CA1124989A - Heteropolyanion compounds containing tungsten combined with antimony - Google Patents
Heteropolyanion compounds containing tungsten combined with antimonyInfo
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- CA1124989A CA1124989A CA292,227A CA292227A CA1124989A CA 1124989 A CA1124989 A CA 1124989A CA 292227 A CA292227 A CA 292227A CA 1124989 A CA1124989 A CA 1124989A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
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- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01G—COMPOUNDS CONTAINING METALS NOT COVERED BY SUBCLASSES C01D OR C01F
- C01G41/00—Compounds of tungsten
- C01G41/006—Compounds containing, besides tungsten, two or more other elements, with the exception of oxygen or hydrogen
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2002/00—Crystal-structural characteristics
- C01P2002/80—Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70
- C01P2002/82—Crystal-structural characteristics defined by measured data other than those specified in group C01P2002/70 by IR- or Raman-data
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- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2006/00—Physical properties of inorganic compounds
- C01P2006/32—Thermal properties
- C01P2006/37—Stability against thermal decomposition
Abstract
ABSTRACT OF THE DISCLOSURE
The invention relates to novel chemical compounds of the formula [MSb9W21O86]n- in which M can be absent or represent an alkali or alkaline-earth metal other than sodium and n is equal to 19 if W is absent and to n-p if p is the charge of the metal W. Compounds with in the scope of the invention correspond to this formula [MSb9W21O86]W'18, in which M is an alkali or alkaline-earth metal and M' is a similar metal or ammonium. These compounds are useful agents for the treatment of viral infections and pathological processes due to the viruses of leukemias and sarcomas.
The invention relates to novel chemical compounds of the formula [MSb9W21O86]n- in which M can be absent or represent an alkali or alkaline-earth metal other than sodium and n is equal to 19 if W is absent and to n-p if p is the charge of the metal W. Compounds with in the scope of the invention correspond to this formula [MSb9W21O86]W'18, in which M is an alkali or alkaline-earth metal and M' is a similar metal or ammonium. These compounds are useful agents for the treatment of viral infections and pathological processes due to the viruses of leukemias and sarcomas.
Description
11249~9 The invention relates to novel heteropolyanion compounds containing tungsten combined with antimony The invention also relates to processes for the manu-facture of such compounds. The novel compounds are useful as active agents in the treatment of viral infections in man and animals as well as of the pathological processes due to viruses.
The invention also relates to pharmaceutical compositions con-taining a therapeutically effective amount of at least one of said compounds.
Co-pending patent application no. 205.780 relates to heteropolyanions possessing anti-viral properties, in particular a compound of tungsten and antimony denoted by the reference HPA 23.
In general to prepare the compound HPA 23 in the form of its ammonium salt, an aqueous solution containing the SbII
ion is reacted hot with a lM solution of sodium tungstate and the reaction medium is kept substantially at neutrality by the ad-dition of concentrated ammonium hydroxide in a sufficient amount to make the medium colourless, which results in the precipitation of the desired ammonium salt which is recovered by filtration and subsequently treated in the usual manner.
The reaction temperature is less than the boiling temp-erature of the reaction medium, for example in the vicinity of 80C. The aqueous solution containing the SbI I ion is advan-tageously prepared by dissolving SbC13 in a saturated solution of NH4Cl.
As later studies have shown, the product HPA 23 is a heteropolyanion corresponding to the formula:
~ 9 21 8~
In the form of its ammonium salt, the product has the formula:
[Na Sb9 W21 8~ (NH4) 18~
and it can be in various forms, notably a hydrate with 8 mole-cules of water. ~
112~139 The present invention relates to novel heteropolyanion compounds in which the position of the sodium atom of the com-pound HPA 23 is vacant or occupied by other metallic ion. The invention also relates to such heteropolyanion compounds in their metallic form, that is to say the form of their salts with metals or with ammonium.
According to a first aspect, the invention relates there-fore to a novel general class of heteropolyanions of the formula (I) ~ 9 21 86~ (I) in which M can be absent or represent an alkali or alkaline-earth metal, other than sodium, and n is equal to 19 if M is absent, or to l9-p, if p is the charge of the M ion. The overall negative charge of the ion is hence equal to 19.
The polyion (I) can notably be isolated in the solid state in the form of its ammonium salt of formula (II) [ 9 21 8~ ( 4)19 (II) The IR spectrum of the compound (II) is shown in Figure 1 which has been divided into Figures la and lb for convenience of presentation (concentration 6/600 mg, phase KBr, apparatus Perkin-Elmer 225).
To prepare compound (II) an aqueous solution of ammonium tungstate is taken to which is added hot (60-80 C) a solution of Sb203 in HCl (or SbC13 in saturated NH4Cl), the addition of concentrated ammonia then causing, after removal of an insoluble part, the precipitation of the desired ammonium salt.
The aqueous solution of ammonium tungstate is prepared by reacting tungstic anhydride W03 at boiling temperature with ammonia.
The molar proportions to be respected between W03 and Sb203 are 4.5 to 5 moles of W03 per mole of Sb203.
llZ4989 Other compounds containing heteropolyanion of formula (I) correspond to formula (III) ~ 9 21 86~ 18 in which formula M represents an alkali or alkaline-earth metal other than sodium, such as potassium, calcium or magnesium and M' is an alkali metal such as cesium, rubidium or potassium or alkaline-earth metal, such as calcium or barium, or again ammon-ium or quartena~y ammonium.
In particular, the invention relates to a novel heter-opolyanion compound corresponding to the formula (IV) ~K Sb9 W21 8~ 18 (IV) This novel product may be considered as a 9-antimonio-III-21-tungsto-VI-potassium compound. It can occur as such or in the form of ammonium or metal salts, in particular of the alkali or alkaline-earth metals. A typical example is the ammonium salt of formula:
~ Sbg W21 86~ (NH4)18 Another particularly advantageous example is the potassium salt of the heteropolyanion (IV), this salt corresponding to the formula (VI) rK Sb9 W21 86~ K18 The compound (VI) decomposes above 340C. Its IR
spectrum is shown in Figure 2 of the accompanying drawings which have been divided into Figure 2a and 2b for convenience of presentation.
The IR spectrum obtained has been produced on a Beckmann IR-12 spectrophotometer with a KBr pastille.
The Raman spectrum of the compound (VI) is shown in Figure 3. The following data were used:
compound (VI) in powder form 5145 A 400 mW
interference filter llZ~9~9 PM 720 V resolution 4 cm speed 50 cm l/min Cod-rg PHO Spectrometer The polyanion (II) can be applied as such in the form of the distilled water solution. The polyanionic structure is however instable in the presence of metallic ions in aqueous solution and this observation enables the preparation according to a first process of other compounds according to the invention.
In this regard it will be noted that the compound HPA 23 de-scribed in copending application no. 205.780 can be obtained by the treatment of the polyanion (II) in aqueous solution by means of an 0.5 M solution of NaCl.
The compound (V) can be obtained from the polyanion (II)by treatment of the latter in aqueous solution by means of a solution of KCl, for example 0.5 M.
Other compounds according to the invention can be pre-pared in similar manner by the treatment of the polyanion (II) by means of a solution of a salt of the metal that it is desired to introduce into the ionic structure. By way of example, there may be mentioned the compound of magnesium obtained by treatment of the polyanion (II) with a solution of 0.5 M MgC12.
Of course, the compounds according to the invention can also be prepared by direct synthesis, as will be illustrated by the following examples.
The invented products can exist in the form of numerous hydrates.
All the hydrated forms of said products fall within the scope of the present invention.
