JP2011515450A - Parpおよびチューブリン重合阻害剤としてのテトラヒドロフェナントリジノンおよびテトラヒドロシクロペンタキノリノン - Google Patents
Parpおよびチューブリン重合阻害剤としてのテトラヒドロフェナントリジノンおよびテトラヒドロシクロペンタキノリノン Download PDFInfo
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- JP2011515450A JP2011515450A JP2011501234A JP2011501234A JP2011515450A JP 2011515450 A JP2011515450 A JP 2011515450A JP 2011501234 A JP2011501234 A JP 2011501234A JP 2011501234 A JP2011501234 A JP 2011501234A JP 2011515450 A JP2011515450 A JP 2011515450A
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- alkyl
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- phenyl
- compound
- cyano
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- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 title claims description 48
- 239000012661 PARP inhibitor Substances 0.000 title abstract description 17
- 239000003744 tubulin modulator Substances 0.000 title description 2
- FFFLACVXJQXTQE-UHFFFAOYSA-N 1,3,4,4a-tetrahydrocyclopenta[h]quinolin-2-one Chemical compound N1C(CCC2C=CC=3C(=C12)C=CC=3)=O FFFLACVXJQXTQE-UHFFFAOYSA-N 0.000 title 1
- NXHQOGQCVYTDHU-UHFFFAOYSA-N 3,4,4a,5-tetrahydro-2h-phenanthridin-1-one Chemical compound C1=CC=CC2=C3C(=O)CCCC3NC=C21 NXHQOGQCVYTDHU-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 198
- MQLACMBJVPINKE-UHFFFAOYSA-N 10-[(3-hydroxy-4-methoxyphenyl)methylidene]anthracen-9-one Chemical compound C1=C(O)C(OC)=CC=C1C=C1C2=CC=CC=C2C(=O)C2=CC=CC=C21 MQLACMBJVPINKE-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 163
- 239000002904 solvent Substances 0.000 claims description 68
- -1 quinoxazolinyl Chemical group 0.000 claims description 64
- 238000002360 preparation method Methods 0.000 claims description 60
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 43
- 229910052739 hydrogen Inorganic materials 0.000 claims description 40
- 239000001257 hydrogen Substances 0.000 claims description 40
- 125000005843 halogen group Chemical group 0.000 claims description 36
- 238000011282 treatment Methods 0.000 claims description 33
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 32
- 238000000034 method Methods 0.000 claims description 32
- 125000004076 pyridyl group Chemical group 0.000 claims description 30
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 30
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- 125000003118 aryl group Chemical group 0.000 claims description 26
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- 238000006243 chemical reaction Methods 0.000 claims description 22
- 239000003814 drug Substances 0.000 claims description 22
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 21
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 20
- 229910052760 oxygen Inorganic materials 0.000 claims description 20
- 150000002431 hydrogen Chemical class 0.000 claims description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 19
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 16
- 125000002757 morpholinyl group Chemical group 0.000 claims description 16
- 125000004193 piperazinyl group Chemical group 0.000 claims description 16
- 125000003386 piperidinyl group Chemical group 0.000 claims description 16
- 125000003545 alkoxy group Chemical group 0.000 claims description 15
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- 125000001424 substituent group Chemical group 0.000 claims description 14
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- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 9
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- 230000001404 mediated effect Effects 0.000 claims description 9
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- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 8
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- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 7
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- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 5
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- 125000005090 alkenylcarbonyl group Chemical group 0.000 claims description 4
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 4
- 125000006620 amino-(C1-C6) alkyl group Chemical group 0.000 claims description 4
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- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 4
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 claims description 4
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- SFZULDYEOVSIKM-UHFFFAOYSA-N chembl321317 Chemical compound C1=CC(C(=N)NO)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(=N)NO)O1 SFZULDYEOVSIKM-UHFFFAOYSA-N 0.000 claims description 4
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 claims description 4
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- 125000000842 isoxazolyl group Chemical group 0.000 claims description 4
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 claims description 4
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 claims description 4
- 125000002971 oxazolyl group Chemical group 0.000 claims description 4
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- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 claims description 4
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 claims description 4
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- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
- 125000001422 pyrrolinyl group Chemical group 0.000 claims description 4
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 4
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 4
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 4
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- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 4
- 125000000335 thiazolyl group Chemical group 0.000 claims description 4
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 4
- 125000004306 triazinyl group Chemical group 0.000 claims description 4
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- 230000009466 transformation Effects 0.000 claims description 3
