Stable, but weakly air and light sensitive. Incompatible with strong oxidizing agents.- 2.7 StorageTemp
- Sealed in dry,2-8°C
3. Use and Manufacturing
- 3.1 Usage
- Progestogen; an injectable contraceptive.
4. Safety and Handling
- 4.1 Symbol
- GHS08
- 4.1 Hazard Codes
- Xn
- 4.1 Signal Word
- Warning
- 4.1 Risk Statements
- R40;R48
- 4.1 Safety Statements
- S22;S36/37/39;S45
- 4.1 Fire Hazard
- Flash point data for Medroxyprogesterone 17-acetate are not available; however, Medroxyprogesterone 17-acetate is probably combustible.
- 4.2 Hazard Declaration
- H351
- 4.2 RIDADR
- NONH for all modes of transport
- 4.2 Safety Profile
- Suspected carcinogen with experimental carcinogenic, neoplastigenic, tumorigenic, and teratogenic data. Human systemic effects by intravenous route: increased intraocular pressure. Human teratogenic effects by an unspecified route: developmental abnormalities of the urogenital system. Human reproductive effects by multiple routes: spermatogenesis, menstrual cycle changes or dlsorders, postpartum effects, female fertility effects, abortion, newborn behavioral effects. Human mutation data reported. Experimental reproductive effects. A drug for the treatment of secondary amenorrhoea and dysfunctional uterine bleeding. When heated to decomposition it emits acrid smoke and irritating fumes.
- 4.3 Caution Statement
- P281
- 4.3 WGK Germany
- 3
- 4.3 RTECS
- TU5010000
- 4.3 Safety
-
Hazard Codes: Xn
Risk Statements: 40-48
R40: Limited evidence of a carcinogenic effect
R48: Danger of serious damage to health by prolonged exposur
Safety Statements: 22-36/37/39-45
S22: Do not breathe dust
S36/37/39: Wear suitable protective clothing, gloves and eye/face protection
S45: In case of accident or if you feel unwell, seek medical advice immediately (show the label whenever possible.)
WGK Germany: 3
RTECS: TU5010000
- 4.4 Specification
-
Incompatibilities: Flammable and/or toxic gases are generated by combination with with alkali metals, nitrides, and strong reducing agents Reacts with oxoacids and carboxylic acids to form esters plus water Incompatible with oxidizing agents.
- 4.5 Toxicity
-
| Organism |
Test Type |
Route |
Reported Dose (Normalized Dose) |
Effect |
Source |
| dog |
LD50 |
oral |
> 5gm/kg (5000mg/kg) |
|
Drugs in Japan Vol. -, Pg. 1196, 1990. |
| mouse |
LD50 |
intraperitoneal |
> 1500mg/kg (1500mg/kg) |
|
Kiso to Rinsho. Clinical Report. Vol. 18, Pg. 6135, 1984. |
| mouse |
LD50 |
oral |
> 16gm/kg (16000mg/kg) |
ENDOCRINE: ADRENAL CORTEX HYPOPLASIA |
Kiso to Rinsho. Clinical Report. Vol. 18, Pg. 6135, 1984. |
| mouse |
LD50 |
subcutaneous |
> 1500mg/kg (1500mg/kg) |
|
Kiso to Rinsho. Clinical Report. Vol. 18, Pg. 6135, 1984. |
| rat |
LD50 |
intraperitoneal |
> 900mg/kg (900mg/kg) |
|
Kiso to Rinsho. Clinical Report. Vol. 18, Pg. 6135, 1984. |
| rat |
LD50 |
oral |
> 6400mg/kg (6400mg/kg) |
LIVER: OTHER CHANGES |
Kiso to Rinsho. Clinical Report. Vol. 18, Pg. 6135, 1984. |
| rat |
LD50 |
subcutaneous |
> 900mg/kg (900mg/kg) |
|
Kiso to Rinsho. Clinical Report. Vol. 18, Pg. 6135, 1984. |
| women |
TDLo |
intravenous |
10mg/kg (10mg/kg) |
SENSE ORGANS AND SPECIAL SENSES: INCREASED INTRAOCULAR PRESSURE: EYE |
Advances in Planned Parenthood. Vol. 8, Pg. 103, 1972. |
| women |
TDLo |
intravenous |
21mg/kg (21mg/kg) |
SENSE ORGANS AND SPECIAL SENSES: INCREASED INTRAOCULAR PRESSURE: EYE |
Advances in Planned Parenthood. Vol. 8, Pg. 103, 1972. |
- View all
5. MSDS
