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[ CAS No. 302962-49-8 ] {[proInfo.proName]}

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Chemical Structure| 302962-49-8
Chemical Structure| 302962-49-8
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Product Citations

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Leclercq, Gabrielle ; Haegel, Hélène ; Toso, Alberto , et al. DOI: PubMed ID:

Abstract: Background: T cell engaging therapies, like chimeric antigen receptor T cells and T cell bispecific antibodies (TCBs), efficiently redirect T cells towards tumor cells, facilitating the formation of a cytotoxic synapse and resulting in subsequent tumor cell killing, a process that is accompanied by the release of cytokines. Despite their promising efficacy in the clinic, treatment with TCBs is associated with a risk of cytokine release syndrome (CRS). The aim of this study was to identify small molecules able to mitigate cytokine release while retaining T cell-mediated tumor killing. Methods: By screening a library of 52 Food and Drug Administration approved kinase inhibitors for their impact on T cell proliferation and cytokine release after CD3 stimulation, we identified mTOR, JAK and Src kinases inhibitors as potential candidates to modulate TCB-mediated cytokine release at pharmacologically active doses. Using an in vitro model of target cell killing by human peripheral blood mononuclear cells, we assessed the effects of mTOR, JAK and Src kinase inhibitors combined with 2+1 T cell bispecific antibodies (TCBs) including CEA-TCB and CD19-TCB on T cell activation, proliferation and target cell killing measured by flow cytometry and cytokine release measured by Luminex. The combination of mTOR, JAK and Src kinase inhibitors together with CD19-TCB was evaluated in vivo in non-tumor bearing stem cell humanized NSG mice in terms of B cell depletion and in a lymphoma patient-derived xenograft (PDX) model in humanized NSG mice in terms of antitumor efficacy. Results: The effect of Src inhibitors differed from those of mTOR and JAK inhibitors with the suppression of CD19-TCB-induced tumor cell lysis in vitro, whereas mTOR and JAK inhibitors primarily affected TCB-mediated cytokine release. Importantly, we confirmed in vivo that Src, JAK and mTOR inhibitors strongly reduced CD19-TCB-induced cytokine release. In humanized NSG mice, continuous treatment with a Src inhibitor prevented CD19-TCB-mediated B cell depletion in contrast to mTOR and JAK inhibitors, which retained CD19-TCB efficacy. Ultimately, transient treatment with Src, mTOR and JAK inhibitors minimally interfered with antitumor efficacy in a lymphoma PDX model. Conclusions: Taken together, these data support further evaluation of the use of Src, JAK and mTOR inhibitors as prophylactic treatment to prevent occurrence of CRS.

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Fouad S. Moghrabi ; Aktham Aburub ; Hala M. Fadda DOI: PubMed ID:

Abstract: Purpose: pH-dependent drug-drug interactions (DDIs) with poorly soluble, weakly basic drugs may lead to clinical implications. Dasatinib is a tyrosine kinase inhibitor with reduced absorption in patients on acid-reducing agents (ARAs). The objective of this study is to investigate the influence of gastric pH on dasatinib supersaturation and determine if vitamin C (L-ascorbic acid) can improve dasatinib concentrations under simulated hypochlorhydric gastric conditions. Methods: A dynamic, in vitro, multi-compartment, simulated stomach duodenum (SSD) model mimicking fluid volumes and transfer rates was used to investigate the concentration of BCS class IIb drugs versus time curves. Dasatinib and lamotrigine were explored under normal, fasted, simulated gastric fluids (pH 2) (FaSGF), hypochlorhydric simulated gastric fluids (pH 4.5) (FaSGFhypo) and FaSGFhypo with 1000 mg of vitamin C. Results: Significant supersaturation of dasatinib was observed in the duodenum compartment of the SSD model in FaSGF. A 90% reduction in dasatinib AUC∞ was observed in FaSGFhypo. Upon addition of vitamin C to FaSGFhypo, drug concentrations were restored to those observed in FaSGF. Lamotrigine AUC∞ in the duodenal compartment were similar in both FaSGF and FaSGFhypo. The in vitro trends observed for dasatinib and lamotrigine are reflective of the trends observed in vivo in subjects receiving treatment with ARAs. Conclusions: The SSD model serves as a good in vitro tool for assessing the effect of pH-dependent DDIs on bioavailability of weakly basic drugs with solubility/ dissolution limited absorption. Vitamin C provides a promising approach for improving bioavailability of poorly soluble, weakly basic drugs in hypochlorhydric patients.

