JP5701758B2 - Hdm2配位子としてのピロリジン−2−オン - Google Patents
Hdm2配位子としてのピロリジン−2−オン Download PDFInfo
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- JP5701758B2 JP5701758B2 JP2011526418A JP2011526418A JP5701758B2 JP 5701758 B2 JP5701758 B2 JP 5701758B2 JP 2011526418 A JP2011526418 A JP 2011526418A JP 2011526418 A JP2011526418 A JP 2011526418A JP 5701758 B2 JP5701758 B2 JP 5701758B2
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- heteroalkyl
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 64
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- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 55
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- 206010028980 Neoplasm Diseases 0.000 claims description 53
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- 125000003118 aryl group Chemical group 0.000 claims description 45
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 43
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- 125000004404 heteroalkyl group Chemical group 0.000 claims description 40
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- 125000006413 ring segment Chemical group 0.000 claims description 39
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- 125000004432 carbon atom Chemical group C* 0.000 claims description 31
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 19
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- WTHRRGMBUAHGNI-LCYNINFDSA-N quinupristin Chemical compound N([C@@H]1C(=O)N[C@@H](C(N2CCC[C@H]2C(=O)N(C)[C@@H](CC=2C=CC(=CC=2)N(C)C)C(=O)N2C[C@@H](CS[C@H]3C4CCN(CC4)C3)C(=O)C[C@H]2C(=O)N[C@H](C(=O)O[C@@H]1C)C=1C=CC=CC=1)=O)CC)C(=O)C1=NC=CC=C1O WTHRRGMBUAHGNI-LCYNINFDSA-N 0.000 description 1
- 229960005442 quinupristin Drugs 0.000 description 1
- 108700028429 quinupristin Proteins 0.000 description 1
- 230000004223 radioprotective effect Effects 0.000 description 1
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 1
- 229960004622 raloxifene Drugs 0.000 description 1
- 229960004432 raltitrexed Drugs 0.000 description 1
- 229950001588 ramosetron Drugs 0.000 description 1
- NTHPAPBPFQJABD-LLVKDONJSA-N ramosetron Chemical compound C12=CC=CC=C2N(C)C=C1C(=O)[C@H]1CC(NC=N2)=C2CC1 NTHPAPBPFQJABD-LLVKDONJSA-N 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000020129 regulation of cell death Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 229960000888 rimantadine Drugs 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- HJORMJIFDVBMOB-UHFFFAOYSA-N rolipram Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OC1CCCC1 HJORMJIFDVBMOB-UHFFFAOYSA-N 0.000 description 1
- 229950005741 rolipram Drugs 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229960002530 sargramostim Drugs 0.000 description 1
- 108010038379 sargramostim Proteins 0.000 description 1
- 229960005399 satraplatin Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000009758 senescence Effects 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 239000002911 sialidase inhibitor Substances 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 201000003708 skin melanoma Diseases 0.000 description 1
- 239000004055 small Interfering RNA Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- MIXCUJKCXRNYFM-UHFFFAOYSA-M sodium;diiodomethanesulfonate;n-propyl-n-[2-(2,4,6-trichlorophenoxy)ethyl]imidazole-1-carboxamide Chemical compound [Na+].[O-]S(=O)(=O)C(I)I.C1=CN=CN1C(=O)N(CCC)CCOC1=C(Cl)C=C(Cl)C=C1Cl MIXCUJKCXRNYFM-UHFFFAOYSA-M 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 208000020431 spinal cord injury Diseases 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 229940063683 taxotere Drugs 0.000 description 1