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- 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
- 229960000424 rasburicase Drugs 0.000 description 1
- 108010084837 rasburicase Proteins 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000007420 reactivation Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000031539 regulation of cell division Effects 0.000 description 1
- 230000008844 regulatory mechanism Effects 0.000 description 1
- 230000003362 replicative effect Effects 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 208000032253 retinal ischemia Diseases 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- 229960003452 romidepsin 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
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000010956 selective crystallization Methods 0.000 description 1
- 230000009834 selective interaction Effects 0.000 description 1
- CYOHGALHFOKKQC-UHFFFAOYSA-N selumetinib Chemical compound OCCONC(=O)C=1C=C2N(C)C=NC2=C(F)C=1NC1=CC=C(Br)C=C1Cl CYOHGALHFOKKQC-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 206010040560 shock Diseases 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 231100000188 sister chromatid exchange Toxicity 0.000 description 1
- 230000009759 skin aging Effects 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- MFBOGIVSZKQAPD-UHFFFAOYSA-M sodium butyrate Chemical compound [Na+].CCCC([O-])=O MFBOGIVSZKQAPD-UHFFFAOYSA-M 0.000 description 1
- 239000000264 sodium ferrocyanide Substances 0.000 description 1
- GTSHREYGKSITGK-UHFFFAOYSA-N sodium ferrocyanide Chemical compound [Na+].[Na+].[Na+].[Na+].[Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] GTSHREYGKSITGK-UHFFFAOYSA-N 0.000 description 1
- 235000012247 sodium ferrocyanide Nutrition 0.000 description 1
- PFUVRDFDKPNGAV-UHFFFAOYSA-N sodium peroxide Chemical compound [Na+].[Na+].[O-][O-] PFUVRDFDKPNGAV-UHFFFAOYSA-N 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 210000001082 somatic cell Anatomy 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 239000004544 spot-on Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 238000004808 supercritical fluid chromatography Methods 0.000 description 1
- 230000008093 supporting effect Effects 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 235000019527 sweetened beverage Nutrition 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 description 1
- YVSQVYZBDXIXCC-INIZCTEOSA-N telomestatin Chemical compound N=1C2=COC=1C(N=1)=COC=1C(N=1)=COC=1C(N=1)=COC=1C(N=1)=COC=1C(=C(O1)C)N=C1C(=C(O1)C)N=C1[C@@]1([H])N=C2SC1 YVSQVYZBDXIXCC-INIZCTEOSA-N 0.000 description 1
- 208000001608 teratocarcinoma Diseases 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical group 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 208000030901 thyroid gland follicular carcinoma Diseases 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 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
- QVMPZNRFXAKISM-UHFFFAOYSA-N tirapazamine Chemical compound C1=CC=C2[N+]([O-])=NC(=N)N(O)C2=C1 QVMPZNRFXAKISM-UHFFFAOYSA-N 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
- 201000006134 tongue cancer Diseases 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 230000009529 traumatic brain injury Effects 0.000 description 1
- RTKIYFITIVXBLE-QEQCGCAPSA-N trichostatin A Chemical compound ONC(=O)/C=C/C(/C)=C/[C@@H](C)C(=O)C1=CC=C(N(C)C)C=C1 RTKIYFITIVXBLE-QEQCGCAPSA-N 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 230000005747 tumor angiogenesis Effects 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- ZOCKGBMQLCSHFP-KQRAQHLDSA-N valrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)CCCC)[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1 ZOCKGBMQLCSHFP-KQRAQHLDSA-N 0.000 description 1
- 229960000653 valrubicin Drugs 0.000 description 1
- 230000006496 vascular abnormality Effects 0.000 description 1
- 239000004066 vascular targeting agent Substances 0.000 description 1
- 230000028973 vesicle-mediated transport Effects 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
- 229940004212 yondelis Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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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
-
- 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
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
- C07D221/10—Aza-phenanthrenes
- C07D221/12—Phenanthridines
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Heart & Thoracic Surgery (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
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- Plural Heterocyclic Compounds (AREA)
Abstract
Description
本発明はPARPおよびチューブリン重合の阻害剤に関し、そして化合物および開示される化合物を含有する組成物を提供する。さらに、本発明は、例えば薬剤としての開示されるPARPおよびチューブリン重合阻害剤の使用方法を提供する。
核酵素ポリ(ADP−リボース)ポリメラーゼ−1(PARP−1)は、PARP酵素ファミリーのメンバーである。この増加するファミリーの酵素は、例えば、PARP−1、PARP−2、PARP−3およびVault−PARPのようなPARP;ならびに例えば、TANK−1およびTANK−2のようなタンキラーゼ(Tankyrase:TANK)からなる。またPARPは、ポリ(アデノシン5’−ジホスホ−リボース)ポリメラーゼまたはPARS(ポリ(ADP−リボース)シンテターゼ)とも呼ばれる。
タンキラーゼ1(TANK−1)とは異なる。しかし両タンパク質が類似の細胞下での局在性を有し、互いに会合し、そして多くの同じタンパク質に結合すると仮定すれば、タンキラーゼ−2は恐らくタンキラーゼ−1と幾つか重複する機能を有するだろう。
たはPARG阻害は、細胞のエネルギーレベルを保持し、それによって発作後の虚血組織の生存を強化することが期待される。
あり、これに対して体細胞は機能的BRCAタンパク質を保持している(BRCA2+/−)。BRCA1−またはBRCA2−欠失のバックグラウンドでのPARP活性の阻害は、通常、姉妹染色分体交換により修復されるDNA損傷の生成をもたらし、染色分体の逸脱および生存能の喪失を引き起こす。BRCA−欠失細胞の急性の感受性を仮定すれば、比較的低レベルのPARP−1阻害剤だけが治療的効果を生じるために必要とされるのかもしれない。これは通常は必須ではないDNA修復タンパク質の阻害剤が腫瘍を処置するために単独の作用物質として使用できる別の例である。
は、血管内皮細胞の細胞骨格が微小管の解重合を通して破壊されるが、これは微小管を形成するためのチューブリンの重合を阻害することからもたらされる。微小管の長さは、解重合対重合の割合に依存する。重合の阻害による微小管の解重合は、内皮細胞の形態における変化をもたらし、これが血流の封鎖または閉鎖を引き起こす。癌性腫瘍の場合には、病的組織への血流が停止されて、腫瘍から酸素および栄養物を奪って壊死的細胞死をもたらす。新生血管系はこれらの作用物に対してより感受性である、何故ならば、それらは、アクチンに基づく細胞骨格構造によってまた支持される正常で健全な血管内皮細胞よりも微小管細胞骨格に一層依存しているからである。チューブリンのコルヒチン結合部位を標的とする多数のチューブリン重合の阻害剤では、血管標的様相が抗増殖様相よりも低いインビボ濃度において達成することができる。このようにチューブリンのコルヒチン結合性ドメインを標的とする作用物は、潜在的に二重様式、すなわち抗有糸分裂と抗血管性の作用物となることができる。
2003年12月11日に公開された特許文献2は、細胞増殖関連障害の処置のための2−オキソ−1,3,4−トリヒドロキナゾリニル誘導体を開示する。
