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US3124592A - Water-insoluble salts of basic anti- - Google Patents

Water-insoluble salts of basic anti- Download PDF

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US3124592A
US3124592A US3124592DA US3124592A US 3124592 A US3124592 A US 3124592A US 3124592D A US3124592D A US 3124592DA US 3124592 A US3124592 A US 3124592A
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

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  • a conventional method of improving the taste of pharmaceutical compounds consists in providing water-insoluble derivatives thereof. These derivatives must meet with the following conditions:
  • the water-soluble salts of basic antihistaminic compounds have a very bitter, harsh, and tart taste and exert an anesthetizing effect. Attempts have been made to eliminate the disagreeable taste of basic antihistaminic compounds by converting them into their insoluble salts. Such almost insoluble salts are the acid addition salts of fatty acids of high molecular weight and the salicylates. However, these compounds are not completely free of a disagreeable taste. Salts of basic antihistaminic compounds with tannic acid have also been prepared (German Patent No. 1,001,455). However, such salts can be obtained in a pure state only With some difiiculties. Furthermore, tannic acid, which is split off in the gastro-intestinal tract, is certainly not inert.
  • Another object of the present invention is to provide a simple and effective process of making such compounds.
  • the salts of basic antihistaminic compounds with the acid esters of sulfuric acid and higher aliphatic alcohols which contain from 14 to 20 carbon atoms completely meet with the requirements, as specified hereinabove, for a substantially tasteless antihistaminic drug.
  • These new alkyl sulfates are insoluble in water and, hence, completely tasteless. They release the active constituent in the body very rapidly and are well tolerated.
  • these salts have the additional advantageous property that they are readily soluble in organic solvents. This property renders such salts especially suitable for certain kinds of drug preparations.
  • the acid addition salt of the antihistaminic compound is precipitated in the form of a stable emulsion so that addition of an emulsifier is not necessary.
  • the resulting emulsion is tasteless. Due to this property the new salts can readily be used as preparations to be applied by means of medicine droppers and as juices.
  • the acid-addition salts according to the pfesent'inVention can be prepared according to known methods by reacting the water-soluble salts of basic anti-histaminic compounds, for instance, their hydrochlorides, with the alkali metal salts of the acid esters of sulfuric acid and higher aliphatic alcohols in an aqueous solution. It is also possible to react the basic antihistaminic compounds with the free alkyl sulfuric acids in a suitable organic solvent and to distill off the solvent.
  • Example 1 30.55 g. of the hydrochloride of B-dimethylamino ethyl- Z-methyl benzhydryl ether are dissolved in about ten times its amount of cold water. 34.4 g. of sodium cetyl sulfate are dissolved in about 10 times its amount of hot water. Both solutions are combined While stirring. A white oil precipitates Which accumulates at the bottom of the vessel and solidifies, after standing for some time in a refrigerator. The supernatant liquid is poured off. The solid cake is triturated with cold water and washed until free of sodium chloride on a Buechner funnel. The resulting salt is dried in a vacuum at room temperature. Melting point: 43-45" C.
