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JBI-802

  • Myeloid Leukemia Therapy
  • Solid Tumors Therapy

Epigenetic Modifier Modulators

  • Histone Deacetylase 6 (HDAC6) Inhibitors
  • Lysine-Specific Histone Demethylase 1A (KDM1A; LSD1) Inhibitors

Jubilant Therapeutics Announces Successful Completion of Pre-IND Meeting with FDA for its Novel Dual LSD1 and HDAC6 Inhibitor JB1-802

https://markets.businessinsider.com/news/stocks/jubilant-therapeutics-announces-successful-completion-of-pre-ind-meeting-with-fda-for-its-novel-dual-lsd1-and-hdac6-inhibitor-jb1-802-1030834551
PRESS RELEASE PR Newswire

Sep. 30, 2021, 10:23 AM

BEDMINSTER, NJ, Sept. 30, 2021 /PRNewswire/ — Jubilant Therapeutics Inc., a biopharmaceutical company advancing small molecule precision therapeutics to address unmet medical needs in oncology and autoimmune diseases, today announced the successful completion of a pre-IND (Investigational New Drug) meeting with the U.S. Food and Drug Administration (FDA) regarding the development plan, clinical study design and dosing strategy for the Phase I/II trial of JB1-802, a dual inhibitor of LSD1 and HDAC6, for the treatment of small cell lung cancer, treatment-induced neuro-endocrine prostate cancer and other mutation-defined neuroendocrine tumors.

Jubilant Therapeutics LogoA pre-IND meeting provides the drug development sponsor an opportunity for an open communication with the FDA to discuss the IND development plan and to obtain the agency’s guidance regarding planned clinical evaluation of the sponsor’s new drug candidate. After reviewing the preclinical data provided, plans for additional data generation and the Phase I/II clinical trial protocol, the FDA addressed Jubilant Therapeutics’ questions, provided guidance and aligned with the sponsor on the proposed development plan for JBI-802.

“We appreciate the FDA’s guidance as we endeavor to find an innovative new treatment for high unmet-need tumors with devastatingly low survival rates,” said Hari S Bhartia, Chairman, Jubilant Therapeutics Inc.

“We are pleased with the outcome of the pre-IND meeting with the FDA and plan to submit the IND application by the end of 2021,” said Syed Kazmi, Chief Executive Officer, Jubilant Therapeutics Inc.

About Jubilant TherapeuticsJubilant Therapeutics Inc. is a patient-centric biopharmaceutical company advancing potent and selective small molecule modulators to address unmet medical needs in oncology and autoimmune diseases. Its advanced discovery engine integrates structure-based design and computational algorithms to discover and develop novel, precision therapeutics against both first-in-class and validated but intractable targets in genetically defined patient populations. The Company plans to file an IND later this year for the first in class dual inhibitor of LSD1/HDAC6, followed by two additional INDs in 2022 with novel modulators of PRMT5 and PAD4 in oncology and inflammatory indications. Jubilant Therapeutics is headquartered in Bedminster NJ and guided by globally renowned key opinion leaders and scientific advisory board members. For more information, please visit www.jubilanttx.com or follow us on Twitter @JubilantTx and LinkedIn.

View original content:https://www.prnewswire.com/news-releases/jubilant-therapeutics-announces-successful-completion-of-pre-ind-meeting-with-fda-for-its-novel-dual-lsd1-and-hdac6-inhibitor-jb1-802-301388983.html

SOURCE Jubilant Therapeutics Inc.

Mohd Zainuddin

Mohd Zainuddin

Director at Jubilant Therapeutics Inc

PATENT

IN 201641016129

PATENT

US20200308110 – CYCLOPROPYL-AMIDE COMPOUNDS AS DUAL LSD1/HDAC INHIBITORS

https://patentscope.wipo.int/search/en/detail.jsf?docId=US306969204&tab=NATIONALBIBLIO&_cid=P21-KUANET-85789-2ApplicantsJubilant Epicore LLC
Inventors

Sridharan RAJAGOPAL
Mahanandeesha S. HALLUR
Purushottam DEWANG
Kannan MURUGAN
Durga Prasanna KUMAR C.H.
Pravin IYER
Chandrika MULAKALA
Dhanalakshmi SIVANANDHAN
Sreekala NAIR
Mohd ZAINUDDIN
Subramanyam Janardhan TANTRY
Chandru GAJENDRAN
Sriram RAJAGOPAL
Priority Data201641016129 09.05.2016 IN

Sridharan Rajagopal

Sridharan Rajagopal

Vice President-Head of Medicinal Chemistry at Jubilant Therapeutics Inc

Dhanalakshmi Sivanandhan

Dhanalakshmi Sivanandhan

Vice President at Jubilant Therapeutics Inc

Mahanandeesha Hallur

Mahanandeesha Hallur

Associate Director at Jubilant Biosys

Sreekala Nair

Sreekala Nair

Chandrika Mulakala

Chandrika Mulakala

  

