AP795A - Indazole derivatives. - Google Patents
Indazole derivatives. Download PDFInfo
- Publication number
- AP795A AP795A APAP/P/1997/001080A AP9701080A AP795A AP 795 A AP795 A AP 795A AP 9701080 A AP9701080 A AP 9701080A AP 795 A AP795 A AP 795A
- Authority
- AP
- ARIPO
- Prior art keywords
- alkyl
- compound
- indazole
- phenyl
- mmol
- Prior art date
Links
- 125000003453 indazolyl group Chemical class N1N=C(C2=C1C=CC=C2)* 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 231
- 125000000217 alkyl group Chemical group 0.000 claims description 87
- 238000000034 method Methods 0.000 claims description 69
- -1 cyano, hydroxy Chemical group 0.000 claims description 58
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 48
- 229910052799 carbon Inorganic materials 0.000 claims description 42
- 125000001424 substituent group Chemical group 0.000 claims description 37
- 125000003118 aryl group Chemical group 0.000 claims description 36
- 125000005843 halogen group Chemical group 0.000 claims description 34
- 239000002253 acid Substances 0.000 claims description 29
- 125000003545 alkoxy group Chemical group 0.000 claims description 25
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 25
- 150000003839 salts Chemical class 0.000 claims description 23
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 18
- 102000003390 tumor necrosis factor Human genes 0.000 claims description 18
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 claims description 17
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 claims description 17
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 16
- 125000004076 pyridyl group Chemical group 0.000 claims description 16
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 13
- 206010040070 Septic Shock Diseases 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 11
- ISIQAMHROGZHOV-UHFFFAOYSA-N 3,5-dichloropyridin-4-amine Chemical compound NC1=C(Cl)C=NC=C1Cl ISIQAMHROGZHOV-UHFFFAOYSA-N 0.000 claims description 10
- 208000030507 AIDS Diseases 0.000 claims description 10
- 125000003342 alkenyl group Chemical group 0.000 claims description 10
- 150000001408 amides Chemical class 0.000 claims description 10
- 201000010099 disease Diseases 0.000 claims description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
- 230000005764 inhibitory process Effects 0.000 claims description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
- 241000124008 Mammalia Species 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 125000001153 fluoro group Chemical group F* 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 125000000335 thiazolyl group Chemical group 0.000 claims description 8
- 229910052684 Cerium Inorganic materials 0.000 claims description 7
- 206010040047 Sepsis Diseases 0.000 claims description 7
- 125000001544 thienyl group Chemical group 0.000 claims description 7
- 206010001513 AIDS related complex Diseases 0.000 claims description 6
- 206010006895 Cachexia Diseases 0.000 claims description 6
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 6
- 208000015181 infectious disease Diseases 0.000 claims description 6
- 125000001624 naphthyl group Chemical group 0.000 claims description 6
- 125000002971 oxazolyl group Chemical group 0.000 claims description 6
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 6
- 238000011282 treatment Methods 0.000 claims description 6
- 125000001425 triazolyl group Chemical group 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000002883 imidazolyl group Chemical group 0.000 claims description 5
- 208000027866 inflammatory disease Diseases 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 5
- 230000036303 septic shock Effects 0.000 claims description 5
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 4
- 208000005314 Multi-Infarct Dementia Diseases 0.000 claims description 4
- 201000004681 Psoriasis Diseases 0.000 claims description 4
- 206010039085 Rhinitis allergic Diseases 0.000 claims description 4
- 201000004810 Vascular dementia Diseases 0.000 claims description 4
- 102100026383 Vasopressin-neurophysin 2-copeptin Human genes 0.000 claims description 4
- 201000010105 allergic rhinitis Diseases 0.000 claims description 4
- 206010003246 arthritis Diseases 0.000 claims description 4
- 125000004104 aryloxy group Chemical group 0.000 claims description 4
- 208000006673 asthma Diseases 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
- 206010006451 bronchitis Diseases 0.000 claims description 4
- 201000010064 diabetes insipidus Diseases 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
- 125000006729 (C2-C5) alkenyl group Chemical group 0.000 claims description 3
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 3
- 206010002556 Ankylosing Spondylitis Diseases 0.000 claims description 3
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 3
- 208000011231 Crohn disease Diseases 0.000 claims description 3
- 201000004624 Dermatitis Diseases 0.000 claims description 3
- 206010014824 Endotoxic shock Diseases 0.000 claims description 3
- 206010018367 Glomerulonephritis chronic Diseases 0.000 claims description 3
- 201000005569 Gout Diseases 0.000 claims description 3
- 206010018634 Gouty Arthritis Diseases 0.000 claims description 3
- 206010019617 Henoch-Schonlein purpura Diseases 0.000 claims description 3
- 208000031814 IgA Vasculitis Diseases 0.000 claims description 3
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 3
- 208000000112 Myalgia Diseases 0.000 claims description 3
- 206010028980 Neoplasm Diseases 0.000 claims description 3
- 206010037660 Pyrexia Diseases 0.000 claims description 3
- 206010063837 Reperfusion injury Diseases 0.000 claims description 3
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims description 3
- 206010044248 Toxic shock syndrome Diseases 0.000 claims description 3
- 231100000650 Toxic shock syndrome Toxicity 0.000 claims description 3
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 3
- 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 3
- 125000004450 alkenylene group Chemical group 0.000 claims description 3
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- 230000002917 arthritic effect Effects 0.000 claims description 3
- 208000019664 bone resorption disease Diseases 0.000 claims description 3
- 201000011510 cancer Diseases 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 230000001684 chronic effect Effects 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 125000001072 heteroaryl group Chemical group 0.000 claims description 3
- 208000015446 immunoglobulin a vasculitis Diseases 0.000 claims description 3
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 3
- 208000018937 joint inflammation Diseases 0.000 claims description 3
- 208000011379 keloid formation Diseases 0.000 claims description 3
- 208000032839 leukemia Diseases 0.000 claims description 3
- 201000004792 malaria Diseases 0.000 claims description 3
- 230000036210 malignancy Effects 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 201000006417 multiple sclerosis Diseases 0.000 claims description 3
- 201000008383 nephritis Diseases 0.000 claims description 3
- 201000008482 osteoarthritis Diseases 0.000 claims description 3
- 230000002685 pulmonary effect Effects 0.000 claims description 3
- 201000003651 pulmonary sarcoidosis Diseases 0.000 claims description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
- 231100000241 scar Toxicity 0.000 claims description 3
- 208000011580 syndromic disease Diseases 0.000 claims description 3
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 3
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 3
- 230000009772 tissue formation Effects 0.000 claims description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
- 125000004530 1,2,4-triazinyl group Chemical group N1=NC(=NC=C1)* 0.000 claims description 2
- JDMFXJULNGEPOI-UHFFFAOYSA-N 2,6-dichloroaniline Chemical compound NC1=C(Cl)C=CC=C1Cl JDMFXJULNGEPOI-UHFFFAOYSA-N 0.000 claims description 2
- 201000010001 Silicosis Diseases 0.000 claims description 2
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000001589 carboacyl group Chemical group 0.000 claims description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 2
- VDBCTDQYMZSQFQ-UHFFFAOYSA-N glycine hydroxamate Chemical compound NCC(=O)NO VDBCTDQYMZSQFQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 claims description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
- 206010022000 influenza Diseases 0.000 claims description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 2
- 125000002757 morpholinyl group Chemical group 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N sulfur dioxide Inorganic materials O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 7
- 229910014585 C2-Ce Inorganic materials 0.000 claims 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- JMOMIZNLLRYUDW-UHFFFAOYSA-N 1-cyclopentyl-3-ethyl-6-thiophen-2-ylindazole Chemical compound C12=CC(C=3SC=CC=3)=CC=C2C(CC)=NN1C1CCCC1 JMOMIZNLLRYUDW-UHFFFAOYSA-N 0.000 claims 1
- VMJNTFXCTXAXTC-UHFFFAOYSA-N 2,2-difluoro-1,3-benzodioxole-5-carbonitrile Chemical group C1=C(C#N)C=C2OC(F)(F)OC2=C1 VMJNTFXCTXAXTC-UHFFFAOYSA-N 0.000 claims 1
- BAAQJFBTHFOHLY-UHFFFAOYSA-N 2-amino-n-hydroxypropanamide Chemical compound CC(N)C(=O)NO BAAQJFBTHFOHLY-UHFFFAOYSA-N 0.000 claims 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims 1
- 125000004608 5,6,7,8-tetrahydroquinolinyl group Chemical group N1=C(C=CC=2CCCCC12)* 0.000 claims 1
- 206010012289 Dementia Diseases 0.000 claims 1
- 206010061216 Infarction Diseases 0.000 claims 1
- 125000005530 alkylenedioxy group Chemical group 0.000 claims 1
- 208000024908 graft versus host disease Diseases 0.000 claims 1
- 125000001984 thiazolidinyl group Chemical group 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 57
- 229930182558 Sterol Natural products 0.000 abstract 1
- 239000000427 antigen Substances 0.000 abstract 1
- 102000036639 antigens Human genes 0.000 abstract 1
- 108091007433 antigens Proteins 0.000 abstract 1
- 239000001397 quillaja saponaria molina bark Substances 0.000 abstract 1
- 229930182490 saponin Natural products 0.000 abstract 1
- 150000007949 saponins Chemical class 0.000 abstract 1
- 150000003432 sterols Chemical class 0.000 abstract 1
- 235000003702 sterols Nutrition 0.000 abstract 1
- 229960005486 vaccine Drugs 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 194
- 239000011541 reaction mixture Substances 0.000 description 74
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 71
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 70
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 69
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 68
- 235000019439 ethyl acetate Nutrition 0.000 description 65
- 229940093499 ethyl acetate Drugs 0.000 description 64
- 239000000243 solution Substances 0.000 description 64
- 239000007787 solid Substances 0.000 description 57
- 239000007858 starting material Substances 0.000 description 50
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 36
- 239000012267 brine Substances 0.000 description 36
- 239000000706 filtrate Substances 0.000 description 36
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 36
- 239000002585 base Substances 0.000 description 35
- 238000003756 stirring Methods 0.000 description 35
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 30
- 238000001035 drying Methods 0.000 description 30
- 239000003921 oil Substances 0.000 description 29
- 235000019198 oils Nutrition 0.000 description 29
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 28
- 238000005481 NMR spectroscopy Methods 0.000 description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- 238000001914 filtration Methods 0.000 description 26
- 238000002360 preparation method Methods 0.000 description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 25
- 239000000741 silica gel Substances 0.000 description 24
- 229910002027 silica gel Inorganic materials 0.000 description 24
- 239000007832 Na2SO4 Substances 0.000 description 22
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 22
- 229910052938 sodium sulfate Inorganic materials 0.000 description 22
- 238000010992 reflux Methods 0.000 description 19
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 18
- 150000004702 methyl esters Chemical class 0.000 description 18
- 239000000843 powder Substances 0.000 description 18
- 150000002148 esters Chemical class 0.000 description 17
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 17
- 239000013078 crystal Substances 0.000 description 15
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 15
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
- 239000000284 extract Substances 0.000 description 14
- 238000010189 synthetic method Methods 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 229910000029 sodium carbonate Inorganic materials 0.000 description 9
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
- 239000004533 oil dispersion Substances 0.000 description 8
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 8
- QUKDARNAEGBEOY-UHFFFAOYSA-N 1-cyclopentyl-3-ethylindazole-6-carboxylic acid Chemical compound C12=CC(C(O)=O)=CC=C2C(CC)=NN1C1CCCC1 QUKDARNAEGBEOY-UHFFFAOYSA-N 0.000 description 7
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 239000000499 gel Substances 0.000 description 7
- 238000005984 hydrogenation reaction Methods 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- 239000002024 ethyl acetate extract Substances 0.000 description 6
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 6
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 6
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- LNMBCRKRCIMQLW-UHFFFAOYSA-N 2-tert-butylsulfanyl-2-methylpropane Chemical compound CC(C)(C)SC(C)(C)C LNMBCRKRCIMQLW-UHFFFAOYSA-N 0.000 description 5
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 238000007796 conventional method Methods 0.000 description 5
- 125000004122 cyclic group Chemical group 0.000 description 5
- 239000006260 foam Substances 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 5
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical class C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 4
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000007983 Tris buffer Substances 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 4
- 125000001246 bromo group Chemical group Br* 0.000 description 4
- 229910002092 carbon dioxide Inorganic materials 0.000 description 4
- 239000012954 diazonium Substances 0.000 description 4
- 230000005484 gravity Effects 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000006396 nitration reaction Methods 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000003880 polar aprotic solvent Substances 0.000 description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 235000010288 sodium nitrite Nutrition 0.000 description 4
- WMXCDAVJEZZYLT-UHFFFAOYSA-N tert-butylthiol Chemical compound CC(C)(C)S WMXCDAVJEZZYLT-UHFFFAOYSA-N 0.000 description 4
- 0 *C(c1c2)N=C(*)c1ccc2C(**C(*)=O)=O Chemical compound *C(c1c2)N=C(*)c1ccc2C(**C(*)=O)=O 0.000 description 3
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 3
- CUYKNJBYIJFRCU-UHFFFAOYSA-N 3-aminopyridine Chemical compound NC1=CC=CN=C1 CUYKNJBYIJFRCU-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 3
- 235000011054 acetic acid Nutrition 0.000 description 3
- UDMBCSSLTHHNCD-KQYNXXCUSA-N adenosine 5'-monophosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O UDMBCSSLTHHNCD-KQYNXXCUSA-N 0.000 description 3
- 229950006790 adenosine phosphate Drugs 0.000 description 3
- 230000029936 alkylation Effects 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- BRTFVKHPEHKBQF-UHFFFAOYSA-N bromocyclopentane Chemical compound BrC1CCCC1 BRTFVKHPEHKBQF-UHFFFAOYSA-N 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 3
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- HYDZPXNVHXJHBG-UHFFFAOYSA-N o-benzylhydroxylamine;hydron;chloride Chemical compound Cl.NOCC1=CC=CC=C1 HYDZPXNVHXJHBG-UHFFFAOYSA-N 0.000 description 3
- 235000011056 potassium acetate Nutrition 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 239000011534 wash buffer Substances 0.000 description 3
- GBMZDOXWVBULDD-DDWIOCJRSA-N (2r)-2-amino-n-phenylmethoxypropanamide;hydrochloride Chemical compound Cl.C[C@@H](N)C(=O)NOCC1=CC=CC=C1 GBMZDOXWVBULDD-DDWIOCJRSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- ZVQVGXQEQBEHGE-UHFFFAOYSA-N 1-cyclobutyl-3-ethylindazole-6-carboxylic acid Chemical compound C12=CC(C(O)=O)=CC=C2C(CC)=NN1C1CCC1 ZVQVGXQEQBEHGE-UHFFFAOYSA-N 0.000 description 2
- LQBQDLNKPVZVGB-UHFFFAOYSA-N 1-cyclopentyl-3-ethylindazole-6-carbonyl chloride Chemical compound C12=CC(C(Cl)=O)=CC=C2C(CC)=NN1C1CCCC1 LQBQDLNKPVZVGB-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- ZJSQZQMVXKZAGW-UHFFFAOYSA-N 2H-benzotriazol-4-ol hydrate Chemical compound O.OC1=CC=CC2=C1N=NN2 ZJSQZQMVXKZAGW-UHFFFAOYSA-N 0.000 description 2
- MJFDEQYMXUJFQE-UHFFFAOYSA-N 3-amino-4-propylbenzoic acid Chemical compound CCCC1=CC=C(C(O)=O)C=C1N MJFDEQYMXUJFQE-UHFFFAOYSA-N 0.000 description 2
- IOFMZLVHJDNLKP-UHFFFAOYSA-N 3-ethyl-1-(4-fluorophenyl)indazole-6-carboxylic acid Chemical compound C12=CC(C(O)=O)=CC=C2C(CC)=NN1C1=CC=C(F)C=C1 IOFMZLVHJDNLKP-UHFFFAOYSA-N 0.000 description 2
- NWNSMAXWOXQTNY-UHFFFAOYSA-N 3-ethyl-2h-indazole-6-carboxylic acid Chemical compound OC(=O)C1=CC=C2C(CC)=NNC2=C1 NWNSMAXWOXQTNY-UHFFFAOYSA-N 0.000 description 2
- GXRWLPVXYJGNTK-UHFFFAOYSA-N 3-nitro-4-propylbenzoic acid Chemical compound CCCC1=CC=C(C(O)=O)C=C1[N+]([O-])=O GXRWLPVXYJGNTK-UHFFFAOYSA-N 0.000 description 2
- NUKYPUAOHBNCPY-UHFFFAOYSA-N 4-aminopyridine Chemical compound NC1=CC=NC=C1 NUKYPUAOHBNCPY-UHFFFAOYSA-N 0.000 description 2
- FJAWZBJMVMDKCZ-UHFFFAOYSA-N 5-bromo-2-propylaniline Chemical compound CCCC1=CC=C(Br)C=C1N FJAWZBJMVMDKCZ-UHFFFAOYSA-N 0.000 description 2
- FCLDDXMLCBBXKS-UHFFFAOYSA-N 6-bromo-1-cyclopentyl-3-ethylindazole Chemical compound C12=CC(Br)=CC=C2C(CC)=NN1C1CCCC1 FCLDDXMLCBBXKS-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- 208000033962 Fontaine progeroid syndrome Diseases 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 229940124639 Selective inhibitor Drugs 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- 238000010936 aqueous wash Methods 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 125000002091 cationic group Chemical group 0.000 description 2
- 208000015114 central nervous system disease Diseases 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 150000001989 diazonium salts Chemical class 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- XNXVOSBNFZWHBV-UHFFFAOYSA-N hydron;o-methylhydroxylamine;chloride Chemical compound Cl.CON XNXVOSBNFZWHBV-UHFFFAOYSA-N 0.000 description 2
- 150000002473 indoazoles Chemical class 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 125000002346 iodo group Chemical group I* 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 238000010907 mechanical stirring Methods 0.000 description 2
- XADIHHWTQYSWCS-UHFFFAOYSA-N methyl 1-cyclopentyl-3-ethylindazole-6-carboxylate Chemical compound C12=CC(C(=O)OC)=CC=C2C(CC)=NN1C1CCCC1 XADIHHWTQYSWCS-UHFFFAOYSA-N 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 150000002828 nitro derivatives Chemical class 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- TXQWFIVRZNOPCK-UHFFFAOYSA-N pyridin-4-ylmethanamine Chemical compound NCC1=CC=NC=C1 TXQWFIVRZNOPCK-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- XMIAFAKRAAMSGX-UHFFFAOYSA-N quinolin-5-amine Chemical compound C1=CC=C2C(N)=CC=CC2=N1 XMIAFAKRAAMSGX-UHFFFAOYSA-N 0.000 description 2
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 2
- 238000001665 trituration Methods 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- OIVHTTFUVRTULK-UHFFFAOYSA-N (1-cyclopentyl-3-ethylindazol-6-yl)methanol Chemical compound C12=CC(CO)=CC=C2C(CC)=NN1C1CCCC1 OIVHTTFUVRTULK-UHFFFAOYSA-N 0.000 description 1
- AITNMTXHTIIIBB-UHFFFAOYSA-N 1-bromo-4-fluorobenzene Chemical compound FC1=CC=C(Br)C=C1 AITNMTXHTIIIBB-UHFFFAOYSA-N 0.000 description 1
- NUPWGLKBGVNSJX-UHFFFAOYSA-N 1-bromo-4-propylbenzene Chemical compound CCCC1=CC=C(Br)C=C1 NUPWGLKBGVNSJX-UHFFFAOYSA-N 0.000 description 1