2.Hazard identification 2.1 Classification of the substance or mixture Carcinogenicity, Category 2 2.2 GHS label elements, including precautionary statements | Pictogram(s) |  | | Signal word | Warning | | Hazard statement(s) | H351 Suspected of causing cancer | | Precautionary statement(s) | | | Prevention | P201 Obtain special instructions before use. P202 Do not handle until all safety precautions have been read and understood. P280 Wear protective gloves/protective clothing/eye protection/face protection. | | Response | P308+P313 IF exposed or concerned: Get medical advice/ attention. | | Storage | P405 Store locked up. | | Disposal | P501 Dispose of contents/container to ... | 2.3 Other hazards which do not result in classification none
7. Synthesis Route
71-58-9Total: 16 Synthesis Route
9. Other Information
- 9.0 Merck
- 13,5817
- 9.1 BRN
- 2066112
- 9.2 Description
- Medroxyprogesterone 17-acetate is a synthetic progestogen.1,2,3 It prevents fertilization and increases the rate of transport of eggs from the fallopian tubes to the uterus in female ferrets when administered prior to ovulation.1 Medroxyprogesterone 17-acetate reversibly blocks ovulation in rats when injected on the last day of diestrus.2 It also has anti-androgenic activity in rats, decreasing plasma testosterone (Item Nos. 15645 | ISO60154) levels via induction of hepatic testosterone reductase activity.3 Medroxyprogesterone 17-acetate exhibits immunosuppressive effects in vitro and in vivo, inhibiting the production of IFN-γ by CD2/CD3/CD28-stimulated peripheral blood mononuclear cells (PBMCs) at concentrations ≥10 nM and extending the survival of rabbit skin allografts.4,5 Injectable formulations containing medroxyprogesterone 17-acetate have been used as contraceptives.6
- View all
- 9.3 Chemical Properties
- White or almost white, crystalline powder.
- 9.4 Originator
- Provera,Upjohn,US,1959
- 9.5 Uses
- Progestogen; an injectable contraceptive.
- 9.6 Uses
- antiprotozoal
- 9.7 Uses
- A synthetic progesterone receptor agonist
- 9.8 Manufacturing Process
- Preparation of 17α-Hydroxyprogesterone 3,20-Bis-(Ethylene Ketal): A solution was prepared containing 50.0 g of 17α-hydroxyprogesterone in 1,000 ml of benzene, 100 ml of ethylene glycol and 2.5 g of p-toluenesulfonic acid monohydrate. This mixture was refluxed for a period of 17 hours using a calcium carbide water-trap to remove the water formed in the reaction. After this period of reflux 6.5 ml of pyridine was added to the solution, and the mixture cooled to room temperature.
The lower glycol layer was separated and washed with benzene. The benzene layer and the benzene washings were combined and the combined solution was divided into two equal portions, one of which was used for the isolation of 17α-hydroxyprogesterone 3,20-bis-(ethylene ketal) as follows. The benzene solution was washed with 5% sodium carbonate solution, water and saturated sodium chloride solution. After being dried over anhydrous magnesium sulfate the solution was concentrated to dryness at reduced pressure, The residue was recrystallized by taking up in hot methylene chloride, adding acetone and boiling to remove the methylene chloride until a final volume of about 200 ml was reached.
The solution was then refrigerated overnight and 17.8 g of crystals were removed by filtration. A second crop was obtained yielding 3.7 g of compound. The total yield of 17α-hydroxyprogesterone 3,20-bis-(ethylene ketal) was 20.3 g (64.3% of theory). Recrystallization of the crude 17αhydroxyprogesterone 3,20-bis-(ethylene ketal) from methanol gave the pure bisketal of MP 209° to 211°C.
Preparation of 5α,6α-Oxido-17α-Hydroxyallopregnane-3,20-dione 3,20-Bis- (Ethylene Ketal): A solution was prepared by heating 19.96 g (0.0477 mol) of 17α-hydroxyprogesterone 3,20-bis-(ethylene ketal) and 500 ml of benzene. After the solution was effected the flask was cooled to 5°C and a mixture of 3.68 g (0.0449 mol) of sodium acetate and 174 ml of 40% peracetic acid was added with stirring. The reaction mixture was stirred in the ice bath for 3 hours. The lower peracid layer was separated, diluted with water and extracted twice with benzene.
