EP0448583A1

EP0448583A1 - Organometallic compounds, process for producing them and pharmaceutical compositions containing them

Info

Publication number: EP0448583A1
Application number: EP90900160A
Authority: EP
Inventors: Ludo Maes; Emmanuel Bajyana-Songa; Raymond Hamers
Original assignee: BAJYANA SONGA EMMANUEL
Current assignee: BAJYANA SONGA EMMANUEL
Priority date: 1988-12-13
Filing date: 1989-12-13
Publication date: 1991-10-02
Also published as: JPH04502311A; WO1990006931A1; FR2640269A1; FR2640269B1; US5281588A

Abstract

La présente invention a pour objet des composés de formule générale (I) dans laquelle: M représente l'arsenic (As) ou l'antimoine (Sb), Y et Z identiques ou différents représentent un atome de soufre ou d'oxygène, R1 à R5 représentent un atome d'hydrogène ou -NH2, ou NO2, ou -COOH, ou -OH, ou (a), ou (b) avec R6 = CH3 ou -NH, ou un groupe de la formule (II); A1 représente un groupe alkylène de 3 à 21 atomes de carbone, notamment de 4 à 6 atomes de carbone, éventuellement substitué par un ou plusieurs groupes, identiques ou différents, de formule -(CH2)n-R7 avec R7 représentant -H, ou -OH, ou -COOH, ou -NH2, ou SO3H et n = 0 à 10, ou par un ou plusieurs sel(s) de ce groupe.The subject of the present invention is compounds of general formula (I) in which: M represents arsenic (As) or antimony (Sb), Y and Z which are identical or different represent a sulfur or oxygen atom, R1 to R5 represent a hydrogen atom or -NH2, or NO2, or -COOH, or -OH, or (a), or (b) with R6 = CH3 or -NH, or a group of formula (II); A1 represents an alkylene group of 3 to 21 carbon atoms, in particular of 4 to 6 carbon atoms, optionally substituted by one or more groups, identical or different, of formula - (CH2) n-R7 with R7 representing -H, or -OH, or -COOH, or -NH2, or SO3H and n = 0 to 10, or by one or more salt (s) from this group.

Description

ORGANOMETALLIC COMPOUNDS, METHODS OF PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

The present invention relates to organometallic compounds, their methods of preparation, as well as pharmaceutical compositions comprising said compounds. A more particular subject of the invention is the use of these pharmaceutical compositions in the treatment of parasitic diseases such as trypanoso iases and filariasis.

The chemotherapeutic treatment of these parasitic diseases in humans and animals currently poses serious problems.

The compound Mel B, discovered by E. FRIEDHEIM (patent deposited in the UNITED STATES and published in 1953 under the number 2,659,723), is the drug most used for the treatment of human trypanosomiasis in the second stage. However, this compound has many drawbacks, one of the most serious of which is the triggering of unpredictable lethal encephalopathies which occur in 5% of individuals treated with Mel B (WHO / FAO EXPERT COMMITY (1979), The African Trypanosomiases. WHO TECHNICAL REPORT SERIES, N 635).

This patent also describes other compounds related to Mel B having an arsenic (As) or antimony (Sb) atom engaged in a pentacyclic structure. A process capable of leading to the production of a derivative related to Mel B in which an antimony atom is engaged in a hexacyclic structure, is described by way of example in this patent.

However, no physicochemical or biological characteristic of the product capable of being obtained in the above-mentioned example (which would correspond to the p (diamino-4,6-s-triazinyl-2 amino) phenyl-2dithia-stibane-1,3,2-triol-4,5,6) was not indicated in this patent.

The compound Mel W (FRIEDHEIM E.A.H (1966) German patent No. 1,229,543) is a water-soluble derivative of Mel B, and has been used in veterinary and human therapy. However, the latter application was discontinued due to numerous toxicity issues.

In addition to the problem of the toxic effect of the abovementioned drugs, a large number of strains of trypanosomes resistant to these products have also been discovered.

