WO2018081211A1 - 7-cyclopentyl-n,n-diméthyl-2-((5- (pipérazin-1-yl)pyridin-2-yl)amino)-7h- pyrrolo[2,3-d]pyrimidine-6-carboxamide deutéré - Google Patents

7-cyclopentyl-n,n-diméthyl-2-((5- (pipérazin-1-yl)pyridin-2-yl)amino)-7h- pyrrolo[2,3-d]pyrimidine-6-carboxamide deutéré Download PDF

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WO2018081211A1
WO2018081211A1 PCT/US2017/058201 US2017058201W WO2018081211A1 WO 2018081211 A1 WO2018081211 A1 WO 2018081211A1 US 2017058201 W US2017058201 W US 2017058201W WO 2018081211 A1 WO2018081211 A1 WO 2018081211A1
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compound
mmol
compounds
amino
cyclopentyl
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PCT/US2017/058201
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George Y. Li
Duanjie Hou
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Li George Y
Duanjie Hou
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Publication of WO2018081211A1 publication Critical patent/WO2018081211A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds

Definitions

  • the present invention relates to an isotopologue of Compound 1 substituted with one or more deuteriums.
  • the isotopologues of this invention are selective CDK4/6 kinase inhibitors and possess unique biopharmaceutical and metabolic properties compared to Compound 1. They may also be used to accurately determine the concentration of Compound 1 in biological fluids and to determine metabolic patterns of Compound 1 and its isotopologues.
  • the invention further provides compositions comprising these deuterated isotopologues and methods for treating pRb-positive tumor types including HR-positive and HER2-negative breast cancer in combination with additional agents (i.e. letrozole). See Rader J, el al. "Dual CDK4/CDK6 Inhibition Induces Cell-Cycle Arrest and Senescence in Neuroblastoma.” Clin Cancer Res. 2013, 19(22), 6173-82.
  • Compound 1 salts, solvates, hydrates, and polymorphs thereof, are known as selective CDK4/6 inhibitors.
  • This comrjound and oharmaceutical comDositions comDrisine it mav have utility in the treatment of pRb-positive tumor types including HR-positive and HER2- negative breast cancer in combination with additional agents ⁇ i.e. letro/.ole).
  • Compound 1 also known as Ribociclib (LEE-01 1 ), selectively binds to cyclin- dependent kinases 4 and 6 (CDK4/6) and inhibits the activity of CDK4/6 thereby inhibiting retinoblastoma (Rb) protein phosphorylation. Inhibition of Rb phosphorylation prevents CDK-mediated G l -S phase transition, therefore arresting the cell cycle in the Gl phase, suppressing DNA synthesis and inhibiting cancer cell growth.
  • Rb phosphorylation prevents CDK-mediated G l -S phase transition, therefore arresting the cell cycle in the Gl phase, suppressing DNA synthesis and inhibiting cancer cell growth.
  • Overexpression of CDK.4/6 as seen in certain types of cancer, causes cell cycle deregulation and uncontrolled cellular proliferation.
  • MONALEESA-2 is a pivotal Phase III trial of ribociclib in combination with letro/ole, compared to lelro/ole alone in postmenopausal women who had received no prior therapy lor their HR+/HER2- advanced breast cancer. It has validated the belief that ribociclib in combination with letro/ole can be a beneficial treatment option for women diagnosed with HR+/HER2- advanced breast cancer. See Novartis announcement, https://www.novartis.com/news/media-releases/monaleesa-2- Irial-novartis-leeO 1 1 -ribociclib-stopped-due-positive-efficacy
  • Ribociclib is currently evaluated in combination with additional endocrine agents as part of the MONALEESA clinical trial program.
  • the MONALEESA-3 trial is evaluating ribociclib in combination with fulvestrant compared to fulvestrant alone in men and postmenopausal women with HR+/HER2- advanced breast cancer who have received no or a maximum of one prior endocrine therapy.
  • the MONALEESA-7 trial is investigating ribociclib in combination with endocrine therapy and goserelin compared to endocrine therapy and goserelin alone in pre-menopausai women with HR+/HER2- advanced breast cancer who have not previously received endocrine therapy.
