Phenylbutazone

Phenylbutazone, often referred to as "bute," is a nonsteroidal anti-inflammatory, antipyretic, and analgesic drug (NSAID) for the short-term treatment of pain and fever results from rheumatoid arthritis, ankylosing spondylitis, gouty arthritis, and osteoarthritis. Phenylbutazone has been removed from the United States market due to the availability of newer drugs with less adverse effects. Phenylbutazone is a nonsteroidal anti-inflammatory drug (NSAID) effective in treating fever, pain, and inflammation in the body. As a group, NSAIDs are non-narcotic relievers of mild to moderate pain of many causes, including injury, menstrual cramps, arthritis and other musculoskeletal conditions.
Phenylbutazone Basic information
Abstract Chemical Property Mechanism of action Pharmacokinetic Study Attention and Taboo Preparation Acute toxicity Flammability hazard properties Storage characteristics Extinguishing agent References
Product Name:Phenylbutazone
Synonyms:Ecobutazone;Elmedal;Equi bute;equibute;equipalazone;Eributazone;'Esteve';exrheudonn
CAS:50-33-9
MF:C19H20N2O2
MW:308.37
EINECS:200-029-0
Product Categories:API;AZOLID;Heterocycles;Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals;50-33-9
Mol File:50-33-9.mol
Phenylbutazone Structure
Phenylbutazone Chemical Properties
Melting point 106-108 °C (lit.)
Boiling point 448.76°C (rough estimate)
density 1.1591 (rough estimate)
refractive index 1.6140 (estimate)
storage temp. 2-8°C
solubility Practically insoluble in water, sparingly soluble in alcohol. It dissolves in alkaline solutions.
form Powder
pka4.5(at 25℃)
color White to almost white
Water Solubility <0.1 g/100 mL at 23.5 ºC
Merck 14,7277
BRN 290080
Stability:Stable. Incompatible with strong oxidizing agents, strong acids, strong bases.
InChIKeyVYMDGNCVAMGZFE-UHFFFAOYSA-N
LogP3.160
CAS DataBase Reference50-33-9(CAS DataBase Reference)
NIST Chemistry ReferencePhenylbutazone(50-33-9)
IARC3 (Vol. 13, Sup 7) 1987
EPA Substance Registry SystemPhenylbutazone (50-33-9)
Safety Information
Hazard Codes Xn,T,F
Risk Statements 36/37/38-20/21/22-42/43-45-36-11
Safety Statements 36/37/39-26-45-22-53-36/37-16
RIDADR 3249
WGK Germany 3
RTECS UQ8225000
TSCA Yes
HazardClass 6.1(b)
PackingGroup III
HS Code 29331990
Hazardous Substances Data50-33-9(Hazardous Substances Data)
ToxicityLD50 oral in rabbit: 781mg/kg
MSDS Information
ProviderLanguage
4-Butyl-1,2-diphenyl-3,5-pyrazolidinedione English
ACROS English
ALFA English
Phenylbutazone Usage And Synthesis
AbstractPhenylbutazone, often referred to as "bute,"is a nonsteroidal  anti-inflammatory, antipyretic, and analgesic drug (NSAID) for the short-term treatment of pain and fever results from rheumatoid arthritis, ankylosing spondylitis, gouty arthritis, and osteoarthritis.
Phenylbutazone has been removed from the United States market due to the availability of newer drugs with less adverse effects. Phenylbutazone is a nonsteroidal anti-inflammatory drug (NSAID) effective in treating fever, pain, and inflammation in the body. As a group, NSAIDs are non-narcotic relievers of mild to moderate pain of many causes, including injury, menstrual cramps, arthritis and other musculoskeletal conditions.
Chemical PropertyIt is soluble in acetone, chloroform or benzene freely; soluble in ethanol or ether; hardly soluble in water; soluble in sodium hydroxide solution.
