OA11353A - Therapeutically active compounds based on indazolebioisostere replacement of catechol in PDE4 inhib itors. - Google Patents

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Publication number

OA11353A

OA11353A OA1200000126A OA1200000126A OA11353A OA 11353 A OA11353 A OA 11353A OA 1200000126 A OA1200000126 A OA 1200000126A OA 1200000126 A OA1200000126 A OA 1200000126A OA 11353 A OA11353 A OA 11353A

Authority

OA

OAPI

Prior art keywords

group

consisting essentially

alkyl

independently selected

member independently

Prior art date

1997-11-04

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• 150000001875 compounds Chemical class 0.000 title claims abstract description 178
• YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 title claims abstract description 33
• 239000002587 phosphodiesterase IV inhibitor Substances 0.000 title description 10
• 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 title description 9
• 125000001424 substituent group Chemical group 0.000 claims abstract description 89
• 239000000203 mixture Substances 0.000 claims abstract description 77
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 39
• 239000001257 hydrogen Substances 0.000 claims abstract description 39
• 201000010099 disease Diseases 0.000 claims abstract description 37
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 37
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 23
• BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 claims abstract description 20
• 206010040070 Septic Shock Diseases 0.000 claims abstract description 18
• 208000006673 asthma Diseases 0.000 claims abstract description 15
• 206010006451 bronchitis Diseases 0.000 claims abstract description 13
• 230000001225 therapeutic effect Effects 0.000 claims abstract description 12
• 150000002431 hydrogen Chemical class 0.000 claims abstract description 11
• 239000000126 substance Substances 0.000 claims abstract description 11
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims abstract description 10
• 208000011231 Crohn disease Diseases 0.000 claims abstract description 9
• 206010003246 arthritis Diseases 0.000 claims abstract description 9
• 206010006458 Bronchitis chronic Diseases 0.000 claims abstract description 8
• 206010014561 Emphysema Diseases 0.000 claims abstract description 8
• 208000022559 Inflammatory bowel disease Diseases 0.000 claims abstract description 8
• 208000007451 chronic bronchitis Diseases 0.000 claims abstract description 8
• 208000018937 joint inflammation Diseases 0.000 claims abstract description 8
• 201000004681 Psoriasis Diseases 0.000 claims abstract description 7
• 208000023504 respiratory system disease Diseases 0.000 claims abstract description 7
• 108010044467 Isoenzymes Proteins 0.000 claims abstract description 6
• 206010063837 Reperfusion injury Diseases 0.000 claims abstract description 6
• 206010044248 Toxic shock syndrome Diseases 0.000 claims abstract description 6
• 231100000650 Toxic shock syndrome Toxicity 0.000 claims abstract description 6
• 201000000596 systemic lupus erythematosus Diseases 0.000 claims abstract description 6
• 206010014824 Endotoxic shock Diseases 0.000 claims abstract description 5
• 239000003112 inhibitor Substances 0.000 claims abstract description 5
• 125000000217 alkyl group Chemical group 0.000 claims description 188
• -1 1,3-benzodioxol-5-yl Chemical group 0.000 claims description 124
• 125000001153 fluoro group Chemical group F* 0.000 claims description 60
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 50
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 45
• 125000001246 bromo group Chemical group Br* 0.000 claims description 41
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 41
• 125000003118 aryl group Chemical group 0.000 claims description 40
• 125000003545 alkoxy group Chemical group 0.000 claims description 39
• 125000002883 imidazolyl group Chemical group 0.000 claims description 36
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 34
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 33
• 125000000335 thiazolyl group Chemical group 0.000 claims description 32
• NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 claims description 31
• 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 30
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 29
• 125000002971 oxazolyl group Chemical group 0.000 claims description 29
• 125000001425 triazolyl group Chemical group 0.000 claims description 29
• 238000006243 chemical reaction Methods 0.000 claims description 28
• 125000000623 heterocyclic group Chemical group 0.000 claims description 28
• 125000004076 pyridyl group Chemical group 0.000 claims description 28
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 25
• 125000003831 tetrazolyl group Chemical group 0.000 claims description 24