本発明は、立体化学的異性体形を含む式(I):
YはCH2またはCH2−CH2であり;
R1はアリールまたはHetであり;
ここでアリールはフェニルまたはナフタレニルであり;
ここでHetはチエニル、ピロリル、ピロリニル、オキサゾリル、チアゾリル、イミダゾリル、ピラゾリル、イソキサゾリル、イソチアゾリル、オキサジアゾリル、トリアゾリル、テトラゾリル、チアジアゾリル、フラニル、ピペリジニル、ピリジニル、ピリダジニル、ピリミジニル、ピペラジニル、ピラジニル、トリアジニル、インドリジニル、アザインドリジニル、インドリル、インドリニル、ベンゾチエニル、インダゾリル、ベンゾキサゾリル、ベンズイミダゾリル、ベンゾフラニル、ベンゾチアゾリル、ベンゾトリアゾリル、クロマニル、プリニル、キノリニル、シンノリニル、フタラジニル、キナゾリニル、キノキサゾリニル、ナフチリジニルまたはプテリジニルであり;
アリールまたはHet上の2個の炭素原子は
−O−CH2−CH2−O− (a−1)、
−CH2−O−CH2−O− (a−2)、
−O−CH2−CH2−CH2− (a−3)、
−O−CH2−CH2−NR8− (a−4)、
−O−CR8 2−O− (a−5)、
−O−CH2−CH2− (a−6)、
−CH2−N−CH2−CH2− (a−7)、
−(CH2)3− (a−8)または
−(CH2)4− (a−9)
から選択される二価の基で架橋されることができ(すなわち、二もしくは三環系部分を形成する);
各アリール、Het、架橋化アリールまたは架橋化Hetは、ハロ、シアノ、ニトロ、ヒドロキシカルボニル、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、C3−6シクロアルキル、C3−6シクロアルキルアミノ、メチルエチルアミノ、アミノC3−6シクロアルキル、ハロC1−6アルキル、トリハロC1−6アルキル、C1−
6アルキルカルボニル、C1−6アルキルオキシカルボニル、C2−6アルケニルカルボニル、オキシム、C1−6アルキルオキシム、アミドキシム、−C≡C−CH2O−CH3、−C≡C−CH2N(CH3)2、−C≡C−Si(CH3)3、ヒドロキシC1−6アルキル、ヒドロキシC2−6アルケニル、ヒドロキシC2−6アルキニル、シアノC1−6アルキル、シアノC2−6アルケニル、アミノカルボニルC1−6アルキル、C1−6アルキルスルホニルC1−6アルキル、C1−6アルキルスルホニルC2−6アルケニル、C1−6アルキルスルホニルC2−6アルキニル、−PO(OC1−6アルキル)2、−B(OH)2、−S−CH3、SF5、C1−6アルキルスルホニル、−NR8R9、−C1−6アルキルNR8R9、−OR8、−C1−6アルキルOR8、−CONR8R9、ピペリジニルC1−6アルキル、ピペラジニルC1−6アルキル、C1−6アルキルピペラジニルC1−6アルキル、モルホリニルC1−6アルキル、ピペリジニル、ピペラジニル、C1−6アルキルピペラジニル、モルホリニル、フェニル、チエニル、ピラゾリル、ピロリル、ピロリジニル、ピリジニル、ピリミジニル、オキサジアゾリル、イミダゾリル、イミダゾリルC2−6アルキニル、C1−6アルキルイミダゾリルC2−6アルキニル、シアノピリジニル、フェニルC1−6アルキル、フェニルC2−6アルケニル、モルホリニルC1−6アルキル、C1−6アルキルオキシフェニル、トリハロC1−6アルキルフェニル、メチルピラゾリル、ハロピリミジニルまたはジメチルアミノピロリジニルからそれぞれ独立して選択される1、2、3、4もしくは5個の置換基により置換されることができ;あるいは
R1は式
式中、X2はCH2、C=O、O、NHまたはN−CH3であり;
式中、R10はフェニル、ピリジニル、ピリダジニルまたはピリミジニルであり、ここで各フェニル、ピリジニル、ピリダジニルまたはピリミジニルは、ハロ、ヒドロキシ、シアノ、C1−6アルキル、アミノ、ポリハロC1−6アルキルまたはC1−6アルキルオキシからそれぞれ独立して選択される1もしくは2個の置換基により置換されることができる、
の基であるか;あるいは
R1は式
の基であり;
R2はメチル、エチル、プロピルまたはC3−6シクロアルキルであり;
各R3およびR4は、水素、メチル、エチル、プロピル、ヒドロキシ、トリフルオロメチル、メチルオキシから独立して選択され;あるいはR3およびR4はそれらに結合している炭素原子と共にシクロプロピル環または式C(=O)の基を形成し;
各R5およびR6は水素、ハロ、C1−6アルキルオキシ、シアノ、C1−6アルキル
、−OCH2CH2NR8R9、−CH2OCH2CH2NR8R9、−OCH2CH2CH2NR8R9から独立して選択され;
R7は水素、メチルまたはフルオロであり;
各R8およびR9は、水素、ハロ、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、カルボニル、C1−6アルキルスルホニルC1−6アルキル、C1−6アルキルオキシC1−6アルキル、ヒドロキシC1−6アルキル、ジヒドロキシC1−6アルキル、シアノC1−6アルキル、トリハロC1−6アルキル、フェニルC1−6アルキル、(ジC1−6アルキル)アミノC1−6アルキル、C1−6アルキルスルホニル、モルホリニルC1−6アルキル、モルホリニルカルボニル、ピペラジニルC1−6アルキル、C1−6アルキルピペラジニルC1−6アルキル、ピペリジニルC1−6アルキル、チオモルホリニルC1−6アルキル、C3−6シクロアルキルメチル、ピリジニル、ピリミジニル、フェニル、ハロフェニル、オキサニルC1−6アルキル、C1−6アルキルスルホニルC1−6アルキルまたはC1−6アルキルカルボニルアミノC1−6アルキルから独立して選択される]
の化合物、それらのN−オキシド形、それらの製薬学的に許容され得る付加塩、およびそれらの溶媒和物に関する。
クロブチル、シクロペンチル、シクロヘキシルなどを含む。
a)YがCH2−CH2であり;
b)アリールがフェニルであり;
c)Hetがピリジニル、ピリミジニル、ベンズイミダゾリルまたはインダソリルでありd)各アリールまたはHetが、ハロ、シアノ、C1−6アルキル、C1−6アルキルオ
キシカルボニル、C1−6アルキルNR8R9または−OR8からそれぞれ独立して選択される1もしくは2個の置換基により置換されることができ;
e)X1がCH2またはN−CH3であり;
f)X2がCH2、C=OまたはOであり;
g)R10がシアノにより置換されることができるフェニルであり;
h)R2がメチルであり;
j)R3およびR4が水素であり;
k)R5およびR6が水素であり;
l)R7が水素であり;または
m)各R8およびR9が水素、ハロ、C1−6アルキルまたはトリハロC1−6アルキルから独立して選択される。
a)YがCH2−CH2であり;
b)R1がフェニル、ピリジニルまたはピリミジニルであり;
c)各フェニル、ピリジニルまたはピリミジニルは、ハロ、シアノまたはC1−6アルキルオキシからそれぞれ独立して選択される1もしくは2個の置換基により置換されることができ;
e)X1がCH2であり;
f)X2がOであり;
g)R10がシアノにより置換されたフェニルであり;
d)R2がメチルであり;
e)R3およびR4が水素であり;
h)R5およびR6が水素であり;または
i)R7が水素である。
リウム塩またはリチウムジイソプロピルアミドを、式(III)の中間体に、式(IV)の中間体(式中、Haloはクロロ、ブロモである)の存在下で、テトラヒドロフラン、ジオキサンまたはジメチルホルムアミドのような適切な溶媒中にて加えることにより調製することができる。
YはCH2またはCH2−CH2であり;
R1はアリールまたはHetであり;
ここでアリールはフェニルまたはナフタレニルであり;
ここでHetはチエニル、ピロリル、ピロリニル、オキサゾリル、チアゾリル、イミダゾリル、ピラゾリル、イソキサゾリル、イソチアゾリル、オキサジアゾリル、トリアゾリル、テトラゾリル、チアジアゾリル、フラニル、ピペリジニル、ピリジニル、ピリダジニル、ピリミジニル、ピペラジニル、ピラジニル、トリアジニル、インドリジニル、アザインドリジニル、インドリル、インドリニル、ベンゾチエニル、インダゾリル、ベンゾキサゾリル、ベンズイミダゾリル、ベンゾフラニル、ベンゾチアゾリル、ベンゾトリアゾリル、クロマニル、プリニル、キノリニル、シンノリニル、フタラジニル、キナゾリニル、キノキサゾリニル、ナフチリジニルまたはプテリジニルであり;
アリールまたはHet上の2個の炭素原子は
−O−CH2−CH2−O− (a−1)、
−CH2−O−CH2−O− (a−2)、
−O−CH2−CH2−CH2− (a−3)、
−O−CH2−CH2−NR8− (a−4)、
−O−CR8 2−O− (a−5)、
−O−CH2−CH2− (a−6)、
−CH2−N−CH2−CH2− (a−7)、
−(CH2)3− (a−8)または
−(CH2)4− (a−9);
から選択される二価の基で架橋されることができ(すなわち、二もしくは三環系部分を形成する);
各アリール、Het、架橋化アリールまたは架橋化Hetは、ハロ、シアノ、ニトロ、ヒドロキシカルボニル、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、C3−6シクロアルキル、C3−6シクロアルキルアミノ、メチルエチルアミノ、アミノC3−6シクロアルキル、ハロC1−6アルキル、トリハロC1−6アルキル、C1−6アルキルカルボニル、C1−6アルキルオキシカルボニル、C2−6アルケニルカルボニル、オキシム、C1−6アルキルオキシム、アミドキシム、−C≡C−CH2O−CH3、−C≡C−CH2N(CH3)2、−C≡C−Si(CH3)3、ヒドロキシC1−6アルキル、ヒドロキシC2−6アルケニル、ヒドロキシC2−6アルキニル、シアノC1−6アルキル、シアノC2−6アルケニル、アミノカルボニルC1−6アルキル、C1−6アルキルスルホニルC1−6アルキル、C1−6アルキルスルホニルC2−6アルケニル、C1−6アルキルスルホニルC2−6アルキニル、−PO(OC1−6アルキル)2、−B(OH)2、−S−CH3、SF5、C1−6アルキルスルホニル、−NR8R9、−C1−6アルキルNR8R9、−OR8、−C1−6アルキルOR8、−CONR8R9、ピペリジニルC1−6アルキル、ピペラジニルC1−6アルキル、C1−6アルキルピペラジニルC1−6アルキル、モルホリニルC1−6アルキル、ピペリジニル、ピペラジニル、C1−6アルキルピペラジニル、モルホリニル、フェニル、チエニル、ピラゾリル、ピロリル、ピロリジニル、ピリジニル、ピリミジニル、オキサジアゾリル、イミダゾリル、イミダゾリルC2−6アルキニル、C1−6アルキルイミダゾリルC2−6アルキニル、シアノピリジニル、フェニルC1−6アルキル、フェニルC2−6アルケニル、モルホリニルC1−6アルキル、C1−6アルキルオキシフェニル、トリハロC1−6アルキルフェニル、メチルピラゾリル、ハロピリミジニルまたはジメチルアミノピロリジニルからそれぞれ独立して選択される1、2、3、4もしくは5個の置換基により置換されることができ;あるいは
R1は式
式中、X2はCH2、C=O、O、NHまたはN−CH3であり;
式中、R10はフェニル、ピリジニル、ピリダジニルまたはピリミジニルであり、ここで各フェニル、ピリジニル、ピリダジニルまたはピリミジニルは、ハロ、ヒドロキシ、シアノ、C1−6アルキル、アミノ、ポリハロC1−6アルキルまたはC1−6アルキルオキシからそれぞれ独立して選択される1もしくは2個の置換基により置換されることができる、
の基であるか;あるいは
R1は式
の基であり;
R2はメチル、エチル、プロピルまたはC3−6シクロアルキルであり;
各R3およびR4は、水素、メチル、エチル、プロピル、ヒドロキシ、トリフルオロメチル、メチルオキシから独立して選択され;あるいはR3およびR4はそれらに結合している炭素原子と共にシクロプロピル環または式C(=O)の基を形成し;
各R5およびR6は水素、ハロ、C1−6アルキルオキシ、シアノ、C1−6アルキル、−OCH2CH2NR8R9、−CH2OCH2CH2NR8R9、−OCH2CH2CH2NR8R9から独立して選択され;
R7は水素、メチルまたはフルオロであり;
各R8およびR9は、水素、ハロ、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、カルボニル、C1−6アルキルスルホニルC1−6アルキル、C1−6アルキルオキシC1−6アルキル、ヒドロキシC1−6アルキル、ジヒドロキシC1−6アルキル、シアノC1−6アルキル、トリハロC1−6アルキル、フェニルC1−6アルキル、(ジC1−6アルキル)アミノC1−6アルキル、C1−6アルキルスルホニル、モルホリニルC1−6アルキル、モルホリニルカルボニル、ピペラジニルC1−6アルキル、C1−6アルキルピペラジニルC1−6アルキル、ピペリジニルC1−6アルキル、チオモルホリニルC1−6アルキル、C3−6シクロアルキルメチル、ピリジニル、ピリミジニル、フェニル、ハロフェニル、オキサニルC1−6アルキル、C1−6アルキルスルホニルC1−6アルキルまたはC1−6アルキルカルボニルアミノC1−6アルキルから独立して選択される]
の中間体、それらのN−オキシド形、それらの製薬学的に許容され得る付加塩、およびそれらの溶媒和物に関する。
−微小管を安定化し、微小管の解重合を阻害し、微小管を安定化し、または微小管構造をフリーズ(freeze)する
−微小管の重合を途絶し、そして微小管の形成を途絶する、または
−微小管を不安定化し、そして微小管の形成を防止する
化合物を同定するために使用される。
