MX2007015718A - Tubulin inhibitor and process for its preparation. - Google Patents
Tubulin inhibitor and process for its preparation.Info
- Publication number
- MX2007015718A MX2007015718A MX2007015718A MX2007015718A MX2007015718A MX 2007015718 A MX2007015718 A MX 2007015718A MX 2007015718 A MX2007015718 A MX 2007015718A MX 2007015718 A MX2007015718 A MX 2007015718A MX 2007015718 A MX2007015718 A MX 2007015718A
- Authority
- MX
- Mexico
- Prior art keywords
- pyrazin
- process according
- amine
- phenyl
- chloro
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 68
- 238000002360 preparation method Methods 0.000 title claims description 19
- 229940122429 Tubulin inhibitor Drugs 0.000 title abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 43
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims abstract description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 43
- OYRRZWATULMEPF-UHFFFAOYSA-N pyrimidin-4-amine Chemical compound NC1=CC=NC=N1 OYRRZWATULMEPF-UHFFFAOYSA-N 0.000 claims description 41
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 37
- 239000000203 mixture Substances 0.000 claims description 35
- 239000002585 base Substances 0.000 claims description 31
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 30
- -1 malonic acid ester Chemical class 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 29
- 235000019441 ethanol Nutrition 0.000 claims description 28
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 28
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 26
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 26
- 239000000243 solution Substances 0.000 claims description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- 239000000010 aprotic solvent Substances 0.000 claims description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 16
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 13
- 229910052783 alkali metal Inorganic materials 0.000 claims description 13
- 239000001530 fumaric acid Substances 0.000 claims description 13
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 13
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 12
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 12
- SSWSRCWGJRYVTL-LBPRGKRZSA-N C[C@@H](C(F)(F)F)NC1=NC(C2=NC=CN=C2)=NC=C1C(C(F)=CC(OCCCNC)=C1)=C1F Chemical compound C[C@@H](C(F)(F)F)NC1=NC(C2=NC=CN=C2)=NC=C1C(C(F)=CC(OCCCNC)=C1)=C1F SSWSRCWGJRYVTL-LBPRGKRZSA-N 0.000 claims description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- RAZDJZZSHLZQFL-UHFFFAOYSA-N 4-hydroxy-2-pyrazin-2-yl-5-(2,4,6-trifluorophenyl)-1h-pyrimidin-6-one Chemical compound OC1=NC(C=2N=CC=NC=2)=NC(O)=C1C1=C(F)C=C(F)C=C1F RAZDJZZSHLZQFL-UHFFFAOYSA-N 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 9
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- SAWHIQMQGZZGTO-UHFFFAOYSA-N 4,6-dichloro-2-pyrazin-2-yl-5-(2,4,6-trifluorophenyl)pyrimidine Chemical compound FC1=CC(F)=CC(F)=C1C1=C(Cl)N=C(C=2N=CC=NC=2)N=C1Cl SAWHIQMQGZZGTO-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 8
- 229910000102 alkali metal hydride Inorganic materials 0.000 claims description 7
- 150000008046 alkali metal hydrides Chemical class 0.000 claims description 7
- CEEVRMDYKKNRAW-UHFFFAOYSA-N pyrazine-2-carboximidamide Chemical compound NC(=N)C1=CN=CC=N1 CEEVRMDYKKNRAW-UHFFFAOYSA-N 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 6
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 6
- 235000019270 ammonium chloride Nutrition 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
- FCVKLVNLBIBCCU-UHFFFAOYSA-N hydron;pyrazine-2-carboximidamide;chloride Chemical compound Cl.NC(=N)C1=CN=CC=N1 FCVKLVNLBIBCCU-UHFFFAOYSA-N 0.000 claims description 6
- 150000007522 mineralic acids Chemical class 0.000 claims description 6
- 239000011591 potassium Substances 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 5
- 150000003863 ammonium salts Chemical class 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 229910052700 potassium Inorganic materials 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- SNMLKBMPULDPTA-REOHCLBHSA-N (2s)-1,1,1-trifluoropropan-2-amine Chemical compound C[C@H](N)C(F)(F)F SNMLKBMPULDPTA-REOHCLBHSA-N 0.000 claims description 4
- 241000124008 Mammalia Species 0.000 claims description 4
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 4
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- XLOLWBTYFFTMCW-UHFFFAOYSA-N 1,2,3,5,6,7-hexahydroimidazo[1,5-a]pyridine Chemical compound C1CCN2CNCC2=C1 XLOLWBTYFFTMCW-UHFFFAOYSA-N 0.000 claims description 3
- USZDFOPAUAEWBC-ZETCQYMHSA-N 6-chloro-2-pyrazin-2-yl-5-(2,4,6-trifluorophenyl)-n-[(2s)-1,1,1-trifluoropropan-2-yl]pyrimidin-4-amine Chemical compound FC(F)(F)[C@H](C)NC1=NC(C=2N=CC=NC=2)=NC(Cl)=C1C1=C(F)C=C(F)C=C1F USZDFOPAUAEWBC-ZETCQYMHSA-N 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 3
- PMSVVUSIPKHUMT-UHFFFAOYSA-N cyanopyrazine Chemical compound N#CC1=CN=CC=N1 PMSVVUSIPKHUMT-UHFFFAOYSA-N 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 230000002401 inhibitory effect Effects 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 229960005235 piperonyl butoxide Drugs 0.000 claims description 3
- KRGXWTOLFOPIKV-UHFFFAOYSA-N 3-(methylamino)propan-1-ol Chemical compound CNCCCO KRGXWTOLFOPIKV-UHFFFAOYSA-N 0.000 claims description 2
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims description 2
- 239000004202 carbamide Substances 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 238000005660 chlorination reaction Methods 0.000 claims description 2
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- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 210000004881 tumor cell Anatomy 0.000 claims description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims 3
- DUFGYCAXVIUXIP-UHFFFAOYSA-N 4,6-dihydroxypyrimidine Chemical compound OC1=CC(O)=NC=N1 DUFGYCAXVIUXIP-UHFFFAOYSA-N 0.000 claims 1
- 239000003513 alkali Substances 0.000 claims 1
- 150000004703 alkoxides Chemical class 0.000 claims 1
- 230000005907 cancer growth Effects 0.000 claims 1
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 claims 1
- 239000012895 dilution Substances 0.000 claims 1
- 238000010790 dilution Methods 0.000 claims 1
- 238000010438 heat treatment Methods 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 8
- 201000011510 cancer Diseases 0.000 abstract description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 24
- 239000007787 solid Substances 0.000 description 21
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 235000019439 ethyl acetate Nutrition 0.000 description 10
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 150000001414 amino alcohols Chemical class 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
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- 102100033350 ATP-dependent translocase ABCB1 Human genes 0.000 description 2
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- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
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- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
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- 235000019289 ammonium phosphates Nutrition 0.000 description 1
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- 229910052799 carbon Inorganic materials 0.000 description 1
- HFNQLYDPNAZRCH-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O.OC(O)=O HFNQLYDPNAZRCH-UHFFFAOYSA-N 0.000 description 1
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- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 1
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- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
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- 239000000417 fungicide Substances 0.000 description 1
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- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
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- HCWCAKKEBCNQJP-UHFFFAOYSA-N magnesium orthosilicate Chemical compound [Mg+2].[Mg+2].[O-][Si]([O-])([O-])[O-] HCWCAKKEBCNQJP-UHFFFAOYSA-N 0.000 description 1
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- 230000002829 reductive effect Effects 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
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- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
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- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 description 1
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- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention provides 6-chloro-5-{2,6-difluoro-4-[3-(methylamino)propoxy]phenyl}-2-py razin-2-yl-N-[(1S)-2,2,2-trifluoro-1-methylethyl]pyrimidin-4-ami ne hemifumarate which is a tubulin inhibitor useful in the treatment of cancer and processes of making said hemifumarate.