  • the stoichiornetric content of base in said salt is 45.5%.
  • Acontent'of 45:3 was calculated from the ultraviolet absorption at 259 m
  • Example 2 28.0 g. of pyrrolidyl ethyl phenyl benzylamine are dissolved in 200 cc. of carbon tetrachloride. The solution is mixed with a solution of 32.2 g. or" cetyl sulfuric acid in 300 cc. of carbon tetrachloride. After evaporation of the solvent, pyrrolidyl ethylphenyl benzylamine cetyl sulfate is obtained. Melting point: 6870 C.
  • Example 3 30.55 g. of the hydrochloride of p-dimethylamino ethyl- 2-methyl benzhydryl ether are dissolved in about ten times its amount of cold Water. 37.36 g. of the sodium salt of stearyl sulfuric acid are dissolved in about ten times its amount of hot water. Both solutions are combined while stirring. Thereby, the stearyl sulfate of the antihistaminic compound precipitates. The precipitate is worked up as described in Example 1. Melting point: 43 46 C.
  • Example 4 31.7 g. of the hydrochloride of pyrrolidyl ethyl phenyl benzylamine are dissolved in about ten times its amount of cold water. 37.36 g. of the sodium salt of stearyl sulfuric acid are dissolved in about 10 times its amount of hot Water. Both solutions are combined while stirring. Thereby, the stearyl sulfate of the 'anti-histaminic compound precipitates. The precipitate is Worked up as described in Example 1. Melting point of the stearyl sulfate of pyr rolidyl ethyl phenyl benzylamine: 69 C.
  • Example 28.0 g. of py-rrolidyl ethyl phenyl benzylamine are dissolved in 200 cc. of carbon tetrachloride. The solution is mixed with a solution of 70.06 g. of stearyl sulfuric acid in 500 cc. of carbon tetrachloride. After evaporation of the solvent the distearyl sulfate of pyrrolidyl ethyl phenyl benzylamine is obtained in the form of a wax-1ike compound of an unsharp melting point between about 50 C. and about 60 C.
  • antihistaminic bases and their hydrochlorides as used in the preceding examples, there may be reacted equimolecular amounts of other basic antihistaminic compounds, such as 2-[p ChlOIO-oc-(Z dimethylamino ethoxy) benzyl] pyridine,
  • the preferred compounds are those described in the preceding examples.
  • other water soluble acid addition salts such as the hydrobromides, phosphates, maleates, succinates.
  • the new acid addition salts are characterized by their extreme insolubility in Water, so that they are absolutely tasteless; by their rapid cleavage in the gastrointestinal tract so that they exert their antihistaminic activity shortly after administration; by their property of yielding on cleavage, in addition to the antihistaminic agent, substantially non-toxic, Well tolerated degradation products; and by their high solubility in organic solvents such as ethanol.
  • the new acid addition salts are administered in the form of solid shaped preparations such as tablets, pills, dragees, and the like, or in the form of aqueous emulsions and emulsions in sugar sirup, fruit juices, and the like, which do not require the addition of emulsifying agents.
  • the preparation of such compositions is effected in the manner conventionally used in the pharmaceutical industry.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyrrole Compounds (AREA)