- 229960000565 tazarotene Drugs 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- 208000001608 teratocarcinoma Diseases 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229950007967 tesmilifene Drugs 0.000 description 1
- 230000002381 testicular Effects 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- CFMYXEVWODSLAX-QOZOJKKESA-N tetrodotoxin Chemical compound O([C@@]([C@H]1O)(O)O[C@H]2[C@@]3(O)CO)[C@H]3[C@@H](O)[C@]11[C@H]2[C@@H](O)N=C(N)N1 CFMYXEVWODSLAX-QOZOJKKESA-N 0.000 description 1
- 229950010357 tetrodotoxin Drugs 0.000 description 1
- CFMYXEVWODSLAX-UHFFFAOYSA-N tetrodotoxin Natural products C12C(O)NC(=N)NC2(C2O)C(O)C3C(CO)(O)C1OC2(O)O3 CFMYXEVWODSLAX-UHFFFAOYSA-N 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- PLHJCIYEEKOWNM-HHHXNRCGSA-N tipifarnib Chemical compound CN1C=NC=C1[C@](N)(C=1C=C2C(C=3C=C(Cl)C=CC=3)=CC(=O)N(C)C2=CC=1)C1=CC=C(Cl)C=C1 PLHJCIYEEKOWNM-HHHXNRCGSA-N 0.000 description 1
- 229950009158 tipifarnib Drugs 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 229940086542 triethylamine Drugs 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 230000005740 tumor formation Effects 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- YCOYDOIWSSHVCK-UHFFFAOYSA-N vatalanib Chemical compound C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 YCOYDOIWSSHVCK-UHFFFAOYSA-N 0.000 description 1
- 229950000578 vatalanib Drugs 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 229960002555 zidovudine Drugs 0.000 description 1
- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 description 1
- 229960004276 zoledronic acid Drugs 0.000 description 1
Classifications
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
- C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A61P25/00—Drugs for disorders of the nervous system
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- A61P25/00—Drugs for disorders of the nervous system
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/10—Spiro-condensed systems
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Description
治療としてHDM2を阻害する妥当性は、様々なp53状態を有する複数のヒトの癌モデルにおいて著しい抗腫瘍活性を示すアンチセンスHDM2阻害剤によってまず証明された(Zhang等,Proc.Natl.Acad.Sci.U.S.A.2003,100,11636−11641:非特許文献11参照)。
VはC=O、C=SまたはCH2(特にC=O)であり;
Xは硫黄、酸素または式CH2、CR4bR4c、NH、NR4b、SOもしくはSO2の基または結合であり;
Yは式CONR6、CH2NR6、CO、COO、CH2O、SO2NR6、NR6CO、NR6SO2、NR5aCONR6、NR6COO、OCONR6、CONR5aNR6、CONR5aOR6、CH2COCH2CONR6、CH2COO、COCR5aR6の基または結合であり;
nは1、2、3または0であり;
好ましくは、ここに記載の全てのアルキル、アルケニル、アルキニル、ヘテロアルキル、アリール、ヘテロアリール、シクロアルキル、ヘテロシクロアルキル、アルキルシクロアルキル、ヘテロアルキルシクロアルキル、アラルキルおよびヘテロアラルキル基は任意に置換されている。
さらに好ましいのは、Yが式CONR6の基である式(I)の化合物である。
さらに好ましいのは、nが0または1、特に1である式(I)の化合物である。
さらに好ましいのは、R7が水素である、式(I)の化合物である。
その上さらに好ましいのは、R8が水素である、式(I)の化合物である。
R1は、水素原子またはアルキル、アルケニル、アルキニル、ヘテロアルキル、アリール、ヘテロアリール、シクロアルキル、アルキルシクロアルキル、ヘテロアルキルシクロアルキル、ヘテロシクロアルキル、アラルキルもしくはヘテロアラルキル基であり;
特に好ましくは、 R1は、好ましくはF、ClおよびBrから選択される1または2個のハロゲン原子で、任意に置換された、式−A−フェニル(特に−CH2−フェニル)の基であって、Aは式−CHR1a−(R1aはC1−C6ヘテロアルキル基(例えば、COOH、CH2COOH))の基であるのが好ましい。
さらに好ましいのは式(I)または(Ia)の化合物であって、R2が水素である化合物である。
特に好ましくは、mは1、oは1、そしてQはN−CO−R6aである。R6aは、好ましくは、C1−C4アルキルまたはNH−C1−C4アルキル(例えば、CH3またはNHCH2CH3)である。
R1が、いずれもF、Br、Cl、I、メチルまたはシアニドで置換されていてもよい、アリール、ヘテロアリール、アリールアルキルまたはヘテロアリールアルキルであり;
R2が水素であり;
R3が、いずれもF、Br、Cl、I、メチルまたはシアニドで置換されていてもよい、アリール、ヘテロアリール、アリールアルキルまたはヘテロアリールアルキルであり;
R4がアリール、ヘテロアリールまたはヘテロアリールアルキルであり;
R5およびR6が、水素、アルキル、ヘテロアルキル、アリール、アルケニル、アルキニル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、アリールアルキルまたはヘテロアリールアルキルから独立して選択されるか、あるいはR5およびR6が、1つのヘテロアリール、ヘテロシクロアルキル、ヘテロアルキルシクロアルキルまたはヘテロアリールアルキル環系の一部であってもよく、
他の残基および基が上記定義どおりである
化合物に関する。
R1が、いずれもF、Br、Cl、I、メチルまたはシアニドで置換されていてもよい、アリール、ヘテロアリール、アリールアルキルまたはヘテロアリールアルキルであり;