Description
TUBULIN INHIBITOR AND PROCESS FOR PREPARATION
This application vindicates the priority of the applications for Provisional Patenies of the US-American Serial Number 60/690016, filed on June 13, 2005, and the unknown Serial Number, filed on May 24, 2006. The entirety of the application is incorporated herein by reference. .
FIELD OF THE INVENTION
The present invention relates to a compound of 5 - [(phenyl trisusituitute)] -pyrazinylpyrimidine which is an inhibitor of tubulin useful in the eradication of cancer and with a process for its preparation.
BACKGROUND OF THE INVENTION
Substance the need in the technique for cynotoxic agents for use in cancer therapy. The anlimicrolubule drugs are a greater number of analogous agents (Rowinsky, EK, and Tolcher, AW Aníimicroíubule agenís. In: VT Deviía, Jr., S. Hellman, and SA Rosenberg (eds.), Cancer Principies and Practice, Ed 6, pp. 431-452, Philadelphia: üppincotí Williams and Wilkins, 2001). The anlimicrolúbulo drugs work when interfering with the function of cellular microtubules, particularly the mytholic spindle. The interruption of the normal spindle function leads to the death of the apoptotic cell.
Many tumors are inherently resistant (eg, colon tumors) or become resistant after multiple cycles of treatment, at least because of the expression of drug transporters located in the membranes of the cancer cell that pumps the drug outside cells and therefore reduces its effectiveness (Goilesman, MM Mechanisms of Cancer Drug Resistance, Annu. Rev. Med., 53:
615-627, 2002). The best known of these transporters is the P-glycoprotein. According to this, the need for new agents with effects similar to the iaxa in the polymerization of microlubules that are not P-glycoprotein subtypes or you will hear from the pumps and that will therefore overcome this cause of resistance to the taxane in patients, subsists.
According to this, there is a new search for new clinical candidates. There is also a search for new and improved methods of preparing those selected clinical candidates. i
The preparation and use of 5-phenylpyrimidines that have the following general formula
as fungicides is described in WO02 / 074753 A2. ! The preparation and use of 4-amino-2- (pyrin-2-yl) pyrimidines has the following general formula
as microbicidal aclivals as described in US 2003/0092718 A1.
The patent application published US2005-0075357A1 describes 5-arylpyrimidines as aninineoplastic agents. The reference describes 6-chloro-5-. { 2,6-difluoro-4- [3- (methylamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1S) -2,2,2-trifluoro-1-methyleryl] pyrimidin-4-amine and its hydrochloride. It has been found that the hydrochloride has the disadvantage of being very hygroscopic.
The following invention overcomes the disadvantages of the hygroscopicity of the hydrochloride salt.
BRIEF DESCRIPTION OF THE INVENTION
The present invention is based on the unexpected discovery that the selection of the hemifumarate salt of 6-chloro-5-. { 2,6-difluoro-4- [3- (meitylamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1S) -2,2,2-lrifluoro-1-methyleryl] pyrimidin-4-amine essentially avoids the disadvantage of the hygroscopicity associated with the hydrochloride.
The present invention in one embodiment is related to the hemifumaraio of 6-chloro-5-. { 2,6-d.fluoro-4- [3- (meitylamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1S) -2,2,2-if-fluoro-1-methyleryl] pyrimidin-4-amine.
In another embodiment of the invention, a process for the preparation of 6-chloro-5 hemifumarate is provided. { 2,6-difluoro-4- [3- (meitylamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1 S) -2,2,2-trifluoro-1-methylaryl] pyrimidin-4-amine;
whose process includes:
react 6-chloro-5-. { 2,6-difluoro-4- [3- (meitylamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1S) -2,2,2-lrifluoro-1-mellylethyl] pyrimidin-4-amine of the formula
in an apróíico solvent with fumaric acid in an alcohol to give said húmifumaraío.In a further embodiment of the invention it also concerns a process for the preparation of 6-chloro-5- hemifumaraio. { 2,6-difluoro-4- [3- (meitylamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1S) -2,2,2-trifluoro-1-melilethyl] pyrimidin-4-amine;
whose process includes the stages of:
to. reacting pyrazine-2-carbonitrile with base A in an alcohol and irrala with an ammonium salt of an inorganic acid to give inorganic pyrazine-2-carboxamidine acid salt;
b. reacting the inorganic pyrazine-2-carboxamidine acid salt with a malonic acid ester of the formula
wherein R1 and R2 are independently d-C3 alkyl in an aprolic solvent in the presence of a base and acidify to obtain 2-pyrazin-2-yl-5- (2,4,6-uro-fluoro-phenyl) -pyrimidine-4 , 6-diol of the formula
c. chlorinating 2-pyrazin-2-yl-5- (2,4,6-trifluoro-phenyl) -pyrimidine-4,6-diol with phosphorus oxychloride (POCI3) as a chlorination reagent in the presence of an amine base in an aprotic solvent to give 4,6-dichloro-2-pyrazin-2-yl-5- (2,4,6-nifluoro-phenyl) -pyrimidine of the formula
d. reacting 4,6-dichloro-2-pyrazin-2-yl-5- (2,4,6-lrifluoro-phenyl) -pyrimidine with (S) -2,2,2-trifluoro-1-methyl-elylamine which has the formula
in an aprolic solution to give 6-chloro-2-pyrazin-2-yl-N - [(1S) -2,2,2-l-trifluoro-1-methylethyl] -5- (2,4,6-trifluorophenyl) pyrimidine -4-amine that has the formula
and. react 3-methylamino-propan-1-ol with base B in an aprotic solvent and add 6-chloro-2-pyrrazin-2-yN - [(1S) -2,2,2-trifluoro-1- mellethyl] -5- (2,4,6-trifluorophenyl) pyrimidin-4-amine to give 6-chloro-5-. { 2,6-difluoro-4- [3- (methylamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1S) -2,2,2-trifluoro-1-melilethyl] pyrimidin-4-amine of the formula
; Y
F. react 6-chloro-5-. { 2,6-difluoro-4- [3- (methylamino) propoxy] phenyl} -2- pyrazin-2-yl-N - [(1S) -2,2,2-trifluoro-1-methylethyl] pyrimidin-4-amine in an aprotic solvent with fumaric acid in alcohol to give said hemifumarate.
The 6-Chloro-5-. { 2,6-difluoro-4- [3- (methylamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1S) -2,2,2-trifluoro-1-methylethyl] pyrimidin-4-amine can also be called S-. { 6-Chloro-5- [2,6-difluoro-4- (3-methylamino-propoxy) -phenyl] -2-pyrazin-2-yl-pyrimidin-4-yl} - (2,2,2-trifluoro-1-methyl-ethyl) -amine.
In particular, one embodiment of the invention is a process for the preparation of 6-chloro-5 hemifumarate. { 2,6-difluoro-4- [3- (methylamino) propoxy] phenyl} -2-pyrazin-2-l-N - [(1 S) -2,2,2-trifluoro-1-methyl-ethyl] -pyrimidine-4-amine
comprising the stages of:
to. , reacting pyrazine-2-carbonitrile with sodium methoxide in a methyl alcohol and treating with ammonium chloride to give pyrazine-2-carboxamidine hydrochloride;
b. reacting pyrazine-2-carboxamidine hydrochloride with a malonic acid diethyl ester of the formula
in diglyme in the presence of potassium carbonate and acidify to give 2-pyrazin-2-yl-5- (2,4,6-trifluoro-phenyl) -pyrimidine-4,6-diol of the formula
c. halogenating 2-pyrazin-2-yl-5- (2,4,6-trifluoro-phenyl) -pyrimidine-4,6-diol with phosphorus oxychloride in the presence of N, N-diisopropylethylamine in toluene to give 6- Dichloro-2-pyrazin-2-yl-5- (2,4,6-trifluoro-phenyl) -pyrimidine of the formula
d. reacting 6-dichloro-2-pyrazin-2-yl-5- (2,4,6-trifluoro-phenyl) -pyrimidine with (S) -2,2,2-trifluoro-1-methyl-ethylamine having the formula
and? 1-Methyl-2-pyrrolidinone to give 6-chloro-2-pyrazin-2-yl-N - [(1S) -2,2,2-trifluoro-1-methylethyl] -5- (2,4, 6-trifluorophenyl) pyrimidin-4-amine of the formula
ß react an aminoalcohol HO- (CH2) 3-NHCH3 with potassium t-butoxide in telrahydrofuran and add 6-chloro-2-pyrazin-2-yl-N - [(1S) -2,2,2-fluorine -1-methylethyl] -5- (2,4,6-trifluorophenyl) pyrimidin-4-amine to give 6-chloro-5-. { 2,6-difluoro-4- [3- (methylamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1S) -2,2,2-trifluoro-1-methylethyl] pyrimidin-4-amine of the formula
F. react 6-chloro-5-. { 2,6-difluoro-4- [3- (methylamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1S) -2,2,2-trifluoro-1-methylethyl] pyrimidin-4-amine in ethyl acetate with fumaric acid in ethyl alcohol to give said hemifumarate.
