1197160-78-3

Basic information

• Product Name: PF-05212384
• Synonyms: PF-05212384;PKI587;N-[4-[[4-(Dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N'-[4-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]phenyl]urea;PF-05212384 (PKI-587);1-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)-3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)urea;Gedatolisib (PF-05212384, PKI-587);N-[4-[[4-(Dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N'-[4-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]phenyl]urea PF-05212384 (PKI-587);PKI-587 N-[4-[[4-(Dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N'-[4-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]phenyl]urea
• CAS NO: 1197160-78-3
• Molecular Formula: C₃₂H₄₁N₉O₄
• Molecular Weight: 615.72584
• EINECS: -0
• Product Categories: PI3K/Akt/mTOR;Inhibitors;Akt;mTOR;PI3K
• Mol File: 1197160-78-3.mol

Chemical Properties

• Appearance: /
• Density: 1.364
• Storage Temp.: Refrigerator
• Solubility: DMSO
• PKA: 13.97±0.70(Predicted)
• CAS DataBase Reference: PF-05212384(CAS DataBase Reference)
• NIST Chemistry Reference: PF-05212384(1197160-78-3)
• EPA Substance Registry System: PF-05212384(1197160-78-3)

Safety Data

• Hazardous Substances Data: 1197160-78-3(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
PF-05212384 is used as a potent PI3K/mTOR dual inhibitor for its inhibitory activity against PI3K-α, PI3K-γ, and mTOR. This makes it a promising candidate for the development of targeted therapies in cancer treatment, as it can potentially disrupt key signaling pathways involved in tumor growth and progression.

Biological Activity

pf-05212384 is an inhibitor of pi3k/mtor with ic50 values of 0.4nm, 6nm, 8nm, 6nm and 1.4nm for pi3kα, pi3kβ, pi3kγ, pi3kδ and mtor, respectively [1].pf-05212384 is a pan-pi3k/mtorinhibitor and shows to be highly selective for pi3k and mtor. besides the wt p13k, pf-05212384 can also inhibit mutant p13k with ic50 values of 0.6nm for both h1047r and e545k mutants. in cellular assay, pf-05212384 potently inhibits tumor growth in mda-361 and pc3-mm2 cell lines with ic50 values of 4nm and 13.1nm, respectively. meanwhile, pf-05212384 suppresses the phosphorylation of pi3k/mtor signaling pathway proteins in cells. it inhibits the phosphorylation of akt as well as the akt effector proteins including gsk3 kinase, enos and pras 40. moreover, pf-05212384 has potent anti-tumor activity in a variety of xenograft models including h1975, bt474, hct116, h1975 and u87mg [1, 2]

Enzyme inhibitor

This dual PI3K/mTOR (phosphoinositide-3-kinase and mammalian target of rapamycin) signal-transduction pathway inhibitor and antineoplastic agent (F.Wt. = 615.73; CAS 1197160-78-3); Solubility (25°C): 2 mg/mL DMSO, <1 mg/mL Water), also known as PF-05212384 and systematically as 1-(4- (4-(dimethylamino)piperidine-1-carbonyl)phenyl)-3-(4-(4,6-dimorpholino- 1,3,5-triazin-2-yl)phenyl)urea, inhibits PI3K-α, PI3K-γ and mTOR with IC50 of 0.4 nM, 5.4 nM and 1.6 nM, respectively. PKI-587 also inhibits mutant forms of PI3Kα, including the PI3Kα-H1047R and PI3Kα-E545K with IC50 of 0.6 nM and 0.6 nM, respectively.

references

[1] venkatesan a m, dehnhardt c m, delos santos e, et al. bis (morpholino-1, 3, 5-triazine) derivatives: potent adenosine 5′-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors: discovery of compound 26 (pki-587), a highly efficacious dual inhibitor. journal of medicinal chemistry, 2010, 53(6): 2636-2645.[2] mallon r, feldberg l r, lucas j, et al. antitumor efficacy of pki-587, a highly potent dual pi3k/mtor kinase inhibitor. clinical cancer research, 2011, 17(10): 3193-3203.

