US2828306A - Stable water soluble salts of oestrone sulfate and process of making same - Google Patents
Stable water soluble salts of oestrone sulfate and process of making same Download PDFInfo
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- US2828306A US2828306A US691147A US69114757A US2828306A US 2828306 A US2828306 A US 2828306A US 691147 A US691147 A US 691147A US 69114757 A US69114757 A US 69114757A US 2828306 A US2828306 A US 2828306A
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- oestrone
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- sulfate
- oestrone sulfate
- quaternary ammonium
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J75/00—Processes for the preparation of steroids in general
Definitions
- This invention relates to novel stable water soluble salts of oe'stronesulfate. More particularly, the invention concerns new oestrone sulfate salts derived fromorganic bases,'and tojthe method of their preparation.
- bivalent saturated alkyl radical attached to the nitrogen atom imparts markedly increased solubility.
- the second bon d of such alkyl rad-' ical' may alsobe attached to the quaternary nitrogen atom to form a heterocyclic ring.
- the bivalent alkyl radical may impart 'even greater increase'in water solubility when it is interrupted by the presence of other hetero-. atoms, such'as, for'exam'ple, oxygen or nitrogen atoms.
- the quaternary ammonium base which, is used is ppeha ins the e if mula r ew P ttimQ nary N atom by one valence, and joined together by other valences to form a member of'the group consisting of a heterocyclic ring, and an oxygen containing heterocyclic ring.
- The. oestrone sulfate starting material' may be prepared by any. suitable method, butiit has beenfound prefer-' Method
- A.l .0 g. of oestrone is converted by heating under reflux for 1 hour with 1.18 g. of pyridine-S adduct (prepared from freshly distilled chlorsulfonic acid or stabilized S0 and dry pyridine in 12 ml. of chloroform.
- pyridine-S adduct prepared from freshly distilled chlorsulfonic acid or stabilized S0 and dry pyridine in 12 ml. of chloroform.
- thechloroform and the pyridine are removed by distillation and the oily residue is worked up with absolute ether.
- the solidified precipitate is separated from the ether by decantation, dissolved in 100 ml. 0f methanol, filtered, and the solution used for the preparation of the salts described in Examples 1, 2, and 3, below.
- M eth0d B.- g. of oestrone are converted into the sulfate by heating with stirring with 11 g. aminosulfonic acid dissolved in 50 cc. of pyridine for approximately minutes at about 100 C. under an atmosphere of nitrogen. After distilling off the pyridine in vacuo, the residueis dried in vacuo at 70 C. There is obtained 24 g. of material (instead of the calculated 21 g.).
- the v24 g. are ground in a mortar with 150 cc. of methanol for /2 hour, filtered by suction and washed in portions with 60 cc. of methanol.
- the a total methanol solution amounted to 210 cc. and was divided into 3 equal portions for further treatment, in accordance with Examples 4, 5, and 6, below.
- The'rnethod of preparing the novel quaternary ammonium salts of ocstrone may be illustrated by the fol-' lowing examples, but the invention is not to be considered 7 as limited thereto.
- Example ium salt 'of oestrone sulfate To 50 ml. of the methanol solution of oestrone sulfate,
- a precipitate which formed is filtered off.
- the filtrate is adjusted to about 20 ml. and a little ether is carefully added thereto.
- An oil is precipitated, which after settling,
- oestrone sulfate may be separated from the supernatant liquid by de- 2.--N.N-dimethyl-morpholinium oestrone sulfate To 50 ml. of oestrone sulfate solution (method A), corresponding to 500 mg. of oestrone,there is-added, as
- Example 3 Tetramethylamm0nium salt of oestrone sulfate 7
- a solution of 2 g; ofoestrone sulfate prepared as-described under method A isv treated with a solution of tetramethylammonium hydroxide in methanol, until a pH value of 9.2is reached. After standingfor several hours (no precipitation) the solution is treated withan equal amount ofether, thev resulting precipitate-isfiltered V 4 7 product 1.96 g. of the tetramethylammonium salt, having a M. Pt. of 229230 C. (decomposition), yield 62.7%
- the mother liquor is again treated with the 7 same volume of ether and yields as a second crystallization product 0.86 g. having a melting point of 232-237" C., corresponding to 27.5% of theory, total yield 90.2% of theory.