A particular embodiment of the invention is a process for the preparation of 6-chloro-5- hemifumarate. { 2,6-difluoro-4- [3- (methylamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1S) -2,2,2-trifluoro-1-methylethyl] pyrimidin-4-amine
Whose process includes the stages of:
to. reacting an aminoalcohol HO- (CH2) 3-NHCH3 with potassium t-buidoxide in hexahydrofuran and add 6-chloro-2-pyrazin-2-yl-N - [(1S) -2,2,2-fluoride- 1-methylethyl] -5- (2,4,6-l-trifluorophenyl) pyrimidin-4-amine of the formula
to give 6-chloro-5-. { 2,6-difluoro-4- [3- (meitylamino) propoxy] phenyl} -2-pyra? In-2-l-N - [(1S) -2,2,2-urea-1-methylethyl] pyrimidin-4-amine of the formula
add a solution of fumaric acid in ethyl alcohol to a solution of 6-chloro-5-. { 2,6-difluoro-4- [3- (methylamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1S) -2,2,2-ylfluoro-1-methylethyl] pyrimidin-4-amine in ethyl acetate to give said hemifumaralo, and
c. Isolate said hemifumarate. I 1 Preferably the ratio of ethyl acetate to alcohol is 1: 1 V V.
! The absolute configuration of any compound that includes the compound of this invention can be determined by conventional X-ray crylography.
; The present invention provides 6-chloro-5 hemifumarate. { 2,6-difluoro-4- [3- (methylamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1S) -2,2,2-lrifluoro-1-mellylethyl] pyrimidin-4-amine which is useful in the treatment of cancer and molasses for synthesizing said hemifumaralo.
The present invention provides a method for tracing or inhibiting the growth of cancerous tumor cells and associated diseases in a mammal by administering an effective amount of hemifumarate 6-chloro-5-. { 2,6-difluoro-4- [3-! (?? ethylamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1S) -2,2,2-trifluoro-1-methylethyl] pyrimidin-4-anjiine.
The present invention further provides a pharmaceutical composition comprising an effective amount of 6-chloro-5 hemifumarate. { 2,6-difluoro-4- [3- (methylamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1S) -2,2,2-trifluoro-1-methylethyl] pyrimidin-4-amine together with a pharmaceutically acceptable carrier.
The invention will additionally supply the 6-chloro-5- hemifumaraio compound. { 2,6-difluoro-4- [3- (meitylamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1S) -2,2,2-ρ-fluoro-1-methylethyl] pyrimidin-4-amine produced by the process comprising:
to. reacting an amino alcohol HO- (CH2) 3-NHCH3 with potassium t-oxide hydroxide and add 6-chloro-2-pyrazin-2-yl-N - [(1S) -2,2,2-trifluoro- 1-methylethyl] -5- (2,4,6-trifluorophenyl) pyrimidin-4-amine of the formula
at room temperature to give 6-chloro-5-. { 2,6-difluoro-4- [3- (methylamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1S) -2,2,2-irifluoro-1-methylethyl] pyrimidin-4-amine of the formula
b. add a solution of fumaric acid in ethyl alcohol to a solution of 6-chloro-5-. { 2,6-difluoro-4- [3- (meitylamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1S) -2,2,2-lrifluoro-1-m-8-lylethyl] pyrimidin-4-amine in ethyl acetate to give said hemifumaralo; Y
c. isolate said hemifumaralo.
DEFINITIONS
The term "alkyl" means a straight or branched alkyl of 1 to 3 carbon atoms.
Halogenating agent, means the chlorinating agent, phosphorus oxychloride (POCI3).
Aprotic solvents include N, N-dimethylformamide, 1-methyl-2-pyrrolidinone and diglyme. In some embodiments of the invention, the aprotic solvents include additionally tetrahydrofuran (THF) or loluene. In further embodiments of the invention, the aprotic solvents include íoluene and efyl acetate.
The alkali metal hydride includes lithium, potassium or sodium hydride.
Alkaline alkali metal alkoxide includes lithium, poisonous or sodium alkoxide. In some embodiments of the invention the alkali metal alkoxide includes poasium iobuoxide.
Alcohol includes methyl, ethyl and isopropyl alcohols.
A base is selected from alkali metal hydroxide, alkali metal carbonate, and alkali metal hydride. In some embodiments of the invention, alkali metal carbonate is sodium or carbonate carbonate. A preferred embodiment is potassium carbonate.
Base A is a alkali metal alkoxide or alkali metal hydroxide.
Base B is an alkali metal alkoxide or an alkali metal hydride. In some embodiments of the invention, the alkali metal alkoxide is preferably polystyrene-butoxide and an alkali metal hydride is preferably sodium hydride.
An amine base is selected from 1,8-diazabicyclo [4.3.0] non-5-ene (DBU), N, N-djisopropylethylamine, trilamylamine and iaryrylamine.
Ammonium salts of an inorganic acid include ammonium chloride, ammonium bromide, ammonium sulfate, ammonium phosphate, and ammonium nitrate.
Salts of inorganic acid include hydrochlorides, bromhydraphos, sulfates, hydroiodides and nitrates.
DETAILED DESCRIPTION OF THE INVENTION
The Reaction scheme 1 of the present invention illustrates the process of preparing 6-chloro-5- hemifumaraio. { 2,6-difluoro-4- [3- (methylamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1 S) -2,2,2-lrifluoro-1-methyl-ethyl] -pyrimidin-4-amine (I).
SCHEME 1
stage b
O) According to Scheme 1, step a, pyrazine-2-carbonylryl 1 is reacted in an alcohol solvent, preferably meityl alcohol in the presence of a base A selected from an alkali metal hydroxide or an alkali metal alkoxide , preferably sodium methoxide and more preferably sodium meioxide in an amount of about 1: 1 (mol / mol) in a range of about 20-40 ° C, preferably in the range of about 28-32 ° C for about 3-12 h, preferably in the range of 4-5 h, followed by treatment with an ammonium salt of an inorganic acid, for example, ammonium chloride for a period of about 16-48 h, preferably in the range of 20 hr. -24 to about 25 ° C or optionally for about 3-6 h to reflux. Methyl f-bulyl ether was added to the mixture and it was stirred for approximately 15 to 30 min and the solid formed was collected by filtration, washed with methyl f-butyl ether and then dried at approximately 40 ° C under vacuum to give hydrochloride of pyrazine-2-carboxamidine 2 as a white solid. Optionally, after refluxing the volatiles are removed to a residue and the residue is crystallized from ethanol-diethyl ether and the product is collected. In particular, the described procedure has higher performances as compared to the technique (S. Kushner et al, J. Amer. Chem. Soc, 74, 3617-3621 (1952) and published patent application US2005-0075357A1).