  • Ribociclib has also been evaluated in a phase I monotherapy study and shown to have an acceptable safety profile with less prominent hematologic and gastrointestinal toxicity than the other two CDK4/6 inhibitors, palbociclib and abemaciclib.
  • the recommended dose was 600 mg daily, 3 weeks on, i week off. See, Infante JR, Shapiro G, Witteveen P. "A phase I study of the single-agent CDK 4/6 inhibitor LEE01 1 in patients with advanced solid tumors and lvmDhomas.” J Clin Oncol. 32:5s. 2014 tsuDol: abstr 2528V
  • compound 1 may be primarily metabolized by CYP3A and sulfotransferase in a similar manner to that of its structurally related analog, palbociclib.
  • the primary metabolic pathways for compound 1 may involve oxidation and sulfonation.
  • Various deuteration patterns can be used to a) reduce or eliminate unwanted metabolites, b) increase the half-life of the parent drug, c) decrease the number of doses needed to achieve a desired effect, d) decrease the amount of a dose needed to achieve a desired effect, e) increase the formation of active metabolites, if any are formed, and/or 0 decrease the production of deleterious metabolites in specific tissues and/or create a more effective drug and/or a safer drug for polypharmacy, whether the polypharmacy be intentional or not.
  • the deuteration approach has strong potential to slow the metabolism via various oxidative and other modification mechanisms.
  • Compound 1 refers to a compound wherein all hydrogen and all carbon atoms are present at their natural isotopic abundance percentages. It is recognized that some variation of natural isotopic abundance occurs depending upon the origin of chemical materials. The concentration of naturally abundant stable hydrogen and carbon isotopes, not withstanding this variation, is small and immaterial with respect to the degree of stable isotopic substitution of compounds of this invention. (See for instance Wada E and Hanba Y, Seikagaku 1994 66: 15; Ganes L Z et. al., Comp, Biochem. Physiol. A Mol. Integr.
  • the altered properties of the compounds of this invention will not obliterate their ability to bind to their protein target. This is because such binding is primarily dependent upon non-covalent binding between the protein and the inhibitor which may be impacted both positively and negatively by isotopic substitution, depending on the specific substitution involved, and any negative effects that a heavy atom of this invention may have on the highly optimized non-covalent binding between compounds of formula I and its target proteins will be relatively minor.
  • Major factors contributing to the noncovalent recognition of small molecules by proteins and the binding strength between them include: Van der Waals forces, hydrogen bonds, ionic bonds, molecular reorganization, desolvation energy of the small molecule, hydrophobic interactions and, in certain instances, displacement energy for pre-existing bound ligands.
  • the compounds of this invention possess molecular topology that is very similar to Compound 1 , since exchange of deuterium for hydrogen does not alter molecular shape and exchange of U C for l 2 C is conformatioinally neutral (Holtzer M E et. al., Biophys. J. 2001 80: 939). Deuterium replacement does cause a slight decrease in Van der Waals radius (Wade D, Chem. Biol. Interact. 1999 1 17: 191 ); but applicant believes that such decrease will not greatly reduce binding affinity between the molecule and its receptor. Furthermore, the slightly smaller size of the deuterated compounds of this invention Drevents their beine involved in new undesirable steric clashes with the bindine Drotein relative to the Compound 1.
  • deuterium nor 13 C atoms in the compounds of this invention contribute significantly to hydrogen bonding or ionic interactions with the protein receptors. This is because the major hydrogen bond and ionic: interactions formed by Compound 1 with serotonin uptake proteins are mediated by the oxygens, nitrogens, and the amine-bound hydrogens within Compound 1. Any deuterium atoms attached to the amine nitrogen will be rapidly exchanged with bulk solvent protons under physiological conditions. Protein reorganization or side chain movement will be identical between a compound of this invention and Compound 1. Desolvation energy of a compound of this invention will be equivalent to or less than that of Compound 1, resulting in neutral or increased binding affinity for the receptor; Turowski M et. al., J. Am. Chem. Soc. 2003 125: 13836. The replacement of n C in place of l 2 C in compounds of this invention will have no practical change in desolvation.
