599-79-1 Usage
Description
Salicylazosulfapyridine, also known as Sulfasalazine, is an anti-inflammatory sulfa drug developed in the 1950s to treat rheumatoid arthritis. It is a derivative of mesalazine and is formed by combining sulfapyridine and salicylate with an azo bond. It is a prodrug of the anti-inflammatory agent 5-aminosalicylic acid, which is covalently linked to the antibiotic sulfapyridine by an azo bond. This bond is rapidly cleaved by bacteria in the terminal ileum and colon, releasing the active anti-inflammatory component.
Used in Pharmaceutical Industry:
Salicylazosulfapyridine is used as an anti-inflammatory agent for the treatment of inflammatory bowel disease and rheumatoid arthritis. It is used for its ability to induce T lymphocyte apoptosis, modulate inflammatory mediators from both cyclooxygenase/5-lipoxygenase pathways and NF-κB signaling pathways, attenuate transcription of proinflammatory cytokines, and activate PPARγ.
Used in Gastrointestinal Applications:
Salicylazosulfapyridine is used as an anti-inflammatory agent for gastrointestinal conditions such as granulomatous colitis and colitis. It is used for its ability to reduce inflammation and alleviate symptoms associated with these conditions.
Used in Drug Development:
Salicylazosulfapyridine is used as an inhibitor of GSH-H-transferase and NF-kB activation and an apoptosis inducer. It is used in the development of new drugs targeting these pathways to treat various diseases and conditions.
Brand Name(s)
Azulfidine (Salazopyrin in Canada)
Indications
Sulfasalazine is used in the treatment of inflammatory bowel disease, including ulcerative colitis and Crohn's disease. It is also indicated for use in rheumatoid arthritis and used in other types of inflammatory arthritis (e.g. psoriatic arthritis) where it has a beneficial effect. It is often well tolerated compared to other DMARDS. In clinical trials for the treatment of chronic alcoholics, sulfasalazine has been found to reverse the scarring associated with cirrhosis of the liver . Cells called myofibroblasts, which contribute to scar tissue in a diseased liver, also appear to secrete proteins that prevent the breakdown of the scar tissue. Sulfasalazine appears to retard this secretion.
Indications
Sulfasalazine (Azulfidine) is approved for the treatment
of rheumatoid arthritis and ulcerative colitis. It is also
used to treat ankylosing spondylitis and Crohn’s disease.
Comparisons of sulfasalazine with other DMARDs suggest
that it is more effective than hydroxychloroquine,
azathioprine, and oral gold compounds. It is at least as
effective as intramuscular gold and penicillamine. It has
a greater degree of toxicity than hydroxychloroquine
but less than gold compounds and penicillamine. After 5
years, approximately 75% of patients have discontinued
sulfasalazine therapy, primarily because of a lack of efficacy
as opposed to intolerable side effects.
Indications
Sulfasalazine (Azulfidine) was first introduced in 1940
as a treatment for rheumatoid arthritis. It was found
that a number of patients with coexistent inflammatory
bowel disease showed improvement of their GI symptoms,
and the drug has subsequently been used for the
treatment of patients with inflammatory bowel disease.
Air & Water Reactions
Light sensitive and may be sensitive to prolonged exposure to air. Dust can be explosive when suspended in air at specific concentrations. Insoluble in water.
Fire Hazard
Flash point data for Salicylazosulfapyridine are not available; however, Salicylazosulfapyridine is probably combustible.
Pharmaceutical Applications
One of the earliest and most successful sulfonamides to be
developed was sulfapyridine, which fell into disuse because
of unwanted effects such as crystalluria. Later, a number of
salicylazosulfonamides, developed because of their increased
water solubility, showed anti-inflammatory properties; one of
them, sulfasalazine (salicylazosulfapyridine), has come into
general use for ulcerative colitis.
