CA2440184A1 - Heterocyclic derivatives for the treatment of cancer and other proliferative diseases - Google Patents

Info

Publication number

CA2440184A1

CA2440184A1 CA002440184A CA2440184A CA2440184A1 CA 2440184 A1 CA2440184 A1 CA 2440184A1 CA 002440184 A CA002440184 A CA 002440184A CA 2440184 A CA2440184 A CA 2440184A CA 2440184 A1 CA2440184 A1 CA 2440184A1

Authority

CA

Canada

Prior art keywords

substituted

adamantyl

thiazolidinedione

cancer

residue

Prior art date

2001-03-07

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Abandoned

Links

• Espacenet
• Global Dossier
• CIPO
• Discuss

• 125000000623 heterocyclic group Chemical group 0.000 title claims abstract description 74
• 206010028980 Neoplasm Diseases 0.000 title claims abstract description 55
• 238000011282 treatment Methods 0.000 title claims abstract description 44
• 201000011510 cancer Diseases 0.000 title claims abstract description 29
• 201000010099 disease Diseases 0.000 title claims abstract description 27
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 27
• 230000002062 proliferating effect Effects 0.000 title description 4
• 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 95
• 125000003118 aryl group Chemical group 0.000 claims abstract description 91
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 65
• 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 51
• 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 48
• 239000001257 hydrogen Substances 0.000 claims abstract description 46
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 46
• 125000000547 substituted alkyl group Chemical group 0.000 claims abstract description 46
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 29
• 125000005346 substituted cycloalkyl group Chemical group 0.000 claims abstract description 24
• 150000003839 salts Chemical class 0.000 claims abstract description 23
• 229910052760 oxygen Inorganic materials 0.000 claims abstract description 22
• 229910052717 sulfur Inorganic materials 0.000 claims abstract description 13
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 5
• -1 mono-substituted amino Chemical group 0.000 claims description 190
• 150000001875 compounds Chemical class 0.000 claims description 166
• 238000000034 method Methods 0.000 claims description 73
• 125000004432 carbon atom Chemical group C* 0.000 claims description 57
• 125000005431 alkyl carboxamide group Chemical group 0.000 claims description 43
• 125000005432 dialkylcarboxamide group Chemical group 0.000 claims description 39
• 150000002431 hydrogen Chemical group 0.000 claims description 26
• 125000003545 alkoxy group Chemical group 0.000 claims description 21
• 239000008194 pharmaceutical composition Substances 0.000 claims description 21
• 125000005415 substituted alkoxy group Chemical group 0.000 claims description 20
• 125000004438 haloalkoxy group Chemical group 0.000 claims description 17
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 16
• 229940123464 Thiazolidinedione Drugs 0.000 claims description 14
• 125000000392 cycloalkenyl group Chemical group 0.000 claims description 14
• 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 13
• 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 13
• 201000002528 pancreatic cancer Diseases 0.000 claims description 13
• 208000008443 pancreatic carcinoma Diseases 0.000 claims description 13
• 125000000304 alkynyl group Chemical group 0.000 claims description 12
• 125000002252 acyl group Chemical group 0.000 claims description 11
• 125000003342 alkenyl group Chemical group 0.000 claims description 11
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 11
• 125000005017 substituted alkenyl group Chemical group 0.000 claims description 10
• 125000004426 substituted alkynyl group Chemical group 0.000 claims description 10