R2およびR3が一緒になって、いずれもF、Br、Cl、I、メチルまたはシアニドで置換されていてもよい、ヘテロアリール、ヘテロアラルキル、ヘテロシクロアルキルまたはヘテロアルキルシクロアルキル環系、例えば、限定されないが、1,3−ジヒドロインドール、1,3−ジヒドロインドール−2−オン、2,3−ジヒドロ−1H−インダゾール、テトラヒドロ−キノリン、テトラヒドロ−キノリン−2−オン、3,4−ジヒドロ−1H−キノリン−2−オン、3,4−ジヒドロ−1H−キナゾリン−2−オンであり;
R4がアリール、ヘテロアリール、アリールアルキルまたはヘテロアリールアルキルから選択され;
R5およびR6が、水素、アルキル、ヘテロアルキル、アリール、アルケニル、アルキニル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、アリールアルキルまたはヘテロアリールアルキルから独立して選択されるか、あるいはR5およびR6が、1つのヘテロアリール、ヘテロシクロアルキル、ヘテロアルキルシクロアルキルまたはヘテロアリールアルキル環系の一部であってもよく、
他の残基および基が上記定義どおりである
本発明のさらに好ましい態様は、式(I)、(Ia)、(Ic)、(Id)、(Ie)または(If)の化合物であって、R3とR4基を有するスルファニル基(すなわち、Xを有する基)とがシス位置にある(特に、R2がHであるとき)化合物に関する。
特に好ましい態様は、式(I)、(Ia)、(Ic)、(Id)、(Ie)または(If)の光学対掌的に純粋な化合物である。
1.Ng等,Angew.Chem.Int.Ed.2007,46,5352−5355および
2.Ng等,Organic Letters 2006,V0l.8,No.8,3999−4002(およびそれらを裏づける情報)
に記載の化合物は本出願および/または特許の範囲から除く。
さらに好ましくは、R3がp−C6H5CH2OH(またはNg等,Angew.Chem.Int.Ed.2007,46,5352−5355に記載のような固相に結合するその誘導体)である式(I)または(Ia)の化合物は除く。
従って、本発明の化合物はHDM2および/またはMDMXに関連する次の癌の治療または予防に特に有用である:
本発明の化合物の治療に有効な量すなわち投与量は広い範囲で変えることができ、本技術分野における当業者に公知の方法で決定しうる。そのような投与量は、各ケースにおける個々の要件、例えば投与される特定の化合物、投与ルート、治療される状態、並びに治療される患者に応じる。
1)M.R.Linder,J.Podlech,Organic Letters 2001,Vol.3,No.12,1849−1851;
2)J.Podlech,M.R.Linder,J.Org.Chem.1997,62,5873−5883;
3)J.Cesar,M.Sollner Dolenc,Tetrahedron Letters 42(2001)7099−7102。
ここに記載の反応手順は、相当する光学対掌的に純粋な化合物を得るために、プロリン誘導触媒のようなキラル触媒(www.organic−chemistry.org/Highlights/2007/25March.shtmに記載のような)の存在下でも行いうる
5−オキソ−3−スルファニル−ピロリジン−3−カルボキサミド(I)を合成する一般的な手順:
トルエン中の無水マレイン酸(IV、1mmol)、チオール(V、1mmol)、アルデヒドまたはケトン(III、mmol)、およびアミン(II、1mmol)を封管中で24時間150℃に加熱した。室温に冷却した後、溶液を真空濃縮した。溶出液(酢酸エチル:メタノール=9:1〜1:1)を用いるシリカゲル上での精製で式(VI)の化合物をジアステレオマー混合物として得た。その後、2種のジアステレオマーを分取HPLCクロマトグラフィーによって分離した。分取分離はRPポラリスC18カラム(長さ:250mm、直径:21mm;粒子サイズ:5μm)上でアセトニトリル−水溶出剤(+0.1%ギ酸)を用いて通常行った。一般に、良好な分離はイソクラチック系(70%アセトニトリル:30%水)を用いることによって観察された(2種のシス/トランスジアステレオマーの保持時間は1〜2分の差があった)。
8mL酢酸エチル中の1−(3−ジメチルアミノプロピル)−3−エチルカルボジイミド塩酸塩EDCI(1.5mmol)の懸濁液へ、ペンタフルオロフェノール(3mmol)を0℃で加えた。
2mL乾燥THF中の5−オキソ−ピロリジン−3−カルボン酸ペンタフルオロフェニルエステルVII(5mmol)の懸濁液へ、望ましいアミンVIII(5mmol)を室温で加えた。反応混合物を1時間室温で攪拌した。その後、20mL塩化メチレンを加えた。得られた有機層を炭酸水素ナトリウムの飽和水溶液20mLで洗浄し、硫酸マグネシウムで乾燥し、溶媒を真空除去した。最後に、粗生成物を適当な溶出液を用いるシリカゲル上でのクロマトグラフィーによって精製して望ましい5−オキソ−ピロリジン−3−カルボキサミドIを白色固体として得た。
実施例1の一般的な手順に従って、次の化合物を製造した:
2.1 シス−2−(6−クロロ−1−メチル−1H−インドール−3−イル)−1−[(4−クロロフェニル)メチル]−3−[(4−メチルフェニル)スルファニル]−5−オキソ−N−(ピリジン−2−イルメチル)ピロリジン−3−カルボキサミド
分子式=C34H30Cl2N4O2S。分子量=629.599。観察された[M+H]+=629.1。単離収率34.08%。
分子式=C34H30Cl2N4O2S。分子量=629.599。観察された[M+H]+=629.1。単離収率3.78%。
分子式=C33H29Cl2N3O2S2。分子量=634.638。観察された[M+H]+=656.0。単離収率3.04%。
分子式=C33H29Cl2N3O2S2。分子量=634.638。観察された[M+H]+=656.0。単離収率27.34%。
分子式=C33H28Cl2N4O2S。分子量=615.572。観察された[M+H]+=615.1。単離収率2.78%。
分子式=C33H28Cl2N4O2S。分子量=615.572。観察された[M+H]+=615.2。単離収率25.06%。
分子式=C33H28Cl2N4O2S。分子量=615.572。観察された[M+H]+=615.2。単離収率12.50%。
分子式=C33H28Cl2N4O2S。分子量=615.572。観察された[M+H]+=615.2。単離収率4.56%。
分子式=C33H34Cl2N4O3S。分子量=637.619。観察された[M+H]+=637.2。単離収率7.30%。
分子式=C33H34Cl2N4O3S。分子量=637.619。観察された[M+H]+=637.2。単離収率7.18%。
分子式=C34H36Cl2N4O3S。分子量=651.646。観察された[M+H]+=651.2。単離収率5.18%。
分子式=C34H36Cl2N4O3S。分子量=651.646。観察された[M+H]+=651.2。単離収率7.74%。
分子式=C33H34Cl2N4O3S。分子量=637.619。観察された[M+H]+=637.2。単離収率2.82%。
分子式=C33H34Cl2N4O3S。分子量=637.619。観察された[M+H]+=637.2。単離収率3.81%。
分子式=C34H36Cl2N4O3S。分子量=651.646。観察された[M+H]+=651.2。単離収率2.65%。
分子式=C34H36Cl2N4O3S。分子量=651.646。観察された[M+H]+=651.2。単離収率1.36%。
分子式=C33H33Cl3N4O3S。分子量=672.064。観察された[M+H]+=671.1。単離収率6.65%。
分子式=C33H33Cl3N4O3S。分子量=672.064。観察された[M+H]+=673.1。単離収率19.04%。
分子式=C33H35ClN4O3S。分子量=603.174。観察された[M+H]+=603.0。単離収率4.31%。
分子式=C33H35ClN4O3S。分子量=603.174。観察された[M+H]+=603.0。単離収率4.59%。
分子式=C34H36Cl2N4O3S。分子量=651.646。観察された[M+H]+=650.9。単離収率4.91%。
分子式=C34H36Cl2N4O3S。分子量=651.646。観察された[M+H]+=651.0。単離収率4.86%。
分子式=C34H36BrClN4O3S。分子量=696.097。観察された[M+H]+=697.1。単離収率9.27%。