- the mother liquor is evaporated to dryness, taken up with 8 cc. of methanol, and precipitated with ether, whereby there is obtained as a third crystallization product 0.1 g. of material having a M. Pt. 232234 C., corresponding to 3.19% of theory.
- the total yield is thus 93.4% of theory.
- the [a] is 969 C. in water.
- Example 4N-methyl-pyridinium salt of oestrone sulfate To 70 cc. 'of methanolic oestrone sulfate solution prepared in accordance with method B above, and corresponding to 3.3' g. of oestrone, there is added 63 cc. of a. methanol solution. of N-methyl-pyridinium hydroxide, which contains 0.074 g; ofbase in 5 cc., until a pH of 10.2 is reached. The solution is then treated with 130 cc. of absolute ether.' The amorphous by-product'thereby precipitated. (80 mg.) is filtered off by suction. Further addition. to the filtrate of 130 cc. of ether yield after two hours standing at':0 C. a precipitate of 2.27 g. of
- N-methylpyridinium salt 41.5% of theory, M. Pt. 15,2-'-155; solubility in water is 2.5% by weight; at 23 C., [ab l is 933 C. in water.
- fresidual syrup is' rubbed with isopropyl alcohol.
- the solubilityofthesaltin water is, 6.7%. at 23;.
- R R and R are alkyl radicals
- R is a member of the group consisting of alkyl radicals and hydroxyalkyl radicals
- R and R are bivalent alkylene radicals joined to the quaternary N atom by one valence, and joined together by the other valence to form a member of the group consisting of a heterocyclic ring, and an oxygen containing heterocyclic ring, said salts being stable and possessing good water solubility.
- Quaternary ammonium salts of oestrone sulfate which are derived from quaternary ammonium bases having 4 alkyl radicals attached to the nitrogen atom, said salts being stable and possessing good water solubility.
- Quaternary ammonium salts of oestrone sulfate which are derived from quaternary ammonium bases having 3 alkyl radicals and 1 hydroxyalkyl radical attached to the nitrogen atom, said salts being stable and possessing good water solubility.
- Quaternary ammonium salts of oestrone sulfate which are derived from quaternary ammonium bases which contain at least one alkyl radical attached to the nitrogen atom, and in which said nitrogen atom forms part of a six-membered heterocyclic ring, said salts being stable and possessing good water solubility.
- Quaternary ammonium salts of oestrone sulfate which are derived from quaternary ammonium bases which contain at least one alkyl radical attached to the nitrogen atom, and in which said nitrogen atom forms part of a S-membered heterocyclic ring, said salts being stable and possessing good water solubility.
- Quaternary ammonium salts of oestrone sulfate which are derived from quaternary ammoniumbases which contain at least one alkyl radical attached to the nitrogen atom, and in which said nitrogen atom forms part of a 6-membered oxygen containing heterocyclic ring, said salts being stable and possessing good water solubility.
- N.N-dimethyl-morpholinium salt of oestrone sulfate 10.
- the method of preparing stable, water soluble quaternary ammonium salts of oestrone sulfate which comprises reacting the oestrone sulfate with a quaternary ammonium bases having the general formula wherein R R and R are alkyl radicals, R is a member of the group consisting of alkyl radicals and hydroxyalkyl radicals; when R and R are alkyl, R and R are bivalent alkylene radicals joined to the quaternary N atom by one valence, and joined together by the other valence to form a member of the group consisting of a heterocyclic ring, and an oxygen containing heterocyclic ring, said salts being stable and possessing good water solubility.
Description
STABLE -WATER SOLUBLE SALTS OF OESTRONE SULFATE AND PROCESS OF MAKING SAME This invention relates to novel stable water soluble salts of oe'stronesulfate. More particularly, the invention concerns new oestrone sulfate salts derived fromorganic bases,'and tojthe method of their preparation.