In scheme 1, step b, diester 3 of 2- (2,4,6-lrifluoro-phenyl) -malonic acid in doh of R1 and R2 are independent alkyl of 1 to 3 carbon atoms, preferably ethyl is reacted with hydrochloride of pyrazine-2-carboxamidine 2 in a ratio of about 1: 1 to 1: 1.5 mol / mol, preferably in the range of 1: 1.2 mol / mol in the presence of a base selected from an alkali metal hydroxide, carbonate alkali metal and an alkali metal hydride, or optionally an amine base selected from 1,8-diazabicyclo [4.3.0] non-5-ene (DBU), NN-diisopropylethylamine and eryrylamine in an aprroic solvent to form 2-pyrazine -2-yl-5- (2,4,6-ylfluoro-phenyl) -pyrimidine-4,6-diol 4. In a preferred embodiment of the base is a carbonate of alkali metal. In a more preferred embodiment, the base is poahaium carbonate in a ratio of 1: 1.2 mol / mol in diglyme or alternatively in a ratio of 1: 2 mol / mol for DBU in 1-meityl-2-pyrrolidinone (NMP). In a preferred embodiment the aprroic solvent is selected from N, N-dimethylylformamide, 1-meityl-2-pyrrolidinone (NMP) and 2-meioxtethyl ether (diglyme), more preferably diglyme and NMP, in a temperature range of about 80 °. at 180 ° C, preferably 120-140 ° C in diglyme with potassium carbonate and preferably about 95 ° C in NMP with DBU for about 3-10 h, preferably in the range of 4-6 h to form the 2-pyraz N-2-yl-5- (2,4,6-lrifluoro-phenyl) -pyrimidine-4,6-diol 4. The reaction mixture in diglyme with potassium carbonate is cooled to 25-30 ° C, water is added, followed by the addition of acetic acid, followed by aqueous HCl, or other mineral acid at a pH of about 1-3, preferably about 2-3 to form a solid which is filtered, washed with water and optionally lava with isopropyl alcohol respectively. The solid is dried at approximately 60 ° C / 0-10 mmHg for about 24 hr to give 2-pyrazin-2-yl-5- (2,4,6-l-fluoro-feriyl) -pyrimidine-4,6- diol 4 as a solid that is used directly for the next layer.
The reaction mixture under the alternative conditions of the DBU amine base with the aprolytic NMP solution is cooled to approximately 50 ° C and aqueous HCl is added to form a solid which is filtered and washed with water. The solid is dried at about 60 ° C / 0-10 mmHg for about 24 h to give 2-pyrazin-2-yl-5- (2,4,6-trifluoro-phenyl) -pyrimidine-4,6-diol 4 as a solid that is used directly for the next stage.
According to scheme 1, step c, for a mixture of 2-pyrazin-2-yl-5- (2,4,6-trifluoro-phenyl) -pyrimidine-4,6-diol 4 in an aprotic solvent preferably toluene (g / ml) preferably 5-15 parts, more preferably in 5-10 parts, more preferably in 7 parts, lenimamenle is added in approximately 10-15 ° C, phosphorus oxychloride. Following the addition of the phosphorus oxychloride, N, N-diisopropylethylamine in a molar ratio of approximately 1: 1 to 1: 5, preferably in the range of 1: 4 is added lenimane at approximately 10-15 ° C and the mixture it is heated to reflux for about 6 to 24 h, preferably about 6 h. The volatiles are removed by distillation to a residue which is further distilled with toluene, preferably twice to produce a sterile residue. The additional residue is dissolved in a solvent selected from ethyl acetate, dichloromethane and toluene, preferably ethyl acetate, then parity when it is poured into water while maintaining the temperature between about 5-15 ° C. The solvent layer is separated, washed with water, it is dried over sodium sulfate and filtered through a filter pad fal as diaímaceous earths or through magnesium hydroxide silica and most of the volatiles removed to a residue to which hepno is added forming a precipitated prod. The production of precipitated 4,6-dichloro-2-pyrazin-2-yl-5- (2,4,6-trifluoro-phenyl) -pyrimidine 5 is collected and has a purity of > 95% as shown by liquid pressure chromatography (HPLC). Additionally, 4,6-dichloro-2-pyrazin-2-yl-5- (2,4,6-trifluoro-phenyl) -pyrimidine 5 is formed and isolated without chromatography.
In scheme 1, step d, the solution of 4,6-dichloro-2-pyrazin-2-yl-5- (2,4,6-trifluoro-phenyl) -pyrimidine 5 in an aprotic solvent, preferably 1 -methyl-2-pyrrolidinone (NMP) in a ratio of 1-10 mL NMP / g of 4,6-dichloro-2-pyrazin-2-yl-5- (2,4,6-lrifluoro-phenyl) -pyrimidine 5, preferably 1-5 mL NMP / g of 4,6-dichloro-2-pyrazin-2-yl-5- (2,4,6-urea) pyrimidine 5, more preferably 1 mL NMP / g of 4,6-dichloro-2-yl) irazin-2-yl-5- (2,4,6-trifluoro-phenyl) -pyrimidine 5 is added (S) -2,2,2-trifluoro-1 -melil-eti-amine 6 in a mole ratio of 4,6-dichloro-2-pyrrazin-2-yl-5- (2,4,6-trifluoro-phenyl) -pipmidine 5 a (S) - 2,2,2-lrifluoro-1-meityl-eylamine 6 is 1: 2-1: 3 (mol / mol) preferably 1: 2.5 (mol / mol) with stirring for 24-48 h, preferably at about 24 hours in a range of about 90 to 125 ° C, more preferably to about 110 ° C for about 24 hours. In an optional embodiment of the invention, the reaction is sealed to prevent the loss of (S) -2,2,2-trifluoro-1-methyl-eylamine 6. The reaction mixture is diluted with isopropyl alcohol (IPA), IPA to NMP (V / V) lasts approximately 1: 1-1: 5 preferably approximately 1: 3, then agitated water is added at approximately 10-20 ° C in a ratio of NMP to water (v / v) of approximately 1: 1-1: 5 (v / v), preferably approximately 1: 3 (v / v) with approximately 30 minutes of additional agitation and collection, without the need for chromatography, the solid product, washed with water and dried to give e-chloro ^ -pyrazin-1-yl-N-IIS ^^^ - trifluoro-l-methylethylj-d ^ .a-trifluorophenyl) pyrimidin-4-amine 7. In a preferred embodiment of the invention, , 6-dichloro-2-pyrazin-2-yl-5- (2,4,6-trifluoro-phenyl) -pyrimidine in 1-methyl-2-pyrrolidinone (NMP) is treated cop (S) -2, 2,2-Trifluoro-1-methyl-ethyllamine at about 110 ° C in about 24 hyl The reaction mixture is diluted with IPA, then water is added 1: 3 (v / v) slowly forming a precipitated product. The precipitated product is filtered, washed co? water, and dried to give a solid yield of 92%, which has an HPLC purity of 96% and an enantiomeric excess of >99% The product 6-chloro-2-pyrazin-2-yl-N - [(1 S) -2,2,2-trifluoro-1-methylethyl] -5- (2,4,6-trifluorophenyl) pyridinimide- 4-amine 7 is collected without the need for chromatography.