置または予防するため;他の状態および/または障害、例えば年齢に関連する筋肉変性、AIDSおよび他の免疫老化疾患、炎症、痛風、関節炎、動脈硬化症、悪液質、癌、複製老化が関与する骨格筋の変性疾患、糖尿病、頭部外傷、炎症性腸障害(例えば大腸炎およびクローン病)、筋ジストロフィー、骨関節炎、骨粗鬆症、慢性および/または急性疼痛(例えば神経病性疼痛)、腎不全、網膜虚血、敗血症ショック(例えば内毒素ショック)、および皮膚の老化を処置するため;細胞の寿命および増殖能力を拡大するため;老化細胞の遺伝子発現を改変するため;(低酸素の)腫瘍細胞を化学増感および/または放射線増感するために、PARP活性を阻害するのに十分な量の先に同定された化合物の治療学的有効量を投与する方法に関する。また、本発明は、先に同定された化合物の治療学的有効量を動物、特にヒトに投与することを含んでなる、該動物の疾患および状態の処置に関する。特に本発明は、先に同定された化合物の治療学的有効量を動物、特にヒトに投与することを含んでなる、該動物の神経学的障害を処置、予防または抑制する方法に関する。神経学的障害は、肉体的傷害または疾病状態によって惹起される末梢神経病、外傷性脳傷害、脊髄に対する物理的損傷、脳損傷に伴う卒中、巣状虚血、全虚血、再灌流傷害、脱髄疾患および神経変性に関連する神経学的障害からなる群から選択される。
− 白金配位化合物、例えば場合によりアミホスチン(amifostine)、カルボプラチンまたはオキサリプラチン(oxaliplatin)と組み合わせたシスプラチン;
− タキサン化合物、例えばパクリタキセル、パクリタキセルタンパク質結合粒子(Abraxane(商標))またはドセタキセル;
− トポイソメラーゼI阻害剤、例えばカンプトテシン化合物、例えばイリノテカン、SN−38、トポテカン、トポテカンhcl;
− トポイソメラーゼII阻害剤、例えば抗腫瘍性エピポドフィロトキシンまたはポドフィロトキシン誘導体、例えばエトポシド、リン酸エトポシドまたはテニポシド;
− 抗腫瘍性ビンカアルカロイド、例えばビンブラスチン、ビンクリスチンまたはビノレルビン;
− 抗腫瘍性ヌクレオシド誘導体、例えば5−フルオロウラシル、ロイコボリン、ゲムシ
タビン、ゲムシタビンhcl、カペシタビン、クラドリビン(cladribine)、フルダラビン(fludarabine)、ネララビン(nelarabine);
− アルキル化剤、例えばナイトロジェンマスタードまたはニトソロウレア、例えば場合によりメスナ(mesna)、ピポブロマン、プロカルバジン、ストレプトゾシン、テロゾロミド(telozolomide)、ウラシルと組み合わせたシクロホスファミド、クロラムブシル、カルムスチン、チオテパ、メファラン(メルファラン)、ロムスチン、アルトレタミン(altretamine)、ブスルファン、ダカルバジン、エストラムスチン、イフォスファミド(ifosfamide);
− 抗腫瘍性アントラサイクリン誘導体、例えば場合によりデクスラゾキサン(dexrazoxane)、ドキシル(doxil)、イダルビシン、ミトザントロン、エピルビシン(epirubicin)、エピルビシンhcl、バルルビシン(valrubicin)と組み合わせたダウノルビシン、ドキソルビシン;
−IGF−1受容体を標的とする分子、例えばピクロポドフィリン(picropodophilin);
−テトラカルシン(tetracarcin)誘導体、例えばテトラカルシンA;
−グルココルチコイデン(glicocorticoiden)、例えばプレドニソン;−抗体、例えばトラスツズマブ(HER2抗体)、リタキシマブ(CD20抗体)、ゲムツズマブ(gemtuzumab)、ゲムツズマブオゾガマイシン(ozogamicin)、セツキシマブ(cetuximab)、ペルツズマブ(pertuzumab)、ベバシズマブ(bevacizumab)、アレムツズマブ(alemtuzumab)、エクリズマブ(eculizumab)、イブリツモマブ チウキセタン(ibritumomab tiuxetan)、ノフェツモマブ(nofetumomab)、パニツムマブ(panitumumab)、トシツモマブ(tositumomab)、CNTO328;
− エストロゲン受容体拮抗薬または選択的エストロゲン受容体モジュレーター、またはエストロゲン合成の阻害剤、例えばタモキシフェン、フルベストラント(fulvestrant)、トレミフェン、ドロロキシフェン(droloxifene)、ファスロデックス(faslodex)、ラロキシフェンまたはレトロゾール(letrozole);
− アロマターゼ阻害剤、例えばエキセメスタン、アナストロゾール、レトラゾール(letrazole)、テストラクトンおよびボロゾール(vorozole);
− 分化誘導薬、例えばレチノイド、ビタミンDまたはレチノイン酸およびレチノイン酸代謝遮断薬(RAMBA)、例えばアキュタン(accutane);
− DNAメチルトランスフェラーゼ阻害剤、例えばアザシチジンまたはデシタビン(decitabine);
−葉酸拮抗薬、例えば プレメトレキセド(premetrexed)二ナトリウム;
−抗生物質、例えばアンチノマイシン(antinomycin)D、ブレオマイシン、マイトマイシンC、ダクチノマイシン、カルミノマイシン(carminomycin)、ダウノマイシン、レバミゾール、プリカマイシン(plicamycin)、ミトラマイシン;
−代謝拮抗物質、例えばクロファラビン(clofarabine)、アミノプテリン、シトシンアラビノシドまたはメトトレキセート、アザシチジン、シタラビン、フロクスウリジン、ペントスタチン、チオグアニン;
−アポトーシス誘導剤および血管新生抑制剤、例えばBcl−2阻害剤、例えばYC137、BH312、ABT737、ゴシポール、HA14−1、TW37またはデカン酸;−チューブリン−結合剤、例えばコンブレスタチン(combrestatin)、コルヒチンまたはノコダゾール(nocodazole);
− キナーゼ阻害剤(例えばEGFR(上皮増殖因子受容体)阻害剤、MTKI(マルチターゲットキナーゼ阻害剤)、mTOR阻害剤)、例えばフラボペリドール(flavoperidol)、イマチニブ(imatinib)メシル酸、エルロチニブ(erlo
tinib)、ゲフィチニブ(gefitinib)、ダサチニブ(dasatinib)、ラパチニブ(lapatinib)、二トシル酸ラパチニブ、ソラフェニブ(sorafenib)、スニチニブ(sunitinib)、リンゴ酸スニチニブ、テムシロリムス(temsirolimus);
−ファルネシルトランスフェラーゼ阻害剤、例えばチピファルニブ(tipifarnib);
− ヒストンデアセチラーゼ(HDAC)阻害剤、例えば酪酸ナトリウム、サブエロイルアニリドヒドロキサミン酸(SAHA)、デプシペプチド(FR901228)、NVP−LAQ824、R306465、JNJ−26481585、トリコスタチン(trichostatin)A、ボリノスタット;
− ユビキチン−プロテアソーム経路の阻害剤、例えばPS−341、MLN.41またはボルテゾミブ;
− ヨンデリス(Yondelis);
− テロメラーゼ阻害剤、例えばテロメスタチン(telomestatin);
− マトリクスメタロプロテイナーゼ阻害剤、例えばバチマスタット(batimastat)、マリマスタット(marimastat)、プリノスタット(prinostat)またはメタスタット(metasta);
−組換えインターロイキン、例えばアルデスロイキン(aldesleukin)、デニロイキン ディフィティトックス(denileukin difititox)、インターフェロン アルファ2a、インターフェロン アルファ2b、ペグインターフェロン
アルファ2b;
−MAPK阻害剤;
−レチノイド、例えばアリトレチノイン(alitretinoin)、ベキサロテン(bexarotene)、トレチノイン(tretinoin);
−三酸化ヒ素
−アスパラギナーゼ
−ステロイド、例えばプロピオン酸ドロモスタノロン、酢酸メゲストロール、ナンドドロン(デカノエート、フェンプロピオネート)、デキサメタゾン;
−性腺刺激ホルモン放出ホルモン作用薬または拮抗薬、例えばアバレリックス(abarelix)、酢酸ゴセレリン、酢酸ヒストレリン、酢酸ロイプロリド;
−サリドマイド、レナリドミド(lenalidomide);
−メルカプトプリン、ミトーテン、パミトロネート、ペガデマーゼ(pegademase)、ペガスパルガーゼ(pegaspargase)、ラスブリカーゼ(rasburicase);
−BH3ミメティックス、例えばABT−737;
−MEK阻害剤、例えばPD98059、AZD6244、CI−1040;
−コロニー刺激因子類似体、例えばフィルグラスチム(filgrastim)、ペグフィルグラスチム(pegfilgrastim)、サルグラモスチム(sargramostim)、エリスロポエチンまたはそれらの類似体(例えばダルベポエチン(darbepoetin)アルファ);インターロイキン11;オプレルベキン(oprelvekin);ゾレドロネート(zoledronate)、ゾレドロン酸(zoledronic acid);フェンタニル;ビスホスホネート;パリフェルミン(palifermin)である。
および細胞分裂に関与する基本的メカニズムを乱すものである。急速に増殖している組織中のDNA機能および完全性を阻害するアルキル化剤の能力が、それらの治療的応用および多数のそれらの毒性の基礎を提供する。ナイトロジェンマスタードまたニトロウレアのようなアルキル化剤は、処置の過程で100〜500mg/体表面積の平方メートル(mg/m2)、例えば120〜200mg/m2の投薬用量で有利に投与され、特にシクロホスファミドに関しては約100〜500mg/m2の投与用量で、クロラムブシルに関しては約0.1〜0.2mg/m2の投薬用量で、カルムスチンに関しては約150〜200mg/m2の投薬用量で、そしてロムスチンに関しては約100〜150mg/m2の投薬用量で有利に投与される。
ス)に関与するキナーゼの強力な阻害剤を含んでなる。
。該副用量は、例えば単位剤形あたり0.05〜500mg、そして特に0.1mg〜200mgの有効成分を含有する単位剤形として調合することができる。
今後、“DMF”はN,N−ジメチルホルムアミドと定義し、“DCM”はジクロロメタンと定義し、“DIPE”はジイソプロピルエーテルと定義し、“DMSO”はジメチルスルフォキシドと定義し、“EtOAc”は酢酸エチルと定義し、“MeOH”はメタノールと定義し、“THF”はテトラヒドロフランと定義する。
実施例A1
a)中間体1の調製
b)中間体2の調製
c)中間体3の調製
e)中間体4の調製
f)中間体5の調製
g)中間体6の調製
h)中間体7の調製
を3時間撹拌し、飽和塩化アンモニウムでクエンチし、そしてEtOAcで抽出した。有機層をブラインで洗浄し、乾燥し(MgSO4)、濾過し、そして溶媒を減圧下で蒸発させた。残渣をシリカゲルでのカラムクロマトグラフィーにより精製した(溶出液:石油エーテル/EtOAcを95/5から90/10)。純粋な画分を集め、そして溶媒を蒸発させて0.159g(99%)の中間体7が得られた。
i)中間体7aおよび7bの調製
中間体8の調製
中間体9の調製
中間体10の調製
中間体11の調製
中間体12の調製
中間体13の調製
中間体14の調製
中間体15の調製
中間体16の調製
中間体17の調製
a)中間体18の調製
b)中間体19の調製
中間体19が得られ、これをさら精製せずに次の反応工程に使用した。
c)中間体20の調製
中間体21の調製
a)中間体22の調製
b)中間体23の調製
c)中間体24の調製
d)中間体25の調製
99/1/0.1;3.4μm)。純粋な画分を集め、そして溶媒を蒸発乾固して、0.197g(47%)の中間体25(油)が得られた。
e)中間体26の調製
f)中間体27の調製
98/2/0.1)。純粋な画分を集め、そして溶媒を蒸発乾固して0.07g(71%)の中間体27(油)が得られた。
g)中間体28の調製
中間体29の調製
中間体30の調製
実施例B1
a)化合物1の調製
b)化合物2および3の調製
化合物4の調製
a)化合物5の調製
b)化合物5aおよび5bの調製
そして溶媒を蒸発させた。エナンチオマーAはジエチルエーテルから結晶化した。沈殿を濾過し、そして乾燥させて、0.102g(32%)の化合物5a(融点226℃;[α]D 20=+90.7(DMF;c=0.34)が得られた。エナンチオマーBはジエチルエーテルから結晶化した。沈殿を濾過し、そして乾燥して、0.098g(31%)の化合物5b(融点222℃;[α]D 20=−82.09(DMF;c=0.335)が得られた。
化合物6の調製
a)化合物7の調製
a)化合物8の調製
化合物9の調製
化合物10の調製
化合物11の調製
化合物12の調製
化合物13の調製
)が得られた。
化合物14の調製
化合物15の調製
化合物16の調製
化合物17の調製
化合物18の調製
化合物19の調製
LCMS
LCMS一般法
HPLC測定は、Gilson215オートサンプラーおよび下記の各方法において指定されるカラムを含んでなる、Watersダイオード−アレイ検出器(DAD)とともにWaters 1512ポンプを使用して実施された。カラムからの流液はMS分光計に分配された。イオン化は、化合物の種類に応じて、エレクトロスプレーまたはAPCI(大気圧化学的イオン化)のいずれかであった。