• 206010006187 Breast cancer Diseases 0.000 claims description 9
• 208000026310 Breast neoplasm Diseases 0.000 claims description 9
• 241000124008 Mammalia Species 0.000 claims description 9
• 206010060862 Prostate cancer Diseases 0.000 claims description 9
• 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 9
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
• 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 8
• 208000020816 lung neoplasm Diseases 0.000 claims description 8
• BLSIZBBWSIGWCE-UHFFFAOYSA-N 5-[6-[3-(1-adamantyl)-4-hydroxyphenyl]naphthalen-2-yl]-1,3-thiazolidine-2,4-dione Chemical compound C1=C(C23CC4CC(CC(C4)C2)C3)C(O)=CC=C1C(C=C1C=C2)=CC=C1C=C2C1SC(=O)NC1=O BLSIZBBWSIGWCE-UHFFFAOYSA-N 0.000 claims description 7
• IXXKNSSOLZTGKV-UHFFFAOYSA-N 5-[6-[3-(1-adamantyl)-4-methoxyphenyl]naphthalen-2-yl]-1,3-thiazolidine-2,4-dione Chemical compound C1=C(C23CC4CC(CC(C4)C2)C3)C(OC)=CC=C1C(C=C1C=C2)=CC=C1C=C2C1SC(=O)NC1=O IXXKNSSOLZTGKV-UHFFFAOYSA-N 0.000 claims description 7
• 206010009944 Colon cancer Diseases 0.000 claims description 7
• 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 7
• 125000005530 alkylenedioxy group Chemical group 0.000 claims description 7
• 125000004429 atom Chemical group 0.000 claims description 7
• 230000004663 cell proliferation Effects 0.000 claims description 7
• 208000029742 colonic neoplasm Diseases 0.000 claims description 7
• 208000032839 leukemia Diseases 0.000 claims description 7
• 201000005202 lung cancer Diseases 0.000 claims description 7
• 150000002825 nitriles Chemical class 0.000 claims description 7
• PBVKCABKORQRAV-UHFFFAOYSA-N 3-[6-[3-(1-adamantyl)-4-methoxyphenyl]naphthalen-2-yl]-5-methylidene-1,3-thiazolidine-2,4-dione Chemical compound C1=C(C23CC4CC(CC(C4)C2)C3)C(OC)=CC=C1C(C=C1C=C2)=CC=C1C=C2N1C(=O)SC(=C)C1=O PBVKCABKORQRAV-UHFFFAOYSA-N 0.000 claims description 6
• 201000009030 Carcinoma Diseases 0.000 claims description 6
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
• JSOWTZMOSQAQSJ-UHFFFAOYSA-N 3-[6-[7-(1-adamantyl)-1,3-benzodioxol-5-yl]naphthalen-2-yl]-5-methylidene-1,3-thiazolidine-2,4-dione Chemical compound O=C1C(=C)SC(=O)N1C1=CC=C(C=C(C=C2)C=3C=C(C=4OCOC=4C=3)C34CC5CC(CC(C5)C3)C4)C2=C1 JSOWTZMOSQAQSJ-UHFFFAOYSA-N 0.000 claims description 5
• NXVICXWVTQTUGX-UHFFFAOYSA-N 5-[[4-[7-(1-adamantyl)-1,3-benzodioxol-5-yl]phenyl]methylidene]-1,3-thiazolidine-2,4-dione Chemical compound S1C(=O)NC(=O)C1=CC1=CC=C(C=2C=C(C=3OCOC=3C=2)C23CC4CC(CC(C4)C2)C3)C=C1 NXVICXWVTQTUGX-UHFFFAOYSA-N 0.000 claims description 5
• MLDJAEAPGBPGKL-UHFFFAOYSA-N 5-methylidene-3-[6-(7-pyridin-3-yl-1,3-benzodioxol-5-yl)naphthalen-2-yl]-1,3-thiazolidine-2,4-dione Chemical compound O=C1C(=C)SC(=O)N1C1=CC=C(C=C(C=C2)C=3C=C(C=4OCOC=4C=3)C=3C=NC=CC=3)C2=C1 MLDJAEAPGBPGKL-UHFFFAOYSA-N 0.000 claims description 5
• 208000008839 Kidney Neoplasms Diseases 0.000 claims description 5
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
• YNVPMXPPSWMAGA-UHFFFAOYSA-N 3-[6-(3-tert-butyl-4-methoxyphenyl)naphthalen-2-yl]-5-methylidene-1,3-thiazolidine-2,4-dione Chemical compound C1=C(C(C)(C)C)C(OC)=CC=C1C1=CC=C(C=C(C=C2)N3C(C(=C)SC3=O)=O)C2=C1 YNVPMXPPSWMAGA-UHFFFAOYSA-N 0.000 claims description 4
• RCAUVJUCTOFGQI-UHFFFAOYSA-N 3-[6-(4-methoxy-3-phenylphenyl)naphthalen-2-yl]-5-methylidene-1,3-thiazolidine-2,4-dione Chemical compound COC1=CC=C(C=2C=C3C=CC(=CC3=CC=2)N2C(C(=C)SC2=O)=O)C=C1C1=CC=CC=C1 RCAUVJUCTOFGQI-UHFFFAOYSA-N 0.000 claims description 4
• HLULGOVUOBHVLG-UHFFFAOYSA-N 3-[6-[4-methoxy-3-(1-methylcyclohexyl)phenyl]naphthalen-2-yl]-5-methylidene-1,3-thiazolidine-2,4-dione Chemical compound COC1=CC=C(C=2C=C3C=CC(=CC3=CC=2)N2C(C(=C)SC2=O)=O)C=C1C1(C)CCCCC1 HLULGOVUOBHVLG-UHFFFAOYSA-N 0.000 claims description 4
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