In Scheme 1, step e, to a solution of a base B selected from alkali metal alkoxide preferably p-lysium bromide or a suspension of alkali metal hydride preferably sodium hydride (60% in mineral oil) in an aprotic solvent preferably anhydrous lerahydrofuran (THF), optionally dimethisulfoxide (DMSO) is added in the form of an alcohol-amino-GO- (CH2) 3-NHCH3 amide at a temperature ranging from about 10-40 ° C, preferably at about 23 ° C for about 30 min. wherein the proportion of apolyl dissolve for amino alcohol is preferably about 5 mL THF / g of amino alcohol HO- (CH2) 3-NHCH3. A solution of 6-chloro-2-pyrazin-2-yl-N - [(1S) -2,2,2-trifluoro-1-methylethyl] -5- (2,4,6-trifluorophenyl) pyrim din-4-amine 7 in tetrahydrofuran, preferably in a ratio of THF to 6-chloro-2-pyrazin-2-yl-N - [(1 S) -2,2,2-if-trifluoro-1-? r? ethylethyl] -5- (2,4,6-trifluorophenyl) pyrimidin-4-amine 7 of about 2 mL of THF / g is added for about 10-30 min. The mixture is stirred at 23 ± 2 ° C for about 18-40 h, preferably about 24 h. The reaction mixture is stirred with cold water at about 5-15 ° C, preferably at about 10 ° C, at a ratio of water to 6-chloro-2-pyrazin-2-yl-N - [(1S) -2 , 2,2-lrifluoro-1-mellylethyl] -5- (2,4,6-trifluorophenol) pyrimidin-4-amine 7 of approximately 14 mL / g. The reaction mixture is extracted with acetone or ethyloluene and the organic phase is ethyl or toluene, preferably ethyl acetate is separated, washed with water and dried. In step f, a solution of fumaric acid in ethanol is added to the organic phase, preferably acetyl derivative in a ratio of 1: 1 (V V) to give the pharmaceutically acceptable acid-withdrawing salt that was collected. The geheral production is 80-90% with a purity of ~ 98% HPLC. The optional elements e and f can be combined in a single layer.
A pharmaceutical composition comprising 6-chloro-5 hemifumaraio is also provided by this invention. { 2,6-difluoro-4- [3- (methylamino) propoxy] phenyl} -2-pyr $? Zin-2-yl-N - [(1S) -2,2,2-ylfluoro-1-methyleryl] pyrimidin-4-amine in combination or combination with a pharmaceutically acceptable carrier. Additionally, the invention provides a method for treating, inhibiting the growth of, or eradicating a tumor in a mammal in need thereof, wherein said tumor is resistant to at least one chemotherapeutic agent, which comprises administering to said mammal an effective amount of 6-chloro-5 hemifumarate. { 2,6-difluoro-4- [3- (methylamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1S) -2,2,2-lrifluoro-1-melilel] lyrimidin-4-amine.
The effective dose of 6-chloro-5- hemifumarate. { 2,6-difluoro-4- [3- (methylamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1S) -2,2,2-trifluoro-1-melileiyl] pyrimidin-4-amine used may vary depending on the mode of administration and severity of the condition to be traced. However, the general satisfactory results are obtained when administered in amounts that range from about EYO to about 100 mg / kg of body weight per day. A preferred regimen for optimal results may be from about 1 mg to about 20 mg / kg of body weight per day and those dose units are employed in a total of about 70 mg to about 1400 mg of 6-chloro-5- hemifumarate. . { 2,6-difluoro-4- [3- (methylamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1 S) -2,2,2-trifluoro-1-methylethyl] pyrimidin-4-amine for a human subject of approximately 70 kg of body weight is administered in a period of 24 hours.
The dose regimen can be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may optionally be reduced as indicated by the requirements of the therapeutic situation.
A decidedly practical approach is the hemifumaraio of 6-chloro-5-. { 2,6-difluoro-4- [3- (methylamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1S) -2,2,2-ylfluoro-1-methylethyl] pyrimidin-4-amine may be administered in any convenient form such as oral, iniravenous, inramuscular or subcutaneous route .
The hemifumaralo of 6-chloro-5- 2,6-difluoro-4- [3- (melilamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1 S) -2,2,2-rifluoro-1-methylelyl] pyrimidin-4-amine can be administered orally, for example, with an inert diluent or with a carrier edible, or it can be included in gelatin capsules of soft or hard cover, or they can be compressed into tablets or they can be incorporated directly with the diet food. For oral lepraeuic administration, the hemifumaraio 6-chloro-5-. { 2,6-difluoro-4- [3- (methylamino) propoxy] phenyl} -2-p -razin-2-ylN - [(1S) -2,2,2-nifluoro-1-methylethyl] pyrimidin-4-amine may be incorporated with excipients and used in the form of ingestible tablets, tablets mouths, pills, capsules, elixirs, suspensions, syrups, glas and the like. Such compositions and preparations must contain at least 0.1% hemifumaralo 6-chloro-5-. { 2,6-difluoro-4- [3- (methylamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1S) -2,2,2-trifluoro-1-methylethyl] pyrimidin-4-amine. The percentage of compositions and preparations may, of course, be varied and may conveniently range from about 2% to about 60% of the weight of the unit. The amount of hemifumarate 6-chloro-5-. { 2,6-difluoro-4- [3- (methylamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1S) -2,2,2-trifluoro-1-methylethyl] pyrimidin-4-amine in such useful compositions is that a suitable dose can be obtained. Preferred compositions or preparations according to the present invention are prepared in such a way that an oral dosage unit form contains between 10 and 1000 mg of hemifumaraio 6-chloro-5-. { 2,6-difluoro-4- [3- (methylamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1S) -2,2,2-trifluoro-1-methyleryl] pyrimidin-4-amine.
The tablets, pills, pills, capsules and the like may also contain the following: a linker such as gum tragacanth, acacia, corn starch or gelatin; excipients such as calcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium extract; A sweetening agent such as sucrose, lactose or saccharin can be added or a flavoring agent such as peppermint, oil of gaulíeria or cherry flavor. When the dosage unit form is the capsule, it may contain, in addition to the materials of the above type, a liquid carrier. Several other materials may be present as coatings or may modify the physical form of the dose unit. For example, the pill tablets or capsules may be covered with shellac, sugar or both. A syrup or elixir may contain 6-chloro-5 hemifumarate. { 2,6-difluoro-4- [3- (methylamino) propoxy] phenyl} -2-pyra? In-2-yl-N - [(1S) -2,2,2-trifluoro-1-methylethyl] pyrimidin-4-amine, sucrose, as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in the preparation of any form of dosage unit must be pharmaceutically pure and subsancially non-toxic in the amounts used.
The hemifumaraío of 6-Chloro-5-. { 2,6-difluoro-4- [3- (methylamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1S) -2,2,2-lrifluoro-1-melleyleyl] pyrimidine-4-amine may also be administered parenterally or intraperitoneally. The solutions or dispersions can be prepared in water by mixing suitably with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures of these in oil. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or sterile dispersions and powders for the exten- sive preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid so that there is easy reach of the syringe. This must be stable under the conditions or manufacture and storage and must be prepared with the action of the microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
Invenous administration is a preferred form of administration of 6-chloro-5 hemifumarate. { 2,6-D-fluoro-4- [3- (mlamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1S) -2,2,2-lrifluoro-1-mephyll] pyrimidin-4-amine. For invarvenous administration examples of suitable non-limiting carriers include physiological saline, bacleriosltatic water, Cremofor ELTM (BASF, Parsippany, N.J.) or buffered saline (PBS). The composition must be sterile and must be fluid so that there is easy reach of the syringe. It must be stable under conditions of manufacture and storage and must be preserved with the action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, nol, polyol (for example, glycerol, propylene glycol, and liquid polylene glycol, and the like), and suitable mixtures thereof. The prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as manilol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be avoided by including in the composition an agent that breaks down the absorption, for example, monosleaing of aluminum and gelatin.
The following examples are presented to illustrate certain embodiments of the present invention, but should not be construed as limiting the scope of this invention.
Example 1
Pyrazine-2-earboxamidine hydrochloride
To a solution of sodium meloxide (NaOCH3) (51.4 g, 0.952 mol) in melanol (3800 ml) is added cyanopyridine (1.00 KG, 9.53 mol) at room temperature. The mixture was heated to 30 ° C and stirred for 6 h. The mixture is cooled to 25 ° C followed by the addition of ammonium chloride (NH CI) (572 g, 10.5 mol). The reaction mixture is stirred for 22 h and ml-butyl r (4000 mL) is added and the mixture is stirred for 15 min to form a solid. The solid is filtered and washed with ml-butyl r (2k1000mL) then dried at 40 ° C / 0 -10 mmHg for 17 h to give the white solid product (1435 g) in 95% yield in 95% yield. HPLC purity. 1 H NMR (DMSO-De): d 9.7 (bs, 3 H), 9.49 (d, 1 H, J = 1.5 Hz), 9.04 (m, 1 H), 8.93 (1, 1 H, J = 1.5 Hz).
