CAS No:- [152459-95-5]
IUPAC Name:- 4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]benzamide
M. P.:- 211-213 °C
Imatinib (INN), marketed by Novartis as Gleevec (Canada, South Africa and the USA) or Glivec (Australia, Europe and Latin America), and sometimes referred to by its investigational name STI-571, is a tyrosine-kinase inhibitor used in the treatment of multiple cancers, most notably Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML).
Like all tyrosine-kinase inhibitors, imatinib works by preventing a tyrosine kinase enzyme, in this case BCR-Abl, fromphosphorylating subsequent proteins and initiating the signalling cascade necessary for cancer growth and survival, thus preventing the growth of cancer cells and leading to their death by apoptosis. Because the BCR-Abl tyrosine kinase enzyme exists only in cancer cells and not in healthy cells, imatinib works as a form of targeted therapy—only cancer cells are killed through the drug’s action. In this regard, imatinib was one of the first cancer therapies to show the potential for such targeted action, and is often cited as a paradigm for research in cancer therapeutics.
Imatinib has been cited as the first of the exceptionally expensive cancer drugs, costing $92,000 a year. Doctors and patients complain that this is excessive, given that its development costs have been recovered many times over, and that the costs of synthesizing the drug are orders of magnitude lower. In the USA, the patent protecting the active principle will expire on 4 January 2015 while the patent protecting the beta crystal form of the active principal ingredient will expire on 23 May 2019.
bcr-abl kinase (green), which causes CML, inhibited by imatinib (red; small molecule).
Chronic myelogenous leukemia
The U.S. Food and Drug Administration (FDA) has approved imatinib as first-line treatment for Philadelphia chromosome-positive CML, both in adults and children. The drug is approved in multiple Philadelphia chromosome-positive cases of CML, including after stem cell transplant, in blast crisis, and newly diagnosed.
Gastrointestinal stromal tumors
The FDA first granted approval for advanced GIST patients in 2002. On 1 February 2012, imatinib was approved for use after the surgical removal of KIT-positive tumors to help prevent recurrence. The drug is also approved in unresectable KIT-positive GISTs.
The FDA has approved imatinib for use in adult patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), myelodysplastic/ myeloproliferative diseases associated with platelet-derived growth factor receptor gene rearrangements, aggressive systemic mastocytosis without or an unknown D816V c-KIT mutation, hypereosinophilic syndrome and/or chronic eosinophilic leukemia who have the FIP1L1-PDGFRα fusion kinase (CHIC2 allele deletion) or FIP1L1-PDGFRα fusion kinase negative or unknown, unresectable, recurrent and/or metastaticdermatofibrosarcoma protuberans. On 25 January 2013, Gleevec was approved for use in children with Ph+ ALL.
For treatment of progressive plexiform neurofibromas associated with neurofibromatosis type I, early research has shown potential for using the c-KIT tyrosine kinase blocking properties of imatinib.
Legal challenge to generics
In 2007, imatinib became a test case through which Novartis challenged India’s patent laws. A win for Novartis would make it harder for Indian companies to produce generic versions of drugs still manufactured under patent elsewhere in the world. Doctors Without Borders argues a change in law would make it impossible for Indian companies to produce cheap generic antiretrovirals (anti-HIV medication), thus making it impossible for Third World countries to buy these essential medicines. On 6 August 2007, the Madras High Court dismissed the writ petition filed by Novartis challenging the constitutionality of Section 3(d) of Indian Patent Act, and deferred to the World Trade Organization (WTO) forum to resolve the TRIPS compliance question. As of 2009 India has refused to grant patent exclusivity..
On April 01, 2013 Supreme Court of India dismissed the plea of Novartis for the grant of patent.
Mechanism of action
|Therapeutic use||chronic myelogenous leukemia|
|Biological target||ABL, c-kit, PDGF-R|
|Mechanism of action||Tyrosine-kinase inhibitor|
|PDB ligand id||STI:,|
There are a large number of TK enzymes in the body, including the insulin receptor. Imatinib is specific for the TK domain inabl(the Abelson proto-oncogene), c-kit and PDGF-R (platelet-derived growth factorreceptor).
In chronic myelogenous leukemia, the Philadelphia chromosome leads to a fusion protein of abl with bcr(breakpoint cluster region), termed bcr-abl. As this is now aconstitutively active tyrosine kinase, imatinib is used to decrease bcr-abl activity.