The two drugs, Mel B and Mel W, are similar compounds of the dithiarsolane type with 5 vertices (pentacycle); the only structural difference between these two compounds is a different substituent on the pentacycle. The synthesis of this pentacycle is carried out from vicinal dithiols (that is to say carried by two neighboring carbon atoms).

The present invention relates to the organometallic compounds represented by the following general formula:

in which:

- M represents arsenic (As) or antimony (Sb),

- Y and Z identical or different represent a sulfur or oxygen atom,

- RR ₂ , R ₃ , R ^ and g, identical or different, represent: . a hydrogen atom,

. a primary amine-NH ₂ , or a secondary or tertiary amino substituted by one or two al groups of 1 to 18 carbon atoms,. a group of formula O

-NH-CR ₆ in which Ε ^ represents a methyl -CH ₃ or an amine -NH ₂ ,

. a group

. a group -N0 ₂

. -COOH group

. a hydroxyl -OH

. a group of the type

in which X represents a nitrogen atom or a CH group, - A _T represents an alkylene group of 3 to 21 carbon atoms, in particular of 4 to 6 carbon atoms, this alkylene group being, where appropriate, substituted:. either by a group of formula - (CH ₂ ) _n -R ₇ in which R ₇ represents a hydrogen atom, or a hydroxyl function -OH, or acid -COOH, or amino -NH ₂ , or sulfonic -SO ₃ H , and n represents an integer varying from 0 to 10, or by several identical or different groups of formula - (CH ₂ ) _n -R ₇ mentioned above,. either by one or more salt (s) from the group of for - (CH ₂ ) _n -R ₇ defined above, in particular one or more salt (s) of Na or K when R ₇ represents an acid function, or a or more hydrochloride (s) when R ₇ represents a amino function, with the exception of the compound of formula (I)

designated below by: p (diamino-4,6-s-triazinyl-2-amino) phenyl-2 dithia-stibane-1,3,2-triol-4,5,6 _#

The present invention relates more particularly to the compounds represented by the following general formula:

in which :

- M represents arsenic (As) or antimony (Sb),

- Y and Z identical or different represent a sulfur or oxygen atom,

- R represents a hydrogen atom or a group of the following formula:

H - A represents an alkylene group of 1 to 18 carbon atoms, in particular of 2 to 4 carbon atoms, optionally substituted by one or more, hydroxyl function (s), - OH.

The subject of the invention is more particularly the following compounds:

The present invention also relates to the process for obtaining the compounds defined above, comprising the reaction between - on the one hand the compound of formula

in which R ,, R ₂ , R ₃ , ^ and ₅ have the meanings indicated above, and M represents an oxide, or acid form, or acid salt, or arsenic dichloride (As) or d 'antimony (Sb), - and on the other hand the compound of formula HY-A ^ ZH in which Y, A ₁ and Z have the meanings indicated above, followed by the recovery and the purification of the compounds obtained.

A more particular subject of the present invention is the process for obtaining the specific compounds defined above, comprising the reaction between - on the one hand the compound of formula

in which

R has the meaning indicated above and M represents an oxide, or acid, or acid salt, or arsenic dichloride (As) or antimony (Sb) form,

- and on the other hand the compound of formula

HY-CH ₂ -A-CH ₂ -ZH in which Y, Z and A have the meanings given above, followed by recovery and purification of the compounds.

Conditions under which the starting compounds of the above-mentioned reaction are obtained and brought into contact are well known to those skilled in the art and appear in particular in the detailed description which is of the synthesis of the derivatives of the invention.

The invention also relates to the use of the compounds defined above, including the derivative of formula (I) mentioned above, for obtaining medicaments intended for the treatment of trypanosomiasis, leishmaniases, diseases caused by filaria ( filariasis), and Pneumocystis carinii infections, especially in people with AIDS.

The subject of the invention is pharmaceutical compositions comprising one or more of the trypanocidal compounds defined above, including the derivative of formula (I) mentioned above, in combination with a phar aceutically acceptable vehicle.