After oral administration, some intact compound is
absorbed from the upper gastrointestinal tract, appearing in
the blood in 1–2 h, but most is cleaved by colonic bacteria
to yield sulfapyridine and 5-aminosalicylic acid (mesalamine,
mesalazine). Controlled trials have confirmed the efficacy of
5-aminosalicylic acid alone in ulcerative colitis, the sulfonamide
component merely acting as a carrier. Thus, in remarkable
extension of the good fortune that attended the discovery
of sulfanilamide as the unexpected active principle of Prontosil, a cleavage product appears to be responsible for
the beneficial effect of sulfasalazine. Since most of the side
effects associated with sulfasalazine are attributable to sulfapyridine,
there seems little reason, other than cost, to use it
in preference to mesalamine.
Sulfasalazine is also of benefit in Crohn’s disease and rheumatoid
arthritis, but the role, if any, of sulfapyridine in the
overall effect is unclear.
Mechanism of action
Sulfasalazine is composed of sulfapyridine and 5-
ASA molecules linked by an azo bond. Sulfapyridine
has no effect on the inflammatory bowel disease, and instillation
of this agent into the colon does not heal
colonic mucosa.
Pharmacology
Sulfasalazine is a prodrug of which 70% is converted
by colon bacteria to two active metabolites, sulfapyridine
and 5-aminosalicylic acid (mesalamine). Sulfapyridine
has antibacterial activities, and 5-aminosalicylic
acid is antiinflammatory; however, these effects do
not account for the ability of this drug to slow the
processes of rheumatoid arthritis. Recent research suggests
additional activities of sulfasalazine that may be
relevant to these effects: its ability to increase adenosine
levels, its inhibitory effects on IL-1 and TNF-
release, and its inhibition of NF-κB.
Pharmacokinetics
sulfasalazine is poorly absorbed, with approximately 20% of the ingested sulfasalazine
reaching the systemic circulation. The remainder of the ingested dose is metabolized by colonic bacteria into its
components, sulfapyridine and mesalamine (5-ASA). Most of the sulfapyridine metabolized from sulfasalazine
(60–80%) is absorbed in the colon following oral administration, and approximately 25% of the 5-ASA metabolized
from sulfasalazine is absorbed in the colon.
Clinical Use
Sulfasalazine (Azulfidine) was first introduced in 1940
as a treatment for rheumatoid arthritis.
Clinical Use
Sulfasalazine (2-hydroxy-5[[4-[(2-pyridinylamino)sulfonyl]phenyl]azo]benzoic acid or 5-[p-(2-pyridylsulfamoyl)phenylazo]salicylic acid) is a brownish yellow, odorlesspowder, slightly soluble in alcohol but practically insolublein water, ether, and benzene.Sulfasalazine is broken down in the body to m-aminosalicylicacid and sulfapyridine. The drug is excreted throughthe kidneys and is detectable colorimetrically in the urine,producing an orange-yellow color when the urine is alkalineand no color when the urine is acid.
Side effects
Sulfsalazine metabolizes to sulfa pyridine. Serum levels should be monitored every three months, and more frequently at the outset. Serum levels above 50 μg / l are associated with side effects. In rare cases, Sulfasalazine can cause severe depression in young males. It can also cause temporary infertility. Immune thrombocytopenia has been reported. Sulfasalazine inhibits dihydrofolate reductase, and can cause folate deficiency and megaloblastic anemia. Sulfasalazine can cause hemolytic anemia in people with G6PD deficiency.
Side effects
It is, however, responsible for most of
sulfasalazine’s side effects, including sulfa allergic reactions.
5-ASA, the active metabolite, may inhibit the synthesis
of mediators of inflammation.
Side effects
Mild to moderate side effects, including nausea, vomiting,
abdominal pain, diarrhea, anorexia, and headache,
occur in up to 33% of patients taking this drug. Skin
rash and discoloration, fever, reversible male infertility,
and liver enzyme elevation occur less frequently. Rare
hematological abnormalities, such as agranulocytosis,
aplastic anemia, hemolytic anemia, neutropenia, or
other blood dyscrasias, can be fatal. Hypersensitivity reactions
occur rarely.
