JP2011523646A - キナーゼ阻害剤としてのリン誘導体 - Google Patents
キナーゼ阻害剤としてのリン誘導体 Download PDFInfo
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- JP2011523646A JP2011523646A JP2011510716A JP2011510716A JP2011523646A JP 2011523646 A JP2011523646 A JP 2011523646A JP 2011510716 A JP2011510716 A JP 2011510716A JP 2011510716 A JP2011510716 A JP 2011510716A JP 2011523646 A JP2011523646 A JP 2011523646A
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- ring
- compound
- phenyl
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- 229940043355 kinase inhibitor Drugs 0.000 title description 7
- 239000003757 phosphotransferase inhibitor Substances 0.000 title description 6
- 150000003017 phosphorus Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 532
- -1 cycloalkynyl Chemical group 0.000 claims description 207
- 125000003118 aryl group Chemical group 0.000 claims description 94
- 125000000623 heterocyclic group Chemical group 0.000 claims description 93
- 125000001072 heteroaryl group Chemical group 0.000 claims description 90
- 125000000217 alkyl group Chemical group 0.000 claims description 87
- 125000001424 substituent group Chemical group 0.000 claims description 77
- 229920006395 saturated elastomer Polymers 0.000 claims description 59
- 238000000034 method Methods 0.000 claims description 58
- 125000004122 cyclic group Chemical group 0.000 claims description 46
- 125000000304 alkynyl group Chemical group 0.000 claims description 36
- 125000003342 alkenyl group Chemical group 0.000 claims description 32
- 229910052760 oxygen Inorganic materials 0.000 claims description 32
- 229910052736 halogen Inorganic materials 0.000 claims description 31
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 30
- 150000002367 halogens Chemical class 0.000 claims description 30
- 125000005842 heteroatom Chemical group 0.000 claims description 30
- 229910052717 sulfur Inorganic materials 0.000 claims description 28
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 25
- 150000003839 salts Chemical class 0.000 claims description 23
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 21
- 125000004429 atom Chemical group 0.000 claims description 18
- 229910052698 phosphorus Inorganic materials 0.000 claims description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims description 16
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 125000006413 ring segment Chemical group 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 230000002401 inhibitory effect Effects 0.000 claims description 7
- 125000004437 phosphorous atom Chemical group 0.000 claims description 7
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 5
- 125000004385 trihaloalkyl group Chemical group 0.000 claims description 3
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
- 230000004663 cell proliferation Effects 0.000 claims 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 9
- 239000000243 solution Substances 0.000 description 200
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 189
- 238000006243 chemical reaction Methods 0.000 description 172
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 169
- 239000000203 mixture Substances 0.000 description 148
- 239000011541 reaction mixture Substances 0.000 description 127
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 117
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 103
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 102
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 102
- 238000003786 synthesis reaction Methods 0.000 description 80
- 230000015572 biosynthetic process Effects 0.000 description 75
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 68
- 235000019441 ethanol Nutrition 0.000 description 63
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 62
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 62
- 239000000543 intermediate Substances 0.000 description 59
- 235000019439 ethyl acetate Nutrition 0.000 description 58
- 239000000047 product Substances 0.000 description 55
- 239000007787 solid Substances 0.000 description 54
- 238000002953 preparative HPLC Methods 0.000 description 52
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 51
- 206010028980 Neoplasm Diseases 0.000 description 50
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 48
- 229910052757 nitrogen Inorganic materials 0.000 description 46
- 238000010898 silica gel chromatography Methods 0.000 description 45
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 43
- 201000011510 cancer Diseases 0.000 description 34
- 230000000670 limiting effect Effects 0.000 description 34
- 239000012044 organic layer Substances 0.000 description 34
- 229910021529 ammonia Inorganic materials 0.000 description 31
- 239000002585 base Substances 0.000 description 31
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 30
- 238000011282 treatment Methods 0.000 description 29
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 28
- 239000000460 chlorine Substances 0.000 description 27
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 26
- 235000002639 sodium chloride Nutrition 0.000 description 26
- 239000002904 solvent Substances 0.000 description 26
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 description 25
- 125000004432 carbon atom Chemical group C* 0.000 description 25
- 230000002829 reductive effect Effects 0.000 description 25
- 101710168331 ALK tyrosine kinase receptor Proteins 0.000 description 24