  • a compound of this invention advantageously retains substantial selective CDK4/6 inhibitory activity with reduced rate of metabolite generation.
  • the compounds and compositions of this invention are also useful as analytical reagents for determining the concentration of the Compound 1 (the active component) in solution.
  • the present invention provides an isolated compound of formula I:
  • At least one of the positions represented as D independently has deuterium enrichment of no less than about 1 %, no less than about 5%, no less than about 10%, no less than about 20%, no less than about 50%, no less than about 70%, no less than about K()%, no less than about 90%, or no less than about 98%.
  • the deuterated compound as disclosed herein may also contain less prevalent isotopes for other elements, including, but not limited to, ,3 C or 14 C for carbon, 15 N for nitrogen, and 17 0 or 18 0 for oxygen.
  • the deuterated compounds disclosed herein maintain the beneficial aspects of the corresponding non-isotopically enriched molecules while substantially increasing the maximum tolerated dose, decreasing toxicity, increasing the half-life ( ⁇ 2 ), lowering the maximum plasma concentration (C max ) of the minimum efficacious dose (MED), lowering the efficacious dose and thus decreasing the non- mechanism-related toxicity, and/or lowering the probability of drug-drug interactions.
  • a salt of a compound of this invention is formed between an acid and a basic group of the corrmound. such as an amino functional eroiiD. or a base and an acidic crouD of the compound, such as a carboxyl functional group.
  • the compound is a pharmaceutically acceptable acid addition salt.
  • prodrug means a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide a compound of this invention. Prodrugs may only become active upon such reaction under biological conditions, or they may have activity in their unreacted forms.
  • prodrugs contemplated in this invention include, but are not limited to, analogs or derivatives of compounds of any one of the formulae disclosed herein that comprise biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues.
  • biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues.
  • Other examples of prodrugs include derivatives of compounds of any one of the formulae disclosed herein that comprise—NO,— NO.sub.2,— ONO, or— ONO.sub.2 moieties.
  • Prodrugs can typically be prepared using well-known methods, such as those described by Burger's Medicinal Chemistry and Drug Discovery ( 1995) 172- 178, 949-982 (Manfred E. Wolff ed., 5th ed); see also Goodman and Gilman's, The Pharmacological basis of Therapeutics, 8th ed., McGraw-Hill, Int. Ed. 1992, "Biotransforrnation of Drugs”.
  • biohydrolyzable amide means an amide, ester, carbamate, carbonate, ureide, or phosphate analogue, respectively, that either: 1 ) does not destroy the biological activity of the compound and confers upon that compound advantageous properties in vivo, such as uptake, duration of action, or onset of action; or 2) is itself biologically inactive but is converted in vivo to a biologically active compound.
  • biohydrolyzable amides include, but are not limited to, lower alkyl amides, .alpha.-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides.
  • biohydrolyzable esters include, but are not limited to, lower alkyl esters, alkoxyacyloxy esters, alkyl acylamino alkyl esters, and choline esters.
  • biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, amino acids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, ' and ⁇ oolv ml ether amines.
  • a prodrug salt is a compound formed between an acid and a basic group of the prodrug, such as an amino functional group, or a base and an acidic group of the prodrug, such as a carboxyl functional group.
  • the prodrug salt is a pharmaceutically acceptable salt.
  • the counterion to the saltable prodrug of the compound of formula I is pharmaceutically acceptable.
  • Pharmaceutically acceptable counterions include, for instance, those acids and bases noted herein as being suitable to form pharmaceutically acceptable salts.
  • Particularly favored prodrugs and prodrug salts are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or central nervous system) relative to the parent species.
  • Preferred prodrugs include derivatives where a group that enhances aqueous solubility or active transport through the gut membrane is appended to the structure of formulae described herein. See, e.g., Alexander, J. et al. Journal of Medicinal Chemistry 1988, 31 , 3 18-322; Bundgaard, H.