The active sites of tyrosine kinases each have a binding site for ATP. The enzymatic activity catalyzed by a tyrosine kinase is the transfer of the terminal phosphate from ATP to tyrosine residues on its substrates, a process known as protein tyrosinephosphorylation. Imatinib works by binding close to the ATP binding site of bcr-abl, locking it in a closed or self-inhibited conformation, and therefore inhibiting the enzyme activity of the protein semi-competitively. This fact explains why many BCR-ABL mutations can cause resistance to imatinib by shifting its equilibrium toward the open or active conformation.
Imatinib is quite selective for bcr-abl – it does also inhibit other targets mentioned above (c-kit and PDGF-R), but no other knowntyrosine kinases. Imatinib also inhibits the abl protein of non-cancer cells but cells normally have additional redundant tyrosine kinases which allow them to continue to function even if abl tyrosine kinase is inhibited. Some tumor cells, however, have a dependence on bcr-abl. Inhibition of the bcr-abl tyrosine kinase also stimulates its entry in to the nucleus, where it is unable to perform any of its normal anti-apoptopic functions.
The Bcr-Abl pathway has many downstream pathways including the Ras/MapK pathway, which leads to increased proliferation due to increased growth factor-independent cell growth. It also affects the Src/Pax/Fak/Rac pathway. This affects the cytoskeleton, which leads to increased cell motility and decreased adhesion. The PI/PI3K/AKT/BCL-2 pathway is also affected. BCL-2 is responsible for keeping the mitochondria stable; this suppresses cell death by apoptosis and increases survival. The last pathway that Bcr-Abl affects is the JAK/STAT pathway, which is responsible for proliferation.
Imatinib is known as an inhibitor of protein-tyrosine kinase and is indicated for the treatment of chronic myeloid leukemia (CML). Imatinib also has potential for the treatment of various other cancers that express these kinase including acute lymphocyte leukemia and certain solid tumors. It can also be used for the treatment of atherosclerosis, thrombosis, restenosis, or fibrosis. Thus, imatinib can also be used for the treatment of non-malignant diseases. Imatinib is usually administered orally in the form of a suitable salt, e.g., in the form of imatinib mesylate.
The chemical name of Imatinib is 4-(4-methyl piperazine -1- methyl) -N-4-methyl-3-[4- (3- pyridyl) pyrimidine-2-amino] – benzamide and is represented by the following structural formula:
Imatinib Mesylate is an inhibitor of signal transduction (STI571) invented by Novartis AG after 7 years of hard work; it is the first inhibitor of cancer signal transduction ratified in the whole world. It is sold by Novartis as Gleevec capsules containing imatinib mesylate in amounts equivalent to 100 mg or 400 mg of imatinib free base.
Imatinib Mesylate is the rare drug in America, European Union and Japan. In May 10, 2001, it was ratified by American Food and Drug Administration (FDA) to treat the chronic myelogenous leukemia patients. EP0564409 (US5521 184) describes the process for the preparation of imatinib and the use thereof, especially as an anti tumour agent.
There are generally two synthetic routes for synthesis of Imatinib, suitable for the industrial production. One synthetic process as described in scheme-I comprises using 2-methyl-5-nitroaniline as the raw material which is reacted with cyanamide to obtain guanidine; cyclization reaction with 3-dimethylamino-l-(3-pyridyl)-2-propylene-l- ketone; reduction step of nitro to amine and condensation reaction with 4- (Chloromethyl)benzoyl chloride and N-methylpiperazidine to obtain Imatinib (WO 2004/108669). -I
Scheme-2 describes the successful process for the synthesis of Imatinib using 4-methyl-3- nitroanilines as the raw material, comprising reacting 4-methyl-3-nitroanilines with 4- (Chloromethyl)benzoyl chloride and N-methyl piperazidine in turns; followed by reduction of nitro group to amino group; then reaction with cyanamide to obtain guanidine; finally cyclization reaction with 3- dimethyl amino- 1 -(3- pyridyl)-2- propylene-1 -ketone to obtain Imatinib (WO 03/066613). The said PCT application discloses the use of 4-4-(methyl piperazin-l-ylmethyl)-benzoic acid methyl ester as one of the raw material but rest of the reactants are different from that of N-(5-amino -2- methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine in presence of trimethyl aluminium.