The polyanion (IV) is composed of a central bicyclic cavity formed of Sb-O-W-O-Sb chains having at its centre a K+
ion. Around this cavity exist other atoms of W and Sb, the over-all ratio r=W/Sb being in the vicinity of 2.4.
The invention relates also to all the isomeric forms of the heteropolyanion concerned. It relates also to mixtures llZ~ 9 obtainable by conversion of heteropolyanion compounds under the influence of variations in the pH and in the nature of the solu-tions in which they are placed.
As has been previously noted, the heteropolyanion (II) is not stable in aqueous solution. To stabilise it, it should be placed in aqueous solution in the presence of metallic ions which are introducible inside the complex, these ions being preferably sodium, potassium, magnesium or calcium ions.
In aqueous medium containing potassium ions, in partic-ular a dilute aqueous solution of potassium chloride, the hetero-polyanion (II) provides compound V (ammonium salt).
The HPA 23 compound can also be subjected to an ionic exchange reaction in the course of which the potassium takes the place of the sodium and ammonium ions. This can be carried out simply by dissolving the compound HPA 23 in a concentrated aqueous solution of potassium chloride. In this way a mixture of the compound HPA 23, (V) and (VI) is obtained.
It is advantageous, however, to prepare the compound (VI) by a direct process starting from SbC13, KCl and K2W04.
According to this process, a first solution is prepared, containing the Sb ion, by dissolving SbC13 hot in a saturated aqueous solution of KCl, said first solution is added to a second solution consisting of an aqueous solution of K2WO4, the reaction temperature being from 60-90 C, in particular about 80C, and at the end of the reaction a saturated solution of potassium bi-carbonate is introduced until the reaction medium is colourless and its pH is about 7.
The compound (VI) precipitates in the course of the reaction and continues to deposit during cooling. For purifi-cation, the precipitate is filtered, then washed with a solution of KCl, for example 0.5 molar, and finally recrystallised in distilled water.
1~2~39 The proportions of the constituents of the reaction are selected so that the heteropolyanion corresponding to the com-pound (VI) is obtained. To this end, 1 part by weight of SbC13 is used per 3.4 parts of K2W04. For example, an aqueous molar solution of K2W04 is used and the corresponding amount of SbC13 must be dissolved in the saturated KCl solution, is calculated.
Thus the present invention provides a process for pro-ducing the heteropolyanion compound of the formula Mm Sb9 W21 86 M n (III') wherein M is selected from a group consisting of alkali metal ions other than sodium and alkaline earth metal ions, M' is selected from a group consisting of alkali metal ions, alkaline earth metal ions, ammonium and quaternary ammonium ion, m is 0 or 1 and n is l9-p, wherein p is the charge of said M ion, said process comprising adding to an aqueous solution of the tungstate of M' a solution containing SbIII ions, then adding concentrated ammonia or a saturated solution of a salt of M' to precipitate the compound of the formula III' wherein m is 0 and M' is ammonium or the compound of the formula III' wherein m is 1 and M and m are as hereinabove defined, and optionally reacting the compound of formula III' wherein m is 0 and M' is ammonium with an aqueous solution containing an alkali metal ion other than sodium or an alkaline earth metal ion to form the compound of the formula III'.
In a specific embodiment the invention provides a process for producing the compound of the formula Sb9 W21 8~ K ~ (VI) III
comprising preparing a first solution containing the Sb ions by dissolving SbC13 in a saturated aqueous solution of KCl, add-ing said first solution to a second solution consisting of an aqueous solution of K2W04, and introducing a saturated potassium bicarbonate solution until the reaction medium is colourless and its pH is in the vicinity of 7 to obtain the desired compound of formula VI.
~4,r 1~ - 6 -llZ~9~39 In a further embodiment the present invention provides a process for producing the compound of the formula ~ Sbg W21 o ~ (NH4)18 (V) comprising adding to an aqueous solution of ammonium tungstate a solution of antimony trioxide Sb203 in HCl, then adding concen-trated ammonia to precipitate the desired ammonium salt, and treating the obtained ammonium salt in an aqueous solution by means of a solution of KCl in order to obtain compound of formula V.
The following examples illustrate the invention without being in any way limiting.
Preparation of ¦Sb9 21 ~ ( 4)19 : compound of formula (II) An aqueous solution of ammonium tungstate is prepared by reacting at boiling temperature 81 g of tungstic anhydride (W03) with NH3 (1 liter of 1.2 molar ammonia).
To this solution, is added gradually at 80C, a solution obtained by dissolving 21;8 g of antimony trioxide (Sb203) in 100 ml of 6 M HCl.
At the end of the operation, about 20 ml of 12 M NH3 are added. An insoluble precipitate forms and it is filtered hot rapidly. The ammonium salt ~b9 W21 0 ~ ~NH4)19 crystallises in the course of cooling from the supernatent solution.
The crystals obtained are filtered and then washed with a saturated solution of NH4Cl.
Preparation of the compound K Sb9 W21 86 K18 : compound of formula (VI) A solution containing 12.2 g of SbC13 dissolved hot in 50 ml of a saturated solution of KCl is added gradually to 125 ml of an aqueous molar solution of K2W04 previously brought to 80 C.
At the end of the operation, about 20 ml of a saturated solution llZ49~9 of potassium kicarbonate îs added, so that the mixture is colour-less and its pH close to 7.
The potassium salt of the heteropolyanion precipitates in the course of the preparation and continues to deposit during cooling. The precipitate is filtered and then washed with a solution of 0.5 molar KCl and finally recrystallised in distilled water. In this way about 25 g of the compound (VI) of the formula indicated above are obtained. Its IR and Raman spectra are shown in Figures 2 and 3 respectively.
The present invention relates also to the application of the heteropolyanion compounds of formulas (II) and (III), in particular the compound (VI), denoted below by the abbreviated reference HPA 39, as medicament for the preventive and curative treatment of viral infections in man and in animals and of the pathological processes due to viruses. Thus, the invention also relates to pharmaceutical compositions containing, as active agents, the heteropolyanion (III) compounds, in particular the compound HPA 39, in association with pharmaceutically acceptable vehicle. In a particular embodiment, the pharmaceutical compo-sitions according to the invention are conditioned in injectable form, for example in aqueous solution (physiological solution) at a pH in the neighbourhood of neutrality, for injection into man or into animal.
In the first pharmacological tests reported below, the heteropolyanion applied is the product of formula (VI) denoted by the abbreviated reference HPA 39. The activity of HPA 39 was compared with the sodium compound of the formula ~ a Sbg W21 8~ (NH4) 18' the latter compound being denoted by the abbreviation HPA 23.
The tests were applied to the treatment of viruses of ~riend's leukemia.
11249t39 Pharmacological Tests In the experiments, DBA2 mice, male or female, aged from
The invention also relates to pharmaceutical compositions con-taining a therapeutically effective amount of at least one of said compounds.
Co-pending patent application no. 205.780 relates to heteropolyanions possessing anti-viral properties, in particular a compound of tungsten and antimony denoted by the reference HPA 23.
In general to prepare the compound HPA 23 in the form of its ammonium salt, an aqueous solution containing the SbII
ion is reacted hot with a lM solution of sodium tungstate and the reaction medium is kept substantially at neutrality by the ad-dition of concentrated ammonium hydroxide in a sufficient amount to make the medium colourless, which results in the precipitation of the desired ammonium salt which is recovered by filtration and subsequently treated in the usual manner.