These pharmaceutical compositions are particularly effective for the treatment of parasitic diseases such as those caused by trypanosomes, notably sleeping sickness, and by filaria; these compositions also seem to be particularly effective for the treatment of other diseases such as pneumonia caused by Pneumocystis carinii.

Advantageously, the compounds of the invention are combined with a pharmaceutically acceptable vehicle in the form of a suspension in a physiological liquid for intramuscular or subcutaneous administration. Such compositions are particularly advantageous compared to current trypanocidal drugs such as Mel B, the latter being administered in an irritating organic solvent causing painful inflammations which limits its use.

The pharmaceutical compositions of the invention can be used for the purpose of preventing or treating parasitic diseases mentioned above in humans or animals (veterinary application).

These compositions have also been found to be active against strains of melarsoprol-resistant trypanosomes (Mel B).

According to the results obtained from studies carried out on mice, the compounds of the invention are much less toxic than the derivatives arsenic or antimony trypanocides currently used.

The good stability as well as the low solubility of the compounds of the invention in physiological fluids make them products of choice for use in pharmaceutical compositions with slow release and therefore with long action time.

The invention is more particularly illustrated with the aid of the following examples: Example 1:

Synthesis of the following compound:

The synthesis is carried out from diamino-4,6-chloro-2-s-triazine which is condensed by reflux with p-arsanilic acid (Banks).

The product thus obtained, 2- (p-arsonoanilino) - diamino-4,6, s-triazine of formula:

H ₂ N

is reduced with sulfur dioxide to give p (diamino-4,6-s-triazinyl-2-amino) -phenylarsenone, dihydrate (II) of formula

Then 246 mg (0.75 mmol) of this intermediate product (II) are dissolved in 10 ml of methanol. The solution is stirred vigorously under nitrogen at room temperature. Then 127 mg (0.825 mmol) of dimercapto-1,4, butanediol-2,3 of formula HS-CH ₂ -CHOH-CHOH-CH ₂ -SH (JANSSEN) dissolved in 5 ml of methanol are added slowly, all while now a nitrogen atmosphere. A white precipitate is formed and stirring is continued for 1 hour. The suspension is then filtered through a glass filter. After washing, the white solid obtained is dried in a vacuum desiccator. The reaction yield is about 98%. The compound obtained is p (diamino-4,6, s-triazinyl 2-amino) phenyl-2 dithiarsepane-1,3,2, diol-5,6; PF = 220 ^β C.

The last step of this synthesis can also be carried out in an aqueous medium.

In mice infected with Trypanosoma evansi (or T. evansi), the trypanosomes from the blood are eliminated within 24 hours with a dose of 5 mg / kg of the derivative of the invention described above by subcutaneous injection or with a dose 2.5 mg / kg by intramuscular injection.

In the case of 1 ^• infection of mice with T.gambiense, the trypanosomes from the blood are eliminated within 48 hours with a dose of 5 mg / kg of the abovementioned derivative of the invention by subcutaneous or intramuscular injection. The parasite, ie obtained by infection of mice with a T. rhodesiense strain resistant to melarsoprol, disappears after three days using an intramuscular dose of 10 mg / kg. With a single dose of 5 mg / kg intramuscularly, prophylaxis of approximately 12 days is obtained against T. evansi. The drug is well tolerated; the treated mice show no local reaction or any clinical sign of toxicity of the central nervous system after subcutaneous injection up to 500 mg / kg.

Example 2a:

Synthesis of the following compound:

219mg (1 mmol) of p-aminophenylarsenone dihydrate of formula

obtained by the reduction of p-arsanilic acid using sulfur dioxide according to methods known to those skilled in the art, are dissolved in 8 ml of methanol. The solution is put under nitrogen. 170 mg (1.1 mmol) of dimercapto-1,4-butanediol-2,3 dissolved in 2 ml of methanol are then added slowly, while the solution is well stirred. An opal-colored sticky material rushes onto the walls of the container. Agitation is continued for 3 hours; in the meantime, the appearance of the product becomes a solid white precipitate. The reaction mixture is filtered, and the recovered product is washed with methanol and dried.