The upper layer was neutralized by the addition of cold 10% sodium hydroxide solution while stirring in an ice bath. The rate of addition of the sodium hydroxide was regulated to keep the temperature below 10°C. The benzene extracts from the peracid layer were combined and washed with cold 10% sodium hydroxide solution and with saturated sodium chloride solution. All the aqueous layers were washed again with the same portion of benzene. The combined benzene layers were dried over anhydrous magnesium sulfate and concentrated to dryness at reduced pressure.
The residue was recrystallized from acetone using methylene chloride to aid in solution. The crystalline material was removed by filtration and was recrystallized from methylene chloride-acetone to yield a total of 8 g of 5α,6αoxido-17α-hydroxyallopregnane-3,20-dione 3,20-bis-(ethylene ketal) of MP 211° to 215°C. For analytical purposes, another recrystallization from methylene chloride-acetone gave pure 5α,6α-oxido-17α-hydroxyallopregnane3,20-dione 3,20-bis-(ethylene ketal) of MP 216° to 218.5°C.
Preparation of 5α,17α-Dihydroxy-6β-Methylallopregnane-3,20-dione 3,20-bis- (Ethylene Ketal): To a solution of 91.6 g of 5α,6α-oxido-17αhydroxyallopregnane-3,20-dione 3,20-bis-(ethylene ketal) in 3,500 ml of freshly distilled tetrahydrofuran was added 1,170 ml of commercial 3 molar methyl magnesium bromide in ether solution. The reaction mixture was boiled to remove 1,800 ml of solvent by distillation and thereafter 1,000 ml of freshly distilled tetrahydrofuran was added.
Boiling was continued under reflux for a period of 16 hours. The solution was then concentrated to about one-half its original volume by distillation and was poured slowly with vigorous stirring into a large volume of ice water containing 340 g of ammonium chloride. The aqueous solution was saturated with sodium chloride and extracted with benzene. The benzene extract was washed with saturated brine, and both aqueous layers were washed again with the same portions of benzene.
The combined benzene layers were dried over anhydrous sodium carbonate and the solvent was removed at reduced pressure to give 90.5 g of crude crystalline 5α,17α-dihydroxy-6β-methylallopregnane-3,20-dione 3,20-bis- (ethylene ketal). Half of the residue, 45.2 g, was recrystallized from acetone and some methylene chloride to give 34.4 g of 5α,17α-dihydroxy-6βmethylallopregnane-3,20-dione 3,20-bis-(ethylene ketal). A sample recrystallized from acetone and methylene chloride for analysis melted at 160° to 163°C.
Preparation of 5α,17α-Dihydroxy-6β-Methylallopregnane-3,20-dione: A solution was prepared containing 38.9 g of 5α,7α-dihydroxy-6βmethylallopregnane-3,20-dione 3,20-bis-(ethylene ketal) in 389 ml of boiling acetone. Thereto was added 39 ml of 1 N sulfuric acid in portions under swirling and seeding with product. Boiling was continued for a period of 2 minutes and the mixture was allowed to stand at room temperature. Thereafter the mixture was diluted with 1,500 ml of water, chilled and filtered.
The precipitate was washed with water, dilute ammonium hydroxide and water, and dried in a vacuum oven overnight. The yield was 31.2 g which was recrystallized by dissolving in 1,200 ml of dimethylformamide, heating to 150°C, cooling slightly, and adding 12 ml of hot water. The recrystallized 5α,17α-dihydroxy-6β-methylallopregnane-3,20-dione thus obtained was 28.75 g of MP 270° to 275.5°C. After an additional recrystallization from aqueous dimethylformamide, the MP was 274° to 279°C.
Preparation of 6α-Methyl-17α-Hydroxyprogesterone: A suspension was made by introducing 2 g of 5α,17α-dihydroxy-6β-methylallopregnane-3,20-dione into 200 ml of chloroform. The suspension was chilled in an ice bath with stirring, and thereupon hydrogen chloride was bubbled through the reaction mixture for 80 minutes with continuous cooling and stirring. After bubbling in nitrogen for a period of 15 minutes the solution was washed with water, 1 N sodium bicarbonate solution and again with water.
