KR20140077911A - 암의 치료를 위한 포스파티딜이노시톨 3-키나아제 저해제 - Google Patents
암의 치료를 위한 포스파티딜이노시톨 3-키나아제 저해제 Download PDFInfo
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- KR20140077911A KR20140077911A KR1020147009539A KR20147009539A KR20140077911A KR 20140077911 A KR20140077911 A KR 20140077911A KR 1020147009539 A KR1020147009539 A KR 1020147009539A KR 20147009539 A KR20147009539 A KR 20147009539A KR 20140077911 A KR20140077911 A KR 20140077911A
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- South Korea
- Prior art keywords
- nhc
- phenyl
- compound
- amino
- alkyl
- Prior art date
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- 206010028980 Neoplasm Diseases 0.000 title claims description 81
- 238000011282 treatment Methods 0.000 title claims description 57
- 201000011510 cancer Diseases 0.000 title claims description 21
- 239000002935 phosphatidylinositol 3 kinase inhibitor Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 248
- 238000000034 method Methods 0.000 claims abstract description 99
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 claims abstract description 68
- 229960003881 letrozole Drugs 0.000 claims abstract description 66
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 48
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 41
- 206010014733 Endometrial cancer Diseases 0.000 claims abstract description 34
- 206010014759 Endometrial neoplasm Diseases 0.000 claims abstract description 34
- 201000003914 endometrial carcinoma Diseases 0.000 claims abstract description 12
- -1 3 - {[2-chloro-5- (methoxy) phenyl] amino} quinoxalin-2-yl Chemical group 0.000 claims description 313
- 125000000217 alkyl group Chemical group 0.000 claims description 184
- 229910052739 hydrogen Inorganic materials 0.000 claims description 169
- 239000001257 hydrogen Substances 0.000 claims description 169
- 230000004044 response Effects 0.000 claims description 96
- 125000003545 alkoxy group Chemical group 0.000 claims description 83
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 76
- 125000001072 heteroaryl group Chemical group 0.000 claims description 68
- 239000000203 mixture Substances 0.000 claims description 68
- 150000003839 salts Chemical class 0.000 claims description 65
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 60
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 46
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 41
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 40
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- DTXOCJGLLMAFBX-UHFFFAOYSA-N oxo-[[1-[2-[[4-(oxoazaniumylmethylidene)pyridin-1-yl]methoxy]ethoxymethyl]pyridin-4-ylidene]methyl]azanium;dichloride Chemical compound [Cl-].[Cl-].C1=CC(=C[NH+]=O)C=CN1COCCOCN1C=CC(=C[NH+]=O)C=C1 DTXOCJGLLMAFBX-UHFFFAOYSA-N 0.000 claims description 30
- 239000002775 capsule Substances 0.000 claims description 29
- 239000012453 solvate Substances 0.000 claims description 26
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 25
- OSDBJMYIUDLIRI-UHFFFAOYSA-N oxo-[[1-[[4-[[4-(oxoazaniumylmethylidene)pyridin-1-yl]methoxy]cyclohexyl]oxymethyl]pyridin-4-ylidene]methyl]azanium;dichloride Chemical compound [Cl-].[Cl-].C1=CC(=C[NH+]=O)C=CN1COC1CCC(OCN2C=CC(=C[NH+]=O)C=C2)CC1 OSDBJMYIUDLIRI-UHFFFAOYSA-N 0.000 claims description 25
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 23
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- 125000004985 dialkyl amino alkyl group Chemical group 0.000 claims description 20
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- 125000004103 aminoalkyl group Chemical group 0.000 claims description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims description 19
- 229910052799 carbon Inorganic materials 0.000 claims description 18
- 125000000278 alkyl amino alkyl group Chemical group 0.000 claims description 17
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 15
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- HQMLIDZJXVVKCW-REOHCLBHSA-N L-alaninamide Chemical compound C[C@H](N)C(N)=O HQMLIDZJXVVKCW-REOHCLBHSA-N 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- VZCDEMVDPSFCRX-UHFFFAOYSA-N CC(N)(C)C(=O)N.ClC1=C(C=C(C=C1)OC)NC=1C=NC2=CC=CC=C2N1 Chemical compound CC(N)(C)C(=O)N.ClC1=C(C=C(C=C1)OC)NC=1C=NC2=CC=CC=C2N1 VZCDEMVDPSFCRX-UHFFFAOYSA-N 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- MRKYULNLKHJVTB-UHFFFAOYSA-N 8-ethyl-4-methyl-6-(1H-pyrazol-5-yl)-7H-pyrido[2,3-d]pyrimidin-2-amine Chemical compound NC=1N=C(C2=C(N1)N(CC(=C2)C2=CC=NN2)CC)C MRKYULNLKHJVTB-UHFFFAOYSA-N 0.000 claims 3
- 125000001475 halogen functional group Chemical group 0.000 claims 3
- 230000007012 clinical effect Effects 0.000 claims 2
- UDJFFSGCRRMVFH-UHFFFAOYSA-N pyrido[2,3-d]pyrimidine Chemical compound N1=CN=CC2=CC=CN=C21 UDJFFSGCRRMVFH-UHFFFAOYSA-N 0.000 claims 1
- 230000002195 synergetic effect Effects 0.000 claims 1
- 229940126062 Compound A Drugs 0.000 description 109
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 109
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 93
- 125000003342 alkenyl group Chemical group 0.000 description 74
- 125000005843 halogen group Chemical group 0.000 description 72
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- 125000003118 aryl group Chemical group 0.000 description 50
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- 206010057190 Respiratory tract infections Diseases 0.000 description 44