Pravin Iyer

Pravin Iyer

Purushottam (M.) Dewang

Purushottam (M.) Dewang

ERRORS CALL ME , +919321316780

AND TO ADD TOO

SCHEMBL19590792.png

 EXAMPLE

CAS 2152635-16-8

C20 H20 F N O22-​Propenoic acid, 3-​[4-​[[[2-​(4-​fluorophenyl)​cyclopropyl]​amino]​methyl]​phenyl]​-​, methyl ester, (2E)​-Molecular Weight, 325.38

Patent

WO2017195216

I-3methyl (E)-3-(4-(((tert-butoxycarbonyl)(2-(4-((4-fluorobenzyl)oxy)phenyl) cyclopropyl)amino)methyl)phenyl)acrylate

Figure imgf000167_0001

The compound was synthesized using amine B6 and (E)-3-(4-Formyl-phenyl)-acrylic acid methyl esterfoUowing the procedure for the synthesis of 1-2. LC-MS m/z calcd for C32H34FN05, 531.2; found 532.2 [M+H]+.

Figure imgf000166_0003
Publication NumberTitlePriority DateGrant Date
EP-3455204-A1Cyclopropyl-amide compounds as dual lsd1/hdac inhibitors2016-05-09
WO-2017195216-A1Cyclopropyl-amide compounds as dual lsd1/hdac inhibitors2016-05-09
US-2020308110-A1Cyclopropyl-amide compounds as dual lsd1/hdac inhibitors2016-05-09
wdt-16

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Step 2: (E)-3-[4-({tert-Butoxycarbonyl-[2-(4-fluoro-phenyl)-cyclopropyl]-amino}-methyl)-phenyl]-acrylic acid methyl ester (I-2)


(MOL)(CDX)
      To a stirred solution of (E)-3-(4-{[2-(4-fluoro-phenyl)-cyclopropylamino]-methyl}-phenyl)-acrylic acid methyl ester (XLVI, 0.25 g, 0.76 mmol) in tetrahydrofuran and water mixture (6 mL, 1:1) was added sodium bicarbonate (0.087 g, 2.3 mmol) and Boc anhydride (0.22 mL, 0.92 mmol) at room temperature and the resulting mixture was stirred at that temperature for 2 h. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with ethylacetate and the organic portion was washed with water and brine solution, dried over sodium sulphate and concentrated under reduced pressure to get the crude product which was purified by column chromatography using ethylacetate-hexane gradient to afford the titled product as sticky oil (I-2, 0.19 g, 58%). LC-MS m/z calcd for C 2528FNO 4, 425.2; found 326.3 [M-Boc+1] +.
      The following compounds were synthesized using procedure for the synthesize of I-2

REFJBI-802, novel dual inhibitor of LSD1-HDAC6 for treatment of cancerSivanandhan, D.; Rajagopal, S.; Nair, S.; et al.Annu Meet Am Assoc Cancer Res (AACR) · 2020-06-22 / 2020-06-24 · Virtual, N/A · Abst 1756Synthesis and optimization of a novel series of LSD1-HDAC dual inhibitors led to the discovery of JBI-802 as the lead compound, with IC50 of 0.05 mcM against LSD1 and isoform selective HDAC6/8 activity, with IC50 of 0.011 and 0.098 mcM for HDAC6 and HDAC8, respectively. The candidate also showed excellent selectivity against other HDACs, with approximately 77-fold selectivity for HDAC6. In vitro, JBI-802 showed strong antiproliferative activity on selected cell lines, including acute myeloid leukemia, chronic lymphocytic leukemia, lymphoma and certain solid tumors, such as small cell lung cancer and sarcoma. In vivo, JBI-802 demonstrated strong efficacy in erythroleukemia xenograft model, leading to prolonged survival of mice bearing HEL92.1.7 tumors. The candidate showed excellent dose-response and superior efficacy compared to single agents in this model, with ED50 of approximately 6.25 mg/kg twice-daily by oral administration. When evaluated in CT-26 syngeneic model, JBI-802 showed promising activity as single agent and in the combination of JBI-802 plus anti-programmed cell death protein 1 (PD-1) monoclonal antibody (MAb), with approximately 80% tumor growth inhibition observed for the combination. Exploratory toxicology studies showed that JBI-802 was well tolerated at efficacious doses. Further preclinical IND-enabling studies are currently underway for this molecule, which is to be developed as a clinical candidate for the treatment of acute myeloid leukemia and other tumor types. 