The reaction temperature is less than the boiling temp-erature of the reaction medium, for example in the vicinity of 80C. The aqueous solution containing the SbI I ion is advan-tageously prepared by dissolving SbC13 in a saturated solution of NH4Cl.
As later studies have shown, the product HPA 23 is a heteropolyanion corresponding to the formula:
~ 9 21 8~
In the form of its ammonium salt, the product has the formula:
[Na Sb9 W21 8~ (NH4) 18~
and it can be in various forms, notably a hydrate with 8 mole-cules of water. ~
112~139 The present invention relates to novel heteropolyanion compounds in which the position of the sodium atom of the com-pound HPA 23 is vacant or occupied by other metallic ion. The invention also relates to such heteropolyanion compounds in their metallic form, that is to say the form of their salts with metals or with ammonium.
According to a first aspect, the invention relates there-fore to a novel general class of heteropolyanions of the formula (I) ~ 9 21 86~ (I) in which M can be absent or represent an alkali or alkaline-earth metal, other than sodium, and n is equal to 19 if M is absent, or to l9-p, if p is the charge of the M ion. The overall negative charge of the ion is hence equal to 19.
The polyion (I) can notably be isolated in the solid state in the form of its ammonium salt of formula (II) [ 9 21 8~ ( 4)19 (II) The IR spectrum of the compound (II) is shown in Figure 1 which has been divided into Figures la and lb for convenience of presentation (concentration 6/600 mg, phase KBr, apparatus Perkin-Elmer 225).
To prepare compound (II) an aqueous solution of ammonium tungstate is taken to which is added hot (60-80 C) a solution of Sb203 in HCl (or SbC13 in saturated NH4Cl), the addition of concentrated ammonia then causing, after removal of an insoluble part, the precipitation of the desired ammonium salt.
The aqueous solution of ammonium tungstate is prepared by reacting tungstic anhydride W03 at boiling temperature with ammonia.
The molar proportions to be respected between W03 and Sb203 are 4.5 to 5 moles of W03 per mole of Sb203.
llZ4989 Other compounds containing heteropolyanion of formula (I) correspond to formula (III) ~ 9 21 86~ 18 in which formula M represents an alkali or alkaline-earth metal other than sodium, such as potassium, calcium or magnesium and M' is an alkali metal such as cesium, rubidium or potassium or alkaline-earth metal, such as calcium or barium, or again ammon-ium or quartena~y ammonium.
In particular, the invention relates to a novel heter-opolyanion compound corresponding to the formula (IV) ~K Sb9 W21 8~ 18 (IV) This novel product may be considered as a 9-antimonio-III-21-tungsto-VI-potassium compound. It can occur as such or in the form of ammonium or metal salts, in particular of the alkali or alkaline-earth metals. A typical example is the ammonium salt of formula:
~ Sbg W21 86~ (NH4)18 Another particularly advantageous example is the potassium salt of the heteropolyanion (IV), this salt corresponding to the formula (VI) rK Sb9 W21 86~ K18 The compound (VI) decomposes above 340C. Its IR
spectrum is shown in Figure 2 of the accompanying drawings which have been divided into Figure 2a and 2b for convenience of presentation.
The IR spectrum obtained has been produced on a Beckmann IR-12 spectrophotometer with a KBr pastille.
The Raman spectrum of the compound (VI) is shown in Figure 3. The following data were used:
compound (VI) in powder form 5145 A 400 mW
interference filter llZ~9~9 PM 720 V resolution 4 cm speed 50 cm l/min Cod-rg PHO Spectrometer The polyanion (II) can be applied as such in the form of the distilled water solution. The polyanionic structure is however instable in the presence of metallic ions in aqueous solution and this observation enables the preparation according to a first process of other compounds according to the invention.
In this regard it will be noted that the compound HPA 23 de-scribed in copending application no. 205.780 can be obtained by the treatment of the polyanion (II) in aqueous solution by means of an 0.5 M solution of NaCl.
The compound (V) can be obtained from the polyanion (II)by treatment of the latter in aqueous solution by means of a solution of KCl, for example 0.5 M.
Other compounds according to the invention can be pre-pared in similar manner by the treatment of the polyanion (II) by means of a solution of a salt of the metal that it is desired to introduce into the ionic structure. By way of example, there may be mentioned the compound of magnesium obtained by treatment of the polyanion (II) with a solution of 0.5 M MgC12.
Of course, the compounds according to the invention can also be prepared by direct synthesis, as will be illustrated by the following examples.
The invented products can exist in the form of numerous hydrates.
All the hydrated forms of said products fall within the scope of the present invention.
The polyanion (IV) is composed of a central bicyclic cavity formed of Sb-O-W-O-Sb chains having at its centre a K+
ion. Around this cavity exist other atoms of W and Sb, the over-all ratio r=W/Sb being in the vicinity of 2.4.
The invention relates also to all the isomeric forms of the heteropolyanion concerned. It relates also to mixtures llZ~ 9 obtainable by conversion of heteropolyanion compounds under the influence of variations in the pH and in the nature of the solu-tions in which they are placed.
As has been previously noted, the heteropolyanion (II) is not stable in aqueous solution. To stabilise it, it should be placed in aqueous solution in the presence of metallic ions which are introducible inside the complex, these ions being preferably sodium, potassium, magnesium or calcium ions.
In aqueous medium containing potassium ions, in partic-ular a dilute aqueous solution of potassium chloride, the hetero-polyanion (II) provides compound V (ammonium salt).
The HPA 23 compound can also be subjected to an ionic exchange reaction in the course of which the potassium takes the place of the sodium and ammonium ions. This can be carried out simply by dissolving the compound HPA 23 in a concentrated aqueous solution of potassium chloride. In this way a mixture of the compound HPA 23, (V) and (VI) is obtained.
It is advantageous, however, to prepare the compound (VI) by a direct process starting from SbC13, KCl and K2W04.
According to this process, a first solution is prepared, containing the Sb ion, by dissolving SbC13 hot in a saturated aqueous solution of KCl, said first solution is added to a second solution consisting of an aqueous solution of K2WO4, the reaction temperature being from 60-90 C, in particular about 80C, and at the end of the reaction a saturated solution of potassium bi-carbonate is introduced until the reaction medium is colourless and its pH is about 7.
The compound (VI) precipitates in the course of the reaction and continues to deposit during cooling. For purifi-cation, the precipitate is filtered, then washed with a solution of KCl, for example 0.5 molar, and finally recrystallised in distilled water.
1~2~39 The proportions of the constituents of the reaction are selected so that the heteropolyanion corresponding to the com-pound (VI) is obtained. To this end, 1 part by weight of SbC13 is used per 3.4 parts of K2W04. For example, an aqueous molar solution of K2W04 is used and the corresponding amount of SbC13 must be dissolved in the saturated KCl solution, is calculated.
Thus the present invention provides a process for pro-ducing the heteropolyanion compound of the formula Mm Sb9 W21 86 M n (III') wherein M is selected from a group consisting of alkali metal ions other than sodium and alkaline earth metal ions, M' is selected from a group consisting of alkali metal ions, alkaline earth metal ions, ammonium and quaternary ammonium ion, m is 0 or 1 and n is l9-p, wherein p is the charge of said M ion, said process comprising adding to an aqueous solution of the tungstate of M' a solution containing SbIII ions, then adding concentrated ammonia or a saturated solution of a salt of M' to precipitate the compound of the formula III' wherein m is 0 and M' is ammonium or the compound of the formula III' wherein m is 1 and M and m are as hereinabove defined, and optionally reacting the compound of formula III' wherein m is 0 and M' is ammonium with an aqueous solution containing an alkali metal ion other than sodium or an alkaline earth metal ion to form the compound of the formula III'.