Synthetic route

dimethyl-piperidin-4-yl-amine (50533-97-6) + 4-(3-(4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid (1197160-66-9) → PKI-587 (1197160-78-3)

Conditions	Yield
Stage #1: 4-(3-(4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran at 50℃; for 2h; Stage #2: dimethyl-piperidin-4-yl-amine In tetrahydrofuran at 53℃; for 16h; Product distribution / selectivity;	88%
Stage #1: 4-(3-(4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 20℃; Stage #2: dimethyl-piperidin-4-yl-amine In 1-methyl-pyrrolidin-2-one at 20℃;	52%

(4-aminophenyl)(4-(dimethylamino)piperidin-1-yl)methanone (50534-08-2) + phenyl (4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)carbamate → PKI-587 (1197160-78-3)

Conditions	Yield
In dimethyl sulfoxide at 65℃; for 3h; Green chemistry;	88%
In N,N-dimethyl-formamide at 90℃; for 12h;	16.3%

(4-aminophenyl)(4-(dimethylamino)piperidin-1-yl)methanone (50534-08-2) + 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline (1197159-91-3) + phenyl chloroformate (1885-14-9) → PKI-587 (1197160-78-3)

Conditions	Yield
Stage #1: 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline; phenyl chloroformate With pyridine In N,N-dimethyl-formamide at 5 - 20℃; Stage #2: (4-aminophenyl)(4-(dimethylamino)piperidin-1-yl)methanone In N,N-dimethyl-formamide at 90℃; for 12h;	17.8%

4-nitrobenzonitrile (619-72-7) → PKI-587 (1197160-78-3)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: potassium hydroxide / ethanol / 3 h / 78 °C / Green chemistry 2.1: sodium hydride / mineral oil; N,N-dimethyl-formamide / 65 °C / Inert atmosphere; Green chemistry 3.1: hydrogen / tetrahydrofuran / 12 h / 20 °C / Green chemistry 4.1: pyridine / dichloromethane / 5 °C / Green chemistry 4.2: 2 h / 5 °C / Green chemistry 5.1: dimethyl sulfoxide / 3 h / 65 °C / Green chemistry View Scheme
Multi-step reaction with 4 steps 1.1: potassium hydroxide / 2-methoxy-ethanol / 4 h / 90 °C 2.1: sodium hydride / N,N-dimethyl acetamide / 0.17 h / 55 - 60 °C / Inert atmosphere 2.2: 4.5 h / Inert atmosphere 3.1: nickel; hydrogen / tetrahydrofuran / 20 h / 20 °C 4.1: pyridine / N,N-dimethyl-formamide / 5 - 20 °C 4.2: 12 h / 90 °C View Scheme
Multi-step reaction with 5 steps 1.1: potassium hydroxide / 2-methoxy-ethanol / 4 h / 90 °C 2.1: sodium hydride / N,N-dimethyl acetamide / 0.17 h / 55 - 60 °C / Inert atmosphere 2.2: 4.5 h / Inert atmosphere 3.1: nickel; hydrogen / tetrahydrofuran / 20 h / 20 °C 4.1: pyridine / N,N-dimethyl-formamide / 2 h / 5 - 20 °C 5.1: N,N-dimethyl-formamide / 12 h / 90 °C View Scheme

2,4-diamino-6-(4-nitrophenyl)-1,3,5-triazine (29366-73-2) → PKI-587 (1197160-78-3)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sodium hydride / mineral oil; N,N-dimethyl-formamide / 65 °C / Inert atmosphere; Green chemistry 2.1: hydrogen / tetrahydrofuran / 12 h / 20 °C / Green chemistry 3.1: pyridine / dichloromethane / 5 °C / Green chemistry 3.2: 2 h / 5 °C / Green chemistry 4.1: dimethyl sulfoxide / 3 h / 65 °C / Green chemistry View Scheme
Multi-step reaction with 3 steps 1.1: sodium hydride / N,N-dimethyl acetamide / 0.17 h / 55 - 60 °C / Inert atmosphere 1.2: 4.5 h / Inert atmosphere 2.1: nickel; hydrogen / tetrahydrofuran / 20 h / 20 °C 3.1: pyridine / N,N-dimethyl-formamide / 5 - 20 °C 3.2: 12 h / 90 °C View Scheme
Multi-step reaction with 4 steps 1.1: sodium hydride / N,N-dimethyl acetamide / 0.17 h / 55 - 60 °C / Inert atmosphere 1.2: 4.5 h / Inert atmosphere 2.1: nickel; hydrogen / tetrahydrofuran / 20 h / 20 °C 3.1: pyridine / N,N-dimethyl-formamide / 2 h / 5 - 20 °C 4.1: N,N-dimethyl-formamide / 12 h / 90 °C View Scheme

