US2566358A - Androgenic compositions - Google Patents
Androgenic compositions Download PDFInfo
- Publication number
- US2566358A US2566358A US97485A US9748549A US2566358A US 2566358 A US2566358 A US 2566358A US 97485 A US97485 A US 97485A US 9748549 A US9748549 A US 9748549A US 2566358 A US2566358 A US 2566358A
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- United States
- Prior art keywords
- testosterone
- beta
- oil
- solution
- ester
- 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.)
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Classifications
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
Definitions
- the acid bromide obtained by the action temn b t h effect p sis s o a io up o of thionyl bromide (on beta-cyclopentylpropionic days or lo low n a s g e i j ti nacid, may be used instead oi the acid chloride, if
- dsirgg :5gta, gyplgpgntylpiropionate 3,159 be d II.- prepared by other methods known to the art such Table I as hee int chan e f a lo e -a kvl te o Castrated rates, received on the first experibetaeyclopemylprppiomc.
- ventlon can be prepared by dissolving the ester in ether, mixing the other solution with a nontoxic, glyceride 'oil suitable for parental adminisweightofseminalvesjclein tratiqn such as peanut, cottonseed, corn or semilligramsafter" same oil and removing the other under reduced Ompmmd 40 piessui c.
- the concentration of the ester in the 3 12 18 24 oil is limited only by its solubility and stable soludays days days days days days days tions containing about 500 milligrams of testosterone beta-cyolopentylpropionate per millimegg gg 52 5g; 4g ter have been prepared.
- the use of ether or other es similar low boiling non-reactive solvents speeds fl g gig cfi; 7 7 s 9 11 s 10 the solution of the ester in the oil, but their use is not essential, as the ester may be dissolved di- 1 rectly in the oil with stirring and gentle warm- Tabdg H ing, if desired.
- Thixotropic gels may be prein peanut oil containing two percent aluminum pared by adding about two percent by weight per monostearate. At the end of each period of time volume of oil of aluminum monostearate to an indicated, six of the animals were sacrified and oil solution of the ester at room temperature.
- Example 1 Teestosterone beta-cyclopentylpropionate
- beta-cyclopentylpropionyl chloride [J. Chem. Soc. (1939), page 1065] was added to a solution of 3.0 grams of testosterone in 7.0 grams of dry pyridine at a substantially uniform rate over a period of ten minutes.
- the reaction temperature was maintained at about five degrees centigrade during the addition.
- the temperature of the mixture was then raised to 26 degrees centigrade, and after being held there for four and one-half hours, the mixture was poured into 50 milliliters of cold aqueous G-normal sulfuric acid and extracted four times with 25-milliliter portions of isopropyl ether.
- Example 2 A solution of three grams of dry, crystalline testosterone beta-cyclopentylpropionate in 20 milliliters of ethyl ether was added, with stirring, to 100 milliliters of U. S. P. XII cottonseed oil contained in a 300-milliliter balloon flask; The flask was fitted with a capillary ebullator attached to a stream of nitrogen, evacuated and warmed on a steam bath. After about an hour, all of the other had been removed and a clear oil solution remained containing 30 milligrams per milliliter of testosterone beta-cyclopentylpropionate.
- chlorobutanol For the purpose of preservation, five milligrams of chlorobutanol per milliliter of solution may be added either to the hot oil or to the ether solution of the ester.
- solutions of testosterone beta-cyclopentylpropionate were prepared using sesame, peanut or corn oil.
- Example 3 To vigorously stirred solution of three grams of testosterone beta-cyclopentylpropionate in milliliters of peanut oil at 24 degrees centigrade, 1.9 grams of dry aluminum monostearate was added at a substantially uniform rate over a period of five minutes. The temperature of the mixture was then raised at a rate of 10 degrees centigrade per minute until a temperature of 120 degrees centigrade was obtained, and held at 120 degrees centigrade for 10 minutes. Stirring was discontinued and the clear syrupy product was allowed to cool at room temperature. There was thus obtained milliliters of a thixotropie gel containing 30 milligrams of testosterone betacyclopentylpropionate per milligram. Upon agitation, a free-flowing liquid was obtained which is suitable for injection.
- a therapeutic composition for parental administration having a prolonged androgenic efiect comprising: a sterile solution of testosterone beta-cyolopentylpropionat in a non-toxic vegetable oil.
- a therapeutic composition for parental administration having a prolonged androgenic efiect comprising: a sterile solution of testosterone beta-cyclopentylpropionate and aluminum monostearate in a non-toxic vegetable oil.
- a therapeutic composition for parental administration having a prolonged androgenic effect comprising: a sterile solution of testosterone beta-cyclopentylpropionate in peanut oil.