- 229910000160 potassium phosphate Inorganic materials 0.000 description 24
- 235000011009 potassium phosphates Nutrition 0.000 description 24
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 23
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 23
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 23
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 23
- 239000003814 drug Substances 0.000 description 23
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 23
- 229910052938 sodium sulfate Inorganic materials 0.000 description 23
- 235000011152 sodium sulphate Nutrition 0.000 description 23
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 20
- 239000002253 acid Substances 0.000 description 20
- 239000002246 antineoplastic agent Substances 0.000 description 20
- WQAWEUZTDVWTDB-UHFFFAOYSA-N dimethyl(oxo)phosphanium Chemical compound C[P+](C)=O WQAWEUZTDVWTDB-UHFFFAOYSA-N 0.000 description 20
- 239000012467 final product Substances 0.000 description 20
- 239000012071 phase Substances 0.000 description 20
- 239000000725 suspension Substances 0.000 description 20
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 19
- 201000010099 disease Diseases 0.000 description 17
- 239000003921 oil Substances 0.000 description 17
- 235000019198 oils Nutrition 0.000 description 17
- 238000010992 reflux Methods 0.000 description 17
- 229910000104 sodium hydride Inorganic materials 0.000 description 17
- 239000003643 water by type Substances 0.000 description 17
- 125000004093 cyano group Chemical group *C#N 0.000 description 16
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 16
- GIKMWFAAEIACRF-UHFFFAOYSA-N 2,4,5-trichloropyrimidine Chemical compound ClC1=NC=C(Cl)C(Cl)=N1 GIKMWFAAEIACRF-UHFFFAOYSA-N 0.000 description 15
- 108091000080 Phosphotransferase Proteins 0.000 description 15
- 102000020233 phosphotransferase Human genes 0.000 description 15
- 229940002612 prodrug Drugs 0.000 description 15
- 239000000651 prodrug Substances 0.000 description 15
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 14
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 14
- 229910000027 potassium carbonate Inorganic materials 0.000 description 14
- WWVLDJAVSQZSKO-UHFFFAOYSA-N 2,5-dichloro-n-(2-propan-2-ylsulfonylphenyl)pyrimidin-4-amine Chemical compound CC(C)S(=O)(=O)C1=CC=CC=C1NC1=NC(Cl)=NC=C1Cl WWVLDJAVSQZSKO-UHFFFAOYSA-N 0.000 description 13
- GMLAMRMKROYXNZ-UHFFFAOYSA-N 2-propan-2-ylsulfonylaniline Chemical compound CC(C)S(=O)(=O)C1=CC=CC=C1N GMLAMRMKROYXNZ-UHFFFAOYSA-N 0.000 description 13
- MILIRVVSCVAODI-UHFFFAOYSA-N 4-chloro-n-(4-dimethylphosphorylphenyl)-5-(trifluoromethyl)pyrimidin-2-amine Chemical compound C1=CC(P(C)(=O)C)=CC=C1NC1=NC=C(C(F)(F)F)C(Cl)=N1 MILIRVVSCVAODI-UHFFFAOYSA-N 0.000 description 13
- PRFFBKPDGZUVGF-UHFFFAOYSA-N 6-chloro-n-(4-dimethylphosphorylphenyl)pyrimidin-4-amine Chemical compound C1=CC(P(C)(=O)C)=CC=C1NC1=CC(Cl)=NC=N1 PRFFBKPDGZUVGF-UHFFFAOYSA-N 0.000 description 13
- 229940079593 drug Drugs 0.000 description 13
- 150000002148 esters Chemical class 0.000 description 13
- CVICEEPAFUYBJG-UHFFFAOYSA-N 5-chloro-2,2-difluoro-1,3-benzodioxole Chemical group C1=C(Cl)C=C2OC(F)(F)OC2=C1 CVICEEPAFUYBJG-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 238000006069 Suzuki reaction reaction Methods 0.000 description 12
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- 210000004027 cell Anatomy 0.000 description 12
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- 229910052739 hydrogen Inorganic materials 0.000 description 12
- 238000006467 substitution reaction Methods 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 11
- 239000003153 chemical reaction reagent Substances 0.000 description 11
- 238000010438 heat treatment Methods 0.000 description 11
- 125000006239 protecting group Chemical group 0.000 description 11
- XSUFWLZYYKQQRC-UHFFFAOYSA-N 4-dimethylphosphoryl-2-methoxyaniline Chemical compound COC1=CC(P(C)(C)=O)=CC=C1N XSUFWLZYYKQQRC-UHFFFAOYSA-N 0.000 description 10
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 10
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- 239000001257 hydrogen Substances 0.000 description 10
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 10
- 208000032004 Large-Cell Anaplastic Lymphoma Diseases 0.000 description 9
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- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 9
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- OYRRZWATULMEPF-UHFFFAOYSA-N pyrimidin-4-amine Chemical compound NC1=CC=NC=N1 OYRRZWATULMEPF-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- CKUZBDQFWACTPR-UHFFFAOYSA-N 2-chloro-n-(2-propan-2-ylsulfonylphenyl)-5-(trifluoromethyl)pyridin-4-amine Chemical compound CC(C)S(=O)(=O)C1=CC=CC=C1NC1=CC(Cl)=NC=C1C(F)(F)F CKUZBDQFWACTPR-UHFFFAOYSA-N 0.000 description 8
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 8
- 206010073478 Anaplastic large-cell lymphoma Diseases 0.000 description 8
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- 102000001253 Protein Kinase Human genes 0.000 description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 8
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
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Classifications
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Abstract
【化345】
Description
本発明の化合物は、ガン(ガンの中でも、とりわけリンパ腫、充実性腫瘍及び白血病を含む)、中でも進行がん並びに1種若しくは2種以上の他の治療法に耐性又は治療抵抗性の症例を含むガンの治療用の薬剤組成物及び治療方法におけるそれらの使用を可能にする、有用な広範囲の生物学的及び薬理学的活性を有することができる。
