JP2006503906A5 - - Google Patents
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- Publication number
- JP2006503906A5 JP2006503906A5 JP2005501216A JP2005501216A JP2006503906A5 JP 2006503906 A5 JP2006503906 A5 JP 2006503906A5 JP 2005501216 A JP2005501216 A JP 2005501216A JP 2005501216 A JP2005501216 A JP 2005501216A JP 2006503906 A5 JP2006503906 A5 JP 2006503906A5
- Authority
- JP
- Japan
- Prior art keywords
- hydroxy
- thio
- amino
- methylethyl
- alkyl
- 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.)
- Granted
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- 125000000217 alkyl group Chemical group 0.000 claims description 30
- 150000001875 compounds Chemical class 0.000 claims description 28
- 150000002148 esters Chemical class 0.000 claims description 28
- 238000001727 in vivo Methods 0.000 claims description 26
- -1 hydroxy, amino Chemical group 0.000 claims description 25
- 125000001424 substituent group Chemical group 0.000 claims description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 5
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- IAYSDKUKIIYRRA-UHFFFAOYSA-N 1-(isocyanatomethylsulfonyl)-4-methylbenzene Chemical compound CC1=CC=C(S(=O)(=O)CN=C=O)C=C1 IAYSDKUKIIYRRA-UHFFFAOYSA-N 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims 23
- 125000005843 halogen group Chemical group 0.000 claims 18
- 239000012453 solvate Substances 0.000 claims 18
- 229910052739 hydrogen Inorganic materials 0.000 claims 12
- 239000001257 hydrogen Substances 0.000 claims 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims 7
- 239000003814 drug Substances 0.000 claims 7
- 125000001072 heteroaryl group Chemical group 0.000 claims 7
- 150000002431 hydrogen Chemical class 0.000 claims 7
- 239000008194 pharmaceutical composition Substances 0.000 claims 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 6
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 5
- 125000001153 fluoro group Chemical group F* 0.000 claims 5
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims 4
- 206010028980 Neoplasm Diseases 0.000 claims 4
- 208000001132 Osteoporosis Diseases 0.000 claims 4
- 201000004681 Psoriasis Diseases 0.000 claims 4
- 206010039085 Rhinitis allergic Diseases 0.000 claims 4
- 125000003545 alkoxy group Chemical group 0.000 claims 4
- 201000010105 allergic rhinitis Diseases 0.000 claims 4
- 208000006673 asthma Diseases 0.000 claims 4
- 201000011510 cancer Diseases 0.000 claims 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 4
- 201000008482 osteoarthritis Diseases 0.000 claims 4
- 239000000651 prodrug Substances 0.000 claims 4
- 229940002612 prodrug Drugs 0.000 claims 4