- a therapeutic composition for parental ad ministration having a prolonged androgenic effeet after a single injection comprising a sterile solution of testosterone beta-cyclopentylpropionate and about two percent by weight of aluminum monostearate of the volume of the oil used in peanut oil.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dermatology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Steroid Compounds (AREA)
Description
Patented Sept. 4, 1951 ANDROGENIC ooMPosrrIoNs Arnold (J, Ott, Kalamazoo, Mich., assignor to The Upjohn Company, Kalamazoo, Mich., a corpora o f Michigan No Drawing, Application Junefi, 19%9, Serial No. 97485 Claims. (Cl. 167-7174) 1 T i i en o e ates t thera e icall us tul compositions having an exceptionally pro? longed androgenic effect. More particularly, this invention relates to testosterone beta-cyclopentylpropionate and to androgenically active corn- 2 the average weight of the seminal vesicles determined and recorded. The following results were obtained:
Weight of Seminal vesicle in I) positions containing the said ester. l gr m e The esterification of the l7-hydroxyl group of 1209 1 9 4 testosterone to produce certain esters having a 3 6 l 1 2 greater and a more prolonged effect than testodays days days days (lays days days sterone is hown in United States Patent 2,109,400, lo T t t e em and their injectilm in l Solutions i wn b 97 270 522 525 e94 343 Miescher, Wettstein and lischopp, Biochem. J. 30, l 24 3. 13 0 37 1983 (1936,), In these references, it is clearly 1mg given) :8 9 t 1;; 9 0 s shown that the maximum efiectiveness of the E t re q l d i5 fil d n ab 12 110 16 Testosterone beta-cyc1opentylpropionate can da s after injec ion. be prepared by reacting testosterone with beta- .I ha 9 e n. fo n t t h 11 1 wmcyclopentylpropionyl chloride (obtained from the p u s te o e eta c clop nt lpmpion action of thionyl chloride on beta-cyclopentyle h n in e in an 01 Solution, B9B on y gives a propionic acid), in the presence of a tertiary base ma imu in the i h of t emi l such as pyridine or dimethylaniline, and there- Vesicle of a castrated Tat, much higher han t t after recovering the ester from the reaction mixobtai with p vi s y n n este te t tule. The acid bromide, obtained by the action temn b t h effect p sis s o a io up o of thionyl bromide (on beta-cyclopentylpropionic days or lo low n a s g e i j ti nacid, may be used instead oi the acid chloride, if These facts are more clearly shown dsirgg :5gta, gyplgpgntylpiropionate 3,159 be d II.- prepared by other methods known to the art such Table I as hee int chan e f a lo e -a kvl te o Castrated rates, received on the first experibetaeyclopemylprppiomc. aciqwith testgstemng 1" by the az o r mc. ester catlon of te t stero e mental darn, e1 1 quantity of the designated ester with betwcyclopntylpropiomc acig inthe pres? equivalen 0 ve milhgrams of testosterone, d1sgnce of benzene or toluene and paIWtO-luene sub solved in peanut 011. At the end of each period foni I c ar bo on t l uo e o ot er se ate of time indicated, five of the animals were sacrilysts and'reactioh media i dicates thresult obtained, ventlon can be prepared by dissolving the ester in ether, mixing the other solution with a nontoxic, glyceride 'oil suitable for parental adminisweightofseminalvesjclein tratiqn such as peanut, cottonseed, corn or semilligramsafter" same oil and removing the other under reduced Ompmmd 40 piessui c. The concentration of the ester in the 3 12 18 24 oil is limited only by its solubility and stable soludays days days days days days days tions containing about 500 milligrams of testosterone beta-cyolopentylpropionate per millimegg gg 52 5g; 4g ter have been prepared. The use of ether or other es similar low boiling non-reactive solvents speeds fl g gig cfi; 7 7 s 9 11 s 10 the solution of the ester in the oil, but their use is not essential, as the ester may be dissolved di- 1 rectly in the oil with stirring and gentle warm- Tabdg H ing, if desired.
Castrated rats received on the first experiment- For some purposes, it is desirable to add alumial day a quantity of the designated ester equivnum monostearate to the oil solution to obtain a alent to five milligrams of testosterone, dissolved thixotropic gel. Thixotropic gels may be prein peanut oil containing two percent aluminum pared by adding about two percent by weight per monostearate. At the end of each period of time volume of oil of aluminum monostearate to an indicated, six of the animals were sacrified and oil solution of the ester at room temperature.
- 3 The solution is then heated to about 120 degrees centigrade, held at that temperature for about ten minutes and the solution thereafter cooled. A thixotropic gel results which is solid at ordinary temperatures, but which will liquefy, if shaken.
The following examples are given to illustrate a method for preparing the products of this invention, but the said invention is not to be limited thereto.
Example 1.-Testosterone beta-cyclopentylpropionate One and eight-tenth grams of beta-cyclopentylpropionyl chloride [J. Chem. Soc. (1939), page 1065] was added to a solution of 3.0 grams of testosterone in 7.0 grams of dry pyridine at a substantially uniform rate over a period of ten minutes. The reaction temperature was maintained at about five degrees centigrade during the addition. The temperature of the mixture was then raised to 26 degrees centigrade, and after being held there for four and one-half hours, the mixture was poured into 50 milliliters of cold aqueous G-normal sulfuric acid and extracted four times with 25-milliliter portions of isopropyl ether. The ether extracts were combined, washed with dilute acid, water,dilute sodium bicarbonate and water. After drying, filtering and evaporating, light yellow crystals formed which were recrystallized from normal hexane. There was thus obtained 3.4 grams (80 percent of the theoretical yield) of testosterone beta-cyclopentylpropionate, melting at 101-102 degrees centigrade, [a]D +76.4 (chloroform).
