146464-95-1

Usage

Uses

Used in Oncology:
10-Propargyl-10-deazaaminopterin is used as an antifolate agent for the treatment of various types of cancer, particularly T-cell lymphoma. It exhibits high affinity for the reduced folate carrier-type 1 and has been shown to produce marked complete and durable remissions in a diversity of chemotherapy-refractory cases of T-cell lymphoma.
Used in the Treatment of Peripheral T-Cell Lymphoma (PTCL):
10-Propargyl-10-deazaaminopterin is used as a dihydrofolate reductase (DHFR) inhibitor for the treatment of patients with relapsed or refractory PTCL. PTCL is an aggressive form of non-Hodgkin's lymphoma (NHL) characterized by the proliferation of abnormal T-lymphocytes that circulate in the peripheral bloodstream. The inhibition of the folate enzymes DHFR and thymidylate synthase by 10-Propargyl-10-deazaaminopterin is a well-validated method of cancer treatment.
Used in the Inhibition of Cancer Cell Growth:
10-Propargyl-10-deazaaminopterin is used as an inhibitor of cancer cell growth in various types of cancer, including CCRF-CEM acute lymphocytic leukemia, MDA-468, SK-BR-3, and ZR-75-1 breast cancer cells, and SK-LC8 and SK-LC16 non-small cell lung cancer cells (NSCLC). It is transported into cells via the reduced folate carrier (RFC) and undergoes polyglutamation by folylpolyglutamate synthetase (FPGS) to a greater extent than methotrexate or pemetrexed, leading to more potent inhibition of cell growth.
Used in the Treatment of Relapsed or Refractory Peripheral T Cell Lymphoma:
10-Propargyl-10-deazaaminopterin is used in formulations for the treatment of relapsed or refractory peripheral T cell lymphoma. In vivo studies have shown that pralatrexate increases median survival from 21 to 40 days when administered in 4 doses of 15 mg/kg over 11 days in an H9 T cell lymphoma mouse xenograft model.
Brand Name:
Folotyn

Originator

SRI International/ Southern Research Institute/Sloan-Kettering (US)

Clinical Use

Pralatrexate, an injectable dihydrofolate reductase (DHFR) inhibitor, has a superior potency and toxicity profile compared to other DHFR inhibitors. In 2009, the compound was launched by Allos and approved in the U.S. for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) as a single agent. It is the first drug approved for this indication.70 In 2010, orphan drug designation was received in the E.U. for the treatment of cutaneous T-cell lymphoma (CTCL).

Side effects

The most common adverse reactions associated with pralatrexate are mucositis, thrombocytopenia, nausea, and fatigue. Folic acid and vitamin B12 supplements are administered as adjunct therapies to potentially reduce pralatrexate-related hematological toxicity and mucositis.

Synthesis

The chemical synthesis of pralatrexate starts with the alkylation of the anion of dimethyl homoterephthalate with propargyl bromide, promoted by potassium hydride in dimethylformamide, to afford the corresponding a-propargyl diester. Further alkylation of the potassium salt of a-propargyl diester with 2,4-diamino-6-(bromomethyl)pteridine followed by saponification with sodium hydroxide yields a diacid intermediate (2,4diamino- 4-deoxy-10-propargyl-10-deazapteroic acid). Mono-decarboxylation of the diacid intermediate by heating in dimethylsulfoxide at 120 C, followed by coupling with diethyl L-glutamate, and subsequent ester hydrolysis with sodium hydroxide yields pralatrexate.

references

[1]. izbicka e, diaz a, streeper r, et al. distinct mechanistic activity profile of pralatrexate in comparison to other antifolates in in vitro and in vivo models of human cancers. cancer chemother pharmacol, 2009, 64(5): 993-999. [2]. serova m, bieche i, sablin mp, et al. single agent and combination studies of pralatrexate and molecular correlates of sensitivity. br j cancer, 2011, 104(2): 272-280.