- BBLLEIPSRCTESJ-UHFFFAOYSA-N 1-cyclobutyl-3-ethylindazole Chemical compound CCC1=NN(C2=CC=CC=C21)C3CCC3 BBLLEIPSRCTESJ-UHFFFAOYSA-N 0.000 description 1
- OQLKIYVZKHBREJ-UHFFFAOYSA-N 1-cyclopentyl-3-ethyl-N,N-dimethyl-2H-indazole-3-carboxamide Chemical compound C12=CC=CC=C2C(CC)(C(=O)N(C)C)NN1C1CCCC1 OQLKIYVZKHBREJ-UHFFFAOYSA-N 0.000 description 1
- SHKRCTUJEJDUSW-UHFFFAOYSA-N 1-cyclopentyl-n-(3,5-dichloropyridin-4-yl)indazole-6-carboxamide Chemical compound ClC1=CN=CC(Cl)=C1NC(=O)C1=CC=C(C=NN2C3CCCC3)C2=C1 SHKRCTUJEJDUSW-UHFFFAOYSA-N 0.000 description 1
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 1
- RIZUCYSQUWMQLX-UHFFFAOYSA-N 2,3-dimethylbenzoic acid Chemical compound CC1=CC=CC(C(O)=O)=C1C RIZUCYSQUWMQLX-UHFFFAOYSA-N 0.000 description 1
- SDGJECHNGUZOAM-UHFFFAOYSA-N 2-(methylamino)-n-phenylmethoxyacetamide Chemical compound CNCC(=O)NOCC1=CC=CC=C1 SDGJECHNGUZOAM-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- AUWGCKQDHVHZJG-UHFFFAOYSA-N 2-amino-n-methoxyacetamide Chemical compound CONC(=O)CN AUWGCKQDHVHZJG-UHFFFAOYSA-N 0.000 description 1
- NAMYKGVDVNBCFQ-UHFFFAOYSA-N 2-bromopropane Chemical compound CC(C)Br NAMYKGVDVNBCFQ-UHFFFAOYSA-N 0.000 description 1
- OLZSOCFSHKWPRS-UHFFFAOYSA-N 2-cyclopentylindazole-6-carboxylic acid Chemical compound N1=C2C=C(C(=O)O)C=CC2=CN1C1CCCC1 OLZSOCFSHKWPRS-UHFFFAOYSA-N 0.000 description 1
- CYWGSFFHHMQKET-UHFFFAOYSA-N 2-methylsulfanylethanamine Chemical compound CSCCN CYWGSFFHHMQKET-UHFFFAOYSA-N 0.000 description 1
- IDLHTECVNDEOIY-UHFFFAOYSA-N 2-pyridin-4-ylethanamine Chemical compound NCCC1=CC=NC=C1 IDLHTECVNDEOIY-UHFFFAOYSA-N 0.000 description 1
- KAWUBNUJMFOOOE-UHFFFAOYSA-N 3-amino-3-(3,5-dibromo-4-hydroxyphenyl)propanoic acid Chemical compound OC(=O)CC(N)C1=CC(Br)=C(O)C(Br)=C1 KAWUBNUJMFOOOE-UHFFFAOYSA-N 0.000 description 1
- XKFIFYROMAAUDL-UHFFFAOYSA-N 3-amino-4-methylbenzoic acid Chemical compound CC1=CC=C(C(O)=O)C=C1N XKFIFYROMAAUDL-UHFFFAOYSA-N 0.000 description 1
- PNPCRKVUWYDDST-UHFFFAOYSA-N 3-chloroaniline Chemical compound NC1=CC=CC(Cl)=C1 PNPCRKVUWYDDST-UHFFFAOYSA-N 0.000 description 1
- UXTHALSOMRLGGI-UHFFFAOYSA-N 3-ethyl-1-[6-(4-phenylbutoxy)hexyl]indazole-6-carboxylic acid Chemical compound C12=CC(C(O)=O)=CC=C2C(CC)=NN1CCCCCCOCCCCC1=CC=CC=C1 UXTHALSOMRLGGI-UHFFFAOYSA-N 0.000 description 1
- DPDFVUWCLDYLDW-UHFFFAOYSA-N 3-ethyl-1-propan-2-ylindazole-6-carboxylic acid Chemical compound OC(=O)C1=CC=C2C(CC)=NN(C(C)C)C2=C1 DPDFVUWCLDYLDW-UHFFFAOYSA-N 0.000 description 1
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 1
- NIGDWBHWHVHOAD-UHFFFAOYSA-N 4,6-dichloropyrimidin-5-amine Chemical compound NC1=C(Cl)N=CN=C1Cl NIGDWBHWHVHOAD-UHFFFAOYSA-N 0.000 description 1
- HYRIAERKUPZOCS-UHFFFAOYSA-N 4-(6-bromohexoxy)butylbenzene Chemical compound BrCCCCCCOCCCCC1=CC=CC=C1 HYRIAERKUPZOCS-UHFFFAOYSA-N 0.000 description 1
- KWFFEQXPFFDJER-UHFFFAOYSA-N 4-[3-(4-aminophenoxy)propoxy]aniline Chemical compound C1=CC(N)=CC=C1OCCCOC1=CC=C(N)C=C1 KWFFEQXPFFDJER-UHFFFAOYSA-N 0.000 description 1
- XUOWMAHUTJJSLH-UHFFFAOYSA-N 4-amino-N-phenylmethoxybenzamide Chemical compound C1=CC(N)=CC=C1C(=O)NOCC1=CC=CC=C1 XUOWMAHUTJJSLH-UHFFFAOYSA-N 0.000 description 1
- VGJCCTYTFGHTHN-UHFFFAOYSA-N 4-bromo-2-nitro-1-propylbenzene Chemical compound CCCC1=CC=C(Br)C=C1[N+]([O-])=O VGJCCTYTFGHTHN-UHFFFAOYSA-N 0.000 description 1
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 1
- 125000004606 5,6,7,8-tetrahydroisoquinolinyl group Chemical group C1(=NC=CC=2CCCCC12)* 0.000 description 1
- XZRBYJWQQQBHLP-UHFFFAOYSA-N 6-bromo-3-ethyl-2h-indazole Chemical compound C1=C(Br)C=CC2=C(CC)NN=C21 XZRBYJWQQQBHLP-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 1
- DODKRIJQXNNQTJ-UHFFFAOYSA-N C12=CC=CC=C2C(CC)=NN1C1CCCC1 Chemical compound C12=CC=CC=C2C(CC)=NN1C1CCCC1 DODKRIJQXNNQTJ-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- UDMBCSSLTHHNCD-UHFFFAOYSA-N Coenzym Q(11) Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(O)=O)C(O)C1O UDMBCSSLTHHNCD-UHFFFAOYSA-N 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 206010012434 Dermatitis allergic Diseases 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 229920001917 Ficoll Polymers 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 239000012981 Hank's balanced salt solution Substances 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 description 1
- 150000001204 N-oxides Chemical class 0.000 description 1
- 229910017711 NHRa Inorganic materials 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 210000005091 airway smooth muscle Anatomy 0.000 description 1
- 229960003767 alanine Drugs 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003674 animal food additive Substances 0.000 description 1
- 230000001088 anti-asthma Effects 0.000 description 1
- 239000000924 antiasthmatic agent Substances 0.000 description 1
- 230000006502 antiplatelets effects Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 1
- KXVUSQIDCZRUKF-UHFFFAOYSA-N bromocyclobutane Chemical compound BrC1CCC1 KXVUSQIDCZRUKF-UHFFFAOYSA-N 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000009109 curative therapy Methods 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 description 1
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- NIDZUMSLERGAON-UHFFFAOYSA-N ethyl 2-(methylamino)acetate;hydron;chloride Chemical compound Cl.CCOC(=O)CNC NIDZUMSLERGAON-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 229960004979 fampridine Drugs 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000005227 gel permeation chromatography Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 208000024798 heartburn Diseases 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- COQRGFWWJBEXRC-UHFFFAOYSA-N hydron;methyl 2-aminoacetate;chloride Chemical compound Cl.COC(=O)CN COQRGFWWJBEXRC-UHFFFAOYSA-N 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- AOHCBEAZXHZMOR-ZDUSSCGKSA-N hypaphorine Chemical compound C1=CC=C2C(C[C@H]([N+](C)(C)C)C([O-])=O)=CNC2=C1 AOHCBEAZXHZMOR-ZDUSSCGKSA-N 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 235000015250 liver sausages Nutrition 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- MIKKOBKEXMRYFQ-WZTVWXICSA-N meglumine amidotrizoate Chemical compound C[NH2+]C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CC(=O)NC1=C(I)C(NC(C)=O)=C(I)C(C([O-])=O)=C1I MIKKOBKEXMRYFQ-WZTVWXICSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- RFQHVMXJFCDIHI-UHFFFAOYSA-N methyl 1-cyclohex-2-en-1-yl-3-ethylindazole-6-carboxylate Chemical compound C12=CC(C(=O)OC)=CC=C2C(CC)=NN1C1CCCC=C1 RFQHVMXJFCDIHI-UHFFFAOYSA-N 0.000 description 1
- TUSICEWIXLMXEY-UHFFFAOYSA-N methyl 1h-indazole-6-carboxylate Chemical compound COC(=O)C1=CC=C2C=NNC2=C1 TUSICEWIXLMXEY-UHFFFAOYSA-N 0.000 description 1
- LYTJHSRWUNHCEB-UHFFFAOYSA-N methyl 2-cyclopentylindazole-6-carboxylate Chemical compound N1=C2C=C(C(=O)OC)C=CC2=CN1C1CCCC1 LYTJHSRWUNHCEB-UHFFFAOYSA-N 0.000 description 1
- YPMZUOOVMUMULT-UHFFFAOYSA-N methyl 3-ethyl-1-(4-fluorophenyl)indazole-6-carboxylate Chemical compound C12=CC(C(=O)OC)=CC=C2C(CC)=NN1C1=CC=C(F)C=C1 YPMZUOOVMUMULT-UHFFFAOYSA-N 0.000 description 1
- CSQGAIUWKCKTHI-UHFFFAOYSA-N methyl 3-ethyl-2h-indazole-6-carboxylate Chemical compound COC(=O)C1=CC=C2C(CC)=NNC2=C1 CSQGAIUWKCKTHI-UHFFFAOYSA-N 0.000 description 1
- LZXXNPOYQCLXRS-UHFFFAOYSA-N methyl 4-aminobenzoate Chemical compound COC(=O)C1=CC=C(N)C=C1 LZXXNPOYQCLXRS-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- RADJGGDAWUGNAJ-UHFFFAOYSA-N n-hydroxy-2-(methylamino)acetamide Chemical compound CNCC(=O)NO RADJGGDAWUGNAJ-UHFFFAOYSA-N 0.000 description 1
- 229960000988 nystatin Drugs 0.000 description 1
- VQOXZBDYSJBXMA-NQTDYLQESA-N nystatin A1 Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/CC/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 VQOXZBDYSJBXMA-NQTDYLQESA-N 0.000 description 1
- XYEOALKITRFCJJ-UHFFFAOYSA-N o-benzylhydroxylamine Chemical compound NOCC1=CC=CC=C1 XYEOALKITRFCJJ-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- 208000024981 pyrosis Diseases 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000004648 relaxation of smooth muscle Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000003118 sandwich ELISA Methods 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000004317 sodium nitrate Substances 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- OSBSFAARYOCBHB-UHFFFAOYSA-N tetrapropylammonium Chemical compound CCC[N+](CCC)(CCC)CCC OSBSFAARYOCBHB-UHFFFAOYSA-N 0.000 description 1
- ARYHTUPFQTUBBG-UHFFFAOYSA-N thiophen-2-ylboronic acid Chemical compound OB(O)C1=CC=CS1 ARYHTUPFQTUBBG-UHFFFAOYSA-N 0.000 description 1
- CVNKFOIOZXAFBO-UHFFFAOYSA-J tin(4+);tetrahydroxide Chemical compound [OH-].[OH-].[OH-].[OH-].[Sn+4] CVNKFOIOZXAFBO-UHFFFAOYSA-J 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—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
- C07D403/12—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 linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
-
- 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
- C07D401/12—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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—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
- C07D409/04—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 directly linked by a ring-member-to-ring-member bond
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pulmonology (AREA)
- Diabetes (AREA)
- Virology (AREA)
- Immunology (AREA)
- Dermatology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Physical Education & Sports Medicine (AREA)
- Rheumatology (AREA)
- Emergency Medicine (AREA)
- Molecular Biology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pain & Pain Management (AREA)
- Tropical Medicine & Parasitology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Orthopedic Medicine & Surgery (AREA)
- AIDS & HIV (AREA)
- Endocrinology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention relates to a vaccine composition comprising an antigen, an immunoiogically active saponin fraction and a sterol.
Description
INDAZOLE DERIVATIVES
This invention relates to novel indazole analogs. The compounds are selective inhibitors of phosphodiesterase (PDE) type IV and the production of tumor necrosis factor (TNF), and as such are useful in the treatment of asthma, arthritis, bronchitis, chronic obstructive airway disease, psoriasis, allergic rhinitis, dermatitis, and other inflammatory diseases, central nervous system disorders such as depression and multiinfarct dementia, AIDS, septic shock and other diseases involving the production of TNF. This invention also relates to a method of using such compounds in the treatment of the foregoing diseases in mammals, especially humans, and to pharmaceutical compositions containing such compounds.
The following co-pending United States provisional patent applications also disclose and claim indazole derivatives that are selective inhibitors of PDE type fV and the production of TNF: United States provisional application number 60/021,072, filed June 27,1996; United States provisional application number 60/020,385, filed June 25, 1996; and United States provisional application number 60/016,861, filed May 3,1996. The foregoing co-pending United States provisional patent applications are incorporated t
herein by reference in their entirety.
Since the recognition that cyclic adenosine phosphate (AMP) is an intracellular second messenger (E.W. Sutherland, and T. W. Rail, Pharmacol· Rev., 12, 265, (1960)), inhibition of the phosphodiesterases has been a target for modulation and, accordingly, therapeutic intervention in a range of disease processes. More recently, distinct classes of PDE have been recognized (J. A. Beavo et al., Trends in Pharm. Sd. (TIPS). 11,150, (1990)), and their selective inhibition has led to improved drug therapy (C. D. Nicholson, M. S. Hahid, TIPS, 12, 19, (1991)). More particularly, it has been recognized that inhibition of PDE type IV can lead to inhibition of inflammatory mediator release (M. W. Verqhese et al.. J. Mol. Cell Cardiol·, 12 (Suppl. II), S 61, (1989)) and airway smooth muscle relaxation (T.J. Torphy in Directions for New Anti-Asthma Drugs, eds S.R. O’Donnell and C. G. A. Persson, 1988,37 Birkhauser-Vertag). Thus, compounds that inhibit PDE type IV, but which have poor activity against other PDE types, would inhibit the release of inflammatory mediators and relax airway smooth musde without causing cardiovascular effects or antiplatelet effects, ft has also been disclosed that PDE IV inhibitors are useful in the treatment of diabetes insipidus (Kidney Int. 37:362, 1990; Kidney Int 35:494) and central nervous system disorders
AP/P/ 97/01080
Ap.ϋ Ο 7 9 5
-2such as depression and multi-infarct dementia (PCT international application WO 92719594 (published November 12. 1992)).
TNF is recognized to be involved in many infectious and auto-immune diseases (W. Friers, Fed, of Euro. Bio. Soc. (FEBS) Letters, 285, 199, (1991)). Furthermore, it 5 has been shown that TNF is the prime mediator of the inflammatory response seen in sepsis and septic shock (C. E. Spooner et aL, Clinical Immunology and
Immunopathology, 62, S11, (1992)).
Summary of the Invention
The present invention relates to compounds of the formula I
and to pharmaceutically acceptable salts thereof, wherein:
R is H, C,-Ct alkyl, -<CHj)m(5 to 10 membered heterocycfyf) wherein m is 0 to
2, (C,-Ce alkoxyX^-C, alkyl, C2-C, alkenyl, or -(Z^fZ^C.-C*, aryl) wherein b and c are independently 0 or 1, Z,'» C,-C, alkylene or Cj-C, alkenylene, and Zj is O, S, SO* or NR12, and wherein said R groups are optionally substituted by 1 to 3 substituents independently selected from the group consisting of halo, hydroxy, C,-C, alkyl, C2-C5 alkenyl, Ο,-C» alkoxy, trifluoromethyl, nitro, -COjR^, -CiOJNR^* -NR12Ri3 and -S0jNR12R13:
R, is H, C,-C, alkyl, Cj-C, alkenyl, or phenyl, wherein said alkyl, afeenyt and phenyl R^ groups are optionally substituted by 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, trffluoromethyt, and halo;
Ra is R1t, -C(O)NRn(CHRu).C(O)NRnO(CHa),(C.-C,0 aryl), -C(=NRM)NH(CH2),(C,-C„ aryl), -C(O)NR.(CHR12).C(0)NR12(CH2)r0R12,
-C(O)NR12(CHR12)mS(C,-C4 alkyl), -C^NOCPJR^Rj,. -CR^CHRj.NR^SOjtCKjJ.A
-CR^CHRaNRJXOXOFQCiOXC,-^ alkyl), -CR^CHR^R^OXC,-^ alkoxy),, -Zj-R7, or-<CR17R1^mNRt(C(O))^w wherein p is 0 to 2, m is 1 to6, and q is 1 or2;
AP/P/ 9 7 / 0 1 0 8 0 ώΡ.00795
<Ic> <Id> (Ie)
(If)
AP/P/ 9 7 / 0 1 0 8 0
(Ii) <Ih>
&P .00795
-4wherein in said formulas (laHli), the structures of formulas (If) and (lg) are attached to formula I at carbons 5, 6, or 7 of said formulas (If) and (lg), the dashed line in formulas (Ic) and (Id) indicates a single bond or double bond, except R« is absent in formulas (Ic) and (Id) where said dashed line indicates a double bond, n is 0 to 2, p is
0 to 6, and m is 0 or 1;
Ra is -C(O)N(CH3)(OCHa) or -(CHJnOH wherein n is 0 to 4;
R« and Rj are independently selected from the group consisting of H, ethyl, -CO2H and -C(O)NHOH;
Rg is H, cyano, hydroxy, C,-C, alkyl, C,-C, alkoxy, -OC(0)(C,-C, alkyl) or 10 OC(O)(C,-CW aryl);
R7 is C,-C,o aryl or 5 to 10 membered heterocyclyl, wherein said R7 groups are optionally substituted by 1 to 3 substituents independently selected from halo, trifluoromethyf, cyano, nitro, -COjR,^ C,-C4 alkoxy, -OC(OXC,-C4 alkyl), -NRUC(O)(C,C4 aikyi), -CiOJNH*, -C(0)NHOH, -C(O)O(C,-C4 alkyl), C,-C4 alkyl, -S(O)rR„ wherein n is 0 to 2, benzoyl, -NR12RU, -OR^, C,-C, alkanoyi, -Υ,χΟ,-Ο^ aryl), -C(O)O(C,-C10 aryl), -NH(C.-C,0 aryl), -C(O)NH(C,-CW aryl), -CtOJNR^OiCHJJCg-C^ aryl) wherein n is 1 to 3, and -SOjNHfCg-C^ aryl);
R, is H, C,*C, alkyl, or aryl) wherein n is 0 to 4;
R, is H, -OR^, -(d-y^A or -CHjCXCHJ^A wherein m is 0 to 2;
R,o i® C,-C4 alkyl, -OR12, -CRi2R13OR12, -CR12R13NR12R13,
-CR12(OR13)CRt2R„ORl2, 2,2-dimethyl-1,3-dioxolan-4-yl, -NRt2C(O)NR12R13, -S(CR12R13)aCH3 wherein n is 0 to 5, -NR^CH^fpyridyf) wherein q is 0 or 1, -P(OXC,C4 alkoxy)*, -NR^, -NR^OR*. -NR12NR13R11, -NR^CH^, -OCH^R^CiOJR,,. -OC^CfONR,^, -OCHR^OCfOXC.-C, aikyi), -OCHR12C(OXCt-C3 alkoxy), or -NR^CH^J^, wherein m is 0 to 2;
R,, is H or A;
each and R^ is independently H or C,-C4 afcyl;
R„ is methyl or phenyl;
R^ is H, methyl, ethyl, or «CHjCHjOH;
Ru is H, methyl, ethyl, -CHjCiOJNHj, or -CHjCHjOH;
each R,7 is independently H, hydroxy, cyano, halo, Ο,-C, alkyl, Ο,-C, alkoxy,
-NR^, -CfOJOR*, -CtOJR^, -OkCR^, -C-CR^, -CHjNR^R», -CHjOR^
AP/P/ 9 7 / 0 1 0 8 0
AP. Ο Ο 7 9 5
-5-C(O)NR12RUl -C(Ys)H, or -CH2NR12C(O)C(O)NR12R13, provided that when R,7 is hydroxy then R1t is H or C,-C4 alkyl;
each R1g is independently H, fluoro, cyano, or C,-C4 alkyl, wherein said methyl is optionally substituted by 1 to 3 fluoro substituents;
or R,7 and R„ are taken together to form an oxo (=O) moiety;
R,e is phenyl, naphthyl, pyrrolyl, furanyl, thienyl, oxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, quinolinyi, isoquinolinyl, 5,6,7,8-tetrahydroquinoIinyl, or 5,6,7,8tetrahydroisoquinolinyl, wherein said R1# groups, except said phenyl, are optionally substituted by 1 to 3 R^ substituents, and wherein said phenyl R1# group is optionally substituted by 1 to 3 substituents independently selected from and R^;
R» is -0(0^, -C(O)C(O)R21, -0(0)0^,)0(0^ or
Xx/*21
R« is H, -ORa,-NHRa, -NHOH, -NHNH^ -(CHJXipbenyt) or^CH^Y^yridyi) wherein n is 0 to 4;
R,, is H, C,-C, alkyl, (phenyl) or -<CH2)BYj(pyridyi) wherein n is 0 to 4;
each R^ is independently halo, 0,-C, alkyl, 0,-0, alkoxy, C2-C, alkytenedioxy, trifluoromethyl, -NR12R13, nitro, -C(NRu)NRQRtt, -C(O)NR12RUC(O)R12, -C(NORt2)Rt3, -C(NCN)NR12R13, -CiNChOSR^, -{CHjXJCN) wherein m is 0 to 3, hydroxy, -0(0)^ -C(O)NR12OR13, -CiONR^R^,, -OC(O)NR12R13, -NR,2C(0)R12, -0(0)0(0)^^,
-COjR^ -SOjRw -SOjNR^R^, -C(O)NRt2R33> -NR^SOjR^ or -NR^CtONR^· each R>, is independently imidazolyl, pyrazolyl, triazolyl, tetrazotyl oxazolyl, '«oxazolyl, oxadiazotyl, thiadiazoiyt, thiazolyl, oxazoBdinyf, thiazofeflnyl, or imidazoftdinyl, wherein each of the foregoing R^ substituents is optionally substituted by 1 to 3 R^ substituents;
Ra is -NR12R13, -NH(C,-CW aryl), 0,-0, alkoxy, or C,-Cw aryloxy;
Rj, is H, C,-Ca alkyl or -(CH2)MY4(phenyi) wherein m is 0 to 4 and the phenyl moiety of said -(CH2)niY4(phenyl) Rj, group is optionally substituted by halo, -OR^, 0,C, alkanoyloxy, C,-C,o aryloxy, -NR12Rt3, -NH(C,-CM aryl), or -NHC(0XC,-C4 alkyl);
AP/P/ 9 7 / 0 1 0 80
AP .00795
-6each R27 is independently halo, -(CH2)pNR12C(O)CH3 wherein p is 1 to 5, nitro, cyano, -NR12R13, -CO2R12, -OR12, -COQNR^R,,, -NR,2C(NCN)S(C,-C, alkyl), -NR,2C(NCN)NR12R13, -NR12C(O)NR12R,3i -NR12C(O)C(O)NR,2R,3i -C(=NR12)NR12R„, -S(O)mCH3 wherein m is 0 to 2, -C(=NR,2)S(C1-C3 alkyl), -NR12SO2(C,-C3 alkyl),
-OC(O)R12, -OCiOJNRttR,,. -NR12SO2CF3, -NR12C(O)C(O)OR12, -NR12C(O)R,2,
-NR,2C(O)OR12i imidazoiyl, thiazolyl, oxazolyl, pyrazolyi, triazolyl, or tetrazolyl;
Rj, is K. fluoro, cyano, or C,-C2 alkyl, wherein said alkyl is optionally substituted by 1 to 3 substituents independently selected from halo, -CiOJNR^R,,. and -C{O)OR12;
is phenyl optionally substituted by 1 or 2 substituents independently selected from -NR12Ru, nitro, halo, -OR^ -NHR^ -NR^R^, and -0(0)0^ each Rao and Ra, is independently C,-C, alkyl or C2-C, alkenyl;
Rj2 is pyridtn-4-yl optionally substituted by 1 or 2 substituents independently selected from halo and C,-C4 alkyl;
each A is independently C,-C, alkyl, pyridyl, morpholinyl, piperidinyl, imidazoiyl, thienyl, pyrimidyl, thiazolyl, triazolyl, quinottnyl, phenyl, or naphthyl, wherein the foregoing A groups are optionally substituted with 1 to 3 R^ substituents, or A is -(CH,),S(Ct-C4. alkyl) wherein q is 1 or 2;
W is Ο, NOH, NNH* NOC(O)CHj, or NNHCfOJCH,;
Y, is O or S;
Y2 is O, NOH or Hj,·
Y3 is a bond or -CH=CK-;
Y4 is a bond, O, S, or -NH-;
Y8 is O, NRW NOR^, NCN, CfCN^ CR^NO^ CR^CfOjOR^ CR12C{0)NRt2R13, C(CN)NO2, C(CN)C(O)ORu or CiCNXXOjNR,^; and,
Z, is -NFL-, -{CHJ»-. -CHjC(O)NH-. -NHCHjC<OE -CHjCfYJCHj-, -CH=CH-,
-C-C-, -CH(Y,H)-t -C(YJ-, -CHaCCGE -CCTJCH,-, -CVJCtfJ-, -CH/JR^-, -CiY^R.iCHRJ,-, -NRcC{Y,XCHRu),-, -NHCH,-, -Y,-CH,-, -SOCH^. -CHjSO-, -SO2CH2-, -CHjSOj-, -OCfY,)-, -N=N-, -NKSO2-, -SOjNH-. -ΟΟ',ΧΧΥ,ΧΜΗ-, -NHC(O)O-, -OC(O)NH- or -NHC(O)NH-, wherein in said Zj moieties n is 0 to 4 and m is 1 to 3.