Keywords: Dissolution ; Ionization ; In vitro in?vivo correlations ; Proton pump inhibitors ; Oral drug delivery

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Leclercq, Gabrielle ;

Abstract: T cell bispecific antibodies (TCBs) are a novel class of T cell engagers redirecting T cells towards tumor cells, facilitating the formation of a cytotoxic synapse and resulting in tumor celllysis. On-target activity of TCBs may come with a risk of Cytokine Release Syndrome (CRS), characterized by elevated levels of pro-inflammatory cytokines in the serum, such as IL-6, IL-1β, TNF-α or IFN-γ and over activation of immune cells. Besides, the expression of the tumorassociated antigen on healthy cells may induce off-tumor activity of the TCB and contribute to inflammation. Despite the use of step-up dosing, glucocorticoids, or tocilizumab to manage or prevent these safety liabilities, they remain the major dose-limiting toxicities associated with the treatment of T cell engagers, highlighting the need to develop preventive mitigation treatments. To this aim, we investigated the biological mechanisms and the chronology of events involved in TCB-mediated cytokine release and explored mitigation strategies that might retain profound treatment efficacy while reducing cytokine release. Using an in vitro co-culture of peripheral blood mononuclear cells (PBMCs) or total leukocytes(PBMCs + neutrophils) and target cells with the respective TCBs, or whole blood treated with a B cell depleting TCB, we confirmed the contribution of T cell and myeloid cells and revealed the role of neutrophils in the TCB-mediated cytokine release. In the same model, the use of anticytokine neutralizing antibodies provided insights into the chronology of events triggering the cascade of cytokines after TCB stimulation. Ultimately this work guided the evaluation of mitigation strategies directed against T-cell derived cytokine release by targeting kinases involved in signaling pathways downstream of the T cell receptor (TCR) after stimulation with TCBs. A novel small molecule-kinase inhibitors screen identified mTOR, JAK and Src inhibitors as candidates to switch-off T-cell derived cytokine release. We validated the effects of these kinase inhibitors and fine-tuned their effective doses in in vitro co-cultures of peripheral blood mononuclear cells (PBMCs) and tumor cells with the respective TCBs. In vivo, we used nontumor or tumor-bearing-humanized NSG mice to assess the effect of mTOR, JAK and Srcinhibitors on CD19-TCB-mediated cytokine release and anti-tumor efficacy. Altogether, we confirmed the biological mechanisms of the TCB-mediated cytokine cascade and revealed the contribution of neutrophils. Our work on kinase inhibitors highlights their differential activities on the inhibition of cytokine release and/or T cell cytotoxicity and demonstrates the decoupling between both mechanisms. Our data open new horizons for the prophylactic mitigation of CRS with the use of FDA approved mTOR and JAK inhibitors or the transient use of the Src inhibitor dasatinib. Finally, our results also indicate that dasatinib may serve as an “antidote” against adverse events related to the treatment with TCBs such as high grade CRS or unpredictable off-tumor activity of TCBs, a strategy which is now implemented the clinic.

