罗西替尼 роцилетиниб روسيليتينيب Rociletinib, CO-1686. Third generation covalent EGFR inhibitors

Rociletinib (CO-1686)

AVL-301,CNX-419

Celgene (Originator) , Clovis Oncology

N-(3-{[2-{[4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl]amino}-5- (trifluoromethyl)pyrimidin-4-yl]amino}phenyl)prop-2-enamide

1374640-70-6  CAS

1446700-26-0 (Rociletinib Hydrobromide)

Tyrosine kinase inhibitor; EGFR inhibitorIndication：Non small cell lung cancer (NSCLC)

N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxyanilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide

FREE FORM

• Molecular FormulaC27H28F3N7O3
• Average mass555.552
• HYDROBROMIDE 1446700-26-0
  

  Molecular Weight	636.46
  Formula	C27H28F3N7O3 ● HBr

Cellular proliferation IC507–32 nM against EGFRm+ NSCLC cells
547 nM against A431 cell with WT EGFR

Ongoing, not currently recruiting
Phase I/II (NCT01526928)

Recruiting
Phase III (NCT02322281, TIGER-3)

SYNTHESIS COMING……….

Evaluate safety, PK and efficacy of previously treated NSCLC patients, Compare the efficacy of oral single agent versus single agent cytotoxic chemotherapy in patients with EGFRm+ NSCLC after failure of at least 1 previous EGFR-directed TKI and at least 1 line of platinum-containing doublet therapy. Compare the safety and efficacy of CO-1686 versus erlotinib as first line treatment of patients with EGFRm+ NSCLC

Rociletinib (CO-1686): Rociletinib is an orally administered irreversible inhibitor currently in several clinical trials targeting both the activating EGFR mutations and the acquired T790M resistance mutation while sparing WT EGFR. It is a potent inhibitor of EGFR T790M/L858R double mutant with a kinact/Ki of 2.41 × 105 M−1 s−1. It has a 22-fold selectivity over WT EGFR (kinact/Ki of 1.12 × 104 M−1 s−1). In NSCLC cell lines containing EGFR mutations, rociletinib demonstrates the following cellular pEGFR IC50: 62 nM in NCI-1975 (L858R/T790M), 187 nM in HCC827 (exon 19 deletion), 211 nM in PC9 (exon 19 deletion). In cell lines expressing WT EGFR, cellular pEGFR IC50 are: >4331 nM in A431, >2000 nM in NCI-H1299, and >2000 nM in NCI-H358.

Rociletinib displayed good oral bioavailability (65%) and long half-life when dosed at 20 mg/kg in female Nu/Nu mice. In tumor bearing mice when rociletinib was dosed orally once daily as a single agent, the compound showed dose-dependent tumor growth inhibition in various EGFR-mutant models. In NCI-H1975 as well as in patient-derived LUM 1868 lines expressing the EGFR T790M/L858R double mutation that are erlotinib-resistant models, rociletinib caused tumor regressions at 100 mg/kg/d. In the HCC827 xenograft model that expresses the del-19 activating EGFR mutation, rociletinib showed antitumor activity that was comparable with erlotinib and the second-generation EGFR TKI, afatinib. The wild-type sparing feature of rociletinib was further demonstrated through its minimal inhibition (36%) of tumor growth in the A431 xenograft model that is dependent on WT EGFR for proliferation.

In a Phase I/II study (TIGER-X), rociletinib was administered to patients with EGFR mutated NSCLC who had disease progression during treatment with a previous line of EGFR TKI therapy.The Phase I trial was a dose escalation study to assess safety, side-effect profile and pharmacokinetic properties of rociletinib, and the Phase II trial was an expansion arm to evaluate efficacy. T790M positivity was confirmed before enrollment in the Phase II portion. At the dose of 500 mg BID, the objective response rate in 243 centrally confirmed tissues from T790M positive patients was 60% and the disease control rate was 90%. The estimated overall median PFS at the time of the publication (May 2015) was 8.0 months among all centrally confirmed T790M positive patients. Rociletinib also showed activity in centrally confirmed T790M negative patients with the overall response rate being 37%. The common dose-limiting adverse event was grade 3 hyperglycemia occurring in 17% of patients at a dose of 500 mg BID. Grade 3 QTc prolongation was observed in 2.5% of the patients at the same dose. Treatment-related adverse events leading to drug discontinuation was seen in only 2.5% of patients at 500 mg BID.

Patent

 WO2012061299A1

http://www.google.co.in/patents/WO2012061299A1?cl=en

EXAMPLE 1

Intermediate 1

Scheme 1

Step 1 :

In a 25 mL 3-neck RBF previously equipped with a magnetic stirrer, Thermo pocket and CaCl2 guard tube, N-Boc-l,3-diaminobenzene (0.96 g) and n-butanol (9.00 mL) were charged. Reaction mixture was cooled to 0 °C. 2,4-Dichloro-5-trifluoromethylpyrimidine (1.0 g) was added dropwise to the above reaction mixture at 0 °C. The DIPEA (0.96 mL) was dropwise added to the above reaction mixture at 0 °C and the reaction mixture was stirred for 1 hr at 0 °C to 5 °C. Finally the reaction mixture was allowed to warm to room temperature. Reaction mixture was stirred for another 4 hrs at room temperature. Completion of reaction was monitored by TLC using hexane: ethyl acetate (7: 3). The solid precipitated out was filtered off and washed with 1-butanol (2 mL). Solid was dried under reduced pressure at 40 °C for 1 hr. ^-NMR (DMSO-d6, 400 MHz) δ 1.48 (S, 9 H), 7.02 (m, 1 H), 7.26 (m, 2 H), 7.58 (S, 1 H), 8.57 (S, 1 H), 9.48 (S, 1 H), 9.55 (S, 1 H).