AP/P/ 9 7 / 0 1 0 8 0
AP. 0079 5
-7The present invention also relates to compounds of the formula
and to pharmaceutically acceptable salts thereof, wherein R and R, are as 10 defined above and X is -C(O)Cl. The compounds covered by the above formula are intermediates that are useful in the preparation of the compounds of formula I.
Specific compounds of formula I include those wherein Rj is -Z,-R7 wherein Z, is -CCQNH-, -CCOCH,-, -NHCff,)-, -Υ,-ΟΗ^, OC{0)-, -CH=CH-, ογ-0(Υ,)0(Υ,)-, and R7 is an optionally substituted aryl or heteroaryl group selected from phenyl, pyridyl, pyrazinyl, thienyl, pyrimidinyl, 2,4-dioxopyrimidin-5-yl1 isoxazolyl, isothiazolyl, pyridazinyl, and 1,2,4-triazinyl. More specifically, R7 is substituted phenyl, 2,6-dihak>substituted phenyl, or 3,5-dihalo-pyrid-4-yl.
Other specific compounds of formula I indude those wherein Rj is -Zj-R7 wherein Z> is -C^NHfCH^- or -NHCfOXCHjV, wherein n is 0 or 1, and R7 is phenyl or pyridyl optionally substituted by 1 to 3 substituents independently selected from halo, nitro, trifiuoromethyl, -COjCH* methyl, methoxy, and -C^OJNKj.
Other specific compounds of formula I indude those wherein Rj is -Z,-R7 wherein Z, is -O(O)NK- and R, is phenyl or pyridyl optionally substituted by 1 to 3 substituents independently selected from halo, C,-C4 alkyl, C,-C« alkoxy, cyano, carboxy and -OC(OXCt-C4 alkyl).
Other specific compounds of formula I indude those wherein R, is R^ wherein
Rj, is optionally substituted pyrimidinyl or optionaiy substituted pyridazinyl.
Other specific compounds offormula I include those wherein Rj ts a substituent of formula (lh) wherein R^, is -CfOJR^, -0(0)0(0^, or
AP/P/ 9 7 / 0 1 0 8 0
AP · 0 ϋ 7 9 5
wherein is -OR^, -NHR^, or -NHOH, and is H, C,-C3 alkyl, benzyl or pyridylmethyl.
Other specific compounds of formula I indude those wherein Rj is phenyl substituted by R^ wherein said R^ is oxadiazolyl, thiadiazolyl or tetrazotyl wherein said R^ groups are optionally substituted by C,-C2 alkyl, or wherein Rj is phenyl substituted by cyanomethyl, hydroxy or formyl.
Other specific compounds of formula I indude those wherein Rj is wherein Z3 is -C(Y,)NH-, and R7 is phenyl, pyrazinyl, pyrimidinyl, isoxazolyi, or pyridyl, wherein each of said R7 groups is optionally substituted by 1 to 3 substituents independently selected from halo, methoxycarbonyl, trifluoromethyl, benzoyl, acetyl, dimethylamino, hydroxy, nitro, methyl, cyano, methylsulphonyt, and methylthio.
Other specific compounds of formuia I indude those «Therein R, is -C(=NOC(O)R2S)Rai wherein R» is amino and R^ is H, C,-C, alkyl or -(CH^ipbenyl) wherein m is 1 to 4 and said phenyl moiety is optionally substituted by halo, hydroxy, acetoxy, amino or acetamido.
Other specific compounds of formula I include those wherein R, is -{CRt7Rtt)eiNRt(C{0)),R10 wherein m is 2, q is 2, each R57 is independently H, cyano or methyl, each R„ is independently H or methyl, R, is H or methyl, and Rw is amino, hydroxy, methoxy or hydroxyamino.
Other specific compounds of formula I indude those wherein R, is wherein m β 2, q '» 1, each R^ is independently H,
-CfOJNHj, -CmCH, cyano, formyl, hydroxymethyl, or trifluoromethyl, each R* is independently H or cyano, and is C,-C4 alkyl.
Other specific compounds of formula I indude those wherein R, is a substituent of formula (Ic), (Id) or (le), wherein, in formulas (Ic) and (Id), R, is H, hydroxy, C,-C4 aflcyl or C,-C4 alkoxy.
AP/P/ 97/01080
A.p .00795
-9Other specific compounds of formula I include those wherein R2 is -C(O)NR,(CHRl2)mC(O)NR,2(CH2)pOR12 or -C(O)NR12(CHR12)mS(C,-C4 alkyl), wherein R,. Rt2, m and p are as defined above.
Specific compounds of formula I include those selected from the group consisting of:
1-Cyciopentyf-3-ethyHH-indazole-5-ca!t>oxylic add (3,5-dichloro-pyridin-4-yl)-amide;
1-Cydopentyf-3-ethyl-1H-indazole-6-carboxylic add (2,6-dichloro-phenyI)-amide;
1-Cydobutyl-3-ethyl-1H-indazole-6-carboxylic add (3,5-dichloro-pyridin-4-yf}-amide;
3-EthyH-isopropyl-1H-indazole-6-carboxy1ic add (3,5-dichloro-pyridin-4-yl)-amide;
1-Cydopropylmethyl-3-ethyt-1H-indazole-6-carboxyfic add (3,5-d'tchloro-pyridin-4-yi}amide;
1-Cydohexyf-3-ethyt-1H-indazole-6-carboxylic add (3,5-dichloro-pyridin-4-yI)amide;
3- Ethyl-1-{4-fluoro-phenyi)-1H-indazote-6-carboxyfic add (3,5-dichloro-pyridin4- yf}-amide;
1-Cydopentyt-3-ethyt-1 H-indazole-6-carboxylic add hydroxycarbamoylmethyl-amkte; 1-Cydopentyl-3-ethyl-1K-indazole-6-cartx5xyttc add (2-methyisuffany)-ethyl}-arnide; 1-Cydopentyt-3-ethyHH-indazole-5-cart>oxytic add hydroxycarbamoylmethyl-methyl amide;
5- 1-Cydopenty1-3-ethyt-1H-indazole-e-carboxyfic add (1-benzytoxycarbamoyt-ethyt)amide;
R-1 -Cydopentyt-3-ethyf-1 K4ndazole-6-carboxytic add (1 -hydroxycarbamoyt-ethyf}amide; 1-Cyctopentyb3-ethyi-6-thiophen-2-yl-1H-indazote; 1-Cydopentyt-3-ethyt-6phenyf-1 H-indazoie; and the pharmaceutically acceptable salts of the foregoing compounds.
The present invention further relates to a pharmaceutical composition for the inhibition of phosphodiesterase (PDE) type IV or the production of tumor necrosis factor (TNF) comprising a pharmaceutically effective amount of a compound according to formula I, as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The present invention further relates to a method for the inhibition of phosphodiesterase (PDE) type IV or the production of tumor necrosis factor (TNF) by
AP/P/ 97 / 0 1 0 8 0
0 7 9 5
-10administering to a patient an effective amount of a compound according to formula I, as defined above, or a pharmaceutically acceptable salt thereof.
The present invention further relates to a pharmaceutical composition for the prevention or treatment of asthma, joint inflammation, rheumatoid arthritis, gouty arthritis, rheumatoid spondylitis, osteoarthritis, and other arthritic conditions; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, acute respiratory distress syndrome, cerebal malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption diseases, reperfusion injury, graft vs. host reaction, allograft rejections, fever and myalgias due to infection, such as influenza, cachexia secondary to infection or malignancy, cachexia secondary to human acquired immune deficiency syndrome (AIDS), AIDS, HIV, ARC (AIDS related complex), keloid formation, scar tissue formation, Crohn’s disease, ulcerative colitis, pyrosis, multiple sclerosis, type 1 diabetes mellitus, diabetes insipidus, autoimmune diabetes, systemic lupus erythematosis, bronchitis, chronic obstructive airway disease, psoriasis,
Bechet’s disease, anaphylactoid purpura nephritis, chronic glomerulonephritis, inflammatory bowel disease, leukemia, allergic rhinitis, dermatitis, depression or multiinfarct dementia, comprising a pharmaceuticafiy effective amount of a compound according to formula I, as defined above, or a pharmaceutically acceptable salt, thereof together with a pharmaceutically acceptable carrier.
The present invention further relates to a method of treating or preventing the foregoing specific diseases and conditions by administering to a patient an effective amount of a compound according to formula I, as defined above, or a pharmaceuticaly acceptable salt thereof.
The term halo, as used herein, unless otherwise indicated, includes fluoro, chloro, bromo or iodo. Preferred halo groups are fluoro, chloro and bromo.
The term alkyl, as used herein, unless otherwise indicated, indudes salivated monovalent hydrocarbon radicals having straight, cycfic or branched moieties. R is to be understood that where cyclic moieties are intended, at least throe carbons in said alkyl must be present Such cycfic moieties include cydopropyi, cydobutyl, cydopentyl, cyciohexyl and cycloheptyl.
The term alkoxy, as used herein, unless otherwise indicated, indudes -O-akyl groups wherein alkyl is as defined above.
AP/P/ 9 7 / 0 1 0 8 0
AP.00795
-11The term alkanoyl, as used herein, unless otherwise indicated, includes -C(O>alkyl groups wherein alkyl is as defined above.
The term aryl, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl.
The term 5 to 10 membered heterocyclyl, as used herein, unless otherwise indicated, includes aromatic and non-aromatic heterocyclic groups containing one or more heteroatoms each selected from O, S and N, wherein each heterocyclic group has from 5 to 10 atoms in its ring system. The heterocyclic groups include benzo-fused ring systems and ring systems substituted with one or more oxo moieties. An example of a 5 membered heterocyclic group is thiazolyl, and an example of a 10 membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyi, piperidino, morpholino, thiomorpholino and piperazinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazoiyl, pyrazinyl, tetrazolyl,.furyl, thienyl, isoxazoiyl and thiazolyl. Heterocyclic groups having a fused benzene ring include benzimidazolyl.
The term heteroaryt, as used herein, unless otherwise indicated, includes aromatic heterocyclic groups wherein heterocyclic is as defined above.
The phrase “pharmaceuticaRy acceptable salt(s), as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of formula I.
Certain compounds of formula i may have asymmetric centers and therefore exist in different enantiomeric forms. This invention relates to the use of all optical isomers and stereoisomers of the compounds of formula I and mixtures thereof. The compounds of formula I may also exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof.
Detailed Description of the Invention
The following reaction Schemes 1-8 fflustrate the preparation of the compounds of the present invention. In the following Schemes, unless otherwise indicated, R, R1,
R7, R*. and R,2 are as defined above. In the following Schemes, Me means methyl and Ph means phenyl.
AP/P/ 9 7 / 0 1 0 8 0
AP .θ 0 7 9 5
-12Scheme 1
VII
AP . Ο ο 7 9 5
-13Scheme 1 continued
X
AP .0 0 7 9 5
-14Scheme 2
AP/P/ 9 7 / 0 1 0 8 0 ftp . υ ύ 7 9 5
-15Scheme 3
AP. Ο ϋ 7 9 5
-16Scheme 4
ΑΡ/Ρ/ 9 7 / Ο 1 Ο 8 Ο
AP.00795
-17Scheme 5
XXX
I
R
AP/P/ 9 7 / 0 1 0 8 0
0 7 9 5
-1810
Scheme 6
XXXI
XXXII
XXXIII
AP/P/ 9 7 / 0 1 0 8 0
XXXIV
AP.00795
-19Scheme 7
XXXIII
XXXVII o
oo o
co cn
CL ί
<
AP.00795
-20Scheme 8
XVI--
XXXVII I
AP/P/ 9 7 / 0 1 0 8 0
XXXVIII
AP.00795
-21The preparation of compounds of formula I can be carried out by one skilled in the art according to one or more of the synthetic methods outlined in Schemes 1-8 above and the examples referred to below. In step 1 of Scheme 1, the carboxylic acid of formula II, which is available from known commercial sources or can be prepared according to methods known to those skilled in the art, is nitrated under standard conditions of nitration (HNOj/b^SC^, O’C) and the resulting nitro derivative of formula III is hydrogenated in step 2 of Scheme 1 using standard hydrogenation methods (Ffy Pd/C under pressure) at ambient temperature (20-25’C) for several hours (2-10 hours) to provide the compound of formula IV. In step 3 of Scheme 1, the amino benzoic add of formula IV is reacted with a base such as sodium carbonate under aqueous conditions and gently heated until mostly dissolved. The reaction mixture is chilled to a lower temperature (about O’C) and treated with sodium nitrate in water. After about 15 minutes, the reaction mixture is slowty transferred to an appropriate container holding crushed ice and a strong acid such as hydrochloric add. The reaction mixture is stirred for 10-20 minutes and then added, at ambient temperature, to a solution of excess t-butyl thiol in an aprotic solvent such as ethanol. The reaction mixture is acidified to a pH of 4-5 through addition of an inorganic base, preferably saturated aqueous Na2CO3, and the reaction mixture is allowed to stir at ambient temperature for 1-3 hours. Addition of brine to the reaction mixture, followed by filtration, provides the sulfide of formula V.
In step 4 of Scheme 1, the sulfide of formula V is converted to the corresponding indazoie carboxylic add of formula VI by reacting the sulfide of formula V with a strong base, preferably potassium t-butoxide, in dimethyl sulfoxide (DMSO) at ambient temperature. After stirring for several hours (1-4 hours), the reaction mixture is acidified with a strong add, such as hydrochloric or sulfuric add, and then extracted using conventional methods. In step 5 of Scheme 1, the indazoie carboxylic add of formula VI is converted to the corresponding ester of formula VII by conventional methods known to those skilled in the art In step 6 of Scheme 1, the compound of formula VIII is provided through alkylation of the ester of formula Vii by subjecting the ester to conventional alkylation conditions (strong base/various alkylating agents and, optionally, a copper catalyst such as CuBrJ in a polar aprotic solvent, such as tetrahydrofuran (THF), N-methylpyrrofidinone or dimethylformamide (DMF), at ambient or higher temperature (25-200’C) for about 6-24 hours, preferably about 12 hours. In
AP/P/ 9 7 / 0 1 0 8 0
AP.00795
-22step 7 of Scheme 1, the compound of formula VIII is converted to the corresponding alcohol of formula IX by following conventional methods known to those skilled in the art for reducing esters to alcohols. Preferably, the reduction is effected through use of a metal hydride reducing agent, such as lithium aluminum hydride, in a polar aprotic solvent at a low temperature (about 0®C). In step 8 of Scheme 1, the alcohol of formula IX is oxidized to the corresponding aldehyde of formula X according to conventional methods known to those skilled in the art. For example, the oxidation can be effected through use of a catalytic amount of tetrapropylammonium pemrtenate and excess N-methylmorpholine-N-oxide, as described in J. Chem. Soc., Chem. Commun.,
1625 (1987). in an anhydrous solvent, preferably methylene chloride. In step 9 of
Scheme 1, the ester of formula VIII is converted to the corresponding acid of formula XI by methods known to those skilled in the art, such as by treating the starting compound with sodium hydroxide in methanol and heating the mixture to reflux for several hours (2 or more hours). The add of formula Xl, like the aldehyde of formula
X, is a useful intermediate for the preparation of various compounds of formula I.
Scheme 2 illustrates an alternative method of preparing the aldehyde of formula
X and the add of formula XI, as well as a method of preparing the compound of formula XVII. In step 1 of Scheme 2, the compound of formula XII is nitrated using conventional nitration conditions (nitric and sulfuric add) to provide the compound of formuia XIII. In step 2 of Scheme 2, the nitro derivative of formula XIII is reduced to the corresponding amine of formula XIV according to conventional methods known to those sfcfted in the art Preferably, the compound of formula XIII is reduced to the amine of formula XIV using anhydrous stannous chloride in an anhydrous aprotic solvent such as ethanol. In step 3 of Scheme 2, the amine of formula XIV is converted to the corresponding indazote of formula XV by preparing the corresponding diazonium tetrafluoroborates as described in A. Roe, Organic Reactions, Vol. 5, Wiley, New York, 1949, pp. 198-206, foSowed by phase transfer catalyzed cydzation as ctescrfoed in R. A. Bartsch and I. W. Yang, J. Het Chem. 21, 1063 (1984). In step 4 of Scheme 2, alkylation of the compound of formula XV is performed using standard methods known to those skilled in the art (i.e. strong base, polar aprotic solvent and an alkyl halide) to provide the N-akytated compound of formula XVI. In step 5 of Scheme 2, the compound of formula XVI is subjected to metal halogen exchange employing an alkyl lithium, such as n-butyt lithium, in a polar aprotic solvent such as THF, at low
AP/P/ 9 7 / 0 1 0 8 0
AP. Ο ϋ 7 9 5
-23temperature (-50”C - 1OO°C (-78eC preferred)) followed by quenching with DMF at low temperature and warming to ambient temperature to provide the aldehyde intermediate of formula X, or the mixture containing the compound of formula XVI is quenched with CO2, warmed to ambient temperature, and then quenched with an add, such as hydrochloric add, to provide the add of formula XI. In step 6 of Scheme 2, the compound of formula XVI is converted to a compound of formula I wherein Rj is R1t which, as defined above, represents an aryl, heteroaryl, or heterocycfic moiety. In step 6 of Scheme 2, the compound of formula XVII is prepared by reacting the compound of formula XVI with a compound of formula R18-B(OH)2, wherein R^ is as defined above, in the presence of PdiPPhJ, in aqueous Na2CO3 at reflux for about 4 hours.
Scheme 3 illustrates the preparation of a compound of formula I wherein R, is
H and Ra is -C(O)NHR7 wherein R7 is as defined above. In step 1 of Scheme 3, the compound of formula XVIII is treated with boron trifluoride etherate in ethanoWtee chloroform at a temperature of about -20*C. After a short period, such as about 5 minutes, t-butyl nitrite is added to the mixture and the reaction is stirred at about 0C for about 2 hours. Potassium acetate followed by 18-crown-6 are then added to provide the compound of formula XIX (1H-indazole-€-cartx)xyfic add). In step 2 of Scheme 3, the compound of formula XIX is treated with concentrated sulfuric add in methanol at reflux for about 8 hours followed by stirring at ambient temperature for about 18 hours to provide the compound of formula XX. In step 3 of Scheme 3, the compound of formula XX is reacted with a compound of the formula R-X, wherein R is as defined above and X is a leaving group such as chloro, bromo, or iodo, preferably *
bromo, in the presence of sodium hydride in DMF for about 10-24 hours, preferably 24 hours, at ambient temperature to provide the ester of formula XXI. In step 4 of Scheme
3, the ester of formula XXI is converted to the add of formula XXII in accord with the procedure of step δ of scheme 1. In step 5 of Scheme 3, the compound of formula XXII b treated with thionyl chloride and DMF (as a catalyst) in anhydrous toluene at reflux for about 3 hours to provide the corresponding add chloride. Separately, a compound of the formula Ry-NHj, wherein R7 b as defined above, b added to a mixture of sodium hydride in anhydrous THF which is cooled to a temperature of about 0*C.
To thb second mixture, the add chloride, referred to above, in THF b added and the mixture b stirred at ambient temperature for a period of 4-24 hours to provide the compound of formula XXIII.
AP/P/ 9 7 / 0 1 0 8 0
AP.00795
-24Scheme 4 illustrates the preparation of compounds of formula I wherein R2 is -C(O)NHR7 or -C(O)NH(CH2)nR7, wherein n is 1 to 4, and R7 is as defined above. In step 1 of Scheme 4, the add of formula XI is converted to the corresponding add chloride of formula XXIV by treating the starting compound with thionyl chloride and
DMF (as a catalyst) in anhydrous toluene at reflux for about 3 hours. The add chloride of formula XXIV can be converted to the compound of formula XXV by reacting the starting compound with a compound of the formula R^NH^ wherein R7 is as defined above, in the presence of sodium hydride in anhydrous THF at a temperature of about O’C, followed by warming to ambient temperature, for a period of 4-24 hours. This method is preferred where R7 is substituted or unsubstituted pyridinyl. In the alternative, the compound of formula XXIV can be converted to the compound of formula XXV by reacting the starting compound with a compound of the formula R7NHj, wherein R7 is as defined above, in the presence of sodium hydride in anhydrous DMF at ambient temperature for a period of 4-24 hours. This method is preferred where R7 is substituted or unsubstituted pyrimidinyl. in the alternative, the compound of formula XXIV can be converted to the compound of formula XXV by adding a compound of the formula R7-NHj, wherein R7 is as defined above, to the reaction mixture in which the acid chloride is prepared and then heating the mixture to a temperature of about 200*C for a short period, such as about 15 minutes.
