JP2007527413A5

JP2007527413A5 -

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Publication number: JP2007527413A5
Authority: JP; Japan
Prior art keywords: optionally substituted; alkyl; compound; amino; phenyl
Prior art date: 2004-10-22
Legal status : Granted

Application number

JP2006536929A

Other languages

English (en)

Japanese (ja)

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JP2007527413A (ja

JP4800216B2 (ja

Filing date

2004-10-22

Publication date

2007-12-06

2004-10-22 Application filed filed Critical

2004-10-22 Priority claimed from PCT/US2004/035470 external-priority patent/WO2005039506A2/en

2007-09-27 Publication of JP2007527413A publication Critical patent/JP2007527413A/ja

2007-12-06 Publication of JP2007527413A5 publication Critical patent/JP2007527413A5/ja

2011-10-26 Application granted granted Critical

2011-10-26 Publication of JP4800216B2 publication Critical patent/JP4800216B2/ja

2024-10-22 Anticipated expiration legal-status Critical

Status Expired - Fee Related legal-status Critical Current

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150000001875 compounds Chemical class 0.000 claims description 201
125000000217 alkyl group Chemical group 0.000 claims description 130
-1 6-amino-5-cyano-2-methylsulfanyl-pyrimidin-4-ylsulfanyl Chemical group 0.000 claims description 125
230000000694 effects Effects 0.000 claims description 68
239000000203 mixture Substances 0.000 claims description 64
108010013238 70-kDa Ribosomal Protein S6 Kinases Proteins 0.000 claims description 59
125000000623 heterocyclic group Chemical group 0.000 claims description 53
238000000034 method Methods 0.000 claims description 52
108091000080 Phosphotransferase Proteins 0.000 claims description 48
102000020233 phosphotransferase Human genes 0.000 claims description 48
125000004429 atom Chemical group 0.000 claims description 43
229910052736 halogen Inorganic materials 0.000 claims description 42
150000002367 halogens Chemical class 0.000 claims description 41
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 39
201000010099 disease Diseases 0.000 claims description 36
125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 30
125000003118 aryl group Chemical group 0.000 claims description 26
125000003710 aryl alkyl group Chemical group 0.000 claims description 25
150000003839 salts Chemical class 0.000 claims description 24
125000003107 substituted aryl group Chemical group 0.000 claims description 24
102000001253 Protein Kinase Human genes 0.000 claims description 20
239000008194 pharmaceutical composition Substances 0.000 claims description 18
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 17
229910052799 carbon Inorganic materials 0.000 claims description 17
125000005010 perfluoroalkyl group Chemical group 0.000 claims description 17
108060006633 protein kinase Proteins 0.000 claims description 17
125000004953 trihalomethyl group Chemical group 0.000 claims description 16
125000004093 cyano group Chemical group *C#N 0.000 claims description 15
125000003342 alkenyl group Chemical group 0.000 claims description 13
125000000304 alkynyl group Chemical group 0.000 claims description 13
125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 12
239000003153 chemical reaction reagent Substances 0.000 claims description 11
239000003937 drug carrier Substances 0.000 claims description 10
230000005764 inhibitory process Effects 0.000 claims description 10
238000012216 screening Methods 0.000 claims description 10
230000002159 abnormal effect Effects 0.000 claims description 9
229940002612 prodrug Drugs 0.000 claims description 9
239000000651 prodrug Substances 0.000 claims description 9
230000001413 cellular effect Effects 0.000 claims description 8
230000035755 proliferation Effects 0.000 claims description 8
125000000547 substituted alkyl group Chemical group 0.000 claims description 8
125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 8
CTWFYCGKNTWPNP-UHFFFAOYSA-N 2-(2-amino-5-cyano-6-methylsulfanylpyrimidin-4-yl)sulfanyl-n-[3-(trifluoromethyl)phenyl]acetamide Chemical compound CSC1=NC(N)=NC(SCC(=O)NC=2C=C(C=CC=2)C(F)(F)F)=C1C#N CTWFYCGKNTWPNP-UHFFFAOYSA-N 0.000 claims description 7
125000001072 heteroaryl group Chemical group 0.000 claims description 7
230000002503 metabolic effect Effects 0.000 claims description 7
239000002207 metabolite Substances 0.000 claims description 7
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
125000005843 halogen group Chemical group 0.000 claims description 6
238000001727 in vivo Methods 0.000 claims description 6
229910052760 oxygen Inorganic materials 0.000 claims description 6
125000001188 haloalkyl group Chemical group 0.000 claims description 5
230000002401 inhibitory effect Effects 0.000 claims description 5
125000001624 naphthyl group Chemical group 0.000 claims description 5
125000004076 pyridyl group Chemical group 0.000 claims description 5
229910052717 sulfur Inorganic materials 0.000 claims description 5
125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 4
PCILYMWQEGDZQY-UHFFFAOYSA-N 2-(2-amino-5-cyano-6-methylsulfanylpyrimidin-4-yl)sulfanyl-n-(1,3-benzothiazol-2-yl)acetamide Chemical compound CSC1=NC(N)=NC(SCC(=O)NC=2SC3=CC=CC=C3N=2)=C1C#N PCILYMWQEGDZQY-UHFFFAOYSA-N 0.000 claims description 4
MKVLMRMKUVWVEX-UHFFFAOYSA-N 2-(2-amino-5-cyano-6-methylsulfanylpyrimidin-4-yl)sulfanyl-n-(1,3-thiazol-2-yl)acetamide Chemical compound CSC1=NC(N)=NC(SCC(=O)NC=2SC=CN=2)=C1C#N MKVLMRMKUVWVEX-UHFFFAOYSA-N 0.000 claims description 4