It is known that the alkali metal salts of oestrone sulfate; which as water soluble derivatives .of oestrone possess considerable industrial importance in the manufacture of pharmaceutical and cosmetic preparations, cannot be preserved as such for prolonged periods of time; because these salts, even when stored in the anhydrous state and with careful exclusion ofmoisture, spontaneously decompose withliberation of acid, after a brief period of time; V V
' Attempts have been made previously to increasethe storability of' oestrone sulfate by transforming it into other salts, such as salts'of organic bases. All efforts in this direction, even after. seemingly promising beginnings have ultimately proved to'be failures.
Only certain salts of oestrone sulfate with quaternary ammonium basesdid in'fact exhibit good stability on storage. Unfortunately, the solubility in water of these stable salts was insufficient for industrial applications of the type previously mentioned; the solubility was, in fact, so-limited, that these same salts served admirably as a means of precipitating the oestrone present in urine in very low concentrations; On the'basis of this previous work the view was widely held in the art thaflquaternarysalts of oestrone sulfate were to be, considered as having a general characteristic of low solubility.
-In accordance with the present invention, it was found.
unexpectedly, and in contradiction of thegforegoing assumption concerning solubility, that certain new and previously undescribed salts-of oestronesulfate with qua ternary ammonium bases possessed both the properties of excellent stability and surprisingly high watersolubile ity. The new quaterenary ammonium bases which possess these. advantages are those which contain alkyl groups fattachedto the quaternary nitrogen atom, instead of aryl or aralkyl groups as inthe case of the previously used bases. 4
It has been found in accordancewith this invention at the presence of a bivalent saturated alkyl radical attached to the nitrogen atom imparts markedly increased solubility. The second bon d of such alkyl rad-' ical' may alsobe attached to the quaternary nitrogen atom to form a heterocyclic ring. The bivalent alkyl radical may impart 'even greater increase'in water solubility when it is interrupted by the presence of other hetero-. atoms, such'as, for'exam'ple, oxygen or nitrogen atoms.
An additional increase in solubility is obtained through thpresence of a hydroxy-groupin one of the other alkyl groups attached to the quaternary nitrogen atom.
Thus, the quaternary ammonium base which, is used is ppeha ins the e if mula r ew P ttimQ nary N atom by one valence, and joined together by other valences to form a member of'the group consisting of a heterocyclic ring, and an oxygen containing heterocyclic ring..
The improvement in solubility resulting from the formation of thenovel quaternary ammonium base derivatives of oestrone sulfate in accordance with the present invention will be readily apparent from the solubility properties of several of these new compounds as set forth in the following table:
TABLE 1 Water solubility of i the corresponding Quaternary Ammonium Base Oestrone Sulfate 7 salt in percent by weight at 23 C.
1 (ornjlN on 1.1
2 [QHa-N] H 3. mount-Manama s I I l CH3 N :lon 6.7
no OEHZ CH2 5. N fB]OH 8.0
on5 a 6 N O]OH 20 H0.0z H4 4 V GHQ 7; I: Ni' ]on 3 s Ho.ozHi
By way of comparison, there are given the solubil ities of two typical examples of salts of arylated or Among thequaternary ammonium bases which may be successfully used in preparing the novel oestrone sul fate derivatives of this invention there may be mentioned: N-(fl-hydroxyethyl)-N-methyl-morpholinium hydroxide, N-methylpyridinium hydroxide, N-p-hydroxyethyl-Ninethylpiperidiniurn hydroxide, tetramethyl-animonium hydroxide, and N-B-hydroxyethyl-N-methyl-pyp rolidinium hydroxide, but it will be understood that any base of this type which has the previously indicated characteristics maybe used.
, able to proceed in either of two ways:
The. oestrone sulfate starting material'may be prepared by any. suitable method, butiit has beenfound prefer-' Method A.l .0 g. of oestrone is converted by heating under reflux for 1 hour with 1.18 g. of pyridine-S adduct (prepared from freshly distilled chlorsulfonic acid or stabilized S0 and dry pyridine in 12 ml. of chloroform. Finally thechloroform and the pyridine are removed by distillation and the oily residue is worked up with absolute ether. The solidified precipitate is separated from the ether by decantation, dissolved in 100 ml. 0f methanol, filtered, and the solution used for the preparation of the salts described in Examples 1, 2, and 3, below.