- 125000006239 protecting group Chemical group 0.000 claims 4
- 206010039073 rheumatoid arthritis Diseases 0.000 claims 4
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims 3
- 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 claims 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 3
- 125000004452 carbocyclyl group Chemical group 0.000 claims 3
- 238000002648 combination therapy Methods 0.000 claims 3
- 238000004519 manufacturing process Methods 0.000 claims 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims 2
- 125000005213 alkyl heteroaryl group Chemical group 0.000 claims 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 2
- 229910052736 halogen Inorganic materials 0.000 claims 2
- 208000002551 irritable bowel syndrome Diseases 0.000 claims 2
- 238000000034 method Methods 0.000 claims 2
- 229910052760 oxygen Inorganic materials 0.000 claims 2
- 239000008177 pharmaceutical agent Substances 0.000 claims 2
- 238000006467 substitution reaction Methods 0.000 claims 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- XWBYCFHOAKBXGL-MRVPVSSYSA-N 2-[(2,3-difluorophenyl)methylsulfanyl]-4-[[(2R)-1-hydroxypropan-2-yl]amino]-5-(5-methyl-1,2,4-oxadiazol-3-yl)-1H-pyrimidin-6-one Chemical compound N=1C(O)=C(C=2N=C(C)ON=2)C(N[C@@H](CO)C)=NC=1SCC1=CC=CC(F)=C1F XWBYCFHOAKBXGL-MRVPVSSYSA-N 0.000 claims 1
- UEGHVVUVMNKAPR-LLVKDONJSA-N 2-[(2,3-difluorophenyl)methylsulfanyl]-5-[2-(dimethylamino)ethylsulfanyl]-6-[[(2r)-1-hydroxypropan-2-yl]amino]-1h-pyrimidin-4-one Chemical compound OC1=C(SCCN(C)C)C(N[C@@H](CO)C)=NC(SCC=2C(=C(F)C=CC=2)F)=N1 UEGHVVUVMNKAPR-LLVKDONJSA-N 0.000 claims 1
- VUQQMRUDKKDPKO-SSDOTTSWSA-N 2-[(2,3-difluorophenyl)methylsulfanyl]-5-fluoro-6-[[(2r)-1-hydroxypropan-2-yl]amino]-1h-pyrimidin-4-one Chemical compound OC1=C(F)C(N[C@@H](CO)C)=NC(SCC=2C(=C(F)C=CC=2)F)=N1 VUQQMRUDKKDPKO-SSDOTTSWSA-N 0.000 claims 1
- HMGXLMHKWCLGAW-MRVPVSSYSA-N 2-[(2,3-difluorophenyl)methylsulfanyl]-6-[[(1r)-1,2-dihydroxyethyl]amino]-4-oxo-1h-pyrimidine-5-carboxamide Chemical compound N1=C(N[C@H](O)CO)C(C(=O)N)=C(O)N=C1SCC1=CC=CC(F)=C1F HMGXLMHKWCLGAW-MRVPVSSYSA-N 0.000 claims 1
- BDEVPJHJXCRSII-SNVBAGLBSA-N 2-[(2,3-difluorophenyl)methylsulfanyl]-6-[[(1r)-1,2-dihydroxyethyl]amino]-n,n-dimethyl-4-oxo-1h-pyrimidine-5-carboxamide Chemical compound N1=C(N[C@H](O)CO)C(C(=O)N(C)C)=C(O)N=C1SCC1=CC=CC(F)=C1F BDEVPJHJXCRSII-SNVBAGLBSA-N 0.000 claims 1
- CFZNGUJBYNJOOA-SECBINFHSA-N 2-[(2,3-difluorophenyl)methylsulfanyl]-6-[[(2r)-1-hydroxypropan-2-yl]amino]-5-(1,2,4-oxadiazol-3-ylmethylsulfanyl)-1h-pyrimidin-4-one Chemical compound N=1C(O)=C(SCC2=NOC=N2)C(N[C@@H](CO)C)=NC=1SCC1=CC=CC(F)=C1F CFZNGUJBYNJOOA-SECBINFHSA-N 0.000 claims 1