REFNovel dual inhibitor of LSD1-HDAC6/8 for treatment of cancerDhanalakshmi, S.; Rajagopal, S.; Sadhu, N.; et al.62nd Annu Meet Am Soc Hematol · 2020-12-05 / 2020-12-08 · Virtual, N/A · Abst 3378 Blood 2020, 136(Suppl. 1) 


REFJubilant Therapeutics Presents Preclinical Data at the American Association for Cancer Research, Reveals Unique Dual-Action Anti-Cancer Mechanism Underscoring First-in-Class Pipeline Asset in Hematological Tumors 
Jubilant Therapeutics Press Release 2020, June 22

////////////////JB1-802, JUBILANT, CANCER,  PRECLINICAL

EXTRAS…………

PATENTWO2021062327 – FUSED PYRIMIDINE COMPOUNDS, COMPOSITIONS AND MEDICINAL APPLICATIONS THEREOFhttps://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021062327&_cid=P21-KUAMRR-83330-1PCT/US2020/052953

Priority Data

201941039277 27.09.2019 IN

Inventors

  • VENKATESHAPPA, Chandregowda
  • SIVANANDHAN, Dhanalakshmi
  • RAJAGOPAL, Sridharan
  • ROTH, Bruce
  • PANDEY, Anjali
  • SAXTON, Tracy
  • HALLUR, Gurulingappa
  • MADHYASTHA, Naveena
  • SADHU M, Naveen

Lung cancer accounts for the greatest number of cancer deaths, and approximately 85% of lung cancer cases are non-small cell lung cancer (NSCLC). The development of targeted therapies for lung cancer has primarily focused on tumors displaying specific oncogenic drivers, namely mutations in epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK). Three generations of tyrosine kinase inhibitors (TKIs) have been developed for cancers with the most frequently observed EGFR mutations, however, other oncogenic drivers in the EGFR family of receptor tyrosine kinases have received less research and development focus and several oncogenic drivers, including insertions in the exon 20 gene of EGFR, have no currently approved therapeutics to treat their cancers.

[0003] The mutation, amplification and/or overexpression of human epidermal growth factor receptor 2 (HER2), another member of the human epidermal growth factor receptor family of receptor tyrosine kinases, has been implicated in the oncogenesis of several cancers, including lung, breast, ovarian, and gastric cancers. Although targeted therapies such as trastuzumab and lapatinib have shown clinical efficacy especially in breast tumors, their utility in lung cancer has been limited. It is likely that this variation is due to tissue-specific factors, including the low potency of kinase inhibitors like lapatinib for the mutagenic alterations in HER2 that are observed in the lung cancer patient population, including insertions in the exon 20 gene of HER2.

[0004] Given that many patients with mutations in EGFR and HER2 do not derive clinical benefit from currently available therapies against these targets, there remains a significant unmet need for the development of novel therapies for the treatment of cancers associated with EGFR and HER2 mutations.

Compound 49: (E)-N-(3-(3-benzyl-7-((1-methyl-1H-pyrazol-4-yl)amino)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)-4-(dimethylamino)but-2-enamide

Step 1: Synthesis of (E)-4-(dimethylamino)but-2-enoyl chloride

[0280] To a stirred mixture of acetonitrile (2 mL) and DMF (2 drop) under N2 atmosphere was added N,N-dimethylamino crotonic acid hydrochloride (0.1 g, 0.77 mmol). After 10 min, this solution was cooled to 0-5 °C. Oxalyl chloride (0.122 g, 0.968 mmol) was added and the reaction mixture was maintained at 0-5 °C for 30 min. It was allowed to warm to RT and stirring was continued for 2 h. It was then heated to 40 °C for 5 min and again brought to RT and stirred for 10 min. Formation of product was confirmed by TLC and the reaction mass was used as such to the next step without any workup.

Step-2: Synthesis of (E)-N-(3-(3-benzyl-7-((1-methyl-1H-pyrazol-4-yl)amino)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)-4-(dimethylamino)but-2-enamide (Compound 49)

[0281] 1-(3-Aminophenyl)-3-benzyl-7-((1-methyl-1H-pyrazol-4-yl)amino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.11g, 0.7 mmol) in DMP (2 mL) was cooled to -15 °C and then (E)-4-(dimethylamino)but-2-enoylchloride was added. The reaction mixture was stirred for 1 h at -15 °C to RT. After the completion of reaction, the reaction mass was quenched with ice water, sodium bicarbonate solution and extracted with DCM (100 mL x 2). The combined organic layer was washed with cold water (3 x 50 mL), brine solution (10 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain crude product. The crude product was purified by prep HPLC to get pure product (E)-N-(3-(3-benzyl-7-((1-methyl-1H-pyrazol-4-yl)amino)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)-4-(dimethylamino)but-2-enamide (Compound 49, 0.022 g, 16 % yield) as white solid.1H NMR (400 MHz, DMSO-d6): δ 10.21 (s, 1H), 9.32 (s, 1H), 8.06 (s, 1H), 7.76 (bs, 1H) 7.65 (s, 1H), 7.48 (bs, 1H), 7.39-7.29 (m, 5H), 7.03 (d, J = 7.2 Hz, 2H), 6.74-6.68 (m, 1H), 6.62 (s, 1H), 6.25 (d, J = 15.2 Hz, 1H), 4.62 (s, 2H), 4.37 (s, 2H), 3.47 (s, 3H), 3.03 (d, J = 5.6 Hz, 2H), 2.15 (s, 6H); LCMS Calcd for [M+H] + 538.2, found 538.5

Compound 50: (E)-N-(3-(3-benzyl-7-((1-methyl-1H-pyrazol-4-yl)amino)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)-3-chloroacrylamide