  • pharmaceutically acceptable refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound or a prodrug of a compound of this invention.
  • pharmaceutically acceptable counterion is an ionic portion of a salt that is not toxic when released from the salt upon administration to a recipient.
  • Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, as well as organic acids such as para-toluenesulfonic, salicylic, tartaric, bitartaric, ascorbic, maleic, besylic, fumaric, gluconic, glucuronic, formic, glutamic, methanesulfonic, ethanesulfonic, benzenesulfonic, lactic, oxalic, para- bromophenylsulfonic, carbonic, succinic, citric, benzoic and acetic acid, and related inorganic and organic acids.
  • Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,
  • Preferred pharmaceutically acceptable acid addition salts include those formed with mineral acids such as
  • hydrochloric acid and hydrobromic acid and especially those formed with organic acids such as maleic acid.
  • hydrate means a compound which further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent
  • solvate means a compound which further includes a stoichiometric or non-stoichiometric amount of solvent such as water, acetone, elhanol, methanol, dichloromethane, 2-propanol, or the like, bound by non-covalent intermolecular forces.
  • polymorph means solid crystalline forms of a compound or complex thereof which may be characterized by physical means such as, for instance, X- ray powder diffraction patterns or infrared spectroscopy. Different polymorphs of the same compound can exhibit different physical, chemical and/or spectroscopic properties. Different physical properties include, but are not limited to stability (e.g., to heat, light or moisture) '. ' comD l ressibilitv ml and densitv ml ( ⁇ im ⁇ rjortant in formulation and 1 Droduct manufacturing), hygroscopicity, solubility, and dissolution rates and solubility (which can affect bioavailability).
  • Differences in stability can result from changes in chemical reactivity (e.g., differential oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph) or mechanical characteristics (e.g., tablets crumble on storage as a kinetically favored polymorph converts to thermodynamically more stable polymorph) or both (e.g., tablets of one polymorph are more susceptible to breakdown at high humidity).
  • chemical reactivity e.g., differential oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph
  • mechanical characteristics e.g., tablets crumble on storage as a kinetically favored polymorph converts to thermodynamically more stable polymorph
  • both e.g., tablets of one polymorph are more susceptible to breakdown at high humidity.
  • Different physical properties of polymorphs can affect their processing. For example, one polymorph might be more likely to form solvates or might be more difficult to filter or wash free of impurities than another
  • the compounds of formula I may be prepared by the processes described herein m the following reaction scheme (Scheme A). Examples of suitable reagents and procedures for conducting these reactions appear hereinafter and in the working examples included therein. Protection and deprotection in the schemes herein may be carried out by procedures generally known in the art [See, for example, T.W. Greene & P.G. M.Wuts, P r otecting G roups in Or ganic S ynth esis,3r d Editio n , Wi ley , ( 1 999 ) ⁇ .
  • Reduction of the compound of formula IV to the compound of formula V can be carried out in an organic solvent or in an organic solvent in mixture with water.
  • Suitable organic solvents are for example alcohol and ethers, preferably methanol.
  • reaction can be carried out in the presence of a catalyst, such as 10% Pd/C or Raney Nickel and/or hydrogen.
  • a catalyst such as 10% Pd/C or Raney Nickel and/or hydrogen.
  • the reaction is carried out in an autoclave reactor pressurized to 1 to 10 bar hydrogen. Particularly preferred conditions are 10% Pd/C in methanol under hydrogen at atmospheric pressure.
  • Reaction of the compound of formula V with a compound of formula VI to obtain a compound of formula VII can be achieved through the Buchwald coupling reaction.
  • the reaction can be carried out in a suitable organic solvent, such as dioxane, DME, DMF or toluene, preferably toluene, in the presence of a palladium catalyst such as Pd2(dba); and a phosphorous compound such as BINAP.
  • the reaction can be carried out with addition of an alkaline compound, such as sodium tert-butoxide. Further, the reaction is performed at temperature of 50 °C to 120 °C, preferably 100 °C.