- DITRKEPVVGJVDD-MRVPVSSYSA-N 2-[(2,3-difluorophenyl)methylsulfanyl]-6-[[(2r)-1-hydroxypropan-2-yl]amino]-5-(1h-1,2,4-triazol-5-ylsulfanyl)-1h-pyrimidin-4-one Chemical compound N=1C(O)=C(SC2=NNC=N2)C(N[C@@H](CO)C)=NC=1SCC1=CC=CC(F)=C1F DITRKEPVVGJVDD-MRVPVSSYSA-N 0.000 claims 1
- PSEIUNUXNKDTGN-GFCCVEGCSA-N 2-[(2,3-difluorophenyl)methylsulfanyl]-6-[[(2r)-1-hydroxypropan-2-yl]amino]-5-(2-oxo-2-piperazin-1-ylethyl)sulfanyl-1h-pyrimidin-4-one Chemical compound N=1C(O)=C(SCC(=O)N2CCNCC2)C(N[C@@H](CO)C)=NC=1SCC1=CC=CC(F)=C1F PSEIUNUXNKDTGN-GFCCVEGCSA-N 0.000 claims 1
- KGZDVJCGRDNQTA-SECBINFHSA-N 2-[(2,3-difluorophenyl)methylsulfanyl]-6-[[(2r)-1-hydroxypropan-2-yl]amino]-5-[(4-methyl-1,2,4-triazol-3-yl)sulfanyl]-1h-pyrimidin-4-one Chemical compound N=1C(O)=C(SC=2N(C=NN=2)C)C(N[C@@H](CO)C)=NC=1SCC1=CC=CC(F)=C1F KGZDVJCGRDNQTA-SECBINFHSA-N 0.000 claims 1
- FPFSUADNTGBDJG-SECBINFHSA-N 2-[(2,3-difluorophenyl)methylsulfanyl]-6-[[(2r)-1-hydroxypropan-2-yl]amino]-5-[(4-methyl-1,3-oxazol-2-yl)sulfanyl]-1h-pyrimidin-4-one Chemical compound N=1C(O)=C(SC=2OC=C(C)N=2)C(N[C@@H](CO)C)=NC=1SCC1=CC=CC(F)=C1F FPFSUADNTGBDJG-SECBINFHSA-N 0.000 claims 1
- VEIJSJVGBDNKHZ-LLVKDONJSA-N 2-[(2,3-difluorophenyl)methylsulfanyl]-6-[[(2r)-1-hydroxypropan-2-yl]amino]-5-[(5-pyridin-4-yl-1,3,4-oxadiazol-2-yl)sulfanyl]-1h-pyrimidin-4-one Chemical compound N=1C(O)=C(SC=2OC(=NN=2)C=2C=CN=CC=2)C(N[C@@H](CO)C)=NC=1SCC1=CC=CC(F)=C1F VEIJSJVGBDNKHZ-LLVKDONJSA-N 0.000 claims 1
- QYKRJSGNMFASGF-SSDOTTSWSA-N 2-[(2,3-difluorophenyl)methylsulfanyl]-6-[[(2r)-1-hydroxypropan-2-yl]amino]-5-iodo-1h-pyrimidin-4-one Chemical compound OC1=C(I)C(N[C@@H](CO)C)=NC(SCC=2C(=C(F)C=CC=2)F)=N1 QYKRJSGNMFASGF-SSDOTTSWSA-N 0.000 claims 1
- YUJVPYIFRUBTMY-SSDOTTSWSA-N 2-[(2,3-difluorophenyl)methylsulfanyl]-6-[[(2r)-1-hydroxypropan-2-yl]amino]-5-nitro-1h-pyrimidin-4-one Chemical compound OC1=C([N+]([O-])=O)C(N[C@@H](CO)C)=NC(SCC=2C(=C(F)C=CC=2)F)=N1 YUJVPYIFRUBTMY-SSDOTTSWSA-N 0.000 claims 1
- AXHVOCIVCVOLNJ-LLVKDONJSA-N 2-[(2,3-difluorophenyl)methylsulfanyl]-6-[[(2r)-1-hydroxypropan-2-yl]amino]-5-pyridin-4-ylsulfanyl-1h-pyrimidin-4-one Chemical compound N=1C(O)=C(SC=2C=CN=CC=2)C(N[C@@H](CO)C)=NC=1SCC1=CC=CC(F)=C1F AXHVOCIVCVOLNJ-LLVKDONJSA-N 0.000 claims 1
- RFASCQZXYHDJES-QMMMGPOBSA-N 2-[(2,3-difluorophenyl)methylsulfanyl]-6-[[(2s)-1-hydroxypropan-2-yl]amino]-4-oxo-1h-pyrimidine-5-carbonitrile Chemical compound OC1=C(C#N)C(N[C@H](CO)C)=NC(SCC=2C(=C(F)C=CC=2)F)=N1 RFASCQZXYHDJES-QMMMGPOBSA-N 0.000 claims 1