In a specific embodiment the invention provides a process for producing the compound of the formula Sb9 W21 8~ K ~ (VI) III
comprising preparing a first solution containing the Sb ions by dissolving SbC13 in a saturated aqueous solution of KCl, add-ing said first solution to a second solution consisting of an aqueous solution of K2W04, and introducing a saturated potassium bicarbonate solution until the reaction medium is colourless and its pH is in the vicinity of 7 to obtain the desired compound of formula VI.
~4,r 1~ - 6 -llZ~9~39 In a further embodiment the present invention provides a process for producing the compound of the formula ~ Sbg W21 o ~ (NH4)18 (V) comprising adding to an aqueous solution of ammonium tungstate a solution of antimony trioxide Sb203 in HCl, then adding concen-trated ammonia to precipitate the desired ammonium salt, and treating the obtained ammonium salt in an aqueous solution by means of a solution of KCl in order to obtain compound of formula V.
The following examples illustrate the invention without being in any way limiting.
Preparation of ¦Sb9 21 ~ ( 4)19 : compound of formula (II) An aqueous solution of ammonium tungstate is prepared by reacting at boiling temperature 81 g of tungstic anhydride (W03) with NH3 (1 liter of 1.2 molar ammonia).
To this solution, is added gradually at 80C, a solution obtained by dissolving 21;8 g of antimony trioxide (Sb203) in 100 ml of 6 M HCl.
At the end of the operation, about 20 ml of 12 M NH3 are added. An insoluble precipitate forms and it is filtered hot rapidly. The ammonium salt ~b9 W21 0 ~ ~NH4)19 crystallises in the course of cooling from the supernatent solution.
The crystals obtained are filtered and then washed with a saturated solution of NH4Cl.
Preparation of the compound K Sb9 W21 86 K18 : compound of formula (VI) A solution containing 12.2 g of SbC13 dissolved hot in 50 ml of a saturated solution of KCl is added gradually to 125 ml of an aqueous molar solution of K2W04 previously brought to 80 C.
At the end of the operation, about 20 ml of a saturated solution llZ49~9 of potassium kicarbonate îs added, so that the mixture is colour-less and its pH close to 7.
The potassium salt of the heteropolyanion precipitates in the course of the preparation and continues to deposit during cooling. The precipitate is filtered and then washed with a solution of 0.5 molar KCl and finally recrystallised in distilled water. In this way about 25 g of the compound (VI) of the formula indicated above are obtained. Its IR and Raman spectra are shown in Figures 2 and 3 respectively.
The present invention relates also to the application of the heteropolyanion compounds of formulas (II) and (III), in particular the compound (VI), denoted below by the abbreviated reference HPA 39, as medicament for the preventive and curative treatment of viral infections in man and in animals and of the pathological processes due to viruses. Thus, the invention also relates to pharmaceutical compositions containing, as active agents, the heteropolyanion (III) compounds, in particular the compound HPA 39, in association with pharmaceutically acceptable vehicle. In a particular embodiment, the pharmaceutical compo-sitions according to the invention are conditioned in injectable form, for example in aqueous solution (physiological solution) at a pH in the neighbourhood of neutrality, for injection into man or into animal.
In the first pharmacological tests reported below, the heteropolyanion applied is the product of formula (VI) denoted by the abbreviated reference HPA 39. The activity of HPA 39 was compared with the sodium compound of the formula ~ a Sbg W21 8~ (NH4) 18' the latter compound being denoted by the abbreviation HPA 23.
The tests were applied to the treatment of viruses of ~riend's leukemia.
11249t39 Pharmacological Tests In the experiments, DBA2 mice, male or female, aged from
2 to 3 months, of a weight close to 20 g were used.
A polycythemia strain of Friend's virus (VFP) was used maintained for some years in the laboratory. The viral stock was constituted by an acellular supernatent liquid obtained by cen-trifugation of ground leukemic spleens, formed in a 0.5 M PBS-saccharose solution. Titration of the stock was done in vivo, according to the method of Reed and Meunch (American Journal of Hygiene 1938, 27, 493-497). The measurement was expressed as SD50 ( Spleen enlarging dose 50%").
Experimental Procedure:
The Friend's virus was injected in the mouse by the intra-peritoneal route. The animal then developed a characteristic splenomegaly. Death appearing three weeks after the viral innoc-ulation, at the doses normally employed, the animals were sacri-ficed on the 21st day after infection, for study of the splenomegaly. The spleens were taken out and then weighed indi-vidually. Any spleen whose weight exceeded 250 mg was considered as pathological.
The HPA 23 and HPA 39 heteropolyanions were diluted usually in physiological serum or distilled water.
They were administered like the virus by the intraper-itoneal route in a single dose or in repeated doses at times varied with respect to the viral innoculation period.
Results: 1. Protective Effect of HPA 39 against Friend's Leukemia.
Table 1 below summarises the results of two consecutive experiments wherein the mice, innoculated with 20 SD50 of VFP, received a single dose of HPA 39 ranging from 0.5 mg to 2 mg, the same day as the virus.
The survival percentage was established on the 62nd day after the viral injection.
_g_ ~1249~B9 2. Study of the Response to HPA 39 as a function of the Innoculated Vira'L Dose.
-From the point of view of the splenomegaly, a study wasmade of the effect of a single injection of 2 mg of HPA 39 in the case where the animals were innoculated with increasing doses of VFP ranging from 5 to 50 SD50 per animal.
The results are summarised in the following Table II.
A polycythemia strain of Friend's virus (VFP) was used maintained for some years in the laboratory. The viral stock was constituted by an acellular supernatent liquid obtained by cen-trifugation of ground leukemic spleens, formed in a 0.5 M PBS-saccharose solution. Titration of the stock was done in vivo, according to the method of Reed and Meunch (American Journal of Hygiene 1938, 27, 493-497). The measurement was expressed as SD50 ( Spleen enlarging dose 50%").
Experimental Procedure:
The Friend's virus was injected in the mouse by the intra-peritoneal route. The animal then developed a characteristic splenomegaly. Death appearing three weeks after the viral innoc-ulation, at the doses normally employed, the animals were sacri-ficed on the 21st day after infection, for study of the splenomegaly. The spleens were taken out and then weighed indi-vidually. Any spleen whose weight exceeded 250 mg was considered as pathological.
The HPA 23 and HPA 39 heteropolyanions were diluted usually in physiological serum or distilled water.
They were administered like the virus by the intraper-itoneal route in a single dose or in repeated doses at times varied with respect to the viral innoculation period.
Results: 1. Protective Effect of HPA 39 against Friend's Leukemia.
Table 1 below summarises the results of two consecutive experiments wherein the mice, innoculated with 20 SD50 of VFP, received a single dose of HPA 39 ranging from 0.5 mg to 2 mg, the same day as the virus.
The survival percentage was established on the 62nd day after the viral injection.
_g_ ~1249~B9 2. Study of the Response to HPA 39 as a function of the Innoculated Vira'L Dose.
-From the point of view of the splenomegaly, a study wasmade of the effect of a single injection of 2 mg of HPA 39 in the case where the animals were innoculated with increasing doses of VFP ranging from 5 to 50 SD50 per animal.
The results are summarised in the following Table II.
3. Test of Treatment of Friend's Leukemia by Repeated Injections of HPA 39.
In this experiment, animals previously innoculated with 20 SD50 of VFP were used. The effect of 5-day treatments com-prising one daily injection of 0.5 mg of HPA 39, were studied.