In step 3 of Scheme 4, the compound of formula XXIV is converted to the compound of formula XXVI, wherein n is 1 to 4 and R, is as defined above, by reacting the starting compound with a compound with a compound of the formula H2N-C(O)NH(CH2)nR7, wherein n is 1 to 4, and R7 is as defined above, in the presence of triethylamine, and optionalty dimethytaminopyridine (DMAP), in methylene chloride at ambient temperature for about 10-48 hours. In the alternative, the compound of formula XXIV can be converted to the compound of formula XXVI by reacting the starting compound with a compound of βιβ formula KjNRCHjX'Rt, wherein n is 1 to 4, and R7 is as defined above, in anhydrous pyridine at about 40’C for about 1 hour. This alternative method for step 3 of Scheme 4 is preferred where R, is a nitrogen30 containing heterocyclic moiety such as pyridinyl.
Scheme 5 Blustrates the preparation of compounds of formula I wherein R, b
-Z,-R7 wherein Z, b -C(O)NH- and R, b aryl, such as phenyl or naphthyl, substituted by -C(O)NHOH. Scheme 5 begins with a compound of the formula XXVII, wherein X
08010//6 /d/dV
AP.00795
-25is an aryl moiety, as the starting material. The compound of formula XXVII is prepared according to the method illustrated in Scheme 4. In step 1 of Scheme 5, the compound of formula XXVII is hydrolyzed to the corresponding acid of formula XXVIII which can be done according to methods known to those skilled in the art, such as by treating the compound of formula XXVII with sodium hydroxide in methanol at reflux for about 30 minutes to 1 hour. In step 2 of Scheme 5, the acid of formula XXVII, is converted to the compound of formula XXIX by treating the arid with 1-(3-dimethyIaminopropyI)-3ethylcarbodiimide hydrochloride andO-benzylhydroxylamine hydrochloride in methylene chloride at ambient temperature for about 4-24 hours. In step 3 of Scheme 5, the compound of formula XXIX is converted to the compound of formula XXX by treating the starting compound with 10% Pd/C in ethyl acetate and methanol under an Hj atmosphere (about 30 psi) at ambient temperature for about 30 minutes to 1 hour.
Scheme 6 illustrates the preparation of compounds of formula I wherein Rj is -C(O)NR12(CHRl2)mSR (compound of formula XXXI), wherein R » C,-C4 alkyl, m is 1 to6, and R^ is as defined above, or wherein Rj » -C(O)NR^CHR^C(O)NHOMe (compound of formula XXXIV), wherein R12 is as defined above, m is 1 to 6, and Me is methyl, in step 1 of Scheme 6, the compound of formula XI is treated with a compound of the formula H2N-(CHR12)mSR, wherein R“, R^ and m are as defined above. 1 -(3<iimethyiaminopropyf)-3-ethykarbodiimide hydrochloride, and triethylamine in methylene chloride at ambient temperature for a period of about 18 hours to provide the compound of formula XXXI. in step 2 of Scheme 6, the compound of formula XXXII is prepared in accord with the method Bustrated in Scheme 4. tn step 3 of Scheme 6, the compound of formula XXXIII is prepared by heating to refiux the compound of formula XXXII in ethanol or methanol and sodium hydroxide for about 1 hour. In step
4 of Scheme 8, the compound of formula XXXIV is prepared by treating the compound of formula XXXIII with methoxylamine hydrochloride, H3-dimethytaminopropyI)-3ethytearbocfimide hydrochloride, 1-hydroxybenzotriazoie hydrate and triethylamine in methylene chloride at ambient temperature for a period of about 18 hours.
Scheme 7 illustrates the preparation of compounds of formula I wherein R, is
-C(O)NH(CHR12)WC(O)N(CH3)OH (compound of formula XXXV), wherein m is 1 to 6, or wherein Rj is -C(0)NR12(CHRt2)eiC(0)NHOH (compound of formula XXXVII), wherein
Ru is as defined above and m is 1 to 6. In step 1 of Scheme 7, the compound of formula XXXV is prepared by treating the compound of formula XXXII with sodium and
AP/P/ 9 7 / 0 1 0 8 0
AP.00795
-26N-methylhydroxylamine hydrochloride in methanol at ambient temperature for about 16 hours. In step 2 of Scheme 7, the compound of formula XXXIII is prepared in accord with step 3 of Scheme 6. In step 3 of Scheme 7. the compound of formula XXXVI is prepared by treating the compound offormula XXXIII with O-benzylhydroxylamine, 15 hydroxybenzotriazole hydrate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and triethylamine in methylene chloride at ambient temperature for a period of about 18 hours. In step 4 of Scheme 7, the compound of formula XXXVII is prepared by treating the compound of formula XXXVI with 10% Pd/C in methanol and ethyl acetate under a K, atmosphere (about 30 psi) at ambient temperature for about
30 minutes to 1 hour.
Scheme 8 illustrates the preparation of compounds of formula XXXVIII. In step 1 of Scheme 8, the compound of formula XVI, which is prepared according to the method of Scheme 2, is treated with n-butyl fithium in anhydrous THF at a low temperature, such as about -78*C, for about 30 minutes, followed by quenching the mixture with a compound of the formula R/-CN, wherein R7 is as defined above, and allowing the mixture to warm to ambient temperature over a period of about 30 minutes to 1 hour to provide the compound of formula XXXVIII. This method of preparing the compound of formula XXXVIII is preferred for compounds in which R7 is a nitrogencontaining heteroaryl moiety. Steps 2 and 3 of Scheme 8 Kustrate an alternative method of preparing the compound of formula XXXVIII which is preferred for those compounds in which R? is a substituted or unsubstituted aryl moiety. In step 2 of Scheme 8, the compound of formula XVI is treated as descrfoed in step 1 of Scheme 8 except a compound of the formula R^CCOJH is substituted for the compound of formula Rj-CN, wherein R7 is as defined above. In step 3 of Scheme 8, the compound of formula XXXIX is oxidized to provide the compound of formula XXXVII! according to methods known to those skilled in the art as described in step 8 of Scheme 1.
The compounds of formula I can also be prepared foflowing one or more synthetic methods that are disclosed in issued patents or published patent appfications. In particular, using the intermediates described in Schemes 1-8, referred to above, in particular the intermediates of formulas VIII, X, XI, XVI, and XXIV, those skilled in the art can prepare the compounds of formula I using analogous synthetic methods that have been descrfoed for compounds in which a phenyl ring is substituted for the indazole ring in the compounds of formula I. Such analogous synthetic methods are
AP/P/ 97/01080
AP.00795
-27disclosed in the following issued patents and published patent applications: United States Patent 5,449,676 (issued September 12,1995); United States Patent 5,459,151 (issued October 17,1995); United States Patent 5,491,147 (issued February 13,1996); European patent application EP 470,805 (published February 12, 1992); European patent application EP 497,564 (published August 5,1992); European patent application EP 723,962 (published July 15, 1996); WO 92/00968 (published January 23, 1992); WO 93/15044 (published August 5,1993); WO 93/15045 (published August 5,1993); WO 93/18024 (published September 16, 1993); WO 93/25517 (published December 23, 1993); WO 94/02465 (published February 3, 1994); WO 95/01338 (published
January 12, 1995); WO 95/04045 (published February 9, 1995); WO 95/04046 (published February 9, 1995); WO 95/05386 (published February 23, 1995); WO 95/20578 (published August 3,1995); WO 95/22520 (published August 24,1995); WO 95/27692 (published October 19, 1995); WO 96/00218 (published January 4, 1996); and WO 96/21435 (published July 18, 1996). The foregoing issued patents and published European and PCT international patent applications are incorporated herein by reference in their entirety.
Specifically, the compounds of formula , wherein Rj is -Zj-R7 can be prepared by following analogous synthetic methods disclosed in WO 94/02485, WO 95/01338, WO 93/25517, WO 95/20578, WO 96/00218 and EP 497,564, each of which is referred to above. The compounds of formula I wherein Rj is FL,, can be prepared by following analogous synthetic methods disclosed in United States Patent 5,491,147, WO 95/27692 and WO 95/22520, each of which is referred to above. The compounds of formula I wherein R, is a substituent of formula (If) or (lg) can be prepared by following analogous synthetic methods disclosed in WO 95/22520, which is referred to above.
The compounds of formula 1 wherein Rj is a substituent of formula (lh) can be prepared by following analogous synthetic methods disclosed in United States Patent 5,459,151, which is referred to above. The compounds of formula I wherein R, is -C(=NOC(O)Rai)Ra, can be prepared by following analogous synthetic methods disclosed in EP 470,805, which is referred to above. The compounds of formula I wherein Rj is -(CRi7Rtt)mNRt(C(O)),Rw can be prepared by following analogous synthetic methods disclosed in WO 92/00968, WO 95/05386, WO 93/15044, and WO
93/15045, each of which is referred to above. The compounds of formula I wherein R, » -CF^7RttCHReNR^O2(CH2),A, -CR17RwCHR2tNRtP(OXOR12)C(OXC1-C4 alkyl), or
AP/P/ 9 7 / 0 1 0 8 0
AP.00795
-28-CR^R^CHRaNRjPtOJiC,^ alkoxy), can be prepared by following analogous synthetic methods disclosed in WO 95/05386, which is referred to above. The compounds of formula I wherein R2 is a substituent of formula (Ic), (Id) or (le) can be prepared by following analogous synthetic methods disclosed in WO 93/18024, which is referred to above. The compounds of formula I wherein R, is a substituent of formula (li) can be prepared by following analogous synthetic methods disclosed in EP 723,962, which is referred to above. The compounds of formula I wherein R, is -C(=NRXj)NH(CH2)f(Cj-Cw aryl) can be prepared by following analogous synthetic methods disclosed in WO 96/21435, which is referred to above.
The compounds of formula I can be resolved into separate enantiomers by using a chiral LC technique according to the following conditions: column: Chiralcel® OD (250 x 4.6 mm); mobile phase: 50:50:0.1 (Hexane:2-propanol:diethylamine); flow rate: 1 mL/minute; detection: UV (230 nm); temperature: ambient (20-25*C); injection volume: 20 pL. The compounds of formula I can also be resolved into separate enantiomers according to other techniques famiGar to those skffied in the art, including those described in J. March, Advanced Organic Chemistry, (4th Edition, J. Wiley & Sons), 1992, pages 118-125.
The compounds of formula I that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic adds. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of formula I from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an afcaGne reagent and subsequently convert the latter free base to a pharmaceuticaBy acceptable add addition salt The add addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantial equivalent amount of the chosen mineral or organic add in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon evaporation of the solvent, the desired sofid salt is readily obtained. The desired add addition salt can also be precipitated from a solution of the free base in an organic solvent by adding to the solution an appropriate mineral or organic add. Cationic salts of the compounds of formula I are simBarty prepared except through reaction of a carboxy group with an appropriate cationic salt reagent such as sodium, potassium, calcium, magnesium, ammonium, N,N*AP/P/ 9 7 / 0 1 0 8 0
AP . Ο Ο 7 9 5
-29dibenzylethylenediamine, N-methylglucamine (meglumine), ethanolamine, tromethamine, or diethanolamine.
For administration to humans in the curative or prophylactic treatment of inflammatory diseases, a variety of conventional routes may be used including orally, parenterally, topically, and rectally (suppositories), in single or divided doses. Oral dosages of a compound of formula I or a pharmaceutically acceptable salt thereof (the active compounds) are generally in the range of 0.1 to 1000 mg daily for an average adult patient (70 kg), in single or divided doses. Individual tablets or capsules should generally contain from 0.1 to 100 mg of active compound, in a suitable pharmaceutically acceptable vehicle or carrier. Dosages for intravenous administration are typically within the range of 0.1 to 10 mg per single dose as required. For intranasal or inhaler administration, the dosage is generally formulated as a 0.1 to 1% (w/v) solution. In practice the physician will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient The above dosages are exemplary of the average case but there can, of course, be individual instances where higher or lower dosage ranges are merited, and alt such dosages are within the scope of this invention.
For administration to humans for the inhibition of TNF, a variety of conventional routes may be used including oraBy, parenterafiy, topicaBy, and rectaHy (suppositories), in single or divided doses, tn general, the active compound we be administered oraBy or parenteraly at dosages between about 0.1 and 25 mg/kg body weight of the subject to be treated per day, preferably from about 0.3 to 5 mg/kg, in single or divided doses. However, some variation in dosage wifi necessarily occur depending on the condition of the subject being treated. The person responsible for administration wifl, in any event, determine the appropriate dose for the individual subject
For human use, the active compounds of the present invention can be administered alone, but w· geoeraBy be administered in an admixture wfth a pharmaceutical diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, the active compounds can be administered oraBy in the form of tablets containing such excipients as starch or lactose, or in capsules either alone or in admixture with excipients, or in the form of efixirs or suspensions containing flavoring or coloring agents. The active compounds may be Injected parenterally; for example, intravenously, intramuscularly
AP/P/ 9 7 / 0 1 0 8 0
AP. ο Ο 7 9 5
-30or subcutaneously. For parenteral administration, the active compounds are best used in the form of a sterile aqueous solution which may contain other substance; for example, enough salts or glucose to make the solution isotonic.
Additionally, the active compounds may be administered topically when treating inflammatory conditions of the skin and this may be done by way of creams, jellies, gels, pastes, and ointments, in accordance with standard pharmaceutical practice.
The therapeutic compounds may also be administered to a mammal other than a human. The dosage to be administered to a mammal will depend on the animal species and the disease or disorder being treated. The therapeutic compounds may be administered to animals in the form of a capsule, bolus, tablet or liquid drench. The therapeutic compounds may also be administered to animals by injection or as an implant Such formulations are prepared in a conventional manner in accordance with standard veterinary practice. As an alternative the therapeutic compounds may be administered with the animal feedstuff and for this purpose a concentrated feed additive or premix may be prepared for mixing with the normal animal feed.
The ability of the compounds of formula I or the pharmaceutically acceptable salts thereof to hhftxt PDE IV may be determined by the following assay.
Thirty to forty grams of human lung tissue is placed in 50 mi of pH 7.4
Tris/phenyfanethyisdfonyf fluoride (PMSF)/sucrose buffer and homogenized using a
Tekmar Ttssumizer® (Tekmar Co., 7143 Kemper Road, Cincinnati, Ohio 45249) at fun speed for 30 seconds. The homogenate is centrifuged at 48,000 x g for 70 minutes at 4*C. The supernatant is tittered twice through a 0.22 pm fitter and applied to a Mono-Q FPLC column (Pharmacia LKB Biotechnology, 800 Centennial Avenue, Piscataway, New Jersey 08854) pre-equWxated with pH 7.4 Tris/PMSF Buffer. A flow rate of 1 ml/minute n used to apply the sample to the column, followed by a 2 ml/minute flow rate for subsequent washing and elution. Sample is ekrted using an increasing, stepwise Nad gradient in the pH 7.4 Tris/PMSF buffer. Eight ml fractions are coBected. Fractions are assayed for specific PDE^ activity determined by fHJcAMP hydrolyse and the abSty of a known PDE^ inhibitor (e.g. rofipram) to inhibit that hydrolyse.
Appropriate fractions are pooled, diluted with ethylene glycol (2 ml ethylene gfycol/5 ml of enzyme prep) and stored at -20*C until use.
Compounds are dissolved in cfimethylsuffoxide (DMSO) at a concentration of 10 mM and diluted 1:25 in water (400 pM compound, 4% DMSO). Further serial dilutions
AP/P/9 7/0 1 0 8 0
AP,00795
-31are made in 4% DMSO to achieve desired concentrations. The final DMSO concentration in the assay tube is 1%. In duplicate the following are added, in order, to a 12 x 75 mm glass tube (all concentrations are given as the final concentrations in the assay tube).
| 5 | i) | 25 fA compound or DMSO (1%, for control and blank) |
| «) | 25 fA pH 7.5 Tris buffer | |
| iii) | [sH]cAMP (1 μΜ) | |
| iv) | 25 fA PDEIV enzyme (for blank, enzyme is preincubated in boiling water for 5 minutes) | |
| 10 | The | reaction tubes are shaken and placed in a water bath (37’C) for 20 |
minutes, at which time the reaction is stopped by placing the tubes in a boiling water bath for 4 minutes. Washing buffer (0.5 mi, 0.1M 4-{2-hydroxyethy1}-1-piperazineethanesulfonic add (HEPES)/0.1M nad, pH 8.5) is added to each tube on an ice bath. The contents of each tube are filed to an AFF-Gel 601 column (Biorad Laboratories,
P.O. Box 1229, 85A Marcus Drive, Melvile, New York 11747) (boronate affinity gel, 1 ml bed volume) previously equilibrated with washing buffer. [ViJcAMP is washed with 2 x 6 ml washing buffer, and [Ψβδ’ΑΜΡ is then eluted with 4 ml of 0.25M acetic add. After vortextng, 1 ml of the elution is added to 3 ml sdntfllation fluid in a suitable vial, vortexed and counted for [Vi], % inhibition = 1 - average com (test compound - average cmp (blank) average cpm (control) - average cpm (blank)
ΙΟ,β is defined as that concentration of compound which inhibits 50% of specific hydrolysis of fHJcAMP to fHJS’AMP.
The ability of the compounds I or the pharmaceuticaBy acceptable salts thereof to inhibit the production of TNF and, consequently, demonstrate their effectiveness for treating disease involving the production of TNF is shown by the foflowing in vitro assay:
Peripheral blood (100 mis) from human volunteers is collected in ethytenediaminetetraacetic add (EDTA). Mononuctear cells are isolated by
FICOLL/Hypaque and washed three tones in incomplete HBSS. CeBs are resuspended in a final concentration of 1 x 10* cells per mi in pre-warmed RPMI (containing 5%
FCS, glutamine, pen/step and nystatin). Monocytes are plated as 1 x 10* cels in 1.0 ml in 24-wefl plates. The celts are incubated at 37*C (5% carbon dioxide) and allowed
AP/P/ 9 7 / 0 1 0 8 0
AP . 0 0 7 9 5
-32to adhere to the plates for 2 hours, after which time non-adherent cells are removed by gentle washing. Test compounds (10//1) are then added to the cells at 3-4 concentrations each and incubated for 1 hour. LPS (10//1) is added to appropriate wells. Plates are incubated overnight (18 hrs) at 37’C. At the end of the incubation period TNF was analyzed by a sandwich ELISA (R&D Quantikine Kit). IC» determinations are made for each compound based on linear regression analysis.
The following Examples illustrate the invention. In the following Examples, min.· means minute(s), psi means pounds per square inch, h means hour(s), equiv means equivalents), and cone. means concentrated.
PREPARATION 1
1-Cvdopentvl-3-ethvl-1H-indazole-6-carboxvric add methvl ester
A. 3-Nrtro-4-propyt-benzoic add. 9.44 g (57.5 mmol, 1.0 equiv) of 4propylbenzoic add were partially dissolved in 50 mL concentrated HjSO, and chilled in an ice bath. A solution of 4.7 mL (74.7 mmol, 1.3 equiv) concentrated HNO, in 10 mL'concentrated HjSO4 was added dropwise over 1-2 min. After stirring 1 hour at O’C, the reaction mixture was poured into a 1 L beaker half foil with ice. After stirring 10 min., the white solid that formed was filtered, washed 1 x HjO, and dried to give 12.01 g (100%) of the title compound: mp 106-109’C; IR (KBr) 3200-3400, 2966, 2875, 2667, 2554,1706,1618,1537,1299. 921 cm'1; Ή NMR (300 MHz, DMSO-dJ 40.90 (t, 3H >7.4 Hz), 1.59 (m, 2H), 2.82 (m, 2H), 7.83 (d. 1H,> 8.0 Hz), 8.12 (dd. 1H, >1.7, 8.0 Hz), 8.33 (d, 1H, >1.7 Kz); “C NMR (75.5 MHz, DMSOdJ 4 14.2, 23.7, 34.2, 125.4, 130.5, 132.9, 133.8, 141.4, 149.5, 165.9; AnaL calcd for 0,οΗ„Ν04·1ΜΗ,0: C, 56.20; H, 5.42; N, 6.55. Found: C, 56.12; H, 5.31; N, 6.81.
B. 3-Amino-4-prppvl-benzoic add. A mixture of 11.96 g (57.2 mmol) 3-nitro25 4-propyt-benzoic acid and 1.5 g 10% PdZC, 50% water wet, In 250 mL CH,OH was placed on a Parr hydrogenation apparatus and shaken under 25 psi Hj at ambient temperature (20-25’C). After 1 hour, the reaction mixture was fltered through Ce&te®(trademarkXSfO2 based Staring agent), and the filtrate concentrated and dried to give .9.80 g (96%) of a pale yelow crystaffine so8d: mp 139.5-142.5’C; IR (KBr)
3200-2400, 3369, 3298,2969,2874, 2588,1690,1426,1260,916,864 cnV1; Ή NMR (300 MHz, DMSO-d,) 4 0.90 (t, 3H. >7.2 Hz), 1.52 (m, 2H), 2.42 (m, 2H), 5.08 (br s.
2H), 6.96 (d, 1H, >7.8 Hz), 7.05 (dd, 1H. >1.7, 7.8 Hz), 7.20 (d, 1H. >1.7 Hz), MS
AP/P/ 9 7 / 0 1 0 8 0
ΛΡ.00795
-33(Cl, NHj) m/z 180 (M+H*. base); Anal, calcd for C10H13NO2«1/3H2O: C, 64.85; N, 7.89; N, 7.56. Found: C, 64.69; H, 7.49; N, 7.86.
C. 3-Carboxy-6-propyl-benzenediazo t-butyl sulfide. A mixture of 8.80 g (49.1 mmol, 1.0 equiv) 3-amino-4-propyl-benzoic add and 2.34 g (22.1 mmol, 0.45 equiv) sodium carbonate in 55 mL IfyO was heated gently with a heat gun until mostly dissolved. The reaction mixture was chilled in an ice bath, and a solution of 3.73 g (54.0 mmol, 1.0 equiv) sodium nitrite in 27 mL HjO was added dropwise. After 15 minutes, the reaction mixture was transferred to a dropping funnel and added over 10 minutes to a beaker containing 55 g of crushed ice and 10.6 mL concentrated HCI.