The aqueous layers were rewashed with one portion of chloroform, and the washings combined with the remainder of the chloroform solution. After drying over anhydrous magnesium sulfate, the chloroform solution was concentrated to dryness, then taken up in a small volume of methylene chloride, treated with Magnesol anhydrous magnesium silicate and filtered. Acetone was added to the solution and the solution was boiled to remove the methylene chloride. After the solution was concentrated to a volume of about 15 ml it was chilled and the crystals were collected through filtration. The 1.37 g of crystals so obtained were recrystallized from acetone to give pure 6α-methyl-17α-hydroxyprogesterone of MP 220° to 223.5°C.
Preparation of 6α-Methyl-17-Hydroxyprogesterone 17-Acetate: 1 g of 6αmethyl-17α-hydroxyprogesterone was dissolved in a mixture of 10 ml of acetic acid and 2 ml of acetic anhydride by heating. After solution was effected the mixture was cooled to 15°C, and 0.3 g of p-toluenesulfonic acid was added. After allowing the mixture to stand for a period of 2.5 hours at room temperature, the pink solution was poured into ice water to give an amorphous solid which was recovered by filtration.
The precipitate was washed carefully with water and was then dissolved in 10 ml of methanol and 1.5 ml of methylene chloride. The solution was concentrated to 10 ml, diluted with 0.5 ml of 10% sodium hydroxide, boiled for one minute and cooled. The product, which crystallized on cooling, was recrystallized to give flakes of 6α-methyl-17α-hydroxyprogesterone 17- acetate, having a MP 205° to 209°C, according to US Patent 3,147,290. - View all
- 9.9 Brand name
- Amen (Amarin); Curretab (Solvay Pharmaceuticals); Cycrin (ESI); Provera (Pharmacia & Upjohn);Clinovie;Cliovir;Dep0-clinover;Dep0-map;Depcorlutin;Depo-prodasone;Depo-progevera;Depo-promone;Deporone;Dugen;Farlurin;Farlutale;Gesinal;Gestapuran;Gestapuron;G-farlutal;Hysron;Intex;Luteocrin orale;Luteodione;Luteos;Lutoporal;Metigestene;Nadigest;Nogest;Onco-provera;Perlutest;Petogen;Piermap;Povera;Promone-e;Pronone;Proverone;Provest;Sindomens;Sodelut "g";Supprestal;Verafen;Veramix plus v.
- 9.10 Therapeutic Function
- Progestin
- 9.11 World Health Organization (WHO)
- A depot preparation containing 150 mg medroxyprogesterone acetate was introduced over 20 years ago for use as a long-acting injectable contraceptive. Subsequently, positive results of carcinogenicity studies carried out in beagle bitches led to refusal of registration in the United States. These findings were later considered irrelevant to contraceptive use in women and the drug was approved by the Food and Drug Administration. Menstrual irregularities are the most common adverse effect associated with depot medroxyprogesterone acetate. Risk-benefit judgements differ significantly from country to country, having regard to differing national circumstances. The preparation is, however, widely available and is included in the WHO Model List of Essential Drugs. (Reference: (WHTAC4) The Use of Essential Drugs, 4th Report of the WHO Expert Committee, 796, , 1990)
- 9.12 General Description
- MPA, 17-acetyloxy-6α-methylpregn-4-ene-3,20-dione (Provera), adds a6α-methyl group to the basic 17α-hydroxyprogesteronestructure to greatly decrease the rate of reduction of the 4-ene-3-one system. The 17α-acetate group also decreases reductionof the 20-one, similar to the 17α-caproate. MPA isvery active orally and has such a long durationof action intramuscularly that it cannot be routinely usedintramuscularly for treating many menstrual disorders. TheIM formulation is useful in the palliative treatment of advancedendometrial, breast, and renal carcinomas. MPA alsohas an important role in several birth control products (Depo-Provera, Depo-SubQ Provera 104).
- 9.13 General Description
- Odorless white to off-white microcrystalline powder.
- 9.14 Air & Water Reactions
- Medroxyprogesterone 17-acetate is sensitive to prolonged exposure to air and light. Insoluble in water.
- 9.15 Reactivity Profile
- Flammable and/or toxic gases are generated by the combination of alcohols with alkali metals, nitrides, and strong reducing agents. They react with oxoacids and carboxylic acids to form esters plus water. Oxidizing agents convert them to aldehydes or ketones. Alcohols exhibit both weak acid and weak base behavior. They may initiate the polymerization of isocyanates and epoxides.
- 9.16 Hazard
- Possible carcinogen.