X1はNRb1又はCRbであり;
X2はNRc1又はCRcであり;
X3はNRd1又はCRdであり;
X4はNRe1又はCReであり;
環Aはアリール、又はN、O及びS(O)rから選ばれた1〜4個のヘテロ原子を含有する5若しくは6員環のヘテロアリール環であり;
Ra、Rb、Rc、Rd、及びReは、出てくる毎に独立して、ハロゲン、−CN、−NO2、−R1、−OR2、−O−NR1R2、−NR1R2、−NR1−NR1R2、−NR1−OR2、−C(O)YR2、−OC(O)YR2、−NR1C(O)YR2、−SC(O)YR2、−NR1C(=S)YR2、−OC(=S)YR2、−C(=S)YR2、−YC(=NR1)YR2、−YC(=N-OR1)YR2、−YC(=N−NR1R2)YR2、−YP(=O)(YR3)(YR3)、−Si(R3a)3、−NR1SO2R2、−S(O)rR2、−SO2NR1R2、及び−NR1SO2NR1R2よりなる群から選ばれ、そしてRb1、Rc1、Rd1及びRe1は存在せず、各Yは独立して、単結合、−O−、−S−又は−NR1−であるか;或いは
Rb、Rb1、Rc、Rc1、Rd、Rd1、Re及びRe1から選ばれた2つの隣接する置換基又は2つの隣接するRa部分は、それらが結合している原子と共に、N、O及びS(O)rから選ばれた0〜4個のヘテロ原子を含有し、1〜4個のRf部分で置換された、飽和、部分飽和若しくは不飽和の5、6若しくは7員環を形成していてもよく;ここで
各Rf部分は、独立して、ハロゲン、=O、=S、−CN、−NO2、−R1、−OR2、−O−NR1R2、−NR1R2、−NR1−NR1R2、−NR1−OR2、−C(O)YR2、−OC(O)YR2、−NR1C(O)YR2、−SC(O)YR2、−NR1C(=S)YR2、−OC(=S)YR2、−C(=S)YR2、−YC(=NR1)YR2、−YC(=N-OR1)YR2、−YC(=N−NR1R2)YR2、−YP(=O)(YR3)(YR3)、−Si(R3a)3、−NR1SO2R2、−S(O)rR2、−SO2NR1R2、及び−NR1SO2NR1R2よりなる群から選ばれるか、又は2つの隣接するRf部分が、それらが結合している原子と共に、N、O及びS(O)rから選ばれた0〜4個のヘテロ原子を含有する、場合により置換されていてもよい、飽和、部分飽和若しくは不飽和の5、6若しくは7員環を形成していてもよく;
Ra、Rb、Rc、Rd、Re、Rf、Rb1、Rc1、Rd1、及びRe1の少なくとも1つは、それが存在する場合、−P(=O)(R3)2であるか又はそれを含むか、或いは環の構成部分として−P(=O)(R3)−部分を含有する環系であるか、それを含み;
rは0、2又は2であり;
sは1、2、3、4又は5であり;
nは0又は1であり;
Yは出てくるごとに独立して、単結合、−O−,−S−又は−NR1−であり;
R1及びR2は出てくるごとに独立して、H、アルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、シクロアルキニル、アリール、ヘテロアルキル、ヘテロ環基(=ヘテロサイクル)及びヘテロアリールから選ばれ;
R3は出てくるごとに独立して、アルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、シクロアルキニル、アリール、ヘテロアルキル、ヘテロ環基及びヘテロアリールから選ばれるか、又は隣接する2つのR3部分が一緒になってリン原子を含有する環系を形成していてもよく、
R3aは出てくるごとに独立して、アルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、シクロアルキニル、アリール、ヘテロアルキル、ヘテロ環基及びヘテロアリールから選ばれ;
或いは、各NR1R2部分は、N、O及びS(O)rから選ばれた追加の0〜2個のヘテロ原子を含有する、場合により置換されていてもよい、飽和、部分飽和又は不飽和の5、6又は7員環であってもよく;
上記のアルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、シクロアルキニル、アリール、ヘテロアリール、及びヘテロ環部分は場合により置換されていてもよい。
2.化合物の特定化された種類とそれらの用途、一般説明
本発明で使用するのに特に興味ある1つの種類の化合物は、X2がCRcであり、X3がCRdであり、X4がCReである、上記パート1に記載した通りの一般式Iで示される化合物である。この種の化合物は次の一般式IAで示される化合物により例示される。
X1はN又はCRbであり、そして環A、Ra、Rb、Rc、Rd、Re、n及びsは上で一般式Iにおいて定義した通りである。
別の種類の興味ある化合物としては、環Aが5又は6員環ヘテロアリールである化合物が挙げられる。
興味ある別の下位種としては、nが1である一般式IBの化合物が挙げられる。
興味ある別の下位種としては、環Aがフェニルである一般式IBの化合物がある。
興味ある別の下位種としては、nが1である一般式ICの化合物が挙げられる。
興味ある別の下位種としては、環Aがフェニルである一般式ICの化合物がある。
本発明で使用するのに特に興味ある1つの種類の化合物は上記一般式IIで示される化合物において、X2がCRcであり、X3がCRdであり、X4がCReであるものである。この種類は次の一般式IIAで示される化合物により例示される。
興味ある1つの下位種は、mが0である一般式II又は一般式IIAで示される化合物である。別の下位種ではmは1である。
興味ある別の下位種は、XがCRbである一般式II又は一般式IIAで示される化合物である。
特に興味ある1つの種類の化合物は、環Aがフェニルである一般式IIAで示される化合物である。
本発明で使用するのに特に興味ある1つの種類の化合物は、上記の通りの一般式IIIで示される化合物において、X2がCRcであり、X3がCRdであり、X4がCReであり、Rc及びRd部分は、それらが結合している原子と共に、5、6若しくは7員環の飽和、部分飽和若しくは不飽和環Bを形成している化合物である。この種類は次の一般式IIIAで示される化合物により例示される。
ある特定の態様では、1つのRaが−P(=O)(R3)2であるか又はそれを含むか、或いは環の構成部分として−P(=O)(R3)−部分を含有する環系であるか又はそれを含む(例えば、−(CH2)m−P(=O)(アルキル)2、ここでmは0、1、2、3又は4、並びに上に列挙した環式のものを含むリン含有置換基の他の例)。別の特定の態様では、RfがP(=O)(R3)2であるか又はそれを含むか、或いは環の構成部分として−P(=O)(R3)−部分を含有する環系であるか又はそれを含む(例えば、−(CH2)m−P(=O)(アルキル)2、ここでmは0、1、2、3又は4、並びに上に列挙した環式のものを含むリン含有置換基の他の例)。
この種類の化合物を例示すると、 下記の一般式IIIAで示される化合物である。
この種類の代表例を例示すると、下記の一般式IVで示される化合物である。
この態様のある特定の形態では、1つのRaが、−P(=O)(R3)2であるか又はそれを含み、或いは環の構成部分として−P(=O)(R3)−部分を含有する環系であるか又はそれを含む。
この態様の別の形態では、RcがP(=O)(R3)2であるか又はそれを含み、或いは環の構成部分として−P(=O)(R3)−部分を含有する環系であるか又はそれを含む。
この種類の化合物を例示すると、下記の一般式IVAで示される化合物である。
この種類の化合物例を例示すると、下記の一般式Vで示される化合物である。
この態様のある特定の形態では、1つのRaが、−P(=O)(R3)2であるか又はそれを含み、或いは環の構成部分として−P(=O)(R3)−部分を含有する環系であるか又はそれを含む。
この種類の化合物を例示すると、下記の一般式VAで示される化合物である。
X1はNRb1又はCRbであり;
X3はNRd1又はCRdであり;
X4はNRe1又はCReであり;
環Aはアリール、又はN、O及びS(O)rから選ばれた1〜4個のヘテロ原子を含有する5若しくは6員環ヘテロアリール環であり;
環Eは、アリール環、炭素環、又は炭素原子と独立してO、N及びS(O)rから選ばれた1〜4個のヘテロ原子とを含む5、6若しくは7員ヘテロ環又はヘテロアリール環を表し、環Eは場合により5、6若しくは7員環の飽和、部分飽和若しくは不飽和環と縮合しており、そして環Eは、炭素原子上又はヘテロ原子上で1〜7個のRg基により置換されている。
Rb、Rb1、Rd、Rd1、Re及びRe1から選ばれた2つの隣接する置換基又は2つの隣接するRa部分は、それらが結合している原子と共に、N、O及びS(O)rから選ばれた0〜4個のヘテロ原子を含有し、1〜4個のRf部分で置換された飽和、部分飽和若しくは不飽和の5、6若しくは7員環を形成していてもよく;ここで
各Rf部分は、独立して、ハロゲン、=O、=S、−CN、−NO2、−R1、−OR2、−O−NR1R2、−NR1R2、−NR1−NR1R2、−NR1−OR2、−C(O)YR2、−OC(O)YR2、−NR1C(O)YR2、−SC(O)YR2、−NR1C(=S)YR2、−OC(=S)YR2、−C(=S)YR2、−YC(=NR1)YR2、−YC(=N-OR1)YR2、−YC(=N−NR1R2)YR2、−YP(=O)(YR3)(YR3)、−Si(R3a)3、−NR1SO2R2、−S(O)rR2、−SO2NR1R2、及び−NR1SO2NR1R2よりなる群から選ばれるか、又は2つの隣接するRf部分が、それらが結合している原子と共に、N、O及びS(O)rから選ばれた0〜4個のヘテロ原子を含有する、場合により置換されていてもよい、飽和、部分飽和若しくは不飽和の5、6若しくは7員環を形成していてもよく;
各Rg部分は独立して、ハロゲン、=O、=S、−CN、−NO2、−R1、−OR2、−O−NR1R2、−NR1R2、−NR1−NR1R2、−NR1−OR2、−C(O)YR2、−OC(O)YR2、−NR1C(O)YR2、−SC(O)YR2、−NR1C(=S)YR2、−OC(=S)YR2、−C(=S)YR2、−YC(=NR1)YR2、−YC(=N-OR1)YR2、−YC(=N−NR1R2)YR2、−YP(=O)(YR3)(YR3)、−Si(R3a)3、−NR1SO2R2、−S(O)rR2、−SO2NR1R2、及び−NR1SO2NR1R2よりなる群から選ばれ、ここで各Yは独立して単結合、−O−、−S−又は−NR1−であり;、そしてRa、Rb、Rd、Re又はRgの少なくとも1つは、それが存在する場合、−P(=O)(R3)2であるか又はそれを含み、或いは環の構成部分として−P(=O)(R3)−部分を含有する環系であるか、それを含み;
rは0、1又は2であり;
sは1、2、3、4又は5であり;
nは0又は1であり;
pは1、2、3又は4であり;
Yは出てくるごとに独立して、単結合、−O−,−S−又は−NR1−であり;
R1及びR2は出てくるごとに独立して、H、アルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、シクロアルキニル、アリール、ヘテロアルキル、ヘテロ環基及びヘテロアリールから選ばれ;
R3は出てくるごとに独立して、アルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、シクロアルキニル、アリール、ヘテロアルキル、ヘテロ環基及びヘテロアリールから選ばれるか、又は隣接する2つのR3部分が一緒になってリン原子を含有する環系を形成していてもよく、
R3aは出てくるごとに独立して、アルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、シクロアルキニル、アリール、ヘテロアルキル、ヘテロ環基及びヘテロアリールから選ばれ;
或いは、各NR1R2部分は、N、O及びS(O)rから選ばれた追加のヘテロ原子0〜2個を含有する、場合により置換されていてもよい、飽和、部分飽和又は不飽和の5、6又は7員環であってもよく;
上記のアルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、シクロアルキニル、アリール、ヘテロアリール、及びヘテロ環部分のそれぞれは場合により置換されていてもよい。
別の態様において、一般式VIで示される化合物ではRgの1つが−P(=O)(R3)2であるか又はそれを含む。
ある特定の態様では、環Eは次式で示される。