Step-1: Synthesis of (Z)-3-chloroacrylic acid

[0282] To a stirred solution propiolic acid (2 g, 28.5 mmol) in DMF (15 mL) under N2 atmosphere was added thionyl chloride (4.07 g, 34.2 moles) slowly and the reaction mixture was maintained at 25 °C for 1 h. The reaction was monitored by TLC, after the completion of reaction, the residue was poured into ice and the resulting aqueous solution was extracted with ether (3 x100 mL). The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain crude product. The crude product was purified to get pure product (Z)-3-chloroacrylic acid (1.9 g, 62.9 % yield). LCMS Calcd for [M-H] +, 104.98, found 105.1

Step-2: Synthesis of (Z)-3-chloroacryloyl chloride

[0283] To a stirred solution of acetonitrile (3 mL) and DMF (3 drop) under N2 atmosphere was added of (Z)-3-chloroacrylic acid (0.2 g, 1.87 mmol). After 10 min this solution was cooled 0-5 °C. Oxalyl chloride (0.122 g, 0.968 mmol) was added and the reaction mixture was maintained at 0-5 °C for 30 min. It was allowed to warm to RT and stirring was continued for 2 h to get (Z)-3-chloroacryloyl chloride. Formation of product was confirmed by TLC and the reaction mass was used as such to the next step without any workup.

Step-3: Synthesis of (E)-3-((3-(3-benzyl-7-((1-methyl-1H-pyrazol-4-yl)amino)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)amino)acryloyl chloride (Compound 50)

[0284] A solution of 1-(3-Aminophenyl)-3-benzyl-7-((1-methyl-1H-pyrazol-4-yl)amino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.11 g, 0.7 mmol) in DMP (2 mL) was cooled to -15 °C and then (Z)-3-chloroacryloyl chloride was added. The reaction mixture was stirred for 1 h at -15 °C to RT. The reaction was monitored by TLC. After the completion of reaction, reaction mass was quenched with ice water and sodium bicarbonate solution. The aqueous layer was e 0.028 g, 22% yield) as a white solid.1H NMR (400 MHz, DMSO-d6): δ 10.35 (s, 1H), 9.32 (s, 1H), 8.06 (s, 1H), 7.74 (s, 1H), 7.59 (s, 1H), 7.51 (s, 1H), 7.41-7.35 (m, 5H), 7.30-7.29 (m, 1H), 7.08-7.02 (m, 2H), 6.62-6.58 (m, 2H), 4.62 (s, 2H), 4.37 (s, 2H), 3.47 (s, 3H); LCMS Calcd for [M+H] + 515.1, LCMS found 515.2

Compound 51: (E)-N-(3-(7-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-3-phenyl-2-thioxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)-4-(dimethylamino)but-2-enamide

Step-1: Synthesis of 2,4-dichloro-5-(chloromethyl)pyrimidine

[0285] Title compound was prepared in a similar manner to general procedure I.5-(hydroxymethyl)pyrimidine-2,4-diol (15 g, 106 mmol) gave 2,4-dichloro-5-(chloromethyl)pyrimidine (11.50 g, 55% yield) as a white solid.1H NMR (400 MHz, CDCl3): δ 8.66 (s, 1H), 4.65 (s, 2H).

Step-2: Synthesis of 2,4-dichloro-5-(iodomethyl)pyrimidine

[0286] Title compound was prepared in a similar manner to general procedure J.2,4-dichloro-5-(chloromethyl)pyrimidine (11.50 g, 58.20 mmol) on treatment with NaI (10.50 g, 69.0 mmol) in acetone (100 mL) resulted in 2,4-dichloro-5-(iodomethyl)pyrimidine (15.20 g, 91% yield). The solid was immediately taken up in toluene and stored under refrigeration.1H NMR (400 MHz, CDCl3): δ 8.60 (s, 1H), 4.39 (s, 2H).

Step-3: Synthesis of N-((2,4-dichloropyrimidin-5-yl)methyl)aniline

[0287] A solution of iodo compound (18, 7.0 g, 24.20 mmol) in toluene (50 mL) was cooled to 0 °C and aniline (2.20 g, 24.20 mmol) was added. The reaction mixture was stirred for 30 min at 0 °C. Then a solution of sodium hydroxide (1.30 g, 32.50 mmol) in water (5 ml) was added and reaction mixture was stirred for 16 h at RT. The reaction was monitored by TLC. After completion of the reaction, water (25 mL) was added and extracted with ethyl acetate (2 x 100 mL). The organic layer was washed with brine solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude residue. The crude compound was purified by silica gel column chromatography to afford the title compound as a white solid (10 g, 81% yield). LCMS Calcd for [M+H] + 254.11, found 254.09

Step-4: Synthesis of tert-butyl (3-((2-chloro-5-((phenylamino)methyl)pyrimidin-4-yl)amino)phenyl)carbamate

