US2748169A - Novel chemotherapeutic agents comprising dialkynyl ethers of diethylstilbestrol - Google Patents
Novel chemotherapeutic agents comprising dialkynyl ethers of diethylstilbestrol Download PDFInfo
- Publication number
- US2748169A US2748169A US237661A US23766151A US2748169A US 2748169 A US2748169 A US 2748169A US 237661 A US237661 A US 237661A US 23766151 A US23766151 A US 23766151A US 2748169 A US2748169 A US 2748169A
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- US
- United States
- Prior art keywords
- diethylstilbestrol
- dialkynyl
- ethers
- chemotherapeutic agents
- estrogenic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/075—Ethers or acetals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/205—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings
- C07C39/21—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings with at least one hydroxy group on a non-condensed ring
- C07C39/215—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings with at least one hydroxy group on a non-condensed ring containing, e.g. diethylstilbestrol
Definitions
- This invention relates generally to organic chemical compounds useful in chemotherapy and, in a more particular sense, it is concerned with certain new estrogenically active derivatives of diethylstilbestrol.
- esters of the compound have been prepared by esterifying the two hydroxyl groups with a lower aliphatic carboxylic acid such as propionic acid, and preparations of this type have been found to be relatively slowly absorbed, producing a low concentration in the bloodstream which is of long duration.
- One of the objects of this invention is to provide a compound of this type having the full potency, as an estrogenic agent, which is characteristic of idethylstilbestrol, and which has the property of maintaining high blood levels of the estrogenic material over a long period of time following administration.
- the class of compounds which may be denominated the dialkynyl ethers of 4:4'-dihydroxy-a-fl-diethylstilbene (diethylstilbestrol) It has been found that this class of compounds, and particularly the dipropargyl ether of diethylstilbestrol as a member of the class, are estrogenic agents of high activity which are very well suited to administration by parenteral routes and which, when so administered, provide a high level of the estrogenic substance in the bloodstream over a relatively long period of time following administration.
- novel compounds of this invention can be readily prepared by conventional synthetic routes, for example, salts of diethylstilbestrol may be reacted with suitable alkynylating agents such as reactive esters of the desired alkynylol.
- suitable alkynylating agents such as reactive esters of the desired alkynylol.
- hydrohalic esters of the alkynylols or ice esters of alkynylols with aliphatic or aromatic sulfonic acids also may be used as alkynylating agents in producing the desired ether compounds of this invention.
- the alkynyl ethers of diethylstilbestrol are novel compounds and are useful chemotherapeutic agents for use in treating estrogenic disorders, and although the members of this class-of compounds-have the property in common of being slowly utilized-in the blood stream after administration, one member of this class, the dipropargyl ether of diethylstilbestrol, has outstanding properties in this respect and is the preferred embodiment of this invention.
- This substance may be readily synthesized by reacting a salt of diethylstilbestrol, such as the disodium salt or any other desired dialkali salt, with a reactive ester of propargyl alcohol, preferably a propargyl halide, such as propargyl bromide.
- the reaction product is obtained as a crystalline powder which is readily soluble in oleaginous materials of the type used as vehicles for parenteral administration of chemotherapeutic agents.
- Example 1 About 5 grams of the sodium salt of 4:4-dihydroxya-B-diethylstilbene are dissolved in alcoholic acetone and approximately 5 grams of propargyl bromide are added thereto, dropwise, while the solution is heated on a water bath. After all of the propargyl bromide has been added, which requires about an hour, the mixture of the reactants and the reaction products is cooled and the solids are removed from the mixture by distillation under reduced pressure. then with caustic soda solution (one-half to one normal) and finally the product is recrystallized from ethanol. This product is obtained as a crystalline mass which melts at 106-107 C. and which is easily soluble in oily vehicles suitable for injection purposes to provide an estrogenic composition characterized by long activity after administration.
- Example 2 About 5 grams of 4:4'-dihydroxy-u: S-diethylstilbene are treated with about 5.2 grams of potassium carbonate in cc. of acetone. The mixture is heated for about two hours, then cooled and a mixture of about 5 grams of propargyl bromide and 20 cc. of acetone is added dropwise. Subsequently the reaction mixture is boiled for about six hours, then cooled and filtered, yielding a residue of the desired dipropargyl ether of diethylstilbestrol which may be further processed and purified, as described in Example 1.
- dialkynyl ethers of diethylstilbestrol can be easily prepared by substituting the desired dialkynyl bromide for the propargyl bromide used in the processes of either of these examples, stoichiometrical relations of the reactants being observed, of course, when thus modifying the processes.