  • the compound of formula VI may be prepared from the compound of formula VIII by the processes similar to those described in the reference [Ref: WO 2010/02067S] (Scheme B).
  • Method B Shima/u GC-2010/GCMS-QP201 OS.
  • Primary column SLB-5ms 30m x 0.25 mm, 0.25 ⁇ ;
  • GC oven temperature program total 15 min, 45 °C to 300 °C at 40 °C /min with 10 min-hold at 300 °C;
  • Carrier gas He Inlet pressure 50 kPa;
  • Step 1 tert-Butyl 4-(6-nitropyridin-3-yl-2,4,5-d3)pipera/.ine-l -carboxylate
  • Step 2 tert-butyl 4-(6-aminopyridin-3-yl-2,4,5-d;0piperazine-l -carboxylate
  • Step 3 ter/-Butyl 4-(6-((7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrroloL2,3- d
  • Step 4 7-Cyclopentyl-N,N-dimethyl-2-((5-(pipera/.in-l-yl)pyridin-2-yl-3,4,6- d3)amino)-7H-pyrrolo
  • Example 3 was prepared from 2-chloro-7-cyclopentyl-N, N-dimethyl-7H-pynolo[2,3-d
  • Example 4 was prepared from 2-chloro-7-cyclopentyl-N, Nslimemyl-7H-pyrrolo
  • Step 1 tert-Bulyl 4-(pyridin-3-yl-d 4 )piperazine-l-carboxylate
  • (commercially available, 500 mg, 3.09 mmol), piperazine-l-carboxylic acid ten-butyl ester (690 mg, 3.70 mmol), PdC12(dppf) (1 13 mg, 0.15 mmol), and potassium tert butoxide (800 mg, 7.1 mmol) was degassed and stirred at 100°C for 14 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, water (10 mL) was added, followed by extraction twice with dichloromethane (50 ml).
  • Step 2 tert-butyl 4-(6-bromopyridin-3-yl-2,4,5-d 3 )piperazine-l-carboxylate
  • Step 3 tert-Butyl 4-(6-((7-cyclopentyI-6-(dimethylcarbainoyI)-7H-pyrrolof2,3- d]pyrimidin-2-y l)amino)pyridin-3-yl-2,4,5-d ⁇ iperazine- 1 -carboxylate
  • 6- carboxamide 120 mg, 0.44 mmol
  • Pd(dba) 2 (12.6 mg, 0.022 mmol)
  • BINAP 20 mg, 0.032 mmol
  • CS2CO3 420 mg, 1.29 mmol
  • the reaction mixture is partitioned between dichloromethane and saturated NaHCOj solution. After separation, the aqueous layer was further extracted with dichloromethane. The combined organic layers were washed with brine, dried (MgSO.0, filtered and concentrated.
  • the crude product was purified by flash column chromatography (Combiflash RF+, 0 to 10% methanol / dichloromethane) to give the title product ( 108 mg, 47 % Yield).
  • Step 4 7-Cyclopentyl-N,N-dimethyl-2-((5-(piperazin- 1 -yl)pyridin-2-yl-3 ,4,6- d3)amino)-7H-pyrrolo
  • Example S was prepared from /erf-butyl 4-(6-((7-cyclopentyl-6-(diniethylcarbamoyl)-7H-pyrrolo
  • 1 H NMR 300MHz, CDCI3: ⁇ 8.72 (s, 1H), 8.15 (s, 1H), 6.44 (s, 1 H), 4.79 (m, 1 H), 3.20 - 3.06 (m, 14H), 2.09 - 2.03 (m, 4H), 1.78 - 1.76 (m, 4H).
  • LCMS Methodhod A: m/z 438.4 ([M+H] + ), HPLC Rt 5.30 min (98.5 % purity).
  • Example 6 was prepared from 2-amino-7-cyclopentyl-N, N-dimethyl-7H-pyrrolo[2,3-d
  • LCMS Methodhod A: m/z 437.3 ([ ⁇ + ⁇ ).
