CA2850617A1 - Pyrrolopyrimidine compounds for the treatment of cancer - Google Patents
Pyrrolopyrimidine compounds for the treatment of cancer Download PDFInfo
- Publication number
- CA2850617A1 CA2850617A1 CA2850617A CA2850617A CA2850617A1 CA 2850617 A1 CA2850617 A1 CA 2850617A1 CA 2850617 A CA2850617 A CA 2850617A CA 2850617 A CA2850617 A CA 2850617A CA 2850617 A1 CA2850617 A1 CA 2850617A1
- Authority
- CA
- Canada
- Prior art keywords
- compound
- alkyl
- mmol
- pyrrolo
- cancer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 206010028980 Neoplasm Diseases 0.000 title claims description 17
- 201000011510 cancer Diseases 0.000 title claims description 16
- 238000011282 treatment Methods 0.000 title claims description 12
- 150000004944 pyrrolopyrimidines Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 90
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims abstract description 7
- 239000000203 mixture Substances 0.000 claims description 48
- 125000000217 alkyl group Chemical group 0.000 claims description 43
- -1 heteroaryalkyl Chemical group 0.000 claims description 35
- 125000003118 aryl group Chemical group 0.000 claims description 34
- 150000003839 salts Chemical class 0.000 claims description 34
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 22
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 11
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 9
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 7
- 125000001188 haloalkyl group Chemical group 0.000 claims description 7
- 125000005647 linker group Chemical group 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 230000002496 gastric effect Effects 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 3
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 206010033128 Ovarian cancer Diseases 0.000 claims description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 3
- 206010038389 Renal cancer Diseases 0.000 claims description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 3
- 208000002495 Uterine Neoplasms Diseases 0.000 claims description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 3
- 210000000481 breast Anatomy 0.000 claims description 3
- 210000001072 colon Anatomy 0.000 claims description 3
- 208000029742 colonic neoplasm Diseases 0.000 claims description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 206010017758 gastric cancer Diseases 0.000 claims description 3
- 125000005885 heterocycloalkylalkyl group Chemical group 0.000 claims description 3
- 210000003734 kidney Anatomy 0.000 claims description 3
- 201000010982 kidney cancer Diseases 0.000 claims description 3
- 210000004185 liver Anatomy 0.000 claims description 3
- 201000007270 liver cancer Diseases 0.000 claims description 3
- 208000014018 liver neoplasm Diseases 0.000 claims description 3
- 210000004072 lung Anatomy 0.000 claims description 3
- 201000005202 lung cancer Diseases 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- 208000003747 lymphoid leukemia Diseases 0.000 claims description 3
- 201000001441 melanoma Diseases 0.000 claims description 3
- 208000025113 myeloid leukemia Diseases 0.000 claims description 3
- 230000002611 ovarian Effects 0.000 claims description 3
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- 206010046766 uterine cancer Diseases 0.000 claims description 3
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 3
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 abstract description 7
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 abstract description 4
- 210000004027 cell Anatomy 0.000 abstract description 2
- 238000011161 development Methods 0.000 abstract description 2
- 230000005014 ectopic expression Effects 0.000 abstract description 2
- 239000003112 inhibitor Substances 0.000 abstract description 2
- 108090000623 proteins and genes Proteins 0.000 abstract description 2
- 102000027426 receptor tyrosine kinases Human genes 0.000 abstract description 2
- 108091008598 receptor tyrosine kinases Proteins 0.000 abstract description 2
- 150000003384 small molecules Chemical class 0.000 abstract description 2
- 230000004083 survival effect Effects 0.000 abstract description 2
- 210000004881 tumor cell Anatomy 0.000 abstract description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
- 239000000243 solution Substances 0.000 description 38
- 229910001868 water Inorganic materials 0.000 description 26
- 239000000047 product Substances 0.000 description 21