Example 2
2 ^ pyrazin-2-l-5- (2.4.6Jr¡flüoro-feni?) - pirimiain-4 • dici
A mixture of dil ester of 2- (2,4,6-trifluoro-phenyl) -malonic acid (200 g, 0.67 mol), pyrazine-2-carboxamidine hydrochloride (132 g, 0.828 mol) and potassium carbonate ( 114 g, 0.828 mol) in 2-mloxyelyl r (diglyme, 600 mL) is heated to 120 ° C and stirred for 4 h, then heated to 140 ° C and stirred for an additional 2 h. The mixture is cooled to ambient temperature (25-30 ° C) and water (1200 mL) is added for approximately 15 min. Acetic acid (50 g) is added and for 15 min. and 82 ml of HCl is added for 15 minutes and the mixture is agitated for approximately 15 minutes at ambient temperature at a pH of about 2-3. The solid is filtered and washed with water (2x400 mL) and isopropyl alcohol (IPA) (400 mL) and dried at 60 ° C / 1 OmmHg for 24 h to give a white solid yield 69% with 95% purity HO 1 H NMR (DMSO-d 6): d 12.45 (bs, 2H), 9.41 (s, 1 H), 8.91 (s, 1 H), 8.46 (m, 1 H), 7.23 (m, 2H).
Example 3
2-pyrazin-2-yl-5- (2,4,6-trifluoro-phenin-pyrimidine-4-diol)
1,8-Diazabicyclo [5.4.0] undec-7-ene (DBU, 14.4 g, 0.0944 mol) is added to a mixture of dil ester of 2- (2,4,6-triflorophenyl) malonic acid (14.3 g. 0.0472 mol) and pyrazine-2-carboxamidine hydrochloride (9.00 g, 0.0566 mol) in 1-ml-2-pyrrolidinone solvent (NMP, 50 mL). The resulting mixture was heated to 95 ° C while stirring for 7 hours. The mixture is cooled to approximately 50 ° C and then HCl solution (37%) is added dropwise., 5.6 mL), maintaining the temperature below 50 ° O The mixture is then allowed to cool to approximately 20 ° O Water (50 mL) is added in drop form for 20 min., Resulting in the product precipitating as a solid of the mixture (20-25 ° C). The solid was collected by filtration, and the product cake was washed with water (300 mL). The solid is allowed to dry at 23 ° C under atmospheric pressure for 24 hours, giving a yellow solid (11.5 g, 97% HPLC area, 76% yield) 1 H NMR (DMSO-d6): d 12.45 (bs, 2H ), 9.41 (s, 1 H), 8.91 (s, 1 H),
8.46 (m, 1 H), 7.23 (m, 2H).
Example 4
4,8-dichloro-2-pyrazin-2-yl-5 2A6-trifluoro-phenyl) -pyoimidine
To a mixture of 2-pyrazin-2-yl-5- (2,416-trifluoro-phenyl) -pyrimidine-4,6-diol (228 g, 0.713 mol) in toluene (1600 mL) is added phosphorus oxychloride ( 682 mL) at 10-15 ° C for 30 min. The mixture is cooled to 10 ° C and added in the form of diisopropylethylamine gofa (367 g, 2.85 mol) for 30 min and then the mixture is heated to reflux for about 6 h. The solvent is removed by distillation to a residue and the residue is stripped with toluene (2 × 500 mL). The residue is then dissolved in ethyl acetate (EtOAc) (1000 mL) and the mixture is poured into water (3000 g) while the temperature is maintained at 5-15 ° C. The reaction mixture is filtered through a diafomaceous iron pad. The organic phase is separated and the aqueous phase is extracted with EtOAc (1000 mL). The combined organic phase is washed with water (1000 mL), dried over Na2SO and filtered through a pad of water magnesium silicate. The volatiles are removed by distillation to dryness to give a solid (234 g, 92%, 95% HPLC area purity). 1 H NMR (DMSO-D 6): 9.56 (d, 1H, J = 0.9 Hz), 8.93 (m, 2H), 7.60 (m, 2H).
Example 5
ß-chloro-2-pyrazin-2-H-N-r (1S) -2.2.2-trifluoro-1-methylethyl-1-S- (2,4-trifluorophenyl) pyrimidin-4-amine
It is added to 4,6-dichloro-2-pyrazin-2-yl-5- (2,4,6-lrifluoro-phenyl) -pyrimidine (40 g, 0.H2 mol) in 1-meityl-2-pyrrolidinone ( 40 mL) (S) -2,2,2-ír-fluoro-1-meityl-ethylamine (31.6 g, 0.28 mol). The mixture is sealed and heated at 110 ° C and agitated for 24 h. The reaction mixture is cooled to ambient temperature and diluted with IPA (120 mL) and water is added slowly (120 mL) for 30 minutes to form a solid. The solid is filtered and washed with water (2x60 mL) to give 6-chloro-2-pyrazin-2-yl-N - [(1S) -2,2,2-trifluoro-1-methyleryl] -5- ( 2,4,6-l-trifluorophenyl) pyrimidin-4-amine in 84% yield and has 98% HPLC purity and an enantiomeric excess of > 99% 1 H NMR (DMSO-Dβ): 9.58 (d, 1H, J = 1.1 Hz), 8.85 (m, 2H), 7.72 (d, 1H, J = 8.8 Hz), 7.49 (m, 2H), 5.52 (m, 1H), 1.35 (d, 3H, J = 7.0 Hz).
Example 6
6-Chloro-5 2,6-difluoro-4-r3-fmethylaminolpropoxyphenyl > -2-pyrazin-2-yl-N-rfaS-2.2.2- trifluoro-1-methylethypyrimidin-4-amine and its hemifumarat® salt
To a solution of polasium l-butoxide (KOf-Bu) (27.1 g, 0.242 mol) in anhydrous lelhydrofuran (THF) (175 mL) is added 3-meylamino-propan-1-ol (18.5 g, 0.208 mol) to ambient temperature (23 + 2 ° C) in the form of a drop for 30 min. The mixture is agitated for 30 min followed by the addition of a solution of 6-chloro-2-pyrazin-2-yl-N - [(1 S) -2,2,2-trifluoro-1-methylene] -5- (2,4,6-nifluorophenyl) pyrimidin-4-amine (35.0 g, 0.0806 mol) in THF (70 mL) for 15 min. The mixture was stirred for 23 h. The reaction mixture is added to cold water (245 mL) (5-15 ° C) while the temperature is maintained at 5-15 ° C. The reaction mixture is extracted with EOAc (250 mL). The organic phase is washed with 10% aqueous sodium chloride solution (NaCl) and dried over magnesium sulfate (MgSO4) and filtered to give a filtrate containing 6-chloro-5-. { 2,6-difluoro-4- [3- (methylamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1 S) -2,2,2-nifluoro-1-methyleryl] pyrimidin-4-amine.
A solution of fumaric acid (4.67 g, 0.0403 mol) in elanol (250 mL) is slowly added to the filtrate and the mixture is agitated for 1 h. The solid product is filtered, washed with ethanol (3x70 mL) and dried at 25 ° C / 10 mmHg for 20 h to give a white solid with 80% yield and > 99% purity area HPLC and 99% ee.