- 9.17 Fire Hazard
- Flash point data for Medroxyprogesterone 17-acetate are not available; however, Medroxyprogesterone 17-acetate is probably combustible.
- 9.18 Biochem/physiol Actions
- Medroxyprogesterone 17-acetate (MPA) is a synthetic progestin used as a contraceptive, in hormone replacement therapy and for the treatment of endometriosis. It is a more potent progestin that the nonacetylated form.
- 9.19 Safety Profile
- Suspected carcinogen with experimental carcinogenic, neoplastigenic, tumorigenic, and teratogenic data. Human systemic effects by intravenous route: increased intraocular pressure. Human teratogenic effects by an unspecified route: developmental abnormalities of the urogenital system. Human reproductive effects by multiple routes: spermatogenesis, menstrual cycle changes or dlsorders, postpartum effects, female fertility effects, abortion, newborn behavioral effects. Human mutation data reported. Experimental reproductive effects. A drug for the treatment of secondary amenorrhoea and dysfunctional uterine bleeding. When heated to decomposition it emits acrid smoke and irritating fumes.
- 9.20 Veterinary Drugs and Treatments
- In cats, MPA has been used when either castration is ineffective or undesirable to treat sexually dimorphic behavior problems such as roaming, inter-male aggressive behaviors, spraying, mounting, etc. MPA has also been used as a tranquilizing agent to treat syndromes such as feline psychogenic dermatitis and alopecia, but treatment with “true” tranquilizing agents may be preferable.
In humans, parenteral MPA has been used as a long-acting contraceptive in females, to decrease sexually deviant behavior in males, and as an antineoplastic agent for some carcinomas (see Pharmacology section above). Oral MPA is used in human females to treat secondary amenorrhea and to treat abnormal uterine bleeding secondary to hormone imbalances.
- 9.21 Metabolism
- Among the first of these substituted 17α-acetoxyprogesterone analogues to be utilized therapeutically was medroxyprogesterone acetate, a 6α-methyl progesterone analogue. This analogue is 25-fold more active than ethisterone. Following oral administration, medroxyprogesterone acetate is completely and rapidly deacetylated by first-pass metabolism to medroxyprogesterone. Medroxyprogesterone is extensively metabolized via pathways similar to those for progesterone, except for 6α-hydroxylation. Most medroxyprogesterone acetate metabolites are excreted in the urine, primarily as glucuronide conjugates. Plasma protein binding for medroxyprogesterone is approximately 86%, primarily to serum albumin, with no binding to SHBG.
10. Computational chemical data
- Molecular Weight: 386.53g/mol
- Molecular Formula: C24H34O4
- Compound Is Canonicalized: True
- XLogP3-AA: null
- Exact Mass: 386.24570956
- Monoisotopic Mass: 386.24570956
- Complexity: 767
- Rotatable Bond Count: 3
- Hydrogen Bond Donor Count: 0
- Hydrogen Bond Acceptor Count: 4
- Topological Polar Surface Area: 60.4
- Heavy Atom Count: 28
- Defined Atom Stereocenter Count: 7
- Undefined Atom Stereocenter Count: 0
- Defined Bond Stereocenter Count: 0
- Undefined Bond Stereocenter Count: 0
- Isotope Atom Count: 0
- Covalently-Bonded Unit Count: 1
- CACTVS Substructure Key Fingerprint: AAADcfB4OAAAAAAAAAAAAAAAAAAAAYAAAAAwYIAAAAAAAGDAAAAAGgAAAAAAD0SAgAACCAAABACIAqDSCAIAAAAgAAAACAFAAEgAABIAAQQCAAAEgAAIAQOIyPCPgAAAAAAAAACAAAQAACAAAYAADAAAAA==
11. Question & Answer
-
Medroxyprogesterone Acetate is a synthetic form of progesterone, which is naturally secreted by the ovaries. It has a significant impact on the shape of the uterine lining stimulated by estrogen and i..
-
With the development of social work and increased mental stress, many people experience various cancerous changes such as breast cancer, endometrial cancer, and other types of cancer. Medroxyprogester..
-
Medroxyprogesterone Acetate is a synthetic progestin that is commonly used as a contraceptive. It is particularly suitable for individuals who have experienced threatened or habitual miscarriages, an..
-
Medroxyprogesterone Acetate is a progestin medication that acts on the endometrium of the uterus. It promotes the proliferation and secretion of the endometrium and inhibits the release of luteinizing..
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