[0288] To a stirred solution of N-((2,4-dichloropyrimidin-5-yl)methyl)aniline (4.0 g, 15.08 mmol) in IPA (30 mL), tert-butyl (3-aminophenyl)carbamate (4.90 g, 23.0 mmol) and DIPEA (8.20 mL, 47 mmol) were added. The reaction mixture was heated at 100 °C for 16 h in a sealed tube. Solvent was then evaporated and the crude thus obtained was purified by flash column chromatography to afford the title compound as off white solid (2.50 g, 37% yield). LCMS Calcd for [M+H] + 425.92, found 426.35

Step-5: Synthesis of tert-butyl (3-(7-chloro-3-phenyl-2-thioxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate

[0289] To a solution of tert-butyl (3-((2-chloro-5-((phenylamino)methyl)pyrimidin-4-yl)amino)phenyl)carbamate (1.50 g, 3.50 mmol) in THF (35 mL) was added DIPEA (2.40 mL, 14.10 mmol) and thiophosgene (0.27 g, 3.50 mmol) at 0 °C. The reaction mixture was stirred at RT for 24 h with TLC monitoring. After completion of the reaction, sodium bicarbonate solution was added. The reaction mixture was partitioned between DCM (2 x 100 mL) and water (50 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain crude product. The crude product was purified by silica gel column chromatography to afford the title compound as a yellow solid (1.36 g, 82% yield). LCMS Calcd for [M+H] + 467.97, found 468.27

Step-6: Synthesis of tert-butyl (3-(7-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-3-phenyl-2-thioxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate

[0290] To a solution of tert-butyl (3-(7-chloro-3-phenyl-2-thioxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (1.30 g, 2.78 mmol) in IPA (15 mL) was added 3-

chloro-1-methyl-1H-pyrazol-4-amine (0.44 g, 3.34 mmol) and TFA (1 mL). The reaction mixture was heated for 16 h at 110 °C. Reaction was monitored by TLC. After the completion of reaction, the reaction mixture was concentrated, water (10 mL) and saturated sodium bicarbonate (20 mL) solution were added to the residue and extracted with DCM (3 x 200 mL). The combined organic layer was washed with brine solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the title compound (1.30 g) that was used as such for the next step without further purification. LCMS Calcd for [M+H] + 563.08, found 562.90

Step-7: Synthesis of 1-(3-aminophenyl)-7-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-thione

[0291] To an ice-cold solution of tert-butyl (3-(7-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-3-phenyl-2-thioxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (1.30 g, 2.30 mmol) in DCM (20 mL) and MeOH (10 mL) was added 4N HCl in dioxane (5 mL). The reaction mixture was stirred for 16 h at RT. The reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated followed by addition of water (10 mL) and saturated sodium bicarbonate (20 mL) solution and extraction with DCM (3 x 200 mL). The combined organic layer was washed with brine solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain crude product. The crude product was purified by silica gel column chromatography to afford the title compound as a brown solid (0.20 g). LCMS Calcd for [M+H] + 462.96, found 463.0. Purity: 68%

Step-8: Synthesis of (E)-N-(3-(7-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-3-phenyl-2-thioxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)-4-(dimethylamino)but-2-enamide (Compound 51)

[0292] To an ice-cold solution of 1-(3-aminophenyl)-7-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-thione (0.18 g, 0.39 mmol) and trans-N,N-dimethylaminocrotonic acid hydrochloride (0.077 g, 0.47 mmol) in dichloromethane (10 mL) was added triethyl amine (1.2 mmol) followed by drop wise addition of propylphosphonic anhydride (T3P) (0.26 g, 0.97 mmol). The mixture was stirred at RT for 6 h. Completion of the reaction was monitored by TLC. The reaction mixture was portioned between 5% methanol in dichloromethane and saturated bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude obtained was purified by silica gel chromatography to afford the title compound as off white solid (Compound 51, 0.010 g, 5% yield).1H NMR (400 MHz, DMSO-d6): δ 10.36 (bs, 1H), 8.97 (bs, 1H), 8.25 (s, 1H), 7.72 (bs, 2H), 7.48-7.42 (m, 5H), 7.36-7.32 (m, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.76-6.60 (m, 2H), 6.30 (d, J = 14.8 Hz, 1H), 4.95 (s, 2H), 3.50 (s, 3H), 3.12 (bs, 2H), 2.21 (s, 6H); LCMS Calcd for [M+H] + 574.10, found 574.41

Scheme 28: Preparation of (E)-N-(3-(3-benzyl-7-((1-methyl-1H-pyrazol-3-yl)amino)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)-4-(dimethylamino)but-2-enamide (Compound 52):

 Step 1: Preparation of ethyl 4-((3-((tert-butoxycarbonyl) amino) phenyl) amino)-2-(methylthio) pyrimidine-5-carboxylate (106):

[0293] Title compound (106) was prepared as off-white solid (142 g; Yield: 74%) in a manner substantially similar to procedure mentioned in General procedure O.1H-NMR (400 MHz, CDCl3): ^ 10.36 (s, 1H), 8.77 (d, 1H), 7.89 (s, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.25-7.22 (m, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.51 (s, 1H), 4.35 (q, J = 7.2 Hz, 2H), 2.54 (s, 3H), 1.51 (s, 9H), 1.42-1.38 (m, 3H). LCMS: [M+H]+ 405.21, 89.28%.