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 20
- 238000009472 formulation Methods 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- 125000003342 alkenyl group Chemical group 0.000 description 18
- 125000000304 alkynyl group Chemical group 0.000 description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 15
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 14
- 239000012044 organic layer Substances 0.000 description 14
- 150000003254 radicals Chemical class 0.000 description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
- 125000001424 substituent group Chemical group 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 10
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 10
- 235000019341 magnesium sulphate Nutrition 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 125000005843 halogen group Chemical group 0.000 description 9
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 8
- 235000015320 potassium carbonate Nutrition 0.000 description 8
- 239000000651 prodrug Substances 0.000 description 8
- 229940002612 prodrug Drugs 0.000 description 8
- 239000007832 Na2SO4 Substances 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 239000012267 brine Substances 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Chemical group C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical group C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- 101150041968 CDC13 gene Proteins 0.000 description 5
- 229910003827 NRaRb Inorganic materials 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 5
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 239000002502 liposome Substances 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical group OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical group C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000004202 carbamide Substances 0.000 description 4
- 125000004093 cyano group Chemical group *C#N 0.000 description 4
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- 238000001990 intravenous administration Methods 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
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- 125000003396 thiol group Chemical class [H]S* 0.000 description 4
- 230000000699 topical effect Effects 0.000 description 4
- SQQIUDPUHXGYOS-UHFFFAOYSA-N 5-bromo-2-chloro-7h-pyrrolo[2,3-d]pyrimidine Chemical compound ClC1=NC=C2C(Br)=CNC2=N1 SQQIUDPUHXGYOS-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A—HUMAN NECESSITIES
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- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
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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
- C07D487/12—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 three hetero rings
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| PCT/US2012/058298 WO2013052417A1 (en) | 2011-10-03 | 2012-10-01 | Pyrrolopyrimidine compounds for the treatment of cancer |
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| EP2925752A4 (en) | 2012-11-27 | 2016-06-01 | Univ North Carolina | PYRIMIDINE COMPOUNDS FOR CANCER TREATMENT |
| US9555031B2 (en) | 2014-04-11 | 2017-01-31 | The University Of North Carolina At Chapel Hill | Therapeutic uses of selected pyrrolopyrimidine compounds with anti-mer tyrosine kinase activity |
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| CN114127071B (zh) * | 2019-04-02 | 2024-03-22 | 梅里克斯股份有限公司 | 激酶抑制剂的多晶型、含有该化合物的药物组合物、制备方法、及应用 |
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| CN103958510B (zh) | 2016-10-19 |
| US20160151372A1 (en) | 2016-06-02 |
| AU2012318896A1 (en) | 2014-05-22 |
| JP2017101043A (ja) | 2017-06-08 |
| KR102063098B1 (ko) | 2020-01-08 |
| US9795606B2 (en) | 2017-10-24 |
| RU2631655C2 (ru) | 2017-09-26 |
| JP2014532060A (ja) | 2014-12-04 |
| BR112014007788A2 (pt) | 2017-04-18 |
| EP2763988B1 (en) | 2017-09-20 |
| EP2763988A4 (en) | 2015-06-03 |
| MX2014004086A (es) | 2014-09-22 |
| JP6316925B2 (ja) | 2018-04-25 |
| ES2650630T3 (es) | 2018-01-19 |
| HK1201256A1 (en) | 2015-08-28 |
| US9273056B2 (en) | 2016-03-01 |
| AU2012318896B2 (en) | 2017-03-02 |
| CN103958510A (zh) | 2014-07-30 |
| US10179133B2 (en) | 2019-01-15 |
| EP2763988A1 (en) | 2014-08-13 |
| IL231835A0 (en) | 2014-05-28 |
| KR20140095471A (ko) | 2014-08-01 |
| US20180104247A1 (en) | 2018-04-19 |
| US20140243315A1 (en) | 2014-08-28 |
| WO2013052417A1 (en) | 2013-04-11 |
| RU2014115847A (ru) | 2015-11-10 |
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