Step 2:

To the above crude (3.1 g) in DCM (25 mL) was added TFA (12.4 mL) slowly at 0 °C. The reaction mixture was allowed to warm to room temperature. Reaction mixture was stirred for another 10 min at room temperature. The crude was concentrated under reduced pressure.

Step 3:

The concentrated crude was dissolved in DIPEA (2.0 mL) and DCM (25 mL), and then cooled to -30 °C. To the reaction mixture was slowly added acryloyl chloride (0.76 g) at -30 °C. The reaction mass was warmed to room temperature stirred at room temperature for 1.0 hr. The reaction was monitored on TLC using hexane: ethyl acetate (7:3) as mobile phase. Reaction got completed after 1 hr. 1H-NMR (DMSO-d6, 400 MHz) δ 5.76 (dd, J = 2.0, 10.0 Hz, 1 H), 6.24 (dd, J = 2.0, 17.2 Hz, 1 H), 6.48 (m, 1 H), 7.14 (d, J = 8.8 Hz, 1 H), 7.37 (t, J = 8.0 Hz, 1 H), 7.94 (S, 1 H), 8.59 (S, 1 H), 9.60 (S, 1 H), 10.26 (S, 1 H).

EXAMPLE 3

Compound 1-4 N- henylamino)-5-

(trifluor mide)

 Using 2-methoxy-4-(4-acteylpiperazinyl)aniline and intermediate 1 in Example 1, the title compound 1-4 was prepared as described in Example 2. 1H-NMR (DMSO-d6, 400 MHz) δ 10.2 (S, 1 H), 8.2 (br, 1 H), 8.30 (S, 1 H), 7.73 (br, 1 H), 7.52 (d, J = 7.8 Hz, 1 H), 7.45 (d, J = 7.8 Hz, 1 H), 7.26 (J = 8.2 Hz, 1 H), 7.14 (be, 1 H), 6.60 (S, 1 H), 6.42 (dd, J = 11.4, 16.9 Hz, 1 H), 6.24 (d, J = 16.9 Hz, 1 H), 5.75 (d, J = 11.4 Hz, 1 H), 3.76 (S, 3 H), 3.04 (br, 4 H), 2.04 (S, 3 H); calculated mass for C27H28F3N7O3 : 555.2, found: 556.2 (M+H+).

Patent ID	Date	Patent Title
US2015344441	2015-12-03	SALTS OF AN EPIDERMAL GROWTH FACTOR RECEPTOR KINASE INHIBITOR
US2015246040	2015-09-03	HETEROCYCLIC COMPOUNDS AND USES THEREOF
US2015225422	2015-08-13	HETEROARYLS AND USES THEREOF
US8975249	2015-03-10	Heterocyclic compounds and uses thereof
US2013267531	2013-10-10	SALTS OF AN EPIDERMAL GROWTH FACTOR RECEPTOR KINASE INHIBITOR
US2013267530	2013-10-10	SOLID FORMS OF AN EPIDERMAL GROWTH FACTOR RECEPTOR KINASE INHIBITOR

References

• A.O. Walter, R.T.T. Sjin, H.J. Haringsma, K. Ohashi, J. Sun, K. Lee, A. Dubrovskiy, M. Labenski, Z. Zhu, Z. Wang, M. Sheets, T. St. Martin, R. Karp, D. van Kalken, P. Chaturvedi, D. Niu, M. Nacht, R.C. Petter, W. Westlin, K. Lin, S. Jaw-Tsai, M. Raponi, T. Van Dyke, J. Etter, Z. Weaver, W. Pao, J. Singh, A.D. Simmons, T.C. Harding, A. Allen, Cancer Disc., 3 (2013), p. 1404

////Rociletinib, CO-1686, Clovis, Third generation,  covalent EGFR inhibitors, AVL-301, CNX-419

CC(=O)N1CCN(CC1)C2=CC(=C(C=C2)NC3=NC=C(C(=N3)NC4=CC(=CC=C4)NC(=O)C=C)C(F)(F)F)OC

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Compound name  AND  SMILES string
Rociletinib COC(C=C(N1CCN(C(C)=O)CC1)C=C2)=C2NC3=NC=C(C(F)(F)F)C(NC4=CC=CC(NC(C=C)=O)=C4)=N3
Osimertinib CN(CCN(C)C)C(C(NC(C=C)=O)=C1)=CC(OC)=C1NC2=NC=CC(C3=CN(C)C4=C3C=CC=C4)=N2
EGF816 ClC1=C2C(N=C(NC(C3=CC(C)=NC=C3)=O)N2[C@H]4CN(C(/C=C/CN(C)C)=O)CCCC4)=CC=C1
PF-06747775 CN1C2=NC(N3C[C@@H](NC(C=C)=O)[C@H](F)C3)=NC(NC4=CN(C)N=C4OC)=C2N=C1
PF-06459988 CN(N=C1)C=C1NC2=NC3=C(C(Cl)=CN3)C(OC[C@H]4CN(C(C=C)=O)C[C@@H]4OC)=N2
WZ4002 ClC1=CN=C(NC2=C(OC)C=C(N3CCN(C)CC3)C=C2)N=C1OC4=CC=CC(NC(C=C)=O)=C4