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Tofacitinib powder, whose molecular formula is C16H20N6O, molecular weight is 312.38 g/mol, CAS 477600-75-2. It is a white to off-white solid, usually in the form of powder or crystal, and has no obvious odor or taste. It is a lipophilic compound that can be dissolved in various organic solvents, such as dimethyl sulfoxide, methanol, ethanol, toluene and acetone. It is a molecule with a chiral center and exists as two stereoisomers. Its optical rotation is -90° (c=1, methanol), which belongs to the left-handed substance. is a novel, orally administered small molecule compound for the treatment of rheumatoid arthritis (RA) and other autoimmune diseases such as ulcerative colitis and psoriasis. It is a Janus kinase (JAK) inhibitor that blocks multiple signaling pathways in cells, reducing inflammation and overactive immune system.
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Tofacitinib, also known as citrate tofacitinib tablets or tofacitinib, is an oral Janus kinase (JAK) inhibitor that exerts anti-inflammatory and immunomodulatory effects by inhibiting the JAK-STAT signaling pathway and blocking the signaling of various inflammatory cytokines.
Background of treatment:
Rheumatoid arthritis is a chronic inflammatory autoimmune disease characterized by inflammatory proliferation of synovial tissue and progressive destruction of articular cartilage.
The JAK-STAT signaling pathway is highly expressed in synovial tissue of RA patients and plays an important role in the pathogenesis of RA.
Therapeutic effect:
Tofacitinib inhibits JAK phosphorylation, prevents STAT phosphorylation, reduces downstream inflammatory cytokine synthesis, and blocks the synthesis and secretion of various cytokines such as IL-2, IL-6, IL-7, IL-17, IL-21, IFN - γ, etc.
Inhibit CD4+T cell proliferation and recruitment of other inflammatory cells, alleviate synovial inflammation and joint damage in RA patients, and improve clinical symptoms.
Clinical research:
Multiple clinical trials have confirmed the effectiveness and safety of tofacitinib in the treatment of RA.
In a 6-month clinical trial, 610 RA patients who did not respond well to anti rheumatic drugs (DMARDs) received tofacitinib (5mg or 10mg, orally, twice a day) or placebo for 3 months followed by tofacitinib treatment. The results showed that after treatment with tofacitinib, the evaluation of the Health Assessment Questionnaire Disability Index (HAQ-DI) improved significantly, the ACR20 response rate increased significantly, and the disease activity score improved significantly.
In a 12-month international multicenter, randomized double-blind, placebo-controlled clinical trial involving 20 domestic hospitals, a total of 792 patients with moderate to severe active RA who did not respond well to DMARDs treatment were randomly divided into three groups and given tofacitinib 5mg, 10mg, and placebo, respectively.
The experimental results showed that tofacitinib powder can significantly improve the condition of active RA patients who have poor response to DMARD treatment, increase the ACR20 response rate, and with the increase of dose, the time of ACR70 response rate increase is advanced.
Medication plan:
The recommended dosage for adults is usually 5 milligrams twice a day. Depending on the response and tolerance of the condition, the dosage may sometimes be adjusted.
Tofacitinib can be taken before or after meals and is not significantly affected by food.
Psoriatic arthritis (PsA)
Background of treatment:
Psoriatic arthritis is a chronic inflammatory disease mediated by immune imbalance in a multi gene genetic background, characterized by infiltration of inflammatory cells such as T cells, dendritic cells, macrophages, natural killer cells, and neutrophils.
The pro-inflammatory cytokine IL-15 is highly expressed in the affected areas of psoriasis skin and can induce the production of anti apoptotic keratinocytes.
Therapeutic effect:
Tofacitinib, as a JAK inhibitor, can further inhibit the production of various cytokines including IL-15 by blocking the JAK-STAT signaling pathway, playing an important role in alleviating psoriasis.
Clinical research:
Currently, two out of five phase III clinical trials of tofacitinib have been successful in adult patients with severe chronic plaque psoriasis. Compared with the control group, the proportion of patients in the tofacitinib group who achieved a 75% decrease in Psoriasis Area and Severity Index (PASI) and a response of "cleared" or "almost cleared" to the Physician Global Assessment Index (PGA) was significantly increased, indicating that tofacitinib significantly alleviated the condition of psoriasis patients.
Medication plan:
The recommended dosage for rheumatoid arthritis is the same, which is 5 milligrams twice a day.
Ulcerative colitis (UC)
Background of treatment:
Ulcerative colitis is a chronic non-specific inflammatory disease affecting the intestine, and its pathogenesis is not fully understood. Currently, it is believed to be related to multiple factors such as genetics, environment, microbial infections, and immunity, among which immunological mechanisms play an important role in the pathogenesis of UC.