分子式=C34H36BrClN4O3S。分子量=696.097。観察された[M+H]+=697.0。単離収率11.14%。
分子式=C33H34BrClN4O3S。分子量=682.07。観察された[M+H]+=682.9。単離収率3.71%。
分子式=C33H34BrClN4O3S。分子量=682.07。観察された[M+H]+=682.8。単離収率4.65%。
分子式=C32H33Cl2N5O3S。分子量=638.607。観察された[M+H]+=638.0。単離収率3.76%。
分子式=C32H33Cl2N5O3S。分子量=638.607。単離収率1.46%。
分子式=C31H28Cl2N4O3S。分子量=607.55。観察された[M+H]+=607.2。単離収率4.44%。
分子式=C31H28Cl2N4O3S。分子量=607.55。観察された[M+H]+=607.2。単離収率4.09%。
分子式=C31H28Cl2N4O3S。分子量=607.55。観察された[M+H]+=608.8。単離収率2.62%。
分子式=C31H28Cl2N4O3S。分子量=607.55。観察された[M+H]+=606.9。単離収率1.89%。
分子式=C33H34ClFN4O3S。分子量=621.164。観察された[M+H]+=621.0。単離収率2.98%。
分子式=C33H34ClFN4O3S。分子量=621.164。観察された[M+H]+=621.0。単離収率4.72%。
分子式=C31H28BrClN4O3S。分子量=652.001。観察された[M+H]+=651.3。単離収率8.00%。
分子式=C34H36BrClN4O3S。分子量=696.097。観察された[M+H]+=697.2。単離収率8.39%。
分子式=C34H36BrClN4O3S。分子量=696.097。観察された[M+H]+=697.1。単離収率3.45%。
分子式=C34H36Br2N4O3S。分子量=740.548。観察された[M+H]+=740.5。単離収率10.00%。
分子式=C34H35Cl2FN4O3S。分子量=669.636。観察された[M+H]+=669.1。単離収率14.85%。
分子式=C34H35Cl2FN4O3S。分子量=669.636。観察された[M+H]+=669.0。単離収率4.48%。
分子式=C34H35Cl2FN4O3S。分子量=669.636。観察された[M+H]+=669.1。単離収率4.88%。
分子式=C34H35Cl2FN4O3S。分子量=669.636。観察された[M+H]+=669.1。単離収率1.08%。
分子式=C33H34Cl2N4O3S。分子量=637.619。観察された[M+H]+=637.0。単離収率7.67%。
分子式=C33H35Cl2N5O3S。分子量=652.634。観察された[M+H]+=652.0。単離収率6.04%。
分子式=C34H36Cl2N5O3S。分子量=651.646。観察された[M+H]+=651.1。単離収率7.97%。
分子式=C33H34BrClN4O3S。分子量=682.07。観察された[M+H]+=683.0。単離収率5.35%。
分子式=C30H29BrClN3O3S。分子量=642.991。観察された[M+Na]+=668.1。単離収率6.92%。
分子式=C31H28BrClN4O3S。分子量=652.001。観察された[M+H]+=653.1。観察された[M+Na]+=675.3。単離収率3.39%。
分子式=C33H34BrClN4O3S。分子量=682.07。観察された[M+H]+=683.1。単離収率7.30%。
分子式=C35H38BrClN4O3S。分子量=710.123。観察された[M+H]+=711.0。単離収率7.08%。
分子式=C31H31BrClN3O3S。分子量=641.018。観察された[M+Na]+=664.2。単離収率7.32%。
分子式=C33H34BrClN4O2S。分子量=666.071。観察された[M+H]+=668.2。単離収率7.51%。
分子式=C35H38BrClN4O3S。分子量=710.123。観察された[M+H]+=711.1。単離収率17.16%。
分子式=C35H38BrClN4O3S。分子量=710.123。観察された[M+H]+=711.0。単離収率9.74%。
分子式=C35H38BrClN4O3S。分子量=710.123。観察された[M+H]+=711.0。単離収率6.38%。
分子式=C33H33BrClN5O5S。分子量=727.068。観察された[M+H]+=726.0。単離収率3.00%。
分子式=C33H33BrClN5O5S。分子量=727.0681。観察された[M+H]+=727.9。単離収率0.41%。
分子式=C30H29BrClN3O3S。分子量=626.992。観察された[M+H]+=650.6。単離収率8.24%。
分子式=C30H29BrClN3O3S。分子量=626.992。観察された[M+H]+=650.2。単離収率8.04%。
1)4−[5−オキソ−ピロリジン−3−カルボニル]−ピペラジン−1−カルボン酸エチルアミド化合物の合成
トルエン(50mL)中の無水マレイン酸2(6mmol)、チオール4(6mmol)、アルデヒド3(6mmol)およびアミン1(6mmol)をディーン−スターク条件下で150℃に24時間加熱した。室温に冷却した後、溶液を真空濃縮した。シリカゲル上での精製(酢酸エチル:メタノール=9:1〜1:1)で5をジアステレオマー混合物(1.48g、46%)として得た。
ジアステレオマー混合物の分離
上記反応順で2種類のジアステレオマーd1およびd2を50:50比で得た。これらを次の条件を用いて分取HPLCクロマトグラフィーによって分離した:
− カラムRP ポラリス C18(長さ:250mm、φ:21mm、粒子サイズ:5μm)。
− 均一濃度溶出(70%アセトニトリル:30%水、0.1%HCOOH)、21mL/分、Rt=7.62分。
分離はメタノール/水混合物でも行うことができる。
真空中での溶液の濃縮で望ましい純粋なジアステレオマー6(シス、d1)を薄黄色固体(528.9mg、33.6%)として得た。
6の製造の全体収率:15.47%(シス−異性体d1のMCRおよび単離)
8mL酢酸エチル中の1−(3−ジメチルアミノプロピル)−3−エチルカルボジイミド塩酸塩EDCI(267mg、1.4mmol)の懸濁液へ、ペンタフルオロフェノール(512mg、2.8mmol)を0℃で加えた。10分後、化合物6(528.9mg、0.9mmol)を0℃で加え、反応混合物を室温で1時間攪拌した。溶媒の蒸発の後、粗生成物をシリカゲル上でのクロマトグラフィー(酢酸エチル:ヘキサン=1:2→1:1)によって精製して相当するペンタフルオロフェニルエステル7を無色油(632.0mg、92.5%)として得た。
M.Bodanszky,A.Bodanszky,The practice of Peptide Synthesis 第2版、p102、スプリンガー−フェルラーグ ハイデルベルク ニューヨーク(1994)。
16mL乾燥THF中のペンタフルオロフェニルエステル7(1.3g、1.8mmol)の懸濁液へピペラジン(7.2mmol)を室温で加えた。反応混合物を室温で20時間攪拌した。その後、20mL塩化メチレンを加えた。得られた有機層を炭酸水素ナトリウムの飽和水溶液20mLで洗浄し、硫酸マグネシウムで乾燥し、溶媒を真空除去した。最後に、粗生成物をシリカゲル上でのクロマトグラフィー(酢酸エチル:メタノール=9:1→1:1)によって精製して望ましいピペラジンアミド8を白色固体(977.8mg、84.20%)として得た。
15mLTHFエキストラドライ中の化合物8(848.3mg、1.3mmol)の溶液へエチルイソシアネート(283.6mg、4mmol)を−30℃で加えた。−30℃で1時間攪拌した後、20mL塩化メチレンを加えた。得られた有機層を炭酸水素ナトリウムの飽和水溶液20mLで洗浄し、硫酸マグネシウムで乾燥し、溶媒を真空除去した。最後に、粗生成物を酢酸エチル:メタノール 19:1を用いるシリカゲル上でのクロマトグラフィーによって精製してPXN727−d1を白色固体(853.4mg、90.5%)として得た。
IR:3397,3174,2923,1674,1625,1535,1487,1401,1361,1241,1174,1118,1002,794.