M eth0d B.- g. of oestrone are converted into the sulfate by heating with stirring with 11 g. aminosulfonic acid dissolved in 50 cc. of pyridine for approximately minutes at about 100 C. under an atmosphere of nitrogen. After distilling off the pyridine in vacuo, the residueis dried in vacuo at 70 C. There is obtained 24 g. of material (instead of the calculated 21 g.). The v24 g. are ground in a mortar with 150 cc. of methanol for /2 hour, filtered by suction and washed in portions with 60 cc. of methanol. The a total methanol solution amounted to 210 cc. and was divided into 3 equal portions for further treatment, in accordance with Examples 4, 5, and 6, below.
.The'rnethod of preparing the novel quaternary ammonium salts of ocstrone may be illustrated by the fol-' lowing examples, but the invention is not to be considered 7 as limited thereto.
Example ium salt 'of oestrone sulfate To 50 ml. of the methanol solution of oestrone sulfate,
prepared as described under method A, and'corresponding to 500 mg. of oestrone, there is added about 0.5-2
cc. of a methanol solutionof N-fl-hydroxyethyl-N-methyl-v morpholinium hydroxide until a pH of 11.0 is reached.
A precipitate which formed is filtered off. The filtrate is adjusted to about 20 ml. and a little ether is carefully added thereto. An oil is precipitated, which after settling,
may be separated from the supernatant liquid by de- 2.--N.N-dimethyl-morpholinium oestrone sulfate To 50 ml. of oestrone sulfate solution (method A), corresponding to 500 mg. of oestrone,there is-added, as
' Example morpholinium hydroxide until a pH of 10.2 is reached. The solution is then concentrated in vacuo to 20ml. and treated with ether. There results a turbidity, from which crystals are formed of the N.N-dimethylmorpholinium salt of oestrone sulfate, which have the following proper ties:
Yield 445 mg., M. Pt 173-176. C., [eth l-91f C; in water. Solubility in water at 25 C. 8%.
Example 3.--Tetramethylamm0nium salt of oestrone sulfate 7 A solution of 2 g; ofoestrone sulfate prepared as-described under method A isv treated with a solution of tetramethylammonium hydroxide in methanol, until a pH value of 9.2is reached. After standingfor several hours (no precipitation) the solution is treated withan equal amount ofether, thev resulting precipitate-isfiltered V 4 7 product 1.96 g. of the tetramethylammonium salt, having a M. Pt. of 229230 C. (decomposition), yield 62.7%
of theory. The mother liquor is again treated with the 7 same volume of ether and yields as a second crystallization product 0.86 g. having a melting point of 232-237" C., corresponding to 27.5% of theory, total yield 90.2% of theory. The mother liquor is evaporated to dryness, taken up with 8 cc. of methanol, and precipitated with ether, whereby there is obtained as a third crystallization product 0.1 g. of material having a M. Pt. 232234 C., corresponding to 3.19% of theory. The total yield is thus 93.4% of theory.
, at room temperature; the [a] is 969 C. in water.
Example 4.N-methyl-pyridinium salt of oestrone sulfate To 70 cc. 'of methanolic oestrone sulfate solution prepared in accordance with method B above, and corresponding to 3.3' g. of oestrone, there is added 63 cc. of a. methanol solution. of N-methyl-pyridinium hydroxide, which contains 0.074 g; ofbase in 5 cc., until a pH of 10.2 is reached. The solution is then treated with 130 cc. of absolute ether.' The amorphous by-product'thereby precipitated. (80 mg.) is filtered off by suction. Further addition. to the filtrate of 130 cc. of ether yield after two hours standing at':0 C. a precipitate of 2.27 g. of
acolor'ed crude product, which is then recrystallized from ethanol, and finally from methanol-ether.
