446-86-6 Usage
Application in Particular Diseases
In Rheumatic Arthritis:
Azathioprine is a purine analog that is converted to 6-mercaptopurine and is thought to interfere with DNA and RNA synthesis. Antirheumatic effects may be seen in 3 to 4 weeks. It should be discontinued if no response is observed after 12 weeks at maximal doses. Its major adverse effects are bone marrow suppression (leukopenia, macrocytic anemia, thrombocytopenia, pancytopenia), stomatitis, GI intolerance, infections, drug fever, hepatotoxicity, and oncogenic potential.
Description
This immunosuppressive and antineoplastic drug is
derived from 6-mercaptopurine. It caused occupational
dermatitis in a pharmaceutical worker, reconditioner
of old tablet packaging machines and in a production
mechanic, working in packaging for a pharmaceutical
company.
Chemical Properties
Different sources of media describe the Chemical Properties of 446-86-6 differently. You can refer to the following data:
1. Yellow Solid
2. Azathioprine is a complex heterocyclic
compound which forms pale yellow crystals.
Originator
Imuran,Wellcome,UK,1964
Uses
Different sources of media describe the Uses of 446-86-6 differently. You can refer to the following data:
1. Azathioprine is an immunosuppressive purine antimetabolite. The mechanism of action of azathioprine is as a nucleic acid synthesis inhibitor. It has shown promise in treatment of alopecia areata (autoimmune hair loss), with no difference in effectiveness between genders.
2. immunosuppressant, antineoplastic, antirheumatic
3. An immunosuppressive antimetabolite. Also active as disease modifying antirheumatic drug (DMARD). Azathioprine is a purine analog with immunosuppressive effects.
Definition
ChEBI: A thiopurine that is 6-mercaptopurine in which the mercapto hydrogen is replaced by a 1-methyl-4-nitroimidazol-5-yl group. It is a prodrug for mercaptopurine and is used as an immunosuppressant, prescribed for the treatment of inflammatory conditions and a
ter organ transplantation and also for treatment of Crohn's didease and MS.
Indications
Azathioprine (Imuran) is a cytotoxic agent that preferentially
destroys any rapidly dividing cell. Since immunologically
competent cells are generally rapidly dividing
cells, azathioprine is very effective as an
immunosuppressive drug. Unfortunately, any cell that is
replicating is a target for this action. This lack of specificity
leads to serious side effects.
Azathioprine, in combination with corticosteroids,
has historically been used more widely than any other
drug in immunosuppressive therapy. It is classified as a
purine antimetabolite and is a derivative of 6-mercaptopurine.
Manufacturing Process
N,N'-Dimethyloxaldiamide is reacted with PCl5, to give 4-chloro-1-methyl
imidazole. This is nitrated with HNO3 to give 5-nitro-1-methyl-4-
chloroimidazole. Then, a mixture of 4.6 grams of anhydrous 6-
mercaptopurine, 5 grams of 1-methyl-4-chloro-5-nitroimidazole and 2.5 grams
of anhydrous sodium acetate in 100 ml of dry dimethyl sulfoxide was heated
at 100°C for 7 hours.
After standing overnight at room temperature, the mixture was poured into
200 ml of cold water and the yellow precipitate of 6-(1'-methyl-4'-nitro-5'-
imidazolyl)mercaptopurine (7.0 grams) collected. After recrystallization from
50% aqueous acetone, the product melted at 243-244°C, dec., and had an UV
spectrum with λ maximum = 280 nm at pH 1 and λ max. = 285 nm at pH 11.
Brand name
Imuran (Promethus).
General Description
Pale yellow crystals or yellowish powder. Decomposes at 243-244°C. Used for the treatment of rheumatoid arthritis. A known carcinogen.
Air & Water Reactions
Sensitive to oxidation in the air. Insoluble in water.
Reactivity Profile
Azathioprine may react exothermically with acids. Incompatible with isocyanates, peroxides, phenols, epoxides, anhydrides, and acid halides. Hydrolyzed by strongly basic solutions . May react with strong reducing agents to generate flammable gaseous hydrogen or hydrogen sulfide.
Hazard
Confirmed carcinogen.
Fire Hazard
Flash point data for Azathioprine are not available. Azathioprine is probably combustible.
Contact allergens
This immunosuppressive and antineoplastic drug is
derived from 6-mercaptopurine. It caused allergic contact
dermatitis in a mother crushing tablets for her leukemic
son, and occupational dermatitis in a pharmaceutical
reconditioner of old tablet packaging machines, and in a
production mechanic working in packaging for a pharmaceutical
company.