Therapeutic effect:
Multiple research results have shown that the JAK1, JAK3, and JAK-STAT signaling pathways play important roles in the occurrence and development of UC. Tofacitinib reduces intestinal inflammation, alleviates symptoms such as diarrhea, abdominal pain, and rectal bleeding by inhibiting these pathways.
Clinical research:
In an 8-week phase II clinical trial, patients with moderate to severe UC were treated with tofacitinib, and the treatment group showed better clinical response, clinical remission, and intestinal mucosal repair than the control group. The concentrations of C-reactive protein (CRP) and fecal calprotectin were significantly reduced compared to the control group.
Medication plan:
The initial dose may be 10 milligrams twice daily for 8 weeks, and may be adjusted to 5 milligrams twice daily as maintenance therapy based on treatment response.
Other diseases
Crohn's disease (CD):
Tofacitinib has also been used in clinical trials to treat Crohn's disease and has shown some efficacy. It can alleviate disease symptoms and improve patients' quality of life by inhibiting inflammatory reactions.
In a 4-week phase II clinical trial, patients with moderate to severe CD were treated with tofacitinib, and compared with the control group, the concentrations of CRP and fecal calprotectin in the tofacitinib treatment group were significantly reduced.
Alopecia areata:
Some small-scale clinical studies have shown that tofacitinib may have certain efficacy in treating alopecia areata. It can promote hair regeneration and improve the symptoms of alopecia areata patients.
The mechanism of action of tofacitinib in treating alopecia areata may be related to its inhibition of the JAK signaling pathway. The JAK signaling pathway also plays a role in hair growth and development.
By inhibiting JAK kinase, tofacitinib may regulate the growth and differentiation of hair follicle cells, promoting hair regeneration.
Ankylosing spondylitis (AS):
Tofacitinib is suitable for adult patients with active ankylosing spondylitis, especially those who do not respond well to adequate treatment with nonsteroidal anti-inflammatory drugs (NSAIDs).
Research has shown that MRI activity scores can significantly reduce spinal inflammation (such as inflammation of the vertebral body and posterior lateral elements). A small-scale clinical study observed that after 12 weeks of treatment, the degree of inflammation in the sacroiliac joint can be effectively improved (evaluated by SPARCC score).
However, at present, the indication has not been officially approved by the drug regulatory authorities in Chinese Mainland, and the specific application needs to be evaluated by doctors according to the patient's situation.
Tofacitinib powder, also known as CP-690,550, is a novel oral small molecule JAK inhibitor indicated for the treatment of rheumatoid arthritis and other autoimmune diseases. Various synthetic methods of Tofacitinib will be introduced in detail below.
Synthetic method one: Favipiravir synthesis:
The first synthetic method of Tofacitinib uses Favipiravir as a raw material, which is converted into the target compound Tofacitinib through a multi-step reaction. The main steps are as follows:
1. First, Favipiravir is reacted with tert-butyl chloroformate to generate Favipiravir tert-butyl carbamate.
2. The above product is reduced to the corresponding alcohol, and further protected to generate terpyrizin-4-yl acetamide.
3. Using copper as a catalyst, the nitrogen atom of the above product is substituted with bromoacetone to form 3-(2-chloroacetyl)-1-(terpyrazin-4-yl)-4-(6- Bromo-1H-benzimidazol-5-yl)piperidine.
4. Through reduction, deprotection and other reactions, Tofacitinib is finally prepared.
The overall yield of this synthetic method is slightly lower, and it needs to use less environmentally friendly organic solvents, so it is no longer recommended.
Synthetic method two: primary amine synthesis:
In the synthesis of primary amine, firstly, 3-(primary amine)-1-(benzimidazol-5-yl)-4-(chloro)piperidine is synthesized through the reaction of primary ammonia and benzimidazole-5-iodate Pyridine. Then, the compound is dehalogenated by heating to generate the target product Tofacitinib.
Synthetic method three: epoxy compound method synthesis:
In the synthesis of epoxy compounds that are easy to realize large-scale production, methyl isothiocyanate is first used to convert benzimidazole-5-carbaldehyde into the corresponding isothiocyanate compound. Then, the product is epoxidized with 3-chloro-1-(benzimidazol-5-yl)-4-(trimethylsilyloxy)piperidine, and then demethylated, deprotected, epoxyamine Ring-opening and other reaction steps finally produce Tofacitinib.
Synthetic method four: Reductive coupling synthesis:
Reductive coupling synthesis mainly includes two parts, namely Birch coupling and Stille coupling. Specific steps are as follows:
1. First, convert benzimidazole-5-carboxylic acid to benzimidazole-5-ol using reagents such as phenol/sodium sand (NaH) or bromobenzene/isopropyllithium (i-BuLi).