別の興味ある種類は、Rgが−R1、−P(=O)(R3)2、−OR2、−NR1R2、−C(O)YR2、−NR1C(O)YR2、−NR1SO2R2、−S(O)rR2、−SO2NR1R2及び−NR1SO2NR1R2よりなる群から選ばれる上記種類の化合物である。別の興味ある下位種では、Rgが−NHC(O)R1、−NHC(O)NR1R2、−C(O)NHR1、−C(O)NR1R2、−NR1R2、アリール、ヘテロアリール、置換アルキル又はヘテロ環基である上記態様の化合物である。Rgの制限しない例は、−(CH2)yC(=O)NR1R2、−(CH2)yNHC(=O)R2、−(CH2)yNR1R2、−(CH2)yOR2、−(CH2)yヘテロ環、−(CH2)yアリール、−(CH2)yヘテロアリール、−NH−アリール、−NH−ヘテロアリール及び−NHヘテロ環、−(CH2)mP(=O)(アルキル)2であり、ここでy及びmは独立して0、1、2、3及び4から選ばれ、アルキルは直鎖(すなわち、非分岐若しくは非環式)、分岐、及び環式アルキル基を包含し、そしてアルキル、アリール、ヘテロアリール及びヘテロ環基は場合により置換されていてもよい。
特に興味あるのは、Rgが−R1、−P(=O)(R3)2、−OR2、−NR1R2、−C(O)YR2、−NR1C(O)YR2、−NR1SO2R2、−S(O)rR2、−SO2NR1R2及び−NR1SO2NR1R2よりなる群から選ばれる上記種類の化合物である。別の興味ある下位種では、Rgが−NHC(O)R1、−C(O)NHR1、−C(O)NR1R2、−NHC(O)NHR1、−NR1R2、アリール、ヘテロアリール、置換アルキル又はヘテロ環基である上記態様の化合物である。Rgの制限しない例は、−(CH2)yC(=O)NR1R2、−(CH2)yNHC(=O)R2、−(CH2)yNR1R2、−(CH2)yOR2、−SO2NR1R2、−(CH2)ySR2、−(CH2)yヘテロ環、−(CH2)yアリール、−(CH2)yヘテロアリール、−NH−アリール、−NH−ヘテロアリール、−NHヘテロ環及び−(CH2)mP(=O)(アルキル)2であり、ここでy及びmは独立して0、1、2、3及び4から選ばれ、アルキルは直鎖(すなわち、非分岐若しくは非環式)、分岐、及び環式アルキル基を包含し、そしてアルキル、アリール、ヘテロアリール及びヘテロ環基は場合により置換されていてもよい。
この種の化合物の制限しない具体例としては、置換された環Eが次式で示されるものである一般式VIで示される化合物が挙げられる。
特に興味あるのは、Rgが−R1、−P(=O)(R3)2、−OR2、−NR1R2、−C(O)YR2、−NR1C(O)YR2、−NR1SO2R2、−S(O)rR2、−SO2NR1R2及び−NR1SO2NR1R2よりなる群から選ばれる上記種類の化合物である。別の興味ある下位種では、Rgが−NHC(O)R1、−NHC(O)NHR1、−C(O)NHR1、−C(O)NR1R2、−NR1R2、アリール、ヘテロアリール、置換アルキル又はヘテロ環基である上記態様の化合物である。Raの制限しない例は、−OCH2CH2NR1R2、−OCH2C(O)NR1R2、−NR1C(O)NR1R2、−(CH2)yC(=O)NR1R2、−(CH2)yNHC(=O)R2、−(CH2)yNR1R2、−(CH2)yOR2、−SO2NR1R2、−(CH2)ySR2、−(CH2)yヘテロ環、−(CH2)yアリール、−(CH2)yヘテロアリール、−NH−アリール、−NH−ヘテロアリール、−NHヘテロ環及び−(CH2)mP(=O)(アルキル)2であり、ここでy及びmは独立して0、1、2、3及び4から選ばれ、アルキルは直鎖(すなわち、非分岐若しくは非環式)、分岐、及び環式アルキル基を包含し、そしてアルキル、アリール、ヘテロアリール及びヘテロ環基は場合により置換されていてもよい。
1態様において、環Eは、5、6若しくは7員環の飽和、部分飽和若しくは不飽和環と縮合しているアリール、炭素環又は5、6若しくは7員環ヘテロ環若しくはヘテロアリール環であって、環Eは場合により1〜5個のRg基により置換されている。
興味ある別の一部の態様では、環Eは6,6−又は6,5−二環式縮合環系である。この種の化合物の制限しない例としては、環Eが次式で示される一般式VIの化合物が挙げられる。
この種の化合物の制限しない具体例としては、置換された環Eが次式で示されるものである一般式VIの化合物が挙げられる。
X1はNRb1又はCRbであり、
X3はNRd1又はCRdであり、
X4はNRe1又はCReであり、
環A及び環Eはそれぞれ独立してアリール又はヘテロアリール環から選ばれ、該ヘテロアリール環はN、O及びS(O)rから選ばれた1〜4個のヘテロ原子を含有する5若しくは6員環であり;
Ra、Rb、Rd、Re及びRgは、出てくる毎に独立して、ハロゲン、−CN、−NO2、−R1、−OR2、−O−NR1R2、−NR1R2、−NR1−NR1R2、−NR1−OR2、−C(O)YR2、−OC(O)YR2、−NR1C(O)YR2、−SC(O)YR2、−NR1C(=S)YR2、−OC(=S)YR2、−C(=S)YR2、−YC(=NR1)YR2、−YC(=N−OR1)YR2、−YC(=N−NR1R2)YR2、−YP(=O)(YR3)(YR3)、−Si(R3a)3、−NR1SO2R2、−S(O)rR2、−SO2NR1R2、及び−NR1SO2NR1R2よりなる群から選ばれ;又はRa及びRgは、それぞれ独立して選ばれた−P(=O)(R3)2部分であるか又はそれを含み、或いは環の構成部分として−P(=O)(R3)−部分を含んだ環系であるか、それを含んでいてもよく;
Rb1、Rd1及びRe1は存在せず;
或いは、Rd、Rd1、Re及びRe1から選ばれた2つの隣接する置換基又は2つの隣接するRa部分は、それらが結合している原子と共に、N、O及びS(O)rから選ばれた0〜4個のヘテロ原子を含有し、ヘテロ環に適した置換基(下記参照)(その多様な例が本書に開示した例示化合物中に示されている)を4個まで含有しうる、飽和、部分飽和若しくは不飽和環の縮合5、6若しくは7員環を形成していてもよく;
RaとRgの少なくとも一方は、−P(=O)(R3)2部分であるか又はそれを含んでいるか、或いは環の構成部分として−P(=O)(R3)−部分を含んだ環系であるか、それを含んでおり;
LはO又はNHであり;
rは0、1又は2であり;
sは1、2、3、4又は5であり;
pは1、2、3又は4であり;
Yは出てくるごとに独立して、単結合、−O−,−S−又は−NR1−であり;
R1及びR2は出てくるごとに独立して、H、アルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、シクロアルキニル、アリール、ヘテロアルキル、ヘテロ環基及びヘテロアリール基から選ばれ;
R3は出てくるごとに独立して、アルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、シクロアルキニル、アリール、ヘテロアルキル、ヘテロ環基及びヘテロアリール基から選ばれるか、又は隣接する2つのR3部分が一緒になってリン原子を含有する環系を形成していてもよく、
R3aは出てくるごとに独立して、アルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、シクロアルキニル、アリール、ヘテロアルキル、ヘテロ環基及びヘテロアリールから選ばれ;
或いは、各NR1R2部分は、N、O及びS(O)rから選ばれた追加のヘテロ原子0〜2個を含有する、場合により置換されていてもよい、飽和、部分飽和又は不飽和の5、6又は7員環であってもよく;
上記のアルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、シクロアルキニル、アリール、ヘテロアリール、及びヘテロ環基は場合により置換されていてもよい。
(1)X1がNである;(2)X3がNで、X4がCReである;(3)X3がCRdで、X4がCReである;(4)X1がCRbである;(5)X3がNで、X4がCReである;又は(6)X3がCRdで、X4がCReである。
さらに興味ある別の種類の化合物は、環Aがフェニルである一般式VIIAで示される化合物である。この種の化合物は、次の一般式VIIBで示される化合物により代表される。
一般式VII、VIIA及びVIIBにおいて、環Aと環Fとは一緒に縮合環系を形成している。一般式VII、VIIA及びVIIBで示される化合物に利用できる縮合環系としては、制限されないが、一般式VIの環Eについて示したもの(下記を参照)及び下記の縮合環系が挙げられる。
上述した全ての種類及び下位種の化合物の1態様において、環Aは1〜5個のRa部分で置換されたフェニル基である。上述した全ての種類及び下位種の化合物のある態様において、環Aは6員環ヘテロアリール(例、ピリジン、ピラジン、ピリダジン、ピリミジン又はトリアジン環)である。上述した全ての種類及び下位種の化合物のさらに別の態様において、環Aは5員環ヘテロアリール(例、イミダゾール、ピラゾール、テトラゾール、オキサゾール、チアゾール、イソオキサゾール又はピロール環)である。
・分子量が質量単位1000未満、好ましくは750未満、より好ましくは600未満である(溶媒和若しくは共析している分子種がある場合のその重量、塩である場合の対イオンの重量を含まないで);或いは
・野生型もしくは変異型(特に臨床に関連する変異型)キナーゼ、特にALK、Met、Jak2、bRaf、EGFR、Tie−2、FLT3又は興味ある他のキナーゼに対する阻害活性が、(任意の科学的に許容されるキナーゼ阻害検定を用いて測定した)IC50値で、1μM以下であり、IC50値は好ましくは500nM又はそれより良好、最適にはIC50値は250nM又はそれより良好である;或いは
・ある特定のキナーゼに対する阻害活性のIC50値が、興味ある他のキナーゼに対するそのIC50値より少なくとも100倍は低い;或いは
・ALK、Met、Jak2、又はb−Rafに対する阻害活性のIC50値がそれぞれについて1μM又はそれより良好である;或いは
・in vitroで維持されているがん細胞系に対する、又は科学的に許容されるがん細胞異種移植片モデルを用いた動物試験における、細胞毒性又は細胞増殖阻害効果がある(特に好ましいのは、Ba/F3 NMP-ALK、Ba/F3 EML4-ALK、Karpas 299および/又はSU-DHL-1細胞の増殖を阻害する効力が、とりわけNVP-TAE684及びPF2341066のような既知のALK阻害剤の効力に対して、比較試験で測定して、少なくとも同等の高さであり、好ましくは既知ALK阻害剤の抗力の少なくとも2倍、より好ましくは既知ALK阻害剤の抗力の少なくとも10倍である本発明の化合物である)。
本書を読むにあたって、特に指示がない限り、下記の情報及び定義があてはまる。
「アルキル」なる用語は、直鎖(すなわち、非分岐又は非環式)、分岐、環式又は多環式の非芳香族炭化水素基を包含する意味であり、場合により1又は2以上の官能基で置換されていてもよい。特に指定しない限り、アルキル基は、1〜8個、好ましくは1〜6個の炭素原子を含有する。C1-6アルキルとはC1、C2、C3、C4、C5、及びC6アルキル基を包含する意味である。低級アルキルとは炭素数1〜6のアルキルを意味する。アルキルの例としては、それらに限られないが、メチル、エチル、n−プロピル、イソプロピル、シクロプロピル、ブチル、イソブチル、sec−ブチル、tert−ブチル、シクロブチル、ペンチル、イソペンチル、tert−ペンチル、シクロペンチル、ヘキシル、イソヘキシル、シクロヘキシルなどが挙げられる。アルキルは置換されていても、非置換でもよい。置換アルキル基の例としては、それらに限られないが、フルオロメチル、ジフルオロメチル、トリフルオロメチル、2−フルオロエチル、3−フルオロプロピル、ヒドロキシメチル、2−ヒドロキシエチル、3−ヒドロキシプロピル、ベンジル、置換ベンジル、フェネチル、置換フェネチルなどが挙げられる。
特に指摘しない限り、ここに示した構造は、その構造の全ての立体化学的形態、すなわち、各不斉中心に対してR配置とS配置の両方、を包含するものである。従って、本発明の化合物の単独の立体化学異性体並びにエナンチオマー(鏡像異性体)混合物及びジアステレオマー混合物が本発明の範囲内である。すなわち、本発明は、他の異性体を実質的に含まないそれぞれのジアステレオマー又はエナンチオマー(モル基準で90%超、好ましくは95%超が他の立体異性体を含まない)、並びにこのような異性体の混合物を包含する。