Description

United States Patent Ofitice 3,124,592 Patented Mar. 10, 1-964 3,124,592 WA'IER-INSOLUBLE SALTS F, BASIC ANTI- HISTAMINIC CONWOUNDS, AND PROCESS 0F MG SE Peter Rieckmann, Mannheim-Waldhof, Germany, assignor to C. F. Boehringer & Soehne G.m.b.H., Mannheim- Waldhof, Germany, a corporation of Germany -N0 Drawing. Filed July 19, 1960, Ser. No. 43,746 Claimspricrity, application Germany July 29, 1959 7 Claims. ((11-260-313) The present invention relates to new and valuable water-insoluble salts of basic anti-histaminic compounds and more particularly to specific acid addition salts of such basic. antihistaminic compounds, and to a process of making same.
It is of considerable importance in therapy, and especially in pediatry, to make administration of a pharmaceutical agent as easy as possible for the patient. This may be a rather decisive factor in achieving satisfactory results in psychiatry, where the patient should not become aware of receiving a drug.
In anurnber of instances, however it has been found impossible to neutralize completely the intensely bad and disagreeable taste of pharmaceutical compounds by the addition of taste-correcting agents. A conventional method of improving the taste of pharmaceutical compounds consists in providing water-insoluble derivatives thereof. These derivatives must meet with the following conditions:
(1) They must be completely insoluble in water; even a very slight solubility in water will make them detectable by the tongue.
(2) The active moiety of the molecule must be released in the organism as rapidly and as completely as possible.
(3) In addition to the active ingredient there must be formed only substantially inert compounds upon cleavage.
The water-soluble salts of basic antihistaminic compounds, in particular, have a very bitter, harsh, and tart taste and exert an anesthetizing effect. Attempts have been made to eliminate the disagreeable taste of basic antihistaminic compounds by converting them into their insoluble salts. Such almost insoluble salts are the acid addition salts of fatty acids of high molecular weight and the salicylates. However, these compounds are not completely free of a disagreeable taste. Salts of basic antihistaminic compounds with tannic acid have also been prepared (German Patent No. 1,001,455). However, such salts can be obtained in a pure state only With some difiiculties. Furthermore, tannic acid, which is split off in the gastro-intestinal tract, is certainly not inert.
It is one object of the present invention .to provide subtantially tasteless water-insoluble salts of basic antihistaminic compounds in which the active constituent is released within the body as rapidly and as completely as possible, and in which the other constituent is substantially inert.
Another object of the present invention is to provide a simple and effective process of making such compounds.
These and other objects of the present invention and advantageous features thereof will become apparent as the description proceeds.
According to the present invention it has. been found that the salts of basic antihistaminic compounds with the acid esters of sulfuric acid and higher aliphatic alcohols which contain from 14 to 20 carbon atoms completely meet with the requirements, as specified hereinabove, for a substantially tasteless antihistaminic drug. These new alkyl sulfates are insoluble in water and, hence, completely tasteless. They release the active constituent in the body very rapidly and are well tolerated. Furthermore, these salts have the additional advantageous property that they are readily soluble in organic solvents. This property renders such salts especially suitable for certain kinds of drug preparations. On dissolving the salts in an organic solvent which is miscible with water, for instance, in ethyl alcohol and pouring the resulting solution in water, the acid addition salt of the antihistaminic compound is precipitated in the form of a stable emulsion so that addition of an emulsifier is not necessary. The resulting emulsion is tasteless. Due to this property the new salts can readily be used as preparations to be applied by means of medicine droppers and as juices.
The acid-addition salts according to the pfesent'inVention can be prepared according to known methods by reacting the water-soluble salts of basic anti-histaminic compounds, for instance, their hydrochlorides, with the alkali metal salts of the acid esters of sulfuric acid and higher aliphatic alcohols in an aqueous solution. It is also possible to react the basic antihistaminic compounds with the free alkyl sulfuric acids in a suitable organic solvent and to distill off the solvent.