  • Example 7 was prepared from 2-amino-7-cyclopentyl-N, N-dimemyl-7H-pyrrolo
  • Example 8 was prepared from 2-amino-7-cyclopentyl-N, N-bis(methyl-d3>-7H-pynrolo
  • Example 9 was prepared from 2-amino-7-cyclopentyl-N, N-bis(methyl-d3)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (commercially available, 100 mg, 0.36 mmol), and /erf-butyl 4-(6-bromopyridin-3- yl)pipera/ine-l-carboxylale-2,2,3,3,5,5,6,6-d8 (comercially available, 160 mg, 0.46 mmol) under the conditions simialr to Steps 3 and 4 in Example 2. 100 mg (62 % Yield) product was obtained.
  • Example 10 was prepared from 2-amino-7-cyclopentyl-N, N-bis(meuhyl-dj)-7H-py-TOlo[2,3-dJpyrimidine-6-carboxamide (commercially available, 100 mg, 0.36 mmol), and /er/-butyl 4-(6-bromopyridin-3-yl- 2,4,S-d3)pipera/jne-l-carboxylate (comercially available, ISO mg, 0.43 mmol) under the conditions simialr to Steps 3 and 4 in Example 2. 104 mg (65 % Yield) product was obtained.
  • LCMS Methodhod A: m/z 444.3 ([M+H]*).
  • Biochem Pharmacol 1994, 47, p. 1469 "Utility of in vitro drug metabolism data in predicting in vivo metabolic clearance”; Iwatsubo, T et al., Pharmacol Ther 1997, 73, p. 147 "Prediction of in vivo drug metabolism in the human liver from in vitro metabolism data”; and Lave, T. et al., Pharm Res 1997, 14, p. 1S2 "The use of human hepatocytes to select compounds based on their expected hepatic extraction ratios in humans”.
  • the objectives of the present study were to determine the metabolic stability of the test compounds in pooled liver microsomal incubations. Samples of the test compounds, exposed to pooled human and rat liver microsomes, were analyzed using UPLC LC- MS/MS detection.
  • Buffer A 1.0 L of 0.1 M monobasic Potassium Phosphate buffer containing 1.0 mM EDTA.
  • Buffer B 1.0 L of 0.1 M Dibasic Potassium Phosphate buffer containing 1.0 mM EDTA.
  • Buffer C 0.1 M Potassium Phosphate buffer, 1.0 mM EDTA, pH 7.4 by titrating 700 mL of buffer B with buffer A while monitoring with the pH meter.
  • 500 ⁇ spiking solution add 10 ⁇ L of 10 mM DMSO stock solution into 190 ⁇ L ⁇ C ⁇ .
  • the positive control compound (Midazolam) was included in the assay. Any value of the compounds that was not within the specified limits was rejected and the experiment was repeated.
  • the negative control was used to exclude the misleading factor that resulted from instability of chemical itself.
  • the In peak area ratio (compound peak area/ internal standard peak area) was plotted against time and the gradient of the line was determined.
  • test compounds were evaluated in the human and rat liver microsome assay described above along with midazolam as a positive control and with no NADPH in reaction system as a negative control.
  • the columns of Table 1 labeled "% remaining" refer to the percentage of each test compound remaining after 0, 5, 15, 30, and 45 minute intervals in the human.
  • the deuterated analog (Example 2) of the invention displayed some stability over time with Ti 2 extended to 74.63 min. from 72.34 min, providing a 3 % increase in human liver microsome; and to 54.61 min. from 52.98 min, providing a 3 % increase in rat liver microsome.
  • the deuterated analog (Example 4) of the invention displayed appreciable stability over time with T 1 .2 extended to 83.5 min. from 72.34 min, providing a 15 % increase in human liver microsome; and to 69.99 min. from 52.98 min, providing a 32 % increase in rat liver microsome.
  • the deuterated analog (Example 4) of the invention also displayed appreciable clearance rate with Clint reduced to 20.82 mlJmin/kg from 24.03 mL/min/kg in human liver microsome and Clim reduced to 35.49 mL/min/kg from 46.88 mL/min/kg in rat liver microsome.