一般法に加えて:逆相HPLCは、Waters Xterra MS 5μ C18カラム(4.6x100mm:ガードカートリッジ付)において流速2ml/分により実施された。2つの移動相(移動相A:超純粋中に10mM重炭酸アンモニウムを含む水;移動相B;アセトニトリル)を使用して、3.5分で95%Aから95%Bまでの勾配状態を流速2ml/分により作動させ、そして2分間保持した。典型的には、2μlから7μlの間の注入容量を含め使用した。
C.1.PARP−1阻害活性についてのインビトロのシンチレーション近接アッセイ(Scintillation Proximity Assay(SPA)
本発明の化合物は、SPA技術(GE healthcareに対する所有権)に基づくインビトロアッセイで試験した。
本発明の化合物は、Ni Flashプレート(96または384ウェル)を用いたSPA技術に基づくインビトロアッセイで試験した。
ATCCから得られたヒト結腸癌腫HCT116細胞は、2mM L−グルタミン、50μg/mlのゲンタマイシンおよび10%の熱失活胎児ウシ血清が補足されたMcCoy’s 5A培地で培養された。
レサズリンはAldrich(Prod.No.199303)から購入した。フェロシアン化ナトリウム、フェリシアン化カリウム、KH2PO4およびK2HPO4は、Sigma(それぞれ、Prod.No.P9387,P8131,P5655およびP8281)から購入した。
384ウェルプレートにおける実験には、細胞は、透明な底をもつ黒色のFalcon384ウェル培養プレート(Life Technologies,Merelbeke,Belgium)中で、45μl培養基中に4.5x103細胞/mlの密度で接種された。細胞は24時間プラスチックに接着させられた。試験する化合物は、予備希釈(培養基中1/50)され、そして5μlの予備希釈化合物がこのウェルに添加された。4日間のインキュベーション後、10μlのアラマーブルー液が各ウェルに添加され、そして細胞は37℃でさらに4時間(HCT116)または24時間(PC−3)インキュベーションされた。蛍光強度は、Fluorescenceプレートリーダー(Fluorskan,Labsystem、540nm励起および590nm発光)で各ウェルについて測定された。
チューブリン重合アッセイは、Bonne,D.et al.(J.Biol.Chem.1985,260:2819−25)により最初に記述されたアッセイの適応である。アッセイキットはCytoskeleton,Inc.(カタログ番号BK011)から購入し、そしてアッセイは次の改変をして供給元により記述されるように行った。アッセイは、384ウェルの黒色Proxiplate(Perkin Elmmer)で実施され、容量はそれに応じて適合された。反応は10μlの最終容量で実施された。化合物は、氷上96ウェルPPプレート(Corning)中の反応混合液の25μlに添加され、そしてこの混合液の10μlが、Fluoroskan Ascentプレートリーダー(Thermo Scientific)で37℃に予備加温された384ウェルProxiplateの2並列中に分配された。蛍光測定値は1時間の間1分毎に採られた。各ウェルの最大傾斜が決定され(4連続点を通しての直線回帰)、そして重合が化合物の不在下で観察される重合のパーセンテージとして算出された。化合物は、化合物の不在下で観察される重合に比較して、20μMで50%より高い阻害を示す化合物について、最初に20μM、次いで5μMの濃度で測定された。結果は、次のように定義されるスコアとして表F−2で報告される:20μMにおいて0〜50%阻害を示す化合物はスコア1として報告され;5μMにおいて50%より高い阻害を示す化合物はスコア3として報告される。スコア2の化合物は、20μMにおいて50%より高い阻害、そして5μMにおいて50%未満の阻害を示す化合物として定義される。
Eb1 コメットアッセイは、間接的な免疫蛍光を使用する、重合中の微小管のプラス末端におけるEb1タンパク質の検出に依存する(Mimori−Kiyosue,2000)。解重合または安定化を介する微小管動力学の破壊は、成長する微小管末端からのEb1の非局在化(delocalization)をもたらし、そしてこれが細胞質のフォーカス(foci)を含有するEb1の消失によって可視化される。
錠剤芯の調製
100gの式(I)の化合物、570gのラクトースおよび200gの澱粉を十分に混合し、その後5gのドデシル硫酸ナトリウムおよび10gのポリビニルピロリドンの溶液(約200mlの水中)を用いて加湿する。湿潤粉末混合物を篩にかけ、乾燥し、そして再度、篩にかける。次いで100gの微晶質セルロースおよび15gの水素化植物油を加える。全体を良く混合し、そして化合物を錠剤に圧縮して、それぞれが10mgの式(I
)の化合物を含んでなる10,000個の錠剤が得られる。
10gのメチルセルロース溶液(75mlの変性エタノール中)に、5gのエチルセルロース溶液(150mlのジクロロメタン中)を加える。次に75mlのジクロロメタンおよび2.5mlの1,2,3−プロパントリオールを加える。10gのポリエチレングリコールを溶融し、そして75mlのジクロロメタンに溶解する。後の溶液を前の溶液に加え、次いで2.5gのオクタデカン酸マグネシウム、5gのポリビニルピロリドンおよび30mlの濃色懸濁液を加え、そして全体を均一にする。このようにして得られた混合物を用いて錠剤の芯をコーティング装置にて被覆する。
Claims (12)
- 式(I):
YはCH2またはCH2−CH2であり;
R1はアリールまたはHetであり;
ここでアリールはフェニルまたはナフタレニルであり;
ここでHetはチエニル、ピロリル、ピロリニル、オキサゾリル、チアゾリル、イミダゾリル、ピラゾリル、イソキサゾリル、イソチアゾリル、オキサジアゾリル、トリアゾリル、テトラゾリル、チアジアゾリル、フラニル、ピペリジニル、ピリジニル、ピリダジニル、ピリミジニル、ピペラジニル、ピラジニル、トリアジニル、インドリジニル、アザインドリジニル、インドリル、インドリニル、ベンゾチエニル、インダゾリル、ベンゾキサゾリル、ベンズイミダゾリル、ベンゾフラニル、ベンゾチアゾリル、ベンゾトリアゾリル、クロマニル、プリニル、キノリニル、シンノリニル、フタラジニル、キナゾリニル、キノキサゾリニル、ナフチリジニルまたはプテリジニルであり;
アリールまたはHet上の2個の炭素原子は
−O−CH2−CH2−O− (a−1)、
−CH2−O−CH2−O− (a−2)、
−O−CH2−CH2−CH2− (a−3)、
−O−CH2−CH2−NR8− (a−4)、
−O−CR8 2−O− (a−5)、
−O−CH2−CH2− (a−6)、
−CH2−N−CH2−CH2− (a−7)、
−(CH2)3− (a−8)、または
−(CH2)4− (a−9);
から選択される二価の基で架橋されることができ(すなわち、二もしくは三環系部分を形成する);
各アリール、Het、架橋化アリールもしくは架橋化Hetは、ハロ、シアノ、ニトロ、ヒドロキシカルボニル、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、C3−6シクロアルキル、C3−6シクロアルキルアミノ、メチルエチルアミノ、アミノC3−6シクロアルキル、ハロC1−6アルキル、トリハロC1−6アルキル、C1−6アルキルカルボニル、C1−6アルキルオキシカルボニル、C2−6アルケニルカルボニル、オキシム、C1−6アルキルオキシム、アミドキシム、−C≡C−CH2O−CH3、−C≡C−CH2N(CH3)2、−C≡C−Si(CH3)3、ヒドロキシC1−6アルキル、ヒドロキシC2−6アルケニル、ヒドロキシC2−6アルキニル、シアノC1−6アルキル、シアノC2−6アルケニル、アミノカルボニルC1−6アルキル、C1−6アルキルスルホニルC1−6アルキル、C1−6アルキルスルホニルC2−6アルケニル、C1−6アルキルスルホニルC2−6アルキニル、−PO(OC1−6アルキル)2、−B(OH)2、−S−CH3、SF5、C1−6アルキルスルホニル、−NR8R9、−C1−6アルキルNR8R9、−OR8、−C1−6アルキルOR8、−CONR8R9、ピペリジニルC1−6アルキル、ピペラジニルC1−6アルキル、C1−6ア
ルキルピペラジニルC1−6アルキル、モルホリニルC1−6アルキル、ピペリジニル、ピペラジニル、C1−6アルキルピペラジニル、モルホリニル、フェニル、チエニル、ピラゾリル、ピロリル、ピロリジニル、ピリジニル、ピリミジニル、オキサジアゾリル、イミダゾリル、イミダゾリルC2−6アルキニル、C1−6アルキルイミダゾリルC2−6アルキニル、シアノピリジニル、フェニルC1−6アルキル、フェニルC2−6アルケニル、モルホリニルC1−6アルキル、C1−6アルキルオキシフェニル、トリハロC1−6アルキルフェニル、メチルピラゾリル、ハロピリミジニルまたはジメチルアミノピロリジニルからそれぞれ独立して選択される1、2、3、4もしくは5個の置換基により置換されることができ;あるいは
R1は式
式中、X2はCH2、C=O、O、NHまたはN−CH3であり;
式中、R10はフェニル、ピリジニル、ピリダジニルまたはピリミジニルであり、ここで各フェニル、ピリジニル、ピリダジニルまたはピリミジニルは、ハロ、ヒドロキシ、シアノ、C1−6アルキル、アミノ、ポリハロC1−6アルキルまたはC1−6アルキルオキシからそれぞれ独立して選択される1もしくは2個の置換基により置換されることができる、
の基であるか; あるいは
R1は式
の基であり;
R2はメチル、エチル、プロピルまたはC3−6シクロアルキルであり;
各R3およびR4は、水素、メチル、エチル、プロピル、ヒドロキシ、トリフルオロメチル、メチルオキシから独立して選択され;あるいはR3およびR4はそれらに結合している炭素原子と共にシクロプロピル環または式C(=O)の基を形成し;
各R5およびR6は水素、ハロ、C1−6アルキルオキシ、シアノ、C1−6アルキル、−OCH2CH2NR8R9、−CH2OCH2CH2NR8R9、−OCH2CH2CH2NR8R9から独立して選択され;
R7は水素、メチルまたはフルオロであり;
各R8およびR9は、水素、ハロ、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、カルボニル、C1−6アルキルスルホニルC1−6アルキル、C1−6アルキルオキシC1−6アルキル、ヒドロキシC1−6アルキル、ジヒドロキシC1−6アルキル、シアノC1−6アルキル、トリハロC1−6アルキル、フェニルC1−6アルキル、(ジC1−6アルキル)アミノC1−6アルキル、C1−6アルキルスルホニル、モルホリニルC1−6アルキル、モルホリニルカルボニル、ピペラジニルC1−6アルキル、C1−6アルキルピペラジニルC1−6アルキル、ピペリジニルC1−6アルキル、チオモルホリニルC1−6アルキル、C3−6シクロアルキルメチル、ピリジニル、ピリミジニル、フェニル、ハロフェニル、オキサニルC1−6アルキル、C1−6アルキルスルホニルC1−6アルキルまたはC1−6アルキルカルボニルアミノC1−6アルキルから独立して選択される]
の化合物であって、その立体化学的異性体形を含む化合物、それらのN−オキシド形、それらの製薬学的に許容され得る付加塩、またはそれらの溶媒和物。 - 式中、YがCH2−CH2であり;アリールがフェニルであり;Hetがピリジニル、ピリミジニル、ベンズイミダゾリルまたはインダソリルであり;各アリールまたはHetが、ハロ、シアノ、C1−6アルキル、C1−6アルキルオキシカルボニル、−C1−6アルキルNR8R9または−OR8からそれぞれ独立して選択される1もしくは2個の置換基により置換されることができ;X1がCH2またはN−CH3であり;X2がCH2、C=OまたはOであり;R10がシアノにより置換されることができるフェニルであり;R2がメチルであり;R3およびR4が水素であり;R5およびR6が水素であり;R7が水素であり;各R8およびR9が水素、ハロ、C1−6アルキルまたはトリハロC1−6アルキルから独立して選択される請求項1に記載の化合物。
- 式中、YがCH2−CH2であり;R1がフェニル、ピリジニルまたはピリミジニルであり;各フェニル、ピリジニルまたはピリミジニルは、ハロ、シアノまたはC1−6アルキルオキシからそれぞれ独立して選択される1もしくは2個の置換基により置換されることができ;X1がCH2であり;X2がOであり;R10がシアノにより置換されたフェニルであり;R2がメチルであり;R3およびR4が水素であり;R5およびR6が水素であり;R7が水素である請求項1または2のいずれかに記載の化合物。
- 医薬として使用するための請求項1ないし4のいずれか1項に記載の化合物。
- 製薬学的に許容され得る担体および有効成分として治療に有効な量の請求項1ないし4のいずれか1項に記載の化合物を含んでなる製薬学的組成物。
- 製薬学的に許容され得る担体および請求項1ないし4のいずれか1項に記載の化合物が完全に混合される請求項6に記載の製薬学的組成物の調製法。
- PARPまたはチューブリン重合が媒介する障害を処置する医薬を製造するための請求項1ないし4のいずれか1項に記載の化合物の使用。
- 請求項1ないし4のいずれか1項に記載の化合物と別の抗癌剤との組み合わせ物。
- 請求項1に記載の化合物の調製法であって:
a)式(II)の中間体を適切な試薬と反応に不活性な溶媒中で反応させて、式(I)
の化合物を形成し;
b)過剰な塩基を、適切な溶媒中で式(IV)の中間体(式中、Haloはクロロまたはブロモである)の存在下で式(III)の中間体に加えるか、