- YEQQHYSCDKBPHY-SSDOTTSWSA-N 2-[(3,4-difluorophenyl)methylsulfanyl]-5-fluoro-6-[[(2r)-1-hydroxypropan-2-yl]amino]-1h-pyrimidin-4-one Chemical compound OC1=C(F)C(N[C@@H](CO)C)=NC(SCC=2C=C(F)C(F)=CC=2)=N1 YEQQHYSCDKBPHY-SSDOTTSWSA-N 0.000 claims 1
- JLNABWGKPPXTSN-MRVPVSSYSA-N 2-[(3-chlorophenyl)methylsulfanyl]-5-fluoro-6-[[(2r)-1-hydroxypropan-2-yl]amino]-1h-pyrimidin-4-one Chemical compound OC1=C(F)C(N[C@@H](CO)C)=NC(SCC=2C=C(Cl)C=CC=2)=N1 JLNABWGKPPXTSN-MRVPVSSYSA-N 0.000 claims 1
- LMNCIJFWDRQFOI-SECBINFHSA-N 2-[(3-chlorophenyl)methylsulfanyl]-6-[[(2r)-1-hydroxypropan-2-yl]amino]-1h-pyrimidin-4-one Chemical compound OC[C@@H](C)NC1=CC(O)=NC(SCC=2C=C(Cl)C=CC=2)=N1 LMNCIJFWDRQFOI-SECBINFHSA-N 0.000 claims 1
- HZGQRFWXSYBGII-SECBINFHSA-N 2-[(3-chlorophenyl)methylsulfanyl]-6-[[(2r)-1-hydroxypropan-2-yl]amino]-5-(1,3,4-thiadiazol-2-ylsulfanyl)-1h-pyrimidin-4-one Chemical compound N=1C(O)=C(SC=2SC=NN=2)C(N[C@@H](CO)C)=NC=1SCC1=CC=CC(Cl)=C1 HZGQRFWXSYBGII-SECBINFHSA-N 0.000 claims 1
- QCRAQJBEYCPPIQ-GFCCVEGCSA-N 2-[[2-[(2,3-difluorophenyl)methylsulfanyl]-6-[[(2r)-1-hydroxypropan-2-yl]amino]-4-oxo-1h-pyrimidin-5-yl]sulfanyl]-n-[2-(dimethylamino)ethyl]acetamide Chemical compound OC1=C(SCC(=O)NCCN(C)C)C(N[C@@H](CO)C)=NC(SCC=2C(=C(F)C=CC=2)F)=N1 QCRAQJBEYCPPIQ-GFCCVEGCSA-N 0.000 claims 1
- AFBWEEDUNDSEOM-SECBINFHSA-N 2-[[2-[(2,3-difluorophenyl)methylsulfanyl]-6-[[(2r)-1-hydroxypropan-2-yl]amino]-4-oxo-1h-pyrimidin-5-yl]sulfanyl]-n-methylacetamide Chemical compound N1=C(N[C@H](C)CO)C(SCC(=O)NC)=C(O)N=C1SCC1=CC=CC(F)=C1F AFBWEEDUNDSEOM-SECBINFHSA-N 0.000 claims 1
- QPYKFRKVUSMKFA-SECBINFHSA-N 2-benzylsulfanyl-5-chloro-6-[[(2r)-1-hydroxypropan-2-yl]amino]-1h-pyrimidin-4-one Chemical compound OC1=C(Cl)C(N[C@@H](CO)C)=NC(SCC=2C=CC=CC=2)=N1 QPYKFRKVUSMKFA-SECBINFHSA-N 0.000 claims 1
- HBIKKARCWGTOOZ-SNVBAGLBSA-N 2-benzylsulfanyl-6-[[(2r)-1-hydroxypropan-2-yl]amino]-1h-pyrimidin-4-one Chemical compound OC[C@@H](C)NC1=CC(O)=NC(SCC=2C=CC=CC=2)=N1 HBIKKARCWGTOOZ-SNVBAGLBSA-N 0.000 claims 1
- HCTRWKSURJPDNF-SSDOTTSWSA-N 5-[(5-amino-1h-1,2,4-triazol-3-yl)sulfanyl]-2-[(2,3-difluorophenyl)methylsulfanyl]-6-[[(2r)-1-hydroxypropan-2-yl]amino]-1h-pyrimidin-4-one Chemical compound N=1C(O)=C(SC=2NC(N)=NN=2)C(N[C@@H](CO)C)=NC=1SCC1=CC=CC(F)=C1F HCTRWKSURJPDNF-SSDOTTSWSA-N 0.000 claims 1
- USVCGKXUVKNWDO-SSDOTTSWSA-N 5-chloro-2-[(2,3-difluorophenyl)methylsulfanyl]-6-[[(2r)-1-hydroxypropan-2-yl]amino]-1h-pyrimidin-4-one Chemical compound OC1=C(Cl)C(N[C@@H](CO)C)=NC(SCC=2C(=C(F)C=CC=2)F)=N1 USVCGKXUVKNWDO-SSDOTTSWSA-N 0.000 claims 1
- AGCSHWVJDVYXMT-MRVPVSSYSA-N 5-chloro-2-[(3-chlorophenyl)methylsulfanyl]-6-[[(2r)-1-hydroxypropan-2-yl]amino]-1h-pyrimidin-4-one Chemical compound OC1=C(Cl)C(N[C@@H](CO)C)=NC(SCC=2C=C(Cl)C=CC=2)=N1 AGCSHWVJDVYXMT-MRVPVSSYSA-N 0.000 claims 1
