115007-34-6 Usage
Description
Mycophenolate mofetil (MMF), also known as Cellcept, is a semisynthetic derivative of mycophenolic acid (MPA), which is derived from the glycolysis product of the mold Penicillin glaucum. It is a white or almost white, crystalline powder with a history of clinical application for over 10 years. MMF is an immunosuppressant and an inhibitor of nucleic acid synthesis, used primarily for the prevention of allograft rejection reactions in organ transplants and the treatment of various autoimmune diseases.
Uses
Used in Organ Transplantation:
Mycophenolate mofetil is used as an immunosuppressant for the prevention of allograft rejection reactions, particularly in renal, heart, and liver transplants. It is especially effective in cases of refractory rejection reactions after transplant and can be combined with cyclosporine and corticosteroids to enhance its efficacy.
Used in Rheumatoid Arthritis:
MMF is used as an immunomodulator for the treatment of rheumatoid arthritis, with a daily dosage of 300 mg.
Used in Autoimmune Diseases:
Mycophenolate mofetil is used as a treatment for various autoimmune diseases, including systemic lupus erythematosus, primary glomerulonephritis, and psoriasis.
Used in Psoriasis Treatment:
MMF is used as a cytostatic agent for the treatment of psoriasis, with oral administration in kidney transplant patients. The initial dose is 2-3 mg/kg per day, with a maintenance dose of 1-2 mg/kg per day, taken 2 to 3 times. The dose can be adjusted according to specific conditions.
Used in Drug Synthesis:
Mycophenolate mofetil is an intermediate in the synthesis of (4Z)-Mycophenolate Mofetil (M831455), a degradation product of MMF, which is also an immunosuppressant.
Pharmacology
After the oral administration of Mycophenolate mofetil, it has a rapid absorption rate in the upper gastrointestinal tract with the main absorption site being located in the stomach. At the same time, it is metabolized into pharmacologically active product of mycophenolic acid (the MPA) by the plasma lipase with the mean bioavailability being 94%. Plasma concentration immediately reaches peak one hour after orally taking the drug, followed by a rapid decline. MPA undergoes glucuronidation metabolism and be converted into stable, non-pharmacological active glucuronide (MPAG) in the liver, and further be excreted via urine. In the gut, the MPAG via biliary excretion enters into the small intestine with the glucosidase of gut microorganisms converting it into MPA, further being reabsorbed by the intestine for forming the enterohepatic circulation, thus reaching the second peak of plasma MPA (6 to 12 hours after administration). About 6% of MPAG is excreted out from the feces.
It undergoes in vivo metabolic activation via its hydrolysis and noncompetitively inhibits the activity of hypoxanthine monophosphate dehydrogenase, blocking the biosynthesis of guanine nucleotide, and thus playing its immunosuppressive effect on lymphocytes with both T lymphocytes and B lymphocytes being significantly affected.
synthetic route
Take mycophenolic acid (2) as the starting material, perform chlorination reaction through thionyl chloride, and then have esterification reaction with 4-(2-hydroxyethyl) morpholinem (4) to get mycophenolate mofetil (1).
Figure 1 the synthesis route of mycophenolate mofetil
Use (2) and (4) as a starting material, choose n-butyl ether or n-amyl ether as the solvent, directly prepare it by direct azeotropic dehydration (1).
Figure 2 The synthesis route of mycophenolate mofetil
For the above two processes, because of the use of n-butyl ether, n-amyl ether as a solvent, method two demands a higher production costs. Instead, although there are two steps of reactions of method one, acyl chloride product of the first step can be directly transferred into the next step without extra processing. The final product only need recrystallization before getting pure product.
The above information is edited by the lookchem of Dai Xiongfeng.
Clinical application
1. Organ Transplantation
Organ transplantation is transplanting the healthy organ of donor into another body for the rapid recovery of that function. The greatest threat of organ transplantation is the rejection reaction, mainly being presented as acute rejection reaction. Although currently there are relative mature protocols of immunosuppression such as the combined therapy of cyclosporine A, azathioprine, tacrolimus, cyclophosphamide, prednisone, and methylprednisolone, but there are still many cases that a considerable number of patients has got transplant rejection which ultimately lead to chronic rejection and transplant failure. In addition, adverse effects of immunosuppressive drugs also further restrict their clinical application. In 1995, people had successfully applied mycophenolate mofetil for organ transplant surgery to prevent and treat graft rejection. On May of the same year, FDA approved the application of mycophenolate mofetil in renal transplantation treatment. In 1996, it had been successfully applied for the first time in kidney transplant patients. Following researchers have found that mycophenolate mofetil in combination with cyclosporine and prednisone can reduce the incidence of acute rejection reaction after kidney transplantation, and also has good efficacy on refractory renal transplant rejection. Mycophenolate mofetil alone can be used as a kind of immunosuppressants for long-term maintenance therapy which can improve renal function and of special benefit for accepting elderly donors with relatively poor renal function.