あるいは所望により式(I)の化合物を技術的に知られている変換に従い互いに転換し、そしてさらに所望により式(I)の化合物を酸での処理により製薬学的に許容され得る酸付加塩に、または塩基での処理により製薬学的に許容され得る塩基付加塩に転換し、あるいは逆に酸付加塩をアルカリでの処理により遊離塩基に転換するか、または塩基付加塩を酸での処理により遊離酸に転換し;そして所望によりそれらの立体化学的異性体形またはN−オキシド形を調製することを特徴とする上記調製法。 - 式(II):
YはCH2またはCH2−CH2であり;
R1はアリールまたはHetであり;
ここでアリールはフェニルまたはナフタレニルであり;
ここでHetはチエニル、ピロリル、ピロリニル、オキサゾリル、チアゾリル、イミダゾリル、ピラゾリル、イソキサゾリル、イソチアゾリル、オキサジアゾリル、トリアゾリル、テトラゾリル、チアジアゾリル、フラニル、ピペリジニル、ピリジニル、ピリダジニル、ピリミジニル、ピペラジニル、ピラジニル、トリアジニル、インドリジニル、アザインドリジニル、インドリル、インドリニル、ベンゾチエニル、インダゾリル、ベンゾキサゾリル、ベンズイミダゾリル、ベンゾフラニル、ベンゾチアゾリル、ベンゾトリアゾリル、クロマニル、プリニル、キノリニル、シンノリニル、フタラジニル、キナゾリニル、キノキサゾリニル、ナフチリジニルまたはプテリジニルであり;
アリールまたはHet上の2個の炭素原子は
−O−CH2−CH2−O− (a−1)、
−CH2−O−CH2−O− (a−2)、
−O−CH2−CH2−CH2− (a−3)、
−O−CH2−CH2−NR8− (a−4)、
−O−CR8 2−O− (a−5)、
−O−CH2−CH2− (a−6)、
−CH2−N−CH2−CH2− (a−7)、
−(CH2)3− (a−8)、または
−(CH2)4− (a−9);
から選択される二価の基で架橋されることができ(すなわち、二もしくは三環系部分を形成する);
各アリール、Het、架橋化アリールもしくは架橋化Hetは、ハロ、シアノ、ニトロ、ヒドロキシカルボニル、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、C3−6シクロアルキル、C3−6シクロアルキルアミノ、メチルエチルアミノ、アミノC3−6シクロアルキル、ハロC1−6アルキル、トリハロC1−6アルキル、C1−6アルキルカルボニル、C1−6アルキルオキシカルボニル、C2−6アルケニルカルボニル、オキシム、C1−6アルキルオキシム、アミドキシム、−C≡C−CH2O−CH3、−C≡C−CH2N(CH3)2、−C≡C−Si(CH3)3、ヒドロキシC1−6アルキル、ヒドロキシC2−6アルケニル、ヒドロキシC2−6アルキニル、シアノC1−6アルキル、シアノC2−6アルケニル、アミノカルボニルC1−6アルキル、C1−6アルキルスルホニルC1−6アルキル、C1−6アルキルスルホニルC2−6アルケニル、C1−6アルキルスルホニルC2−6アルキニル、−PO(OC1−6アルキル)2、−B(OH)2、−S−CH3、SF5、C1−6アルキルスルホニル、−NR8R9、−C1−6アルキルNR8R9、−OR8、−C1−6アルキルOR8、−CONR8R9、ピペリジニルC1−6アルキル、ピペラジニルC1−6アルキル、C1−6アルキルピペラジニルC1−6アルキル、モルホリニルC1−6アルキル、ピペリジニル、ピペラジニル、C1−6アルキルピペラジニル、モルホリニル、フェニル、チエニル、ピラゾリル、ピロリル、ピロリジニル、ピリジニル、ピリミジニル、オキサジアゾリル、イ
ミダゾリル、イミダゾリルC2−6アルキニル、C1−6アルキルイミダゾリルC2−6アルキニル、シアノピリジニル、フェニルC1−6アルキル、フェニルC2−6アルケニル、モルホリニルC1−6アルキル、C1−6アルキルオキシフェニル、トリハロC1−6アルキルフェニル、メチルピラゾリル、ハロピリミジニルまたはジメチルアミノピロリジニルからそれぞれ独立して選択される1、2、3、4もしくは5個の置換基により置換されることができ;あるいは
R1は式
式中、X2はCH2、C=O、O、NHまたはN−CH3であり;
式中、R10はフェニル、ピリジニル、ピリダジニルまたはピリミジニルであり、ここで各フェニル、ピリジニル、ピリダジニルまたはピリミジニルは、ハロ、ヒドロキシ、シアノ、C1−6アルキル、アミノ、ポリハロC1−6アルキルまたはC1−6アルキルオキシからそれぞれ独立して選択される1もしくは2個の置換基により置換されることができる、
の基であるか; あるいは
R1は式
の基であり;
R2はメチル、エチル、プロピルまたはC3−6シクロアルキルであり;
各R3およびR4は、水素、メチル、エチル、プロピル、ヒドロキシ、トリフルオロメチル、メチルオキシから独立して選択され;あるいはR3およびR4はそれらに結合している炭素原子と共にシクロプロピル環または式C(=O)の基を形成し;
各R5およびR6は水素、ハロ、C1−6アルキルオキシ、シアノ、C1−6アルキル、−OCH2CH2NR8R9、−CH2OCH2CH2NR8R9、−OCH2CH2CH2NR8R9から独立して選択され;
R7は水素、メチルまたはフルオロであり;
各R8およびR9は、水素、ハロ、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、カルボニル、C1−6アルキルスルホニルC1−6アルキル、C1−6アルキルオキシC1−6アルキル、ヒドロキシC1−6アルキル、ジヒドロキシC1−6アルキル、シアノC1−6アルキル、トリハロC1−6アルキル、フェニルC1−6アルキル、(ジC1−6アルキル)アミノC1−6アルキル、C1−6アルキルスルホニル、モルホリニルC1−6アルキル、モルホリニルカルボニル、ピペラジニルC1−6アルキル、C1−6アルキルピペラジニルC1−6アルキル、ピペリジニルC1−6アルキル、チオモルホリニルC1−6アルキル、C3−6シクロアルキルメチル、ピリジニル、ピリミジニル、フェニル、ハロフェニル、オキサニルC1−6アルキル、C1−6アルキルスルホニルC1−6アルキルまたはC1−6アルキルカルボニルアミノC1−6アルキルから独立して選択される]
の化合物であって、その立体化学的異性体形を含む化合物、それらのN−オキシド形、それらの製薬学的に許容され得る付加塩、またはそれらの溶媒和物。
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Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MX2010010406A (es) * | 2008-03-27 | 2010-10-25 | Janssen Pharmaceutica Nv | Tetrahidrofenantridinonas y tetrahidrociclopentaquinolinonas como inhibidores de la polimerizacion de poli(adp-ribosa)polimerasa-1 y tubulina. |
EA022623B1 (ru) | 2010-10-06 | 2016-02-29 | ГЛАКСОСМИТКЛАЙН ЭлЭлСи | Производные бензимидазола в качестве ингибиторов pi3-киназ |
MX2014000536A (es) | 2011-07-13 | 2014-12-05 | Novartis Ag | Compuestos de 4-piperidinilo para usarse como inhibidores de tanquirasa. |
WO2013012723A1 (en) | 2011-07-13 | 2013-01-24 | Novartis Ag | Novel 2-piperidin-1-yl-acetamide compounds for use as tankyrase inhibitors |
JP2014520860A (ja) * | 2011-07-13 | 2014-08-25 | ノバルティス アーゲー | タンキラーゼ阻害剤として使用するための4−オキソ−3,5,7,8−テトラヒドロ−4H−ピラノ{4,3−d}ピルミニジニル化合物 |
WO2014085486A2 (en) | 2012-11-30 | 2014-06-05 | Waters Technologies Corporation | Methods and apparatus for the analysis of vitamin d metabolites |
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SG11201811393WA (en) * | 2016-06-24 | 2019-01-30 | Univ California | Phthalazine derivatives as inhibitors of parp1, parp2 and/or tubulin useful for the treatment of cancer |
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US11939335B2 (en) | 2022-05-17 | 2024-03-26 | 858 Therapeutics, Inc. | Substituted imidazo[1,2-a]quinazolines and imidazo [1,2-a]pyrido[4,3-e]pyrimidines as inhibitors of PARG |
WO2023224998A1 (en) * | 2022-05-17 | 2023-11-23 | 858 Therapeutics, Inc. | Inhibitors of parg |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2005521698A (ja) * | 2002-03-26 | 2005-07-21 | 藤沢薬品工業株式会社 | 新規な三環式化合物 |
WO2006003148A1 (en) * | 2004-06-30 | 2006-01-12 | Janssen Pharmaceutica N.V. | Quinazolinedione derivatives as parp inhibitors |
WO2006091246A1 (en) * | 2004-11-01 | 2006-08-31 | University Of Southern California | Novel compounds for treatment of cancer and disorders associated with angiogenesis function |
WO2007041076A2 (en) * | 2005-09-30 | 2007-04-12 | Janssen Pharmaceutica N.V. | 1,2,3,5-tetrahydro-cyclopental[c]quinolin-4-one derivatives as rxr agonists for the treatment of dyslipidemia, hypercholesterolemia and diabetes |
JP2007511574A (ja) * | 2003-11-20 | 2007-05-10 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | ポリ(adp−リボース)ポリメラーゼ阻害剤としての6−アルケニルおよび6−フェニルアルキル置換2−キノリノンおよび2−キノキサリノン |
WO2007095628A1 (en) * | 2006-02-15 | 2007-08-23 | Abbott Laboratories | Pyrazoloquinolones are potent parp inhibitors |
JP2010520262A (ja) * | 2007-03-08 | 2010-06-10 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | Parpおよびtank阻害剤としてのキノリノン誘導体 |
Family Cites Families (72)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB732581A (en) | 1952-01-18 | 1955-06-29 | Ciba Ltd | Manufacture of hydrazine compounds |
DE1006423B (de) | 1952-01-18 | 1957-04-18 | Ciba Geigy | Verfahren zur Herstellung von Hydrazinophthalazinen |
US3274194A (en) | 1963-03-29 | 1966-09-20 | Miles Lab | Quinazolinedione derivatives |
GB1062357A (en) | 1965-03-23 | 1967-03-22 | Pfizer & Co C | Quinazolone derivatives |
GB1293565A (en) | 1969-05-03 | 1972-10-18 | Aspro Nicholas Ltd | Aminophthalazines and pharmaceutical compositions thereof |
US3919425A (en) | 1971-04-09 | 1975-11-11 | Miles Lab | Method of producing vasodilation using certain 3-substituted-quinazoline derivatives |