- AJKNIFDHISHREJ-MRVPVSSYSA-N 5-fluoro-2-[(3-fluorophenyl)methylsulfanyl]-6-[[(2r)-1-hydroxypropan-2-yl]amino]-1h-pyrimidin-4-one Chemical compound OC1=C(F)C(N[C@@H](CO)C)=NC(SCC=2C=C(F)C=CC=2)=N1 AJKNIFDHISHREJ-MRVPVSSYSA-N 0.000 claims 1
- DSSHZEQFUGTVGO-MRVPVSSYSA-N 5-fluoro-2-[(4-fluorophenyl)methylsulfanyl]-6-[[(2r)-1-hydroxypropan-2-yl]amino]-1h-pyrimidin-4-one Chemical compound OC1=C(F)C(N[C@@H](CO)C)=NC(SCC=2C=CC(F)=CC=2)=N1 DSSHZEQFUGTVGO-MRVPVSSYSA-N 0.000 claims 1
- 102000009410 Chemokine receptor Human genes 0.000 claims 1
- 108050000299 Chemokine receptor Proteins 0.000 claims 1
- PNQHCGLTYXBRFH-SECBINFHSA-N [2-[(3-chlorophenyl)methylsulfanyl]-6-[[(2r)-1-hydroxypropan-2-yl]amino]-4-oxo-1h-pyrimidin-5-yl] thiocyanate Chemical compound OC1=C(SC#N)C(N[C@@H](CO)C)=NC(SCC=2C=C(Cl)C=CC=2)=N1 PNQHCGLTYXBRFH-SECBINFHSA-N 0.000 claims 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 1
- 125000003342 alkenyl group Chemical group 0.000 claims 1
- 125000000304 alkynyl group Chemical group 0.000 claims 1
- 125000005214 aminoheteroaryl group Chemical group 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- 230000009286 beneficial effect Effects 0.000 claims 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
- 125000004122 cyclic group Chemical group 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 201000010099 disease Diseases 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 1
- 230000000694 effects Effects 0.000 claims 1
- 239000012039 electrophile Substances 0.000 claims 1
- 238000009472 formulation Methods 0.000 claims 1
- 125000005842 heteroatom Chemical group 0.000 claims 1
- 125000000623 heterocyclic group Chemical group 0.000 claims 1
- KWEWONBYGQMLGC-SECBINFHSA-N n-[2-[(3-chlorophenyl)methylsulfanyl]-6-[[(2r)-1-hydroxypropan-2-yl]amino]-4-oxo-1h-pyrimidin-5-yl]methanesulfonamide Chemical compound OC1=C(NS(C)(=O)=O)C(N[C@@H](CO)C)=NC(SCC=2C=C(Cl)C=CC=2)=N1 KWEWONBYGQMLGC-SECBINFHSA-N 0.000 claims 1
- 150000002825 nitriles Chemical class 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 125000004430 oxygen atom Chemical group O* 0.000 claims 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims 1
- 229910052717 sulfur Inorganic materials 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
- 125000005031 thiocyano group Chemical group S(C#N)* 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 2