2. Immune kidney disease
Immune kidney disease is a group of chronic glomerulus disease caused by variety triggering factors of same immune pathological characteristics. Immunological renal diseases includes anaphylactic purpura nephritis, refractory nephrotic syndrome, primary nephrotic syndrome, lupus nephritis, IgA nephropathy, etc., because of the dysfunction of patient's immune system, the resulting immune complex is deposited in the kidney which cause damage to the inherent cells of the kidney and cause inflammation reactions. This disrupts the normal function of kidney inherent cells, causing symptoms such as proteinuria, hematuria, and edema of the patients.
3. Digestive autoimmune diseases
(1) Autoimmune liver diseases Autoimmune liver diseases (ALD) is an autoimmune response mediated chronic liver disease. 20% of the ALD patients are not sensitive to the hormoneand azathioprine without appropriate treatment for long-term. Studies have shown that researchers believe that for ALD patients on whom traditional methods treatment has no effect, 88% of patients can alleviate the symptoms with applying mycophenolate mofetil. The application of mycophenolate mofetil can significantly reduce the amount of hormones.
(2) Autoimmune pancreatitis Autoimmune pancreatitis (AIP) is a pancreas inflammation lesion caused by the immune response triggered by the CD4+ adjuvant cells’ recognition to the antigen which is the own part of pancreas itself. Mycophenolate mofetil is used in patients of autoimmune pancreatitis mediated by hormone-dependent IgG4 and IgG4 mediated cholangitis. The related patient initially got symptoms alleviated by taking prednisone for 40mg/d. However, when the hormone concentration is reduced to 10mg/d, jaundice, hyperbilirubinemia, and elevated transaminase activities occurred. The patients were not able to tolerate the adverse reactions of adding azathioprine. Subsequent application of 750 mg mycophenolate mofetil for 2 times/d, being combined with 15 mg prednisone caused adverse reactions such as high blood sugar and other hormone-related adverse reactions after 3 months, thus gradually disabled prednisone and increase the dose of mycophenolate mofetil to the amount of 1g/times and 2 times/d. After 4 months, both the energy metabolism as well as blood sugar level of patients got alleviation without seeing any adverse reactions. Application of mycophenolate mofetil solves the problem that patients can’t use hormones. This demonstrates that mycophenolate mofetil or other immunosuppressants can be used to maintain or alleviate autoimmune pancreatitis.
4. Other diseases
(1) Refractory idiopathic thrombocytopenic purpura (ITP) is a common autoimmune bleeding disorder with a complicated pathogenesis and great difficulty of treatment. Traditional treatment usually adopt corticosteroids which although be effective on the majority of patients, however, still leaving some patients with poor results, called refractory idiopathic thrombocytopenic purpura (R-ITP). Mycophenolate mofetil as a new immunosuppressant with fewer adverse reactions, and is an effective approach of R-ITP therapy which has broad clinical application.
(2) Psoriasis is characterized by occurrence of varying sizes of papules skin, erythema with surface being covered with silvery white scales and also clear boundary on the surface of the skin. It mainly occurs in the scalp, extensor limbs and back. The etiology is not yet clear. In recent years, most scholars believed that it is related to heredity, infection, metabolic disorders, immune dysfunction, endocrine disorders and the environment. Studies have shown that there are no celar differences of safety and efficacy between methotrexate and Mycophenolate mofetil in the treatment of psoriasis, but mycophenolate mofetil has better security. Patients who can’t tolerate the side effects of methotrexate or with contraindications can choose mycophenolate mofetil.
(3) Myasthenia gravis (MG) is a chronic autoimmune disease caused by the dysfunction of conduction function between nerve conduction and neuromuscular. Immunosuppressant is important on the treatment of MG with its major mechanism of action of inhibiting the formation of auto-antibodies and reducing the related damage of cholinergic receptors or associated receptors in order to protect the smooth flow of neural excitation pathways, thereby improving the patient's muscle weakness. Compared with other immunosuppressant, mycophenolate mofetil has fewer side effects.
Pharmacokinetics
MMF is absorbed rapidly after oral administration with the intestinal wall, liver and other tissues being de-esterified and being quickly converted into active role of MPA. The average bioavailability of oral administration is about 94% of that of the intravenous injection (based on area under the curve of MPA). MMF can’t be detected in normal blood cycle after oral administration. Split off from the original drug, MPA formed inactive mycophenolic acid glucuronide by the metabolism of glucuronide transferase enzyme in the liver. The MPA concentration reaches peak 1h after oral administration, and reaches a second peak due to the enterohepatic circulation effect after 6~12h of medication. It has a biological half-life of 16~18h; at clinically effective concentration, 97% of MPA bound to plasma proteins. There is a very small amount of MMF (<1%) is excreted from the urine as MPA prototype from the urine with the majority (87%) being in the form of mycophenolic acid glucuronide excreted from urine, 6% being excreted from feces. MMF absorption is closely related to the liver function with smaller absorption with poorer liver function.