Step 2: Preparation of tert-butyl (3-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (107):

[0294] Title compound was prepared in a manner substantially similar to procedure mentioned in General procedure P. The crude was triturated with dichloromethane afforded 107 as off white solid (40.0 g; Yield: 31%).1H-NMR (400 MHz, CDCl3): ^ 8.09 (s, 1H), 7.86 (m, 2H),

7.36 (d, J = 8.0 Hz, 1H), 7.25-7.15 (m, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6.55 (s, 1H), 4.59 (s, 2H), 2.50 (s, 3H), 1.51 (s, 9H). LCMS: [M+H]+ 363.05, 91.24%.

Step 3: Preparation of tert-butyl (3-((5-formyl-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (108):

[0295] Title compound (108) was prepared as a pale yellow solid (31.0 g; Yield: 78%) in a manner substantially similar to procedure mentioned in General procedure Q.1H-NMR (400 MHz, CDCl3): ^ 10.59 (s, 1H), 9.75 (s, 1H), 8.42 (s, 1H), 7.97 (s, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.59 (s, 1H), 3.48 (s, 1H), 2.58 (s, 3H), 1.52 (s, 9H). LCMS: [M+H]+ 361.30, 97.51%.

Step 4: Preparation of tert-butyl (E)-(3-((5-((benzylimino)methyl)-2(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (110):

[0296] Title compound (110) was prepared as a yellow solid (28 g; Yield: 72%) in a manner substantially similar to procedure mentioned in General procedure R.1H-NMR (400 MHz, CDCl3): ^ 12.15 (s, 1H), 8.31 (s, 1H), 8.16 (s, 1H), 7.91 (s, 1H), 7.41 (m, 4H), 7.35-7.33 (m, 1H), 7.32-7.29 (m, 1H), 7.26-7.22 (m, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.46 (s, 1H), 4.84 (s, 2H), 2.59 (s, 3H), 1.52 (s, 9H). LCMS: [M+H]+ 450.38; 99.66%.

Step 5: Preparation of tert-butyl (3-((5-((benzylamino)methyl)-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (111):

[0297] Title compound (111) was prepared as a pale yellow solid (40 g; Yield: 80%) in a manner substantially similar to procedure mentioned in General procedure S. LCMS: [M+H]+ 452.44; 83.57%

Step 6: Preparation of tert-butyl (3-(3-benzyl-7-(methylthio)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (112):

[0298] Title compound was prepared in a manner substantially similar to procedure mentioned in General procedure T. The crude was triturated with diethyl ether afforded 112 as off white solid (12 g; Yield: 28%).1H-NMR (400 MHz, CDCl3): ^ 8.03 (s, 1H), 7.50 (s, 1H), 7.37 (m, 6H), 7.26 (m, 1H), 6.96 (m, 1H), 6.59 (s, 1H), 4.69 (s, 2H), 4.34 (s, 2H), 2.16 (s, 3H), 1.50 (s, 9H). LCMS: [M+H]+ 478.16; 95.62%.

Step 7: Preparation of tert-butyl (3-(3-benzyl-7-(methylsulfonyl)-2-oxo-3,4-dihydropyrimido [4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (113):

[0299] Title compound was prepared in a manner substantially similar to procedure mentioned in General procedure U. The crude was triturated with diethyl ether afforded 113 as an off white solid (8.0 g; Yield: 76%).1H-NMR (400 MHz, CDCl3): ^ 8.39 (s, 1H), 7.63 (s, 1H), 7.40 (m, 6H), 7.17 (d, J = 8.0 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6.61 (s, 1H), 4.71 (s, 2H), 4.48 (s, 2H), 2.97 (s, 3H), 1.49 (s, 9H). LCMS: [M+H]+ 510.31, 93.69%.

Step 8: Preparation of tert-butyl (3-(3-benzyl-7-((1-methyl-1H-pyrazol-3-yl)amino)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (114):

[0300] Title compound was prepared in a manner substantially similar to General procedure V, tert-butyl (3-(3-benzyl-7-(methylsulfonyl)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (113) and 1-methyl-1H-pyrazol-3-amine (41) gave (tert-butyl (3-(3-benzyl-7-((1-methyl-1H-pyrazol-3-yl)amino)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (114) as a brown solid (Yield: 77%), which was used directly for the next step without any further purification. MS: [M+H]+ 527.46.

Step 9: Preparation of 1-(3-aminophenyl)-3-benzyl-7-((1-methyl-1H-pyrazol-3-yl)amino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (115):

[0301] Title compound was prepared in a manner substantially similar to General procedure W, tert-butyl (3-(3-benzyl-7-((1-methyl-1H-pyrazol-3-yl)amino)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (114) gave 1-(3-aminophenyl)-3-benzyl-7-((1-methyl-1H-pyrazol-3-yl)amino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (115) as a brown solid (Yield: 93%), which was used directly for the next step. MS: [M+H]+ 427.44.