Day 0 (Do) being the day of infection, three periods were selected:
from D + 3 to D + 7, from D + 10 to D + 14, from D + 17 to D + 21.
In order to know the stage of the disease at the beginning of each treatment, 10 control animals were sacrificed on days +lO
and +17.
In parallel, the toxicity of this treatment on non-leukemic animals was studied. Although the short-term toxicity seems very low, it should be noted that, 60 days after the end of the treatment, 50% of these animals died.
Table III below gives the average value of the spleen weight 21 days after infection, as well as the average weight of the spleens at the beginning of each treatment.
In this experiment, animals previously innoculated with 20 SD50 of VFP were used. The effect of 5-day treatments com-prising one daily injection of 0.5 mg of HPA 39, were studied.
Day 0 (Do) being the day of infection, three periods were selected:
from D + 3 to D + 7, from D + 10 to D + 14, from D + 17 to D + 21.
In order to know the stage of the disease at the beginning of each treatment, 10 control animals were sacrificed on days +lO
and +17.
In parallel, the toxicity of this treatment on non-leukemic animals was studied. Although the short-term toxicity seems very low, it should be noted that, 60 days after the end of the treatment, 50% of these animals died.
Table III below gives the average value of the spleen weight 21 days after infection, as well as the average weight of the spleens at the beginning of each treatment.
4. Comparative Test of HPA 23 and HPA 39 on Splenomegaly induced by the VFP.
Table IV below summarises the results obtained with a single injection of 1 mg of each of these products on the splen-omegaly induced by VFP 21 days after the injection of 20 SD50.
TABLE I
Effect of HPA 39 on Friend's Leukemia-/
~12~E~
Dose HPA 39 Average weight Limiting Survival Toxicity injected of spleens (g) values % t*) D + 21 (g) D + 21 0 exp 1 = 1.349 0.402-~2.63 NF
exp 2 = 0.897 0.390-~1.598 40 0.5 mg per exp 1 = N.F. N.F. NF
mouse IP exp 2 = 0.711 0.211-~2.036 70 1 mg per exp 1 = 0.3220.252-~0.443 NF
mouse IP exp 2 = 0.258 0.190-~0.348 100 2 mg per exp 1 = 0.3080.225-~0.405 NF
mouse IP exp 2 = 0.262 0.208-~0.291 100 * The to~icity represents the percentage of mortality in lots of 10 non-leukemic animals treated with a dose as indicated.
TABLE II
Dose-effect Relationship of HPA 39 with respect to VFP
Viral HPA 39 Average Spleen Limiting ~alues Innoculum injected Weights (g) (g) (IP) (mg IP)
Table IV below summarises the results obtained with a single injection of 1 mg of each of these products on the splen-omegaly induced by VFP 21 days after the injection of 20 SD50.
TABLE I
Effect of HPA 39 on Friend's Leukemia-/
~12~E~
Dose HPA 39 Average weight Limiting Survival Toxicity injected of spleens (g) values % t*) D + 21 (g) D + 21 0 exp 1 = 1.349 0.402-~2.63 NF
exp 2 = 0.897 0.390-~1.598 40 0.5 mg per exp 1 = N.F. N.F. NF
mouse IP exp 2 = 0.711 0.211-~2.036 70 1 mg per exp 1 = 0.3220.252-~0.443 NF
mouse IP exp 2 = 0.258 0.190-~0.348 100 2 mg per exp 1 = 0.3080.225-~0.405 NF
mouse IP exp 2 = 0.262 0.208-~0.291 100 * The to~icity represents the percentage of mortality in lots of 10 non-leukemic animals treated with a dose as indicated.
TABLE II
Dose-effect Relationship of HPA 39 with respect to VFP
Viral HPA 39 Average Spleen Limiting ~alues Innoculum injected Weights (g) (g) (IP) (mg IP)
5 SD50 0 0.6190.228-_1.552 2 0.2530.158-~0.310 10 SD50 0.7260.323-~0.979 2 0.2690.160-~0.331 20 SD50 0 1.0520.239-~1.989 2 0.4090.233-~0.412 50 SD50 1.6511.328-~2.180 2 0.3500.113-~0.721 ~lZ4~8"
TABLE III
Effect of HPA 39 in the Treatment of Friend's Leukemia Period of Average Spleen Average Spleen Limiting Treatment Weight at the Weight (g) Values (5x0.5 mg) beginning of D + 21(g) the Treatment 0 1.2020.408-~2.594 D + 3-~D + 7 not done 0.610* 0.204-~1.577 D + 10-~D + 14 0.204 0.656* 0.250-~1.250 D + 17-~D + 21 0.500 0.532** 0.263-~0.988 *The increase in weight of the spleen manifests the continuing development of the leukemia.
**Arrest of the leukemia.
TABLE IV
Comparative Anti-viral Effect of HPA 23 and HPA 39: structure-activity relationship TreatmentAverage Spleen Limiting (1 mg - IP) Weight Values (g) 01.426 0.740-~2.063 HPA 230.320 0.222-~0.391 HPA 390.294 0.259-~0.335 The results reported in Table IV show that the products HPA 23 and HPA 39 result in a very marked reduction in splen-omegaly, which demonstrates their effectiveness in inhibiting the development of Friend's leukemia. In addition, HPA 39 manifests an activity higher than that of HPA 23.
As a whole, the above results make it evident that HPA 39, administered to mice infected with Friend's leukemia virus, show no effect of toxicity. HPA 39 arrests the development of the leukemia: thus, a dose of 2 mg of HPA 39 per mouse permits, for 1~2~39 100% of the infected mice, survival up to the 62nd day, the day at which they were sacrificed.
An advantageous property of the product HPA 39 has also been established, namely that this product possesses a synergic action when it is administered at the same time as interferon.
To prove this synergy of HPA-interferon, four groups of mice were used and the products tested were administered under the following conditions:
Interferon: pre-treatment 6 hours before infection - intraperi-10toneal route 5000 U/mouse.
HPA 39: 3 mg/mouse - intraperitoneal route immediately after the innoculation of the virus.
Encephalomyocarditis virus of the mouse - 50 lethal dose/mouse;
innoculation subcutaneous route (SC) Group I: 10 mice received the virus and served as controls Group II: 10 mice received interferon and, 6 hours afterwards, the virus Group III: 10 mice received the virus by the SC route and HPA 39 20by the intraperitoneal route Group IV: 10 mice received interferon and then, 6 hours after-wards, the virus and HPA 39.
Results on the 15th Day Mortality Group I: Control 8/10 Group II: Interferon alone 8/10 Group III: HPA 39 alone 8/10 Group IV: HPA 39 + interferon 3/10 The results recorded above show clearly the superiority of the HPA 39-interferon association with respect to the results ob-tained with one of the substances alone.
Other "in vivo" tests were carried out to test various products according to the invention and various comparison llZ~9~9 products of the prior art for their preventive action against Friend's virus-induced leukemia in the DBA-2 mouse (according to the technique described above).
By way of comparison HPA 23 and two organic cryptates were tested:
Cryptofix 222*(Merck): formula C18H36N206 (MW: 376) Cryptofix 211*(Merck): formula C14H29N206 (MW: 288.35) To gr~ups of ten DBA 2 mice previously innoculated with Friend's virus, were administered each of the products described in the dose of 1 mg per mouse. The control group only received the virus.
The mice were sacrificed 21 days after the innoculation of the virus. The spleens were taken out and then weighed individ-ually. Each spleen weighing more than 250 mg was considered as leukemic. The results of these experiments are assembled in Table V. As this Table shows, all the products according to the invention are capable of reducing in the mouse, splenomegaly induced by Friend's virus, although the known cryptates are in-active, and even toxic.