Common feature of the processes for preparing imatinib according to (WO 2004/108669) and (WO03/066613) lies in use of cyanamide as a reagent. The main difference between the two routes is that the reaction sequence of cyclization of pyrimidine chain is different. Example 10 of PCT International Publication no. WO 2003/066613 is less applicable to industrial purposes. These include the reaction between N-(3-bromo-4-methyl-phenyl)-4- (4-methyl-piperazin-l -ylmethyl)-benzamide and 4-(3-pyridyl)-2-pyrimidineamine which uses a mixture of rac-BINAP (a phosphine oxide catalyst) and Pd2 (dba)3*CHCl3. These catalysts are very expensive, therefore, their use is unfit for commercial production.
CN1630648A describes a process comprising reaction of 3- bromine-4- methyl aniline with 4-(4-methyl-piperazin- methyl) methyl benzoate in presence of trimethyl-Aluminum to obtain N-(4-methyl-3-bromobenzene)-4-(4-methyl-piperazin- 1 -methyl)-benzamide, which further reacts with 2-amino-4-(3-pyridyl)- pyrimidine in presence of palladium as catalyst to obtain Imatinib.
The drawback of the above process is the use of trimethyl-Aluminum, which is flammable and reacts severely when comes in contact with water.
CN101016293A describes another process using N-(4-methyl-3-3- aminophenyl)-4-(4- methyl-piperazin-1 -methyl)- benzamide as the raw material. The said raw material is reacted with 2-halogen-4-(3-pyridyl)- pyrimidine to obtain Imatinib.
The process disclosed in CN 101016293 A comprises use of halogenated agent, such as phosphorus oxychloride, which is used to synthesize 2-halogeno-4- methyl- (3-pyridyl) – pyridine is lachrymator and corrosive and has great influence to the surroundings. EP0564409 describes a coupling reaction between N-(5-amino -2-methylphenyl)-4-(3- pyridyl)-2-pyrimidine amine and 4-(4-methyl piperazin-l-ylmethyl)-benzoyl chloride in the presence of high quantity of pyridine to starting reactant amine N-(5-amino -2- methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine. The ratio of the pyridine to the said reactant is 138 which is equivalent to about 40 parts v/w. Use of such a large quantity of pyridine is unsafe as it is a toxic solvent according to ICH guidelines. The workup of the reaction comprises evaporation of the remaining pyridine and further processing, which finally involves chromatography for purification, which is highly undesirable on industrial scale because it is expensive and time consuming.
US2006/0149061 and US20060223817 also discloses a similar synthetic approach comprising the use of similar pyridine /starting amine ratio (140 equivalents which is equals about 41 parts v/w). The product obtained is purified by slurring in ethyl acetate.
WO2004/074502 describes a coupling reaction between N-(5-amino -2-methylphenyl)-4- (3-pyridyl)-2-pyrimidine amine and 4-(4-methyl piperazin-l-ylmethyl)-benzoyl chloride wherein solvent like dimethyl pharmamide , dimethyl acetamide, N-methyl pyrilidinone are used as solvents instead of pyridine. However the method described in this patent application lacks an advantage in that the coupling reaction produces the hydrohalide salt of imatinib, e.g. imatinib trihydrochloride monohydrate, which has to be treated with a base in order to afford the imatinib base, thus an extra step is required. Further, conventional methods for coupling N-(5-amino -2-methylphenyl)-4-(3-pyridyl)-2- pyrimidine amine require reaction with an acid halide, e.g. 4-(4-methyl piperazin-1- ylmethyl)-benzoyl chloride, which requires an additional production step that can involve harsh and/or toxic chlorinating agent.
WO2008/1 17298 describes a coupling reaction between N-(5-amino -2-methylphenyl)-4- (3-pyridyl)-2-pyrimidine amine and 4-(4-methyl piperazin-l-ylmethyl)-benzoyl chloride in presence of a base selected from potassium carbonate, sodium carbonate, potassium or sodium hydroxide. Use of potassium carbonate as base results into the formation of Imatinib dihydrochloride which ultimately requires an additional operation of neutralization by using excessive base to get imatinib.
WO2008/136010 describes a coupling reaction between N-(5-amino -2-methylphenyl)-4- (3-pyridyl)-2-pyrimidine amine and 4-(4-methyl piperazin-l-ylmethyl)-benzoyl chloride in presence of base potassium hydroxide resulting into 78.6% yield of crude imatinib base. Preparation of crude requires imatinib hydrochloride preparation during the workup which is then basified to get base in crude form. This also describes maleate salt preparation as mode of purification which is again basified to give pure Imatinib base.