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 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 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- LTXYBJCIPCNFFG-SECBINFHSA-N 4-[[(1r)-2-[tert-butyl(dimethyl)silyl]oxy-1-hydroxyethyl]amino]-2,6-dichloro-n,n-dimethylpyrimidine-5-carboxamide Chemical compound CN(C)C(=O)C1=C(Cl)N=C(Cl)N=C1N[C@H](O)CO[Si](C)(C)C(C)(C)C LTXYBJCIPCNFFG-SECBINFHSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000005910 alkyl carbonate group Chemical group 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 125000001721 carboxyacetyl group Chemical group 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000002485 inorganic esters Chemical class 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
Applications Claiming Priority (5)
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| PCT/GB2003/003632 WO2004018435A1 (en) | 2002-08-24 | 2003-08-20 | Pyrimidine derivatives as modulators of chemokine receptor activity |
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| GB0217431D0 (en) | 2002-07-27 | 2002-09-04 | Astrazeneca Ab | Novel compounds |
| US8529625B2 (en) | 2003-08-22 | 2013-09-10 | Smith & Nephew, Inc. | Tissue repair and replacement |
| EP2311827A1 (en) * | 2004-08-28 | 2011-04-20 | AstraZeneca AB | Thiopyrimidine derivative, useful as an intermediate for chemokine receptor modulators. |
| CN101084214A (zh) | 2004-11-17 | 2007-12-05 | 迈卡纳治疗股份有限公司 | 激酶抑制剂 |
| KR101487027B1 (ko) * | 2005-09-30 | 2015-01-28 | 미카나 테라퓨틱스, 인크. | 치환된 피라졸 화합물 |
| KR20090086080A (ko) * | 2006-11-23 | 2009-08-10 | 노파르티스 아게 | 피리미딘 및 그의 ｃｘｃｒ2 수용체 길항제로서의 용도 |
| EP2166849A4 (en) * | 2007-06-11 | 2010-09-15 | Miikana Therapeutics Inc | SUBSTITUTED PYRAZOL COMPOUNDS |
| US9273077B2 (en) | 2008-05-21 | 2016-03-01 | Ariad Pharmaceuticals, Inc. | Phosphorus derivatives as kinase inhibitors |
| MX353308B (es) | 2008-05-21 | 2018-01-08 | Ariad Pharma Inc | Derivados fosforosos como inhibidores de cinasa. |
| WO2009151910A2 (en) * | 2008-05-25 | 2009-12-17 | Wyeth | Combination product of receptor tyrosine kinase inhibitor and fatty acid synthase inhibitor for treating cancer |
| KR20110031462A (ko) * | 2008-07-16 | 2011-03-28 | 아스트라제네카 아베 | 피리미딜 술폰아미드 유도체 및 케모카인 매개 질환의 치료를 위한 그의 용도 |
| US8748623B2 (en) | 2009-02-17 | 2014-06-10 | Syntrix Biosystems, Inc. | Pyridinecarboxamides as CXCR2 modulators |
| JP5731538B2 (ja) | 2009-12-23 | 2015-06-10 | アイアンウッド ファーマシューティカルズ インコーポレイテッド | Ｃｒｔｈ２モジュレーター |
| US20130259830A1 (en) | 2010-07-12 | 2013-10-03 | Ironwood Pharmaceuticals, Inc. | Crth2 modulators |
| WO2012009137A1 (en) | 2010-07-12 | 2012-01-19 | Ironwood Pharmaceuticals, Inc. | Crth2 modulators |
| EP2608672B1 (en) | 2010-08-23 | 2020-12-16 | Syntrix Biosystems, Inc. | Aminopyridine- and aminopyrimidinecarboxamides as cxcr2 modulators |