Description
United States Patent NOVEL CHEMOTHERAPEUTIC AGENTS COMPRIS- ING DIALKYNYL ETHERS OF DIETHYLSTIL- BESTROL No Drawing. Application July 19, 1951, Serial No. 237,661
Claims priority, application Germany July 22, 1950 2 Claims. (Cl. 260-613) This invention relates generally to organic chemical compounds useful in chemotherapy and, in a more particular sense, it is concerned with certain new estrogenically active derivatives of diethylstilbestrol.
It is now well known that certain organic materials which may be totally synthesized exhibit an estrogenic activity comparable to estrogenic hormones from natural sources. Among these substances are the stilbene compounds of which the most active thus far discovered is diethylstilbestrol. This material may be administered by oral or parenteral routes, being entirely effective in either instance, but its degree of efficacy being determined, to some extent, by the skill of the administrator. Administration of the compound by a parenteral route frequently results in undesirable side reactions such as nausea, vomitting and headache which are now believed to be more likely systemic than local in origin and probably due to rapid absorption of the material into the bloodstream. Various attempts have been made in the past to reduce the rate at which the drug is made available into the bloodstream following administration, thereby reducing the incidence of side reactions. To this end, various esters of the compound have been prepared by esterifying the two hydroxyl groups with a lower aliphatic carboxylic acid such as propionic acid, and preparations of this type have been found to be relatively slowly absorbed, producing a low concentration in the bloodstream which is of long duration.
In certain instances, it is desirable to utilize a product which possesses this characteristic of prolonged activity and availability, but which is suited to maintain higher concentrations in the bloodstream than are provided by the compounds of the type above-mentioned. One of the objects of this invention is to provide a compound of this type having the full potency, as an estrogenic agent, which is characteristic of idethylstilbestrol, and which has the property of maintaining high blood levels of the estrogenic material over a long period of time following administration.
In accordance with this invention and in accomplishment of the object of the invention, there is provided the class of compounds which may be denominated the dialkynyl ethers of 4:4'-dihydroxy-a-fl-diethylstilbene (diethylstilbestrol) It has been found that this class of compounds, and particularly the dipropargyl ether of diethylstilbestrol as a member of the class, are estrogenic agents of high activity which are very well suited to administration by parenteral routes and which, when so administered, provide a high level of the estrogenic substance in the bloodstream over a relatively long period of time following administration.
These novel compounds of this invention can be readily prepared by conventional synthetic routes, for example, salts of diethylstilbestrol may be reacted with suitable alkynylating agents such as reactive esters of the desired alkynylol. The hydrohalic esters of the alkynylols or ice esters of alkynylols with aliphatic or aromatic sulfonic acids also may be used as alkynylating agents in producing the desired ether compounds of this invention.
Although the alkynyl ethers of diethylstilbestrol, as a class, are novel compounds and are useful chemotherapeutic agents for use in treating estrogenic disorders, and although the members of this class-of compounds-have the property in common of being slowly utilized-in the blood stream after administration, one member of this class, the dipropargyl ether of diethylstilbestrol, has outstanding properties in this respect and is the preferred embodiment of this invention. This substance may be readily synthesized by reacting a salt of diethylstilbestrol, such as the disodium salt or any other desired dialkali salt, with a reactive ester of propargyl alcohol, preferably a propargyl halide, such as propargyl bromide. The reaction product is obtained as a crystalline powder which is readily soluble in oleaginous materials of the type used as vehicles for parenteral administration of chemotherapeutic agents.
To facilitate a better understanding of the subject matter of this invention and especially of how the compounds of the invention may be easily synthesized from readily available starting materials, two specific examples will now be set forth, it being clearly understood that these examples are provided by way of illustration of the invention merely and are not to be construed as imposing any limitation thereon.
Example 1 About 5 grams of the sodium salt of 4:4-dihydroxya-B-diethylstilbene are dissolved in alcoholic acetone and approximately 5 grams of propargyl bromide are added thereto, dropwise, while the solution is heated on a water bath. After all of the propargyl bromide has been added, which requires about an hour, the mixture of the reactants and the reaction products is cooled and the solids are removed from the mixture by distillation under reduced pressure. then with caustic soda solution (one-half to one normal) and finally the product is recrystallized from ethanol. This product is obtained as a crystalline mass which melts at 106-107 C. and which is easily soluble in oily vehicles suitable for injection purposes to provide an estrogenic composition characterized by long activity after administration.