US patent application 2004/0248918 discloses a different approach using N-(5-amino -2- methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine and 4-(2-chloromethyl)-benzoyl chloride as raw material. The reaction for the preparation of Imatinib is carried out in tetrahydrofuran as a reaction solvent and in the presence of pyridine as a base. However the method described in this patent application lacks an advantage as purification of the product requires column chromatography using chloroform: methanol (3: 1 v/v), which is not suitable purification method when performing the reaction on large scale, followed by crystallizati
US patent application 2008/0103305 discloses a process comprising reacting N-(5-amino -2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine or its alkyl derivative and an acid salt of 4-[(4-methyl-l-piperazinyl)-methyl] benzoyl derivative as given below in the scheme-3 using pyridine in an amount of about 2 to 10 volumes per gram of the said amine. However the drawback associated with this process is use of pyridine especially when reaction is performed on large scale. -3
Inverse synthetic analysis will be divided into four imatinib into fragment A has 1,3 – parents electrical, fragment B are 1,3 – parent nuclear, fragments A and B constitute a pyrimidine ring.
Compound 4 can be obtained in two ways, benzyl bromide 1 and secondary amines 2 by SN2 reaction, or the aldehyde 3 with a secondary amine 2 by reductive amination. Sodium cyanoborohydride electron withdrawing effect of the cyano group, thereby reducing the activity of the negative hydrogen, it may be present in acidic solution. Also in the acidic conditions of aldehydes and secondary amines imine positive ions, which is higher than the activity of aldehyde reduction.This is why the reductive amination reagent with inert negative and hydrogen under acidic conditions. 4 hydrolyzed ester with thionyl chloride into the acid chloride 5 . The reaction of aniline and cyanamide dinucleophile guanidine 7 . Compound 8 and DMF-DMA reaction electrophilic reagent parents 9 , 7 , and 9 ring closure under alkaline conditions to generate 10 . Finally, reduction, amidation, and a salt of imatinib mesylate generated.
An efficient, economic process has been developed for the production of imatinib with 99.99% purity and 50% overall yield from four steps. Formation and control of all possible impurities is described. The synthesis comprises the condensation of N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine with 4-(4-methylpiperazinomethyl)benzoyl chloride in isopropyl alcohol solvent in the presence of potassium carbonate to yield imatinib base.
Imatinib (1), nilotinib (2) and dasatinib (3) are Bcr-Abl tyrosine kinase inhibitors approved for the treatment of chronic myelogenous leukemia (CML). This review collates information from the journal and patent literature to provide a comprehensive reference source of the different synthetic methods used to prepare the aforementioned active pharmaceutical ingredients (API’s).
Medicine for Blood Cancer
‘Imitinef Mercilet’ is a medicine which cures blood cancer.
Its available free of cost at “Adyar Cancer Institute in Chennai”.
Create Awareness. It might help someone.Cancer Institute in Adyar, Chennai
‘Imitinef Mercilet’ is apparently an alternative spelling of the drug Imatinib mesylate which is used in the treatment of some forms of leukemia along with other types of cancer. Imatinib, often referred to a “Gleevec”, has proved to be an effective treatment for some forms of cancers. However, “blood cancer” is a generalized term for cancers that affect the blood, lymphatic system or bone marrow. The three types of blood cancer are listed as leukemia, lymphoma, and multiple myeloma. These three malignancies require quite different kinds of treatments. While drugs (including Imatinib), along with other treatments such as radiation can help to slow or even stop the progress of these cancers, there is currently no single drug treatment that can be said to actually cure all such cancers.
Address: East Canal Bank Road , Gandhi Nagar
Adyar, Chennai -600020
Landmark: Near Michael School
Phone: 044-24910754 044-24910754 ,
044-24911526 044-24911526 , 044-22350241
Imatinib is a small molecule selectively inhibiting specific tyrosine kinases that has emerged recently as a valuable treatment for patients with advanced GIST. The use of imatinib as monotherapy for the treatment of GIST has been described in PCT publication WO 02/34727, which is here incorporated by reference. However, it has been reported that primary resistance to imatinib is present in a population of patients, for example 13.7% of patients in one study. In addition, a number of patients acquire resistance to treatment with imatinib. More generally this resistance is partial with progression in some lesions, but continuing disease control in other lesions. Hence, these patients remain on imatinib treatment but with a clear need for additional or alternative therapy.