After stirring 10 minutes, the contents of the beaker were transferred to a dropping funnel and added over 5 minutes to a room temperature solution of 5.31 mL (47.1 mmol, 0.96 equiv) t-butyl thiol in 130 mL ethanol. The pH was adjusted to 4-5 by addition of saturated aqueous Na2CO3 solution, and the reaction mixture was allowed to stir 1 hour at ambient temperature (20-25’C). 200 mL brine were added, and the mixture was filtered. The solid was washed 1 x HjO and dried overnight to give 12.25 g (89%) of a brown/rust colored powder (caution-stench): mp 102’C (dec); IR (KBr) 3200-2400,2962, 2872,2550,1678,1484,1428,1298,1171 cm-’; Ή NMR (300 MHz, DMSO-dJ δ 0.84 (t, 3H, J=7.3 Hz), 1.48 (m, 2H), 1.55 (s, 9H), 2.42 (m, 2H), 7.29 (d, 1H, 3=1.6 Hz), 7.50 (d, 1H, 3=8.0 Hz), 7.86 (dd. 1H, 3=1.7, 7.9 Hz), 13.18 (br s, 1H);
MS (thermospray, NH4OAc) m/z 281 (M+H+, base); Anal, calcd for CMHa0N2O2S: C, 59.96; H. 7.19; N, 9.99. Found: C, 59.71; H, 7.32; N. 10.02.
D. 3-£thvF1H4ndazole-6-carboxvfic aod. A solution of 12.0 g (42.8 mmol, 1.0 equiv) 3-carboxy-6-propyl-benzenediazo t-butyl sulfide in 150 mL dimethylsulfoxide (DMSO) was added dropwise over 15 minutes to an ambient temperature solution of
44.6 g (398 mmol, 9.3 equiv) potassium tert-butoxide in 200 mL DMSO. After stining hours at ambient temperature, the reaction mixture was poured into 1.5 L of 0*C 1N HCI, stined 5 minutes, then extracted 2 x 350 mL ethyl acetate. The ethyl acetate extracts (caution - stench) were combined, washed 2 x 250 mL HjO, and dried over MgSO4. Filtration, concentration of filtrate and drying gave a tan sofid, which was triturated with 1L of 1:3 E^O/Hexanes and dried to give 7.08 g (87%) of a tan crystaSne powder, mp 248-251 *C; IR (KBr) 3301.3300-2400,2973.2504,1702,1455, 1401,1219 cm ’; Ή NMR (300 MHz, DMSO-dJ δ 1.31 (t, 3H, 3=7.6 Hz), 2.94 (q, 2H, 3=7.6 Hz). 7.63 (dd, 1H, 3=1.1,8.4 Hz), 7.81 (d, 1H, 3=8.4 Hz), 8.06 (d, 1H, 3=1.1. Hz).
AP/P/ 9 7 / 0 1 0 8 0
AP.00795
-3412.95 (br s, 1H); MS (Cl, NHj) m/z 191 (M+H+. base); Anal, calcd for C,0H10N2O2: C, 63.14; H, 5.30; N, 14.73. Found: C, 62.66; H, 5.42; N, 14.80.
E. 3-EthvH H-indazole-6-carboxvlic add methvl ester. 8.78 g (45.8 mmol,
1.1 equiv) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added in one portion to an ambient temperature solution of 7.92 g (41.6 mmol, 1.0 equiv) 3ethyF1H-indazole-6-carboxylic add, 16.9 mL (416 mmol, 10 equiv) methanol and 5.59 g (45.8 mmol, 1.1 equiv) dimethylaminopyridine (DMAP) in 250 mL CH2Cl2. After 18 hours at room temperature, the reaction mixture was concentrated to 150 mL, diluted with 500 mL ethyl acetate, washed 2 x 100 mL 1N HCI, 1 x 100 mL H2O, 1 x 100 mL brine, and dried over NajSO4. Fiftration, concentration of filtrate and drying gave 7.8 g of a brown solid, which was purified on a silica gel column (30% to 50% ethyl acetate/hexane gradient) to give 6.41 g (75%) of a tan solid: mp 107-108°C; IR (KBr) 3100-2950, 1723, 1222 cm'1; Ή NMR (300 MHz, CDClj) <5 8.19 (m, 1H). 7.7-7.8 (m, 2H), 3.96 (s, 3H), 3.05 (q, 2H, J=7.7 Hz), 1.43 (t, 3H. 7.7 Hz); MS (Cl, NH,) mfz 205 . 15 (M+H*, base); Anal, calcd for Ο,,Η^Ο^: C, 64.70; H, 5.92; N, 13.72. Found: C,
64.88; H, 6.01; N, 13.96.
F. 1-Cvck>pentvi-3-ethYl-1H-indazoie-€-carboxYlic add methvl ester. 1.17 g (29.4 mmol, 1.05 equiv) sodium hydride, 60% oil dispersion, were added in one portion to an ambient temperature solution of 5.7 g (27.9 mmol, 1.0 equiv) 3-ethyt-1H20 indazoie-6-cartx)xyic add methyl ester in 125 mL anhydrous DMF. After 20 min., 3.89 mL (36.6 mmol, 1.3 equiv) cydopentyl bromide were added dropwise, and the reaction mixture aHowed to stir overnight at room temperature. The mixture was then poured into 1 L HjO and extracted 3 x 450 mL ethyl acetate. The organic extracts were combined, washed 3 x 400 mL HjO, 1 x 200 mL brine, and dried over Na2SO4.
Fiftration, concentration of fStrate and drying gave an amber ofl, which was purified on a siSca gel column (10% ethyl acetate/hexanes, gravity) to give 5.48 g (72%) of a dear ofc Ή NMR (300 MHz, COCy d8.16 (d, 1H, >1.0 Hz), 7.7 (m, 2H), 5.00 (quintet, 1H, >7.5 Hz), 3.97 (s, 3H), 3.01 (q, 2H, >7.8 Hz), 22 (m, 4H), 2.0 (m, 2H), 1.8 (m, 2H), 1.39 (t, 3H, >7.6 Hz); HRMS calcd for C^HJ^O^: 272.1526. Found: 272.15078.
AP/P/ 9 7/01080
AP .00795
-35G. (1-Cyclopentvl-3-ethvl-1H-indazol-6-vl)-methanol. 7 ml (7.0 mmol, 1.0 equiv) lithium aluminum hydride, 1.0 M solution in tetrahydrofuran (THF), were added to a 0°C solution of 1.02 g (7.05 mmol, 1.0 equiv) 1-cyclopentyl-3-ethyl-1H-indazole-6carboxylic acid methyl ester in 50 mL anhydrous THF. After 20 minutes, 1 mL methanol was added cautiously, then the reaction mixture was poured into 500 mL of 5% H2SO4 and extracted 3 x 50 mL ethyl acetate. The organic extracts were combined, washed 2 x 40 mL H^O, 1 x 40 mL brine, and dried over Na2SO4. Filtration, concentration of filtrate, and drying gave 1.58 g of a dear oil, which was purified on a silica gel column to give 1.53 g (89%) dear oil: IR (CHCy 3606, 3411, 3009, 2972,
2875, 1621, 1490 cm’1; 1H NMR (300 Mhz, CDCy δ 7.65 (d, 1H. J=8.0 Hz) 7.42 (s,
1H), 7.06 (dd, 1H, J=1.0, 8.2 Hz), 4.92 (quintet, 1H, J=7.7 Hz), 4.84 (s, 2H), 2.98 (q, 2H, J=7.6 Hz), 2.2 (m, 4H), 2.0 (m, 2H), 1.7 (m, 3H), 1.38 (t, 3H, J=7.6 Hz); MS (thermospray, NH4OAc) m/z 245 (M+H*. base); HRMS calcd for C^H^O + H: 245.1654. Found: 245.1675.
H. 1-Cvdopentvl-3-ethy1-1 H-jndazote-6-carbaldehvde. 106 mg (0.301 mmol,
0.05 equiv) tetrapropyiammonium perTuthenate(Vll) were added to a room temperature suspension of 1.47 g (6.02 mmol, 1.0 equiv) (1-cyyclopentyl-3-ethyHH-indazol-6-yl>methanol, 1.06 g (9.03 mmol, 1.5 equiv) N-methylmorphoBne N-oxide and 3.01 g 4A molecular sieves in 12 mL anhydrous CHjCIj. After 20 minutes the reaction mixture was filtered through a short column of silica gel (eluted with CHjCy. Fractions containing product were concentrated, and the residue chromatographed on a sSca gel column (15% ethyl acetate/hexanes, flash) to give 924 mg (63% of a pale yellow soBd; mp 41’ C; IR (KBr) 3053, 2966, 2872, 2819,1695 cm'1; Ή NMR (300 MHz, CDCy δ 10.13 (s, 1H), 7.93 (d, 1H, J-0.9 Hz), 7.77 (d, 1H, J=8.4 Hz), 7.60 (dd, 1H, J=1.2, 8.4
Hz), 5.00 (quintet, 1H, >7.5 Hz), 3.01 (q, 2H, J-7.6 Hz), 2.2 (m, 4H), 2.0 (m, 2H), 1.7 (m, 2H), 1.39 (t, 3H, >7.5 Hz); MS (Cl, Nhy m/z 243 (M+H*. base); Anal, calcd for CmH^NjO: C, 74.35; H, 7.49; N, 11.58. Found: C, 74.17; H, 7.58; N, 11.79.
PREPARATION 2
1-Cydopentvl-3-ethvt-1H-indazole-6-carbaldehvde
A. 4-Bromo-2-nitro-1 -propvt-benzene. 125 g (628 mmol, 1.0 equiv) 1bromo-4-propyl-benzene were added in one portion to a 10*C solution of 600 mL cone.
HjSO4 and 200 mL HjO. VSAth vigorous mechanical stirring, an ambient temperature mixture of 43.2 mL (691 mmol, 1.1 equiv) cone. HNOS (69-71%, 16M) in 150 mL cone.
AP/P/ 9 7 / 0 1 0 8 0
AP.00795
-36HjSO4 and 50 mL H2O was added dropwise over 30 minutes. The ice bath was allowed to warm to ambient temperature, and the reaction stirred at room temperature for 68 hours. The reaction mixture was poured into a 4 L beaker, loosely packed full with crushed ice. After stirring 1 hour, the mixture was transferred to a 4 L separatory funnel and extracted 4 x 800 mL isopropyl ether. The organic extracts were combined, washed 3 x 800 mL HjO, 1 x 500 mL brine, and dried over Na2SO4. nitration, concentration of filtrate and drying gave 150 mL of a yellow liquid, which was purified by silica gel chromatography (2 columns, 3 kg siiica gel each, 2% ethyl acetate/hexanes) to afford 63.9 g (42%) of a yellow liquid. The desired regiotsomer is the less polar of the two, which are formed in a 1:1 ratio, bp 108*C, 2.0 mm; IR (CHClj 3031, 2966, 2935, 2875, 1531, 1352 cm’1; Ή NMR (300 MHz. CDCIj) δ 8.01 (d, 1H, J-2.1 Hz), 7.62 (dd, 1H, J=2.1, 8.3 Hz) 7.23 (d, 1H, J=8.3 Hz), 2.81 (m, 2H), 1.67 (m, 2H), 0.98 (t, 3H, J=7.4 Hz); °C NMR (75.5 MHz, CDCIj) δ 13.94,23.74,34.43, 119.6, 127.4, 133.3, 135.7, 136.4,149.8; GCMS (El) m/z 245/243 (M+.), 147 (base);
HRMS calcd for CjH^NOjBr + H: 243.9973. Found: 243.9954.
B. 5-Bromo-2-propyl-phenvlamine· 121 g (639 mmol, 3.0 equiv) of stannous chloride (anhydrous) were added in one portion to a room temperature solution of 51.9 g (213 mmol, 1.0 equiv) 4-bromo-2-nitro-1-propyl-benzene in 1200 mL absolute ethanol and 12 mL (6 equiv) Η/λ After 24 hours at room temperature, most of the ethanol was removed on a rotary evaporator. The residue was poured into a 4 L beaker, 3/4 ful with crushed ice and HjO. 150 g of NaOH peBets were added portionwise, with stirring, untfl the PH = 10 and most of the tin hydroxide has dissolved. The mixture was divided in half, and each half extracted 2 x 750 mL ethyl acetate. AB four ethyl acetate extracts were combined, washed 1 x 500 mL each 1N NaOH, HjO, and brine, then dried over NajSO^ Ffltration, concentration of tatrate and drying gave a yeBow Bquid, which was purified on a 1.2 kg silica gel column (1:12 ethyl acetate/hexanes) to give 41.83 g (92%) of a pale yellow BquW: IR (CHCy 3490,3404, 3008, 2962, 2933, 2873, 1620, 1491 cm*1; Ή NMR (300 MHz, CDCIJ δ 6.8-6.9 (m, 3H), 3.90 (br s, 2H), 2.42 (m, 2H), 1.62 (m, 2H), 0.99 (t, 3H. J=7.3 Hz); GCMS (El) m/z
215/213 (M+.), 186/184 (base); Anal, calcd for Ο,Η,/ΙΒγ. C, 50.49; H, 5.65; N, 6.54.
Found: C. 50.77; H. 5.70; N, 6.50.
AP/P/ 9 7 / 0 1 0 8 0
AP.00795
-37C. 6-Brotno-3-ethyt-1 H-indazole. 49.22 g (230 mmol, 1.0equiv) 5-bromo-2propyl-phenylamine were placed in a 3 L flask and chilled in an ice bath. A 0eC solution of 57.5 mL (690 mmol, 3.0 equiv) cone. HCI in 165 mL H2O was added, and the resulting solid mass which formed was ground up until a fine white suspension resulted. 100 mL more HjO were added, then a solution of 15.9 g (230 mmol, 1.0 equiv) sodium nitrite in 75 mL H2O was added dropwise over 10 minutes. The ice bath was removed, and the reaction allowed to stir at room temperature for 30 minutes. The reaction mixture was then filtered through a sintered glass funnel, precooled to 0’C. The filtrate was chilled in an ice bath, and with mechanical stirring, a 0*C solution/suspension of 32.8 g (313 mmol, 1.36 equiv) ammonium tetrafluorobrate in 110 mL H2O was added dropwise over 10 minutes. The thick white suspension which formed (aryl diazonium tetrafluoroborate salt) was allowed to stir 1.5 hours at 0’C. The mixture was then filtered, and the solid washed 1 x 200 mL 5% aq. NH4BFX (cooled at 0*C), 1 x 150 mL CH,OH (cooled to 0*C), then 1 x 200 mL EtjO. Drying at high vacuum, ambient temperature for 1 hour gave 54.47 g (76%) of the diazonium salt, an · off-white solid.
1500 mL of ethanol free chloroform were placed in a 3-neck flask, then 34.16 g (348 mmol, 2.0 equrv) potassium acetate (powdered and dried) and 2.3 g (8.7 mmol, 0.05 equiv) 18-crown-6 were added. After 10 minutes, the diazonium salt was added
In one portion, and the reaction mixture allowed to stk at room temperature under nitrogen atmosphere for 18 hours. The mixture was then filtered, the solid washed 2 x with CHCt„ and the filtrate concentrated to g'rve 47 g of crude product (brown crystals). Sffica gel chromatography (1.2 kg sffica gel, ethyl aoetate/hexanes gradient 15%, 20%, 40%) gave 21.6 g (55% for second step, 42% overall) of tan crystals: mp
112-114*C; IR (KBr) 3205, 3008, 2969, 2925, 1816, 1340, 1037 cm'1; 1H NMR (300
MHz, CDCt,) «59.86 (br s, 1H), 7.61 (d, 1H, J=1.3 Hz), 7.57 (d, 1H. 3=8.4 Hz), 7.24 (dd, 1H, 3=1.5, 8.6 Hz), 2.99 (q, 2H, 3=7.8 Hz), 1.41 (t, 3H, 3=7.6 Hz); MS (Cl. NH,) m/z 227/225 (M+H*, base); Anal, calcd for CWijBr. C, 48.02; H, 4.03; N, 12.45. Found: C, 48.08; H. 3.87; N, 12.45.
AP/P/ 9 7 / 0 1 0 8 0
AP.00795
-38D. 6-Bromo-1 -cyclopentvl-3-ethyl-1 H-indazole. 2.46 g (61.4 mmol, 1.05 equiv) sodium hydride, 60% oil dispersion, were added in 0.5 g portions to a 10°C solution of 13.17 g (58.5 mmol, 1.0 equiv) 6-bromo-3-ethyl-1 H-indazole in 500 mL anhydrous DMF. The mixture was stirred at ambient temperature for 20 minutes, then a solution of 8.8 mL (81.9 mmol, 1.4 equiv) cyclopentyl bromide in 10 mL anhydrous DMF was added dropwise. After 18 hours, the reaction mixture was poured into 2 L H2O and extracted 2 x 1 L ethyl acetate. The organic extracts were combined, washed 2 x 750 mL HjO, 1 x 500 mL brine, and dried over NajSO4. Filtration, concentration of filtrate and drying gave 20.7 g of crude product, which was purified on a silica gel column (1.1 kg silica gel, 3% ethyl acetate/hexanes) to g'rve 10.6 g (62%) of an amber liquid: IR (CHCy 2972, 2875, 1606, 1501, 1048 cm·’; Ή NMR (300 mHz, CDCIJ δ 7.56 (d, 1H, J=1.3 Hz), 7.52 (d, 1H, J=8.7 Hz), 7.17 (dd, 1H, J= 1.5, 8.5 Hz), 4.83 (quintet, 1H, J=7.6 Hz), 2.96 (q, 2H, J=7.6 Hz), 2.15 (m, 4H), 2.0 (m, 2H), 1.65 (m, 2H), 1.36 (t, 3H, J=7.7 Hz); MS (thermospray, NH4OAc) m/z 295/293 (M+H+, base); Anal.
calcd for C„H17NjBr. C, 57.35; H, 5.84; N, 9.55. Found: C, 57.48; H, 5.83; N, 9.90.
E. 1 -Cvdooentyl-3-ethv1-1 H-indazote-6-carbaldehvde. 11.6mL(28.4mmol, 1.0 equiv) n-BuLi, 2.45 M in hexanes, were added to a -78*C solution of 8.32 g (28.4 mmol, 1.0 equiv) 6-bromo-1 -cydopentyl-3-ethyH H-indazote in 200 mL anhydrous THF. After 30 min. at -78’C, 8.8 mL (114 mmol, 4.0 equiv) anhydrous DMF were added dropwise, and the reaction mixture was allowed to stir an additional 30 minutes at -78*C. The mixture was warmed to room temperature over 1 hour, then 125 mL 1N HCI were added. After stirring for 10 minutes, most of the THF was removed on a rotary evaporator. The residue was dfluted with 500 mL HjO, and extracted 2 x 250 mL ethyl acetate. The organic extracts were combined, washed 1 x 100 mL HjO, 1 x
100 mL brine, and dried over NajSO4. nitration, concentration of filtrate and drying gave a yellow ofl, which was purified on silica gel column (15% ethyl acetate/hexanes, gravity) to give 4.70 g (68%) of a yelow crystaJSne soBd: Ή NMR (300 MHz, CDCy identical to the spectrum of the title compound from Preparation 1.
AP/P/ 97/01080
PREPARATION?
1-Cvdopentvl-3-ethvf-1H-indazote-8-cart>oxvffc add
A.
9.44 g (57.5 mmol, 1.0 equiv) of 4-propyfoenzoic add were partiaRy dissolved in 50 mL cone. H2SO4 and chilled In an ice bath. A solution of 4.7 mL (74.7 mmol, 1.3
AP.00795
-39equiv) cone. HNO3 in mL cone. H-SO4 was added dropwise over 1-2 minutes. After stirring 1 hour at O’C, the reaction mixture was poured into a 1 L beaker half full with ice. After stirring 10 minutes, the white solid which formed was filtered, washed 1 x H2O, and dried to give 12.01 g (100%) of the title compound: mp 106-109’C; IR (KBr)
3200-3400, 2966, 2875, 2667, 2554,1706, 1618,1537, 1299, 921 cm'’; Ή NMR (300
MHz, DMSO-de) <50.90 (t, 3H, 3=7.4 Hz), 1.59 (m, 2H), 2.82 (m, 2H), 7.63 (d, 1H, 3=8.0 Hz), 8.12 (dd, 1H, 3=1.7, 8.0 Hz), 8.33 (d, 1H, J=1.7 Hz); ”C NMR (75.5 MHz, DMSOdj <514.2, 23.7, 34.2, 125.4, 130.5,132.9, 133.6,141.4,149.5,165.9; Anal, calcd for C^H^NOe^lMHjO: C, 56.20; H, 5,42; N, 6.55. Found: C, 56.12; H, 5.31; N, 6.81.
B. 3-Arnino-4-propyt-benzoic add
A mixture of 11.96 g (57.2 mmol) 3-nitro-4-propyFbenzoic acid and 1.5 g 10%
Pd/C, 50% water wet, in 250 mL CH,OH was placed on a Parr hydrogenation apparatus and shaken under 25 psi H, at ambient temperature. After 1 h, the reaction mixture was filtered through Ceiite®, and the filtrate concentrated and dried to give 9.80 g (96%) of a pale yellow crystalline sofid: mp 139.5-142.5’C; IR (KBr) 3200-2400,3369, 3298,2969,2874,2588,1690,1426,1260,916,864 cm’1; Ή NMR (300 MHz, DMSO dj <5 0.90 (t, 3H, 3=7.2 Hz), 1.52 (m, 2H), 2.42 (m, 2H), 5.08 (br s, 2H), 6.96 (d, 1H. 3=7.8 Hz), 7.05 (dd, 1H, 3=1.7, 7.8 Hz), 7.20 (d, 1H, 3=1.7 Hz); MS (Cl, NH,) m/z 180 M+H*. base); Anal, calcd for C^H^NO,· 1/3Η,Ο: C, 64.85; N, 7.89; N, 7.56. Found:
C, 64.69; H, 7.49; N, 7.86.
C. 3-Cartx3xv-6-propyl-benzenediazo t-butyl sulfide A mixture of 8.80 g (49.1 mmol, 1.0 equiv) 3-amino-4-propyt-benzoic add and
2.34 g (22.1 mmol, 0.45 equiv) sodium carbonate in 55 mL Η,Ο was heated gently with a heat gun untfl most dissolved. The reaction mixture was chilled in an ice bath, and a solution of 3.73 g (54.0 mmol, 1.0 equiv) sodium nitrite in 27 mL Η,Ο was added dropwise. After 15 minutes, the reaction mixture was transferred to a dropping funnel and added over 10 minutes to a beaker containing 55 g of crushed ice and 10.6 mL cone. HCI. After stirring 10 minutes, the contents of the beaker were transferred to a dropping funnel and added over 5 minutes to a room temperature solution of 5.31 mL (47.1 mmol, 0.96 equiv) t-butyl thiol in 130 mL ethanol. The pH was adjusted to 4-5 by addition of saturated aqueous Na,CO, solution, and the reaction mixture was allowed to stir 1 hour at ambient temperature. 200 mL brine were added, and the mixture was filtered. The solid was washed 1 x Η,Ο and dried overnight to give 12.25
AP/P/ 97/01080
AP. Ο Ο 7 9 5
-40g (89%) of a brown/rust colored powder (caution - stench): mp 102®C (dec); IR (KBr) 3200-2400, 2962, 2872, 2550, 1678, 1484, 1428, 1298, 1171 cm·’; Ή NMR (300 MHz, DMSO-dJ δ 0.84 (t, 3H, J=7.3 Hz), 1.48 (m, 2H), 1.55 (s, 9H), 2.42 (m, 2H), 7.29 (d, 1H. J=1.6 Hz), 7.50 (d, 1H, J=8.0 Hz), 7.86 (dd, 1H, J=1.7, 7.9 Hz), 13.18 (br s, 1H);
MS (thermospray, NH4OAc) m/z 281 (M+H+, base); Anal, calcd for C^H^jNjO^: C, 59.96; H, 7.19; N, 9.99. Found: C, 59.71; H, 7.32; N, 10.02.
