JP2004500308A5 - - Google Patents

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Publication number: JP2004500308A5
Authority: JP; Japan
Prior art keywords: amino; mmol; compounds; ptpases; ptp
Prior art date: 1999-03-12
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.): Pending

Application number

JP2000535620A

Other languages

English (en)

Japanese (ja)

Other versions

JP2004500308A (ja

Filing date

1999-03-12

Publication date

2004-12-24

1999-03-12 Application filed filed Critical

1999-03-12 Priority claimed from PCT/DK1999/000126 external-priority patent/WO1999046237A1/fr

2004-01-08 Publication of JP2004500308A publication Critical patent/JP2004500308A/ja

2004-12-24 Publication of JP2004500308A5 publication Critical patent/JP2004500308A5/ja

Status Pending legal-status Critical Current

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150000001875 compounds Chemical class 0.000 description 423
-1 5-tetrazolyl Chemical group 0.000 description 302
XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 288
239000000243 solution Substances 0.000 description 166
YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 162
230000002401 inhibitory effect Effects 0.000 description 161
102000002727 Protein Tyrosine Phosphatases Human genes 0.000 description 158
108020000494 Protein Tyrosine Phosphatases Proteins 0.000 description 158
239000000203 mixture Substances 0.000 description 152
239000007787 solid Substances 0.000 description 146
239000003112 inhibitor Substances 0.000 description 127
238000005160 1H NMR spectroscopy Methods 0.000 description 119
VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 118
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 114
LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 107
229920001469 poly(aryloxy)thionylphosphazene Polymers 0.000 description 107
108091006359 Mitochondrial phosphate transporter Proteins 0.000 description 104
102100004022 PTPRU Human genes 0.000 description 104
125000003431 oxalo group Chemical group 0.000 description 95
RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 87
WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 84
210000004027 cells Anatomy 0.000 description 81
HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 81
230000000694 effects Effects 0.000 description 79
230000000051 modifying Effects 0.000 description 77
239000011541 reaction mixture Substances 0.000 description 75
OKKJLVBELUTLKV-MZCSYVLQSA-N cd3od Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 72
239000002904 solvent Substances 0.000 description 71
125000003118 aryl group Chemical group 0.000 description 62
IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 60
ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 60
125000003636 chemical group Chemical group 0.000 description 59
HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 59
DCWXELXMIBXGTH-UHFFFAOYSA-N O(4)-phosphotyrosine Chemical compound OC(=O)C(N)CC1=CC=C(OP(O)(O)=O)C=C1 DCWXELXMIBXGTH-UHFFFAOYSA-N 0.000 description 54
VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 54
230000027455 binding Effects 0.000 description 52
235000018102 proteins Nutrition 0.000 description 49
102000004169 proteins and genes Human genes 0.000 description 49
108090000623 proteins and genes Proteins 0.000 description 49
239000003039 volatile agent Substances 0.000 description 49
239000002244 precipitate Substances 0.000 description 47
DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 46
102100017813 PTPN1 Human genes 0.000 description 41
101700050499 PTPN1 Proteins 0.000 description 41
125000000217 alkyl group Chemical group 0.000 description 39
FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 37
OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
102100005499 PTPRC Human genes 0.000 description 35
101700059076 PTPRC Proteins 0.000 description 35
230000019491 signal transduction Effects 0.000 description 35
NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 34
102000004190 Enzymes Human genes 0.000 description 33
108090000790 Enzymes Proteins 0.000 description 33
102000014400 SH2 domains Human genes 0.000 description 32
108050003452 SH2 domains Proteins 0.000 description 32
238000006243 chemical reaction Methods 0.000 description 32
239000012074 organic phase Substances 0.000 description 32
239000003921 oil Substances 0.000 description 31
235000019198 oils Nutrition 0.000 description 31
239000000758 substrate Substances 0.000 description 31
QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 30
239000012267 brine Substances 0.000 description 30
238000000034 method Methods 0.000 description 30
201000010099 disease Diseases 0.000 description 29
125000004169 (C1-C6) alkyl group Chemical group 0.000 description 28
229940088598 Enzyme Drugs 0.000 description 28
239000008079 hexane Substances 0.000 description 27
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 26
239000012472 biological sample Substances 0.000 description 26
125000004432 carbon atoms Chemical group C* 0.000 description 25
239000011780 sodium chloride Substances 0.000 description 24
102100003367 PTPN6 Human genes 0.000 description 23
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238000004166 bioassay Methods 0.000 description 23
239000003480 eluent Substances 0.000 description 23
239000003446 ligand Substances 0.000 description 23
239000008346 aqueous phase Substances 0.000 description 22
238000007792 addition Methods 0.000 description 21
239000003814 drug Substances 0.000 description 21
239000000284 extract Substances 0.000 description 21
230000011664 signaling Effects 0.000 description 21
VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 21
229910052938 sodium sulfate Inorganic materials 0.000 description 21
206010012601 Diabetes mellitus Diseases 0.000 description 20
239000007832 Na2SO4 Substances 0.000 description 20
WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 20
230000002860 competitive Effects 0.000 description 20
239000012299 nitrogen atmosphere Substances 0.000 description 20
102000003746 Insulin Receptor Human genes 0.000 description 19
108010001127 Insulin Receptor Proteins 0.000 description 19
UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 19
230000003834 intracellular Effects 0.000 description 19
102000003886 Glycoproteins Human genes 0.000 description 18
108090000288 Glycoproteins Proteins 0.000 description 18
201000011510 cancer Diseases 0.000 description 18
239000000463 material Substances 0.000 description 18
239000000126 substance Substances 0.000 description 18
125000003545 alkoxy group Chemical group 0.000 description 17
102000004877 Insulin Human genes 0.000 description 16
108090001061 Insulin Proteins 0.000 description 16
230000003993 interaction Effects 0.000 description 16
239000000741 silica gel Substances 0.000 description 16
229910002027 silica gel Inorganic materials 0.000 description 16
235000002374 tyrosine Nutrition 0.000 description 16
239000005711 Benzoic acid Substances 0.000 description 15
OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 15
CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
230000015572 biosynthetic process Effects 0.000 description 15
238000004128 high performance liquid chromatography Methods 0.000 description 15
230000001965 increased Effects 0.000 description 15
WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 15
239000011664 nicotinic acid Substances 0.000 description 15
238000003756 stirring Methods 0.000 description 15
101700075056 Lar Proteins 0.000 description 14
102100017818 PTPN11 Human genes 0.000 description 14
102100005503 PTPRF Human genes 0.000 description 14
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102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 14
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238000004458 analytical method Methods 0.000 description 14