Step 10: Preparation of (E)-N-(3-(3-benzyl-7-((1-methyl-1H-pyrazol-3-yl)amino)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)-4-(dimethylamino)but-2-enamide (Compound 52):

[0302] Title compound was prepared in a manner substantially similar General procedure X, 1-(3-aminophenyl)-3-benzyl-7-((1-methyl-1H-pyrazol-3-yl)amino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (115) and trans-N,N-dimethylaminocrotonic acid hydrochloride gave (E)-N-(3-(3-benzyl-7-((1-methyl-1H-pyrazol-3-yl)amino)-2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)-4-(dimethylamino)but-2-enamide Compound 52, as a white solid (48 mg; Yield: 13%), after prep-HPLC purification.1H-NMR (400 MHz, CDCl3): δ 10.17 (s, 1H), 9.51 (s, 1H), 8.08 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.60 (s, 1H), 7.43-7.35 (m, 5H), 7.33-7.29 (m, 1H), 7.10 (s, 1H), 7.01 (d, J = 8.8 Hz, 1H), 6.75-6.69 (m, 1H), 6.27 (d, J = 15.3 Hz, 1H), 5.51 (s, 1H), 4.62 (s, 2H), 4.39 (s, 2H), 3.59 (s, 3H), 3.06 (d, J = 4.8 Hz, 2H), 2.17 (s, 6H). MS: [M+H]+ 538.32.

Scheme 30: Alternative Preparation of (E)-N-(3-(7-((3-chloro-1-methyl-1H-pyrazol-4- yl)amino)-2-oxo-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)-4- (dimethylamino)but-2-enamide (Compound 35):

Step 1: Preparation of 5-(hydroxymethyl)pyrimidine-2,4(1H,3H)-dione (119):

[0308] An ice-cold solution of pyrimidine-2,4(1H,3H)-dione (118) (10 g, 89.21 mmol) and paraformaldehyde (9.63 g, 107.05 mmol) in aqueous potassium hydroxide (132 mL, 0.5 M,

66.74 mmol) was heated at 55 °C for 14 hours. After completion of starting material (TLC), the reaction mixture was cooled to 0 °C and the pH was adjusted to 6 with 12N hydrochloric acid, the resulting white precipitate was filtered through sintered funnel and washed with diethyl ether afforded 119 as a white solid (6.3 g, Yield: 50%) which was used directly for the next step.1H-NMR (400 MHz, DMSO-d6): ^ 10.98 (bs, 1H), 10.64 (bs, 1H), 7.24 (s, 1H), 4.78 (m, 1H), 4.12 (d, J = 12.8 Hz, 2H). LCMS: [M+H]+ 143.04 (99.92% purity).

Step 2: Preparation of 2,4-dichloro-5-(chloromethyl)pyrimidine (120):

[0309] To an ice-cold solution of 5-(hydroxymethyl)pyrimidine-2,4(1H,3H)-dione (119) (10 g, 70.36 mmol) in toluene (25 mL) was added phosphoryl chloride (14 mL, 140.72 mmol) then N,N-diisopropylethylamine (37 mL, 211 mmol). The reaction mixture was heated at 120 °C for 16 hours. After the complete disappearance of starting material on TLC, the reaction mixture was quenched slowly with sodium bicarbonate solution and extracted with ethyl acetate (3 x 200 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure afforded 120 as a brown solid (12 g, Yield: 86%) which was used directly for the next step.1H NMR (400 MHz, CDCl3): ^ 8.66 (s, 1H), 4.64 (s, 2H). MS: [M+H]+ 197.0

Step 3: Preparation of 2,4-dichloro-5-(iodomethyl)pyrimidine (121):

[0310] To a solution of 2,4-dichloro-5-(chloromethyl)pyrimidine (120) (8.0 g, 40.51 mmol in acetone (40 mL) was added sodium iodide (9.71 g, 64.82 mmol). The reaction mixture was stirred at room temperature for 30 min and heated to reflux for 2 hours. After completion of reaction (TLC monitoring), the reaction mixture cooled to room temperature. The resulting white precipitate was filtered through sintered funnel and washed with acetone. The filtrate was concentrated under reduced pressure afforded 121 as a brown solid (10 g, Yield: 85%) which was used directly for the next step.1H-NMR (400 MHz, CDCl3): ^ 8.60 (s, 1H), 4.39 (s, 2H). Step 4: Preparation of N-((2,4-dichloropyrimidin-5-yl)methyl)aniline (122):

[0311] To an ice-cold solution of 2, 4-dichloro-5-(iodomethyl)pyrimidine (121) (5.0 g, 17.30 mmol) in acetone (50 mL) was added potassium carbonate (5.26 g, 38.06 mmol) and aniline (1.93 g, 20.76 mmol). The resulting reaction mixture was stirred at room temperature for 16 hours. After completion the reaction (as per TLC monitoring), the resulting white precipitate was filtered through sintered funnel and washed with acetone. The filtrate was concentrated under reduced pressure and crude was purified by column chromatography on silica gel (100-200 mesh) using 15% ethyl acetate-hexane as an eluent afforded 122 as a brown solid (2.5 g, Yield: 57%).1H-NMR (400 MHz, CDCl3): ^ 8.61 (s, 1H), 7.07 (t, J = 7.6 Hz, 2H), 6.58 (m, 3H), 6.30 (bs, 1H), 4.33 (m, 2H). LCMS: [M+H]+ 254.03 (99.01% purity).