The product obtained, which is in the form of easily sprayable white flakes, is p-aminophenyl-2-dithiarsepane-1,3,2-diol-5,6.

It is insoluble in methanol and ethanol; it is soluble in concentrated hydrochloric acid, and in boiling acetic acid.

Example 2b:

Synthesis of the compound described in Example 2a:

0.5 mmol of sodium arsanilate of formula

are dissolved in 10 ml of water. The solution is brought into the presence of nitrogen; a solution of 1.5 mmol of dimercapto-1,4, butanediol-2,3 in 5 ml of water is added with vigorous stirring. The reaction mixture is kept under stirring for 3 hours, then the product is recovered and purified.

Example 3:

Synthesis of the following compound:

0.1 mmol of are dissolved in 10 ml of water. 0.5 mmol of 1,4-dimercapto, 2,3-butanediol are added with stirring and nitrogen atmosphere. After 1 hour of reaction, the product is recovered and purified.

Examples 4 to 8:

Compounds of the type:

for which x = 1,2,3,4 and 6 were respectively obtained according to the same method as that described in Example 1, carried out from p (diamino-4,6-s-triazinyl-2-amino) - phenylarsenone of formula

H ₂ N

and 1,3-dimercapto-propane, HS- (CH ₂ ) ₃ -SH, (Janssen

Chimica)

1,4-dimercapto-butane, HS- (CH ₂ ) ₄ -SH,

1,5-dimercapto-pentane, HS- (CH ₂ ) ₅ -SH,

1,6-dimercapto-hexane, HS- (CH ₂ ) ₆ -SH, and 1,8-dimercapto-octane, HS- (CH ₂ ) ₈ -SH (Aldrich)

Claims

CLAIMS 1. Organometallic compounds characterized by the following general formula:

-

in which:

- M represents arsenic (As) or antimony (Sb),

- Y and Z identical or different represent a sulfur or oxygen atom,

- R _1f R ₂ , R ₃ , R ₄ and Rg, identical or different, represent:

. a hydrogen atom,

. a primary amine-NH ₂ , or a secondary or tertiary amine substituted by one or two alkyl groups of 1 to 18 carbon atoms,

. a group of formula 0 il -NH-CR ^ in which R ₆ represents an ethyl -CH ₃ or an amine -NH ₂ ,

in which X represents a nitrogen atom, or a CH group,

- A ₁ represents an alkylene group of 3 to 21 carbon atoms, in particular from 4 to 6 carbon atoms, this alkylene group being, where appropriate, substituted:. either by a group of formula - (CH ₂ ) _n -R ₇ in which R ₇ represents a hydrogen atom, or a hydroxyl function -OH, or acid -COOH, or amino -NH ₂ , or sulfonic -S ^ H , and n represents an integer varying from 0 to 10, or by several identical or different groups of formula - (CH ₂ ) _n -R ₇ mentioned above,. either by one or more salt (s) from the group of formula - (CH ₂ ) _n -R ₇ defined above, in particular one or more salt (s) of Na or K when R ₇ represents an acid function, or a or more hydrochloride (s) when R ₇ represents an amino function, with the exception of the compound of formula (I)

2. Organometallic compounds according to claim 1, characterized by the following general formula:

in which :

- M represents arsenic (As) or antimony (Sb),

- Y and Z identical or different represent a sulfur or oxygen atom,

- R represents a hydrogen atom or a group of the following formula:

- A represents an alkylene group of 1 to 18 carbon atoms, in particular of 2 to 4 carbon atoms, optionally substituted by one or more, hydroxyl function (s), - OH.

3. Compound according to claim 1 or claim 2, represented by the following formula:

B ₂ »S — CHj HN j tt 'AÀ / / XTHHOOHH

H „N

4. Compound according to claim 1 or claim 2, represented by the following formula:

5. Process for the synthesis of the compounds according to claim 1, characterized in that it comprises: the reaction between on the one hand the compound of formula

in which RR ₂ , R ₃ , R ^ and ₅ have the meanings indicated in claim 1, and M represents an oxide, or acid, or acid salt, or arsenic dichloride (As) or antimony (Sb),

- and on the other hand the compound of formula

HY-A, -ZH wherein Y, A, and Z have the meanings given in claim 1.