NMR indicates that the ratio of acid to base is 0.5 to 1. 1 H NMR (DMSO-D6): d 9.57 (d, 1H, J = 1.2 Hz), 8.84 (m, 2H), 7.71 (d, 1H, J = 8.8 Hz), 6.96 (m, 2H), 6.40 (s, 1H, proton on double bond of fumaric acid), 5.53 (m, 1H), 4.16 (l, 2H, J = 6J), 2.85 (l, 2H , J = 7.1), 2.45 (s, 3H), 2.04 (m, 2H), 1.37 (d, J = 7.1, 3H).
Claims (1)
- CLAIMS Hemifumaraío of 6-Chloro-5-. { 2,6-difluoro-4- [3- (meitylamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1 S) -2,2,2-l-trifluoro-1-methyl-yl] pyrimidin-4-amine. A process for the preparation of hemifumaralo of 6-chloro-5-. { 2,6-difluoro-4- [3- (methylamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1 S) -2,2,2-trifluoro-1-methyl-yl-pyrimidin-4-amine; whose process includes: react 6-chloro-5-. { 2,6-difluoro-4- [3- (methylamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1 S) -2,2,2-lrifluoro-1-methyl-leyl] pyrimidin-4-amine of the formula in an aprotic solvent with fumaric acid in an alcohol to give hemifumarate. A process for the preparation of hemifumaraío 6-chloro-5-. { 2,6-difluoro-4- [3- (methylamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1 S) -2,2,2-trifluoro-1-methyleryl] pyrimidin-4-amine; whose process includes the stages of: to. reacting a pyrazine-2-carbonitrile with a base A in an alcohol and irrala with an ammonium salt of an inorganic acid to give an inorganic pyrazine-2-carboxamidine acid salt; b. reacting the inorganic pyrazine-2-carboxamidine acid salt with a malonic acid ester of the formula where R1 and R2 are independently Ci-C alkyl in an aprolic solvent in the presence of a base and acidify to obtain 2-pyrazin-2-yl-5- (2,4,6-trifluoro-phenyl) -pyrimidine-4, 6-diol of the formula c. chlorinating 2-pyrazin-2-yl-5- (2,4,6-trifluoro-phenyl) -pyrimidine-4,6-diol with phosphorus oxychloride (POCI3) as a chlorination reagent in the presence of an amine base in an aprotic solvent to give 4,6-dichloro-2-pyrazin-2-yl-5- (2,4,6-lrifluoro-phenyl) -pyrimidine of the formula d. reacting 4,6-dichloro-2-pyrazin-2-yl-5- (2,4,6-lrifluoro-phenyl) -pyrimidine with (S) -2,2,2-trifluoro-1-methyl-ethylamine which has the formula in an aprolic solvent to give 6-chloro-2-pyrazin-2-yl-N - [(1S) -2,2,2-lrifluoro-1-methylethyl] -5- (2,4,6-trifluorophenyl) p Rimidin-4-amine that has the formula and. reacting 3-methylamino-propan-1-ol with base B in an aprotic solvent and add 6-chloro-2-pyrazin-2-yl-N - [(1S) -2,2,2-trifluoro-1-methyleryl ] -5- (2,4,6-trifluorophenyl) pyrimidin-4-amine to give 6-chloro-5-. { 2,6-difluoro-4- [3- (methylamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1S) -2,2,2-ylfluoro-1-melilethyl] pyrimidin-4-amine of the formula ; Y F. react 6-chloro-5-. { 2,6-difluoro-4- [3- (methylamino) propoxy] phenyl} - 2-pyrazin-2-yl-N - [(1S) -2,2,2-ylfluoro-1-methyl-yl] pyrimidin-4-amine in an aprotic solvent with fumaric acid in an alcohol to give said hemifumaraio. 4: A process according to claim 3, wherein the alcohol is meianol. 5, A process according to claim 3 or 4, wherein in the step the ammonium salt of an inorganic acid is ammonium chloride. 6, A process according to claim 3, 4, or 5, wherein the step a comprises additionally the dilution with melil t-butyl ether and collecting the salt of inorganic pyrazine-2-carboxamidine acid. 7. A process according to claim 3, 4, 5, or 6, wherein the elapa to the base A is selected from an alkali metal alkoxide or an alkali metal hydroxide. 8. A process according to claim 7, wherein the base A is an alkali metal alkoxide. 9. A process according to claim 8, wherein the alkali metal alkoxide is sodium meioxide in a mole ratio of approximately 1: 1 with pyrazine-2-carbonyiyl. 10. A process according to claim 9, wherein the layer is brought to a lemoperity of about 20-40 ° C for about 3-12 h. 11. A process according to any one of claims 3 to 10, wherein the step is carried out at an approximate time of 25 ° C for about 16-48 h and adding methyl io-butyl ether. 12- A process according to any one of claims 3 to 11, wherein in step b the proportion of inorganic pyrazine-2-carboxamide salt salt of malonic acid ester of the formula is about 1: 1 (mol / mol) to about 1: 1.5 (mol / mol). 13. A process according to any one of claims 3 to 12, wherein in step b the base is selected from an alkali metal hydroxide, alkali metal carbonate and alkali metal hydride or an amine base selected from 1, 8-diazabicyclo [4.3.0] non-5-ene (DBU), N, N-diisopropylethylamine, and triethylamine. 14. A process according to claim 12, wherein the proportion of inorganic pyrazine-2-carboxamide salt salt to malonic acid ester of the formula is approximately 1: 1.2 (mol / mol). 15. A process according to claim 13, wherein the base is a alkali metal carbonate. 1 $. A process according to claim 15, wherein the base is pofasium carbonate. 17. A process according to any one of claims 3 to 16, wherein at appendage B the aprroic solvent is selected from N, N-dimethylformamide, 1-methyl-2-pyrrolidinone (NMP) and 2-meloxyethyl ether (diglyme). . 18. A process according to any one of claims 3 to 16, wherein in step b the aprolic solvent is 2-meloxyethyl ether (diglyme) and the base is potassium carbonate. 19. A process according to any one of claims 3 to 16, wherein in step b the aprotic solvent is 1-methyl-2-pyrrolinedinone (NMP) and the base is DBU. 20. A process according to any one of claims 3 to 19, in I wherein in step b the proportion of inorganic pyrazine-2-carboxamide salt salt to malonic acid ester is of the formula is 1: 1.2, where the base is DBU in NMP. 21. A process according to any one of claims 3 to 20, wherein step b further comprises adjusting the pH to about 1 to 3. 22. A process according to claim 21, wherein the pH is adjusted with acetic acid followed by a mineral acid. 23. A process of any one of claims 3 to 22, wherein in the elapa b the reaction is carried out at a temperature of about 80 ° C to about 180 ° C in diglyme and the base is potassium carbonate. 24. A process according to any one of claims 3 to 22, wherein in step b the reaction lemma is at about 95 ° C in NMP with the base DBU. 25. A process according to any one of claims 3 to 24, wherein in step c the aprroic solvent is toluene. 26. A process according to claim 25, wherein the toluene is approximately 5-15 mL per gram of 2-pyrazin-2-yl-5- (2,4,6-urea) pyrimidine-4,6 -diol. 27. A process according to any one of claims 3 to 24, wherein in step c the molar ratio of phosphorus oxychloride (POCI3) to N, N-diisopropylethylamine is from about 1: 1 to about 1: 5. 2ß. A process according to claim 27, wherein in the molar ratio of POCI3 to N, N-diisopropylethyl amine is about 1: 4. 29. A process according to any one of claims 3 to 28, wherein in step c the mixture is heated to reflux for about 6 to 24 h. 30. A process according to any one of claims 3 to 24, wherein in step d the aprotic solvent is 1-methyl-2-pyrrolidinone (NMP). 