108010042209 insulin receptor tyrosine kinase Proteins 0.000 description 14
238000004519 manufacturing process Methods 0.000 description 14
PVNIIMVLHYAWGP-UHFFFAOYSA-N nicotinic acid Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 14
229910052757 nitrogen Inorganic materials 0.000 description 14
238000010992 reflux Methods 0.000 description 14
VHJLVAABSRFDPM-UHFFFAOYSA-N 1,4-dimercaptobutane-2,3-diol Chemical compound SCC(O)C(O)CS VHJLVAABSRFDPM-UHFFFAOYSA-N 0.000 description 13
CIFFDBUDZABDNZ-UHFFFAOYSA-N 2-imidazol-1-yl-2-oxoacetic acid Chemical compound OC(=O)C(=O)N1C=CN=C1 CIFFDBUDZABDNZ-UHFFFAOYSA-N 0.000 description 13
241000282619 Hylobates lar Species 0.000 description 13
101710018405 PTPN11 Proteins 0.000 description 13
101710009384 SRC Proteins 0.000 description 13
230000001276 controlling effect Effects 0.000 description 13
IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
235000001968 nicotinic acid Nutrition 0.000 description 13
101700056560 PTP-1 Proteins 0.000 description 12
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 12
125000004122 cyclic group Chemical group 0.000 description 12
KCXVZYZYPLLWCC-UHFFFAOYSA-N edta Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 12
230000014509 gene expression Effects 0.000 description 12
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KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 12
238000003786 synthesis reaction Methods 0.000 description 12
230000002194 synthesizing Effects 0.000 description 12
YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
229940098773 Bovine Serum Albumin Drugs 0.000 description 11
108091003117 Bovine Serum Albumin Proteins 0.000 description 11
229920002676 Complementary DNA Polymers 0.000 description 11
108010051696 Growth Hormone Proteins 0.000 description 11
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OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 11
CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Substances ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 11
238000006366 phosphorylation reaction Methods 0.000 description 11
230000000865 phosphorylative Effects 0.000 description 11
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 11
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WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 10
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GFEYTWVSRDLPLE-UHFFFAOYSA-L dihydrogenvanadate Chemical compound O[V](O)([O-])=O GFEYTWVSRDLPLE-UHFFFAOYSA-L 0.000 description 10
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QBYNNSFEMMNINN-UHFFFAOYSA-N 2-(oxaloamino)benzoic acid Chemical compound OC(=O)C(=O)NC1=CC=CC=C1C(O)=O QBYNNSFEMMNINN-UHFFFAOYSA-N 0.000 description 7
XZKIHKMTEMTJQX-UHFFFAOYSA-N 4-Nitrophenyl dihydrogen phosphate Chemical compound OP(O)(=O)OC1=CC=C([N+]([O-])=O)C=C1 XZKIHKMTEMTJQX-UHFFFAOYSA-N 0.000 description 7
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SOBHUZYZLFQYFK-UHFFFAOYSA-K trisodium;hydroxy-[[phosphonatomethyl(phosphonomethyl)amino]methyl]phosphinate Chemical class [Na+].[Na+].[Na+].OP(O)(=O)CN(CP(O)([O-])=O)CP([O-])([O-])=O SOBHUZYZLFQYFK-UHFFFAOYSA-K 0.000 description 1
238000007738 vacuum evaporation Methods 0.000 description 1
WQEVDHBJGNOKKO-UHFFFAOYSA-K vanadic acid Chemical compound O[V](O)(O)=O WQEVDHBJGNOKKO-UHFFFAOYSA-K 0.000 description 1
229910052720 vanadium Inorganic materials 0.000 description 1
LEONUFNNVUYDNQ-UHFFFAOYSA-N vanadium(0) Chemical compound [V] LEONUFNNVUYDNQ-UHFFFAOYSA-N 0.000 description 1
125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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238000002424 x-ray crystallography Methods 0.000 description 1
239000011592 zinc chloride Substances 0.000 description 1
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WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1