BE792206A (ja) | 1971-12-02 | 1973-06-01 | Byk Gulden Lomberg Chem Fab | |
US3879393A (en) | 1973-06-18 | 1975-04-22 | Miles Lab | Derivatives of 1,3-disubstituted 2,4(1h,3h)-quinazolinediones |
FR2436781A1 (fr) | 1978-09-19 | 1980-04-18 | Berri Balzac | Derives d'amino-3 (1h,3h) quinazolinedione-2,4, leur procede de preparation et leurs applications en therapeutique |
US4335127A (en) | 1979-01-08 | 1982-06-15 | Janssen Pharmaceutica, N.V. | Piperidinylalkyl quinazoline compounds, composition and method of use |
JPS5976082A (ja) | 1982-10-23 | 1984-04-28 | Kyowa Hakko Kogyo Co Ltd | 新規なピペリジン誘導体 |
JPS60120872A (ja) | 1983-12-01 | 1985-06-28 | Kyowa Hakko Kogyo Co Ltd | 新規なヘテロ環状化合物及び強心剤 |
PL147465B1 (en) | 1984-03-26 | 1989-06-30 | Janssen Pharmaceutica Nv | Method of obtaining novel pyridazionoamine compounds |
US5001125A (en) | 1984-03-26 | 1991-03-19 | Janssen Pharmaceutica N.V. | Anti-virally active pyridazinamines |
DK623586A (da) | 1985-12-27 | 1987-06-28 | Eisai Co Ltd | Piperidinderivater eller salte deraf og farmaceutiske kompositioner indeholdende forbindelserne |
US5231184A (en) | 1987-11-23 | 1993-07-27 | Janssen Pharmaceutica N.V. | Pridazinamine derivatives |
US5177075A (en) | 1988-08-19 | 1993-01-05 | Warner-Lambert Company | Substituted dihydroisoquinolinones and related compounds as potentiators of the lethal effects of radiation and certain chemotherapeutic agents; selected compounds, analogs and process |
CA2002864C (en) | 1988-11-29 | 1999-11-16 | Eddy J. E. Freyne | (1h-azol-1-ylmethyl) substituted quinoline, quinazoline or quinoxaline derivatives |
GB8827822D0 (en) | 1988-11-29 | 1988-12-29 | Janssen Pharmaceutica Nv | (1h-azol-1-ylmethyl)substituted quinoline derivatives |
US5374637A (en) | 1989-03-22 | 1994-12-20 | Janssen Pharmaceutica N.V. | N-(3-hydroxy-4-piperidinyl)(dihydrobenzofuran, dihydro-2H-benzopyran or dihydrobenzodioxin)carboxamide derivatives |
EP0391462A1 (en) | 1989-04-05 | 1990-10-10 | Janssen Pharmaceutica N.V. | Synergistic compositions containing ketanserin |
US5160727A (en) | 1990-02-13 | 1992-11-03 | Warner-Lambert Company | Tumor cell sensitization method using quinazolinedione derivatives |
IE913473A1 (en) | 1990-10-15 | 1992-04-22 | Fujisawa Pharmaceutical Co | Quinazoline derivatives and their preparation |
DK0637306T3 (da) | 1992-04-23 | 2001-07-30 | Merrell Pharma Inc | 4-Imidomethyl-1-[2'-phenyl-2'-oxoethyl]-piperidiner som serotonin-5HT2-antagonister, deres fremstilling og anvendelse til terapi |
TW294595B (ja) | 1992-11-20 | 1997-01-01 | Janssen Pharmaceutica Nv | |
CA2118117A1 (en) | 1993-02-18 | 1994-08-19 | Shigeki Fujiwara | Adenosine uptake inhibitor |
US6270867B1 (en) * | 1993-06-24 | 2001-08-07 | Pechiney Plastic Packaging, Inc. | Structures of polymers made from single site catalysts |
GB9404485D0 (en) | 1994-03-09 | 1994-04-20 | Cancer Res Campaign Tech | Benzamide analogues |
TW445263B (en) | 1996-02-29 | 2001-07-11 | Janssen Pharmaceutica Nv | Novel esters of 1,4-disubstituted piperidine derivatives |
JPH107572A (ja) | 1996-06-17 | 1998-01-13 | Sumitomo Pharmaceut Co Ltd | 腫瘍壊死因子産生阻害剤 |
EP0927192B1 (de) | 1996-09-10 | 2004-05-12 | Boehringer Ingelheim Pharma GmbH & Co.KG | Abgewandelte aminosäuren, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung |
TW460464B (en) * | 1996-11-25 | 2001-10-21 | Nippon Kayaku Kk | Novel phenanthridinium derivative having an anti-tumor activity and pharmaceutical composition containing the same |
CA2291630A1 (en) | 1997-05-30 | 1998-12-03 | Tetsutaro Niizato | Nitrogen-containing heterocyclic compounds and therapeutic agents for hyperlipidemia comprising the same |
JPH10330377A (ja) | 1997-06-02 | 1998-12-15 | Kyowa Hakko Kogyo Co Ltd | ピペリジン誘導体 |
US6635642B1 (en) | 1997-09-03 | 2003-10-21 | Guilford Pharmaceuticals Inc. | PARP inhibitors, pharmaceutical compositions comprising same, and methods of using same |
US20030069231A1 (en) | 1999-10-12 | 2003-04-10 | Klaus Rudolf | Modified aminoacids, pharmaceuticals containing these compounds and method for their production |
EP1026160A4 (en) | 1997-09-16 | 2003-01-22 | Takeda Chemical Industries Ltd | CONNECTIONS WITH NITROGEN-CONDENSED RINGS, METHOD FOR THEIR PRODUCTION AND MEDICINES |
US6133277A (en) | 1997-12-05 | 2000-10-17 | Janssen Pharmaceutica N.V. | (Benzodioxan, benzofuran or benzopyran) derivatives having fundic relaxation properties |
JP2000191659A (ja) | 1999-01-04 | 2000-07-11 | Sumitomo Pharmaceut Co Ltd | 腫瘍壊死因子産生阻害剤 |
JP4676062B2 (ja) | 1999-01-29 | 2011-04-27 | アボット・ラボラトリーズ | ニコチン性アセチルコリン受容体リガンドとしてのジアザ2環式誘導体 |
US7265115B2 (en) | 1999-01-29 | 2007-09-04 | Abbott Laboratories | Diazabicyclic CNS active agents |
US6566372B1 (en) | 1999-08-27 | 2003-05-20 | Ligand Pharmaceuticals Incorporated | Bicyclic androgen and progesterone receptor modulator compounds and methods |
ATE400558T1 (de) | 2000-10-02 | 2008-07-15 | Janssen Pharmaceutica Nv | Metabotropische glutamatrezeptor-antagonisten |
ITMI20002358A1 (it) | 2000-10-31 | 2002-05-01 | Flavio Moroni | Derivati di tieno ,2, 3-c|isochinolin-3-one come inibitori della poli(a dp-ribosio)polimerasi |
AUPR201600A0 (en) | 2000-12-11 | 2001-01-11 | Fujisawa Pharmaceutical Co., Ltd. | Quinazolinone derivative |
JP2002284699A (ja) | 2001-03-28 | 2002-10-03 | Sumitomo Pharmaceut Co Ltd | 視細胞変性疾患治療剤 |
JPWO2002094790A1 (ja) | 2001-05-23 | 2004-09-09 | 三菱ウェルファーマ株式会社 | 縮合ヘテロ環化合物およびその医薬用途 |
US6924284B2 (en) | 2001-08-15 | 2005-08-02 | Icos Corporation | PARP inhibitors |
WO2003039460A2 (en) | 2001-11-07 | 2003-05-15 | Merck & Co., Inc. | Mitotic kinesin inhibitors |
AUPR975601A0 (en) | 2001-12-24 | 2002-01-31 | Fujisawa Pharmaceutical Co., Ltd. | Quinazolinone derivatives |
CA2479109C (en) | 2002-03-29 | 2011-08-02 | Janssen Pharmaceutica N.V. | Radiolabelled quinoline and quinolinone derivatives and their use as metabotropic glutamate receptor ligands |
US7119111B2 (en) | 2002-05-29 | 2006-10-10 | Amgen, Inc. | 2-oxo-1,3,4-trihydroquinazolinyl derivatives and methods of use |