Biochem/physiol Actions
Has shown promise in treatment of alopecia areata (autoimmune hair loss), with no difference in effectiveness between genders.
Mechanism of action
Azathioprine is a phase-specific drug that is toxic to
cells during nucleic acid synthesis. Phase-specific drugs
are toxic during a specific phase of the mitotic cycle,
usually the S-phase, when DNA synthesis is occurring,
as opposed to cycle-specific drugs that kill both cycling
and intermitotic cells.
Azathioprine is converted in vivo to thioinosinic
acid, which competitively inhibits the synthesis of inosinic
acid, the precursor to adenylic acid and guanylic
acid. In this way, azathioprine inhibits DNA synthesis
and therefore suppresses lymphocyte proliferation.This
effectively inhibits both humoral and cell-mediated immune
responses.
Pharmacology
Azathioprine is well absorbed following oral administration,
with peak blood levels occurring within 1 to 2
hours. It is rapidly and extensively metabolized to 6-
mercaptopurine, which is further converted in the liver
and erythrocytes to a variety of metabolites, including 6-
thiouric acid. Metabolites are excreted in the urine.The
half-life of azathioprine and its metabolites in the blood
is about 5 hours.
Clinical Use
Azathioprine is a relatively powerful antiinflammatory
agent. Although its beneficial effect in various conditions
is principally attributable to its direct immunosuppressive
action, the antiinflammatory properties of the
drug play an important role in its overall therapeutic effectiveness.
Azathioprine has been used widely in combination
with corticosteroids to inhibit rejection of organ transplants,
particularly kidney and liver allografts. However,
it is usually reserved for patients who do not respond to
cyclosporine plus corticosteroids alone.
Azathioprine also has applications in certain disorders
with autoimmune components, most commonly
rheumatoid arthritis. It is as effective as cyclophosphamide
in the treatment of Wegener’s granulomatosis.
It has largely been replaced by cyclosporine in immunosuppressive
therapy. Relative to other cytotoxic
agents, the better oral absorption of azathioprine is the
reason for its more widespread clinical use.
Side effects
The therapeutic use of azathioprine has been limited by
the number and severity of adverse effects associated
with its administration. Bone marrow suppression resulting
in leukopenia, thrombocytopenia, or both may
occur. GI toxicity may be a problem. It is also mildly hepatotoxic.
Because of its immunosuppressive activity,
azathioprine therapy can lead to serious infections. It
has been shown to be mutagenic in animals and humans
and carcinogenic in animals.
Safety Profile
Confirmed human
carcinogen producing bladder tumors and
leukemia. Poison by subcutaneous,
intradermal, and intraperitoneal routes.
Moderately toxic by ingestion. Human
systemic effects: liver changes,
hypermotility, diarrhea, nausea or vomiting,
increased body temperature, BP lowering,
decreased urine volume or anuria,
normocytic anemia, bone marrow changes.
An experimental teratogen. Other
experimental reproductive effects. Human
mutation data reported. When heated to
decomposition it emits very toxic fumes of
NO,xand SOx. An immunosuppressant.
Synthesis
Azathioprine, 6-[(1-methyl-4-nitroimidazol-5-yl)thio]purine (31.2.1), is
synthesized by heteroarylation of the sulfhydrile group of 6-mercaptopurine (30.1.2.9) with
5-chloro-1-methyl-4-nitroimidazol in the presence of sodium acetate as a weak base.
Potential Exposure
Azathioprine is an immunosuppressive
agent, generally used in combination with a corticosteroid
to prevent rejection following renal homotransplantations.
It also is used following transplantation of other organs.
Other uses of azathioprine include the treatment of a variety
of presumed autoimmune diseases, including rheumatoid
arthritis; ankylosing spondylitis; systemic lupus
erythematosus; dermatonyositis, periarteritis nodosa, scleroderma,
refractory thombocytopenic purpura; autoimmune
hemolytic anemia; chronic active liver disease; regional
enteritis; ulcerative colitis; various autoimmune diseases of
the eye; acute and chronic glomerulonephritis; the nephritic
syndrome; Wegener’s granulomatosis; and multiple
sclerosis.
Veterinary Drugs and Treatments
In veterinary medicine, azathioprine is used primarily as an immunosuppressive
agent in the treatment of immune-mediated
diseases in dogs. See Doses below for more information. For autoagglutinizing
immune mediated hemolytic anemia, azathioprine is
generally recommended to start at the time of diagnosis. When used
in combination with cyclosporine, azathioprine has been used to
prevent rejection of MHC-matched renal allografts in dogs.