| EP2704572B1 (en) | 2011-05-04 | 2015-12-30 | Ariad Pharmaceuticals, Inc. | Compounds for inhibiting cell proliferation in egfr-driven cancers |
| WO2013169401A1 (en) | 2012-05-05 | 2013-11-14 | Ariad Pharmaceuticals, Inc. | Compounds for inhibiting cell proliferation in egfr-driven cancers |
| US9611283B1 (en) | 2013-04-10 | 2017-04-04 | Ariad Pharmaceuticals, Inc. | Methods for inhibiting cell proliferation in ALK-driven cancers |
| US10046002B2 (en) | 2013-08-02 | 2018-08-14 | Syntrix Biosystems Inc. | Method for treating cancer using chemokine antagonists |
| US10561676B2 (en) | 2013-08-02 | 2020-02-18 | Syntrix Biosystems Inc. | Method for treating cancer using dual antagonists of CXCR1 and CXCR2 |
| US8969365B2 (en) | 2013-08-02 | 2015-03-03 | Syntrix Biosystems, Inc. | Thiopyrimidinecarboxamides as CXCR1/2 modulators |
| TW201605812A (zh) * | 2013-09-16 | 2016-02-16 | 拜耳製藥股份有限公司 | 經雙取代之三氟甲基嘧啶酮類及其用途 |
| AR097631A1 (es) * | 2013-09-16 | 2016-04-06 | Bayer Pharma AG | Trifluorometilpirimidinonas sustituidas con heterociclos y sus usos |
| WO2016113205A1 (de) | 2015-01-13 | 2016-07-21 | Bayer Pharma Aktiengesellschaft | Substituierte pentafluorethylpyrimidinone und ihre verwendung |
| CN106588784B (zh) * | 2016-11-29 | 2019-07-05 | 同济大学 | 一种银辅助的双取代氨基嘧啶的对位单氟化反应方法及应用 |
| CN113024372A (zh) * | 2021-03-12 | 2021-06-25 | 内蒙古蓝科生物科技有限公司 | 一种2-氯-3-氟-4-三氟甲基苯甲酰氯的合成方法 |
| CN114163383A (zh) * | 2021-12-24 | 2022-03-11 | 江苏丰山集团股份有限公司 | 一种烟嘧磺隆中间体烟酰胺和磺酰胺的绿色生产工艺 |
| CN118767991B (zh) * | 2023-03-30 | 2025-12-30 | 万华化学集团股份有限公司 | 一种催化剂及其制备方法和在环十二酮合成中的应用 |
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| US3673184A (en) | 1970-09-02 | 1972-06-27 | Dainippon Pharmaceutical Co | Certain 2-substituted-5,8-dihydro-5-oxopyrido{8 2,3-d{9 pyrimidine-6-carboxylic acid derivatives |
| JPS61118372A (ja) | 1984-11-12 | 1986-06-05 | Nippon Mektron Ltd | 新規ピリミジン誘導体およびその製造法 |
| JPH03197467A (ja) | 1989-12-26 | 1991-08-28 | Nippon Kayaku Co Ltd | ピリミジノン誘導体その製法及びそれを有効成分とする殺虫・殺ダニ剤 |
| EP0522038A4 (en) | 1990-03-30 | 1993-05-26 | Merck & Co. Inc. | Substituted pyrimidines, pyrimidinones and pyridopyrimidines |
| US5516905A (en) * | 1994-08-30 | 1996-05-14 | University Of Massachusetts Medical Center | Antibiotic compounds and methods to treat gram-positive bacterial and mycoplasmal infections |
| GB9624482D0 (en) | 1995-12-18 | 1997-01-15 | Zeneca Phaema S A | Chemical compounds |
| DE69720965T2 (de) | 1996-02-13 | 2004-02-05 | Astrazeneca Ab | Chinazolinderivate und deren verwendung als vegf hemmer |
| NZ331191A (en) | 1996-03-05 | 2000-03-27 | Zeneca Ltd | 4-anilinoquinazoline derivatives and pharmaceutical compositions thereof |
