1454846-35-5

Basic information

• Product Name: PF-06463922
• Synonyms: PF-06463922;(10R)-7-Amino-12-fluoro-10,15,16,17-tetrahydro-2,10,16-trimethyl-15-oxo-2H-4,8-methenopyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile;PF-06463922, Lorlatinib;(R)-26-amino-55-fluoro-11,4,7-trimethyl-6-oxo-11H-3-oxa-7-aza-2(3,5)-pyridina-1(4,3)-pyrazola-5(1,2)-benzenacyclooctaphane-15-carbonitrile;Lorlatinib,PF-06463922;EOS-60936;Loratinib
• CAS NO: 1454846-35-5
• Molecular Formula: C21H19FN6O2
• Molecular Weight: 406.4129632
• EINECS: 1592732-453-0
• Product Categories: Inhibitors;API
• Mol File: 1454846-35-5.mol
• Article Data: 17

Chemical Properties

• Boiling Point: 675.0±55.0 °C(Predicted)
• Appearance: /
• Density: 1.42±0.1 g/cm3(Predicted)
• Storage Temp.: Hygroscopic, -20°C Freezer, Under inert atmosphere
• Solubility: Chloroform (Slightly), Ethyl Acetate (Slightly)
• PKA: 6.05±0.40(Predicted)
• Stability: Hygroscopic
• CAS DataBase Reference: PF-06463922(CAS DataBase Reference)
• NIST Chemistry Reference: PF-06463922(1454846-35-5)
• EPA Substance Registry System: PF-06463922(1454846-35-5)

Safety Data

• Hazardous Substances Data: 1454846-35-5(Hazardous Substances Data)

Usage

Uses

Used in Oncology:
PF-06463922 is used as an anticancer agent for the treatment of advanced non-small cell lung cancer (NSCLC) in patients who are ALK or ROS1 positive and have developed resistance to other ALK inhibitors. It acts by inhibiting the ALK and ROS1 receptor tyrosine kinases, blocking the downstream signaling, and inducing apoptosis, which results in the inhibition of tumor cell proliferation.
Used in Drug Resistance:
PF-06463922 is used as a potent and selective ROS1/ALK inhibitor capable of blocking crizotinib-resistant ROS1 mutations, overcoming the limitations of current therapies and improving treatment outcomes for patients with advanced NSCLC.
Used in Brain Tumor Treatment:
Lorlatinib is used for the treatment of brain tumors in patients with ALK-positive metastatic non-small cell lung cancer (NSCLC), as it demonstrates efficient blood-brain barrier penetration and produces brain tumor regression in mice harboring EML4-ALK tumors, increasing overall survival.
Used in Clinical Trials:
Lorlatinib (PF-06463922) is currently being evaluated in phase II clinical trials as an oral dose at 100 mg daily for the treatment of the specified subgroup of ALK or ROS1 positive NSCLC patients. If marketed, it will become an additional targeted treatment option for this patient population.

Mechanism of Action

Lorlatinib is a kinase inhibitor with in vitro activity against ALK and number of other tyrosine kinase receptor related targets including ROS1, TYK1, FER, FPS, TRKA, TRKB, TRKC, FAK, FAK2, and ACK Label. Lorlatinib demonstrated in vitro activity against multiple mutant forms of the ALK enzyme, including some mutations detected in tumors at the time of disease progression on crizotinib and other ALK inhibitors Label. Moreover, lorlatinib possesses the capability to cross the blood-brain barrier, allowing it to reach and treat progressive or worsening brain metastases as well. The overall antitumor activity of lorlatinib in in-vivo models appears to be dose-dependent and correlated with the inhibition of ALK phosphorylation Label. Although many ALK-positive metastatic NSCLC patients respond to initial tyrosine kinase therapies, such patients also often experience tumor progression. Various clinical trials performed with lorlatinib, however, have demonstrated its utility to effect tumor regression in ALK-positive metastatic NSCLC patients who experience tumor progression despite current use or having already used various first and second-generation tyrosine kinase inhibitors like crizotinib, alectinib, or ceritinib.

Side effects

A third-generation ALK- and ROS1-inhibitor, lorlatinib, has demonstrated activity following progression on one or more ALK inhibitors.Lorlatinib is approved for ALK-positive NSCLC. Similar to other agents in this category, lorlatinib is associated with hepatotoxicity and interstitial lung disease/pneumonitis. CNS toxicities, hyperlipidemia, and atrioventricular block have also been reported.