The yield" of N-methylpyridinium salt is 41.5% of theory, M. Pt. 15,2-'-155; solubility in water is 2.5% by weight; at 23 C., [ab l is 933 C. in water.
7 Example 5.N fl hydroxyethyl-N-methyl-piperidinium saltof oestrone sulfate 7 methanol solution of 'N- S-hydroxyethyl-N-methylpiperisdlt of V '55 previously described, a methanol solution of N-dimethyl v The residue] (4 g.) is rubbed with 10 cc. ofjsopropyll by suction, and Washed with-a 1.:1- ether-methanolimix dinium hydroxide until a pH of 10.2 is reached. The processing is conducted in such manner that the entire methanol solution is'evaporated to dryness under vacuo.
The fresidual syrup is' rubbed with isopropyl alcohol.
whereupon extensive-crystallization takes place. The crude.
productsofMu Pt.; 140-445 after being recrystallized from methanol-ether mixture furnishes well-formed colorless crystals having a: M. 'Pt. 1of147-149, in good yield (about of theory). ;Theisolubility of the resulting salt ingwater.is-extraordinarily high, namely 36% by weight at 23 C. 'The- Lab?" is +85.0 C. in water Exam learme h am ezh l zmmethytp r lidmium;
' 'salt ofoestrorte sulfate 1 0 70 cc.,..(the last'thirdrof the-solution ofoestrone sulfate. preparedbymethod B, above) there is added a methanol solution of the pyrrolidine base'until a-pH- of 9 is reached, asvdescribed in. the foregoing. examples. The turbid solution is evaporated completely in vacuo.
alcohol; The crystallized; portion is washed twice on the suction filter with 2 cc. of isopropyl' alcohol. The weight of: dried substance amounts to 2.1 g. (36% of theory)' which has a-M. Pt. 14l-148 C. This product is then precipitated from alcohol-ether, and finally recrystallized from methanol-ether. There are obtained fine needlesrhavingaMPt of 148-150. The working up of. the motherliquors" yields additional salt, so that a .yield. of 60%" of: theory-"can be; attainedwithoutdiifie 0;, the re t is1+82 c.
1. Quaternary ammonium salts of oestrone sulfate,
culty. The solubilityofthesaltin water is, 6.7%. at 23;.
wherein R R and R are alkyl radicals, R is a member of the group consisting of alkyl radicals and hydroxyalkyl radicals; when R; and R are alkyl, R and R are bivalent alkylene radicals joined to the quaternary N atom by one valence, and joined together by the other valence to form a member of the group consisting of a heterocyclic ring, and an oxygen containing heterocyclic ring, said salts being stable and possessing good water solubility.
2. Quaternary ammonium salts of oestrone sulfate which are derived from quaternary ammonium bases having 4 alkyl radicals attached to the nitrogen atom, said salts being stable and possessing good water solubility.
3. Quaternary ammonium salts of oestrone sulfate which are derived from quaternary ammonium bases having 3 alkyl radicals and 1 hydroxyalkyl radical attached to the nitrogen atom, said salts being stable and possessing good water solubility.
4. Quaternary ammonium salts of oestrone sulfate which are derived from quaternary ammonium bases which contain at least one alkyl radical attached to the nitrogen atom, and in which said nitrogen atom forms part of a six-membered heterocyclic ring, said salts being stable and possessing good water solubility.
5. Quaternary ammonium salts of oestrone sulfate which are derived from quaternary ammonium bases which contain at least one alkyl radical attached to the nitrogen atom, and in which said nitrogen atom forms part of a S-membered heterocyclic ring, said salts being stable and possessing good water solubility.
6. Quaternary ammonium salts of oestrone sulfate which are derived from quaternary ammoniumbases which contain at least one alkyl radical attached to the nitrogen atom, and in which said nitrogen atom forms part of a 6-membered oxygen containing heterocyclic ring, said salts being stable and possessing good water solubility.