D. 3-Ethyl-1H-indazole-6-cart>oxylic acid
A solution of 12.0 g (42.8 mmol, 1.0 equiv) 3-carboxy-6-propyl-benzenediazo t-butyl sulfide in 150 mL DMSO was added dropwise over 15 minutes to a room temperature solution of 44.6 g (398 mmol, 9.3 equiv) potassium t-butoxide in 200 mL DMSO. After stirring 2 hours at ambient temperature, the reaction mixture was poured into 1.5 L of 0“C 1N HCI, stirred 5 minutes, then extracted 2 x 350 mL ethyl acetate. The ethyl acetate extracts (caution-stench) were combined, washed 2 x 250 mL HjO, and dried over MgSO4. Filtration, concentration of filtrate and drying gave a tan solid, which was triturated with 1 L of 1:3 EtjO/Hexanes and dried to give 7.08 g (87%) of a tan crystalline powder, mp 248-251 *C; IR (KBr) 3301, 3300-2400, 2973, 2504,1702, 1455, 1401, 1219 cm'’; Ή NMR (300 MHz, DMSOO δ 1.31 (t, 3H, J=7.6 Hz), 2.94 (q, 2H, J=7.6 Hz), 7.63 (dd, 1H, J=1.1, 8.4 Hz), 7.81 (d, 1H, J=8.4 Hz), 8.08 (d, 1H, 3=1.1 Hz), 12.95 (br s, 1H); MS (Cl, NHJ m/z 191 (M+H+, base); Anal, calcd for
C^HwNjO* C, 63.14; H, 5.30; N, 14.73. Found: C, 62.66; H, 5.42; N, 14.80.
E. 3^thvF1H-indazole-6-cart>oxySc acid methvl ester
8.78 g (45.8 mmol, 1.1 equiv) 1-<3-dimethyiaminoprx>pyl)-3-ethyfcarbodamide hydrochloride were added in one portion to a room temperature solution of 7.92 g (41.6 mmol, 1.0 equ'rv) 3-ethyi-1 H-indazole-6-carboxytic add, 16.9 mL (416 mmol, 10 equiv) methanol and 5.59 g (45.8 mmol, 1.1 equiv) DMAP in 250 mL CHjCl* After 18 hours at room temperature, the reaction mixture was concentrated to ~150 mL, diluted with 500 mL ethyl acetate, washed 2 x 100 mL 1N HCI, 1 x 100 mL HjO, 1 x 100 mL brine, and dried over Na^O^. Filtration, concentration of filtrate and drying gave 7.8 g of a brown solid, which was purified on a silica gel column (30% to 50% ethyl acetate/hexanes gradient) to give 6.41 g (75%) of a tan sotid: mp 107-108*C; IR (KBr)
3100-2950, 1723,1222 cm1; Ή NMR (300 MHz, CDCy 6 8.19 (m, 1H), 7.7-7.8 (m,
2H), 3.96 (*. 3H), 3.05 (q, 2H. 3=7.7 Hz), 1.43 (t, 3H, 7.7 Hz); MS (a. NH,) m/z 205
AP/P/ 97/01080
AP.00795
-41(M+H+, base); Anal, caicd for CnH12N2O2: C, 64.70; H, 5.92; N, 13.72. Found: C, 64.88; H, 6.01; N, 13.96.
F. 1-Cvdooentyl-3-ethvl-1H-indazole-6-carboxvlic acid methyl ester 1.17 g (29.4 mmol, 1.05 equiv) sodium hydride, 60% oil dispersion, were added in one portion to a room temperature solution of 5.7 g (27.9 mmol, 1.0 equiv) 3-ethyl1 H-indazoIe-6-carboxyiic acid methyl ester in 125 mL anhydrous DMF. After 20 minutes, 3.89 mL (36.6 mmol, 1.3 equiv) cyclopentyl bromide were added dropwise, and the reaction mixture allowed to stir overnight at room temperature. The mixture was then poured into 1 L H2O and extracted 3 x 400 mL H2O, 1 x 200 mL brine, and dried over Na2SO4. Filtration, concentration of filtrate and drying gave an amber oil, which was purified on a silica gel column (10% ethyl acetate/hexanes, gravity) to give 5.48 g (72%) of a dear oil; 1H MR (300 MHz, CDCy <5 8.16 (d, 1H, J=1.0 Hz), 7.7 (m, 2H), 5.00 (quintet, 1H, J=7.5 Hz), 3.97 (s, 3H), 3.01 (q, 2H, J=7.6 Hz), 2.2 (m, 4H), 2.0 (m, 2H), 1.8 (m, 2H), 1.39 (t, 3H, J=7.6 Hz); HRMS calc for C^H^N.O^ 272.1526.
Found; 272.15078.
G. 1 -Cydopentyl-3-ethvt-1 H-indazole-6-carboxvlic acid
A mixture of 5.24 g (19.2 mmol, 1.0 equiv) 1 -cyclopentyl-3-ethyl-1 H-indazole-6carboxylic add methyl ester in 120 mL methanol and 60 mL 1N NaOH was heated to reflux. After 1 hour, the reaction mixture was cooled to room temperature, concentrated to 75 mL, addified to pH -1 with 1N HCI, and extracted 2 x 200 mL ethyl acetate. The organic extracts were combined, washed 1 x 150 mL H2O, 1 x 150 mL brine, and dried over Na2SO4. Filtration, concentration of filtrate and drying gave 4.79 g (96%) of a white solid. A small sample was recrystallized from ethyl acetate/hexanes to obtain analytical data: mp 157-159*C; IR (KBr) 3100-2500, 1683, 1298 cm*1; 1H
NMR (300 MHz, DMSO-d,) δ 13.0 (br s, 1H), 8.21 (s, 1H), 7.79 (d, 1H, J=7.9 Hz), 7.62 (sdd, 1H, J=1.2, 8.4 Hz), 5.18 (quintet, 1H, J=7.5 Hz), 2.92 (q, 2H, J=7.6 Hz), 2.1 (m, 2H), 2.0 (m, 2H), 1.85 (m, 2H), 1.6 (m, 2H), 1.29 (t, 3H, J=7.6 Hz); MS (Cl, NHJ m/z 259 (M+H*, base); Anal, caicd for C^.NjO/ C, 69.74; H, 7.02; N, 10.85. Found: C, 69.77; H, 7.02; N, 10.85.
AP/P/ 97/01080
AP.00795
-42EXAMPLE 1
2-Cvclopentvl-2H-indazole-6-carboxvlicacidf3.5-dichloro-pyridin-4-vl)amideand
-Cyclopentvl-2H-indazole-6-carboxylic acid (3.5-dichloro-pyridin-4-vl)amide
1.A 1H-lndazole-6-carboxylic acid
A partial solution of 15.1 g (100 mmol. 1.0 equiv) 3-amino-4-methylbenzoic acid in 150 mL anhydrous THF was added dropwise to a -20°C solution of 18 mL (146 mmol, 1.46 equiv) boron trifluoride etherate in 450 mL ethanol free chloroform. After 5 minutes, 14 mL (106 mmol, 1.06 equiv) of 90% t-butyl nitrite were added dropwise, and the reaction stirred at 0”C for 2 hours. 49 g (500 mmol, 5.0 equiv) potassium acetate were added portionwise, followed by 2.65 g (10 mmol, 0.1 equiv) 18-crown-6 in one portion. The reaction mixture was allowed to stir at room temperature for 48 hours, then was concentrated on a rotary evaporator. 500 mL of 3:7 acetone/ethyl acetate and 150 mL 1N HCI were added, and the mixture stirred for 2 hours. 150 mL brine were added and the mixture was filtered. The filtrate was transferred to a separatory funnel, the layers separated, and the aqueous layer extracted 2 x 100 mL 3:7 acetone/ethyl acetate. The organic layers were combined and dried over MgS04. Filtration and concentration of the filtrate gave a solid, to which were added 250 mL of acetic acid. The suspension was heated on a steam bath until mostly dissolved, then was removed from the steam bath and 300 mL of ethereal HCI (prepared by passing
HCI (g) through 350 mL EtjO, chilled in an ice bath, for 10 minutes) were added slowly to the still hot acetic acid solution. 250 mL EtjO were added and the mixture stirred at room temperature for 1 hour. Filtration and drying gave a golden brown powder. The powder was suspended in 500 mL of 3:7 acetone/ethyl acetate, 100 mL brine were added, and the mixture stirred for 1 hour at room temperature. The layers were separated, and the aqueous layer was extracted 1 x 100 mL ethyl acetate. The combined organic layers were dried over MgSO4. Filtration, concentration of filtrate and drying at high vacuum, room temperature for 18 hours gave 7.81 g (48%) of a brown powder mp >275eC; MS (Cl, NHJ m/z 180 (M+18*, base).
. 1.B 1H4ndazole-6-carboxylic add methvl ester
A mixture of 7.59 g (46.8 mmol, 1.0 equiv) 1 H-indazole-6-carboxylic add in 500 mL CH3OH and 1 mL cone. H2SO4 was heated to reflux for 8 hours, then allowed to stir at room temperature for 18 hours. The mixture was concentrated to -200 mL, diluted with 1 L ethyl acetate, and washed 1 x 250 mL saturated aqueous NaHCO3, 1 x 250
AP/P/ S7 / 0 10 80
AP.00795
-43mL H2O, 1 x 250 mL brine, and dried over Na2SO4. The aqueous washes were extracted with two portions of ethyl acetate to recover additional product. The organic layers were combined, concentrated, and dried to give 6.75 g (82%) of a yelloworange-tan solid: 1H NMR (300 MHz, CDCI3) δ 10.8 (brs, 1H), 8.28 (dd, 1H, J=0.9, 1.9 Hz), 8.15 (d, 1H, J=1.0 Hz), 7.8 (m, 2H), 3.97 (s, 3H); MS (Cl, NHJ m/z 177 (M+H+, base).
1.C 1 -Cyclo oentyl-1 H-indazole-6-carboxylic add methyl ester and 2z cydopentyl-2H-indazole-6-carboxYlic acid methyl ester
1.60 g (39.9 mmol, 1.05 equiv) sodium hydride, 60% oil dispersion, were added in one portion to a room temperature solution of 6.70 g (38.0 mmol, 1.0 equiv) 1Hindazole-6-carboxylic acid methyl ester in 150 mL anhydrous DMF. After 30 minutes,
4.5 mL (41.8 mmol, 1.1 equiv) cyclopentyl bromide were added dropwise, and the mixture stirred at room temperature for 24 hours. The reaction mixture was diluted with 1.2 liters of ethyl acetate, washed 3 x 350 mL H2O, 1 x 250 mL brine, and dried over Na2SO4. Filtration, concentration of filtrate and drying gave 12 g of an amber oil, which was purified on a 700 g silica gel column (20% ethyl acetate/hexanes, flash) to give
4.26 g of 1-cydopentyMH-indazole-6-carboxylic acid methyl ester (46% yield, less polar isomer) and 3.66 g of 2-cydopentyl-2H-indazole-6-carboxyiic acid methyl ester (39% yield, more polar isomer). Both compounds were orange oils: data for 1Hindazole regioisomer. IR (CHCy 2996, 2955, 2874,1717, 1249 cm'1; HRMS calcd for CMHieN2O2: 244.1213; found: 244.1209; data for 2H-indazole regioisomer. IR (CHClj) 2972, 2955, 2876, 1714, 1242 cm'1; HMRS calcd for CMH„N2O2: 244.1213. Found: 244.1220.
1.D 1-CydooentYHH-indazole-6-carboxvlic acid
A mixture of 3.93 g (16.1 mmol, 1.0 equiv) of 1-cydopentyl-1H-indazole-6carboxylic acid methyl ester, 100 mL CHjOH and 50 mL 1N NaOH was heated to reflux for 30 minutes. The reaction mixture was cooled to room temperature, and most of the CHjOH removed on a rotary evaporator. The residue was diluted with 325 mL H2O and acidified to pH = 1 with 2N HCI. After stirring 5 minutes, the mixture was filtered, and the solid washed 2 x H2O and dried overnight to give 3.42 g (92%) of a yellow powder, mp 172-175’C; Anal, calcd for C13H14N2O2: C, 67.79; H, 6.13; N, 12.16. Found: C, 67.62; H, 5.82; N, 12.19.
8 0 I 0 / L 6 /d/dV
AP. ο Ο 7 9 5
-441.Ε 2-Cyclopentvl-2H-indazole-6-carboxylic acid
This compound was prepared according to the method of Example 1.D, starting with 3.28 g (13.4 mmol) 2-cyclopentyl-2H-indazole-6-carboxylic acid methyl ester, 100 mL CH3OH and 40 mL 1N NaOH, to give 2.71 g (88%) of light yellow powder mp 1905 193’C; Anal, calcd for C13H,4N2O2: C, 67.79; H, 6.13; N, 12.16. Found: C, 67.40; H,
6.04; N, 12.38.
1.F 1-Cyclopentyl-1 H-indazole-6-carboxylic acid (3.5-dichloro-pyridin-4-vl) amide
A suspension of 495 mg (2.15 mmol, 1.0 equiv) 1-cydopentyl-1H-indazole-610 carboxylic acid, 204 pL (2.79 mmol, 1.3 equiv) thionyl chloride, and 10 pL DMF in 10 mL anhydrous toluene was heated to reflux for 3 hours, then cooled to ambient temperature and concentrated to dryness on a rotary evaporator. In a separate flask, a solution of 333 mg (2.04 mmol, 0.95 equiv) 3,5-dichloro-4-aminopyridine in 10 mL anhydrous THF was added dropwise to a O’C suspension of 198 mg (4.95 mmol, 2.3 equiv) sodium hydride, 60% oil dispersion, in 10 mL anhydrous THF. The mixture was » stirred for 15 minutes at room temperature, then was recooled to O’C. A solution of the acid chloride (prepared above) in 10 mL anhydrous THF was added dropwise, and the reaction mixture allowed to stir at room temperature overnight. 4.5 mL 1N HCl were added dropwise to the reaction mixture, which was then diluted with 200 mL
CHjCLj, washed 1 x 30 mL each H2O, 10% aqueous Na2CO3, H2O, then dried over Na2SO4. Purification on a silica gel column (2% Ch^OH/CH/^, flash) gave 0.76 g (94%) of product, a yellow amorphous foam; 1H NMR (300 MHz, CDCIj) δ 8.58 (s, 2H), 8.19 (d, 1Η, J=0.9 Hz), 8.09 (d, 1H, J=0.7 Hz), 7.93 (br s, 1Η), 7.84 (dd, 1H, J=0.7,8.4 Hz), 7.63 (dd, 1H, J=1.4,8.4 Hz), 5.08 (quintet, 1H), 2.2 (m, 4H), 2.0 (m, 2H), 1.75 (m,
2H); MS (Cl, NHJ m/z 375 (M+H*, base); Anal, calcd for C,eHieN4OCI2: C, 57.62; H,
4.30; N. 14.93; found: C, 57.68; H, 4.55; N, 14.55.
1.G 2-Cydopentyl-2H-indazole-6-carboxviic add (3.5-dichloro-pyridin-4vDamide
This compound was prepared according to the method of Example 1 .F, using
424 mg of 2-cydopentyF2H-indazole-6-carboxylic add as starting material to give 406 mg (59%) of a white amorphous foam: 1H NMR (300 MHz, CDCy δ 8.57 (s, 2H), 8.36 (d, 1H, J=1.4 Hz), 8.06 (d, 1H, J=0.7 Hz), 7.84 (br s, 1H), 7.78 (dd, 1H, J=0.7, 8.6 Hz),
7.64 (dd, 1H, J=1.5, 8.7 Hz), 5.00 (quintet, 1H), 2.35 (m, 2H), 2.25 (m, 2H), 2.0 (m,
AP/P/ 9 7 / 0 1 0 8 0
AP.00795
-452H), 1.8 (m, 2H); MS (Cl, NHJ m/z 375 (M+H+, base); Anal, calcd for C18H16N4OCI2: C, 57.62; H, 4.30; N, 14.93. Found: C, 57.39; H, 4.59; N, 14.56.
EXAMPLE 2
3-Nitro-4-propyl-benzoic acid
9.44 g (57.5 mmol, 1.0 equiv) of 4-propylbenzoic acid were partially dissolved in 50 mL cone. HjSO4 and chilled in an ice bath. A solution of 4.7 mL (74.7 mmol, 1.3 equiv) cone. HNO3 in 10 mL cone. H2SO4 was added dropwise over 1-2 min. After stirring 1 h at 0°C, the reaction mixture was poured into a 1 L beaker half full with ice. After stirring 10 min., the white solid which formed was filtered, washed 1 x H2O, and dried to give 12.01 g(100%) of the title compound: mp 106-109°C: IR(KBr) 3200-3400, 2966, 2875,2667,2554,1706,1618,1537,1299, 921 cm’1; 1H NMR (300 MHz, DMSOd,) δ 0.90 (t, 3H, J=7.4 Hz), 1.59 (m, 2H), 2.82 (m, 2H), 7.63 (d, 1H, J=8.0 Hz), 8.12 (dd, 1H, J-1.7, 8.0 Hz), 8.33 (d, 1H, J=1.7 Hz); 15C NMR (75.5 MHz, DMSO-Dg) δ 14.2, 23.7, 34.2, 125.4, 130.5, 132.9, 133.6, 141.4, 149.5, 165.9; Anal, calcd for C10H„NO4.1/4H2O: C, 56.20; H, 5.42; N, 6.55. Found: C, 56.12; H, 5.31; N, 6.81.
EXAMPLE 3
3-Amino-4-propyl-benzoic acid
A mixture of 11.96 g (57.2 mmol) 3-nitro-4-propyl-benzoic acid and 1.5 g 10% Pd/C, 50% water wet, in 250 mL CH3OH was placed on a Parr hydrogenation apparatus and shaken under 25 psi H2 at ambient temperature. After 1 h, the reaction mixture was filtered through Celite®, and the filtrate concentrated and dried to give 9.80 g (96%) of a pale yellow crystalline solid: mp 139.5-142.5eC; IR (KBr) 3200-2400, 3369, 3298, 2969, 2874, 25588,1690,1426, 1260, 916, 864 cm*1; Ή NMR (300 MHz, DMSO-de) δ 0.90 (t, 3H, J=7.2 Hz), 1.52 (m, 2H), 2.42 (m, 2H), 5.08 (br s, 2H), 6.96 (d, 1H, J=7.8 Hz), 7.05 (dd, 1H, J=1.7, 7.8 Hz), 7.20 (d, 1H, J=1.7 Hz); MS (CI.NHJ m/z 180 (M+H*. base); Anal, cacld for C10H13NO2«l/3H2O: C, 64.85; N, 7.89; N, 7.56. Found: C, 64.69; H, 7.49; N, 7.86.
EXAMPLE 4
3-Carboxv-6-propyl-benzenediazo t-butvt sutfide
A mixture of 8.80 g (49.1 mmol, 1.0 equiv) 3-amino-4-propyl-benzoic acid and
2.34 g (22.1 mmol, 0.45 equiv) sodium carbonate in 55 mL H2O was heated gently with a heat gun until mostly dissolved. The reaction mixture was chilled in an ice bath, and a solution of 3.73 g (54.0 mmol, 1.0 equiv) sodium nitrite in 27 mL H2O was added
AP/P/ 9 7 / 0 1 0 8 0
AP.00795
-46dropwise. After 15 min., the reaction mixture was transferred to a dropping funnel and added over 10 min. to a beaker containing 55 g of crushed ice and 10.6 mL cone. HCI. After stirring 10 min., the contents of the beaker were transferred to a dropping funnel and added over 5 min. to a room temperature solution of 5.31 mL (47.1 mmol, 0.96 equiv) t-butyl thiol in 130 mL ethanol. The pH was adjusted to 4-5 by addition of saturated aqueous Na2CO3 solution, and the reaction mixture was allowed to stir 1 h at ambient temperature. 200 mL brine were added, and the mixture was filtered. The solid was washed 1 x H2O and dried overnight to give 12.25 g (89%) of a brown/rust colored powder (caution - stench): mp 102°C (dec); IR (KBr) 3200-2400, 2962, 2872,
2550, 1678,1484, 1428, 1298, 1171 cm'1; Ή NMR (300 MHz, DMSO-dg) δ 0.84 (t, 3H, >7.3 Hz), 1.48 (m, 2H), 1.55 (s, 9H), 2.42 (m, 2H), 7.29 (d, 1H, >1.6 Hz), 7.50 (d. 1H, >8.0 Hz), 7.86 (dd, 1H, >1.7, 7.9 Hz), 13.18 (br s, 1H); MS (thermospray, NH4OAc) m/z 281 (M+H+, base); Anal, calcd for CmH^O^: C, 59.96; H, 7.19; N, 9.99. Found: C, 59.71; H, 7.32; N, 10.02.