Although the drug can be very toxic to bone marrow in cats, it is
sometimes used to treat feline autoimmune
skin diseases.
Drug interactions
Potentially hazardous interactions with other drugs
Allopurinol: enhances effect with increased
toxicity. Reduce azathioprine dose by 50-75% if
administered concomitantly - ideally avoid.
Antibacterials: increased risk of haematological
toxicity with co-trimoxazole.
Anticoagulants: possibly reduced anticoagulant effect
of coumarins.
Antipsychotics: avoid with clozapine.
Antivirals: myelosuppressive effects enhanced by
ribavirin.
Ciclosporin: decreased ciclosporin absorption and
bioavailability.
Cytotoxics may be additive or synergistic in
producing toxicity, particularly on the bone marrow.
Febuxostat: avoid concomitant use.
Vaccines: risk of generalised infections with live
vaccines - avoid.
Carcinogenicity
Azathioprine is known to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in humans.
Metabolism
Azathioprine is extensively metabolised to its active moiety
mercaptopurine, which in turn is activated intracellularly
by conversion to nucleotide derivatives. Mercaptopurine
is rapidly and extensively metabolised in the liver, by
methylation, oxidation and by the formation of inorganic
sulfates. Thiol methylation is catalysed by the enzyme
thiopurine methyltransferase (TPMT). TPMT activity is
highly variable in patients because of a genetic polymorphism
in the TPMT gene. About 10% of a dose of azathioprine is
reported to be split between the sulfur and the purine ring
to give 1-methyl-4-nitro-5-thioimidazole. The proportion of
different metabolites is reported to vary between patients.
Metabolites and small amounts of unchanged azathioprine
and mercaptopurine are eliminated in the urine.
Shipping
UN2811 Toxic solids, organic, n.o.s., Hazard
Class: 6.1; Labels: 6.1-Poisonous materials, Technical
Name Required.
Incompatibilities
Incompatible with reducing agents, such
as hydrides (may cause the release of explosive gases), oxidizers
(chlorates, nitrates, peroxides, permanganates, perchlorates,
chlorine, bromine, fluorine, etc.); contact may
cause fires or explosions. Keep away from alkaline materials,
strong acids (violent exothermic reaction), strong bases.
Check Digit Verification of cas no
The CAS Registry Mumber 446-86-6 includes 6 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 3 digits, 4,4 and 6 respectively; the second part has 2 digits, 8 and 6 respectively.
Calculate Digit Verification of CAS Registry Number 446-86:
(5*4)+(4*4)+(3*6)+(2*8)+(1*6)=76
76 % 10 = 6
So 446-86-6 is a valid CAS Registry Number.
InChI:InChI=1/C9H7N7O2S/c1-15-4-14-7(16(17)18)9(15)19-8-5-6(11-2-10-5)12-3-13-8/h2-5H,1H3
446-86-6Relevant articles and documents
Pd/PTABS: Low-Temperature Thioetherification of Chloro(hetero)arenes
Bandaru, Siva Sankar Murthy,Bhilare, Shatrughn,Cardozo, Jesvita,Chrysochos, Nicolas,Schulzke, Carola,Sanghvi, Yogesh S.,Gunturu, Krishna Chaitanya,Kapdi, Anant R.
, p. 8921 - 8940 (2019/07/08)
The thioetherification of heteroaryl chlorides is an essential synthetic methodology that provides access to bioactive drugs and agrochemicals. Due to their (actual or potential) industrial importance, the development of efficient and low-temperature protocols for accessing these compounds is a requirement for economic and ecologic reasons. A particular highly effective catalytic protocol using the Pd/PTABS system at only 50 °C was developed accordingly. The coupling between chloroheteroarenes and a variety of less reactive arylthiols and alkylthiols was carried out with a high efficiency. Heteroarenes of commercial relevance such as purines and pyrimidines were also found to be useful substrates for the reported transformation. The commercial drug Imuran (azathioprine) was synthesized as an example, and its preparation could be optimized. DFT studies were performed to understand the electronic effects of the tested ligands on the catalytic reaction.
Chemical transformations of 6-[(1-methyl-4-nitro-5-imidazolyl)-thio]purine (azathioprine)
Kochergin,Aleksandrova,Korsunskii
, p. 311 - 318 (2007/10/03)
The chemical transformations of 6-[(1-methyl-4-nitro-5-imidazolyl)thio]purine (azathiopurine)- hydrogenation, acetylation, alkylation by lower alkyl halides at positions 7 and 9 of the purine ring, hydrolytic cleavage at the C(6)-S and S-C(5) bonds - were studied.