7. N-(fl-hydroxyethyl)-N-methyl-morpholinium salt of oestrone sulfate.
8. N-(fl-hydroxyethyl)-N-methyl-pyrrolidinium salt of oestrone sulfate.
9. N-(B-hydroxyethyl)-N-methyl-piperidinium salt of oestrone sulfate.
10. N.N-dimethyl-morpholinium salt of oestrone sulfate.
11. Tetramethylammonium salt of oestrone sulfate.
12. The method of preparing stable, water soluble quaternary ammonium salts of oestrone sulfate which comprises reacting the oestrone sulfate with a quaternary ammonium bases having the general formula wherein R R and R are alkyl radicals, R is a member of the group consisting of alkyl radicals and hydroxyalkyl radicals; when R and R are alkyl, R and R are bivalent alkylene radicals joined to the quaternary N atom by one valence, and joined together by the other valence to form a member of the group consisting of a heterocyclic ring, and an oxygen containing heterocyclic ring, said salts being stable and possessing good water solubility.
13. The method of claim 12 in which the salt forming reaction takes place in methanol solution.
14. The method of claim 13 in which the salt forming reaction is continued until a pH value of 9 to 11 is reached. 7
15. The method of claim 12 in which the quaternary ammonium base contains at least one alkyl radical.
16. The method of claim 12 in which the quaternary ammonium base contains a hydroxyalkyl group attached to the nitrogen atom.
Natelson et al. Nov. 5, 1940 Hasbrouck June 16, 1953 Notice of Adverse Decision in Interference In Interference No. 89,538 involving Patent No. 2,828,306, E. Griebsch, G. Zuehlsdorfi', and K. Pirner, Stable water soluble salts of oestrone sulfate and process of making same, final judgment adverse to the patentees was rendered February 4;, 1959 as to claim 3. [Oflz'cz'al Gazette imam, 1959.]
Claims (1)
1. QUATERNARY AMMONIUM SALTS OF OESTRONE SULFATE, WHICH ARE DERIVED FROM QUATERNARY AMMONIUM BASES HAVING THE GENERAL FORMULA
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2828306X | 1956-11-14 |
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| US2828306A true US2828306A (en) | 1958-03-25 |
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| Application Number | Title | Priority Date | Filing Date |
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| US691147A Expired - Lifetime US2828306A (en) | 1956-11-14 | 1957-10-21 | Stable water soluble salts of oestrone sulfate and process of making same |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3024257A (en) * | 1961-04-10 | 1962-03-06 | Frosst & Co Charles E | Stable preparations of alkali metal salts of estrone sulfate |
| US3152044A (en) * | 1957-10-26 | 1964-10-06 | Schering Ag | Water soluble salts of steroidal-21-acid sulfates and therapeutic compositions containing same |
| US4851214A (en) * | 1988-09-07 | 1989-07-25 | Ici Americas Inc. | Deodorants containing N-soya-N-ethyl morpholinium ethosulfate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2200114A (en) * | 1939-07-22 | 1940-05-07 | Konikoff Harry | Combined lamp and mirror structures |
| US2642427A (en) * | 1951-08-01 | 1953-06-16 | Abbott Lab | Piperazine salts of cyclopentanopolyhydrophenanthrene-3-monosulfates |
-
1957
- 1957-10-21 US US691147A patent/US2828306A/en not_active Expired - Lifetime
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2200114A (en) * | 1939-07-22 | 1940-05-07 | Konikoff Harry | Combined lamp and mirror structures |
| US2642427A (en) * | 1951-08-01 | 1953-06-16 | Abbott Lab | Piperazine salts of cyclopentanopolyhydrophenanthrene-3-monosulfates |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3152044A (en) * | 1957-10-26 | 1964-10-06 | Schering Ag | Water soluble salts of steroidal-21-acid sulfates and therapeutic compositions containing same |
| US3024257A (en) * | 1961-04-10 | 1962-03-06 | Frosst & Co Charles E | Stable preparations of alkali metal salts of estrone sulfate |
| US4851214A (en) * | 1988-09-07 | 1989-07-25 | Ici Americas Inc. | Deodorants containing N-soya-N-ethyl morpholinium ethosulfate |
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