Mechanism of actionRecent studies have found that the generating mechanism from phenylbutazone anti-inflammatory, analgesic and anti-rheumatic effect is not due to pituitary-adrenal excitement may be due to drugs that inhibit the generation of inflammatory tissue inflammation related active substances, such as synthesis of prostaglandins, white blood cells activities and transfer, release and activity of lysosomal enzymes; pain may also inhibit prostaglandin synthesis results.
Pharmacokinetic StudyOral absorption effect is quickly and completely, reached the peak plasma concentration after about 2 hours. Plasma protein binding rate is 98%. The apparent volume of distribution is 0.12L/kg, such as increasing the dose, volume of distribution has also increased, but the blood concentration does not increase. Therefore, when using repeatedly, the steady-state plasma concentration does not increase linearly. The half-life is 56 to 86 hours. It can cross the placenta into the milk. This product is metabolized by the liver, metabolites is hydroxy phenylbutazone and γ-hydroxy phenylbutazone, still active, The final metabolites are excreted in urine and a small amount of bile is excreted through the urine.
Attention and TabooThe side effects of phenylbutazone incidence rate is about 10%~20%, gastrointestinal irritation can cause nausea, vomiting, abdominal pain, constipation, overdose can cause peptic ulcer, blood in the stool. Damages also occur in other systems, such as rash, dizziness, hematuria, hepatitis, etc. Inhibit the bone marrow caused by neutropenia, or even aplastic anemia, such as the timely withdrawal is more recoverable and therefore should be ground check blood, no effect by 1 week, should not be reused. And double coumarin anticoagulants, sulfonamides, tolbutamide hypoglycemic drugs, increase the plasma concentration, toxicity increases. Sodium, chlorine retention effect, hypertension, edema, heart failure patients cannot use it and limit salt intake during the treatment. Patients with weak liver, osteoporosis, and kidney as well as drug allergy history are contraindicated or appropriate caution.
PreparationCyclization reaction of hydrogenated azobenzene and diethylmalonic acid diethyl: hydrazobenzene, butyl diethyl malonate, sodium sulfite and methanol are heated with severe reflux 1.5h, born in Bute salt, acidified with acetic acid to give Bute.
Acute toxicityoral-rat LD50: 245 mg/kg; Oral-Mouse LD50: 270 mg/kg
Irritation Data: Eye – rabbit, 100 mg, moderate
Flammability hazard propertiesthermal decomposition emitted poisonous nitrogen oxides fumes
Storage characteristicsTreasury ventilation low-temperature drying; and food raw materials stored separately
Extinguishing agentWater, carbon dioxide, dry powder, foam
Referenceshttps://en.wikipedia.org/wiki/Phenylbutazone
https://pubchem.ncbi.nlm.nih.gov/compound/phenylbutazone#section=Top
http://www.medicinenet.com/phenylbutazone/article.htm

Chemical PropertiesOff-Whtie Solid
OriginatorButazolidin, Geigy ,US,1952
UsesA non-steroidal anti-inflammatory compound. An inhibitor of cyclooxygenase that is also a substrate for peroxidation by cyclooxygenase
UsesAn inhibitor of Cox.
UsesFor the treatment of backache and ankylosing spondylitis
UsesPhenylbutazone, a nonsteroidal anti-inflammatory drug, is an efficient reducing cofactor for the peroxidase activity of COX. Phenylbutazone-dependent inactivation of COX and prostacyclin synthase is markedly increased in the presence of 100 μM hydrogen peroxide with half-maximal effects at Phenylbutazone concentrations of 100 and 25 μM for COX and prostacyclin synthase, respectively.
DefinitionChEBI: Phenylbutazone is a member of the class of pyrazolidines that is 1,2-diphenylpyrazolidine-3,5-dione carrying a butyl group at the 4-position. It has a role as a non-narcotic analgesic, a non-steroidal anti-inflammatory drug, an antirheumatic drug, a peripheral nervous system drug, a metabolite and an EC 1.1.1.184 [carbonyl reductase (NADPH)] inhibitor.