Imatinib is 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]-benzamide having the formula I
The preparation of imatinib and the use thereof, especially as an anti-tumour agent, are described in Example 21 of European patent application EP-A-0 564 409, which was published on 6 Oct. 1993, and in equivalent applications and patents in numerous other countries, e.g. in U.S. Pat. No. 5,521,184 and in Japanese patent 2706682
The flow-based route required minimal manual intervention and was achieved despite poor solubility of many reaction components
UK chemists have used a combination of flow chemistry methods with solid-supported scavengers and reagents to synthesise the active pharmaceutical ingredient, imatinib, of the anticancer drug Gleevec. The method avoids the need for any manual handling of intermediates and allows the drug to be synthesised in high purity in less than a day.
Gleevec, developed by Novartis, is a tyrosine kinase inhibitor used for the treatment of chronic myeloid leukaemia and gastrointestinal stromal tumours.
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‘Wrapping’ Gleevec Fights Drug-Resistant Cancer, Study Shows
The anti-cancer drug Gleevec® is far more effective against a drug-resistant strain of cancer when the drug wraps the target with a molecular bandage that seals out water from a critical area. This image shows the bandage (black box) on the modified version of the drug, WBZ-7. (Credit: Image courtesy of Rice University)
A new study in Cancer Research finds that the anti-cancer drug Gleevec® is far more effective against a drug-resistant strain of cancer when the drug wraps the target with a molecular bandage that seals out water from a critical area.
FIG 23.8 Optimization of imatinib as a chemotherapeutic agent. The discovery that 2-phenylaminopyrimidine inhibitors of PKC also inhibit the unrelated v-Abl oncogene turned attention to its potential use in the treatment of chronic myelogenous leukaemia. Starting with the 2-phenylaminopyrimidine backbone, addition of the benzamidine group increased activity against tyrosine kinases, the methyl group reduced its activity against PKC (so-called ‘ target hopping ’ ). Addition of a 3’-pyridyl group improved the activity in cellular assays. Subsequent addition of N -methylpiperazine increased water solubility and oral bioavailability, enabling the drug to survive the stomach and to enter the bloodstream.
An automated flow-based synthesis of imatinib: the API of gleevec M.D. Hopkin, I.R. Baxendale, S.V. Ley, J.C.S. Chem. Commun.2010, 46, 2450-2452.
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2796.5(w), 1645.9(m), 1586.0(m), 1575.1(s), 1554.0(m), 1531.5(s), 1510.3(m), 1478.1(m),
1448.9(s), 1416.7(m), 1377.7(m), 1352.2(m), 1334.8(m), 1325.6(m), 1308.8(m), 1290.3(s),
1261.1(m), 1204.3(m), 1164.1(m), 1141.7(m), 1124.6(w), 1102.6(m), 1089.2(w), 1052.0(w),
1024.4(w), 1010.0(m), 992.5(w), 968.3(w), 924.5(w), 886.2(w), 857.9(w), 850.3(w),
807.8(m), 795.7(s), 748.1(m), 703.2(m), 690.1(m), 670.7(m);
10.14 (1 H, s, NH), 9.26 (1 H, d, J = 1.5 Hz, 2H-pyridin-3-yl), 8.95 (1 H, s, NH), 8.66 (1 H, dd,
J = 4.8 and 1.2 Hz, 6H-pyridin-3-yl), 8.49 (1 H, d, J = 5.1 Hz, 6H-pyridin-2-amine), 8.46 (1 H,
ddd, J = 7.9, 1.5 and 1.2 Hz, 4H-pyridin-3-yl), 8.06 (1 H, d, J = 1.5 Hz, 3H-2-aminotoluene),
7.89 (2 H, d, J = 8.1 Hz, 2H-benzamide), 7.50 (1 H, dd, J = 7.9 and 4.8 Hz, 5H-pyridin-3-yl),
7.46 (1 H, dd, J = 8.3 and 1.5 Hz, 5H-2-aminotoluene), 7.42 – 7.40 (3 H, m, 3H-benzamide
and 5H-pyridin-2-amine), 7.18 (1 H, d, J = 8.3 Hz, 6H-2-aminotoluene), 3.51 (2 H, s, CH2),
2.50 – 2.20 (8 H, m, piperazine CH2), 2.20 (3 H, s, CCH3), 2.13 (3 H, s, NCH3);
150 MHz) = 165.42(C), 162.72(C), 160.57(C), 158.99(CH), 151.44(CH), 148.48(CH),
142.52(C), 137.77(C), 136.60(C), 134.92(CH), 133.88(C), 132.66(C), 130.75(CH),
129.28(CH), 127.00(CH), 124.23(C), 123.71(CH), 115.35(CH), 113.19(CH), 108.32(CH),
62.49(CH2), 55.07(CH2), 53.10(CH2), 45.98(CH3), 17.65(CH3);
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THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D