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Pyrimethamin
Pyremethamine · Daraprim · Fansidar · Chloridine · Pirimetamina · PYRIMETHAMIN · wr2978 · bw50-63
Identifikatoren & physikalische Daten
| CAS No. | 58-14-0 |
|---|---|
| Summenformel | C12H13ClN4 |
| Durchschnittliche Molmasse | 248,71 g/mol |
| Monoisotopische Masse | 248,0828741 g/mol |
| SMILES | CCc1nc(N)nc(N)c1-c1ccc(Cl)cc1 |
| InChIKey | WKSAUQYGYAYLPV-UHFFFAOYSA-N |
| PubChem CID | 4993 |
| ChEMBL | CHEMBL36 |
| ChEBI | CHEBI:8673 |
| EC No. | 200-364-2 |
| DTXSID | DTXSID9021217 |
| Lokaler Name | Pyrimethamin |
Chemische & physikalische Eigenschaften
| XLogP | 2,7 |
|---|---|
| Polarare Oberfläche (TPSA) | 77,8 |
| H-Brücken-Donoren | 2 |
| H-Brücken-Akzeptoren | 4 |
| Frei drehbare Bindungen | 2 |
| Schwere Atome | 17 |
| Formalladung | 0 |
| Komplexität | 243 |
| Arzneimittel | Pharmaceuticals -> Listed in ZINC15 |
| SpringerMaterials Properties | 15N nuclear magnetic resonance spectrum |
| LogP (Verteilungskoeffizient) | log Kow = 2.692.7 |
| Color/Form | CrystalsWhite scored tablets contains 25 mg pyrimethamine /Daraprim/ |
| Löslichkeit | less than 0.1 mg/mL at 70 °F (NTP, 1992)In water, 10 mg/L (temperature not specified)Practically insoluble in waterslightly soluble in ethanol (about 9 g/L), in dilute HCl (about 5 g/L)soluble in boiling ethanol (about 25 g/L)Very sparingly soluble in propylene glycol and dimethylacetamide at 70 °C1.79e-01 g/L>37.3 [ug/mL] (The mean of the results at pH 7.4)Prepare the solution immediately before use. Dissolve 0.25 g in a mixture of 1 volume of methanol R and 3 volumes of methylene chloride R and dilute to 10 mL with the same mixture of solvents. The solution is clear (2.2.1) and not more intensely coloured than reference solution BY6 (2.2.2, Method II).<0.01 g/100 mL at 21 ºC |
| Human Drugs | Breast FeedingLactationMilk, HumanAnti-infective AgentsAntiparasitic AgentsAntimalarialsAntiprotozoal AgentsFDA approved drugs -> Active ingredientAntipneumocystosis and antitoxoplasmosis medicines |
| Animal Drugs | Active Ingredients (Pyrimethamine) -> FDA GreenbookPharmaceuticals -> Animal Drugs -> Approved in Taiwan |
| Decomposition | When heated to decomposition it emits very toxic fumes of /HCl and oxides of nitrogen/. |
| Schmelzpunkt | 451 to 453 °F (capillary) (NTP, 1992)233-234 °C (capillary)240-242 °C (copper block)233.5 °C233-234°C |
| Physical Description | Pyrimethamine is an odorless white crystalline powder. Tasteless. An antimalarial drug.Solid |
| Dissociation Constants | 7.34 (at 20 °C)pKa = 7.34 at 20 °C (conjugate acid) |
| Collision Cross Section | 158.8 Ų [M+H]+ [CCS Type: DTBuffer gas: N2Ionization: APCI+Dataset: TOXCASTSource Identifier: DTXSID9021217]155.8 Ų [M+H]+ [CCS Type: TWMethod: calibrated with polyalanine and drug standards]153.6 Ų [M+Na]+ [CCS Type: TW |
| Siedepunkt | 393.35°C (rough estimate) |
| Dichte | 1.2171 (rough estimate) |
| Brechungsindex | 1.6110 (estimate) |
| Lagerbedingungen | Keep in dark place,Inert atmosphere,Room temperature |
| Aggregatzustand | Solid |
| pKa (Säurekonstante) | pKa 7(t=20.0) (Uncertain) |
| Farbe | White to Off-White |
| Merck | 14,7985 |
| BRN | 219864 |
| Henry-Konstante | 9.1×104 mol/(m3Pa) at 25℃, HSDB (2015) |
| BCS Class | 2 (CLogP), 4 (LogP),3 |
| Stabilität | Stable, but light sensitive. Combustible. Incompatible with strong oxidizing agents. |
| Hauptanwendungen | clinical testing |
| InChI | 1S/C12H13ClN4/c1-2-9-10(11(14)17-12(15)16-9)7-3-5-8(13)6-4-7/h3-6H,2H2,1H3,(H4,14,15,16,17) |
| InChIKey | WKSAUQYGYAYLPV-UHFFFAOYSA-N |
| SMILES | CCC1=NC(N)=NC(N)=C1C2=CC=C(Cl)C=C2 |
| CAS Datenbank | 58-14-0(CAS DataBase Reference) |
| NIST chemische Informationen | Pyrimethamine(58-14-0) |
| EPA chemische Informationen | Pyrimethamine (58-14-0) |
Sicherheit & Vorschriften