AR043059A1 (es) | 2002-11-12 | 2005-07-13 | Bayer Pharmaceuticals Corp | Derivados de indolil pirazinona utiles para el tratamiento de trastornos hiper-proliferativos |
US20050075364A1 (en) | 2003-07-01 | 2005-04-07 | Kap-Sun Yeung | Indole, azaindole and related heterocyclic N-substituted piperazine derivatives |
US7855207B2 (en) | 2003-11-20 | 2010-12-21 | Janssen Pharmaceutica, Nv | 6-alkenyl and 6-phenylalkyl substituted 2-quinolinones and 2-quinoxalinones as poly(adpribose) polymerase inhibitors |
WO2005054209A1 (en) | 2003-11-20 | 2005-06-16 | Janssen Pharmaceutica N.V. | 7-phenylalkyl substituted 2-quinolinones and 2 quinoxalinones as poly(adp-ribose) polymerase inhibitors |
EP2277865B1 (en) | 2003-12-03 | 2014-11-12 | YM BioSciences Australia Pty Ltd | Phenyl-substituted 6-ring nitrogen-heterocycles as microtubule polymerisation inhibitors |
NZ547193A (en) | 2003-12-05 | 2010-03-26 | Janssen Pharmaceutica Nv | 6-Substituted 2-quinolinones and 2-quinoxalinones as poly(adp-ribose) polymerase inhibitors |
CA2548273C (en) | 2003-12-10 | 2013-04-16 | Janssen Pharmaceutica N.V. | Substituted 6-cyclohexylalkyl substituted 2-quinolinones and 2-quinoxalinones as poly(adp-ribose) polymerase inhibitors |
PE20060285A1 (es) | 2004-03-30 | 2006-05-08 | Aventis Pharma Inc | Piridonas sustituidas como inhibidores de pol(adp-ribosa)-polimerasa (parp) |
DE102004023332A1 (de) | 2004-05-12 | 2006-01-19 | Bayer Cropscience Gmbh | Chinoxalin-2-on-derivate, diese enthaltende nutzpflanzenschützende Mittel und Verfahren zu ihrer Herstellung und deren Verwendung |
JP4991527B2 (ja) | 2004-06-01 | 2012-08-01 | ユニバーシティ オブ バージニア パテント ファンデーション | 二つの部分からなる低分子量の癌および血管新生の抑制剤 |
JP4969443B2 (ja) | 2004-06-30 | 2012-07-04 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | Parp阻害剤としてのキナゾリノン誘導体 |
EP1771175B1 (en) | 2004-06-30 | 2015-12-23 | Janssen Pharmaceutica NV | Phthalazine derivatives as parp inhibitors |
NZ560712A (en) | 2005-02-17 | 2010-12-24 | Synta Pharmaceuticals Corp | (3,4,5-trisubstituted-phenyl)isoxazole combretastin derivatives for the treatment of disorders |
CA2607727A1 (en) | 2005-04-28 | 2006-11-09 | Mitsubishi Tanabe Pharma Corporation | Cyanopyridine derivative and use thereof as medicine |
CN101316592A (zh) | 2005-08-24 | 2008-12-03 | 伊诺泰克制药公司 | 茚并异喹啉酮类似物及其用法 |
JP5315060B2 (ja) | 2006-02-03 | 2013-10-16 | バイオノミックス リミテッド | 置換ベンゾフラン、ベンゾチオフェン、ベンゾセレノフェンおよびインドールおよびそれらのチューブリン重合阻害剤としての使用 |
US8198448B2 (en) | 2006-07-14 | 2012-06-12 | Amgen Inc. | Fused heterocyclic derivatives and methods of use |
US8466150B2 (en) | 2006-12-28 | 2013-06-18 | Abbott Laboratories | Inhibitors of poly(ADP-ribose)polymerase |
AU2008269128B2 (en) | 2007-06-25 | 2012-08-02 | Amgen Inc. | Phthalazine compounds, compositions and methods of use |
MX2010010406A (es) * | 2008-03-27 | 2010-10-25 | Janssen Pharmaceutica Nv | Tetrahidrofenantridinonas y tetrahidrociclopentaquinolinonas como inhibidores de la polimerizacion de poli(adp-ribosa)polimerasa-1 y tubulina. |
-
2009
- 2009-03-26 MX MX2010010406A patent/MX2010010406A/es active IP Right Grant
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- 2009-03-26 RU RU2010143857/04A patent/RU2490260C2/ru active
- 2009-03-26 US US12/934,753 patent/US8889866B2/en active Active
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- 2009-03-26 DK DK09725177.1T patent/DK2271626T3/en active
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- 2011-06-10 HK HK11105902.3A patent/HK1151796A1/xx not_active IP Right Cessation
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- 2014-10-14 US US14/513,814 patent/US9150540B2/en active Active
-
2015
- 2015-02-04 HR HRP20150139TT patent/HRP20150139T1/hr unknown
- 2015-08-18 US US14/829,493 patent/US9598396B2/en active Active
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2005521698A (ja) * | 2002-03-26 | 2005-07-21 | 藤沢薬品工業株式会社 | 新規な三環式化合物 |
JP2007511574A (ja) * | 2003-11-20 | 2007-05-10 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | ポリ(adp−リボース)ポリメラーゼ阻害剤としての6−アルケニルおよび6−フェニルアルキル置換2−キノリノンおよび2−キノキサリノン |
WO2006003148A1 (en) * | 2004-06-30 | 2006-01-12 | Janssen Pharmaceutica N.V. | Quinazolinedione derivatives as parp inhibitors |
WO2006091246A1 (en) * | 2004-11-01 | 2006-08-31 | University Of Southern California | Novel compounds for treatment of cancer and disorders associated with angiogenesis function |
WO2007041076A2 (en) * | 2005-09-30 | 2007-04-12 | Janssen Pharmaceutica N.V. | 1,2,3,5-tetrahydro-cyclopental[c]quinolin-4-one derivatives as rxr agonists for the treatment of dyslipidemia, hypercholesterolemia and diabetes |
WO2007095628A1 (en) * | 2006-02-15 | 2007-08-23 | Abbott Laboratories | Pyrazoloquinolones are potent parp inhibitors |
JP2010520262A (ja) * | 2007-03-08 | 2010-06-10 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | Parpおよびtank阻害剤としてのキノリノン誘導体 |
Non-Patent Citations (1)
Title |
---|
ALAZARD,J.P. ET AL, BULLETIN DE LA SOCIETE CHIMIQUE DE FRANCE, vol. 133, JPN6013049917, 1996, pages 251 - 266, ISSN: 0002742234 * |
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US8889866B2 (en) | 2014-11-18 |
CA2716726C (en) | 2017-01-24 |
AU2009228943B2 (en) | 2013-04-04 |
RU2490260C2 (ru) | 2013-08-20 |
US9150540B2 (en) | 2015-10-06 |
EP2271626A1 (en) | 2011-01-12 |
US20150038521A1 (en) | 2015-02-05 |
ES2529545T3 (es) | 2015-02-23 |
US9598396B2 (en) | 2017-03-21 |
US20110263622A1 (en) | 2011-10-27 |
RU2010143857A (ru) | 2012-05-10 |
CN101981013A (zh) | 2011-02-23 |
CA2716726A1 (en) | 2009-10-01 |
AU2009228943A1 (en) | 2009-10-01 |
MX2010010406A (es) | 2010-10-25 |
CN101981013B (zh) | 2013-05-29 |
WO2009118382A1 (en) | 2009-10-01 |
HRP20150139T1 (hr) | 2015-05-22 |
BRPI0909017A2 (pt) | 2020-11-10 |
DK2271626T3 (en) | 2015-02-23 |
US20150353526A1 (en) | 2015-12-10 |
HK1151796A1 (en) | 2012-02-10 |
EP2271626B1 (en) | 2014-11-26 |
JP5492183B2 (ja) | 2014-05-14 |
SI2271626T1 (sl) | 2015-03-31 |
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