The following examples serve to illustrate the present invention without, however, limiting the same thereto:
Example 1 30.55 g. of the hydrochloride of B-dimethylamino ethyl- Z-methyl benzhydryl ether are dissolved in about ten times its amount of cold water. 34.4 g. of sodium cetyl sulfate are dissolved in about 10 times its amount of hot water. Both solutions are combined While stirring. A white oil precipitates Which accumulates at the bottom of the vessel and solidifies, after standing for some time in a refrigerator. The supernatant liquid is poured off. The solid cake is triturated with cold water and washed until free of sodium chloride on a Buechner funnel. The resulting salt is dried in a vacuum at room temperature. Melting point: 43-45" C.
Analysis-Found: 68.00% C; 9.51% H; 5.6% S; 2.11% N. Calculated: 68.99% C; 9.71% H; 5.42% S; 2.37% N. (N determined by the Kjeldahl method: 2.25%.)
The stoichiornetric content of base in said salt is 45.5%. Acontent'of 45:3 was calculated from the ultraviolet absorption at 259 m Example 2 28.0 g. of pyrrolidyl ethyl phenyl benzylamine are dissolved in 200 cc. of carbon tetrachloride. The solution is mixed with a solution of 32.2 g. or" cetyl sulfuric acid in 300 cc. of carbon tetrachloride. After evaporation of the solvent, pyrrolidyl ethylphenyl benzylamine cetyl sulfate is obtained. Melting point: 6870 C.
Anulysis.Found: 70.62% C; 9.88% H; 4.71% N; 5.1% S. Calculated: 69.72% C; 9.70% H; 4.65% N; 5.32% S.
When using twice the amount of cetyl sulfuric acid, the 'diicetyl sulfate of pyrrolidyl ethyl phenyl benzylamine is obtained.
Example 3 30.55 g. of the hydrochloride of p-dimethylamino ethyl- 2-methyl benzhydryl ether are dissolved in about ten times its amount of cold Water. 37.36 g. of the sodium salt of stearyl sulfuric acid are dissolved in about ten times its amount of hot water. Both solutions are combined while stirring. Thereby, the stearyl sulfate of the antihistaminic compound precipitates. The precipitate is worked up as described in Example 1. Melting point: 43 46 C.
Analysis.'Found: 67.62% C; 9.64% H; 5.1% S;
1.99% N. Calculated: 69.7% C; 9.92% H; 5.17% S; 2.26% N.
Example 4 31.7 g. of the hydrochloride of pyrrolidyl ethyl phenyl benzylamine are dissolved in about ten times its amount of cold water. 37.36 g. of the sodium salt of stearyl sulfuric acid are dissolved in about 10 times its amount of hot Water. Both solutions are combined while stirring. Thereby, the stearyl sulfate of the 'anti-histaminic compound precipitates. The precipitate is Worked up as described in Example 1. Melting point of the stearyl sulfate of pyr rolidyl ethyl phenyl benzylamine: 69 C.
Analysis.-Found: 71.23% C; 10.12% H; 5.23% S; 4.53% N. Calculated: 70.42% C; 9.91% H; 5.07% S; 4.44 N.
Example 28.0 g. of py-rrolidyl ethyl phenyl benzylamine are dissolved in 200 cc. of carbon tetrachloride. The solution is mixed with a solution of 70.06 g. of stearyl sulfuric acid in 500 cc. of carbon tetrachloride. After evaporation of the solvent the distearyl sulfate of pyrrolidyl ethyl phenyl benzylamine is obtained in the form of a wax-1ike compound of an unsharp melting point between about 50 C. and about 60 C.
Analysis-Found: 68.16% C; 10.07% H; 6.36% S; 2.67% N. Calculated: 67.29% C; 10.28% H; 6.52% S; 2.85% N.
In place of the cetyl sulfuric acid or its sodium salt or of stearyl sulfuric acid or its sodium salt as used in the preceding examples, there may be employed equimolecular amounts of acid esters of sulfuric acid with other higher aliphatic alcohols having 14 to 20 carbon atoms, such as with my-n'styl alcohol, arachidyl alcohol, and the like alcohols. The preferred acid sulfuric acid esters, however, are the esters with cetyl alcohol and stearyl alcohol. In place of the sodium salts, there may be employed the potassium salts or other alkali metal salts of said acid esters. 7
In place of the antihistaminic bases and their hydrochlorides as used in the preceding examples, there may be reacted equimolecular amounts of other basic antihistaminic compounds, such as 2-[p ChlOIO-oc-(Z dimethylamino ethoxy) benzyl] pyridine,
2-[(2-dimethylamino ethyl) (p-rnethoxy benzyl) amino] pyridine,
2-[et-(2-dimethylamino ethoxy) a methyl benzyl] pyridine,
4-diphenyl methoxy-l-methyl piperidine,