| GB9718972D0 (en) | 1996-09-25 | 1997-11-12 | Zeneca Ltd | Chemical compounds |
| GB9714249D0 (en) | 1997-07-08 | 1997-09-10 | Angiogene Pharm Ltd | Vascular damaging agents |
| EA200000840A1 (ru) | 1998-02-17 | 2001-02-26 | Туларик, Инк. | Антивирусные производные пиримидина |
| SE9802729D0 (sv) * | 1998-08-13 | 1998-08-13 | Astra Pharma Prod | Novel Compounds |
| GB9900334D0 (en) | 1999-01-07 | 1999-02-24 | Angiogene Pharm Ltd | Tricylic vascular damaging agents |
| GB9900752D0 (en) | 1999-01-15 | 1999-03-03 | Angiogene Pharm Ltd | Benzimidazole vascular damaging agents |
| WO2000076980A1 (en) * | 1999-06-10 | 2000-12-21 | Yamanouchi Pharmaceutical Co., Ltd. | Novel nitrogen-contaiing heterocyclic derivatives or salts thereof |
| SE9903544D0 (sv) | 1999-10-01 | 1999-10-01 | Astra Pharma Prod | Novel compounds |
| GB2359078A (en) | 2000-02-11 | 2001-08-15 | Astrazeneca Uk Ltd | Pharmaceutically active pyrimidine derivatives |
| JP2003522191A (ja) | 2000-02-11 | 2003-07-22 | アストラゼネカ・アクチエボラーグ | ケモカイン受容体活性のモジュレーターとしてのピリミジン化合物およびそれらの使用 |
| AU2001258628A1 (en) | 2000-05-31 | 2001-12-11 | Astrazeneca Ab | Indole derivatives with vascular damaging activity |
| MXPA02012903A (es) | 2000-07-07 | 2004-07-30 | Angiogene Pharm Ltd | Derivados de colquinol como inhibidores de angiogenesis. |
| MXPA02012905A (es) | 2000-07-07 | 2004-07-30 | Angiogene Pharm Ltd | Derivados de colquinol como agentes de dano vascular.. |
| US7091201B2 (en) | 2000-09-25 | 2006-08-15 | Actelion Pharmaceuticals Ltd. | Arylalkane-sulfonamides having endothelin-antagonist activity |
| AU2002258400A1 (en) | 2001-02-16 | 2002-08-28 | Tularik Inc. | Methods of using pyrimidine-based antiviral agents |
| TWI328007B (en) | 2002-01-16 | 2010-08-01 | Astrazeneca Ab | Novel compounds |
| GB0217431D0 (en) | 2002-07-27 | 2002-09-04 | Astrazeneca Ab | Novel compounds |
-
2003
- 2003-08-20 WO PCT/GB2003/003632 patent/WO2004018435A1/en not_active Ceased
- 2003-08-20 EP EP03792486A patent/EP1539713B1/en not_active Expired - Lifetime
- 2003-08-20 US US10/525,495 patent/US7482355B2/en not_active Expired - Fee Related
- 2003-08-20 JP JP2005501216A patent/JP4694963B2/ja not_active Expired - Fee Related
- 2003-08-20 DE DE60318219T patent/DE60318219T2/de not_active Expired - Lifetime
- 2003-08-20 AU AU2003255819A patent/AU2003255819A1/en not_active Abandoned
- 2003-08-20 ES ES03792486T patent/ES2295685T3/es not_active Expired - Lifetime
- 2003-08-20 AT AT03792486T patent/ATE381546T1/de not_active IP Right Cessation
-
2010
- 2010-12-17 JP JP2010282057A patent/JP2011052025A/ja not_active Withdrawn
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