• RZLLVCDYWFQPGE-UHFFFAOYSA-N 5-[6-[3-(1-adamantyl)-4-methoxyphenyl]naphthalen-2-yl]-3-methyl-1,3-thiazolidine-2,4-dione Chemical compound C1=C(C23CC4CC(CC(C4)C2)C3)C(OC)=CC=C1C(C=C1C=C2)=CC=C1C=C2C1SC(=O)N(C)C1=O RZLLVCDYWFQPGE-UHFFFAOYSA-N 0.000 claims description 4
• MAYXWUVMLYKKLD-UHFFFAOYSA-N 5-[[2-[3-(1-adamantyl)-4-[tert-butyl(dimethyl)silyl]oxyphenyl]phenyl]methylidene]-1,3-thiazolidine-2,4-dione Chemical compound C1=C(C23CC4CC(CC(C4)C2)C3)C(O[Si](C)(C)C(C)(C)C)=CC=C1C1=CC=CC=C1C=C1SC(=O)NC1=O MAYXWUVMLYKKLD-UHFFFAOYSA-N 0.000 claims description 4
• VHLZOIUANZCSMB-UHFFFAOYSA-N 5-[[4-[3-(1-adamantyl)-4-hydroxyphenyl]phenyl]methylidene]-1,3-thiazolidine-2,4-dione Chemical compound C1=C(C23CC4CC(CC(C4)C2)C3)C(O)=CC=C1C(C=C1)=CC=C1C=C1SC(=O)NC1=O VHLZOIUANZCSMB-UHFFFAOYSA-N 0.000 claims description 4
• KQZKKWIAQVWHAQ-UHFFFAOYSA-N 5-[[4-[3-(1-adamantyl)-4-methoxyphenyl]phenyl]methylidene]-1,3-thiazolidine-2,4-dione Chemical compound C1=C(C23CC4CC(CC(C4)C2)C3)C(OC)=CC=C1C(C=C1)=CC=C1C=C1SC(=O)NC1=O KQZKKWIAQVWHAQ-UHFFFAOYSA-N 0.000 claims description 4
• VFPYFEBAKROFBR-UHFFFAOYSA-N 5-[[4-[7-(2-methoxyphenyl)-1,3-benzodioxol-5-yl]phenyl]methylidene]-1,3-thiazolidine-2,4-dione Chemical compound COC1=CC=CC=C1C1=CC(C=2C=CC(C=C3C(NC(=O)S3)=O)=CC=2)=CC2=C1OCO2 VFPYFEBAKROFBR-UHFFFAOYSA-N 0.000 claims description 4
• 206010025323 Lymphomas Diseases 0.000 claims description 4
• 206010033128 Ovarian cancer Diseases 0.000 claims description 4
• 206010061535 Ovarian neoplasm Diseases 0.000 claims description 4
• 206010038389 Renal cancer Diseases 0.000 claims description 4
• 201000010982 kidney cancer Diseases 0.000 claims description 4
• 201000001441 melanoma Diseases 0.000 claims description 4
• VYQWPIJPVXMUJW-UHFFFAOYSA-N 3-[6-(3-tert-butyl-4-methoxyphenyl)naphthalen-2-yl]-5-methylidene-2-sulfanylidene-1,3-thiazolidin-4-one Chemical compound C1=C(C(C)(C)C)C(OC)=CC=C1C1=CC=C(C=C(C=C2)N3C(C(=C)SC3=S)=O)C2=C1 VYQWPIJPVXMUJW-UHFFFAOYSA-N 0.000 claims description 3
• KFBXRFNVBOHFPC-UHFFFAOYSA-N 3-[6-(4-methoxy-3-phenylphenyl)naphthalen-2-yl]-5-methylidene-2-sulfanylidene-1,3-thiazolidin-4-one Chemical compound COC1=CC=C(C=2C=C3C=CC(=CC3=CC=2)N2C(C(=C)SC2=S)=O)C=C1C1=CC=CC=C1 KFBXRFNVBOHFPC-UHFFFAOYSA-N 0.000 claims description 3
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
• 206010005003 Bladder cancer Diseases 0.000 claims description 3
• 208000003174 Brain Neoplasms Diseases 0.000 claims description 3
• 208000017604 Hodgkin disease Diseases 0.000 claims description 3
• 208000010747 Hodgkins lymphoma Diseases 0.000 claims description 3
• 206010029260 Neuroblastoma Diseases 0.000 claims description 3
• 206010035226 Plasma cell myeloma Diseases 0.000 claims description 3
• 206010039491 Sarcoma Diseases 0.000 claims description 3
• 208000000453 Skin Neoplasms Diseases 0.000 claims description 3
• 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 3
• 208000019065 cervical carcinoma Diseases 0.000 claims description 3
• 208000005017 glioblastoma Diseases 0.000 claims description 3
• 201000010536 head and neck cancer Diseases 0.000 claims description 3
• 208000014829 head and neck neoplasm Diseases 0.000 claims description 3
• 201000007270 liver cancer Diseases 0.000 claims description 3
• 208000014018 liver neoplasm Diseases 0.000 claims description 3
• 208000025113 myeloid leukemia Diseases 0.000 claims description 3
• 201000000050 myeloid neoplasm Diseases 0.000 claims description 3
• 208000030761 polycystic kidney disease Diseases 0.000 claims description 3
• 201000000849 skin cancer Diseases 0.000 claims description 3
• 201000005112 urinary bladder cancer Diseases 0.000 claims description 3
• XCSJIQBYYUKENT-UHFFFAOYSA-N 5-[[4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-aminophenyl]methylidene]-1,3-thiazolidine-2,4-dione Chemical compound C=1C=C(C=2C=C(C(O)=CC=2)C23CC4CC(CC(C4)C2)C3)C(N)=CC=1C=C1SC(=O)NC1=O XCSJIQBYYUKENT-UHFFFAOYSA-N 0.000 claims description 2