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Product Details of [ 302962-49-8 ]

CAS No. :302962-49-8 MDL No. :MFCD11046566
Formula : C22H26ClN7O2S Boiling Point : -
Linear Structure Formula :- InChI Key :ZBNZXTGUTAYRHI-UHFFFAOYSA-N
M.W : 488.01 Pubchem ID :3062316
Synonyms :
BMS-354825;Sprycel
Chemical Name :N-(2-Chloro-6-methylphenyl)-2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)thiazole-5-carboxamide

Calculated chemistry of [ 302962-49-8 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 33
Num. arom. heavy atoms : 17
Fraction Csp3 : 0.36
Num. rotatable bonds : 8
Num. H-bond acceptors : 6.0
Num. H-bond donors : 3.0
Molar Refractivity : 138.63
TPSA : 134.75 ?2

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : Yes
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -6.73 cm/s

Lipophilicity

Log Po/w (iLOGP) : 3.37
Log Po/w (XLOGP3) : 3.59
Log Po/w (WLOGP) : 2.36
Log Po/w (MLOGP) : 1.75
Log Po/w (SILICOS-IT) : 3.33
Consensus Log Po/w : 2.88

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 1.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -4.98
Solubility : 0.0051 mg/ml ; 0.0000105 mol/l
Class : Moderately soluble
Log S (Ali) : -6.11
Solubility : 0.000382 mg/ml ; 0.000000783 mol/l
Class : Poorly soluble
Log S (SILICOS-IT) : -6.88
Solubility : 0.0000646 mg/ml ; 0.000000132 mol/l
Class : Poorly soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 3.0
Synthetic accessibility : 3.83

Safety of [ 302962-49-8 ]

Signal Word:Danger Class:9
Precautionary Statements:P260-P264-P270-P271-P273-P280-P301+P312+P330-P304+P340+P312-P305+P351+P338+P310-P314-P391-P403+P233-P405 UN#:3077
Hazard Statements:H302-H318-H336-H373-H410 Packing Group:Ⅲ
GHS Pictogram:

Application In Synthesis of [ 302962-49-8 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 302962-49-8 ]