| GHS-Einstufung | WarningH302 (99.2%): Harmful if swallowed [Warning Acute toxicity, oral]P264, P270, P301+P317, P330, and P501 (click each P-code to see the statement)Aggregated GHS information provided per 133 reports by companies from 7 notifications to the ECHA C&L Inventory. |
|---|---|
| Regulatorische Informationen | Hazard Traits - Developmental Toxicity |
| Weitere Sicherheitsinformationen | IMAP assessments - 2,4-Pyrimidinediamine, 5-(4-chlorophenyl)-6-ethyl-: Environment tier I assessment |
| DOT-Kennzeichnung | Poison |
| Brandgefahren | Flash point data for this chemical are not availablehowever, it is probably combustible. (NTP, 1992) |
| Gesundheitsgefahren | SYMPTOMS: Symptoms of exposure to this compound include megaloblastic anemia, leukopenia, thrombocytopenia, pancytopenia, atrophic glossitis, vomiting, convulsions, respiratory failure and death. Chronic exposure may cause depression of hemopoiesis due to interference in the metabolism of folic acid. Skin rashes may also occur. |
| FDA-Anforderungen | The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including pyrimethamine, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.Oral dosage form new animal drug. Sulfadiazine/pyrimethamine suspension. ... For the treatment of equine protozoal myeloencephalitis (EPM) caused by Sarcocystis neurona. Limitations: Do not use in horses intended for human consumption. Federal law restricts this drug to use by or on the order of a licensed veterinarian.The Generic Animal Drug and Patent Restoration act requires that each sponsor of an approved animal drug must submit to the FDA certain information regarding patents held for the animal drug or its method of use. The Act requires that this information, as well as a list of all animal drug products approved for safety and effectiveness, be made available to the public. Pyrimethamine is included on this list. |
| Reaktive Gruppe | Amines, Phosphines, and Pyridines |
| Reactivity Profile | PYRIMETHAMINE is sensitive to exposure to light (NTP, 1992). Neutralizes acids to form salts plus water in exothermic reactions. May be incompatible with isocyanates, halogenated organics, peroxides, phenols (acidic), epoxides, anhydrides, and acid halides. Flammable gaseous hydrogen may be generated in combination with strong reducing agents, such as hydrides. |
| Air and Water Reactions | Insoluble in water. |
| Hazard Classes and Categories | Acute Tox. 4 (99.2%) |
| Brandbekämpfung | Fires involving this material can be controlled with a dry chemical, carbon dioxide or Halon extinguisher. (NTP, 1992) |
| Erste Hilfe | EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop. |
| Lagerbedingungen | Store at 15 deg to 25 °C (59 deg to 77 °F) in a dry place and protect from light. |
| Freisetung ohne Brand | SMALL SPILLS AND LEAKAGE: If a spill of this chemical occurs, FIRST REMOVE ALL SOURCES OF IGNITION, then you should dampen the solid spill material with acetone and transfer the dampened material to a suitable container. Use absorbent paper dampened with acetone to pick up any remaining material. Seal your contaminated clothing and the absorbent paper in a vapor-tight plastic bag for eventual disposal. Solvent wash all contaminated surfaces with acetone followed by washing with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned. |
| Entsorgungsverfahren | SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash. |
| Isolation and Evacuation | Excerpt from ERG Guide 154 [Substances - Toxic and/or Corrosive (Non-Combustible)]: |
| Personal Protective Equipment (PPE) | RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with a combination filter cartridge, i.e. organic vapor/acid gas/HEPA (specific for organic vapors, HCl, acid gas, SO2 and a high efficiency particulate filter). (NTP, 1992) |