· EXAMPLE 5
3-Ethyl-1 H-indazote-6-carboxylic acid
A solution of 12.0 g (42.8 mmol, 1.0 equiv) 3-carboxy-6-propyl-benzenediazo t-butyl sulfide in 150 mL DMSO was added dropwise over 15 min. to a room temperature solution of 44.6 g (398 mmol, 9.3 equiv) potassium t-butoxide in 200 mL
DMSO. After stirring 2 h at ambient temperature, the reaction mixture was poured into
1.5 L of 0°C 1N HC1, stirred 5 min., then extracted 2 x 350 mL ethyl acetate. Ihe ethyl acetate extracts (caution - stench) were combined, washed 2 x 250 mL KjO, and dried over MgSO4. Filtration, concentration of filtrate and drying gave a tan solid, which was triturated with 1 L of 1:3 Et2O/Hexanes and dried to give 7.08 g (87%) of a tan crystalline powder, mp 248-251 °C; IR (KBr) 3301,3300-2400,2973,2504,1702,1455,
1401, 1219 cm'1; Ή NMR (300 MHz, DMSO-dg) <J 1.31 (t, 3H, J=7.6 Hz), 2.94 (q, 2H), >7.6 Hz), 7.63 (dd, 1H, >1.1,8.4 Hz), 7.81 (d, 1H, >8.4 Hz), 8.06 (d, 1H, >1.1 Hz), 12.95 (br s, 1H); MS (Cl, NHj) m/z 191 (M+H+, base); AnaL calcd for C^^Oj: C, 63.14; H, 5.30; N, 14.73. Found: C, 62.66; H, 5.42; N, 14.80.
EXAMPLE 6
3-Ethvl-1 H-indazote-6-carboxvlic add methyl ester
8.78 g (45.8 mmol, 1.1 equiv) 1-(3-dimethylaminopropyi)-3-ethylcartx>df»mide hydrochloride were added in one portion to a room temperature solution of 7.92 g (41.6
AP/P/ 9 7 / 0 1 0 80
AP . 0 0 7 9 5
-47mmol, 1.0 equiv) 3-ethyl-1H-indazole-6-carboxylic acid, 16.9 mL (416 mmol, 10 equiv) methanol and 5.59 g (45.8 mmol, 1.1 equiv) DMAP in 250 mL CH2CI2. After 18 h at room temperature, the reaction mixture was concentrated to ~150 mL, diluted with 500 mL ethyl acetate, washed 2 x 100 mL 1N HC1,1 x 100 mL H20,1 x 100 mL brine, and dried over Na2SO4. Filtration, concentration of filtrate and drying gave 7.8 g of brown solid, which was purified on a silica gel column (30% to 50% ethyl acetate/hexanes gradient) to give 6.41 g (75%) of a tan solid: mp 107-108°C; IR (KBr) 3100-2950,1723, 1222 cm*1; 1H NMR (300 MHz, CDCQ δ 8.19 (m, 1H, 7.7-7.8 (m, 2H), 3.96 (s, 3H), 3.05 (q, 2H, J=7.7 Hz), 1.43 (t, 3H, 7.7 Hz); MS (Cl, NHj) m/z 205 (M+H+, base); Anal.
calcd for CnH12N2O2: C, 64.70; H, 5.92; N, 13.72. Found: C, 64.86; H, 6.01; N, 13.96. EXAMPLE 7
1-Cyclopentvl-3-ethvl-1H-indazole-6-carboxylic acid methvl ester
1.17 g (29.4 mmol, 1.05 equiv) sodium hydride, 60% oil dispersion, were added in one portion to a room temperature solution of 5.7 g (27.9 mmol, 1.0 equiv) 3-ethyl15 1 H-indazole-6-carboxyIic add methyl ester in 125 mL anhydrous DMF. After 20 min.,
3.89 mL (36.6 mmol, 1.3 equiv) cydopenty! bromide were added dropwise, and the reaction mixture allowed to stir overnight at room temperature. The mixture was then poured into 1 L H2O and extracted 3 x 450 mL ethyl acetate. The organic extracts were combined, washed 3 x 400 mL H2O, 1 x 200 mL brine, and dried over Na2SO4.
Filtration, concentration of filtrate and drying gave an amber oil, which was purified on a silica gel column (10% ethyl acetate/hexanes, gravity) to give 5.48 g (72%) of a dear oil: Ή NMR (300 MHz, CDCI,) *8.16 (d, 1H, J=1.0 Hz), 7.7 (m, 2H), 5.00 (quintet, 1H, J=7.5 Hz), 3.97 (ε, 3H), 3.01 (q, 2H, J=7.6 Hz), 2.2 (m, 4H), 2.0 (m, 2H), 1.8 (m, 2H),
1.39 (t, 3H, J=7.6 Hz); HRMS calcd for CieH»NA 272.1526. Found: 272.15078.
25 EXAMPLE 8
-Cydopentvt-3-ethyl-1 H-indazole-6-carboxylic add A mixture of 5.24 g (19.2 mmol, 1.0 equiv) 1-cydopentyl-3-ethyl-1H-indazole-6carboxylic add methyl ester in 120 mL methanol and 60 mL 1N NaOH was heated to reflux. After 1 h, the reaction mixture was cooled to room temperature, concentrated to 75 mL, acidified to pH = 1 with 1N HCl, and extracted 2 x 200 mL ethyl acetate. The organic extracts were combined, washed 1 x 150 mL H20,1 x 150 mL brine, and dried over NajSO^ Filtration, concentration of filtrate and drying gave 4.79 g (96%) of a white solid. A small sample was recrystallized from ethyl acetate/hexanes to obtain
AP/P/ 9 7 / 0 1 0 8 0
AP . 0 0 7 9 5
-48analytical data: mp 157-159 °C; IR (KBr) 3100-2500, 1683, 1298 cm'1; 1H NMR (300 MHz, DMSO-dj) δ 13.0 (br s, 1H, 8.21 (s, 1H), 7.79 (d, 1H, J=7.9 Hz). 7.62 (sdd, 1H, J=1.2, 8.4 Hz), 5.18 (quintet, 1H, J=7.5 Hz), 2.92 (q, 2H, J=7.6 Hz), 2.1 (m, 2H), 2.0 (m, 2H), 1.85 (m, 2H), 1.6 (m, 2H), 1.29 (t, 3H, J=7.6 Hz); MS (Cl, NH3) m/z 259 (M+H+, base); Anal, calcd for C55H,8N2O2: C, 69.74; H, 7.02; N, 10.85. Found: C,
69.77; H, 7.02; N, 10.85.
EXAMPLE 9
1-Cvclopentvl-3-ethyl-1H-indazole-6-carboxvlic acid (3.5-dichloro-pyridin-4-vl)amide
9.A 1 -Cyclopentyl-3-ethyl-1 H-indazole-6-carboxylic acid
7.73 mL (18.9 mmol, 1.0 equiv) n-butyl lithium, 2.45 M in hexanes, were added dropwise to a -78°C solution of 5.55 g (18.9 mmol, 1.0 equiv) 6-bromo-1-cyclopentyl-3ethyl-1 H-indazole in 100 mL anhydrous THF. After 30 minutes, CO2 (g) was bubbled into the reaction mixture for 15 minutes. The reaction mixture was warmed to room temperature over several hours, then poured into 600 mL H2O, acidified to pH = 1, and extracted 2 X 250 mL ethyl acetate. The organic extracts were combined, washed 1 x 150 mL H2O, 1 x 100 mL brine, and dried over Na2SO4. Filtration, concentration of filtrate and drying gave 4.90 g (100%) of off-white crystals: mp 153-155°C; 1H NMR (300 MHz, DMSO-dg) identical with the spectrum of the product from Example 12.
9.B 1-Cyclopentvl-3-ethvl-1H-indazole-6~C3rbonYl chloride
791 pL (10.8 mmol, 1.4 equiv) thionyi chloride were added to a room temperature solution of 2.00 g (7.74 mmol, 1.0 equiv) 1-cydopentyl-3-ethyt-1Hindazole-6-carboxylic add and 100 pL DMF in 100 mL anhydrous toluene. The reaction mixture was heated to reflux for two hours, then cooled to room temperature, concentrated on a rotary evaporator, and dried at high vacuum, room temperature to give 2.16 g (100%) of brown crystals: mp 46-48°C; MS (Cl, NHj) m/z 279 (M+H*. 37CI), 277 (M+H+, KCl).
9.C 1-Cvdopentvl-3-ethvi-1H-indazole-6-carboxYBc add (3.5-dichloro-pvridin4-vD-amide
This compound was prepared according to the method of example 1.F, using
1.08 g (3.87 mmol) 1-cydopentyl-3-ethyl-1H-indazole-6-carbonyl chloride as starting material, to give 1.327 g (85%) of pale yellow crystalline solid: mp 174-176’C; MS (CI,
AP/P/ 97/01080
AP.00795
-49NH3) m/z 405 (M+H*, 37CI), 403 (M+H*, “Cl); Anal, calcd for C, 59.56;
H, 5.00; N, 13.89. Found: C, 60.23; H, 5.42; N, 14.09.
EXAMPLE 10
1-CydopentyF3-ethvF1H-indazole-6-cart>oxvlic acid (4,6-dichloro-pvrimidin-5-vl)5 amide pL (0.680 mmol, 1.3 equiv) thionyl chloride were added to a room temperature solution of 135 mg (0.523 mmol, 1.0 equiv) 1-cyclopentyP3-ethyl-1Hindazole-6-carboxyIic acid and 10/4. DMF in 5 mL anhydrous toluene. The reaction mixture was heated to reflux for 2 hours, then cooled to room temperature, concentrated to dryness on a rotary evaporator, and dried at high vacuum, room temperature for several hours. 21 mg (0.523 mmol, 1.0 equiv) sodium hydride, 60% oil dispersion, were added to a separate flask containing a room temperature solution of 86 mg (0.523 mmol, 1.0 equiv) 5-amino-4,6-dichloro-pyrimidine in 5 mL anhydrous DMF. After 10 minutes, a solution of the acid chloride (prepared above) in 5 mL anhydrous DMF was added, and the mixture stirred for 24. hours at room temperature. The reaction mixture was then heated to 70°C for 1.5 hours, cooled to room temperature, diluted with 75 mL ethyl acetate, washed 2 x 15 mL H20,1 x 16 mL brine, and dried over MgSO4. The crude product was purified on a silica gel column (20% ethyl acetate/hexanes) to give 31 mg (15%) of white crystalline solid: mp 171-172eC;
Anal, calcd for Ο,^Η,^ΟΟΙ^- C, 56.44; H, 4.74; N, 17.32. Found: C, 56.38; H, 4.76; N, 17.33.
EXAMPLE 11
1-CvdopentYl-3-ethvHH-indazole-6-cait>oxYlic acid phenylamide /4. (0.629 mmol, 1.3 equiv) thionyl chloride were added to a room temperature solution of 125 mg (0.484 mmol, 1.0 equiv) 1-cydopentyl-3-ethyl-1Hindazole-6-carboxylic acid and 5 /4. DMF in 5 mL anhydrous toluene. The reaction mixture was heated to reflux for 2 h, then cooled to room temperature, concentrated to dryness on a rotary evaporator, and dried at high vacuum, room temperature for several hours. The crude add chloride was dissolved in 5 mL CH2CI2 and added to a room temperature solution of 49 /4. (0.532 mmol, 1.1 equiv) aniline and 67 /4. (0.484 mmol, 1.0 equiv) triethylamine in 5 mL CH2CI2. After 18 h at room temperature, the reaction mixture was diluted with 75 mL ethyi acetate, washed 1 x 15 mL each 1N HCI,
H2O, brine, and dried over Na2SO4. Filtration, concentration of filtrate and drying gave
AP/P/ 9 7 / 0 1 0 8 0
AP.00795
-50180 mg of an amber oil, which was purified on a silica gel column to give 160 mg of an off-white solid. Crystallization from ethyl acetate/hexanes gave 130 mg (81%) of a white crystalline solid: mp 146-147°C; Anal, calcd for C21H23N3O: C, 75.65; H, 6.95; N, 12.60. Found: C, 75.65; H, 7.02; N, 12.55.
EXAMPLE 12
4-i(1-Cvclopentvl-3-ethvl-1 H-indazole-6-carbonvlV-aminol-benzoic acid methyl ester
This compound was prepared according to the method of Example 11. using 300 mg (1.16 mmol, 1.0 equiv) 1 -cyclopentyF3-ethyl-1 H-indazole-6-carboxylic acid and
193 mg (1.28 mmol, 1.1 equiv) methyl-4-amino-benzoate as starting materials to give
415 mg (91%) of white crystals: mp 129-132“C; Anal, calcd for C^H^NaOj: C, 70.56;
H, 6.44; N, 10.73. Found: C, 70.36; H, 6.43; N, 10.61.
EXAMPLE 13
1-Cvclopentvl-3-ethvl-1H-indazole-6-carboxylic acid (3-chloro-phenyl)-amide. 15 This compound was prepared according to the method of Example 11, using
150mg (0.581 mmol, 1.0equiv) 1-cyclopentyl-3-ethyHH-indazole-6-carboxylic addand 68 μί. (0.639 mmol, 1.1 equiv) 3-chlono-aniline as starting materials to give 211 mg (99%) of a dear oil: HRMS calcd for C21H22N3CX:i + H: 368.1532. Found: 368.1567.
EXAMPLE 14
1 -Cvdopentyl-3-ethyl-1 H-indazoie-6-carboxylic add(3-methoxy-phenyl)-amide.
mg (0.708 mmol, 1.0 equiv) DMAP were added to a room temperature solution of 196 mg (0.708 mmol, 1.0 equiv) 1-cydopentyt-3-ethyP1H-indazole-6carbonyl chloride, 99 μί. (0.708 mmol, 1.0 equiv) triethylamine and 80 /rL (0.708 mmol,
I. 0 equrv) m-anrsidine in 5 mL CH2Cl2. After 48 hours, the reaction mixture was diluted 25 with 75 mL ethyl acetate, washed 2 x 15 mL 1N HCI, 1 x 15 mL HjO, 1 x 15 mL brine, and dried over MgSO4. Filtration, concentration of filtrate and drying gave 0.27 g of an amber solid, which was purified by silica gel chromatography (ethyl acetate/hexanes gradient 10%, 20%) to give 118 mg of a dear oil. Crystallization from petroleum ether gave 75 mg (29%) of a white powder mp 91-93’C; Anal, calcd for C^^NjOj,: C,
72.71; H, 6.95; N, 11.56. Found: C, 72.35; H, 7.15; N, 11.47.
AP/P/ 97/01080
AP.00795
-51EXAMPLE15
1-Cyclopentvl-3-ethvl-1H-indazole-6-carboxylic add pyridin-4-ylamide 46 μ\- (0.629 mmol, 1.3 equiv) thionyl chloride were added to a room temperature solution of 125 mg (0.484 mmol, 1.0 equiv) 1-cyclopentyl-3-ethyl-1H5 indazole-6-carboxytic add and 5 pL DMF in 5 mL anhydrous toluene. The reaction mixture was heated to reflux for 2 hours, then cooled to room temperature, concentrated to dryness on a rotary evaporator, and dried at high vacuum, room temperature for several hours. The crude add chloride was dissolved in 5 mL anhydrous pyridine, 50 mg (0.532 mmol, 1.1 equiv) 4-aminopyridine were added, and the mixture heated to 40“C for 1 hour. The reaction mixture was cooled to room temperature and allowed to stand overnight. 10 mL H2O were added, and the mixture was concentrated to dryness on a rotary evaporator. The residue was taken up in 50 mL HjO and 25 mL CHjC^, and the layers separated. The aqueous layer was extracted 1 x 25 mL CHjCl^ The organic extracts were combined, washed 1 x 10 mL each H2O, brine, and dried over Na2SO4. Filtration, concentration of filtrate and drying gave 133 mg of a white foam, which was purified on a silica gel column (25% CHaOH/CHjCIj) to give 122 mg of white needles. Recrystallization from ethyl acetate/hexanes gave 101 mg (62%) of white shiny plates; mp 144-146“C; Anal, caicd for C20H22N4O; C, 71.83; H, 6.63; N, 16.75. Found: C, 72.00; H, 7.03; N, 16.16.
EXAMPLE 16
1-CYctopentvF3-ethvt-1H-indazole-e-carboxYlic add pyridin-3-vlamide This compound was prepared according to the method of Example 15, using 58 mg (0.210 mmol, 1.0 equiv) 1-cydopentyP3-ethyl-1H-indazole-6-cart>onyl chloride and 22 mg (0.231 mmol, 1.1 equiv) 3-aminopyridine as starting materials, to give 24 mg (34%) of white crystals: mp 133-135‘C; HRMS caicd for + H: 335.1872.
Found: 335.1900.
EXAMPLE 17
1-Cvdopentyl-3-ethvt-1H-indazole-6-carboxylic add pyridin-2-vlamide . This compound was prepared according to the method of Example 15, using 49 mg (0.177 mmol, 1.0 equiv) 1-cydopentyl-3-ethyl-1H-indazole-6-carbonyi chloride and mg (0.195 mmol, 1.1 equiv) 2-aminopyridine as starting materials, to give 17 mg (34%) of yellow amorphous foam: HRMS caicd for C20H22N4O + H: 335.1872. Pound:
335.1874.
8 0 l 0 / Z 6 /d/dV
AP .00795
-52EXAMPLE 18
1-Cyclo pentyl-3-ethy 1-1 H-indazole-6-carboxylic acid (pyridin-4-vlmethyl)-amide
This compound was prepared according to the method of Example 15, using 51 mg (0.184 mmol, 1.0 equiv) 1-cyclopentyl-3-ethyl-1H-indazole-6-carbonyl chloride and
20//L (0.193 mmol, 1.05 equiv) 4-(aminomethyl)pyridine as starting materials, to give mg (20%) of white crystals: mp 147-149°C; HRMS calcd for C21H24N4O + H: 349.2028. Found: 349.2031.
EXAMPLE 19
1-Cvclopentvl-3-ethvl-1 H-indazole-8-carboxvlic acid(2-pyridin-4-yl-ethvl)-amide
This compound was prepared according to the method of Example 15, using 78 mg (0.282 mmol, 1.0 equiv) 1-cyclopentyl-3-ethyl-1H-indazole-6-carbonyl chloride and 36 //L (0.295 mmol, 1.05 equiv) 4-(2-aminoethyl)pyridine as starting materials, to give 35 mg (35%) of white crystals: mp 123-126°C; Anal, calcd for C^H^N/D'IMHjO: C, 72.01; H. 7.28; N, 15.27. Found: C, 71.77; H, 7.45; N, 15.23.
‘ EXAMPLE 20
1-Cvclopentyl-3-ethvl-1H-indazole-6-carboxvlic add quinolin-5-vlamide
This compound was prepared according to the method of Example 15, using 91 mg (0.329 mmol, 1.0 equiv) 1 -cyclopentyl-3-ethyl-1 H-indazote-6-carbonyl chloride and 52 mg (0.362 mmol, 1.1 equiv) 5-amino-quinoline as starting materials, to give 38 mg (30%) of pate yellow powder mp 176-178°C; Anal, calcd for C24H24N4O; C, 74.96; H,
6.29; N, 14.57. Found: C, 74.33; H, 6.53; N, 14.31.
EXAMPLE 21
1-Cvdopentvt-3-ethyl-1 HHndazole-e-carboxylicaddre.e-dichloro-phenvn-arnide
1.1 mL (15.1 mmol, 1.3 equiv) thionyl chloride were added to a room 25 temperature solution of 3.00 g (11.6 mmol, 1.0 equiv) 1-cydopentyt-3-ethyP1Hindazote-6-carboxylic acid and 150//L DMF in 60 mL anhydrous toluene. The reaction mixture was heated to reflux for two hours, then cooled to room temperature, concentrated on a rotary evaporator, and dried at high vacuum, room temperature to give 3.40 g yellow-brown crystals. 1.88 g (11.6 mmol, 1.0 equiv) 2,6-dichloroaniline were added, and the mixture heated in a 200°C oil bath under nitrogen atmosphere. After 15 minutes, the reaction mixture was cooled to room temperature. 75 mL ethyl acetate and 50 mL saturated aqueous NaHCO, were added, and the mixture stirred for 10 minutes. The layers were separated, and the organic layer was washed 1 x 20 mL
AP/P/ 97/01080
AP.00795
-53saturated NaHCO,, 1 x 20 mL H2O,1 x 20 mL brine, and dried over Na2SO4. Filtration, concentration of filtrate and drying gave a brown solid, which was recrystallized from ethyl acetate/hexanes to give 3.78 g (81%) of tan crystalline solid: mp 177-179’C; Anal, calcd for C21H21N3OCI2: C, 62.69; H, 5.26; N, 10.45. Found: C, 62.67; H, 5.20;
N, 10.43.
EXAMPLE 22
4-f(1-Cvclopentyl-3-ethvl-1 H-indazole-6-carbonvO-aminol-benzoic acid
A mixture of 380 mg (0.971 mmol, 1.0 equiv) 4-((1 -cyclopentyl-3-ethyl-1 Hindazoie-6-carbonyl)-amino]-benzoic acid methyl ester, 4 mL 1N NaOH and 20 mL methanol was heated to reflux for 40 minutes. After cooling to room temperature, the reaction mixture was concentrated on a rotary evaporator, and the residue diluted with 150 mL H2O, acidified to pH = 1, and extracted 2 x 50 mL ethyl acetate. The organic extracts were combined, washed 1 x 25 mL each H2O, brine, and dried over Na2SO4. Filtration, concentration of filtrate, and drying at high vacuum, room temperature gave
298 mg (81%) of a white crystalline solid: mp 249-251*C; Anal, calcd for Ο^Η^Ν,Ο,:
C, 70.00; H, 6.14; N, 11.13. Found: C, 69.66; H, 6.13; N, 11.08.