InChI:InChI=1/C23H23N7O5/c1-2-3-14(10-15-11-26-20-18(27-15)19(24)29-23(25)30-20)12-4-6-13(7-5-12)21(33)28-16(22(34)35)8-9-17(31)32/h1,4-7,11,14,16H,3,8-10H2,(H,28,33)(H,31,32)(H,34,35)(H4,24,25,26,29,30)/t14?,16-/m0/s1

Upstream product

• 1118-89-4 diethyl-L-glutamate hydrochloride 
• 374777-77-2 10-propargyl-10-deazaaminopterin dimethyl ester 
• 76322-80-0 methyl 4-(3-oxobut-1-enyl)benzoate 
• 1445586-50-4 10-propargyl-10-carboxy-4-deoxy-4-amino-10-deazapteroic acid sodium salt 
• 1548618-47-8 10-propargyl-10-carbomethoxy-4-deoxy-4-amino-10-deazapteroic acid methyl ester hydrobromide salt 
• 1571-08-0 methyl 4-formylbenzoate 
• 1445586-44-6 potassium 10-propargyl-4-deoxy-4-amino-10-deazapteroate 

Relevant academic research and scientific papers

Preparation method of pralatrexate

The invention belongs to the technical field of medicine and particularly relates to a preparation method of pralatrexate finished products. The method comprises the following steps: by taking PLQS-6as a raw material and respectively taking acetone, methy

A suitable industrial production pula Qu Sha method for the preparation of

The invention relates to the field of pharmaceutical chemistry technology, and more specifically relates to an anticarcinogen 10-Propargyl-10-deazaaminopterin (Pralatrexate) and synthesis of an intermediate thereof. The invention has the advantages of simple operation, low contents of related impurities, easiness in purification of intermediate, thereby avoiding purification mode of column chromatography, and the invention can be applied to large scale production of Pralatrexate bulk drug as well as preparation and purification method of important intermediates.

IMPROVED PROCESS FOR THE PREPARATION OF PRALATREXATE

An improved process for the preparation of Pralatrexate which is less hazardous. The invention further relates to novel intermediates and process thereof useful for the preparation of Pralatrexate. The present invention also relates to a substantially pure Pralatrexate and a process for obtaining the same in high yield.

SALTS OF PRALATREXATE

The present invention provides salts of Pralatrexate, in particular, sodium, lithium and potassium salts and their polymorphic forms, process for the preparation thereof, pharmaceutical compositions comprising these salts and at least one pharmaceutically

IMPROVED PROCESS FOR THE PREPARATION OF PRALATREXATE

An improved process for the preparation of Pralatrexate which is less hazardous. The invention further relates to novel intermediates and process thereof useful for the preparation of Pralatrexate. The present invention also relates to a substantially pure Pralatrexate and a process for obtaining the same in high yield.

PROCESS FOR PRALATREXATE

The present invention provides a novel process for the purification of alpha-propargylhomoterephthalic acid dimethyl ester substantially free of homoterephthalic acid dimethyl ester. The present invention also provides a novel process for the purification of pralatrexate.

PROCESS FOR PREPARATION OF AN ANTIFOLATE AGENT

The specification relates to a process for preparation of an antifolate compound of formula 7, such as Pralatrexate. Also, disclosed are intermediates and processes for preparation of intermediates useful in the preparation of the antifolate compound. The substituents Y, Z, R, R1 and R2 are as described herein. The processes and intermediates can provide an alternate route to the synthesis of the antifolate compound. Further, the processes can help to avoid distillation or evaporation of high boiling point solvents, chromatographic purification and use of hazardous combination of solvents; and can also provide a product having high purity, all of which are desirable for synthesis on a large scale.

A PROCESS FOR PREPARING INTERMEDIATES OF 10-PROPARGYL-10-DEAZAAMINOPTERIN (PRALATREXATE) SYNTHESIS AND THE INTERMEDIATES THEREOF

A process for preparation of 4-(1-(2,4-diaminopteridin-6-yl)pent-4-yn-2-yl)benzoic acid and other key intermediates in synthesis of 10-propargyl-10-deazaaminopterin (Pralatrexate) and the intermediates thereof. The 10-propargyl-10-deazaaminopterin (Pralatrexate) is obtained by peptide formation and ester hydrolysis of the intermediate compound 4-(1-(2,4-diaminopteridin-6-yl)pent-4-yn-2-yl)benzoic acid by methods known in the art.

PROCESSES AND INTERMEDIATES FOR PREPARING PRALATREXATE

Processes for preparing and purifying Pralatrexate are described in the present application, as well as intermediates in these processes, and salts and solid state forms of the Pralatrexate intermediates.

Optically Pure Diastereomers of 10-Propargyl-10-Deazaaminopterin and Methods of Using Same

The present invention relates to diastereomers of 10-propargyl-10-deazaminopterin, compositions comprising optically pure diastereomers of 10-propargyl-10-deazaminopterin, in particular the two (R,S) diastereomers about the C10 position. Methods of preparation of these diastereomers, compositions containing them, and their use for the treatment of conditions related to inflammatory disorders and cancer are also disclosed.