| Wechselwirkungen | Although the clinical importance is unclear, mild hepatotoxicity has been reported in some patients receiving pyrimethamine and lorazepam concomitantly.Although the clinical importance is unclear, p-aminobenzoic acid (PABA) reportedly interferes with the action of pyrimethamine and probably should not be used in patients receiving pyrimethamine.An increased incidence and severity of adverse effects has been reported when chloroquine was used concomitantly with the fixed combination of sulfadoxine and pyrimethamine compared with use of the fixed combination alone. Sulfadoxine and pyrimethamine is compatible with quinine and with other anti-infectives.Concomitant use of pyrimethamine or sulfadoxine and pyrimethamine with other antifolate agents (e.g., sulfonamides, co-trimoxazole, trimethoprim) is not recommended since such use may increase the risk of bone marrow suppression. If signs of folate deficiency develop, pyrimethamine or sulfadoxine and pyrimethamine should be discontinued and leucovorin administered (if necessary) until normal hematopoiesis is restored.For more Interactions (Complete) data for Pyrimethamine (6 total), please visit the HSDB record page. |
| Umweltverhalten | TERRESTRIAL FATE: Based on a classification scheme(1), estimated Koc values of 1540 and 590(SRC), determined from a structure estimation method(2) and from a log Kow of 2.69(3) and a regression-derived equation(2) respectively, indicate that pyrimethamine is expected to have low mobility in soil(SRC). The pKa of pyrimethamine is 7.34(4), indicating that this compound will exist in cation formin the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(5). Also, aromatic amines are expected to bind strongly to humus or organic matter in soils due to the high reactivity of the aromatic amino group(6,7), suggesting that pyrimethamine may be immobile in some soils(SRC). Volatilization of pyrimethamine from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.08X10-10 atm-cu m/mole(SRC), using a fragment constant estimation method(2). Pyrimethamine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.32X10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(2).AQUATIC FATE: Based on a classification scheme(1), estimated Koc values of 1540 and 590(SRC), determined from a structure estimation method(2) and from a log Kow of 2.69(3) and a regression-derived equation(2) respectively, indicate that pyrimethamine is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(4) based upon an estimated Henry's Law constant of 1.08X10-10 atm-cu m/mole(SRC), developed using a fragment constant estimation method(2). According to a classification scheme(5), an estimated BCF of 28(SRC), from its log Kow and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Pyrimethamine is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(4).ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), pyrimethamine, which has an estimated vapor pressure of 1.32X10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase pyrimethamine is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC)the half-life for this reaction in air is estimated to be 2 hours(SRC), calculated from its rate constant of 2.0X10-10 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(2). Particulate-phase pyrimethamine may be removed from the air by wet or dry deposition(SRC). |
| Expositionspfade | Well absorbed with peak levels occurring between 2 to 6 hours following administration |