Analysis:
Calculated for Carl-R103" C, 78.59 H, 9.77 Found 78.57 9.54
Example 2 A solution of three grams of dry, crystalline testosterone beta-cyclopentylpropionate in 20 milliliters of ethyl ether was added, with stirring, to 100 milliliters of U. S. P. XII cottonseed oil contained in a 300-milliliter balloon flask; The flask was fitted with a capillary ebullator attached to a stream of nitrogen, evacuated and warmed on a steam bath. After about an hour, all of the other had been removed and a clear oil solution remained containing 30 milligrams per milliliter of testosterone beta-cyclopentylpropionate.
For the purpose of preservation, five milligrams of chlorobutanol per milliliter of solution may be added either to the hot oil or to the ether solution of the ester.
In a similar manner, solutions of testosterone beta-cyclopentylpropionate were prepared using sesame, peanut or corn oil.
Example 3 To vigorously stirred solution of three grams of testosterone beta-cyclopentylpropionate in milliliters of peanut oil at 24 degrees centigrade, 1.9 grams of dry aluminum monostearate was added at a substantially uniform rate over a period of five minutes. The temperature of the mixture was then raised at a rate of 10 degrees centigrade per minute until a temperature of 120 degrees centigrade was obtained, and held at 120 degrees centigrade for 10 minutes. Stirring was discontinued and the clear syrupy product was allowed to cool at room temperature. There was thus obtained milliliters of a thixotropie gel containing 30 milligrams of testosterone betacyclopentylpropionate per milligram. Upon agitation, a free-flowing liquid was obtained which is suitable for injection.
Various modifications may be made in the present invention without departing from the spirit or scope thereof, and it is to be understood that I limit myself only as defined in the appended claims.
I claim:
l. A therapeutic composition for parental administration having a prolonged androgenic efiect, comprising: a sterile solution of testosterone beta-cyolopentylpropionat in a non-toxic vegetable oil.
2. A therapeutic composition for parental administration having a prolonged androgenic efiect, comprising: a sterile solution of testosterone beta-cyclopentylpropionate and aluminum monostearate in a non-toxic vegetable oil.
3. A therapeutic composition for parental administration having a prolonged androgenic effect, comprising: a sterile solution of testosterone beta-cyclopentylpropionate in peanut oil.
4. A therapeutic composition for parental ad ministration having a prolonged androgenic effeet after a single injection comprising a sterile solution of testosterone beta-cyclopentylpropionate and about two percent by weight of aluminum monostearate of the volume of the oil used in peanut oil.
5. Testosterone beta-cyclopenty1propionate.
ARNOLD C. OTT.
REFERENCES CITED The following references are of record in the file of this patent:
UNITED STATES PATENTS Name Date Miescher Feb. 22, 1938 OTHER REFERENCES Number
Claims (1)
- 5. TESTOSTERONE BETA-CYCLOPENTYLPROPIONATE.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US97485A US2566358A (en) | 1949-06-06 | 1949-06-06 | Androgenic compositions |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US97485A US2566358A (en) | 1949-06-06 | 1949-06-06 | Androgenic compositions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US2566358A true US2566358A (en) | 1951-09-04 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US97485A Expired - Lifetime US2566358A (en) | 1949-06-06 | 1949-06-06 | Androgenic compositions |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US2566358A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2840508A (en) * | 1951-05-17 | 1958-06-24 | Schering Ag | Injectable steroid hormone preparations and method of making same |
| US2843523A (en) * | 1955-07-07 | 1958-07-15 | Us Vitamin Corp | Androgenic compounds and methods of preparing the same |
| US4948790A (en) * | 1987-08-26 | 1990-08-14 | Sydney Archer | Long-acting androgenic compounds and pharmaceutical compositions thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2109400A (en) * | 1935-10-05 | 1938-02-22 | Soc Of Chemical Ind | Esters of testosterone and process of making same |
-
1949
- 1949-06-06 US US97485A patent/US2566358A/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2109400A (en) * | 1935-10-05 | 1938-02-22 | Soc Of Chemical Ind | Esters of testosterone and process of making same |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2840508A (en) * | 1951-05-17 | 1958-06-24 | Schering Ag | Injectable steroid hormone preparations and method of making same |
| US2843523A (en) * | 1955-07-07 | 1958-07-15 | Us Vitamin Corp | Androgenic compounds and methods of preparing the same |
| US4948790A (en) * | 1987-08-26 | 1990-08-14 | Sydney Archer | Long-acting androgenic compounds and pharmaceutical compositions thereof |
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