本発明の化合物は、放射化標識(放射性同位体標識)された形態でも存在しうる。すなわち、該化合物は、自然界に通常見られる原子質量又は質量数とは異なる原子質量又は質量数を持つ1又は2以上の原子を含有していてもよい。水素、炭素、リン、フッ素及び塩素の放射性同位体としては、それぞれ3H、14C、32P、35S、18F、及び36Clが挙げられる。このような放射性同位体及び/又は他の原子の他の放射性同位体を含有する本発明の化合物も本発明の範囲内である。トリチウム(即ち、3H)と炭素14(即ち、14C)が、製造及び検出が容易であることから特に好ましい放射性同位体である。
当業者は、Ra、Rb、Rc、Rd、Re、Rb1、Rc1、Rd1、Re1、Rf、Rg、並びに環A、B、C、D、E、及びFの各種の選択枝を含む化合物を包含する本発明の化合物の合成、回収及び特性決定に対して有用な合成戦略、保護基並びに他の材料及び方法の指針について、後述の実施例に含まれる情報と組み合わせて採用されうる、複素環及び他の関連する化学的変換、回収及び精製技術についての確立した文献を持っている。
intermediate:中間体
microwave又はmw:マイクロ波(加熱); microwave heating:マイクロ波加熱
Ethanol:エタノール; pyridine:ピリジン; toluene又はTol:トルエン
dioxane:ジオキサン; solvent:溶媒
r.t.又はrt:室温
2-methoxyethanol:2-メトキシエタノール
Suzuki coupling:スズキ・カップリング
base:塩基; Hunig's base:ヒューニッヒ塩基 (=DIPEA)
heat:加熱; reflux:還流加熱
hydrogenation:水素化
overnight:一晩
N,N-dimethylaniline:N,N-ジメチルアニリン。
反応図式11は、一般式IA及びVIAにおいてnが0、LがNH、そしてX1がCHである化合物の合成を示す。
制限しない例として、反応図式15Aは、一般式IIIAにおいてX1がNで、Rc及びRdがピロール環を形成し、環Aが置換フェニルであって、Rfも置換フェニルである化合物の合成を示す。
本発明の化合物において、Ra、Rb、Rb1、Rc、Rc1、Rd、Rd1、Re、Re1、Rf、又はRgの1つは、存在する場合、−P(=O)(R3)2であるか、それを含んでいる。
反応図式17は、環Aが−P(=O)(R3)2で置換されたピリジンである[環A]−NH2部分の合成を例示する。
この反応図式はまた、環Eがナフタレンで、LがNHであり、Rgが−P(=O)(R3)2である[環E]−L部分の合成にも使用できよう。この反応図式はまた一般式VIIAで示される本発明の化合物の合成にも使用することができる。
一部の態様では、−P(=O)(R3)2置換基を含有するRa、Rf又はRgが、環式構造のものとなりうる。
反応図式22は、−P(=O)(R3)2を含有する環式置換基Ra(又はRf又はRg)の合成を示す。
反応図式22Aは、環Aがメトキシ基と−P(=O)(R3)2含有環式置換基とで置換されたフェニルである[環A]−NH2部分の合成を示す。この反応図式は、LがNHで、環Eがメトキシ基と−P(=O)(R3)2含有環式置換基とで置換されたフェニルである[環E]−L部分の合成にも使用することができよう。
制限しない例として、反応図式36Aは、RcとRdとがイミダゾールを形成し、環Aが置換フェニルであり、Rfが置換フェニルである一般式IIIAの化合物の合成を示す。
RdがHである場合、3,5−ジクロロ−1,2,4−トリアジンは、Journal of Organic Chemistry, 23, 1522-4; 1958に記載された方法に従って調製することができ、この方法では、1,2,4−トリアジン−3,5(2H,4H)ジオンをPOCl3と反応させる。3,5−ジクロロ−1,2,4−トリアジンの合成を反応図式41に示す。
制限しない例として、反応図式47Aは、Lが単結合で、[環E]が置換フェニルである一般式VIBの化合物の調製を示す。
制限しない例として、反応図式56Aは、環Bがピラゾール、環Aが置換フェニル、そしてR”がメトキシ基である一般式IIIAの化合物の合成を示す。
医薬用途;適応症
本発明は、キナーゼが関与している可能性のある疾患、かかる疾患の徴候、又はキナーゼが媒介する他の生理学的事象の作用を治療又は改善するのに有益となる生物学的性質を有する化合物を提供する。例えば、本発明の多くの化合物は、がんの成長(増殖)、発生及び/又は転移を媒介すると考えられているチロシンキナーゼ、とりわけALK、fak及びc−metのチロシンキナーゼ活性を阻害することが示された。本発明の多くの化合物はまた、とりわけkarpas299細胞を含むがん細胞系に抗する強力なin vitro活性を有することが認められた。従って、かかる化合物は充実性腫瘍並びにリンパ腫を含み、また他の治療法に耐性であるがんを含むがんの治療に興味あるものとなる。
本発明は、がんに罹患しているか、罹患の危険性がある個体を、該個体に治療有効量の本発明の化合物を投与することにより治療する方法を提供する。
本発明の抗がん剤化合物は、好ましくは投与の容易さと投与量の均一さのために単位剤形の形態で処方される。ここで用いた「単位剤形」とは、抗がん剤が治療を受ける患者に適した形で物理的に分かれている単位を意味する。普通そうであるように、本発明の化合物及び組成物の総日用量は、健全な医学的判断への通常の信頼性を用いて主治医により決定されよう。任意の個々の患者又は生体に対する具体的な治療有効投与量レベルは、治療される疾患の種類;その疾患の重症度;採用された具体的化合物の効力;採用された具体的組成物;患者の年齢、体重、全身健康状態、性別及び食事;投与の経路及び計画;その化合物の代謝及び/又は排泄の速度;治療期間;本発明の化合物の投与と組み合わせて又は同時に使用される薬剤;並びに医学分野で周知の同様な因子を包含する多様な因子に応じて変動しよう。
本発明の化合物は、治療のために遊離形態で存在することができ、或いは、適当であれば、薬剤に許容される塩、エステル又はプロドラッグとして存在することもできる。ここで用いた用語「薬剤に許容される塩」は、健全な医学的判断の範囲内で、過度の毒性、刺激、アレルギー反応等を伴わずにヒト及びより下等な動物の組織との接触に使用するのに適していて、妥当な便益/危険比と釣り合っている塩を意味する。アミン、カルボン酸、リン酸エステルもしくは塩、並びに他の種類の化合物の薬剤に許容される塩は本技術分野において周知である。例えば、S.M. Berge et alは、ここに参考文献として援用する J. Pharmaceutical Science, 66: 1-19 (1977)において、薬剤に許容される塩について詳述している。塩は、本発明の化合物の単離及び精製中にその場で調製するか、又は遊離塩基もしくは遊離酸形態の本発明の化合物をそれぞれ適当な酸もしくは塩基と反応させることにより別に調製することができる。
本発明により、本発明の化合物、又はそのプロドラッグ、薬剤に許容される塩若しくは他の薬剤に許容されるエステルと、1種又は2種以上の薬剤に許容される担体又は賦形剤とを含有する薬剤組成物が提供される。これらの薬剤組成物は場合により1種又は2種以上の追加の治療剤をさらに含有していてもよい。場合により、本発明の化合物を、1種又は2種以上の他の治療介入(例、グリーベック又は他のキナーゼ阻害剤、インターフェロン、骨髄移植、ファルネシルトランスフェラーゼ阻害剤、ビスホスホネート、サリドマイド、がんワクチン、ホルモン療法、抗体、放射線など)を受けている個体に投与してもよい。例えば、本発明の化合物を、併用療法の1成分として使用することができ、この場合、追加の1種又は2種以上の治療剤(例、抗がん剤)が、本発明の化合物と一緒に又は別個に処方されて、該個体に投与される。
眼への局所投与に適した処方組成物は、有効成分を適当な担体、特に有効成分のための水性溶媒に溶解又は懸濁させた点眼剤も包含する。本有効成分は、かかる処方組成物中に0.5〜20%w/w、有利には0.5〜10%、特に約1.5%の濃度で存在することが好ましい。
薬剤の直腸投与のための座剤は、常温では固体であるが、直腸温度では液体となり、したがって直腸内で融解して薬剤を放出する、カカオバター及びポリエチレングリコール類のような適当な非刺激性賦形剤と薬剤を混合することにより調製することができる。
本発明の化合物は、これが唯一の有効薬剤成分である治療計画の部分として投与することもできるが、併用療法の部分として、他の1種又は2種以上の治療剤と組み合わせて使用することもできる。併用療法の1成分として投与する場合、それら複数の治療剤は、同時に又は異なる時点(例、互いに72時間、48時間、24時間の間隔)で逐次的に投与されるそれぞれ別個の組成物として処方することができ、或いはそれら治療剤を単一の薬剤組成物として一緒に処方して同時に投与することもできる。
別の態様では、本発明は、本発明に係る方法を便利かつ効果的に実施するためのキットに関する。一般に、薬剤パック又はキットは、本発明の薬剤組成物の1又は2以上の成分が充填された1又は2以上の容器と、その薬剤組成物をここに記載した方法の一部として投与するための使用説明書(例、ラベル又はパッケージ封入物)とを含んでいる。このようなキットは、特に錠剤又はカプセルのような固体経口剤形の供給に適している。この種のキットは好ましくは複数の単位剤形を含んでいて、それらの剤形を意図したそれらの使用順序に向けさせるカードを含んでいてもよい。所望により、その剤形を投与することができる治療スケジュールの日にちを指定する、例えば、数字、文字、もしくは他のマークの形態で、又はカレンダーにページを、記憶補助具として提供することができる。場合によりかかる容器に組み合わせることができるのは、医薬品の製造、使用又は販売を規制する監督官庁により規定された形態の注意書きであり、この注意書きはヒト用医薬品の製造、使用又は販売官庁による認可事項を反映する。
N-[4-(ジメチルホスホリル)フェニル]-4-(4-メチルピペラジン-1-イル)-5-(トリフルオロメチル)ピリミジン-2-アミン
N2-[4-(ジメチルホスホリル)フェニル]-N4-(トリシクロ「3.3.1.13,7」デク-1-イル)-5-(トリフルオロメチル)ピリミジン-2,4-ジアミン
N2-[4-(ジメチルホスホリル)フェニル]-N4-(モルホリン-4-イル)-5-(トリフルオロメチル)ピリミジン-2,4-ジアミン
4-(2-{[2-{[4-(ジメチルホスホリル)フェニル]アミノ}-5-(トリフルオロメチル)ピリミジン-4-イル]アミノ}エチル)ベンゼンスルホンアミド
N2-[4-(ジメチルホスホリル)フェニル]-N4-(テトラヒドロフラン-2-イル)-5-(トリフルオロメチル)ピリミジン-2,4-ジアミン
N2-[4-(ジメチルホスホリル)フェニル]-N4-(ヘキサヒドロシクロペンタ[c]ピロール-2(1H)-イル)-5-(トリフルオロメチル)ピリミジン-2,4-ジアミン
N2-[4-(ジメチルホスホリル)フェニル]-N4-(モルホリン-4-イル)-5-(トリフルオロメチル)ピリミジン-2,4-ジアミン
N-[4-(ジメチルホスホリル)フェニル]-4-(4-フェニルピペラジン-1イル)-5-(トリフルオロメチル)ピリミジン-2-アミン
N2-[4-(ジメチルホスホリル)フェニル]-N4-[2-(1H-インドール-3-イル)エチル]-5-(トリフルオロメチル)ピリミジン-2,4-ジアミン
N2-[4-(ジメチルホスホリル)フェニル]-N4-[4-メチルピペラジン-1-イル]-5-(トリフルオロメチル)ピリミジン-2,4-ジアミン
N2-[4-(ジメチルホスホリル)フェニル]-N4-[4-トリシクロ[3.3.1.13.7]デク-1-イルメチル]-5-(トリフルオロメチル)ピリミジン-2,4-ジアミン
N2-[4-(ジメチルホスホリル)フェニル]-N4-[4-(4-メチルピペラジン-1-イル)ベンジル]-5-(トリフルオロメチル)ピリミジン-2,4-ジアミン
N4-(3,5-ジメチルフェニル)-N2-[4-(ジメチルホスホリル)フェニル]-5-(トリフルオロメチル)ピリミジン-2,4-ジアミン
5-クロロ-N2-[4-(ジメチルホスホリル)-2-メトキシフェニル]-N4-フェニルピリミジン-2,4-ジアミン
N2-[4-(ジメチルホスホリル)-2-メトキシフェニル]-N4-[2-(プロパン-2-イルスルホニル)フェニル]-5-(トリフルオロメチル)ピリミジン-2,4-ジアミン