MS(+ESI):m/z=709.9[M+H],730.2[M+Na].
全体収率(4つの分取工程およびジアステレオマー分離):10.91%
2)メチレンCH 2 による硫黄S(基X)の入れ代え
(シス)4−[3−ベンジル−1−(4−クロロ−3−フルオロ−ベンジル)−2−(6−クロロ−1H−インドール−3−イル)−5−オキソ−ピロリジン−3−カルボニル]−ピペラジン−1−カルボン酸エチルアミド[PXN790−d1]の合成
トルエン(16mL)中の無水アルファ−ベンジルコハク酸10(850mg、4.5mmol)、アルデヒド3(1mmol)およびアミン11(1mmol)を封管中で24時間150℃に加熱した。室温に冷却した後、溶液を真空濃縮した。シリカゲル上での精製(酢酸エチル:メタノール=9:1〜1:1)での精製でMCR−生成物12をジアステレオマー混合物(210.3mg、9.20%)として得た。
酢酸エチル5mL中の1−(3−ジメチルアミノプロピル)−3−エチルカルボジイミド塩酸塩EDCI(118.2mg、0.671mmol)の懸濁液へ、ペンタフルオロフェノール(227.1mg、1.23mmol)を0℃で加えた。10分後、5−オキソ−ピロリジン−3−カルボン酸12(210.3mg、0.411mmol)を0℃で加え、そして反応混合物を1時間室温で攪拌した。溶媒が蒸発した後、粗生成物をシリカゲル上でのクロマトグラフィー(酢酸エチル:ヘキサン=1:2→1:1)によって精製して相当する(シス)−5−オキソ−ピロリジン−3−カルボン酸ペンタフルオロフェニルエステル13を無色油(78.2mg、28.9%)として得た。
2mLTHFエキストラドライ中の(シス)−5−オキソ−ピロリジン−3−カルボン酸ペンタフルオロフェニルエステル13(78.2mg、0.1154mmol)の懸濁液へピペラジン(39.8mg、0.4616mmol)を室温で加えた。反応混合物を室温で10時間攪拌した。その後、20mL塩化メチレンを加えた。得られた有機層を炭酸水素ナトリウムの飽和水溶液20mLで洗浄し、硫酸マグネシウムで乾燥し、溶媒を真空除去した。最後に、粗生成物をシリカゲル上でのクロマトグラフィー(酢酸エチル:メタノール=9:1→1:1)によって精製して望ましい(シス)−4−(ピペラジン−1−カルボニル)−ピロリジン−2−オン14を白色固体(38.5mg、57.55%)として得た。
3mLTHFエキストラドライ中の化合物14(38.5mg、0.066mmol)の溶液へエチルイソシアネート(14.2mg、0.199mmol)を−30℃で加えた。−30℃で1時間攪拌した後、20mL塩化メチレンを加えた。得られた有機層を炭酸水素ナトリウムの飽和水溶液20mLで洗浄し、硫酸マグネシウムで乾燥し、溶媒を真空除去した。最後に、粗生成物を酢酸エチル:メタノール 19:1から結晶化してPXN790−d1を白色固体(26.9mg、62.24%)として得た。
IR:3043,3165,3033,2964,2930,1677,1615,1538,1449,1401,1262,1240,1207,1119,796,698.
MS(+ESI):m/z=650.1[M+H],672.1[M+Na].
全体収率(4つの分取工程):0.93%
酸素Oによる硫黄S(基X)の入れ代え
(シス)4−[1−(4−クロロ−3−フルオロ−ベンジル)−2−(6−クロロ−1H−インドール−3−イル)−5−オキソ−3−p−トリルオキシ−ピロリジン−3−カルボニル]−ピペラジン−1−カルボン酸エチルアミド[PXN789−d1]の合成
オキソ−置換無水物は3工程合成により得た:
1H−NMR(DMSO,399.83MHz):2.26(s,3H),2.89−2.94(m,1H),3.31−3.46(m,1H),5.44−5.47(m,1H),6.97(d,2H,J=8.4Hz),7.14(d,2H,J=7.6Hz),7.33(d,2H,J=7.2Hz),7.44−7.53(m,3H).
MS(+ESI):m/z=282[M+H].
1H−NMR(DMSO,399.43MHz):2.25(s,3H),3.21−3.27(m,1H),3.52−3.59(m,1H),5.57−5.61(m,1H),6.92(d,2H,J=8.26Hz),7.14(d,2H,J=8.22Hz).
IR:3001,2920,1865,1781,1608,1508,1396,1213,1178,1086,1021,903,806.
MS(+ESI):m/z=207[M+H].