• CLYLAPYROSOQCD-UHFFFAOYSA-N 5-[[4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorophenyl]methylidene]-1,3-thiazolidine-2,4-dione Chemical compound C1=C(C23CC4CC(CC(C4)C2)C3)C(O)=CC=C1C(C(=C1)Cl)=CC=C1C=C1SC(=O)NC1=O CLYLAPYROSOQCD-UHFFFAOYSA-N 0.000 claims description 2
• GTCRBMMHDZQTOA-UHFFFAOYSA-N 5-[[4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-ethoxyphenyl]methylidene]-1,3-thiazolidine-2,4-dione Chemical compound C=1C=C(C=2C=C(C(O)=CC=2)C23CC4CC(CC(C4)C2)C3)C(OCC)=CC=1C=C1SC(=O)NC1=O GTCRBMMHDZQTOA-UHFFFAOYSA-N 0.000 claims description 2
• KGOQVGKERZYASH-UHFFFAOYSA-N 5-[[4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-methylphenyl]methylidene]-1,3-thiazolidine-2,4-dione Chemical compound C=1C=C(C=2C=C(C(O)=CC=2)C23CC4CC(CC(C4)C2)C3)C(C)=CC=1C=C1SC(=O)NC1=O KGOQVGKERZYASH-UHFFFAOYSA-N 0.000 claims description 2
• AFPFWHRROKCCHV-UHFFFAOYSA-N 5-[[4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-nitrophenyl]methylidene]-1,3-thiazolidine-2,4-dione Chemical compound C1=C(C23CC4CC(CC(C4)C2)C3)C(O)=CC=C1C(C(=C1)[N+]([O-])=O)=CC=C1C=C1SC(=O)NC1=O AFPFWHRROKCCHV-UHFFFAOYSA-N 0.000 claims description 2
• LSRRCFUIARWTHD-UHFFFAOYSA-N 5-[[4-[3-(1-adamantyl)-5-chloro-4-hydroxyphenyl]phenyl]methylidene]-1,3-thiazolidine-2,4-dione Chemical compound C1=C(C23CC4CC(CC(C4)C2)C3)C(O)=C(Cl)C=C1C(C=C1)=CC=C1C=C1SC(=O)NC1=O LSRRCFUIARWTHD-UHFFFAOYSA-N 0.000 claims description 2
• 150000002391 heterocyclic compounds Chemical class 0.000 abstract description 6
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 145
• 239000000203 mixture Substances 0.000 description 122
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 114
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 109
• 238000005481 NMR spectroscopy Methods 0.000 description 93
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 74
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• 239000007787 solid Substances 0.000 description 71
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 70
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• 239000000243 solution Substances 0.000 description 66
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 57
• 235000019439 ethyl acetate Nutrition 0.000 description 56
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 48
• 239000012267 brine Substances 0.000 description 48
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 48
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 46
• 238000010992 reflux Methods 0.000 description 41
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 40
• 210000004027 cell Anatomy 0.000 description 40
• 125000001424 substituent group Chemical group 0.000 description 40
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 36
• 229910052786 argon Inorganic materials 0.000 description 35
• 239000000725 suspension Substances 0.000 description 35
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
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• ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical group O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-N 0.000 description 31
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• NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 28
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• 230000001093 anti-cancer Effects 0.000 description 10
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• 239000001301 oxygen Substances 0.000 description 10
• 239000000047 product Substances 0.000 description 10
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 9
• XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 9
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