LNDPBEGXQILTSH-UHFFFAOYSA-N 2-(5-cyano-2-methylsulfanylpyrimidin-4-yl)sulfanyl-n-phenylacetamide Chemical compound CSC1=NC=C(C#N)C(SCC(=O)NC=2C=CC=CC=2)=N1 LNDPBEGXQILTSH-UHFFFAOYSA-N 0.000 claims description 4
DGQKUYNJNIVVAW-UHFFFAOYSA-N 2-(6-amino-3,5-dicyanopyridin-2-yl)sulfanyl-n-phenylacetamide Chemical class C1=C(C#N)C(N)=NC(SCC(=O)NC=2C=CC=CC=2)=C1C#N DGQKUYNJNIVVAW-UHFFFAOYSA-N 0.000 claims description 4
YECJXONJMOAUGJ-UHFFFAOYSA-N 2-amino-4-[2-(3,5-dimethylpyrazol-1-yl)-2-oxoethyl]sulfanyl-6-methylsulfanylpyrimidine-5-carbonitrile Chemical compound CSC1=NC(N)=NC(SCC(=O)N2C(=CC(C)=N2)C)=C1C#N YECJXONJMOAUGJ-UHFFFAOYSA-N 0.000 claims description 4
SCVJRXQHFJXZFZ-KVQBGUIXSA-N 2-amino-9-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-3h-purine-6-thione Chemical compound C1=2NC(N)=NC(=S)C=2N=CN1[C@H]1C[C@H](O)[C@@H](CO)O1 SCVJRXQHFJXZFZ-KVQBGUIXSA-N 0.000 claims description 4
CINMXNFUWNIFCE-UHFFFAOYSA-N 4,5-diamino-2-(2-methoxyethoxy)-n-phenylthieno[2,3-d]pyrimidine-6-carboxamide Chemical compound S1C2=NC(OCCOC)=NC(N)=C2C(N)=C1C(=O)NC1=CC=CC=C1 CINMXNFUWNIFCE-UHFFFAOYSA-N 0.000 claims description 4
PTYWCUNJUBFSSG-UHFFFAOYSA-N 5-amino-2-methylsulfanyl-n-phenylthieno[2,3-d]pyrimidine-6-carboxamide Chemical compound S1C2=NC(SC)=NC=C2C(N)=C1C(=O)NC1=CC=CC=C1 PTYWCUNJUBFSSG-UHFFFAOYSA-N 0.000 claims description 4
125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 4
125000002723 alicyclic group Chemical group 0.000 claims description 4
125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
125000005046 dihydronaphthyl group Chemical group 0.000 claims description 4
125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 4
125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 claims description 4
208000035475 disorder Diseases 0.000 claims description 3
230000004044 response Effects 0.000 claims description 3
241000239366 Euphausiacea Species 0.000 claims description 2
150000004677 hydrates Chemical class 0.000 claims 2
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 107
235000019439 ethyl acetate Nutrition 0.000 description 53
239000007787 solid Substances 0.000 description 40
238000006243 chemical reaction Methods 0.000 description 39
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 34
230000027455 binding Effects 0.000 description 33
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 28
230000015572 biosynthetic process Effects 0.000 description 25
125000004122 cyclic group Chemical group 0.000 description 24
238000003786 synthesis reaction Methods 0.000 description 24
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239000003795 chemical substances by application Substances 0.000 description 22
206010028980 Neoplasm Diseases 0.000 description 21
238000003556 assay Methods 0.000 description 19
229910052739 hydrogen Inorganic materials 0.000 description 19
239000001257 hydrogen Substances 0.000 description 19
150000003254 radicals Chemical class 0.000 description 19
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
239000012267 brine Substances 0.000 description 18
102000004169 proteins and genes Human genes 0.000 description 18
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 18
210000004027 cell Anatomy 0.000 description 17
125000004435 hydrogen atom Chemical group [H]* 0.000 description 17
108090000623 proteins and genes Proteins 0.000 description 17
239000000243 solution Substances 0.000 description 17
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MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 15
239000010410 layer Substances 0.000 description 14
239000011734 sodium Substances 0.000 description 14
102000004190 Enzymes Human genes 0.000 description 13
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239000003446 ligand Substances 0.000 description 13
239000003921 oil Substances 0.000 description 13
235000019198 oils Nutrition 0.000 description 13
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 12
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ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 10
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IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
239000012074 organic phase Substances 0.000 description 10
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
125000001424 substituent group Chemical group 0.000 description 10
238000012360 testing method Methods 0.000 description 10
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
239000008346 aqueous phase Substances 0.000 description 9
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PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
125000002947 alkylene group Chemical group 0.000 description 8
238000005094 computer simulation Methods 0.000 description 8
KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 8
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239000013504 Triton X-100 Substances 0.000 description 7
125000001118 alkylidene group Chemical group 0.000 description 7
239000013058 crude material Substances 0.000 description 7
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IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 7
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JP2006536929A 2003-10-24 2004-10-22 ｐ７０Ｓ６キナーゼモジュレーターおよび使用方法 Expired - Fee Related JP4800216B2 (ja)