6. Process for the synthesis of the compounds according to claim 2, characterized in that it comprises the reaction between:

- on the one hand the compound of formula

in which

R has the meaning indicated in claim 2, and M represents an oxide, or acid, or acid salt, or arsenic dichloride (As) or antimony (Sb) form,

- and on the other hand the compound of formula

HY-CH ₂ -A-CH ₂ -ZH in which Y, Z and A have the meanings indicated in claim 2,

7. Pharmaceutical composition comprising at least one compound corresponding to the following formula:

in which :

- M represents arsenic (As) or antimony (Sb),

- Y and Z identical or different represent a sulfur or oxygen atom,

- R _1f R ₂ , R ₃ , R ₄ and R ₅ , identical or different, represent:

. a hydrogen atom,

. a group of formula O μ

-NH-C- ₆ in which R ₆ represents a methyl -CH ₃ or an amine -NH ₂ ,

. a group 0

.11 -C-NH ₂

. a group -N0 ₂

. -COOH group

. a hydroxyl -OH

. a group of the type

in which X represents a nitrogen atom, or a CH group,

- Ai represents an alkylene group of 3 to 21 carbon atoms, in particular of 4 to 6 carbon atoms, this alkylene group being, where appropriate, substituted:. either by a group of formula - (CH ₂ ) _n -R ₇ in which R ₇ represents a hydrogen atom, or a hydroxyl function -OH, or acid -COOH, or amino -NH ₂ , or sulfonic -S0 ₃ H , and n represents an integer varying from 0 to 10, or by several identical or different groups of formula - (CH) _n -R ₇ mentioned above,. either by one or more salt (s) from the group of formula - (CH ₂ ) _n -R ₇ defined above, in particular one or more salt (s) of Na or K when R ₇ represents an acid function, or a or more hydrochloride (s) when R ₇ represents an amino function, in association with a pharmaceutically acceptable vehicle.

8. Pharmaceutical composition according to claim 7 comprising at least one compound corresponding to the formula

- M represents arsenic (As) or antimony (Sb),

- Y and Z identical or different represent a sulfur or oxygen atom,

- R represents a hydrogen atom or a group of the following formula:

9. Pharmaceutical composition comprising at least the compound according to claim 3, in association with a pharmaceutically acceptable vehicle.

10. A pharmaceutical composition comprising at least the compound according to claim 4, in association with a pharmaceutically acceptable vehicle.

11. Use of one or more compounds corresponding to the following general formula:

in which:

- M represents arsenic (As) or antimony (Sb),

- Y and Z identical or different represent a sulfur or oxygen atom,

- R _1f R ₂ , R ₃ , R ₄ and Rg, identical or different, represent:

. a hydrogen atom,

. a primary amine-NH ₂ , or a secondary or tertiary amine substituted by one or two alk groups from 1 to 18 carbon atoms,

. a group of formula O il -NH-CR ₆ in which _ represents an ethyl -CH ₃ or an amine -NH ₂ ,

in which X represents a nitrogen atom or a CH group, - A., represents an alkylene group of 3 to 21 carbon atoms, in particular of 4 to 6 carbon atoms, this alkylene group being, where appropriate, substituted: . either by a group of formula - (CH ₂ ) _n -R ₇ in which R ₇ represents a hydrogen atom, or a hydroxyl function -OH, or acid -COOH, or amino -NH, or sulfonic -S0 ₃ H, and n represents an integer varying from 0 to 10, or by several identical or different groups of formula - (CH ₂ ) _n -R ₇ mentioned above,. either by one or more salt (s) from the group of for - (CH ₂ ) _n -R ₇ defined above, in particular one or more salt (s) of Na or K when R ₇ represents an acid function, or a or several hydrochloride (s) when R ₇ represents an innate function, for obtaining a medicament intended for the treatment of trypanosomiasis, leishmaniasis, filariasis, and pneumonia caused by Pneumosystis carinii.