| Milk Concentrations | The concentration of chloroquine, dapsone and pyrimethamine in plasma and milk were measured following the coadministration of a single dose of chloroquine and Maloprim to lactating women. The milk to plasma area under the concentration-time curve (AUC) ratio ranged from 1.96 to 4.26 for chloroquine, 0.22 to 0.45 for dapsone and 0.46 to 0.66 for pyrimethamine. Assuming a daily milk ingestion of 1 l by the infant, the maximum percentage of the maternal dose for chloroquine, dapsone and pyrimethamine in milk was 4.2%, 14.3% and 45.6%, respectively, over a 9 day period.Pyrimethamine was detected in raw bovine milk samples collected in Spain at a concentration of 0.15 ug/kg(1) and in whole milk samples at a concentration of 0.21 ug/kgconcentrations in skim milk samples ranged from 0.07-0.17 ug/kg(1).Pyrimethamine is excreted into milk. It is estimated that approximately 3-4 mg of the drug would be ingested by a nursing infant over the first 48-hour period following administration of a single 75-mg oral dose to the mother. |
| Toxizitätsübersicht | Pyrimethamine inhibits the dihydrofolate reductase of plasmodia and thereby blocks the biosynthesis of purines and pyrimidines, which are essential for DNA synthesis and cell multiplication. This leads to failure of nuclear division at the time of schizont formation in erythrocytes and liver. |
| Ongoing Test Status | The following link will take the user to the National Toxicology Program (NTP) Test Agent Search Results page, which tabulates all of the "Standard Toxicology & Carcinogenesis Studies", "Developmental Studies", and "Genetic Toxicity Studies" performed with this chemical. Clicking on the "Testing Status" link will take the user to the status (i.e., in review, in progress, in preparation, on test, completed, etc.) and results of all the studies that the NTP has done on this chemical.[Available from, as of June 21, 2012: http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=ntpsearch.searchresults&searchterm=58-14-0] |
| Soil Adsorption/Mobility | The pKa of pyrimethamine is 7.34(1), indicating that this compound will exist partially in cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(2). Because pyrimethamine ionizes in the environment, two estimated Koc values have been calculated(SRC). Using a structure estimation method based on molecular connectivity indices(3), the Koc of pyrimethamine can be estimated to be 1540(SRC). The Koc of pyrimethamine is estimated as 590(SRC), using a log Kow of 2.69(4) and a regression-derived equation(3). According to a classification scheme(5), these estimated Koc values suggest that pyrimethamine is expected to have low mobility in soil. Also, aromatic amines are expected to bind strongly to humus or organic matter in soils due to the high reactivity of the aromatic amino group(6,7), suggesting that pyrimethamine may be immobile in some soils(SRC). |
| Human Toxicity Excerpts | /SIGNS AND SYMPTOMS/ Following the ingestion of 300 mg or more of pyrimethamine, gastrointestinal and/or central nervous system signs may be present, including convulsions. The initial symptoms are usually gastrointestinal and may include abdominal pain, nausea, severe and repeated vomiting, possibly including hematemesis. Central nervous system toxicity may be manifest by initial excitability, generalized and prolonged convulsions which may be followed by respiratory depression, circulatory collapse, and death within a few hours. Neurological symptoms appear rapidly (30 minutes to 2 hours after drug ingestion), suggesting that in gross overdosage pyrimethamine has a direct toxic effect on the central nervous system./CASE REPORTS/ There have been at least 2 reports of cancer associated with long-term use of pyrimethamine for the treatment of toxoplasmosisone 51-year-old woman developed chronic granulocytic leukemia after receiving the drug for 2 years and one 56-year-old patient developed reticulum cell sarcoma after receiving the drug for 14 months./CASE REPORTS/ Toxoplasmosis is one of the life-threatening infections that can occur after