4,4'-(6-(4-nitrophenyl)-1,3,5-triazine-2,4-diyl)dimorpholine → PKI-587 (1197160-78-3)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hydrogen / tetrahydrofuran / 12 h / 20 °C / Green chemistry 2.1: pyridine / dichloromethane / 5 °C / Green chemistry 2.2: 2 h / 5 °C / Green chemistry 3.1: dimethyl sulfoxide / 3 h / 65 °C / Green chemistry View Scheme
Multi-step reaction with 2 steps 1.1: nickel; hydrogen / tetrahydrofuran / 20 h / 20 °C 2.1: pyridine / N,N-dimethyl-formamide / 5 - 20 °C 2.2: 12 h / 90 °C View Scheme
Multi-step reaction with 3 steps 1: nickel; hydrogen / tetrahydrofuran / 20 h / 20 °C 2: pyridine / N,N-dimethyl-formamide / 2 h / 5 - 20 °C 3: N,N-dimethyl-formamide / 12 h / 90 °C View Scheme

L-Lactic acid (79-33-4) + PKI-587 (1197160-78-3) → 1-(4-((4-(dimethylamino)piperidin-1-yl)carbonyl)phenyl)-3-(4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl)urea L-lactate

Conditions	Yield
In ethyl acetate; N,N-dimethyl-formamide at 23℃; for 24h; Temperature;

Upstream product

• 50533-97-6 dimethyl-piperidin-4-yl-amine 
• 1197160-66-9 4-(3-(4-(4,6-bismorpholine-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid 
• 619-72-7 4-nitrobenzonitrile 
• 29366-73-2 2,4-diamino-6-(4-nitrophenyl)-1,3,5-triazine 
• 50534-08-2 (4-aminophenyl)(4-(dimethylamino)piperidin-1-yl)methanone 
• 7597-22-0 2-chloro-4,6-di-morpholin-4-yl-[1,3,5]triazine 
• 6601-22-5 2,6-Dichloro-4-morpholino-1,3,5-triazine 
• 1197159-91-3 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline 
• 1197160-55-6 methyl 4-({[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]carbamoyl}amino)benzoate 
• 1885-14-9 phenyl chloroformate 

Relevant articles and documents

Synthesis and bioevaluation of diaryl urea derivatives as potential antitumor agents for the treatment of human colorectal cancer

The development of inhibitors targeting the PI3K-Akt-mTOR signaling pathway has been greatly hindered by the on-target AEs, such as hyperglycemia and hepatotoxicities. In this study, a series of diaryl urea derivatives has been designed and synthesized based on clinical candidate gedatolisib (6aa), and most of the newly synthesized derivatives showed kinase inhibitory and antiproliferative activities within nanomolar and submicromolar level, respectively. The terminal l-prolineamide substituted derivative 6 ab showed 8.6-fold more potent PI3Kα inhibitory activity (0.7 nM) and 4.6-fold more potent antiproliferative effect against HCT116 cell lines (0.11 μM) compared with control 6aa. The potential antitumor mechanism and efficacy of 6 ab in HCT116 xenograft models have also been evaluated, and found 6 ab showed comparable in vivo antitumor activity with 6aa. The safety investigations revealed that compound 6 ab exhibited more safer profiles in the selectivity of liver cells (selectivity index: >6.6 vs 1.85) and blood glucose regulation than 6aa. In addition, the in vitro stability assays also indicated our developed compound 6 ab possessed good metabolic stabilities.