まず、アルデヒド3(646.6mg、3.6mmol)およびアミン(478.8mg、3mmol)を3mLトリメチルオルトホルメート中で室温にて10時間凝縮させた。次に、溶媒を真空除去し、残留物を25mL o−キシレンに溶解した。その後、無水コハク酸15(850mg、4.5mmol)を加え、混合物を150℃に24時間ディーン−スターク条件下で加熱した。室温に冷却した後、溶液を真空濃縮した。シリカゲル上での精製(酢酸エチル:メタノール=9:1→1:1)でMCR−生成物をジアステレオマー混合物(33.9mg、2.11%)として得た。
2mL酢酸エチル中の1−(3−ジメチルアミノプロピル)−3−エチルカルボジイミド塩酸塩EDCI(18.5mg,0.096mmol)の懸濁液へ、ペンタフルオロフェノール(35.6mg、0.193mmol)を0℃で加えた。10分後、5−オキソ−ピロリジン−3−カルボン酸16(33.9mg、0.064mmol)を0℃で加え、そして反応混合物を1時間室温で攪拌した。溶媒が蒸発した後、粗生成物をシリカゲル上でのクロマトグラフィー(酢酸エチル:ヘキサン=1:2)によって精製して相当する5−オキソ−ピロリジン−3−カルボン酸ペンタフルオロフェニルエステル17を無色油(40.1mg、89.80%)として得た。
2mLTHFエキストラドライ中の5−オキソ−ピロリジン−3−カルボン酸ペンタフルオロフェニルエステル17(40.1mg、0.0578mmol)の懸濁液へピペラジン(19.9mg、0.231mmol)を室温で加えた。反応混合物を室温で10時間攪拌した。その後、20mL塩化メチレンを加えた。得られた有機層を炭酸水素ナトリウムの飽和水溶液20mLで洗浄し、硫酸マグネシウムで乾燥し、溶媒を真空除去した。最後に、粗生成物をシリカゲル上でのクロマトグラフィー(酢酸エチル:メタノール=9:1→1:1)によって精製して望ましい4−(ピペラジン−1−カルボニル)−ピロリジン−2−オン18を白色固体(12.2mg、45.91%)として得た。
3mLTHFエキストラドライ中の化合物18(12.2mg、0.0204mmol)の溶液へエチルイソシアネート(4.4mg、0.0612mmol)を−30℃で加えた。−30℃で1時間攪拌した後、20mL塩化メチレンを加えた。得られた有機層を炭酸水素ナトリウムの飽和水溶液20mLで洗浄し、硫酸マグネシウムで乾燥し、溶媒を真空除去した。最後に、粗生成物をシリカゲル上でのクロマトグラフィー(塩化メチレン:メタノール 95:5)によって精製してPXN789−d1を黄色固体(9.6mg、70.60%)として得た。
MS(+ESI):m/z=666.1[M+H]
全体収率(4つの分取工程):0.61%
上記手順の1つによって製造されたさらなる実施例:全ての生成物はラセミ化合物として得られ、試験した。細胞活性はp53野生型卵巣奇形癌細胞(PA−1)で測定し、測定されたIC50をミクロモルで示す。CCAはCell Cycle Arrest(細胞サイクル停止)の略である。
様々なアミドは各種アミンを用いてペンタフルオロフェニルエステルのアミノリシスによって合成された。スキーム4に示すように、他の求核性化合物もペンタフルオロフェニルエステルの活性炭素を攻撃して、新規なピロリジン−2−オン誘導体をもたらすのに適している。
置換された無水コハク酸を多成分反応において用いると、R7および/またはR8がH以外である式(I)の化合物を製造することができる(Org.Lett.2007,9(20),4077−4080参照)。
これらの化合物は次のスキームに従って製造しうる:
このビルスマイヤー反応はH.G.O.Becker,Organikum,pp.364−365,Johann Ambrosius Barth Verlag,ハイデルベルグ−ライプチヒ(1996)に従って行った。温度計を備えた三口フラスコ中のDMF5mLへ、15〜20℃の温度範囲で1.8mLのPOCL3を滴加した。次に、DMF2mL中の6−クロロ−1H−インドール1g(6.6mmol)の溶液を20〜30℃の温度範囲で滴加した。反応混合物を37℃で45分間攪拌した。その後、反応混合物を水10mL中の氷15gの混合物へ攪拌しながら注いだ。18mL中の3.4gNaOHを20〜30℃の温度範囲で加えた。得られた混合物を次に5分間還流した。室温に冷却した後、沈殿物を濾過し、10mL冷水で洗浄した。エタノールからの結晶化で6−クロロ−1H−インドール−3−カルブアルデヒドを白色固体(1.04g、88%)として得た。
5000PA−1またはPA−1/E6を96穴フラットボトムプレートの各穴に入れ、5%CO2中で37℃にて一晩培養した。平板培養細胞の成長は7.5μmolのWST−1試薬(ドイツのロシュ・アプライド・サイエンシーズ社)を3つの対照穴に加え、SpectraMax250プレートリーダーでOD650およびOD450吸収度を測定することによって測定した。OD650−OD450値が0.5より上ならば、プレートの残りを式(I)、(Ia)、(Ic)、(Id)、(Ie)および(If)の化合物、他の薬理学的薬剤または溶媒対照での48時間培養に用いた。この培養の後、WST−1試薬をプレートの穴に加え、OD650−OD450値を前のように計算した。3組の穴を各条件について分析し、標準偏差を判定した:全ての実験は少なくとも3回独立して行った。
Annexin VおよびBrdU−合体レベルを製造業者の指示に従いグアバ・パーソナル・セル分析システム(PCAS、グアバ・テクノロジーズ社、カリフォルニア州ヘイワード)を用いてGuava NexinおよびGuava Tunelキットで測定した。1×106PA−1およびPA−1/E6細胞を10%FBSおよび様々な濃度の式(I)の化合物またはDMSOで補充したBME媒質中で24時間培養した。Nutlin−3、ラセミ(カルバイオケム、ロシュ)を10μMでポジティブ対照として施した。Guava Nexin分析では、細胞をトリプシン化し、1000rpmで5分間、4℃にて遠心分離することによって集めた。氷冷した1×Nexinバッファーで洗浄した後、細胞を同じバッファーに再懸濁し、暗所にて氷上で20分間、Annexin V−PEおよび7−アミノアクチノマイシンDで標識付けし、PCASで分析した。製造業者のGuava Tunel分析のプロトコルに従って、細胞を1%パラホルムアルデヒドに再懸濁し、氷上で60分間培養し、氷冷PBSバッファー中で洗浄した。次に、細胞を氷冷70%エタノール中に少なくとも16時間−20℃で固定した。培養後、細胞をBrdU DNAラベリングミックスで60分間37℃にて標識付けし、1000rpmで5分間の遠心分離により集めた。細胞を抗BrdU着色ミックスに再懸濁し、室温で45分間暗所にて培養し、PCASで分析した。
温度に敏感なH1299クローンを6穴プレートに50,000細胞/穴の密度で接種した。Saos2細胞を1×106細胞/100−mmプレートで平板培養した。細胞を32℃にシフトし、温度シフト後に示された時間で採取した。対照細胞は39℃で維持した。TUNELおよびマルチカスペース(multi−caspase)分析は、Guava TUNELおよびマルチカスペース検出キットを用い、グアバ・パーソナル・サイトメーター(グアバ・テクノロジーズ社)を使用し、製造業者(グアバ・テクノロジーズ社)提供の使用説明書に従って、式(I)、(Ia)、(Ic)、(Id)、(Ie)および(If)の化合物について行った。
Claims (10)
- 式(I)の化合物またはその薬学的に許容される塩、溶媒和物もしくは水和物。
VはC=Oであり;
Xは硫黄、酸素または式CH2、SO2の基または結合であり;
Yは式CONR6の基であり;
nは1であり;