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 23
• 125000002632 imidazolidinyl group Chemical group 0.000 claims description 20
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 20
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 19
• 239000002253 acid Substances 0.000 claims description 18
• 125000001715 oxadiazolyl group Chemical group 0.000 claims description 18
• 125000000160 oxazolidinyl group Chemical group 0.000 claims description 18
• 229910052760 oxygen Inorganic materials 0.000 claims description 18
• 125000001984 thiazolidinyl group Chemical group 0.000 claims description 18
• 229910052799 carbon Inorganic materials 0.000 claims description 17
• ZQWPRMPSCMSAJU-UHFFFAOYSA-N methyl cyclohexanecarboxylate Chemical compound COC(=O)C1CCCCC1 ZQWPRMPSCMSAJU-UHFFFAOYSA-N 0.000 claims description 17
• 229910052717 sulfur Inorganic materials 0.000 claims description 17
• 125000001113 thiadiazolyl group Chemical group 0.000 claims description 17
• VZFUCHSFHOYXIS-UHFFFAOYSA-N cycloheptane carboxylic acid Natural products OC(=O)C1CCCCCC1 VZFUCHSFHOYXIS-UHFFFAOYSA-N 0.000 claims description 16
• 125000002757 morpholinyl group Chemical group 0.000 claims description 16
• 125000003386 piperidinyl group Chemical group 0.000 claims description 15
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 14
• 125000001544 thienyl group Chemical group 0.000 claims description 14
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 13
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 13
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 12
• 125000001589 carboacyl group Chemical group 0.000 claims description 12
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
• 125000004193 piperazinyl group Chemical group 0.000 claims description 12
• 125000002541 furyl group Chemical group 0.000 claims description 11
• 230000005764 inhibitory process Effects 0.000 claims description 11
• 206010001513 AIDS related complex Diseases 0.000 claims description 10
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 10
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 10
• 150000003839 salts Chemical class 0.000 claims description 10
• 238000011282 treatment Methods 0.000 claims description 10
• 206010006895 Cachexia Diseases 0.000 claims description 9
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• 125000003342 alkenyl group Chemical group 0.000 claims description 9
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• 238000004519 manufacturing process Methods 0.000 claims description 9
• 125000001624 naphthyl group Chemical group 0.000 claims description 9
• 229910052757 nitrogen Inorganic materials 0.000 claims description 9
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 8
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
• 201000008482 osteoarthritis Diseases 0.000 claims description 8
• 239000008194 pharmaceutical composition Substances 0.000 claims description 8
• 206010039073 rheumatoid arthritis Diseases 0.000 claims description 8
• 125000006592 (C2-C3) alkenyl group Chemical group 0.000 claims description 7
• 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 7
• 241000124008 Mammalia Species 0.000 claims description 7
• 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims description 7
• 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 7
• 150000002148 esters Chemical class 0.000 claims description 7
• 125000005843 halogen group Chemical group 0.000 claims description 7
• 230000036303 septic shock Effects 0.000 claims description 7
• 241000725303 Human immunodeficiency virus Species 0.000 claims description 6
• 125000004104 aryloxy group Chemical group 0.000 claims description 6
• 125000004432 carbon atom Chemical group C* 0.000 claims description 6
• 239000003937 drug carrier Substances 0.000 claims description 6
• 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 6
• 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 6
• 125000003072 pyrazolidinyl group Chemical group 0.000 claims description 6
• 125000002098 pyridazinyl group Chemical group 0.000 claims description 6
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 6
• 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 6
• 125000006729 (C2-C5) alkenyl group Chemical group 0.000 claims description 5
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 5
• GQJHRXMJKSJWLV-UHFFFAOYSA-N 6-bromo-3-ethyl-1-(4-fluorophenyl)indazole Chemical compound C12=CC(Br)=CC=C2C(CC)=NN1C1=CC=C(F)C=C1 GQJHRXMJKSJWLV-UHFFFAOYSA-N 0.000 claims description 5
• 206010002556 Ankylosing Spondylitis Diseases 0.000 claims description 5
• 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 5
• 206010009900 Colitis ulcerative Diseases 0.000 claims description 5
• 201000004624 Dermatitis Diseases 0.000 claims description 5