5-クロロ-N2-[4-(ジメチルホスホリル)-2-メトキシフェニル]-N4-[2-(プロパン-2-イルスルホニル)フェニル]ピリミジン-2,4-ジアミン
5-クロロ-N2-[4-(ジメチルホスホリル)フェニル]-N4-[2-(プロパン-2-イルスルホニル)フェニル]ピリミジン-2,4-ジアミン
5-クロロ-N4-[4-(ジメチルホスホリル)フェニル]-N2-{2-メトキシ-4-[4-(4-メチルピペラジン-1-イル)ピペリジン-1-イル]フェニル}ピリミジン-2,4-ジアミン
N2-[4-(ジメチルホスホリル)-2-メトキシフェニル]-N4-[2-(プロパン-2-イルスルホニル)フェニル]ピリミジン-2,4-ジアミン
N2-[4-(ジメチルホスホリル)-2-メトキシフェニル]-5-メチル-N4-[2-(プロパン-2-イルスルホニル)フェニル]ピリミジン-2,4-ジアミン
5-クロロ-N2-[5-(ジメチルホスホリル)-2-メトキシフェニル]-N4-[2-(プロパン-2-イルスルホニル)フェニル]ピリミジン-2,4-ジアミン
5-クロロ-N2-[4-(ジメチルホスホリル)-2-メチルフェニル]-N4-[2-(プロパン-2-イルスルホニル)フェニル]ピリミジン-2,4-ジアミン
5-クロロ-N2-[4-(ジメチルホスホリル)-2-エチルフェニル]-N4-[2-(プロパン-2-イルスルホニル)フェニル]ピリミジン-2,4-ジアミン
5-クロロ-N2-[4-(ジメチルホスホリル)-2-(トリフルオロメトキシ)フェニル]-N4-[2-(プロパン-2-イルスルホニル)フェニル]ピリミジン-2,4-ジアミン
5-クロロ-N2-[2-クロロ-4-(ジメチルホスホリル)フェニル]-N4-[2-(プロパン-2-イルスルホニル)フェニル]ピリミジン-2,4-ジアミン
5-クロロ-N2-[4-(ジメチルホスホリル)-2-フルオロフェニル]-N4-[2-(プロパン-2-イルスルホニル)フェニル]ピリミジン-2,4-ジアミン
N2-[4-(ジメチルホスホリル)-2-メトキシフェニル]-N4-[2-(プロパン-2-イルスルホニル)フェニル]ピリミジン-2,4,5-トリアミン
2-{[4-(ジメチルホスホリル)-2-メトキシフェニル]アミノ}-9-[2-(プロパン-2-イルスルホニル)フェニル]-7,9-ジヒドロ-8H-プリン-8オン
N2-[2-メトキシ-4-(4-オキシド-1,4-アザホスフィナン-4-イル)フェニル]-N4-[2-(プロパン-2-イルスルホニル)フェニル]ピリミジン-2,4-ジアミン
N2-[4-(ジメチルホスホリル)-2-メトキシフェニル]-N4-[2-(プロパン-2-イルスルホニル)フェニル]-7H-ピロロ[2,3-d]ピリミジン-2,4-ジアミン
5-クロロ-N2-[6-(ジメチルホスホリル)-2-メトキシピリジン-3-イル]-N4-[2-(プロパン-2-イルスルホニル)フェニル]ピリミジン-2,4-ジアミン
5-クロロ-N2-[5-(ジメチルホスホリル)-3-メトキシピラジン-2-イル]-N4-[2-(プロパン-2-イルスルホニル)フェニル]ピリミジン-2,4-ジアミン
5-クロロ-N2-[6-(ジメチルホスホリル)-2-メトキシピリジン-3-イル]-N4-フェニルピリミジン-2,4-ジアミン
N2-[6-(ジメチルホスホリル)-2-メトキシピリジン-3-イル]-N4-[2-(プロパン-2-イルスルホニル)フェニル]-5-(トリフルオロメチル)ピリミジン-2,4-ジアミン
N2-[5-(ジメチルホスホリル)-3-メトキシピラジン-2-イル]-N4-[2-(プロパン-2-イルスルホニル)フェニル]-5-(トリフルオロメチル)ピリミジン-2,4-ジアミン
5-クロロ-N2-[6-(ジメチルホスホリル)-2-メトキシピリジン-3-イル]-N4-[4-(ジメチルホスホリル)フェニル]ピリミジン-2,4-ジアミン
5-クロロ-N2-[5-(ジメチルホスホリル)-3-メトキシピラジン-2-イル]-N4-{2-メトキシ-4-[4-(4-メチルピペラジン-1-イル)ピペリジン-1-イル]フェニル}ピリミジン-2,4-ジアミン
5-クロロ-N-[6-(ジメチルホスホリル)-2-メトキシピリジン-3-イル]-4-(4-メチルピペラジン-1-イル)ピリミジン-2-アミン
N2-[6-(ジメチルホスホリル)-2-メトキシピリジン-3-イル]-N4-(モルホリン-4-イルメチル)-5-(トリフルオロメチル)ピリミジン-2,4-ジアミン
4-(2-{[2-{[6-(ジメチルホスホリル)-2-メトキシピリジン-3-イル]アミノ}-5-(トリフルオロメチル)ピリミジン-4-イル]アミノ}エチル)ベンゼンスルホンアミド
2-[5-(ジメチルホスホリル)-3-メトキシピラジン-2-イル]-4-(4-フェニルピペラジン-1-イル)-5-(トリフルオロメチル)ピリミジン
2-[5-(ジメチルホスホリル)-3-メトキシピラジン-2-イル]-N-[2-(1H-インドール-3-イル)エチル]-5-(トリフルオロメチル)ピリミジン-4-アミン
N2-[4-(ジメチルホスホリル)フェニル]-N4-[4-(4-メチルピペラジン-1-イル)ベンジル]-5-(トリフルオロメチル)ピリミジン-2,4-ジアミン
N2-[6-(ジメチルホスホリル)-2-メトキシピリジン-3-イル]-N4-[2-(プロパン-2-イルスルホニル)フェニル]ピリミジン-2,4-ジアミン
N2-[6-(ジメチルホスホリル)-2-メトキシピリジン-3-イル]-5-メチル-N4-[2-(プロパン-2-イルスルホニル)フェニル]ピリミジン-2,4-ジアミン
5-クロロ-N4-[2-メトキシ-4-(4-メチル-4-オキシド-1,4-アザホスフィナン-1-イル)フェニル]-N2-(チオフェン-2-イルメチル)ピリミジン-2,4-ジアミン
5-クロロ-N4-[2-メトキシ-4-(4-メチル-4-オキシド-1,4-アザホスフィナン-1-イル)フェニル]-N2-[5-(プロパン-2-イル)-1,3-オキサゾール-2-イル]ピリミジン-2,4-ジアミン
5-クロロ-N2-[1-(4-フルオロベンジル)-1H-ピロール-3-イル]-N4-[2-メトキシ-4-(4-メチル-4-オキシド-1,4-アザホスフィナン-1-イル)フェニル]ピリミジン-2,4-ジアミン
2-{[(5-クロロ-4-{[2-メトキシ-4-(4-メチル-4-オキシド-1,4-アザホスフィナン-1-イル)フェニル]アミノ}ピリミジン-2-イル)アミノ]メチル}-N,N-ジエチルチオフェン-3-スルホンアミド
N2-[5-(1,4'-ビピペリジン-1'-イル)-1,3,4-チアジアゾール-2-イル]-5-クロロ-N4-[5-(ジメチルホスホリル)-3-メトキシピラジン-2-イル]ピリミジン-2,4-ジアミン
5-クロロ-N4-[5-(ジメチルホスホリル)-3-メトキシピラジン-2-イル]-N2-{[5-(4-メチルピペラジン-1-イル)-1,3,4-オキサジアゾール-2-イル]メチル}ピリミジン-2,4-ジアミン
5-クロロ-N4-[4-(ジメチルホスホリル)-2-(プロパン-2-イルスルホニル)フェニル]-N2-{5-[4-(ピリジン-2-イル)ピペラジン-1-イル]-1,3,4-オキサジアゾール-2-イル}ピリミジン-2,4-ジアミン
5-クロロ-N4-[4-(ジメチルホスホリル)-2-(プロパン-2-イルスルホニル)フェニル]-N2-{[2-(モルホリン-4-イル)-1,3-チアゾール-4-イル]メチル}ピリミジン-2,4-ジアミン
N2-ベンジル-5-クロロ-N4-[4-(ジメチルホスホリル)-2-(プロパン-2-イルスルホニル)フェニル]ピリミジン-2,4-ジアミン
5-クロロ-N2-(5-シクロプロピル-1,3-オキサゾール-2-イル)-N4-{2-メトキシ-4-[4-(4-メチル-4-オキシド-1,4-アザホスフィナン-1-イル)ピペリジン-1-イル]フェニル}ピリミジン-2,4-ジアミン
5-クロロ-N2-(5-シクロプロピル-1,3-オキサゾール-2-イル)-N4-[4-(1-エチル-4-オキシド-1,4-アザホスフィナン-4-イル)-2-メトキシフェニル]ピリミジン-2,4-ジアミン
5-クロロ-N2-(2-シクロプロピル-1,3-オキサゾール-5-イル)-N4-[4-(ジエチルホスホリル)-2-メトキシフェニル]ピリミジン-2,4-ジアミン
N-[4-(ジメチルホスホリル)フェニル]-6-(4-メチルピペラジン-1-イル)ピリミジン-4-アミン
N-[4-(ジメチルホスホリル)フェニル]-N'-(トリシクロ「3.3.1.13,7」デク-1-イル)ピリミジン-4,6-ジアミン
N-[4-(ジメチルホスホリル)フェニル]-N'-(モルホリン-4-イルメチル)ピリミジン-4,6-ジアミン
4-{2-[(6-{[4-(ジメチルホスホリル)フェニル]アミノ}ピリミジン-4-イル)アミノ]エチル}ベンゼンスルホンアミド
N-[4-(ジメチルホスホリル)フェニル]-N'-(テトラヒドロフラン-2-イル)ピリミジン-4,6-ジアミン
N-[4-(ジメチルホスホリル)フェニル]-N'-(ヘキサヒドロシクロペンタ[c]ピロール-2(1H)-イル)ピリミジン-4,6-ジアミン
N-[4-(ジメチルホスホリル)フェニル]-N'-(モルホリン-4-イル)ピリミジン-4,6-ジアミン
N-[4-(ジメチルホスホリル)フェニル]-6-(4-フェニルピペラジン-1-イル)ピリミジン-4-アミン
N-[4-(ジメチルホスホリル)フェニル]-N'-[2-(1H-インドール-3-イル)エチル]ピリミジン-4,6-ジアミン
(実施例68)
N-[4-(ジメチルホスホリル)フェニル]-N'-(4-メチルピペラジン-1-イル)ピリミジン-4,6-ジアミン
N-[4-(ジメチルホスホリル)フェニル]-N'-(トリシクロ「3.3.1.13,7」デク-1-イルメチル)ピリミジン-4,6-ジアミン
N-[4-(ジメチルホスホリル)フェニル]-N'-[4-(4-メチルピペラジン-1-イル)ベンジル]ピリミジン-4,6-ジアミン
N-(3,5-ジメチルフェニル)-N'-[4-(ジメチルホスホリル)フェニル]ピリミジン-4,6-ジアミン
(実施例72)
N-[4-(ジメチルホスホリル)-2-メトキシフェニル]-2-メチル-N'-フェニルピリミジン-4,6-ジアミン
N3-[4-(ジメチルホスホリル)-2-メトキシフェニル]-N5-[2-(プロパン-2-イルスルホニル)フェニル]ピリダジン-3,5-ジアミン
N-[4-(ジメチルホスホリル)-2-メトキシフェニル]-5-[3-フルオロ-5-(トリフルオロメチル)フェノキシ]ピリダジン-3-アミン
N-{2-メトキシ-4-[4-(4-メチルピペラジン-1-イル)ピペリジン-1-イル]フェニル}-2-メチル-N'-[2-(プロパン-2-イルスルホニル)フェニル]ピリミジン-4,6-ジアミン
N-[6-(ジメチルホスホリル)-2-メトキシピリジン-3-イル]-N'-[2-(プロパン-2-イルスルホニル)フェニル]ピリミジン-4,6-ジアミン
N-[5-(ジメチルホスホリル)-3-メトキシピラジン-2-イル]-N'-[2-(プロパン-2-イルスルホニル)フェニル]ピリミジン-4,6-ジアミン
N-[4-(ジメチルホスホリル)-2-メトキシフェニル]-N'-[2-(プロパン-2-イルスルホニル)フェニル]ピリミジン-4,6-ジアミン
バイアルに入れた2-メトキシエタノール0.5 mL中の6-クロロ-N-[2-(プロパン-2-イルスルホニル)フェニル]ピリミジン-4-アミン (実施例76で調製、0.054 mmol) の溶液に、4-(ジメチルホスホリル)-2-メトキシアニリン (実施例73で調製、0.044 mmol) をHCl塩として加える。このバイアルを密封し、反応液を目的化合物が生成するまで90℃に加熱する。1N NaOH溶液で反応を停止させ、溶液を酢酸エチルで抽出する。有機層を合わせて、飽和塩化ナトリウム溶液で洗浄し、硫酸ナトリウムで乾燥し、濾過し、濃縮する。得られた粗製残渣をシリカゲルクロマトグラフィーで精製することができる。
N2-[4-(ジメチルホスホリル)-2-メトキシフェニル]-N4-[2-(プロパン-2-イルスルホニル)フェニル]ピリジン-2,4-ジアミン
N2-[4-(ジメチルホスホリル)-2-メトキシフェニル]-N4-[2-(プロパン-2-イルスルホニル)フェニル]-5-(トリフルオロメチル)ピリジン-2,4-ジアミン