31. A process according to claim 30, wherein the ratio of 1 (ml) per g of 4,6-dichloro-2-pyrazin-2-yl-5- (2,4,6-trifluorophenyl) -pyrimidine is about 1 -10 ml per g. 32. A process according to claim 31, wherein the radio ratio NMP (ml) per g of 4,6-dichloro-2-pyrazin-2-yl-5- (2,4,6-trifluorophenyl) -pyrimidine is i; of about 1-5 ml / g. i 33. A process according to any one of claims 3 to 32, in | where in step d the proportion of 4,6-dichloro-2-pyrazin-2-yl-5- (2,4,6-trifluorophenyl) -pyrimidine to (S) -2,2,2-trifluoro-1- methyl-ethylamine is approximately 1: 2-1: 3. 34. A process according to claim 33, wherein the ratio of 4,6-, d-chloro-2-pyrazin-2-yl-5- (2,4,6-trifluorophenyl) -pyrimidine to (S) -2 , 2,2-trifluoro-1-methyl-ethylamine is about 1: 2.5 and the additional step comprises heating at about 90 ° C to about 125 ° C for about 24-48 h. 35. A process according to any one of claims 3 to 34, wherein in step d is carried out in a sealed system. 36. A process according to any one of claims 3 to 35, wherein in step d the mixture is poured into water at about 10-20 ° C. | in a ratio of NMP to water (v / v) is about 1: 1-1: 5. 37. A process according to claim 36, wherein the ratio of NMP to water is about 1: 2 (v / v). 38. A process according to any one of claims 3 to 37, wherein in the base and base B is an alkali metal alkoxide. 39. A process according to claim 38, wherein the melal alkoxide! Alkali is potassium iobuoxide. 40. A process according to any one of claims 3 to 39, wherein the aprotic solvent is telhydrofuran anhydrous (THF) or dimethylsulfoxide (DMSO). 41. A process according to any one of claims 2 to 40, wherein the alcohol is ethyl alcohol and the alcohol is ethyl alcohol. 42. A process for the preparation of hemifumaraío 6-chloro-5-. { 2,6-difluoro-4- [3- (methylamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1S) -2,2,2-lrifluoro-1-methylethyl] pyrimidin-4-amine; whose process includes the stages of: to. reacting pyrazine-2-carbonyiril with sodium meioxide in meilic and irraral alcohol with ammonium chloride to produce pyrazine-2-carboxamidine hydrochloride; b. reacting pyrazine-2-carboxamidine hydrochloride with diethyl ester of 2- (2,4,6-if-chlorophenyl) malonic acid of the formula in diglyme in the presence of potassium carbonate and acidify to obtain 2-pyrazin-2-yl-5- (2,4,6-trifluoro-phenyl) -pyrimidine-4,6-diol of the formula P c. halogenate 2-pyrazin-2-yl-5- (2,4,6-trifluoro-phenyl) -pyrimidine-4,6-diol with phosphorus oxychloride in the presence of N, N-diisopropyleflamine in toluene to obtain 4,6-dichloro-2-pyrazin-2-yl-5- (2,4,6-trifluoro-phenyl) -pyrimidine of the formula d. react the compound 4,6-dichloro-2-pyrazin-2-yl-5- (2,4,6-trifluoro-phenyl) -pyrimidine with (S) -2,2,2-trifluoro-1-methyl l-elylamine which is the formula in 1-methyl-2-pyrrolidinone to obtain 6-chloro-2-pyrazin-2-yl-N - [(1 S) -2,2,2-trifluoro-1-methylethyl] -5- (2,4, 6-L-fluorophenyl) pyrimidin-4-amine of the formula and. reacting an aminoalcohol HO- (CH2) 3-NHCH3 with potassium l-butoxide in tetrahydrofuran and add 6-chloro-2-pyrazin-2-yl-N - [(1S) -2,2,2-trifluoro-1 -methylethyl] -5- (2,4,6-trifluorophenyl) pyrimidin-4-amine to obtain 6-chloro-5-. { 2,6-difluoro-4- [3- (meitylamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1S) -2,2,2-ylfluoro-1-methylethyl] pyrimidin-4-amine of the formula; and f. React 6-chloro-5-. { 2,6-difluoro-4- [3- (meitylamino) propoxy] phenyl} - 2-pyrazin-2-yl-N - [(1S) -2,2,2-trifluoro-1-meilylelyl] pyrimidin-4-amine in ethyl acetate with fumaric acid in ethyl alcohol to obtain said hemifumaraio. The process according to claim 42, wherein in step f the proportion of ethyl alcohol with ethyl alcohol is 1: 1 (v / v). A process for the preparation of hemifumaralo of 6-chloro-5-. { 2,6-difluoro-4- [3- (methylamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1S) -2,2,2-trifluoro-1-methylethyl] pyrimidin-4-amine. whose process includes the stages of: to. reacting an aminoalcohol HO- (CH2) 3-NHCH3 with potassium t-butoxide in teirahydrofuran and add 6-chloro-2-pyrazin-2-yl-N - [(1S) -2,2,2-trifluoro-1 -Meleyl] -5- (2,4,6-trifluorophenyl) pyrimidin-4-amine of the formula At room temperature to give 6-chloro-5-. { 2,6-difluoro-4- [3- (meitylamino) propoxy] phenyl} -2-p -razin-2-yl-N - [(1S) -2,2,2-trifluoro-1-methyleryl-3-pyrimidin-4-amine of the formula b. add a solution of fumaric acid in ethyl alcohol to a solution of 6-chloro-5-. { 2,6-difluoro-4- [3- (methylamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1 S) -2,2,2-trifluoro-1-methyleryl] pyrimidin-4-amine in ethyl acetate to give said hemifumarate; Y c. isolate said hemifumaraio. The hemifumaraío compound of 6-chloro-5-. { 2,6-difiuoro-4- [3- (meitylamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1S) -2,2,2-ylfluoro-1-methyleryl] pyrimidin-4-amine produced by the process comprising: reacting an aminoalcohol HO- (CH2) 3-NHCH3 with potassium iobuoxide in leirahydrofuran and add 6-chloro-2-pyrazin-2-yl-N - [(1S) -2,2,2-urea-1 -metilelyl] -5- (2,4,6-l-trifluorophenyl) pyrimidin-4-amine of the formula at room temperature to give 6-chloro-5-. { 2,6-difluoro-4- [3- (methylamino) propoxyJphenyl} -2-pyrazin-2-yl-N - [(1S) -2,2,2-trifluoro-1-methylethyl] pyrimidin-4-amine of the formula b. add a solution of fumaric acid in ethyl alcohol to a solution of 6-chloro-5-. { 2,6-difluoro-4- [3- (methylamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1S) -2,2,2-lrifluoro-1-mellylethyl] pyrimidin-4-amine in ethyl acetate to give said hemifumarate; Y i c. isolate said hemifumaralo. . A method of treating or inhibiting the growth of cancer tumor cells and associated diseases in a mammal by administering an effective amount of 6-chloro-5 hemifumarate. { 2,6-difluoro-4- [3- (methylamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1S) -2,2,2-trifluoro-1-methylethyl] pyrimidin-4-amine. . A pharmaceutical composition comprising an effective amount of 6-chloro-5 hemifumarate. { 2,6-difluoro-4- [3- (methylamino) propoxy] phenyl} -2-pyrazin-2-yl-N - [(1S) -2,2,2-lrifluoro-1-melilethyl] pyrimidin-4-amine with a pharmaceutically acceptable carrier i.
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| WO2017181974A1 (en) * | 2016-04-20 | 2017-10-26 | 苏州苏领生物医药有限公司 | Five-membered heterocyclic compound, preparation method therefor, pharmaceutical composition and use |
| WO2019169111A1 (en) | 2018-03-02 | 2019-09-06 | The Trustees Of The University Of Pennsylvania | [1,2,4]triazolo[1,5-a]pyrimidine compounds and use in stabilizing microtubules |
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| CA2610416A1 (en) | 2006-12-28 |
| TW200716613A (en) | 2007-05-01 |
| BRPI0612145A2 (en) | 2010-10-19 |
| JP2008543838A (en) | 2008-12-04 |
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| AR054392A1 (en) | 2007-06-20 |
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