In addition, the compound (VI) or HPA 39 is more active than HPA 23.
Further pharmacological tests were performed for testing the in vivo activity of the HPA 39 compound.
1. FRIEND'S LEUKEMIA
Friend's leukemia is induced in a DBA2 mouse by the poly-cythemiant strain of virus.
The criteria selected to follow the development of the disease were splenomegaly and survival.
The animals were sacrificed 21 days after injection of the virus. The spleens were taken out and weighed individually.
* Trademarks ~12~39 EEfect of HPA 39 on Splenomegaly As shown in Table VI, HPA 39, injected in a single dose by the intraperitoneal route the same day as the virus (20 SD50), considerably reduced splenomegaly. In this experiment, the doses ranged from 1 to 5 mg. These three doses had substantially the same activity. It is noted, however, that there is a certain toxicity at 5 mg.
Table VII summarises an experiment where HPA was tested, under the same conditions as previously, against increasing doses of virus. It is clear that, whatever the viral innoculum, HPA 39 preserves all its activity.
Effect of HPA 39-on Survival The survival was followed of groups of animals (20) in-noculated by 20 SD50 of virus and treated the same day, by a single dose of HPA 39 of 0.5, 1, and 2 mg.
The median survival of the control group was 56 days, that of the group treated by 0.5 mg, 128 days, that of the group treated by 1 mg, 151 days, and finally, that of the group treated by 2 mg, 108 days.
200 days after the beginning of the experiment, 25~ of the animals treated by 1 or 2 mg were still living.
Time of Action of HPA 39 Table VIII shows the results of treatment tests by HPA 39 on splenomegaly.
The animals all received Do of the experiment, 20 SD50 of Friend's virus. In the first part of the Table, tests of sequen-tial treatments of 5 injections of 0.5 mg per day of HPA 39 are reported.
Under these conditions, HPA 39 preserves notable activity on splenomegaly, but less important than after a single injection of the substance the same day as the virus. In the second part of Table VIII, tests of the effect of a single dose of 2 mg of sub-stance injected on different days with respect to the viral '., ~S--11249~9 innoculation are reported.
Only one injection 2 days after the virus preserved a certain effectiveness, but however the protection level obtained is less than that obtained on injections effected the same day as the virus.
Effect of HPA 39 on the Intrasplenic Virus Ratio Compared were the virus ratio in the spleen of the control animals with that found in the spleen of the animals treated at Do by a dose of HPA 39. Although the treated animals had a spleen weight very much less than the controls, the virus level is com-parable in the two groups. The technique used had been the S+L-titration of ground spleen.
II. ENCEPHALOMYOCARDITIS
The effect of HPA 39 on the lethal effect of encephal-omyocarditis virus in the mouse was also tested.
Strains V77 L3 and S3 (passage in the culture for the strain L3 and in vivo for the strain S3),VR129 L3 and S3 were used.
The substance was injected in a single dose (3 mg) by the intraperitoneal route 30 minutes before the innoculation of 50 LD50 of virus which, itself, is done by the subcutaneous route.
A distinct increase in the number of animals surviving was observed relative to the control animals which had not received an injection of HPA 39.
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11249~9 _ ~a~
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112~39 TAB~E VI~
HPA 39: EFFECT ON SPLENOMEGALY INDUCED BY DIFFERENT DOSES
OF FRIEND'S VIRUS.
Friend's HPA 39 Average WeightLimits Virus of Spleen (g) (g) 5 SD 0.619+0.427 1 551 2 mg 0.253+0.043 0 3510 10 SD50 0.697+0.268 1 120 2 mg 0.269+0.050 o:336 .
O 1.102+0.644 10 2909 20 S~50 2 mg 0.409+0.298 1 2413 l . .
O 1.651+0 r 535 2 0814 2 mg 0.350+0.155 0 278 . 20 .
., . ,, . .. . .. , . ~ .. . ..
l~Z4989 TABLE VIII
HPA 39: EFFECT OF VARIOUS TREATMENTS ON SPLENOMEGALY
INDUCED BY FRIENDS VIRUS.
Treatment Dose Average Weight of Limiting Spleen ~ type Values Deviation 0 1.202+0.6430.488-2.5943 D~ ~ D17 5 x 0.5 mg 0.610+0.4400.204 - 1.577 ~lO ~14 5 x 0.5 ~g 0.658+0.2990.250 - 1.250 ~17 21 5 x 0.5 mg 0.532+0.289o, Z 63_D,95~
0 1.438+0.5500.727-2.493 ~0 ~ 2 mg 0.244+0.0400.185-0.308 D 7 2 mg 1.488+0.4a30.762-2.033 ....
D 4 2 mg 1.827+0.3041.221-2.170 D_2 2 mg 1.668+0.5690.764-2.233 .
D+2 2 mg 0.560+0.3780.202-1.270 . .. .. .
D~4 2 mg 1.179+0.5480.257-1.748 .
D+7 2 mg 1.17G+0.7400.390-2.402 . 21 .
TABLE III
Effect of HPA 39 in the Treatment of Friend's Leukemia Period of Average Spleen Average Spleen Limiting Treatment Weight at the Weight (g) Values (5x0.5 mg) beginning of D + 21(g) the Treatment 0 1.2020.408-~2.594 D + 3-~D + 7 not done 0.610* 0.204-~1.577 D + 10-~D + 14 0.204 0.656* 0.250-~1.250 D + 17-~D + 21 0.500 0.532** 0.263-~0.988 *The increase in weight of the spleen manifests the continuing development of the leukemia.
**Arrest of the leukemia.
TABLE IV
Comparative Anti-viral Effect of HPA 23 and HPA 39: structure-activity relationship TreatmentAverage Spleen Limiting (1 mg - IP) Weight Values (g) 01.426 0.740-~2.063 HPA 230.320 0.222-~0.391 HPA 390.294 0.259-~0.335 The results reported in Table IV show that the products HPA 23 and HPA 39 result in a very marked reduction in splen-omegaly, which demonstrates their effectiveness in inhibiting the development of Friend's leukemia. In addition, HPA 39 manifests an activity higher than that of HPA 23.
As a whole, the above results make it evident that HPA 39, administered to mice infected with Friend's leukemia virus, show no effect of toxicity. HPA 39 arrests the development of the leukemia: thus, a dose of 2 mg of HPA 39 per mouse permits, for 1~2~39 100% of the infected mice, survival up to the 62nd day, the day at which they were sacrificed.
An advantageous property of the product HPA 39 has also been established, namely that this product possesses a synergic action when it is administered at the same time as interferon.
To prove this synergy of HPA-interferon, four groups of mice were used and the products tested were administered under the following conditions:
Interferon: pre-treatment 6 hours before infection - intraperi-10toneal route 5000 U/mouse.
HPA 39: 3 mg/mouse - intraperitoneal route immediately after the innoculation of the virus.
Encephalomyocarditis virus of the mouse - 50 lethal dose/mouse;
innoculation subcutaneous route (SC) Group I: 10 mice received the virus and served as controls Group II: 10 mice received interferon and, 6 hours afterwards, the virus Group III: 10 mice received the virus by the SC route and HPA 39 20by the intraperitoneal route Group IV: 10 mice received interferon and then, 6 hours after-wards, the virus and HPA 39.