N2-[5-(ジメチルホスホリル)-2-メトキシフェニル]-N4-[2-(プロパン-2-イルスルホニル)フェニル]-5-(トリフルオロメチル)ピリジン-2,4-ジアミン
N2-[4-(ジメチルホスホリル)-2-メチルフェニル]-N4-[2-(プロパン-2-イルスルホニル)フェニル]-5-(トリフルオロメチル)ピリジン-2,4-ジアミン
N2-[4-(ジメチルホスホリル)-2-エチルフェニル]-N4-[2-(プロパン-2-イルスルホニル)フェニル]-5-(トリフルオロメチル)ピリジン-2,4-ジアミン
N2-[4-(ジメチルホスホリル)-2-(トリフルオロメトキシ)フェニル]-N4-[2-(プロパン-2-イルスルホニル)フェニル]-5-(トリフルオロメチル)ピリジン-2,4-ジアミン
N2-[2-クロロ-4-(ジメチルホスホリル)フェニル]-N4-[2-(プロパン-2-イルスルホニル)フェニル]-5-(トリフルオロメチル)ピリジン-2,4-ジアミン
N2-[4-(ジメチルホスホリル)-2-フルオロフェニル]-N4-[2-(プロパン-2-イルスルホニル)フェニル]-5-(トリフルオロメチル)ピリジン-2,4-ジアミン
N-[4-(ジメチルホスホリル)-2-(プロパン-2-イルスルホニル)フェニル]-N'-{2-メトキシ-4-[4-(4-メチルピペラジン-1-イル)ピペリジン-1-イル]フェニル}ピリミジン-4,6-ジアミン
N3-[4-(1-エチル-4-オキシド-1,4-アザホスフィナン-4-イル)-2-メトキシフェニル]-N5-[2-(プロパン-2-イルスルホニル)フェニル]ピリダジン-3,5-ジアミン
N3-[2-メトキシ-4-(4-メチル-4-オキシド-1,4-アザホスフィナン-1-イル)フェニル]-N5-[2-(プロパン-2-イルスルホニル)フェニル]ピリダジン-3,5-ジアミン
N3-{2-メトキシ-4-[4-(4-メチル-4-オキシド-1,4-アザホスフィナン-1-イル)ピペリジン-1-イル]フェニル}-N5-[2-(プロパン-2-イルスルホニル)フェニル]ピリダジン-3,5-ジアミン
N3-[4-(ジエチルホスホリル)-2-メトキシフェニル]-N5-[2-(プロパン-2-イルスルホニル)フェニル]ピリダジン-3,5-ジアミン
N-[4-(ジメチルホスホリル)フェニル]-4-(4-メチルピペラジン-1-イル)-1,3,5-トリアジン-2-アミン
N-[4-(ジメチルホスホリル)フェニル]-N'-(トリシクロ[3.3.1.13.7]デク-1-イル)-1,3,5-トリアジン-2,4-ジアミン
N-[4-(ジメチルホスホリル)フェニル]-N'-(モルホリン-4-イルメチル)-1,3,5-トリアジン-2,4-ジアミン
4-{2-[(4-{[4-(ジメチルホスホリル)フェニル]アミノ}-1,3,5-トリアジン-2-イル)アミノ]エチル}ベンゼンスルホンアミド
N-[4-(ジメチルホスホリル)フェニル]-N'-(テトラヒドロフラン-2-イル)-1,3,5-トリアジン-2,4-ジアミン
N-[4-(ジメチルホスホリル)フェニル]-N'-(ヘキサヒドロシクロペンタ[c]ピロール-2(1H)-イル)-1,3,5-トリアジン-2,4-ジアミン
N-[4-(ジメチルホスホリル)フェニル]-N'-(モルホリン-4-イル)-1,3,5-トリアジン-2,4-ジアミン
N-[4-(ジメチルホスホリル)フェニル]-4-(4-フェニルピペラジン-1-イル)-1,3,5-トリアジン-2-アミン
N-[4-(ジメチルホスホリル)フェニル]-N'-[2-(1H-インドール-3-イル)エチル]-1,3,5-トリアジン-2,4-ジアミン
N-[4-(ジメチルホスホリル)フェニル]-N'-(4-メチルピペラジン-1-イル)-1,3,5-トリアジン-2,4-ジアミン
6-クロロ-N-[4-(ジメチルホスホリル)フェニル]-N'-(トリシクロ[3.3.1.13.7]デク-1-イルメチル)-1,3,5-トリアジン-2,4-ジアミン
6-クロロ-N-[4-(ジメチルホスホリル)フェニル]-N'-[4-(4-メチルピペラジン-1-イル)ベンジル]-1,3,5-トリアジン-2,4-ジアミン
6-クロロ-N-(3,5-ジメチルフェニル)-N'-[4-(ジメチルホスホリル)フェニル]-1,3,5-トリアジン-2,4-ジアミン
6-クロロ-N3-[4-(ジメチルホスホリル)-2-メトキシフェニル]-N5-フェニル-1,2,4-トリアジン-3,5-ジアミン
6-クロロ-N3-[4-(ジメチルホスホリル)-2-メトキシフェニル]-N5-[2-(プロパン-2-イルスルホニル)フェニル]-1,2,4-トリアジン-3,5-ジアミン
6-クロロ-N-[4-(ジメチルホスホリル)-2-メトキシフェニル]-5-{[3-フルオロ-5-(トリフルオロメチル)フェニル]スルファニル}-1,2,4-トリアジン-3-アミン
6-クロロ-N5-[4-(ジメチルホスホリル)フェニル]-N3-{2-メトキシ-[4-(4-メチルピペラジン-1-イル)ピペリジン-1-イル]フェニル}-1,2,4-トリアジン-3,5-ジアミン
6-クロロ-N3-[6-(ジメチルホスホリル)-2-メトキシピリジン-3-イル]-N5-[2-(プロパン-2-イルスルホニル)フェニル]-1,2,4-トリアジン-3,5-ジアミン
6-クロロ-N3-[5-(ジメチルホスホリル)-3-メトキシピラジン-2-イル]-N5-[2-(プロパン-2-イルスルホニル)フェニル]-1,2,4-トリアジン-3,5-ジアミン
N5-[4-(ジメチルホスホリル)-2-(プロパン-2-イルスルホニル)フェニル]-N3-{2-メトキシ-4-[(4-メチルピペラジン-1-イル)スルホニル]フェニル}-6-メチル-1,2,4-トリアジン-3,5-ジアミン
6-クロロ-N3-[5-(ジメチルホスホリル)-2-メトキシフェニル]-N5-[2-(プロパン-2-イルスルホニル)フェニル]-1,2,4-トリアジン-3,5-ジアミン
6-クロロ-N3-[4-(ジメチルホスホリル)-2-メチルフェニル]-N5-[2-(プロパン-2-イルスルホニル)フェニル]-1,2,4-トリアジン-3,5-ジアミン
6-クロロ-N3-[4-(ジメチルホスホリル)-2-エチルフェニル]-N5-[2-(プロパン-2-イルスルホニル)フェニル]-1,2,4-トリアジン-3,5-ジアミン
6-クロロ-N3-[4-(ジメチルホスホリル)-2-(トリフルオロメトキシ)フェニル]-N5-[2-(プロパン-2-イルスルホニル)フェニル]-1,2,4-トリアジン-3,5-ジアミン
6-クロロ-N3-[2-クロロ-4-(ジメチルホスホリル)フェニル]-N5-[2-(プロパン-2-イルスルホニル)フェニル]-1,2,4-トリアジン-3,5-ジアミン
6-クロロ-N3-[4-(ジメチルホスホリル)-2-フルオロフェニル]-N5-[2-(プロパン-2-イルスルホニル)フェニル]-1,2,4-トリアジン-3,5-ジアミン
6-クロロ-N3-[4-(1-エチル-4-オキシド-1,4-アザホスフィナン-4-イル)-2-メトキシフェニル]-N5-[2-(プロパン-2-イルスルホニル)フェニル]-1,2,4-トリアジン-3,5-ジアミン
6-クロロ-N3-[2-メトキシ-4-(4-メチル-4-オキシド-1,4-アザホスフィナン-1-イル)フェニル]-N5-[2-(プロパン-2-イルスルホニル)フェニル]-1,2,4-トリアジン-3,5-ジアミン
6-クロロ-N3-{2-メトキシ-4-[4-(4-メチル-4-オキシド-1,4-アザホスフィナン-1-イル)ピペリジン-1-イル]フェニル}-N5-[2-(プロパン-2-イルスルホニル)フェニル]-1,2,4-トリアジン-3,5-ジアミン
6-クロロ-N3-[4-(ジエチルホスホリル)-2-メトキシフェニル]-N5-[2-(プロパン-2-イルスルホニル)フェニル]-1,2,4-トリアジン-3,5-ジアミン
化合物5の合成
化合物5は反応図式122 (下記)に概略を示すようにして合成することができる。
DMF中の2-ヨードアニリン (1.0当量) 及びジメチルホスフィンオキシド (1.1当量) の溶液に、リン酸カリウム (1.1当量)、酢酸パラジウム/Xantphos (触媒量) を加えた。反応混合物を150℃で3時間撹拌し、室温に冷却した。溶媒を蒸発させ、残渣をDCM/水で処理した。得られた粗生成物をカラム (EtOAc/MeOH 10:1) で精製して、化合物1を褐色固体として得た (収率80%)。
DMF中の2,4,5-トリクロロピリミジン (1.57当量)、化合物1 (1.0当量)、及び炭酸カリウム (3.14当量) を60℃で5時間撹拌した後、室温に冷却した。この混合物を濾過し、濾液を濃縮した。残渣をISCO (DCM/MeOH 20:1) で精製して、化合物2を黄色固体として得た (収率61%)。
DMF中の5-フルオロ-2-ニトロアニソール (1.0当量)、1-メチル-4-(ピペリジン-4-イル)ピペラジン (1.0当量)、及び炭酸カリウム (2.0当量)を120℃で6時間撹拌した後、室温に冷却した。この混合物を濾過し、蒸発させた。得られた粗生成物をエタノールから結晶化させて、化合物3を黄色固体として得た (収率72%)。
活性炭担持パラジウムを窒素下で化合物3のエタノール溶液に加えた。得られた懸濁液を次いで水素下 (50 psi) で3時間振盪した。この混合物を濾過し、濾液を蒸発させて、化合物4を紫色固体として定量的収率で得た。
2-メトキシエタノール中の化合物2 (1.0当量)、化合物4 (1.4当量)、及び2.5M HClエタノール溶液(過剰量)の溶液を密封し、撹拌しながら120℃に5.5時間加熱した後、室温に冷却した。この反応を5回繰り返して、反応混合物を合わせた。この混合物を濾過し、蒸発させた。強く撹拌しながら、飽和Na2CO3、次にDCMを加えた。分液し、水層をDCMで抽出した。有機層を合わせて乾燥し、蒸発させ、クロマトグラフィー処理して(EtOAc/MeOH (7M アンモニア) 20:1) 、黄色固体を得た。EtOAcを加え、得られた懸濁液を30分間還流加熱した。室温に冷却後、濾過を行い、得られた固体をDCMに溶解し、濾過し、蒸発させて、化合物5をオフホワイト色固体として得た (収率66%)。
本発明の化合物は、それらの生物学的活性を求めるために多様な検定(アッセイ)により評価される。例えば、本発明の化合物を、興味ある各種プロテインキナーゼを阻害するそれらの能力について試験することができる。試験した化合物の一部は、下記キナーゼに対して強力なナノモルレベルの活性を示した:ALK及びc−Met。さらに、これらの化合物のいくつかは、ヒトKarpas-299及びヒトSU-DHL-1リンパ腫細胞系における抗増殖活性についてスクリーニングしたところ、1〜100nMの範囲内の活性が実証された。本化合物はまた、例えば、以下により詳しく説明し、かついくつかの代表的化合物については上に示したように、興味ある腫瘍細胞に対するそれらの細胞毒性又は増殖阻害効果について評価することができる。例えば、WO 03/000188, 115〜136頁(その全体をここに参考として援用する)を参照。
より具体的には、本書に記載した化合物は次のようにしてキナーゼ阻害活性についてスクリーニングされる。下記のプロトコルに用いるのに適したキナーゼとしては、それらに制限されないが、次のものが挙げられる:ALK,Jak2,b−Raf,c−Met,Tie−2,FLT−3,Abl,Lck,Lyn,Src,Fyn,Syk,Zap−70,Itk,Tec,Btk,EGFR,ErbB2,Kdr,FLT1,Tek,InsR及びAKT。
ALKチロシンキナーゼ活性の阻害はまた、J. Wood et al., Cancer Res. 2000, 60, 2178-2189に記載されたVEDG−Rキナーゼ検定に似た方法でALKの組換えキナーゼドメインを用いて測定することもできる。GST−ALKプロテインチロシンキナーゼを用いたin vitro酵素検定を、20 mM Tris−HCl, pH7.5, 3 mM MgCl2, 10 mM MnCl2, 1 nM DTT, 0.1μCi/検定 (=30μL) [γ-33P]−ATP, 2μM ATP, 3μg/mL ポリ(Glu, tyr 4:1)Poly-EY (Sigma P-0275), 1%DMSO, 25ng ALK酵素中のフィルターバインディング検定として96ウェルプレートで実施することができる。この検定体を室温で10分間インキュベーションすることができる。125 mM EDTAを50μL添加して反応を停止させることができ、反応混合物を予めメタノールで湿らせたMAIPマルチスクリーンプレート(Millipore, ベッドフォード、マサチューセッツ)上に移し、水で5分間再水和させることができる。洗浄(0.5%H3PO4)後、液体シンチレーションカウンターでプレートをカウントすることができる。阻害率(%)の線形回帰解析によりIC50値を算出する。