Images

JP2000535620A 1998-03-12 1999-03-12 プロテインチロシンホスアターゼのモジュレーター Pending JP2004500308A (ja)

Applications Claiming Priority (26)

Application Number	Priority Date	Filing Date	Title
DK34398		1998-03-12
DK34898		1998-03-12
DK34698		1998-03-12
DK34298		1998-03-12
DK35098		1998-03-12
DK34498		1998-03-12
DK34598		1998-03-12
DK34798		1998-03-12
DK47998		1998-04-03
DK47598		1998-04-03
DK47298		1998-04-03
DK47698		1998-04-03
DK47398		1998-04-03
DK47898		1998-04-03
DK48098		1998-04-03
DK47498		1998-04-03
US8291298P	1998-04-24	1998-04-24
DK66798		1998-05-15
US8811598P	1998-06-05	1998-06-05
DKPA199800939		1998-07-15
DKPA199800940		1998-07-15
DKPA199800938		1998-07-15
DKPA199801385		1998-10-28
DKPA199801561		1998-11-26
DKPA199801612		1998-12-07
PCT/DK1999/000126 WO1999046237A1 (fr)	1998-03-12	1999-03-12	Modulateurs de proteine-tyrosine-phosphatases

Publications (2)

Publication Number	Publication Date
JP2004500308A JP2004500308A (ja)	2004-01-08
JP2004500308A5 true JP2004500308A5 (fr)	2004-12-24

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JP2000535620A Pending JP2004500308A (ja)	1998-03-12	1999-03-12	プロテインチロシンホスアターゼのモジュレーター

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EP (1)	EP1080068A1 (fr)
JP (1)	JP2004500308A (fr)
KR (1)	KR20010041811A (fr)
HU (1)	HUP0102612A2 (fr)
NO (1)	NO20004526L (fr)
WO (1)	WO1999046237A1 (fr)

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1999
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- 1999-03-12 JP JP2000535620A patent/JP2004500308A/ja active Pending
- 1999-03-12 HU HU0102612A patent/HUP0102612A2/hu unknown
- 1999-03-12 EP EP99907336A patent/EP1080068A1/fr not_active Withdrawn
- 1999-03-12 KR KR1020007010089A patent/KR20010041811A/ko not_active Application Discontinuation
2000
- 2000-09-11 NO NO20004526A patent/NO20004526L/no unknown

Publication	Publication Date	Title
JP2004500308A5 (fr)	2004-12-24
US6410586B1 (en)	2002-06-25	Modulators of protein tyrosine phosphatases (PTPases)
JP2004500308A (ja)	2004-01-08	プロテインチロシンホスアターゼのモジュレーター
US7019026B1 (en)	2006-03-28	Modulators of Protein Tyrosine Phosphatases (PTPases)
EP1080095B1 (fr)	2005-11-02	Modulateurs de proteine tyrosine phosphatases (ptpases)
EP1214324B1 (fr)	2006-06-14	MODULATEURS DE PROTEINE TYROSINE PHOSPHATASE (PTPases)
WO1999046267A1 (fr)	1999-09-16	Modulateurs de proteine tyrosine phosphatases (ptpases)
US6225329B1 (en)	2001-05-01	Modulators of protein tyrosine phosphatases (PTPases)
US6169087B1 (en)	2001-01-02	Modulators of protein tyrosine phosphatases (PTPases)
US20020019412A1 (en)	2002-02-14	Modulators of protein tyrosine phosphatases (ptpases)
JP2002506073A (ja)	2002-02-26	プロテイン・チロシン・ホスファターゼ（ＰＴＰａｓｅｓ）のモジュレーター
US20020002199A1 (en)	2002-01-03	Modulators of protein tyrosine phosphatases (ptpases)
WO1999046236A1 (fr)	1999-09-16	Modulateurs de proteine tyrosine phosphatases (ptpases)
WO2001017516A2 (fr)	2001-03-15	Procede d'inhibition de la proteine tyrosine phosphatase 1b et/ou de la proteine tyrosine phosphatase de lymphocytes et/ou d'autres ptpases possedant un reste aps en position 48
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US7115624B1 (en)	2006-10-03	Method of inhibiting protein tyrosine phosphatase 1B and/or T-cell protein tyrosine phosphatase 4 and/or other PTPases with an Asp residue at position 48
AU2713999A (en)	1999-09-27	Modulators of protein tyrosine phosphatases
CZ20003229A3 (cs)	2001-07-11	Sloučenina a její použití, farmaceutická kompozice a její použití a způsob úpravy aktivity, izolace, detekce, stanovení množství a funkce proteinových tyrosinfosfatas
MXPA00008921A (es)	2002-04-09	Moduladores de las proteinas tirosina fosfatasas.
EP1062199A1 (fr)	2000-12-27	Modulateurs de proteine tyrosine phosphatases (ptpases)
JP2002506058A (ja)	2002-02-26	プロテインチロシンホスファターゼ（ｐｔｐアーゼ）のモジュレーター
CZ20003228A3 (cs)	2001-05-16	Modulátory proteinu tyrosin fosfatázy
MXPA00008927A (en)	2001-07-09	Modulators of protein tyrosine phosphatases (ptpases)