[ 302962-49-8 ] Synthesis Path-Downstream   1~7

  • 1
  • [ 127116-19-2 ]
  • [ 302964-24-5 ]
  • [ 302962-49-8 ]
YieldReaction ConditionsOperation in experiment
83.2% In 1,4-dioxane; at 75℃; for 3h; 13.4 g (50 mmol) of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamideMethyl-4-chloro-6- (4-hydroxyethyl-piperidinyl) pyrimidine15.4 g (60 mmol)In 1,4-dioxane at 75 C3 hours,Dumped into the water,The organic phase was concentrated and washed with water, then recrystallized from methanol and dried to obtain 20.3 g of dasatinib. The yield was 83.2% and the purity was 99.71%.
With potassium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; at 100 - 110℃; for 20h; To a 250 ml of round bottom flask were charged compound 5C (1.9g, 7.1 mmol), compound 7C (1.5 g, 5.9 mmol), K2CO3 (16g, 115.7 mmol), Pd (OAc) 2 (52 mg, 0.23 mmol) and BINAP (291 mg, 0.46 mmol). The flask was placed under vacuum and flushed with nitrogen. Toluene was added (60 ml). The suspension was heated to 100-110C and stirred at this temperature for 20h. After cooling to room temperature, the mixture was applied to a silica gel column. The column was first eluted with EtOAC, and then with 10% of MeOH in EtOAC. Finally, the column was washed with 10% 2M ammonia solution in MeOH/90% EtOAC. The fractions which contained the desired product were collected and concentrated to give compound IV as a yellow solid (2.3 g).
  • 2
  • [ 302962-49-8 ]
  • [ 863127-77-9 ]
YieldReaction ConditionsOperation in experiment
With water; In ethanol; at 75 - 80℃; An example of the crystallization procedure to obtain the crystalline monohydrate form is shown here: Charge 48, g of the compound of formula (IV). Charge approximately 1056 mL (22 mL/g) of ethyl alcohol, or other suitable alcohol. Charge approximately 144 mL of water. Dissolve the suspension by heating to approximately 75 °C. Optional: Polish filter by transfer the compound of formula (IV) solution at 75 °C through the preheated filter and into the receiver. Rinse the dissolution reactor and transfer lines with a mixture of 43 mL of ethanol and 5 mL of water. Heat the contents in the receiver to 75-80 °C and maintain 75-80 °C to achieve complete dissolution. Charge approximately 384 mL of water at a rate such that the batch temperature is maintained between 75-80 °C. Cool to 75 °C, and, optionally, charge monohydrate seed crystals. Seed crystals are not essential to obtaining monohydrate, but provide better control of the crystallization. Cool to 70 °C and maintain 70 °C for ca. 1 h. Cool from 70 to 5 C over 2 h, and maintain the temperature between 0 at 5 °C for at least 2 h. Filter the crystal slurry. Wash the filter cake with a mixture of 96 mL of ethanol and 96 mL of water. Dry the material at < 50 °C under reduced pressure until the water content is 3.4 to 4. 1percent by KF to afford 41 g (85 Mpercent).
With water; In ethanol; at 0 - 80℃; for 5h; PREPARATION OF CRYSTALS OF COMPOUND I (FREE BASE); A. PREPARATION OF THE MONOHYDRATE CRYSTALLINE FORM OF COMPOUND I (FREE BASE); [00275] Crystals of a monohydrate crystalline form of Compound I may be prepared by the general procedure described below:[00276] A suspension is prepared by admixing 48 g of the Compound I and approximately 1056 mL (22 mL/g) of ethyl alcohol, followed by the addition of approximately 144 mL of water. Next, Compound I is dissolved by heating the suspension to approximately 75°C. The Compound I solution is passed through a preheated filter and into a receiver vessel. The dissolution reactor and transfer lines EPO <DP n="59"/>are rinsed with a mixture of 43 rnL EtOH and 5 mL of water. The contents of the receiver vessel are heated to approximately 75-80°C and maintained at this temperature range to achieve complete dissolution. Next, approximately 384 mL of water is added at a rate such that the batch temperature is maintained between 75- 800C. The contents of the receiver vessel are cooled to 700C and then maintained at 700C for about 1 hour. The temperature is decreased to 50C over a period of 2 hours, and maintained between 0-5°C for at least 2 hours. The resulting crystal slurry is filtered. The filter cake is washed with a mixture of 96 mL EtOH and 96 mL of water. The crystals are dried at < 500C under reduced pressure until the water content is in the range of from 3.4 to 4.1percent by KF to afford 41 g (85 Mpercent).