Synthesis
Sulfasalazine, 5-[p-[(4,6-dimethyl-2-pyridinyl)sulfamoyl]phenylazo]salicylic acid (33.1.22), is a derivative of sulfapyridine drug described above and one of the
few sulfanilamides in which the free amino group in the benzene ring is modified, and it
is synthesized by an azo-coupling reaction of a diazo salt, which is synthesized by reacting sulfapyridine (33.1.21) with nitrous acid and salicylic acid alkaline media.
Veterinary Drugs and Treatments
Sulfasalazine is used for the treatment of inflammatory bowel disease
in dogs and cats. It has also been suggested for adjunctive use
in treating vasculitis in dogs.
Drug interactions
Potentially hazardous interactions with other drugs
Ciclosporin: may reduce ciclosporin levels.
Metabolism
After cleavage of the sulfasalazine molecule about 60 to
80% of available sulfapyridine is absorbed, and undergoes
extensive metabolism in the liver by acetylation,
hydroxylation, and glucuronidation.
Most of a dose of sulfasalazine is excreted in the urine.
Unchanged sulfasalazine accounts for 15% of the original
dose, sulfapyridine and its metabolites 60%, and 5-ASA
and its metabolites 20-33%.
Mode of action
Sulfasalazine, and its metabolite 5-ASA, are poorly absorbed from the gut. Its main mode of action is therefore believed to be inside the intestine. Bowel disease In Crohn's disease and ulcerative colitis, it is thought to be an antinflammatory drug that is essentially providing topical relief inside the intestine. It does this via a number of mechanisms such as reducing the synthesis of inflammatory mediators known as eicosanoids and inflammatory cytokines. However, unlike glucocorticoids ( another class of drug used in the treatment in inflammatory bowel disease ), sulfasalazine is a mild immunosuppressant. Arthritis When treatment for arthritis is successful, pain, joint swelling and stiffness will be reduced and this may slow down or stop the development of joint damage. The precise reasons why sulfasalazine are effective in various forms of arthritis is not clearly understood. Because sulfasalazine and its metabolite 5-ASA are poorly absorbed into the bloodstream, it is surprising that the drug is effective against symptoms outside of the intestine. One possible explanation is that, given that ulcerative colitis produces arthritic symptoms, the arthritic symptoms are actually a product of unrecognized ulcerative colitis , which is effectively treated with sulfazalazine.
Precautions
Sulfasalazine is contraindicated in individuals with hypersensitivityto salicylates, sulfonamides, sulfonylureas,and certain diuretics (furosemide, thiazides, andcarbonic anhydrase inhibitors). Because it can causekernicterus, sulfasalazine is contraindicated in infantsand children under 2 years of age. Sulfasalazine passesinto breast milk and is therefore contraindicated fornursing mothers. Similarly, pregnant women near termshould not use this drug, although it appears to be thesafest of the DMARDs during early pregnancy.Sulfasalazine can precipitate attacks of porphyria andshould not be used by individuals with bowel or urinaryobstruction.Sulfasalazine can inhibit the absorption of cardiacglycosides and folic acid. It may displace certain drugs,including warfarin, phenytoin, methotrexate, tolbutamide,chlorpropamide, and oral sulfonylureas, fromtheir protein binding sites. Sulfasalazine can diminishthe effectiveness of penicillins and estrogen-containingoral contraceptives.