本発明の或る種の化合物はまた、腫瘍又は他のがん細胞系に対する細胞毒性又は増殖阻害効果があることも実証されたので、がん及び他の細胞増殖型疾患の治療に有用である可能性がある。化合物は、当業者には周知のin vivo 及び in vitro検定を用いて抗腫瘍活性について検定される。一般に、抗がん薬候補を見つけるための化合物の初期スクリーニングは細胞検定により行われる。このような細胞系検定において抗増殖活性を有すると認められた化合物は、次いで、抗腫瘍活性と毒性に対して完全生体を使ってその後の検定を受けることができる。一般に、細胞系スクリーニングは、完全生体を使う検定に比べてより迅速かつ低コストで行うことができる。本発明の目的にとって、「抗腫瘍」活性と「抗がん」活性の用語は互換可能に使用される。
式中、ABSは吸光度である。このような実験におけるIC50値は、阻害剤を添加しない対照を用いて得られた細胞数より50%少ない細胞数を生ずる当該試験化合物の濃度であると定義される。
本発明の多様な化合物が、多くの重要なキナーゼ標的を強力に阻害することが見出された。例えば、キナーゼALKの阻害剤として試験した場合に示されたIC50値は、多くの化合物では100nM以下であり、多くの例では10nM以下、時には1nM以下であった。そのような化合物としては、Ra又はRe置換基としてホスフィンオキシド基を含有する化合物、並びにX3及びX4位置が多くの態様において存在している置換又は非置換縮合環の基部である化合物が挙げられる。一部の化合物は、ALK、FER、FLT3、FES/FPS、FAK/PTK2、BRKその他のようなキナーゼを含む1集団のキナーゼに対して一桁ナノモルレベルの阻害剤であった。多様な構造の本発明の化合物が、或る種のキナーゼを他のものより優先的に阻害する優先性と薬物動態学的挙動の変動を示すことが認められた。このことは、この種の化合物が強力な薬剤の供給源として非常に興味ある化合物であることを確認するものである。
薬剤組成物:
下記に例示するような本発明の化合物の代表的な製剤剤形 (本発明の化合物である有効成分を単に「化合物」という)が、ヒトにおける治療及び予防用に提供される。
化合物 100
乳糖 (欧州薬局方) 182.75
クロスカルメロースナトリウム 12.0
コーンスターチペースト (5% w/v ヘ゜ースト) 2.25
ステアリン酸マグネシウム 3.0。
化合物 50
乳糖 (欧州薬局方) 223.75
クロスカルメロースナトリウム 6.0
コーンスターチ 15.0
ポリビニルピロリドン (5% w/v ヘ゜ースト) 2.25
ステアリン酸マグネシウム 3.0。
化合物 1.0
乳糖 (欧州薬局方) 93.25
クロスカルメロースナトリウム 4.0
コーンスターチペースト (5% w/v ヘ゜ースト) 0.75
ステアリン酸マグネシウム 1.0〜76。
化合物 10
乳糖 (欧州薬局方) 488.5
マグネシウム 1.5。
化合物 5.0% w/v
1M 水酸化ナトリウム溶液 15.0% w/v
0.1M 塩酸 (pH 7.6に調整する量)
ポリエチレングリコール400 4.5% w/v
注射用蒸留水を加えて 100%。
化合物 1.0% w/v
リン酸ナトリウムリBP 3.6% w/v
0.1M 水酸化ナトリウム溶液 15.0% w/v
注射用蒸留水を加えて 100%。
化合物 0.1% w/v
リン酸ナトリウムリBP 2.26% w/v
クエン酸 0.38% w/v
ポリエチレングリコール400 3.5% w/v
注射用蒸留水を加えて 100%。
化合物 10.0
ソルビタントリオレエート 13.5
トリクロロフルオロメタン 910.0
ジクロロジフルオロメタン 490.0。
化合物 0.2
ソルビタントリオレエート 0.27
トリクロロフルオロメタン 70.0
ジクロロジフルオロメタン 280.0
ジクロロテトラフルオロエタン 1094.0。
化合物 2.5
ソルビタントリオレエート 3.38
トリクロロフルオロメタン 67.5
ジクロロジフルオロメタン 1086.0
ジクロロテトラフルオロエタン 191.6。
化合物 2.5
大豆レクチン 2.7
トリクロロフルオロメタン 67.5
ジクロロジフルオロメタン 1086.0
ジクロロテトラフルオロエタン 191.6。
化合物 40 mg
エタノール 300μL
水 300μL
1-ドデシルアザシクロヘプタン-2-オン 50μL
プロピレングリコールを加えて 1 mL。
本明細書中で言及した全ての刊行物、特許及び特許出願を、それぞれ独立した個々の刊行物又は特許出願が具体的かつ個別に参考文献として言及されたものである場合と同程度にここに参考文献として援用する。
Claims (22)
- 下記一般式VIaで示される化合物。
X1はNRb1又はCRbであり、
X3はNRd1又はCRdであり、
X4はNRe1又はCReであり、
環A及び環Eはそれぞれ独立してアリール環又はヘテロアリール環から選ばれ、該ヘテロアリール環はN、O及びS(O)rから選ばれた1〜4個のヘテロ原子を含有する5若しくは6員環であり;
Ra、Rb、Rd、Re及びRgは、出てくる毎に独立して、ハロゲン、−CN、−NO2、−R1、−OR2、−O−NR1R2、−NR1R2、−NR1−NR1R2、−NR1−OR2、−C(O)YR2、−OC(O)YR2、−NR1C(O)YR2、−SC(O)YR2、−NR1C(=S)YR2、−OC(=S)YR2、−C(=S)YR2、−YC(=NR1)YR2、−YC(=N−OR1)YR2、−YC(=N−NR1R2)YR2、−YP(=O)(YR3)(YR3)、−Si(R3a)3、−NR1SO2R2、−S(O)rR2、−SO2NR1R2、及び−NR1SO2NR1R2よりなる群から選ばれ;又はRa及びRgは、それぞれ独立して選ばれた、−P(=O)(R3)2部分であるか、若しくは環の構成部分として−P(=O)(R3)−部分を含んだ環系であってもよく;
Rb1、Rd1及びRe1は存在せず;
或いは、Rd、Rd1、Re及びRe1から選ばれた2つの隣接する置換基又は2つの隣接するRa部分は、それらが結合している原子と共に、N、O及びS(O)rから選ばれた0〜4個のヘテロ原子を含有し、4個までの置換基を含有しうる、飽和、部分飽和若しくは不飽和環の縮合5、6若しくは7員環を形成していてもよく;
RaとRgの少なくとも一方は、−P(=O)(R3)2部分であるか又はそれを含んでいるか、或いは環の構成部分として−P(=O)(R3)−部分を含んだ環系であり;
LはO又はNHであり;
rは0、1又は2であり;
sは1、2、3、4又は5であり;
pは1、2、3又は4であり;
Yは出てくるごとに独立して、単結合、−O−,−S−又は−NR1−であり;
R1及びR2は出てくるごとに独立して、H、アルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、シクロアルキニル、アリール、ヘテロアルキル、ヘテロ環基及びヘテロアリール基から選ばれ;
R3は出てくるごとに独立して、アルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、シクロアルキニル、アリール、ヘテロアルキル、ヘテロ環基及びヘテロアリール基から選ばれるか、又は隣接する2つのR3部分が一緒になってリン原子を含有する環系を形成していてもよく、
R3aは出てくるごとに独立して、アルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、シクロアルキニル、アリール、ヘテロアルキル、ヘテロ環基及びヘテロアリールから選ばれ;
或いは、各NR1R2部分は、N、O及びS(O)rから選ばれた追加のヘテロ原子0〜2個を含有する、場合により置換されていてもよい、飽和、部分飽和又は不飽和の5、6又は7員環であってもよく;
上記のアルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、シクロアルキニル、アリール、ヘテロアリール、及びヘテロ環基は場合により置換されていてもよい。 - X1がNである請求項1記載の化合物。
- X3がNで、X4がCReである請求項2記載の化合物。
- X3がCRdで、X4がCReである請求項2記載の化合物。
- X1がCRbである請求項1記載の化合物。
- X3がNで、X4がCReである請求項5記載の化合物。
- X3がCRdで、X4がCReである請求項5記載の化合物。
- RdがCl、F、C1〜C4アルキル、トリハロアルキル、シクロアルキル、C2〜C4アルケニル、及びアルキニルから選ばれる請求項1、2、4、5又は7記載の化合物。
- X3がCRd、X4がCReであって、RdとReは、それらが結合している原子と共に、N、O及びS(O)rから選ばれた0〜4個のヘテロ原子を含有し、4個までの置換基を含有しうる、飽和、部分飽和若しくは不飽和の縮合5、6若しくは7員環を形成している、請求項1記載の化合物。
- sが1、2、3又は4であり、置換基Raのそれぞれが、ハロゲン、−R1、−OR2、−NR1R2及び−P(=O)(R3)2から独立して選ばれ、ここで各R1及びR2部分はさらに置換されていてもよく、又は非置換でもよい、請求項1〜9のいずれかに記載の化合物。
- 少なくとも1つのRa置換基が−OR2であり、R2がC1〜C6アルキル、C2〜C6アルケニル及びC2〜C6アルキニルから選ばれる、請求項10記載の化合物。
- 少なくとも1つのRa置換基が、直接又はエーテル結合を介して環Aに連結した5、6若しくは7員環ヘテロ環部分又は5若しくは6員環ヘテロアリール部分であって、それらはさらにハロゲン、−CN、−NO2、−R1、−OR2、−O−NR1R2、−NR1R2、−NR1−NR1R2、−NR1−OR2、−C(O)YR2、−OC(O)YR2、−NR1C(O)YR2、−SC(O)YR2、−NR1C(=S)YR2、−OC(=S)YR2、−C(=S)YR2、−YC(=NR1)YR2、−YC(=N−OR1)YR2、−YC(=N−NR1R2)YR2、−YP(=O)(YR3)(YR3)、−Si(R3a)3、−NR1SO2R2、−S(O)rR2、−SO2NR1R2、及び−NR1SO2NR1R2から独立して選ばれた1〜3個の置換基で置換されていてもよく、各Yは、独立して単結合、−O−、−S−又は−NR1−である、請求項10又は11記載の化合物。
- 少なくとも1つの置換基Raが−P(=O)(R3)2部分を有し、ここで各R3は独立してC1〜C4アルキル基である請求項10〜13のいずれかに記載の化合物。
- LがNHであり、環Eがアリールであり、そして各Rgが独立して、ハロゲン、−R1、−OR2、−S(O)rR2及び−P(=O)(R3)2から選ばれる、請求項1〜14のいずれかに記載の化合物。
- 環Eが、Lに結合している環原子に対してオルト位置に少なくとも1つのRg基を含んでいる、請求項15記載の化合物。
- 環Eが、Lに結合している環原子に対してメタ位置に少なくとも1つのRg基を含んでいる、請求項15記載の化合物。
- 環Eが、Lに結合している環原子に対してパラ位置に少なくとも1つのRg基を含んでいる、請求項15記載の化合物。
- 少なくとも1つのRg基が−P(=O)(R3)2であり、この−P(=O)(R3)2が−P(=O)(CH3)2又は−P(=O)(CH2CH3)2である、請求項15〜18のいずれかに記載の化合物。
- LがNH、X1がN、X3がCRd、X4がCRe、環Aがアリールであって、場合により2個までのさらなるRa基を含有していてもよく、そして環Eはアリールであって、1〜3個のRg基を含有し、その1つはオルト、メタ又はパラ位置の−P(=O)(R3)2基である、請求項13記載の化合物。
- 請求項1〜20のいずれかに記載の化合物又はその薬学的に許容される塩と薬学的に許容されるビヒクルとを含有する薬剤組成物。
- 個体における細胞増殖を阻害する方法であって、該細胞増殖を阻害するのに有効な量の請求項1〜20のいずれかに記載の化合物を前記個体に投与することを含む方法。
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