Side effects
Mainly include hypertension, atrial fibrillation, orthostatic hypotension, tachycardia, thrombosis, vasodilatation, headache, dizziness, insomnia, anxiety, high cholesterol, blood sugar changes, potassium and calcium metabolism disorders, acidosis, increased alkaline phosphatase, increased creatinine, hyperlipidemia, parathyroid dysfunction, nausea, vomiting, indigestion, and liver function abnormalities. Bone marrow suppression is commonly seen. Disable it upon severe neutropenia. The incidences of fungal dermatitis, skin rashes, Amblyopia and cataract are about 3% to 10%.
Side effects
The main side effects include an
increased incidence of herpes zoster, neutropenia, gastrointestinal symptoms,
and opportunistic infections. In the transplant literature, 1% to 2%
of patients will develop a lymphoproliferative malignancy at the doses
recommended for psoriasis. This is a teratogen and should be avoided in
women of childbearing age.
Precautions
1. Contraindications: People who are allergic to this drug or mycophenolic acid (MPA); pregnant women and lactating women should be disabled.
2. Take with caution: Patients of severe active digestive diseases, bone marrow suppression, being accompanied by hypoxanthine-guanine phosphoribosyltransferase ribose kinase deficiency, severe heart, and liver dysfunction.
Indications
Mycophenolate mofetil (CellCept), in conjunction with
cyclosporine and corticosteroids, has clinical applications
in the prevention of organ rejection in patients receiving
allogeneic renal and cardiac transplants. By effectively
inhibiting de novo purine synthesis, it can
impair the proliferation of both T and B lymphocytes.
Following oral administration, mycophenolate mofetil
is almost completely absorbed from the GI tract, metabolized
in the liver first to the active compound mycophenolic
acid, and then further metabolized to an inactive
glucuronide.
Early clinical trials indicate that mycophenolate
mofetil in conjunction with cyclosporine and corticosteroids
is a more effective regimen than azathioprine
in preventing the acute rejection of transplanted organs.
GI side effects are most common.
Check Digit Verification of cas no
The CAS Registry Mumber 115007-34-6 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,1,5,0,0 and 7 respectively; the second part has 2 digits, 3 and 4 respectively.
Calculate Digit Verification of CAS Registry Number 115007-34:
(8*1)+(7*1)+(6*5)+(5*0)+(4*0)+(3*7)+(2*3)+(1*4)=76
76 % 10 = 6
So 115007-34-6 is a valid CAS Registry Number.
InChI:InChI=1/C23H31NO7/c1-15(5-7-19(25)30-13-10-24-8-11-29-12-9-24)4-6-17-21(26)20-18(14-31-23(20)27)16(2)22(17)28-3/h4,26H,5-14H2,1-3H3
115007-34-6Relevant articles and documents
Preparation method of mycophenolate mofetil
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Paragraph 0018-0025, (2017/09/02)
The invention discloses a preparation method of mycophenolate mofetil. The preparation method of the mycophenolate mofetil comprises the following step: carrying out Mitsunobu reaction on mycophenolic acid and morpholinoethanol under the effects of triphenylphosphine and diisopropyl azodicarboxylate (DIAD) to prepare the mycophenolate mofetil. In the method, the reaction conditions are gentle, the process is simple and convenient, the yield is high, and therefore, the mycophenolate mofetil is suitable for being produced industrially.
PROCESS FOR PREPARATION OF MYCOPHENOLIC ACID, ITS SALT AND ESTER DERIVATIVES
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Page/Page column 6, (2011/07/29)
The present invention discloses an isolation and purification process for mycophenolic acid obtained from the fermentation process. Invention further discloses preparation of sodium salt of mycophenolic acid and mycophenolate mofetil from mycophenolic acid.
PROCESS FOR PREPARING MYCOPHENOLATE MOFETIL
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Page/Page column 13-14, (2009/08/14)
The present invention relates to an improved and efficient process for the preparation of Mycophenolate Mofetil in a high degree of pharmaceutically acceptable purity, which comprises the reaction of Mycophenolic acid or esters, or acid chlorides, or amides with metal salt of morpholino ethanol. A further aspect of the invention relates to the purification of Mycophenolate mofetil through salt formation and release of the free base which on recrystalized from suitable solvents to get highly pure Mycophenolate mofetil. The present invention provided a novel intermediate and process for preparation thereof. Also provided is new impurity of Mycophenolate mofetil and process for preparation thereof.