References
1) Peppercorn (1984),?Sulfasalazine. Pharmacology, clinical use, toxicity, and related drug development; Ann. Intern. Med.,?101?377
2) Wahl?et al. (1998),?Sulfasalazine: a potent and specific inhibitor of nuclear factor kappa B; J. Clin. Invest.,?101?1163
3) Sheldon?et al. (1988),?Effect of sulphasalazine and its metabolites on mitogen induced transformation of lymphocytes D clues to its clinical action?; Br. J. Rheumatol.,?27?344
4) Fujiwara?et al. (1990),?Inhibition of proliferation responses and interleukin 2 production by salazosulfapyridine and its metabolites; Jpn. J. Pharmacol.,?54?121
5) Chung and Sontheimer (2009),?Sulfasalazine inhibits the growth of primary brain tumors in dependent of nuclear factor-κB; J.Neurochem.,?110?182
6) Patel?et al. (2004),?Differentiation of substrate and non-substrate inhibitors of transport system Xc – :an obligate exchanger of L-glutamate and L-cystine; Neuropharmacol.,?46?273
Check Digit Verification of cas no
The CAS Registry Mumber 599-79-1 includes 6 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 3 digits, 5,9 and 9 respectively; the second part has 2 digits, 7 and 9 respectively.
Calculate Digit Verification of CAS Registry Number 599-79:
(5*5)+(4*9)+(3*9)+(2*7)+(1*9)=111
111 % 10 = 1
So 599-79-1 is a valid CAS Registry Number.
InChI:InChI=1/C18H14N4O5S/c23-16-9-6-13(11-15(16)18(24)25)21-20-12-4-7-14(8-5-12)28(26,27)22-17-3-1-2-10-19-17/h1-11,23H,(H,19,22)(H,24,25)/b21-20+
599-79-1Relevant articles and documents
Diazo coupling proces
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Paragraph 0023; 0030-0038, (2021/06/22)
The invention relates to a diazo coupling process. An aromatic primary amine compound solution and a nitrite solution are pumped into a static mixer through a pump to be mixed and then enter a continuous reactor to react. Generated diazotization reaction liquid is sprayed into a reaction kettle through a spraying system and reacts with a coupling component pumped into the reaction kettle to prepare a product. The diazo coupling proces is a brand-new diazo coupling process which is not reported in the prior art. According to the diazo coupling proces, the fully continuous process is achieved, the continuous flow reaction and the kettle type reaction are combined, the spraying system is independently arranged, the reaction units are connected in series for the reaction, and the high-yield and high-purity product is prepared on the continuous basis.
Preparation method of sulfasalazine
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Paragraph 0012; 0032-0060, (2018/07/30)
The invention relates to the technical field of sulfasal, in particular to a synthesis technology of environment-friendly sulfasalazine. A nitroso compound is condensed with ammonia to obtain the sulfasalazine. After adoption of the technical scheme, raw materials are cheap, easy to obtain and stable, and production of unstable diazonium salt is avoided, so that production of a byproduct is avoided; after adoption of the technical scheme, the product sulfasalazine can be directly separated out through simple treatment, so that the reaction yield is high.
Method for synthesizing salazosulfapyridine by utilizing 2-aminopyridine as raw material
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, (2016/10/10)
The invention discloses a method for synthesizing salazosulfapyridine by utilizing 2-aminopyridine as a raw material. The method comprises the steps: step 1, performing a sulfamation reaction on 2-aminopyridine and para-acetylaminobenzene sulfonyl chloride in an aqueous solution of potassium carbonate; step 2, firstly performing hydrolyzation in DMSO-water mixed solution of sodium hydroxide, and then performing hydrochloric acid acidification; step 3, performing a diazo-reaction in an aqueous solution dissolving hydrochloric acid and sodium nitrite; step 4, performing a coupling reaction on diazonium salt and salicylic acid in an aqueous solution of sodium hydroxide. According to the method for synthesizing salazosulfapyridine by utilizing the 2-aminopyridine as the raw material, the 2-aminopyridine is taken as a starting raw material, and then is sequentially subjected to the sulfamation reaction, the hydrolyzation, the acidification, the diazo-reaction and the coupling reaction to obtain the salazosulfapyridine. The diazo-reaction and the coupling reaction have high conversation rate and a few side reaction so as to improve the purity of products and ensure the efficiency; furthermore, the source of the 2-aminopyridine is easy, the production cost is reduced, and the industrial production cost is large.