Biological Activity

pf-06463922 is a potent and selective alk/ros1 inhibitor with ic50 values ranging from 0.19-0.53 nm for the kinase activity of ros1 fusion enzymes [1].the receptor tyrosine kinase c-ros oncogene1 (ros1) is a receptor with a kinase domain that is related to the anaplastic lymphoma kinase/lymphocyte-specific protein tyrosine kinase (alk/ltk) and insulin receptor (insr) rtk families [1].via cellular ros1 autophosphorylation in the recombinant enzyme assay, pf-06463922 showed a 30-fold improved potency against ros1, compared with crizotinib, ceritinib, alectinib and foretinib (xl-880). engineered nih 3t3 cells were expressing oncogenic human ros1 fusions. in these cells, pf-06463922 was more potent than foretinib and crizotinib by >10 folds, more potent than alectinib and ceritinib by >100 folds against cellular ros1 autophosphorylation [1].oncogenic gene fusions involving the 3' region of ros1 kinase had been found in various human cancers [2]. mice bearing cd74-ros1, cd74-ros1g2032r and fig-ros1(s) s.c. tumors (250 mm3) were used. treatments with pf-06463992 at various doses were applied consecutively for 7 or 9 d. at dosages of 0.2 to 1 mg/kg/d, pf-06463922 significantly inhibited the growth of both established figros1(s) and cd74-ros1 tumors compared with vehicle control. at 2-6 mg/kg/d, pf-06463922 significantly made tumor volumes regress (58–85%, p < 0.0001). in animals bearing nih 3t3-cd74-ros1g2032r tumors, treatment with pf-06463922 at 1.0, 3.0, and 10 mg/kg/d significantly inhibited tumor growth by 28%, 44% and 90%, respectively. at 30 mg/kg/d, pf-06463922 made tumor regress by 12%, compared with vehicle [1].

Enzyme inhibitor

This potent, dual ALK/ROS1 inhibitor (FW = 406.41 g/mol; CAS 1454846- 35-5), also named (10R)-7-amino-12-fluoro-10,15,16,17-tetrahydro- 2,10,16-trimethyl-15-oxo-2H-4,8-methenopyrazolo[4,3- h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile, targets the protooncogene tyrosine-protein kinase ROS1 (Ki < 0.02 nM) as well as wild-type anaplastic lymphoma kinase ALKWT (Ki < 0.07 nM) and its Leu-to-Met mutant ALKL1196M (Ki of = 0.7 nM). PF-06463922 significantly inhibits cell proliferation and induces cell apoptosis in the HCC78 human NSCLC cells harboring SLC34A2-ROS1 fusions and the BaF3-CD74-ROS1 cells expressing human CD74-ROS1

references

[1]. zou hy, li q, engstrom ld, et al. pf-06463922 is a potent and selective next-generation ros1/alk inhibitor capable of blocking crizotinib-resistant ros1 mutations. proceedings of the national academy of sciences, 2015, 112(11): 3493-3498.[2]. davies kd, le at, theodoro mf, et al. identifying and targeting ros1 gene fusions in non–small cell lung cancer. clinical cancer research, 2012, 18(17): 4570-4579.

Upstream product

• 1454848-24-8 ((4-bromo-5-cyano-1-methyl-1H-pyrazol-3-yl)methyl)(methyl)carbamic acid tert-butyl ester 
• 1207175-73-2 5-bromo-3-hydroxy-2-tert-butyloxycarbonylaminopyridine 
• 306936-77-6 1,3-dimethyl-1H-pyrazole-5-carbonitrile 
• 10250-59-6 1,3-dimethyl-1H-pyrazole-5-carboxylic acid methyl ester 
• 25016-17-5 3-methyl-1H-pyrazole-5-carboxylic acid methyl ester 
• 20577-61-1 methyl 2,4-dioxopentanoate 

Relevant articles and documents

Conformational Studies and Atropisomerism Kinetics of the ALK Clinical Candidate Lorlatinib (PF-06463922) and Desmethyl Congeners

Lorlatinib (PF-06463922) is an ALK/ROS1 inhibitor and is in clinical trials for the treatment of ALK positive or ROS1 positive NSCLC (i.e. specific subsets of NSCLC). One of the laboratory objectives for this molecule indicated that it would be desirable

Preparation method of anti-tumor drug Lorlatinib

The invention relates to a preparation method of an anti-tumor drug Lorlatinib, which comprises the steps of (1) coupling tert-butyl (5-bromo-3-((trimethylsilane) oxy) pyridine-2-yl) carbamate and 1, 3-dimethyl-1H-pyrazole-5-nitrile to obtain a first intermediate; (2) brominating the first intermediate with NBS to obtain a second intermediate; (3) enabling the second intermediate and (R)-1-(5-fluoro-2-N-methylformamide phenyl)-ethanol to be subjected to a one-pot method under the alkaline condition to obtain and a third intermediate; and (4) removing a protecting group from the third intermediate under an acidic condition to obtain the final product Lorlatinib. The method has the advantages of simple and easily available raw materials, short steps, high total yield, relatively convenient operation, low cost, suitability for industrial production and the like.