Step 5: Preparation of tert-butyl (3-(7-chloro-2-oxo-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (123):

[0312] To an ice-cold solution of N-((2,4-dichloropyrimidin-5-yl)methyl)aniline (122) (500 mg, 1.96 mmol), in isopropanol (5 mL) was added N,N-diisopropylethylamine (1.47 mL, 8.42 mmol) and tert-butyl (3-aminophenyl)carbamate (105) (409 mg, 1.96 mmol). The resulting reaction mixture was heated at 100 °C for 16 hours in a sealed tube. After completion of reaction (TLC monitoring), the solvent was then evaporated under reduced pressure and resulting crude was purified by column chromatography on silica gel (100-200 mesh) using 30% ethyl acetate-hexane as an eluent afforded 123 as a brown solid (500 mg, Yield: 60%).1H-NMR (400 MHz, DMSO-d6): δ 9.41 (s, 1H), 8.96 (s, 1H), 8.10 (s, 1H), 7.73 (s, 1H), 7.25 (m, 2H), 7.12 (m, 3H), 6.61 (m, 3H), 6.14 (t, J = 7.2 Hz, 1H), 4.26 (m, 2H) and 1.53 (s, 9H). LCMS: [M+H]+ 426.14 (93% purity).

Step 6: Preparation of tert-butyl (3-(7-chloro-2-oxo-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (124):

[0313] To an ice-cold solution of tert-butyl (3-(7-chloro-2-oxo-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (123) (500 mg, 1.17 mmol) in tetrahydrofuran (6 mL) was added N,N-diisopropylethylamine (0.81 ml, 4.68 mmol) and triphosgene (139 mg, 0.46 mmol). The reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction (TLC monitoring), aqueous triethylamine solution was added and extracted with dichloromethane (3 times). The combined organic layer was washed with brine and dried over sodium sulfate and evaporated under reduced pressure to obtain the crude residue. The crude was purified by column chromatography on silica gel (100-200 mesh) using 30% ethyl acetate-hexane as an eluent afforded 124 as a brown solid (450 mg, Yield: 85%).1H-NMR (400 MHz, DMSO-d6): δ 9.54 (s, 1H), 8.43 (s, 1H), 7.58 (s, 1H), 7.44 (m, 4H), 7.29 (t, J = 7.2 Hz, 3H), 6.94 (s, 1H), 5.0 (s, 2H) and 1.47 (s, 9H). LCMS: [M+H]+ 452.27 (99% purity).

Step 7: Preparation of tert-butyl (3-(7-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-2-oxo-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (125):

[0314] Title compound was prepared in a manner substantially similar to procedure mentioned in General procedure V, (tert-butyl(3-(7-chloro-2-oxo-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (124) and 3-chloro-1-methyl-1H-pyrazol-4-amine (44) gave tert-butyl (3-(7-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-2-oxo-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (125) as a brown solid in 70% yield, which was used directly for the next step. MS: [M+H]+ 547.17.

Step 8: Preparation of 1-(3-aminophenyl)-7-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (126):

[0315] Title compound was prepared in a manner substantially similar to procedure mentioned in General procedure W, tert-butyl (3-(7-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-2-oxo-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)carbamate (125) gave 1-(3-aminophenyl)-7-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (126) as a brown solid (800 mg, Yield: 82%) which was used directly for the next step. MS: [M+H]+ 447.08.

Step 9: Preparation of (E)-N-(3-(7-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-2-oxo-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-1(2H)-yl)phenyl)-4-(dimethylamino)but-2-enamide (Compound 35):

[0316] Title compound was prepared in a manner substantially similar to procedure mentioned in General procedure X, 1-(3-aminophenyl)-7-((3-chloro-1-methyl-1H-pyrazol-4-yl)amino)-3-phenyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (126) and trans-N,N-dimethylaminocrotonic acid hydrochloride gave the titled compound, which was purified by prep-HPLC purification to afforded the title compound Compound 35 as a white solid (285 mg, Yield: 23%).1H-NMR (400 MHz, DMSO-d6): δ 10.27 (bs, 1H), 8.86 (s, 1H), 8.21 (s, 1H), 7.73 (s, 2H), 7.51-7.40 (m, 5H), 7.30-7.25 (m, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.76-6.70 (m, 2H), 6.29 (d, J = 15.4 Hz, 1H), 4.88 (s, 2H), 3.50 (s, 3H), 3.05 (d, J = 4.8 Hz, 2H) and 2.16 (s, 6H). MS:

[M+H]+ 558.16.

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1 Comment

  1. shivkr2 says:

    Full family photograph on single.molecule

    Thanks& regards
    Dr.S.KYadav
    Chandigarh India
    M.no 8699369719
    ________________________________

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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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