- 125000000753 cycloalkyl group Chemical group 0.000 description 43
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 41
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 38
- 239000003826 tablet Substances 0.000 description 36
- 125000003282 alkyl amino group Chemical group 0.000 description 35
- 125000003710 aryl alkyl group Chemical group 0.000 description 34
- 125000004663 dialkyl amino group Chemical group 0.000 description 32
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 description 32
- 125000001188 haloalkyl group Chemical group 0.000 description 30
- 125000005885 heterocycloalkylalkyl group Chemical group 0.000 description 30
- 125000004438 haloalkoxy group Chemical group 0.000 description 29
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- 239000000243 solution Substances 0.000 description 26
- 239000000543 intermediate Substances 0.000 description 23
- 125000000547 substituted alkyl group Chemical group 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- 125000004414 alkyl thio group Chemical group 0.000 description 21
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 20
- 238000011156 evaluation Methods 0.000 description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 125000004093 cyano group Chemical group *C#N 0.000 description 18
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- 125000001424 substituent group Chemical group 0.000 description 15
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 14
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- 125000002252 acyl group Chemical group 0.000 description 13
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 13
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Images
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4196—1,2,4-Triazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
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- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
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- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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| US61/534,836 | 2011-09-14 | ||
| US201161543529P | 2011-10-05 | 2011-10-05 | |
| US61/543,529 | 2011-10-05 | ||
| US201161562670P | 2011-11-22 | 2011-11-22 | |
| US61/562,670 | 2011-11-22 | ||
| PCT/US2012/055387 WO2013040337A1 (en) | 2011-09-14 | 2012-09-14 | Phosphatidylinositol 3-kinase inhibitors for the treatment of cancer |
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| KR20140077911A true KR20140077911A (ko) | 2014-06-24 |
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| CN113754565B (zh) * | 2021-11-09 | 2022-02-22 | 南京威凯尔生物医药科技有限公司 | 一种连续流微反应器中制备沙库巴曲中间体的方法 |
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| US4107288A (en) | 1974-09-18 | 1978-08-15 | Pharmaceutical Society Of Victoria | Injectable compositions, nanoparticles useful therein, and process of manufacturing same |
| US5145684A (en) | 1991-01-25 | 1992-09-08 | Sterling Drug Inc. | Surface modified drug nanoparticles |
| US7019002B2 (en) | 2001-12-11 | 2006-03-28 | Pharmacia & Upjohn, S.P.A. | Pyridopyrimidinones derivatives as telomerase inhibitors |
| WO2007044729A2 (en) * | 2005-10-07 | 2007-04-19 | Exelixis, Inc. | N- (3-amino-quinoxalin-2-yl) -sulfonamide derivatives and their use as phosphatidylinositol 3-kinase inhibitors |
| EP1940839B1 (en) | 2005-10-07 | 2013-07-31 | Exelixis, Inc. | PYRIDOPYRIMIDINONE INHIBITORS OF PI3Kalpha |
| WO2007044481A1 (en) | 2005-10-07 | 2007-04-19 | Basf Corporation | Clearcoat coating composition |
| RS53020B (sr) * | 2007-04-11 | 2014-04-30 | Exelixis Inc. | Kombinovane terapije koje sadrže hinoksalin inhibitor pi3k-alfa za upotrebu u lečenju kancera |
| WO2010146391A1 (en) * | 2009-06-15 | 2010-12-23 | Generics [Uk] Limited | Regioselective synthesis of letrozole |
| WO2012065057A2 (en) * | 2010-11-12 | 2012-05-18 | Exelixis, Inc. | Phosphatidylinositol 3-kinase inhibitors and methods of their use |
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2012
- 2012-09-14 IN IN2671CHN2014 patent/IN2014CN02671A/en unknown
- 2012-09-14 TW TW101133789A patent/TW201325592A/zh unknown
- 2012-09-14 BR BR112014005858A patent/BR112014005858A2/pt not_active Application Discontinuation
- 2012-09-14 KR KR1020147009539A patent/KR20140077911A/ko not_active Withdrawn
- 2012-09-14 AU AU2012308414A patent/AU2012308414A1/en not_active Abandoned
- 2012-09-14 CA CA2848724A patent/CA2848724A1/en not_active Abandoned
- 2012-09-14 UY UY0001034339A patent/UY34339A/es not_active Application Discontinuation
- 2012-09-14 EP EP12766542.0A patent/EP2755654A1/en not_active Withdrawn
- 2012-09-14 WO PCT/US2012/055387 patent/WO2013040337A1/en not_active Ceased
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2014
- 2014-03-11 IL IL231448A patent/IL231448A0/en unknown
Also Published As
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|---|---|
| IN2014CN02671A (enExample) | 2015-07-03 |
| WO2013040337A1 (en) | 2013-03-21 |
| TW201325592A (zh) | 2013-07-01 |
| IL231448A0 (en) | 2014-04-30 |
| WO2013040337A9 (en) | 2014-04-03 |
| UY34339A (es) | 2013-04-30 |
| CA2848724A1 (en) | 2013-03-21 |
| BR112014005858A2 (pt) | 2017-06-13 |
| EP2755654A1 (en) | 2014-07-23 |
| AU2012308414A1 (en) | 2014-05-01 |
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