Z-{N-benzyl anilino methyD-imidazoline-AZ,
l-(p-bromo phenyl)-l-(Z-pyridyl) 3 dimethyl-amino propane,
Z-[QB-dimethylaminoethyl)-2-thenyl amino] pyridine,
l-(p-chloro benzhydryl)-4-methyl piperazine,
N,N-dimethyl-N'-pmethoxy benzyl-N (2 pyrimidyl) ethylene diamine,
N-(2'-dimethylamino-2-methyl) ethyl phenothiazine,
l-(p-chloro phenyl)-2-phenyl-4-pyrrolidino butene,
2-[(fl-dimethy1amino ethyl)-2-(5-chloro thenyl) amino] pyridine,
N,N-dimethyl-N-benzyl-N-(Z-pyridyl) ethylene diamine,
N-phenyl-N-benZyl-4-amino-l-methyl piperidine and others. The preferred compounds, however, are those described in the preceding examples. In place of their hydrochlorides, there may be used other water soluble acid addition salts, such as the hydrobromides, phosphates, maleates, succinates.
In place of carbon tetrachloride used as solvent for the antihistaminic base and the salt with the sulfuric acid mono-alkyl ester, there may be employed other solvents wherein the base as well as its new sulfuric acid monoester addition salt is soluble, such as chloroform, methylene chloride, methanol, ethanol, acetone.
As stated above, the new acid addition salts are characterized by their extreme insolubility in Water, so that they are absolutely tasteless; by their rapid cleavage in the gastrointestinal tract so that they exert their antihistaminic activity shortly after administration; by their property of yielding on cleavage, in addition to the antihistaminic agent, substantially non-toxic, Well tolerated degradation products; and by their high solubility in organic solvents such as ethanol.
The new acid addition salts are administered in the form of solid shaped preparations such as tablets, pills, dragees, and the like, or in the form of aqueous emulsions and emulsions in sugar sirup, fruit juices, and the like, which do not require the addition of emulsifying agents. The preparation of such compositions is effected in the manner conventionally used in the pharmaceutical industry.
Of course, many changes and variations in basic antihistaminic compound and the sulfuric acid mono-alkyl ester employed, the solvent used, the reaction conditions, the methods of working up the reaction mixture and of isolating and purifying the new acid addition salts, and the like may be made by those skilled in the art in accordance with the principles set forth herein and in the claims annexed hereto.
I claim:
1. The acid addition salt of the (2-methyl phenyl) (phenyl) methyl ether of B-dimethylamino ethanol with cetyl sulfuric acid.
2. The acid addition salt of N-[fi-(N'-phenyl-N-ben- Zylamino)ethyl]pyrrolidine with cetyl sulfuric acid.
3. The acid addition salt of the (Z-methyl phenyl) (phenyl) methyl ether of fi-dimethylamino ethanol with stearyl sulfuric acid.
4. The mono-acidaddition salt of N- [B-(N'-phenyl-N'- benzylamino)etl1yl] pyrrolidine with stearyl sulfuric acid.
5. The di-acid addition salt of N-[B-(N-phenyl-N- benzylamino)ethyl]pyrrolidine with stearyl sulfuric acid.
6. The acid addition salt of the (Z-methyl phenyl) (phenyl) methyl ether of fi-dimethylamino ethanol with an alkyl sulfuric acid, the alkyl radical thereof having 14 to 20 carbon atoms.
7. The acid addition salt of the N-[fi-(N'-phenyl-N'- benzylamino)ethyl1pyrrolidine with an alkyl sulfuric acid, the alkyl radical thereof having 14 to 20 carbon atoms.
References Cited in the file of this patent UNITED STATES PATENTS 2,454,092 Rieveschl Nov. 16, 1948 2,567,351 Rieveschl Sept. 11, 1951 FOREIGN PATENTS 1,001,455 Germany Jan. 24, 1957 OTHER REFERENCES Richters Organic Chemistry, vol. 1, Aliphatic Series,

Claims (1)

  1. 2. THE ACID ADDITION SALT OF N-(B-(N''PHENYL-N''-PHENYL-N''-BENZYLAMINO)ETHYL)PYRROLIDINE WITH CETYL SULFURIC ACID.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2454092A (en) * 1947-06-02 1948-11-16 Parke Davis & Co Benzhydryl amino ethers
US2567351A (en) * 1946-01-29 1951-09-11 Parke Davis & Co Process for the manufacture of benzhydryl ethers
DE1001455B (en) * 1955-11-17 1957-01-24 Schering Ag Process for the production of tasteless preparations of basic antihistamines

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2567351A (en) * 1946-01-29 1951-09-11 Parke Davis & Co Process for the manufacture of benzhydryl ethers
US2454092A (en) * 1947-06-02 1948-11-16 Parke Davis & Co Benzhydryl amino ethers
DE1001455B (en) * 1955-11-17 1957-01-24 Schering Ag Process for the production of tasteless preparations of basic antihistamines

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