Results on the 15th Day Mortality Group I: Control 8/10 Group II: Interferon alone 8/10 Group III: HPA 39 alone 8/10 Group IV: HPA 39 + interferon 3/10 The results recorded above show clearly the superiority of the HPA 39-interferon association with respect to the results ob-tained with one of the substances alone.
Other "in vivo" tests were carried out to test various products according to the invention and various comparison llZ~9~9 products of the prior art for their preventive action against Friend's virus-induced leukemia in the DBA-2 mouse (according to the technique described above).
By way of comparison HPA 23 and two organic cryptates were tested:
Cryptofix 222*(Merck): formula C18H36N206 (MW: 376) Cryptofix 211*(Merck): formula C14H29N206 (MW: 288.35) To gr~ups of ten DBA 2 mice previously innoculated with Friend's virus, were administered each of the products described in the dose of 1 mg per mouse. The control group only received the virus.
The mice were sacrificed 21 days after the innoculation of the virus. The spleens were taken out and then weighed individ-ually. Each spleen weighing more than 250 mg was considered as leukemic. The results of these experiments are assembled in Table V. As this Table shows, all the products according to the invention are capable of reducing in the mouse, splenomegaly induced by Friend's virus, although the known cryptates are in-active, and even toxic.
In addition, the compound (VI) or HPA 39 is more active than HPA 23.
Further pharmacological tests were performed for testing the in vivo activity of the HPA 39 compound.
1. FRIEND'S LEUKEMIA
Friend's leukemia is induced in a DBA2 mouse by the poly-cythemiant strain of virus.
The criteria selected to follow the development of the disease were splenomegaly and survival.
The animals were sacrificed 21 days after injection of the virus. The spleens were taken out and weighed individually.
* Trademarks ~12~39 EEfect of HPA 39 on Splenomegaly As shown in Table VI, HPA 39, injected in a single dose by the intraperitoneal route the same day as the virus (20 SD50), considerably reduced splenomegaly. In this experiment, the doses ranged from 1 to 5 mg. These three doses had substantially the same activity. It is noted, however, that there is a certain toxicity at 5 mg.
Table VII summarises an experiment where HPA was tested, under the same conditions as previously, against increasing doses of virus. It is clear that, whatever the viral innoculum, HPA 39 preserves all its activity.
Effect of HPA 39-on Survival The survival was followed of groups of animals (20) in-noculated by 20 SD50 of virus and treated the same day, by a single dose of HPA 39 of 0.5, 1, and 2 mg.
The median survival of the control group was 56 days, that of the group treated by 0.5 mg, 128 days, that of the group treated by 1 mg, 151 days, and finally, that of the group treated by 2 mg, 108 days.
200 days after the beginning of the experiment, 25~ of the animals treated by 1 or 2 mg were still living.
Time of Action of HPA 39 Table VIII shows the results of treatment tests by HPA 39 on splenomegaly.
The animals all received Do of the experiment, 20 SD50 of Friend's virus. In the first part of the Table, tests of sequen-tial treatments of 5 injections of 0.5 mg per day of HPA 39 are reported.
Under these conditions, HPA 39 preserves notable activity on splenomegaly, but less important than after a single injection of the substance the same day as the virus. In the second part of Table VIII, tests of the effect of a single dose of 2 mg of sub-stance injected on different days with respect to the viral '., ~S--11249~9 innoculation are reported.
Only one injection 2 days after the virus preserved a certain effectiveness, but however the protection level obtained is less than that obtained on injections effected the same day as the virus.
Effect of HPA 39 on the Intrasplenic Virus Ratio Compared were the virus ratio in the spleen of the control animals with that found in the spleen of the animals treated at Do by a dose of HPA 39. Although the treated animals had a spleen weight very much less than the controls, the virus level is com-parable in the two groups. The technique used had been the S+L-titration of ground spleen.
II. ENCEPHALOMYOCARDITIS
The effect of HPA 39 on the lethal effect of encephal-omyocarditis virus in the mouse was also tested.
Strains V77 L3 and S3 (passage in the culture for the strain L3 and in vivo for the strain S3),VR129 L3 and S3 were used.
The substance was injected in a single dose (3 mg) by the intraperitoneal route 30 minutes before the innoculation of 50 LD50 of virus which, itself, is done by the subcutaneous route.
A distinct increase in the number of animals surviving was observed relative to the control animals which had not received an injection of HPA 39.
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1124~9 (1) Polyanion (II) signifie~ the polyanion [Sbg W21 86~
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11249~9 _ ~a~
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112~39 TAB~E VI~
HPA 39: EFFECT ON SPLENOMEGALY INDUCED BY DIFFERENT DOSES
OF FRIEND'S VIRUS.
Friend's HPA 39 Average WeightLimits Virus of Spleen (g) (g) 5 SD 0.619+0.427 1 551 2 mg 0.253+0.043 0 3510 10 SD50 0.697+0.268 1 120 2 mg 0.269+0.050 o:336 .
O 1.102+0.644 10 2909 20 S~50 2 mg 0.409+0.298 1 2413 l . .
O 1.651+0 r 535 2 0814 2 mg 0.350+0.155 0 278 . 20 .
., . ,, . .. . .. , . ~ .. . ..
l~Z4989 TABLE VIII
HPA 39: EFFECT OF VARIOUS TREATMENTS ON SPLENOMEGALY
INDUCED BY FRIENDS VIRUS.
Treatment Dose Average Weight of Limiting Spleen ~ type Values Deviation 0 1.202+0.6430.488-2.5943 D~ ~ D17 5 x 0.5 mg 0.610+0.4400.204 - 1.577 ~lO ~14 5 x 0.5 ~g 0.658+0.2990.250 - 1.250 ~17 21 5 x 0.5 mg 0.532+0.289o, Z 63_D,95~
0 1.438+0.5500.727-2.493 ~0 ~ 2 mg 0.244+0.0400.185-0.308 D 7 2 mg 1.488+0.4a30.762-2.033 ....
D 4 2 mg 1.827+0.3041.221-2.170 D_2 2 mg 1.668+0.5690.764-2.233 .
D+2 2 mg 0.560+0.3780.202-1.270 . .. .. .
D~4 2 mg 1.179+0.5480.257-1.748 .
D+7 2 mg 1.17G+0.7400.390-2.402 . 21 .
Claims (16)
1. A process for producing the heteropolyanion compound of the formula [Mm Sb9 W21 O86]M'n (III') wherein M is selected from a group consisting of alkali metal ions other than sodium and alkaline earth metal ions, M' is selected from a group consisting of alkali metal ions, alkaline earth metal ions, ammonium and quaternary ammonium ion, m is 0 or 1 and n is 19-p, wherein p is the charge of said M ion, said process comprising adding to an aqueous solution of the tungstate of M' a solution containing SbIII
ions, then adding concentrated ammonia or a saturated solution of a salt of M' to precipitate the compound of the formula III' wherein m is 0 and M' is ammonium or the compound of the formula III' wherein m is 1 and M and m are as hereinabove defined, and optionally reacting the compound of formula III' wherein m is 0 and M' is ammonium with an aqueous solution containing an alkali metal ion other than sodium or an alkaline earth metal ion to form the compound of the formula III'.
ions, then adding concentrated ammonia or a saturated solution of a salt of M' to precipitate the compound of the formula III' wherein m is 0 and M' is ammonium or the compound of the formula III' wherein m is 1 and M and m are as hereinabove defined, and optionally reacting the compound of formula III' wherein m is 0 and M' is ammonium with an aqueous solution containing an alkali metal ion other than sodium or an alkaline earth metal ion to form the compound of the formula III'.