R1は、式−A−Arまたは−A−Cyの基であり、ここで、Aは結合、C1−C4アルキルまたはC1−C6ヘテロアルキルであるか、あるいはAは式−CHR1aの基であり、ここで、R1aはC1−C6ヘテロアルキル基であり、Cyは任意に置換されたC3−C7シクロアルキル基または3〜7個の環原子を含む任意に置換されたヘテロシクロアルキル基であり、Arは任意に置換されたフェニル環または5または6個の環原子を含む任意に置換されたヘテロアリール環であり;
R2は、水素原子であり;
R3は、1もしくは2個の環並びにO、SおよびNから選択される1、2、3または4個の複素原子を含む5〜10個の環原子を有する任意に置換されたヘテロアリール残基であり;
R4は、C1−C6アルキル、C2−C6アルケニル、任意に置換されたC1−C4アルキル−C3−C7シクロアルキル、任意に置換されたフェニル環、任意に置換されたベンジル環、または5もしくは6個の環原子を有し、O、SおよびNから選択される1〜3個の複素原子を含む任意に置換されたヘテロアリール環であり;
R5は、次の基:C1−C6アルキル;1〜6個の炭素原子並びにO、SおよびNから選択される1、2または3個の複素原子を含むヘテロアルキル;C1−C4アルキル基またはC1−C4ヘテロアルキル基および5または6個の環原子並びにO、SおよびNから選択される1、2または3個の複素原子を含む任意に置換されたヘテロシクロアルキル基を含むヘテロアルキルシクロアルキル;C1−C4アルキル基またはC1−C4ヘテロアルキル基および5または6個の環原子並びにO、SおよびNから選択される1、2または3個の複素原子を含む任意に置換されたヘテロアリール基を含むヘテロアラルキル;5または6個の環原子並びにO、SおよびNから選択される1、2または3個の複素原子を含む任意に置換されたヘテロアリール;5または6個の環原子並びにO、SおよびNから選択される1、2または3個の複素原子を含む任意に置換されたヘテロシクロアルキルから選択され;
R6は、水素原子またはC1−C4アルキルであり、または
R5およびR6は一緒になって、4、5、6または7個の環原子並びにO、SおよびNから選択される1、2または3個の複素原子を含む任意に置換されたヘテロシクロアルキル環の一部となり;
R7は水素原子であり;
R8は水素原子であり;
任意に置換されたという表現は、1、2、3またはそれ以上の水素原子がフッ素、塩素、臭素もしくはヨウ素原子に代えられている基;OH、=O、SH、=S、NH2、=NH、N3またはNO2基に代えられている基;またはC1−C6アルキル、C2−C6アルケニル、C2−C6アルキニル、C1−C6ヘテロアルキル、C3−C10シクロアルキル、C2−C9ヘテロシクロアルキル、C6−C10アリール、C1−C9ヘテロアリール、C7−C12アラルキルまたはC2−C11ヘテロアラルキル基で置換されている基;を指す。 - 式(Ia)の化合物またはその薬学的に許容される塩、溶媒和物もしくは水和物。
R1は、式−A−Arまたは−A−Cyの基であり、ここで、Aは結合、C1−C4アルキルまたはC1−C6ヘテロアルキルであるか、あるいはAは式−CHR1aの基であり、ここで、R1aはC1−C6ヘテロアルキル基であり、Cyは任意に置換されたC3−C7シクロアルキル基または3〜7個の環原子を含む任意に置換されたヘテロシクロアルキル基であり、Arは任意に置換されたフェニル環または5または6個の環原子を含む任意に置換されたヘテロアリール環であり;
R2は、水素原子であり;
R3は、1もしくは2個の環並びにO、SおよびNから選択される1、2、3または4個の複素原子を含む5〜10個の環原子を有する任意に置換されたヘテロアリール残基であり;
R4は、C1−C6アルキル、C2−C6アルケニル、任意に置換されたC1−C4アルキル−C3−C7シクロアルキル、任意に置換されたフェニル環、任意に置換されたベンジル環、または5もしくは6個の環原子を有し、O、SおよびNから選択される1〜3個の複素原子を含む任意に置換されたヘテロアリール環であり;
R5は、次の基:C1−C6アルキル;1〜6個の炭素原子並びにO、SおよびNから選択される1、2または3個の複素原子を含むヘテロアルキル;C1−C4アルキル基またはC1−C4ヘテロアルキル基および5または6個の環原子並びにO、SおよびNから選択される1、2または3個の複素原子を含む任意に置換されたヘテロシクロアルキル基を含むヘテロアルキルシクロアルキル;C1−C4アルキル基またはC1−C4ヘテロアルキル基および5または6個の環原子並びにO、SおよびNから選択される1、2または3個の複素原子を含む任意に置換されたヘテロアリール基を含むヘテロアラルキル;5または6個の環原子並びにO、SおよびNから選択される1、2または3個の複素原子を含む任意に置換されたヘテロアリール;5または6個の環原子並びにO、SおよびNから選択される1、2または3個の複素原子を含む任意に置換されたヘテロシクロアルキルから選択され;
R6は、水素原子またはC1−C4アルキルであり、または
R5およびR6は一緒になって、4、5、6または7個の環原子並びにO、SおよびNから選択される1、2または3個の複素原子を含む任意に置換されたヘテロシクロアルキル環の一部となり;
任意に置換されたという表現は、1、2、3またはそれ以上の水素原子がフッ素、塩素、臭素もしくはヨウ素原子に代えられている基;OH、=O、SH、=S、NH2、=NH、N3またはNO2基に代えられている基;またはC1−C6アルキル、C2−C6アルケニル、C2−C6アルキニル、C1−C6ヘテロアルキル、C3−C10シクロアルキル、C2−C9ヘテロシクロアルキル、C6−C10アリール、C1−C9ヘテロアリール、C7−C12アラルキルまたはC2−C11ヘテロアラルキル基で置換されている基;を指す。 - Arが任意に置換されたフェニルまたは任意に置換されたピリジル残基である、請求項1または2に記載の式(I)または(Ia)の化合物。
- R5およびR6が一緒になって任意に置換されたピペラジンまたはピペリジン環の一部となる、請求項1〜4のいずれか一項に記載の式(I)または(Ia)の化合物。
- 薬学的に許容される担体と任意に組み合わせた、請求項1〜5のいずれか一項に記載の化合物またはその薬学的に許容される、水和物、溶媒和物または塩を含む医薬組成物。
- 請求項1〜5のいずれか一項に記載の化合物またはその薬学的に許容される塩、溶媒和物もしくは水和物の癌用薬剤製造への使用。
- 請求項6に記載の医薬組成物の癌用薬剤製造への使用。
- 癌の治療に用いるための請求項1〜5のいずれか一項に記載の化合物またはその薬学的に許容される塩、溶媒和物もしくは水和物。
- 癌の治療に用いるための請求項6に記載の医薬組成物。
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JP2011526418A Active JP5701758B2 (ja) | 2008-09-15 | 2009-09-15 | Hdm2配位子としてのピロリジン−2−オン |
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US (2) | US8119623B2 (ja) |
EP (1) | EP2346852B1 (ja) |
JP (1) | JP5701758B2 (ja) |
KR (1) | KR20110063542A (ja) |
CN (1) | CN102149708A (ja) |
AR (1) | AR073578A1 (ja) |
AU (1) | AU2009291155A1 (ja) |
BR (1) | BRPI0918603A2 (ja) |
CA (1) | CA2736295A1 (ja) |
EA (1) | EA201100483A1 (ja) |
NZ (1) | NZ591073A (ja) |
PE (1) | PE20110931A1 (ja) |
TW (1) | TW201011009A (ja) |