Example 2 About 5 grams of 4:4'-dihydroxy-u: S-diethylstilbene are treated with about 5.2 grams of potassium carbonate in cc. of acetone. The mixture is heated for about two hours, then cooled and a mixture of about 5 grams of propargyl bromide and 20 cc. of acetone is added dropwise. Subsequently the reaction mixture is boiled for about six hours, then cooled and filtered, yielding a residue of the desired dipropargyl ether of diethylstilbestrol which may be further processed and purified, as described in Example 1.
It will be obvious to those versed in the art to which this invention relates that other dialkynyl ethers of diethylstilbestrol can be easily prepared by substituting the desired dialkynyl bromide for the propargyl bromide used in the processes of either of these examples, stoichiometrical relations of the reactants being observed, of course, when thus modifying the processes.
Having thus described the subject matter of this invention, what it is desired to secure by Letters Patent is:
1. As a novel chemotherapeutic agent useful in estrogenie therapy and characterized by maintaining high blood levels of estrogenic material for prolonged periods follow- The residue so obtained is stirred with water,
ing parenteral administration, a dialkynyl ether of diethyl- References Cited in the file of this patent stilbestrol represented by the formula: UNITED STATES PATENTS R0 2,270,380 Miescher et a1. Ian. 20, 1942 l v 5 2,502,325 Kaiser et a1 Mar. 28, 1950 FOREIGN PATENTS aHa 2 V 841,145 Germany June 13, 1952 wherein R is an alkynyl radical that comprises at most 696,663 Great Britain Sept. 2, 1953 three carbon atoms. 298,684 witzerland July 16, 1954 2. A novel chemotherapeutic agent as defined in claim 10 1 wherein the dialkynyl ether is dipropargyl ether of 4: 4-dihydroxy-a S-diethylstilbene.
Claims (1)
1. AS A NOVEL CHEMOTHERAPEUTIC AGENT USEFUL IN ESTROGENIC THERAPY NAD CHARACTERIZED BY MAINTAINING HIGH BLOOD LEVELS OF ESTROGENIC MATERIAL FOR PROLONGED PERIODS FOLLOWING PARENTERAL ADMINISTRATION, A DIALKVNYL ETHER OF DIETHYLSTILBESTROL REPRESENTED BY THE FORMULA:
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2748169X | 1950-07-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US2748169A true US2748169A (en) | 1956-05-29 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US237661A Expired - Lifetime US2748169A (en) | 1950-07-22 | 1951-07-19 | Novel chemotherapeutic agents comprising dialkynyl ethers of diethylstilbestrol |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US2748169A (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2270380A (en) * | 1938-03-16 | 1942-01-20 | Ciba Pharm Prod Inc | Sugar derivatives of nonsteroids having the effect of steroid hormones, and process of making the same |
| US2502325A (en) * | 1946-06-06 | 1950-03-28 | Armour & Co | Derivatives of hexestrol |
| DE841145C (en) * | 1950-07-23 | 1952-06-13 | Bayer Ag | Process for the preparation of the dipropargyl ether of 4, 4'-dioxy-ª ‡, ª ‰ -diaethylstilbene |
| GB696663A (en) * | 1950-07-22 | 1953-09-02 | Bayer Ag | Novel chemotherapeutic agents |
| CH298684A (en) * | 1950-07-22 | 1954-05-15 | Bayer Ag | Process for the preparation of the dipropargyl ether of 4,4'-dioxy-a, B-diethyl-stilbene. |
-
1951
- 1951-07-19 US US237661A patent/US2748169A/en not_active Expired - Lifetime
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2270380A (en) * | 1938-03-16 | 1942-01-20 | Ciba Pharm Prod Inc | Sugar derivatives of nonsteroids having the effect of steroid hormones, and process of making the same |
| US2502325A (en) * | 1946-06-06 | 1950-03-28 | Armour & Co | Derivatives of hexestrol |
| GB696663A (en) * | 1950-07-22 | 1953-09-02 | Bayer Ag | Novel chemotherapeutic agents |
| CH298684A (en) * | 1950-07-22 | 1954-05-15 | Bayer Ag | Process for the preparation of the dipropargyl ether of 4,4'-dioxy-a, B-diethyl-stilbene. |
| DE841145C (en) * | 1950-07-23 | 1952-06-13 | Bayer Ag | Process for the preparation of the dipropargyl ether of 4, 4'-dioxy-ª ‡, ª ‰ -diaethylstilbene |
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