CRYSTALLINE LORLATINIB : FUMARIC ACID AND SOLID STATE FORM THEREOF

The present disclosure relates to crystalline Lorlatinib : Fumaric acid, solid state forms thereof, processes for preparation thereof, pharmaceutical compositions and methods of use thereof.

Preparation method of lorlatinib

The invention relates to a preparation method of lorlatinib. Specifically, the invention provides a preparation method of lorlatinib. According to the method, a compound 1-methyl-3-((methyl-t-butyloxycarboryl-amino) methyl)-1H-pyrazole-4-bromine-5-nitrile as shown in a formula VII and a compound 2-(t-butyloxycarboryl-amino)-3-hydroxy-5-bromopyridine as shown in a formula VI are used as raw materials and subjected to a coupling reaction, a Williamson reaction, a hydrolysis reaction, an acidolysis reaction and a condensation reaction, so as to prepare lorlatinib. The preparation method of the lorlatinib has the advantages of being short in synthesis route, simple and convenient to operate, mild in reaction condition, high in yield and the like, and is suitable for industrial production of the lorlatinib.

Preparation method of anticancer drug

The invention provides a preparation method of an anticancer drug lapatinib, which is characterized by comprising the following steps: dissolving a compound of formula A in an organic solvent, addinga condensing agent TBTU and an alkali promoter DBU, stirring uniformly, heating the system to 40-60 DEG C, keeping the temperature to react for 2-3 hours, cooling to room temperature after the reaction is completed through TLC detection, and adding an ammonium chloride solution to quench the reaction, performing extraction and separation to obtain lorlatinib; according to the invention, TBTU is used as a condensing agent, DBU is used as an alkali promoter, and the TBTU and the DBU are combined for use, so compared with the prior art, the use amounts of the condensing agent and the alkali promoter used in the invention are obviously reduced, the reaction time is shorter, but the reaction yield is much higher than that in the prior art, and the method is very suitable for industrial production.

Application of TBTU in preparation of anti-cancer drug

The invention provides application of TBTU in preparation of an anticancer drug Lorlatinib, which is characterized by comprising the following steps: dissolving a compound of formula A in an organic solvent, adding a condensing agent TBTU and an alkali promoter DBU, stirring uniformly, heating the system to 40-60 DEG C, keeping the temperature to react for 23 hours, cooling to room temperature after the reaction is detected by TLC, and adding an ammonium chloride solution to quench the reaction, and performing extraction and separation to obtain the Lorlatinib. According to the invention, theTBTU is used as the condensing agent, DBU is used as the alkali promoter, and the TBTU and the DBU are combined for use, so compared with the prior art, the use amounts of the condensing agent and thealkali promoter used in the invention are obviously reduced, the reaction time is shorter, but the reaction yield is much higher than that in the prior art, and the method is very suitable for industrial production.

Benzoxadiazepine tetradecene derivative and application thereof

The invention discloses a benzoxadiazepine tetradecene derivative and application thereof, belonging to the field of medicines. The benzoxadiazepine tetradecene derivative with a structure as shown ina general formula (I) has excellent anaplastic lymphoma enzyme (ALK) inhibition activity and excellent pharmacodynamic performance, and can obviously prolong the large metabolic half-life period of adrug; the derivative can be safely and effectively used for treating anaplastic lymphoma kinase positive (ALK+) metastatic (advanced) non-small cell lung cancer (NSCLC) and the like, thereby providing a new means for treating cancers, metabolic and immune diseases, cardiovascular diseases, neurological diseases and the like.

Bromo-midbody for synthesizing Lorlatinib and catalytic synthesis method for Lorlatinib

The invention discloses a bromo-midbody for synthesizing Lorlatinib. The structure of the bromo-midbody for synthesizing the Lorlatinib is shown as a compound 1 (The formula is defined in the description). The invention also discloses a method for catalyz

Method for synthesizing lorlatinib

The invention belongs to the technical field of medicines, and relates to a method for synthesizing lorlatinib (PF-06463922), which is finally synthesized from 5-fluoro-3-methyl isobenzofuran-1(3H)-ketone and 1-methyl-3-((methylamino)methyl)-1H-pyrazol-5-

SOLID STATE FORMS OF LORLATINIB AND THEIR PREPARATION

The present disclosure relates to Lorlatinib solid state forms, Lorlatinib salts and solid states thereof, processes for preparation thereof, pharmaceutical compositions and methods of use thereof.