hematopoietic stem cell transplantation (HSCT) and also solid organ transplantation. The standard treatment for toxoplasmosis is combination therapy with pyrimethamine and sulfadiazine, both of which inhibit folate metabolism. Therefore, therapy with these agents could result in marrow toxicity including megaloblastic anemia or pancytopenia, which is reversible or preventable with folate supplementation. Transplant-associated microangiopathy (TAM) is another situation where folate is required to compensate for increased erythropoiesis due to hemolysis after allogeneic HSCT. Here, we report a case of severe marrow toxicity manifesting as pancytopenia due to low-dose pyrimethamine, which was triggered by TAM after HSCT./CASE REPORTS/ Curative treatment of congenital toxoplasmosis is based on the association of pyrimethamine and sulfonamide. There is currently no pediatric galenic formulation. /The investigators/ report the case of a newborn child affected by asymptomatic congenital toxoplasmosis who received an overdose of pyrimethamine. The patient received a dose of pyrimethamine 4 times, equal to 100 times the recommended dose, due to an error in the prescription. He had partial seizures 48 h after the last medicinal absorption. /The investigators/ noted a lack of appetite and vomiting, with a favorable progression in 5 days. Blood analysis showed isolated, spontaneously regressive moderate cholestasis.For more Human Toxicity Excerpts (Complete) data for Pyrimethamine (11 total), please visit the HSDB record page. |
| Artificial Pollution Sources | Pyrimethamine's production and use as an antimalarial and antiprotozoal drug(1) may result in its release to the environment through various waste streams(SRC). |
| Carcinogen Classification | PyrimethamineGroup 3: Not classifiable as to its carcinogenicity to humansVolume 13: (1977) Some Miscellaneous Pharmaceutical Substances1987 |
| Drug Induced Liver Injury | Drug Induced Liver Injury Rank (DILIrank 2.0)PyrimethaminevLess-DILI-concern3Warnings & precautionsDOI:10.1016/j.drudis.2016.02.015 |
| Environmental Bioconcentration | An estimated BCF of 28 was calculated in fish for pyrimethamine(SRC), using a log Kow of 2.69(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC). |
| Wassergefährdungsklasse (WGK) | 3 |
| UN-Transportnummer | 3249 |
| Zollcode | 29335990 |
| RTECS-Nr. | UV8140000 |
| R-Sätze (R) | 22-36 |
| Toxizität | LD50 oral in rat: 440mg/kg |
| Gefahrensymbole | Xn |
| Sicherheitshinweise (S) | 26 |
| Gefahrenklasse | 6.1(b)Acute Tox. 4 Oral |
| Verpackungsgruppe | III |
| Lagerklasse | 11 - Combustible Solids |
| Gefahrstoffdaten | 58-14-0(Hazardous Substances Data) |
Anwendungen & Verwendung
Verwenden
For the treatment of toxoplasmosis and acute malaria; For the prevention of malaria in areas non-resistant to pyrimethamine. Pyrimethamine is a dihydrofolate reductase inhibitor, like the biguanides, and is structurally related to trimethoprim. It is seldom used alone. Pyrimethamine in fixed combinations with dapsone or sulfadoxine is used for treatment and prophylaxis of chloroquine-resistant falciparum malaria. The synergistic activities of pyrimethamine and sulfonamides are similar to those of trimethoprim/sulfonamide combinations. Resistant strains of Plasmodium falciparum have appeared world wide. Prophylaxis against falciparum malaria with pyrimethamine alone is therefore not recommended. Most strains of Plasmodium vivax have remained sensitive. Pyrimethamine is also used in combination with a sulfonamide for the treatment of Toxoplasmosis. It is slowly absorbed from the gastrointestinal tract with peak plasma levels 4–6 hours after dosing. Pyrimethamine is bound to plasma proteins and is extensively metabolized before excretion. Its elimination half-life is 3–5 days.