2. Birch coupling reaction of the above product with chloroacetone to form 3-(benzimidazol-5-yl)-1,3-propanediol.
3. Using PdCl2, triphenylphosphine and other reagents, carry out Stille coupling reaction between the above product and another aromatic compound (such as 2,6-dichlorobenzaldehyde) to obtain the precursor compound of Tofacitinib.
4. After reduction, deprotection and other reaction steps, Tofacitinib was finally prepared.
The above four methods have been verified, among which the primary amine method, epoxy compound method and reductive coupling method are relatively mature and easy to achieve large-scale production, and are the main methods for the current industrial Tofacitinib of Tofacitinib.
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Chemical Formula |
C16H20N6O |
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Exact Mass |
312 |
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Molecular Weight |
312 |
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m/z |
312 (100.0%), 313 (17.3%), 313 (2.2%), 314 (1.4%) |
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Elemental Analysis |
C, 61.52; H, 6.45; N, 26.90; O, 5.12 |
The chemical name of Tofacitinib is (3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate, its molecular formula is C16H20N6O, molecular weight It is 312.38 g/mol. This means that Tofacitinib consists of 16 carbon atoms, 20 hydrogen atoms, 6 nitrogen atoms and 1 oxygen atom.
The molecular structure of Tofacitinib is shown in the figure below:
It can be seen from the structure that Tofacitinib consists of two main structural units: a carbazole ring and a pyrrolopyrimidine ring. A methylamino group and a carboxylate group are attached to the carbazole ring, which can react with other compounds through the carboxylic acid moiety. A methylpurine ring and a trimethylpropylamino group are connected to the pyrrolopyrimidine ring, which can be combined with other ligands. The methylamino group between carbazole and pyrrolopyrimidine constitutes the core structure of Tofacitinib powder.
Tofacitinib is a novel oral small molecule JAK inhibitor for the treatment of various autoimmune diseases. This article will detail the discovery history of Tofacitinib.
1. JAKs and JAK signaling pathway:
Before delving into the discovery process of Tofacitinib, we need to understand the JAKs and JAK signaling pathway.
JAKs (Janus kinases) are a class of signaling proteins that play key roles in cell apoptosis, growth and differentiation. They promote the transmission of cell signals by binding to specific cell membrane receptors. Specifically, JAKs regulate specific downstream targets, such as STATs (signal transducers and activators of transcription), through tyrosine kinase activity, thereby affecting gene expression and cell function.
The JAK signaling pathway affects human health and disease states. Under normal conditions, they provide immune protection and promote cell proliferation and differentiation. However, in some diseases, JAKs and their corresponding receptor factors are abnormally activated, triggering adverse reactions such as autoimmune diseases, cancer and inflammatory responses.
Therefore, JAKs inhibitors have become a research hotspot. They can control autoimmune response and disease development by interfering with JAK signaling pathway, reduce toxic side effects and obtain better therapeutic effect.
2. The discovery process of Tofacitinib:
Tofacitinib was originally discovered by researchers at Pfizer. They initially focused on JAK3 and its signaling pathway because JAK3, as a regulator of cellular immunity, plays a key role in the proliferation, differentiation and function of T cells, B cells and NK cells.
In 2006, researchers at Pfizer began pharmacological screening of some JAK3 selective inhibitors, and finally identified Tofacitinib as a candidate drug for JAK3 inhibitors. However, later findings showed that tofacitinib can affect JAK1 and JAK2 signaling pathways in addition to inhibiting JAK3.
In 2012, the FDA approved Tofacitinib as an oral drug for the treatment of rheumatoid arthritis. Since then, Tofacitinib has been further studied and found that it also has good therapeutic effects in other autoimmune diseases.
3. Pharmacological properties of Tofacitinib:
Tofacitinib powder has multiple pharmacological properties and is an orally administered small molecule JAK inhibitor.
First, Tofacitinib is selective: it primarily inhibits JAK1 and JAK3, and is less selective for JAK2. This selectivity can reduce unwanted toxic side effects that interfere with JAK2 pathways such as platelet and erythropoiesis.
Second, Tofacitinib can be taken orally: Tofacitinib is an oral small molecule compound that is easy to use and take. It is soluble and has good bioavailability, can be absorbed rapidly and form active metabolites in the body.
Third, Tofacitinib has a wide range of indications: Tofacitinib has been proven to have good therapeutic effects in a variety of autoimmune diseases such as rheumatoid arthritis, psoriasis, ulcerative colitis and juvenile arthritis. It can affect the response of the immune system and reduce the symptoms of corresponding diseases by controlling the JAK signaling pathway.
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