WO (1) | WO2010028862A1 (ja) |
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JP6237779B2 (ja) | 2012-11-03 | 2017-11-29 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | サイトメガロウイルスの阻害薬 |
TW201429969A (zh) | 2012-12-20 | 2014-08-01 | Merck Sharp & Dohme | 作爲hdm2抑制劑之經取代咪唑吡啶 |
US11407721B2 (en) | 2013-02-19 | 2022-08-09 | Amgen Inc. | CIS-morpholinone and other compounds as MDM2 inhibitors for the treatment of cancer |
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JP6377123B2 (ja) | 2013-03-14 | 2018-08-22 | アムジエン・インコーポレーテツド | 癌の治療のためのmdm2阻害剤としてのヘテロアリール酸モルホリノン化合物 |
JOP20200296A1 (ar) | 2013-06-10 | 2017-06-16 | Amgen Inc | عمليات صنع وأشكال بلورية من mdm2 مثبط |
CA2929858C (en) | 2013-11-22 | 2022-03-29 | CL BioSciences LLC | Gastrin antagonists (eg yf476, netazepide) for treatment and prevention of osteoporosis |
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IL303422A (en) | 2014-04-15 | 2023-08-01 | Vertex Pharma | Pharmaceutical preparations for the treatment of diseases related to cystic fibrosis transmembrane conductance regulator modulators |
EP3150578B1 (en) | 2014-05-29 | 2020-10-14 | Mitsubishi Tanabe Pharma Corporation | Novel pyrrolidine compound and application as melanocortin receptor agonist |
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US20160052938A1 (en) | 2014-08-21 | 2016-02-25 | Boehringer Ingelheim International Gmbh | Spiro[3h-indole-3,2'-pyrrolidin]-2(1h)-one compounds and derivatives as mdm2-p53 inhibitors |
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US3361759A (en) * | 1963-10-07 | 1968-01-02 | Upjohn Co | 3-(2-pyrrolidinyl)-indoles and method of preparation |
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2009
- 2009-09-11 AR ARP090103497A patent/AR073578A1/es not_active Application Discontinuation
- 2009-09-11 TW TW098130660A patent/TW201011009A/zh unknown
- 2009-09-15 PE PE2011000624A patent/PE20110931A1/es not_active Application Discontinuation
- 2009-09-15 EP EP09778533.1A patent/EP2346852B1/en active Active
- 2009-09-15 CN CN200980135970XA patent/CN102149708A/zh active Pending
- 2009-09-15 BR BRPI0918603A patent/BRPI0918603A2/pt not_active IP Right Cessation
- 2009-09-15 CA CA2736295A patent/CA2736295A1/en not_active Abandoned
- 2009-09-15 WO PCT/EP2009/006670 patent/WO2010028862A1/en active Application Filing
- 2009-09-15 US US12/560,051 patent/US8119623B2/en active Active
- 2009-09-15 AU AU2009291155A patent/AU2009291155A1/en not_active Abandoned
- 2009-09-15 JP JP2011526418A patent/JP5701758B2/ja active Active
- 2009-09-15 NZ NZ591073A patent/NZ591073A/xx not_active IP Right Cessation
- 2009-09-15 EA EA201100483A patent/EA201100483A1/ru unknown
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Also Published As
Publication number | Publication date |
---|---|
BRPI0918603A2 (pt) | 2017-06-20 |
CN102149708A (zh) | 2011-08-10 |
US8119623B2 (en) | 2012-02-21 |
EP2346852A1 (en) | 2011-07-27 |
NZ591073A (en) | 2012-11-30 |
US9045414B2 (en) | 2015-06-02 |
CA2736295A1 (en) | 2010-03-18 |
US20100075949A1 (en) | 2010-03-25 |
PE20110931A1 (es) | 2012-01-25 |
EP2346852B1 (en) | 2015-02-25 |
AR073578A1 (es) | 2010-11-17 |
AU2009291155A1 (en) | 2010-03-18 |
US20120122839A1 (en) | 2012-05-17 |
TW201011009A (en) | 2010-03-16 |
JP2012502887A (ja) | 2012-02-02 |
KR20110063542A (ko) | 2011-06-10 |
WO2010028862A1 (en) | 2010-03-18 |
EA201100483A1 (ru) | 2011-10-31 |
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