Manufacturing Process7.6 parts of sodium are dissolved in 190 parts by volume of absolute alcohol; 65 parts of diethyl-n-butyl malonate and 65 parts of hydrazobenzene are added. The alcohol is slowly distilled off and the reaction mixture heated for 12 hours at a bath temperature of 150°C and finally in vacuo, until no more alcohol comes off.
The product is dissolved in water, clarified with a little animal charcoal and 15% hydrochloric acid is slowly added until an acid reaction to Congo red paper is produced. 1,2-Diphenyl-3,5-dioxo-4-n-butyl-pyrazolidine separates as an oil, which rapidly become crystalline. It crystallizes from alcohol as colorless needles with a MP of 105°C.
Brand nameAzolid (Sanofi Aventis); Butazolidin (Novartis);Algesin;Algirreudin;Algoverine;Alka butazolidin;Alkabutazone;Alka-phenylbutazone;Alka-sterazolidin;Anarthral;Apophenylbutazone;Apo-phenylbutazone;Arteopan;Arthirikin;Artibrin;Artrisin;Artrodesmol extra;Bizolin 20;Bizolin 700;Butacal;Butacol;Butadilat;Butadin;Butadyne;Butafenil;Butagros;Butakvertin;Butaparin;Butaphen;Buta-phen;Butarex;Butartiril;Butatril;Butazolidin alka;Butazolidina;Butial;Butinol;Butiwas;Buto beta;Butoroid cream;Butrex;Carudol;Celestalgon;Celestazone;Colfezone;Corbuvit;Dartranol;Debutazon;Delta-butazolidin;Delta-demoplas;Delta-myogit;Delta-tomanol;Deltawaukobuzon;Dephimixn;Dexa tomanol;Dexa-attritin;Dexa-escopyrin;Dexamed;Dexatrzona;Dibuzon;Direstop;Ditrone;Doctofril;Dolosin dexa;Dolpirina;Ectobutazone;Ethibute;Exraheudon;Exrheudon;F 650;Fenibutina;Flebosil;Glycyl;Hepabuzon;Inflazone;Intrabuzone;Mammyl;Megazone;Mepha-butazone;Mepropyrin;Mi 540;Naupax;Neuro-demoplas;Neuzoline m;Novobutazone;Oluprin;Oppazoen;Osadrinim;Parazolidin;Parzolidon;Pasirheuman;Penetradol;Phenbuff;Phenbutazone;Phenylarthrite;Phenylbetazone;Phenylon plus;Phlebolan;Pirabutil;Pirarreumol-b;Pirarreumol-p;Prebutex;Precirhemin;Prednirheumin;Proxyfezone;Proydynam;Pyrbutal;Ranocor;Reopin;Reumilene;Rheopyrin;Rheosolon;Rheumanoln;Rheumaphen;Rheumycalm;Salzone;Servizolidin;Sigma-elmedal;Sintobutina;Stabilat;Tevocodyn;Tibutazone;Ticinil calcio;Ticinil calico;Trabit;Zolapelin;Zolidinium.
Therapeutic FunctionAntiinflammatory, Antiarthritic
World Health Organization (WHO)Phenylbutazone, a pyrazolone derivative with anti-inflammatory, analgesic and antipyretic activity, was introduced in 1949 for the treatment of rheumatic disorders. Its use was subsequently associated with serious and sometimes fatal adverse reactions, notably cases of aplastic anaemia and agranulocytosis. Many national drug regulatory authorities consider that more recently introduced drugs offer a safer alternative for most, if not all, patients requiring anti-inflammatory agents. Phenylbutazone has thus been either withdrawn at the national level or retained with rigorously restricted indications for patients unresponsive to other therapy. These restrictions also apply, in general, to combination products containing phenylbutazone.