  • deuterated compounds according to the invention may exhibit beneficial properties when administered to patients, e.g., improved metabolic liability.
  • Example 2 Tor its anticancer activities at the Development Therapeutic Program (DTP), National Cancer Institute (NCI), USA, against full NCI 60 cell line panel (six cell lines of Leukemia, nine cell lines of Lung cancer, seven cell lines of Colon cancer, six cell lines of CNS cancer, nine cell lines of Melanoma, seven cell lines of Ovarian cancer, eight cell lines of Renal cancer, two cell lines of Prostate cancer and six cell lines of breast cancer) representing on full nine human systems as Leukemia, Melanoma and cancers of Lung, Colon, Brain, Breast, Ovary, Kidney and Prostate, according to their applied protocol.
  • DTP Development Therapeutic Program
  • NCI National Cancer Institute
  • Example 2 significantly reduced the growth of the cell lines of leukemia RPMI-8226 (reducing to 1 1.5 %), MOLT-4 (reducing to 16.6 %), and HL-60 (TB) (reducing to 28.5 %); of breast cancer MCF7 (reducing to 47.9 %).

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Abstract

La présente invention concerne des composés de Formule (I) : (I) ou un sel pharmaceutiquement acceptable de ceux-ci ; où : Y1, Y2, Y3, Y4, Y4,, Y5, Y5, ; Y6, Y6,, Y7, Y7,, Y8, Y9, Y10, Y10,, Y10,,, Y11, Y11,, Y11,,, Y12, Y12,, Y13, Y13,, Y14, Y14,, Y15, Y15, et Y16 sont choisis dans le groupe constitué par un atome d'hydrogène ou de deutérium, au moins l'un des Y1, Y2, Y3, Y4, Y4,, Y5, Y5,; Y6, Y6,, Y7, Y7,, Y8, Y9, Y10, Y10,, Y10,,, Y11, Y11,, Y11,,, Y12, Y12,, Y13, Y13,, Y14, Y14,, Y15, Y15, et Y16 étant un atome de deutérium ; et éventuellement chaque carbone est indépendamment remplacé par l3C. Des compositions pharmaceutiques comprenant les composés de formule (I) et l'utilisation de ces composés à titre d'inhibiteurs sélectifs de CDK4/6 ayant le potentiel pour traiter les types de tumeurs pRB-positifs dont le cancer du sein HER2-positif et HER2-négatif en combinaison avec d'autres agents à savoir, le létrozole sont en outre décrites.
PCT/US2017/058201 2016-10-26 2017-10-25 7-cyclopentyl-n,n-diméthyl-2-((5- (pipérazin-1-yl)pyridin-2-yl)amino)-7h- pyrrolo[2,3-d]pyrimidine-6-carboxamide deutéré WO2018081211A1 (fr)

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WO2022113003A1 (fr) 2020-11-27 2022-06-02 Rhizen Pharmaceuticals Ag Inhibiteurs de cdk
WO2022149057A1 (fr) 2021-01-05 2022-07-14 Rhizen Pharmaceuticals Ag Inhibiteurs de cdk
EP3902805A4 (fr) * 2018-12-28 2023-03-01 SPV Therapeutics Inc. Inhibiteurs de kinase cycline-dépendants

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US20100105653A1 (en) * 2008-08-22 2010-04-29 Novartis Ag Pyrrolopyrimidine compounds and their uses
US20130203765A1 (en) * 2010-02-19 2013-08-08 Novartis Ag Deuterated pyrrolopyrimidine compounds as inhibitors of cdk4/6
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3902805A4 (fr) * 2018-12-28 2023-03-01 SPV Therapeutics Inc. Inhibiteurs de kinase cycline-dépendants
WO2022113003A1 (fr) 2020-11-27 2022-06-02 Rhizen Pharmaceuticals Ag Inhibiteurs de cdk
WO2022149057A1 (fr) 2021-01-05 2022-07-14 Rhizen Pharmaceuticals Ag Inhibiteurs de cdk

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