New and Practical Synthesis of Gedatolisib

A new, practical, and convergent synthetic route of gedatolisib, an antitumor agent, is developed on a hectogram scale which avoids the Pd coupling method. The key step is adopting 6-(4-nitrophenyl)-1,3,5-triazine-2,4-diamine and 2,2′-dichlorodiethyl ether to prepare the key 4,4′-(6-(4-nitrophenyl)-1,3,5-triazine-2,4-diyl)dimorpholine in 77% yield and 98.8% purity. Gedatolisib is obtained in 48.6% yield over five simple steps and 99.3% purity (HPLC). Purification methods of the intermediates and the final product involved in the route are given.

Gedatolisib intermediates for preparation of (by machine translation)

The invention belongs to the organic synthesis and bulk drug intermediate preparation field, in particular to a method for preparing Gedatolisib, key intermediate and a key intermediate in the preparation method. The nitrobenzene nitrile and dicyanodiamine polyisobutylene triazine cyclization, morpholine link guan huan, hydrogenation of nitro reduction to obtain 4 - (4, 6 - II morpholino - 1, 3, 5 - triazine - 2 - yl) aniline; 4 - oxo-piperidine - 1 - carboxylic acid tert-butyl and dimethylamine salt by addition, de-Boc protecting group, amide, hydrogenation of nitro reduction to get new compounds (4 - aminophenyl) (4 - (dimethyl amino) piperidine - 1 - yl) methyl ketone; adopts the one-pot synthesis, (4, 6 - II morpholino - 1, 3, 5 - triazine - 2 - yl) aniline and chloromethane acid ester after the reaction, then adding (4 - aminophenyl) (4 - (dimethyl amino) piperidine - 1 - yl) methanone, to finally obtain the Gedatolisib. This preparation method has the advantages of easy availability of raw materials, process is simple, easy to operate, high yield and low cost and the like. (by machine translation)

TRIAZINE COMPOUNDS AS PI3 KINASE AND MTOR INHIBITORS

Compounds of formula I wherein: R1 is and R2, R4, and R6-9 are defined herein, and pharmaceutically acceptable salts and esters thereof. These compounds inhibit PI3 kinase and mTOR, and may be used to treat diseases mediated by PI3 kinase and mTOR, such as a variety of cancers. Methods for making and using the compounds of this invention are disclosed. Various compositions containing the compounds of this invention are also disclosed.

PROCESS, PURIFICATION AND CRYSTALLIZATION OF 1-(4-{[4-(DIMETHYLAMINO)PIPERIDIN-1-YL]CARBONYL}PHENYL)-3-[4-(4,6-DIMORPHOLIN-4-YL-1,3,5-TRIAZIN-2-YL)PHENYL]UREA

The invention relates to a method of making compounds of formula VII: (see formula) or a pharmaceutically acceptable salt thereof, wherein the constituent variables are as defined herein.

Bis(morpholino-l,3,5-triazine) derivatives: Potent adenosine 5′-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors: Discovery of compound 26 (PKI-587), a highly efficacious dual inhibitor

The PI3K/Akt signaling pathway is a key pathway in cell proliferation, growth, survival, protein synthesis, and glucose metabolism. It has been recognized recently that inhibiting this pathway might provide a viable therapy for cancer. A series of bis(morpholino-1,3,5-triazine) derivatives were prepared and optimized to provide the highly efficacious PI3K/mTOR inhibitor 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4, 6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea 26 (PKI-587). Compound 26 has shown excellent activity in vitro and in vivo, with antitumor efficacy in both subcutaneous and orthotopic xenograft tumor models when administered intravenously. The structure-activity relationships and the in vitro and in vivo activity of analogues in this series are described.

TRIAZINE COMPOUNDS AS PI3 KINASE AND MTOR INHIBITORS

Compounds of formula I wherein: R1 is and R2, R4, and R6-9 are defined herein, and pharmaceutically acceptable salts and esters thereof. These compounds inhibit PI3 kinase and mTOR, and may be used to treat diseases mediated by PI3 kinase and mTOR, such as a variety of cancers. Methods for making and using the compounds of this invention are disclosed. Various compositions containing the compounds of this invention are also disclosed.