21 g With water; In methanol;Heating; Take 25g of dasatinib into 2000ml of methanol, stir and heat to dissolve, filter it while hot, add 500ml of water under stirring in the filtrate, stop stirring, naturally cool, slowly precipitate fine crystals, leave at room temperature overnight, and then add 1500ml of water After the addition, continue to crystallize for 10 hours.The precipitated white crystals were filtered off with suction, washed with a small amount of methanol, vacuum-dried at 60° C., and phosphorus pentoxide was used for drying to obtain 21 g of a white crystalline solid.
  • 3
  • [ 863127-77-9 ]
  • [ 302962-49-8 ]
YieldReaction ConditionsOperation in experiment
In propan-1-ol; water; at 0 - 5℃; for 1h;Heating / reflux;Product distribution / selectivity; Example 28; Procedure for the Preparation of <strong>[863127-77-9]Dasatinib</strong> Form K3<strong>[863127-77-9]Dasatinib</strong> (form H1-7, 1 g) was dissolved in a mixture of n-PrOH (30 ml) and H2O (5 ml) under reflux. The resulting solution was quickly cooled to 0-5° C. (ice bath). The product was filtered off after 1 h, washed with n-PrOH and dried under reduced pressure at 50° C. for 2 h. Yield 620 mg.
In water; isopropyl alcohol; at 0 - 5℃; for 1h;Heating / reflux;Product distribution / selectivity; Example 30; Procedure for the Preparation of <strong>[863127-77-9]Dasatinib</strong> Form A3<strong>[863127-77-9]Dasatinib</strong> (form H1-7, 1 g) was dissolved in a mixture of iso-PrOH (30 ml) and H2O (14 ml) under reflux. The resulting solution was quickly cooled to 0-5° C. (ice bath). The product was filtered off after 1 h, washed with iso-PrOH and dried under reduced pressure at 50° C. for 2 h. Yield 620 mg.Example 31Procedure for the Preparation of <strong>[863127-77-9]Dasatinib</strong> Form A3<strong>[863127-77-9]Dasatinib</strong> (form H1-7, 1 g) was dissolved in a mixture of iso-PrOH (30 ml) and H2O (8 ml) under reflux. The resulting solution was quickly cooled to 0-5° C. (ice bath). The product was filtered off after 1 h, washed with iso-PrOH and dried under reduced pressure at 50° C. for 2 h. Yield 620 mg.
  • 5
  • [ 863127-76-8 ]
  • [ 302962-49-8 ]
  • 6
  • [ 1035373-85-3 ]
  • [ 7693-46-1 ]
  • [ 302962-49-8 ]
  • C33H46Cl2N8O5S [ No CAS ]
YieldReaction ConditionsOperation in experiment
30% Dasatinib (15 mg, 31 umol)P-Nitrophenyl chloroformate(8. 4 mg, 42 umol, 1.36 equiv)And 10 μL of TEA in 1.8 mL of DMF: THF (2: 1).The reaction was stirred overnight and then added as a solution in DMF2- (2 - ((6-chlorohexyl) oxy) ethoxy) ethan-1-amine hydrochloride(32 mg, 4 equiv)Was added.Additional TEA was also added and the reaction was stirred overnight again.Preparative HPLC (20 - & gt; 60% MeCN in 0.1% aqueous TFA) gave colorlessThe desired product was obtained as a residue (6.7 mg, 30% yield).
  • 7
  • [ 94-26-8 ]
  • [ 302962-49-8 ]
  • N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide butyl paraben [ No CAS ]
YieldReaction ConditionsOperation in experiment
In methanol; at 55℃; Preparation of Form I co-crystal of dasatinib and butyl paraben About 50 mg of dasatinib and about 21 mg of butyl paraben are added to about 5 mL of methanol and heated to about 55 C to obtain a clear solution. The clear solution is placed in the oven under vacuum at about 50C for solvent evaporation. The co-crystal is isolated the following day (about 18-20 h) and identified as Form I of co-crystal of dasatinib and butyl paraben. Alternatively, the solvent in which the dasatinib is dissolved is a mixture of acetone (Ace) and water in a ACE:H20 of 7:3. (0107) Figure VI is the calculated XRPD pattern of Form I co-crystal of dasatinib and butyl paraben obtained by the instant method. Form I co-crystal of dasatinib and butyl paraben is characterized by its XRPD patern peaks and their corresponding intensities that are listed in Table II below. Table II: (0108) (0109) The angle measurements are ± 0.2 2Q. Key defining peaks for solid-state Form I co-crystal of dasatinib and butyl paraben include 4.9, 9.8, 11.3, 14.9, 17.5, 20.8, 21.6, 22.6 and 25.4 2Q degrees. (0110) The single crystal parameters for the Form I co-crystal of dasatinib and butyl paraben as determined by SCXRD are: (0111) Space Group: Monoclinic, P2i/C (0112) a = 18.630 (2) A (0113) b = 8.725 (1) A (0114) c = 22.331 (2) A (0115) a = g = 90, b = 104.575(8) (0116) Volume: 3512.9 A3 (0117) Z = 4, Z? = 1 (0118) Figure VII shows the asymmetric unit of Form I co-crystal of dasatinib and butyl paraben. Figure VIII shows the inter and intra molecular hydrogen bonding between dasatinib and butyl paraben molecules in Form I co-crystal of dasatinib and butyl paraben.
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