• 206010018367 Glomerulonephritis chronic Diseases 0.000 claims description 5
• 206010020751 Hypersensitivity Diseases 0.000 claims description 5
• 208000000112 Myalgia Diseases 0.000 claims description 5
• 101100258328 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) crc-2 gene Proteins 0.000 claims description 5
• 206010037660 Pyrexia Diseases 0.000 claims description 5
• 201000010001 Silicosis Diseases 0.000 claims description 5
• 201000006704 Ulcerative Colitis Diseases 0.000 claims description 5
• 230000007815 allergy Effects 0.000 claims description 5
• 230000001363 autoimmune Effects 0.000 claims description 5
• 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 5
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
• 230000015572 biosynthetic process Effects 0.000 claims description 5
• 210000000988 bone and bone Anatomy 0.000 claims description 5
• 125000000000 cycloalkoxy group Chemical group 0.000 claims description 5
• 125000001072 heteroaryl group Chemical group 0.000 claims description 5
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
• 230000002757 inflammatory effect Effects 0.000 claims description 5
• 208000011379 keloid formation Diseases 0.000 claims description 5
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• 206010039083 rhinitis Diseases 0.000 claims description 5
• 208000011580 syndromic disease Diseases 0.000 claims description 5
• 230000003612 virological effect Effects 0.000 claims description 5
• WQADWIOXOXRPLN-UHFFFAOYSA-N 1,3-Dithiane Natural products C1CSCSC1 WQADWIOXOXRPLN-UHFFFAOYSA-N 0.000 claims description 4
• FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 claims description 4
• VXPGKSAYOBZMSX-UHFFFAOYSA-N 1,3-dioxane;1,3-dioxolane Chemical compound C1COCO1.C1COCOC1 VXPGKSAYOBZMSX-UHFFFAOYSA-N 0.000 claims description 4
• IXFMUXXUQOUUPE-UHFFFAOYSA-N 1-(1-cyclopentyl-3-ethylindazol-6-yl)-4-oxocyclohexane-1-carbonitrile Chemical compound C12=CC(C3(CCC(=O)CC3)C#N)=CC=C2C(CC)=NN1C1CCCC1 IXFMUXXUQOUUPE-UHFFFAOYSA-N 0.000 claims description 4
• YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 4
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 4
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
• 206010028980 Neoplasm Diseases 0.000 claims description 4
• 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 claims description 4
• 230000001580 bacterial effect Effects 0.000 claims description 4
• 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 4
• 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 4
• 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 4
• 201000011510 cancer Diseases 0.000 claims description 4
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
• 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 claims description 4
• 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 claims description 4
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
• PNZXMIKHJXIPEK-UHFFFAOYSA-N cyclohexanecarboxamide Chemical compound NC(=O)C1CCCCC1 PNZXMIKHJXIPEK-UHFFFAOYSA-N 0.000 claims description 4
• 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 4
• 125000002636 imidazolinyl group Chemical group 0.000 claims description 4
• 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 4
• 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 4
• 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 4
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• 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 claims description 4
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• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
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• 125000000466 oxiranyl group Chemical group 0.000 claims description 4
• 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 claims description 4
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• UFEHHWAXLUKWBV-UHFFFAOYSA-N 1-(1-cyclohexyl-3-ethylindazol-6-yl)-4-oxocyclohexane-1-carbonitrile Chemical compound C12=CC(C3(CCC(=O)CC3)C#N)=CC=C2C(CC)=NN1C1CCCCC1 UFEHHWAXLUKWBV-UHFFFAOYSA-N 0.000 claims description 3
• UKVJLLRHTQPKJR-UHFFFAOYSA-N 4-[3-ethyl-1-(4-fluorophenyl)indazol-6-yl]cyclohex-3-ene-1-carboxylic acid Chemical compound C12=CC(C=3CCC(CC=3)C(O)=O)=CC=C2C(CC)=NN1C1=CC=C(F)C=C1 UKVJLLRHTQPKJR-UHFFFAOYSA-N 0.000 claims description 3
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• IMHJVJUMANXYCI-UHFFFAOYSA-N 1,3-dithiane;1,3-dithiolane Chemical compound C1CSCS1.C1CSCSC1 IMHJVJUMANXYCI-UHFFFAOYSA-N 0.000 claims description 2
• 125000005940 1,4-dioxanyl group Chemical group 0.000 claims description 2
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• 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
• 125000002471 4H-quinolizinyl group Chemical group C=1(C=CCN2C=CC=CC12)* 0.000 claims description 2
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