General DescriptionOdorless white or off-white crystalline powder. Tasteless at first, but slightly bitter aftertaste. pH (aqueous solution) 8.2.
Air & Water ReactionsPhenylbutazone is relatively stable at ambient temperatures. Aqueous decomposition of Phenylbutazone occurs by hydrolysis and oxidation. Insoluble in water.
Reactivity ProfilePhenylbutazone is incompatible with strong oxidizers, strong acids and strong bases. .
Fire HazardFlash point data for Phenylbutazone are not available; however, Phenylbutazone is probably combustible.
Biochem/physiol ActionsPhenylbutazone is a hepatotoxin and binds to plasma proteins. It is used to treat inflammation in horse. Phenylbutazone has potential to treat ankylosing spondylitis. It has therapeutic potential to treat myotonic dystrophy type 1 (DM1) by inducing muscle blind-like protein 1 (MBNL1) expression. It also favors the expression of muscle chloride channel in skeletal muscles.
Safety ProfileSuspected human carcinogen producing leukemia. A human poison by parenteral route. An experimental poison by ingestion, intraperitoneal, subcutaneous, intravenous, and intramuscular routes. Human systemic effects by ingestion and possibly other routes: fever, blood pressure increase, other unspecified vascular effects, damage to kidney tubules and glomeruli, decreased urine volume, blood in the urine, reduction in the number of whte blood cells, and agranulocytosis. Experimental teratogenic and reproductive effects. Human mutation data reported. An eye irritant. An antiinflammatory agent. When heated to decomposition it emits toxic fumes of NOx
SynthesisPhenylbutazone, 4-butyl-1,2-diphenyl-3,5-pyrazolidinedione (3.2.6), is synthesized in a single stage by reacting hydrazobenzol with butylmalonic ester [68,69].

Synthesis_50-33-9

Veterinary Drugs and TreatmentsOne manufacturer lists the following as the indications for phenylbutazone: “For the relief of inflammatory conditions associated with the musculoskeletal system in dogs and horses.” (Package Insert; Butazolidin?—Coopers). It has been used primarily for the treatment of lameness in horses and, occasionally, as an analgesic/ antiinflammatory, antipyretic in dogs, cattle, and swine.
Purification MethodsCrystallise the dione from EtOH. Its pK2 3 is 4.52 (in H2O), 4.89 (in 50% aqueous EtOH) and 5.25 (80% 2-methoxyethanol). It complexes with Hg2+, Cd2+ and Zn2+. It has UV with max at 239.5nm in MeOH+50% aqueous HClO4 and 264nm in aqueous 0.1N NaOH. [Beilstein 24 III/IV 1123.]
Phenylbutazone Preparation Products And Raw materials
Raw materialsSodium Methoxide-->1-Butanol-->Sodium sulfite-->Sodium ethoxide-->Diethyl malonate-->1,2-Diphenylhydrazine-->Diethyl butylmalonate-->Phenylbutazone sodium-->Sodium-->Ethanol
Preparation Products4-hydroxyphenylbutazone
Feclobuzone PHENYLBUTAZONE (DIPHENYL-D10) tribuzone PROPACETAMOL HYDROCHLORIDE - REFERENCE SPECTRUM (+/-)-Sulfinpyrazone 4-BUTYL-4-[HYDROXYMETHYL]-1,2-DIPHENYL-3,5-PYRAZOLIDINEDIONE HYDROGEN SUCCINATE [ESTER] PHENYLBUTAZONE-D9 proxifezone Phenylacetone Phenylbutazone lithium OXYPHENBUTAZONE HYDRATE BUTYL OLEATE Zolpidem tartrate PHENYLBUTAZONE SODIUM PHENYLBUTAZONE,1.0MG/MLINACETONITRILE Phenylbutazone magnesium KETOPHENYLBUTAZONE PHENYLBUTAZONE IMP. C (EP): 1,2-DIPHENYLDIAZANE(1,2-DIPHENYLHYDRAZINE)

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