2. A process according to claim 1, wherein the solution containing SbIII ions is a solution of SbCl3 in NH4Cl or KCl.
3. A process for producing the heteropolyanion compound of the formula [Sb9 W21 O86] (NH4)19 (II) comprising adding to an aqueous solution of ammonium tungstate a solution of antimony trioxide Sb2O3 in HCl, then adding concentrated ammonla to precipitate the desired ammonium salt.
4. A process according to Claim 3, wherein the aqueous solution of ammonium tungstate is prepared by reacting tungstic anhydride WO3 at boiling temperature with ammonia.
5. Process according to claim 4, wherein 4.5 to 5 moles of WO3 are used per mole of Sb2O3.
6. A process for producing the compound of the formula [K Sb9 W21 O86] K18 (VI) comprising preparing a first solution containing the SbIII
ions by dissolving SbCl3 in a saturated aqueous solution of KCl, adding said first solution to a second solution con-sisting of an aqueous solution of K2WO4, and introducing a saturated potassium bicarbonate solution until the reaction medium is colourless and its pH is in the vicinity of 7 to obtain the desired compound of formula VI.
ions by dissolving SbCl3 in a saturated aqueous solution of KCl, adding said first solution to a second solution con-sisting of an aqueous solution of K2WO4, and introducing a saturated potassium bicarbonate solution until the reaction medium is colourless and its pH is in the vicinity of 7 to obtain the desired compound of formula VI.
7. Process according to claim 6, wherein 1 to 3.4 parts of SbCl3 are used with respect to an aqueous molar solution of K2WO4.
8. A process according to Claim 1, 3 or 6 wherein the reaction temperature is between 60°C and boiling temperature.
9. A process according to claim 1, 3 or 6, wherein the reaction temperature is about 80°C.
10. Process according to claim 1, wherein the alkali metal or alkaline-earth metal ion is chosen from potassium, calcium and magnesium.
11. Process according to claim 1, wherein the aqueous solution contains as an alkali metal or alkaline-earth metal ion source a salt chosen from potassium chloride and magnesium chloride.
12. A process for producing the compound of the formula [K Sb9 W21 O86] (NH4)18 (V) comprising adding to an aqueous solution of ammonium tungstate a solution of antimony trioxide Sb2O3 in HCl, then adding concentrated ammonia to precipitate the desired ammonium salt, and treating the obtained ammonium salt in an aqueous solution by means of a solution of KCl in order to obtain compound of formula V.
13. A heteropolyanion compound of the formula [Mm Sb9 W21 O86] M'n (III') wherein M is an alkali metal ion other than sodium or an alkaline-earth metal ion, M' is selected from a group consisting of alkali metal ions, alkaline-earth metal ions, ammonium and quaternary ammonium, m is 0 or 1 and n is 19-p, wherein p is the charge of said M ion, whenever prepared by the process of claim 1, 2 or 10 or by an obvious chemical equivalent thereof.
14. A heteropolyanion compound of the formula [Sb9 W21 O86] (NH4)19 (II) whenever prepared by the process of claim 3, 4 or 5 or by an obvious chemical equivalent thereof.
15. A heteropolyanion compound of the formula [K Sb9 W21 O86] K18 (VI) and having a decomposition temperature of 340°C, whenever prepared by the process of claim 6 or 7 or by an obvious ahemical equivalent thereof.
16. A heteropolyanion compound of the formula [K Sb9 W21 O86] (NH4)18 (V) whenever prepared by the process of claim 12 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7636.498 | 1976-12-03 | ||
| FR7636498A FR2372633A2 (en) | 1976-12-03 | 1976-12-03 | COMPOUND OF HETEROPOLYANIONS CONTAINING TUNGSTENE COMBINED WITH ANTIMONY, THEIR OBTAINING AND THEIR APPLICATIONS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1124989A true CA1124989A (en) | 1982-06-08 |
Family
ID=9180628
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA292,227A Expired CA1124989A (en) | 1976-12-03 | 1977-12-02 | Heteropolyanion compounds containing tungsten combined with antimony |
Country Status (7)
| Country | Link |
|---|---|
| JP (2) | JPS5392400A (en) |
| BE (1) | BE861233A (en) |
| CA (1) | CA1124989A (en) |
| CH (1) | CH628005A5 (en) |
| DE (2) | DE2760338A1 (en) |
| FR (1) | FR2372633A2 (en) |
| GB (1) | GB1575940A (en) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0629191B2 (en) * | 1984-09-04 | 1994-04-20 | 株式会社ポリトロニクス | Antitumor agent, antiviral agent |
| IL77188A (en) * | 1984-12-03 | 1989-03-31 | Pasteur Institut | Pharmaceutical compositions containing hpa23 for the treatment of acquired immune deficiency syndrome and analogous syndromes |
| FR2587214B1 (en) * | 1985-09-13 | 1987-12-24 | Pasteur Institut | ANTICOAGULANTS CONSISTING OF TUNGSTIC HETEROPOLYANIONS AND THE USE OF SUCH HETEROPOLYANIONS IN THE PREPARATION OF ANTICOAGULANT DRUGS |
| JP2707252B2 (en) * | 1987-08-03 | 1998-01-28 | 利博 山瀬 | Antiviral agent |
| EP0450065A4 (en) * | 1988-12-16 | 1992-01-02 | Terumo Kabushiki Kaisha | Antiviral agent |
| US5051414A (en) * | 1989-08-03 | 1991-09-24 | Dupont Merck Pharmaceutical Company | Inhibition of HIV and other retroviruses by polyoxoanions |
| WO1994012192A1 (en) * | 1992-12-01 | 1994-06-09 | Commonwealth Scientific And Industrial Research Organisation | Antiviral agents |
| DE4336642C2 (en) * | 1993-10-22 | 1995-08-10 | Deutsches Rheuma Forschungszen | Use of vanadium compounds with antiviral activity |
| JP2005281299A (en) * | 2004-03-01 | 2005-10-13 | Paratex Japan:Kk | Antibacterial/mildewproofing agent and coating material composition using the same |
| JP4824536B2 (en) * | 2006-12-12 | 2011-11-30 | 株式会社サトー | Application ticket sticker and application ticket sticker application method |
-
1976
- 1976-12-03 FR FR7636498A patent/FR2372633A2/en active Granted
-
1977
- 1977-11-25 BE BE182955A patent/BE861233A/en not_active IP Right Cessation
- 1977-11-30 DE DE19772760338 patent/DE2760338A1/de active Pending
- 1977-11-30 DE DE19772753312 patent/DE2753312A1/en not_active Ceased
- 1977-12-02 CA CA292,227A patent/CA1124989A/en not_active Expired
- 1977-12-02 CH CH1480377A patent/CH628005A5/en not_active IP Right Cessation
- 1977-12-02 GB GB50311/77A patent/GB1575940A/en not_active Expired
- 1977-12-03 JP JP14562577A patent/JPS5392400A/en active Granted
-
1985
- 1985-11-08 JP JP60249093A patent/JPS61165336A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| FR2372633B2 (en) | 1980-06-27 |
| DE2753312A1 (en) | 1978-06-08 |
| GB1575940A (en) | 1980-10-01 |
| FR2372633A2 (en) | 1978-06-30 |
| JPH0212933B2 (en) | 1990-03-30 |
| CH628005A5 (en) | 1982-02-15 |
| JPS6221732B2 (en) | 1987-05-14 |
| DE2760338A1 (en) | 1986-03-20 |
| BE861233A (en) | 1978-05-25 |
| JPS61165336A (en) | 1986-07-26 |
| JPS5392400A (en) | 1978-08-14 |
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