6.

EXAMPLE 7

Strontium bis(2-hydroxyethanesulphonate)

The expected product is obtained by reaction of sodium 2-hydroxyethanesulphonate with strontium chloride hexahydrate in accordance with the procedure of Example 6.

EXAMPLE 8

Distrontium 2,2-bis(sulphonatomethyl)-1,3-propanedisulphonate

The expected product is obtained by reaction of 2,2-bis(sulphomethyl)-1,3-propanedisulphonic acid with strontium hydroxide octahydrate in accordance with the procedure of Example 1.

EXAMPLE 9

Strontium 1,5-pentanedisulphonate

The expected product is obtained by reaction of disodium 1,5-pentanedisulphonate with strontium chloride hexahydrate in accordance with the procedure of Example 6.

EXAMPLE 1

Strontium 1,6-hexanedisulphonate

The expected product is obtained by reaction of disodium 1,6-hexanedisulphonate with strontium chloride hexahydrate in accordance with the procedure of Example 6.

EXAMPLE 1

Strontium bis(4-amino-1-butanesulphonate)

The expected product is obtained by reaction of 4-amino-1-butanesulphonic acid with strontium hydroxide octahydrate in accordance with the procedure of Example 1.

EXAMPLE 12

Strontium bis(1-amino-2-benzenesulphonate)

The expected product is obtained by reaction of 1-amino-2-benzenesulphonic acid with strontium hydroxide octahydrate in accordance with the procedure of Example 1.

Pharmacological Study

EXAMPLE 13

In Vitro Study of the Inhibition of Bovine Cartilage Catabolism by the Compound of Example 1

Protocol

The study was carried out on fragments of bovine cartilage in culture medium (96-well plate), the degradation of which is stimulated by adding TNFα and oncostatin M (Schaller, S., Henriksen, K., Hoegh-Andersen, P., Sondergaard, B. C., Sumer, E. U., Tanko, L. B., Qvist, P., Karsdal, M. A. In vitro, ex vivo, and in vivo methodological approaches for studying therapeutic targets of osteoporosis and degenerative joint diseases: how biomarkers can assist? Assay. Drug Dev. Technol. 3, 553-580 (2005).

The duration of the cultivation period is 21 days (culture medium changed every 2 days). A group not treated with TNFα and oncostatin M constitutes the control group. Five lots of stimulated cartilage fragments were treated with the compound of Example 1, each at a different dose: 0.01; 0.1; 1; 3 and 10 mM. 5 replications were carried out for each dose.

On D19, the concentration of CTX II (fragment of type II collagen resulting from the degradation of that collagen by metalloproteases) in the culture medium is measured using an ELISA technique. That parameter is expressed in ng/ml/mg of cartilage.

On D21, the following are measured in the cartilage remaining at the end of cultivation:

• • the quantity of proteins, using the kit marketed by Biorad. For the groups treated with the compound of Example 1, the results of this parameter are expressed as the percentage inhibition of the degradation of the proteins in the cartilage of the untreated control group;
  • and the quantity of glycosaminoglycans (GAGs), using the calorimetric technique with methylene blue (DMB). That parameter, too, is expressed as a percentage inhibition of the degradation of the GAGs evaluated in the control group after culturing for 21 days.

Results

The results of treatment with the compound of Example 1 are:

• • a significant (p<0.001) and dose-dependent inhibition of the salting out of CTX II in the culture medium (IC₅₀=3.5 mM);
  • protection against degradation of the components of the cartilage starting from a dose of 1 mM:

	Dose (mM)
	Components	0.01	0.1	1	3	10
	proteins	/	/	22%	41%	55%*
	GAGs	/	/	4%	8%	26%**
	*p < 0.05;
	**p < 0.01

The treatment is moreover well tolerated by the cells for the 21 days of cultivation (toxicity test employed: Alamar blue—negative whatever the dose).

Those results demonstrate that the compound of Example 1 provides significant protection against the degradation of the characteristic components of cartilage by way of inhibition of collagenolytic activity.

EXAMPLE 14

Pharmaceutical Composition

Preparation formula for a 1 g tablet containing a dose of 500 mg:

Compound of Example 1 . . . 500 mg

Povidone K30 . . . 24 mg

Cellulose Avicel PM102 . . . 417 mg

Carboxymethyl starch Primojel . . . 21 mg

Magnesium stearate . . . 6 mg

Talc . . . 32 mg

Claims

1. A strontium salt of a sulphonic acid selected from those of formula (I): A-B—SO3H   (I)

2. The strontium salt according to claim 1, wherein A represents SO3H or NH2.

3. The strontium salt according to claim 1, wherein B represents an arylene group or a linear or branched C1-C12alkylene chain optionally substituted by one or more groups selected from hydroxy, oxo, amino, SO3H and CO2H, wherein one or more carbon atoms of the alkylene chain may be optionally replaced by an oxygen atom or by an SO2 group.

4. The strontium salt according to claim 3, wherein B represents a linear C1-C6alkylene chain optionally substituted by one or more groups selected from hydroxy, oxo, amino, SO3H and CO2H, wherein one or more carbon atoms of the alkylene chain may be optionally replaced by an oxygen atom or by an SO2 group.

5. The strontium salt according to claim 4, wherein B represents a linear C3-C6alkylene chain optionally substituted by one or more groups selected from hydroxy, oxo, amino, SO3H and CO2H, wherein one or more carbon atoms of the alkylene chain may be optionally replaced by an oxygen atom or by an SO2 group.

6. The strontium salt according to claim 5, wherein A represents a group selected from NH2 and SO3H and B represents an unsubstituted linear or branched C3-C6alkylene chain.

7. The strontium salt according to claim 1, which is selected from: strontium 1,3-propanedisulphonate;strontium bis(3-amino-1-propanesulphonate);strontium sulphonatoacetate;strontium bis(2-amino-1-ethanesulphonate);strontium 1,4-butanedisulphonate; andstrontium 1,2-benzenedisulphonate.

8. A process for the preparation of the strontium salt according to claim 1, comprising reaction of a sulphonic acid of formula (I): A-B—SO3H   (I),

9. A process for the preparation of the strontium salt according to claim 1, comprising reaction of a sodium or potassium salt of a sulphonic acid of formula (I): A-B—SO3H   (I),

10. A pharmaceutical composition comprising as active ingredient a strontium salt of a sulphonic acid selected from those of formula (I): A-B—SO3H   (I)

11. A method of treating a living animal body, including a human, afflicted with osteoarthritis, comprising the step of administering to the living animal body, including a human, an amount of a strontium salt of a sulphonic acid selected from those of formula (I): A-B—SO3H   (I)

12. A method of treating a living animal body, including a human, afflicted with osteoporosis, comprising the step of administering to the living animal body, including a human, an amount of a strontium salt of a sulphonic acid selected from those of formula (I): A-B—SO3H   (I)