EXAMPLE 23
1-Cvdopentvl-3-ethyl-1H-indazole-6-carboxvlic add (4-benzyloxvcarbamovlphenvD-amide
140 mg (0.728 mmol, 1.1 equiv) 1-(3-dimethyiaminopropyi)-3-ethylcarbodiimide hydrochloride were added in one portion to a room temperature solution of 250 mg (0.662 mmol, 1.0 equiv) 4-((1-cydopentyl-3-ethyf-1H-indazole-6-carbony1)-amino]benzoic add, 106 mg (0.662 mmol, 1.0 equiv) O-benzyihydroxyiamine hydrochloride, 101 mg (0.662 mmol, 1.0 equiv) 1-hydroxybenzotriazole hydrate, and 194 //L (1.39 mmol, 2.1 equiv) triethylamine in 25 mL CHjCIj. After 18 hours, the reaction mixture was diluted with 150 mL ethyl acetate, washed 1 x 25 mL each 1N HCI, H2O, brine, and dried over Na2SO4. The crude product was purified on a silica gel column (2% CHjOH/CHjCl^ flash) to give 212 mg (66%) of white crystalline solid: mp 194-198’C; Anal, caicd for C2SH3ON4O3: C, 72.17; H, 7.10; N, 11.61. Found: C, 71.62; H, 6.47; N,
11.85,
AP/F/ 97,01080
AP.00795
-54EXAMPLE 24
1-Cyclopentyl-3-ethyl-1H-indazole-€-carboxylic acid (4-hydroxvcarbamovlphenvD-amide
A mixture of 187 mg (0.387 mmol, 1.0 equiv) 1-cyclopentyl-3-ethyl-1H-indazole5 6-carboxylic acid (4-benzyloxycarbamoyl-phenyl)-amide and 200 mg 10% Pd/C in 10 mL ethyl acetate and 10 mL methanol was placed on a Parr® hydrogenation apparatus and shaken under 30 psi H2 at room temperature for 1 hour. The reaction mixture was filtered through Celite®, and the filtrate concentrated and dried to give a tan solid. Purification on a silica gel column (CH3OH/CH2CI2 gradient 4%, 10%, 20%, flash) gave
74 mg (49%) of a tan solid: mp 175°C (dec); HRMS calcd for C^H^h^Oj + H:
393.1928. Found: 393.1949.
EXAMPLE 25
25Λ 1-Cyclobutyl-3-ethvl-1H-indazole-€-carboxvlic acid methyl ester
This compound was prepared according to the method of Preparation 3, using 15 750 mg (3.67 mmol, 1.0 equiv) 3-ethyH H-indazole-6-carboxylic acid methyl ester and
0.38 mL (4.04 mmol, 1.1 equiv) cyclobutyl bromide as starting materials to give 307 mg (32%) of a clear oil: HRMS calcd for C15H18N2O2 + H: 259.1447. Found: 259.14550.
25.B 3-Ethyl-1 -isopropyl-1 H-indazole-6-carboxylic add methvl ester
This compound was prepared according to the method of Preparation 3, using 20 750 mg (3.67 mmol, 1.0 equiv) 3-ethyHH-indazole-6-carboxylic acid methyl ester and
0.38 mL (4.04 mmol, 1.1 equiv) 2-bromopropane as starting materials to give 359 mg (40%) of a dear oil: HRMS calcd for C14H18N2O2 + H: 247.1448. Found: 247.14530.
25.C 1-Cvdopropylmethvl-3-ethvH H-indazole-6-carboxvlic add methvl ester
This compound was prepared according to the method of Preparation 3, using 25 750 mg (3.67 mmol, 1.0 equiv) 3-ethyH H-indazole-6-carboxylic add methyl ester and
0.39 mL (4.04 mmol, 1.1 equiv) cydopropylmethyl bromide as starting materials to give 338 mg (36%) of a dear oil: HRMS calcd for C15HMN2O2 + H: 259.1447. Found
259.1435.
25.D 1-Cvdohex-2-enyl-3-ethyl-1H-indazole-6-cartooxYric add methvl ester 30 This compound was prepared according to the method of Preparation 3, using
750 mg (3.67 mmol, 1.0 equiv) 3-ethyl-1H-indazole-6-carboxylic add methyl ester and 0.46 mL (4.04 mmol, 1.1 equiv) 3-bromocydohexene as starting materials to give 467 mg (45%) of a dear oil: HRMS calcd for C^joNjO,: 284.1525. Found: 284.1512.
AP/P/97/0 10 80
AP.00795
-5525. E 3-Ethyl-1-f6-(4-phenyl-butoxv)-hexvl1-1 H-indazole-6-carboxylic acid methyl ester
This compound was prepared according to the method of Preparation 3, using 137 mg (0.671 mmol, 1.0 equiv) 3-ethyl-1H-indazole-6-carboxylic acid methyl ester and
273 mg (0.872 mmol, 1.3 equiv) 6-(4-phenyl-butoxy)-hexyl bromide as starting materials to give 163 mg (56%) of a yellow oil: HRMS calcd for Α,Η^ΝΑ + H: 437.2804. Found 437.2833.
EXAMPLE 26
26A 1-Cvdobutyl-3-ethvl-1H-indazole-6-cart>oxylic add 10 This compound was prepared according to the method of Preparation 3, using
225 mg (0.906 mmol, 1.0 equiv) 1-cydobutyl-3-ethyl-1H-indazole-6-carboxylic acid methyl ester as starting material to give 168 mg (76%) of an off white crystalline solid: mp 148-150°C; HRMS calcd for CMHieN2O2 + H: 245.1290. Found: 245.1302.
26. B 3-EthyH -isopropyH H-indazole-6-carboxylic add
This compound was prepared according to the method of Preparation 3, using
300 mg (1.22 mmol, 1.0 equiv) 3-ethyH-isopropyl-1 H-indazole-6-carboxylic acid methyl ester.as starting material to give 260 mg (92%) of a pale yellow crystalline solid: mp 160-163’C; Anal, calcd for C„H16N2O2: C, 67.21; H, 6.94; N, 12.05. Found: C, 67.07; H, 7.04; N, 12.16.
26.C 1 -Cydopropylmethyl-3-ethvl-l H-indazole-6-cartooxvlic add
This compound was prepared according to the method of Preparation 3, using
294 mg (1.14 mmol, 1.0 equiv) 1-cyclopropylmethyf-3-ethyf-1H-indazole-6-cartx3xy1ic acid methyl ester as starting material to give 261 mg (94%) of a pale yellow crystalline solid: mp 126-130’C; Anal, calcd for CUH16N2O2: C, 68.83; H, 6.60; N, 11.46. Found:
C, 68.39; H, 6.67; N, 11.41.
26.D 3-Ethvi-1 -f6-(4-phenyt-butoxy)-hexvn-1 H-indazole-6-carboxvIic add This compound was prepared according to the method of Preparation 3, using
147 mg (0.337 mmol, 1.0 equiv) 3-ethyl-1-{6-(4-phenyl-butoxy}-hexyIJ-1H-indazole-6carboxylic add methyl ester as starting material to give 137 mg (96%) of a pale yellow oil: HRMS calcd for C^H^NA + H: 423.2648. Found: 423.26795.
AP/P/ 9 7 / 0 1 0 8 0
AP.00795
-56EXAMPLE 27
27. A 1-Cyclohexyl-3-ethvl-1H-indazole-6-cart>oxylic acid methvl ester
A mixture of 417 mg (1.47 mmol, 1.0 equiv) 1-cyclohex-2-enyl-3-ethyl-1Hindazole-6-carboxylic acid methyl ester and 50 mg of 10% Pd/C, 50% water wet in 20 mL ethyl acetate was placed on a Parr® hydrogenation apparatus and shaken under 45 psi H2 for 45 minutes. The reaction mixture was filtered through Celite®, and the filtrate concentrated on a rotary evaporator and dried at high vacuum, room temperature to, give 399 mg (95%) of a clear oil: HRMS calcd for + H:
287.1759. Found: 287.1783.
27.B 1-Cyclohexvl-3-ethvl-1 H-indazole-6-cart>oxYlic acid
This compound was prepared according to the method of Preparation 3, using
366 mg (1.28 mmol, 1.0 equiv) 1-cydohexyl-3-ethyl-1H-indazole-6-carboxylic add methyl ester as starting material to give 325 mg (93%) of a pale yellow solid: mp 196197°C; HRMS calcd for Ο,βΗ»Ν2Ο2 + H: 273.1603. Found: 273.1596.
EXAMPLE 28
28_A 3-Ethyl-1-(4-fluoro-phenvl)-1H-indazole-6-carboxYlic acid methvl ester 0.245 mL (2.24 mmol, 2.0 equiv) 1-bromo-4-fluorobenzene were added to a room temperature suspension of 0.23 g (1.12 mmol, 1.0 equiv) 3-ethyH H-indazole-6carboxylic add methyl ester, 0.23 g (1.67 mmol, 1.5 equiv) potassium carbonate, and ~100 mg (0.348 mmol, 0.3 equiv) Cu2Br2 in 6 mL N-methylpyrrolidinone. The reaction mixture was heated to 175°C for 28 hours, then cooled to room temperature, poured into 100 mL H2O, and extracted 3 x 50 mL ethyl acetate. The organic extracts were combined, washed 2 x 50 mL H20,1 x 50 mL brine. The aqueous washes were back extracted 1 x 75 mL with ethyl acetate. All ethyl acetate extracts were then combined and dried over Na2SO4. Filtration, concentration of filtrate and drying gave 0.6 g of brown oil, which was purified on a silica gel column (10% ethyl acetate/hexanes) to give 96 mg (29%) of a white crystalline solid: mp 72-74’C; MS (Cl, NH,) m/z 299 (M+H*. base).
28. B 3-EthvH-(4-fiuoro-phenyl)-1 H-indazole-6-carboxvlic acid
This compound was prepared according to the method of Preparation 3, using mg (0.322 mmol, 1.0equiv) 3-ethyl-1 -(4-fluoro-phenyl)-1 H-indazole-6-carboxylic add methyl ester as starting material to give 64 mg (92%) of a white solid: mp 204-205’C; HRMS calcd for C16H13N2O2F + H: 285.1040. Found: 285.10257.
AP/P/ 9 7 / 0 1 0 8 0
AP.00795
-57EXAMPLE 29
1-Cyclobutyl-3-ethyl-1H-indazole-6-carboxvlic acid (3,5-dichloro-pvridin-4-yl)amide
This compound was prepared according to the method of Example 10, using 5 144 mg (0.589 mmol, 1.0 equiv) 1-cyclobutyl-3-ethyl-1H-indazole-6-carboxylic acid as starting material, to give 44 mg (18%) of an off white crystalline solid: mp 166-168°C;
HRMS calcd for C,eHieN4OCI2 + H: 389.0936.
EXAMPLE 30
3-EthyH-isopropyl-1 H-indazole-6-carboxylic add (3.5-dichloro-pyridin-4-yl)10 amide
This compound was prepared according to the method of Example 10, using 232 mg (1.00 mmol, 1.0 equiv) 3-ethyl-1-isopropyHH-indazole-6-carboxylic add as starting material, to give 73 mg (20%) of an off white crystalline solid: mp 145-148’C; HRMS calcd for C1tH18N4OCI2 + H: 377.0936. Found: 377.0938.
EXAMPLE 31
1-Cydopropvlmethvl-3-ethvl-1H-indazole-6-cart>oxvlic acid (3.5-dichloroPVridin-4-vD-amide
This compound was prepared according to the method of Example 10, using 224 mg (0.917 mmol, 1.0 equiv) 1-cydopropylmethyl-3-ethyl-1-H-indazole-6-carboxylic add as starting material, to give 51 mg (14%) of an off white crystalline solid: mp 148150 °C; HRMS calcd for C1eHwN4OCl2+H:389.0936. Found: 389.091.
EXAMPLE 32
1-Cvdohexyl-3-ethvt-1H-indazole-6-cartx?xvlic add f3,5-dichloro-pyridin-4-viP amide
This compound was prepared according to the method of Example 10, using
300 mg (1.10 mmol, 1.0 equiv) 1-cydohexyP3-ethyHH-indazole-6-cait>oxylic add as starting material, to give 83 mg (18%) of an off white crystalline solid: mp 124-127 °C; MS(CI, NHJ m/z 421 (M+H«., ^CI+^CI), 419(M+H., XCI+37CI, base), 417 (M+H+,
36θί+36^Ι).
AP/P/ 9 7 / 0 1 0 8 0
AP.00795
-58EXAMPLE 33
3- Ethyl-1 -i6-(4-phenyl-butoxy)-hexvn-1 H-indazole-6-carboxylic acid (3.5dichloro-pyridin-4-yl)-amide
This compound was prepared according to the method of Example 1, using 127 mg (0.301 mmol, 1.0 equiv) 3-ethyl-1-[6-(4-phenyl-butoxy)-hexyl]-1H-indazole-6carboxylic acid as starting material, to give 119 mg (70%) of a clear oil, which was crystallized from ether/hexanes to give 72 mg (42%) of white crystals: mp 76-79eC; HRMS calcd for C31HMN4O2CI2+H:567.2294. Found: 567.2288
EXAMPLE 34
3-Ethyl-1-(4-fluoro-phenvl)-1H-indazole-6-carfaoxvlic add (3.5-dichloro-pyridin4- vl)-amide
This compound was prepared according to the method of Example 10, using 80 mg (0.281 mmol, 1.0 equiv) 3-ethyl-1-(4-fluoro-phenyl)-1H-indazole-6-carboxylic acid as starting material, to give 22 mg (18%) of a white crystalline solid: mp 197-199 °C;
HRMS calcd for C2,H15N4OCL2F + H: 429.0688. Found: 429.0704.
EXAMPLE 35 f(1-Cvclopentyl-3-ethvl-1 H-indazole-6-carfeonvl)-aminoI-acetic addmethylester.
134 mg (0.697 mmol, 1.0 equiv) 1-(3-dimethylarninopropyl)-3-ethylcart>odiimide hydrochloride were added in one portion to a room temperature solution of 180 mg (0.697 mmol, 1.0 equiv) 1-cyclopentyl-3-ethyHH-indazole-6-carboxylic acid, 87.5 mg (0.697 mmol, 1.0 equrv) glycine methyl ester hydrochloride, 107 mg (0.697 mmol, 1.0 equiv) 1-hydroxybenzotriazoie hydrate, and 194/rL (1.39 mmol, 2.0 equiv) triethylamine in 5 mL CHjC^. After 18 h, the reaction mixture was diluted with 150 mL ethyl acetate, washed 1 x 25 mL each 1N HCI, H2O, brine,and dried over Na2SO4. The crude product was purified on a silica gel column (40% ethyl acetate/hexanes, flash) to give 187 mg (66%) of a white waxy solid: mp 89-93°C; Anal, calcd for C^H^NjOj; C, 65.63; H, 7.04; N, 12.76. Found: C, 65.74; H, 7.02; N, 12.74.
EXAMPLE 36 . i(1-Cyclopentyl-3-ethyH H-indazole-6-carbonyl)-aminol-acetic add
This compound was prepared according to the method of Preparation 3, using
170mg (0.516mmol, 1.0equiv)[(1-cyclopentyF3-ethyH H-indazole-6-cartx>nyf)-amino}acetic add methyl ester as starting material to give 155 mg (95%) white crystals: mp
AP/P/ 97/91080
AP .00795
-59182-184 °C; Anal, calcd for C17H21N3O3: C, 64.73; H, 6.71; N, 13.32. Found; C, 64.73; H, 6.80; N, 12.81.
EXAMPLE 37
1-Cyclopentyi-3-ethvl-1H-indazole-6-carboxvlic acid (benzyloxycarbamoyl5 methyQ-amide
This compound was prepared according to the method of Example 23, using 144 mg (0.457 mmol, 1.0 equiv) [(1 -cyclopentyl-3-ethyl-1 H-indazole-6-carbonyl)-amino]acetic add as starting material to give 125 mg (65%) of a white amorphous solid: 1H NMR (300 MHz, CDCIj, partial) <5 493 (s, 2H),3.00 (q, 2H, J=7.6 Hz), 2.2 (m, 4H), 2.0 (m, 2H), 1.7 (m, 2H), 1.39 (t, 3H, J=7.6 Hz); MS (Cl, NHJ m/z 421 (M+H+, base).
EXAMPLE 38
1-Cydopentvl-3-ethyl-1H-indazole-6-carboxvlic add hydroxycarbamoylmethylamide
A mixture of 120 mg (0.285 mmol, 1.0 equiv) 1-cydopentyl-3-ethyl-1H-indazole15 6-carboxylic add (benzyioxycarbamoyl-methyl)-amide and 0.08 g 10% Pd/C, 50% water wet, in 10 mL methanol and 10 mL ethyl acetate was placed on a Parr® hydrogenation apparatus and shaken under 30 psi H2 at room temperature for 40 minutes. The reaction mixture was filtered through Celite®, and the filtrate concentrated and dried to give 104 mg of a tan solid. Trituration with hexanes gave 69 mg (73%) of a tan crystalline powder mp 105 °C (dec); HRMS calcd for C^H^NA + H: 331.1772. Found: 331.1769.
EXAMPLE 39
1-Cvdopentyl-3-ethyi-1H-indazole-6-carboxy1ic add (2-methyisutfanyl-ethvl)amide
This compound was prepared according to the method of Example 35, using 57 mg (0.221 mmol, 1.0 equiv) 1-cydopentyl-3-ethyl-1H-indazoie-6-carboxylic add and 20 mg (0.221 mmol, 1.0 equiv) 2-{methylthio)ethylamine as starting materials. Silica gel chromatography (30% ethyl acetate/hexanes) gave 53 mg (73%) of white crystals: mp 81-83 *C; Anal, calcd for C^NA C, 65.21; H, 7.60; N, 12.68. Found: C, 65.26;
H, 7.49; N, 12.81.
AP/P/ 9 7 / 0 1 0 8 0
AP. ο ο 7 9 5
-60EXAMPLE 40
1-CvdopentvL3-ethvHH-indazole-6-carboxylic acid (methoxycarbamoyl-methvl)amide
This compound was prepared according to the method of Example 37, using
222mg (0.704 mmol, 1 .Oequiv) [(1 -cydopentyi-3-ethyl-1 H-indazole-6-carbonyl)-amino]aceticacid and 59 mg (0.704 mmol, 1.0 equiv) methoxylamine hydrochloride as starting materials to give 39 mg of a clear oil, which was crystallized from ether/hexanes to give 34 mg (14%) of white crystals: mp 135-136 °C; Anal, calcd for C18H24N4O3: C, 62.77; H, 7.02; N, 16.27. Found:C, 62.64; H, 6.87; N, 16.47.
EXAMPLE 41
3-f(1-Cvclopentvl-3-ethyl-1 H-indazole-6-carbonyl)-amino1-propionic add ethyl ester
This compound was prepared according to the method of Example 35, using 297 mg (1.15 mmol, 1.0 equiv) 1-cydopentyl-3-ethyHH-indazole-6-carboxyiic acid and
177 mg (1.15 mmol, 1.0 equiv) £>ete-alanine ethyl ester hydrochloride as starting materials to give 372 mg (90%) of white crystals: mp 74-76 C; Anal, calcd for C20H27N3O3: C, 67.21; H, 7.61; N, 11.76. Found: C,67.40; H, 7.56; N, 11.99.
EXAMPLE 42
3-f(1-Cydopentvl-3-ethvl-1 H-indazole-e-carbonyD-aminol-propionic add
A mixture of 330 mg (0.923 mmol, 1.0 equiv) 3-[(1-cydopentyl-3-ethyl-1Hindazole-6-carbonyl)-amino)-propionic acid ethyl ester in 10 mL ethanol and 4 mL 1N NaOH was heated to reflux for 1 h. After cooling to room temperature, the reaction mixture was concentrated, diluted with 75 mL H2O, addified to pH 1, and extracted 3 x 35 mL ethyl acetate. The organic extracts were combined, washed 1 x 25 mL H2O,
1 x 25 mL brine, and dried over Na2SO4. Filtration, concentration of filtrate on a rotary evaporator and drying at high vacuum, room temperature gave 297 mg (98%) of white solid: mp 151-153 *C; Anal, calcd forCieHaN,O3: C, 65.63; H, 7.04; N, 12.76. Found: C, 65.75; H, 7.12; N, 12.91.
EXAMPLE 43
1-Cydopentyi-3-ethyl-1H-indazole-6-carboxvlic acid (2-benzvloxvcarbamovk ethvD-amide
This compound was prepared according to the method of Example 37, using 250 mg (0.759 mmol, 1.0 equiv) 3-[(1-cydopentyl-3-ethyl-1H-indazole-6-carbonyl)AP/P/ 97.01080
AP.00795
-61aminoj-propionic acid and 121 mg (0.759 mmol, 1.0 equiv) O-benzylhydroxylamine hydrochloride as starting materials, to give 237 mg (72%) of a white solid: mp 134-136 °C; Anal, calcd for C^H^N^: C, 69.10; H, 6.96; N, 12.89. Found: C. 69.36; H, 6.75; N, 12.85.
EXAMPLE 44
1-Cyclopentyl-3-ethvl-1H-indazole-6-carboxvlic acid (2-hvdroxycaitiamovlethyl)-amide
This compound was prepared according to the method of Example 38, using 203 mg (0.467 mmol, 1.0 equiv) 1-cydopentyl-3-ethyl-1H-indazole-6-carboxylic acid (210 benzyloxycarbamoyl-ethyl)-amide as starting material and 50 mg of PdCOH^C (Pearlman’s catalyst) as catalyst, to give 147 mg (91%) of a wh'rte powder mp 166-169 °C; Anal, calcd for C18H24N4O3: C,62.77; H, 7.02; N, 16.27. Found: C, 62.58; H, 7.12; N, 16.27.
EXAMPLE 45 f(1-Cyclopentyl-3-ethvf-1H-indazoie-6-cart>onyD-methvl-aminoT-acetic addethyl ester
This compound was prepared according to the method of Example 35, using 284 mg (1.10 mmol, 1.0 equiv) 1-cydopentyl-3-ethyHH-indazole-6-carboxylic add and 169 mg (1.10 mmol, 1.0 equ'rv) sarcosine ethyl ester hydrochloride as starting materials, to give 220 mg (56%) of a dear oil: Anal.calcd for CjoH^jO,: C, 67.21; H, 7.61; N, 11.76. Found: C, 66.93; H, 7.73; N, 11.77.
EXAMPLE 46 [1 -Cvclopentyt-3-ethvt-1 H-indazole-6-cait>onvP-methvl-aminol-acetic add.
This compound was prepared according to the method of Example 42, using 25 201 mg(0.562 mmol, 1.0 equiv) [(1-cyclopentyi-3-ethyl-1 H-indazole-6-carbonyl)-methylamino]-acetic acid ethyl ester as starting material, to give 185 mg (100%) of a white amorphous solid: Anal, calcd for C, 64.74; H, 7.09; N, 12.58.
Found: C, 64.73; H, 7.55; N, 12.47.
EXAMPLE 47
1-Cvdopentyl-3-ethvl-1H-indazole-6-cartX)xylic add fbenzytoxycarbamoylmethvP-methyl amide
This compound was prepared according to the method of Example 37, using 160 mg (0.486 mmol, 1.0 equiv) [(1 -cydopentyk3-ethyl-1 H-indazole-6-carbonyl)-methyl·
AP/P/ 9 7 / 0 1 0 8 0
AP.00795
-62amino]-acetic acid as starting material, to give 134 mg (64%) of a clear oil: HRMS calcd for C2iH30N4O3 + H: 435.2398. Found: 435.2376.
EXAMPLE 48
1-Cyclopentvl-3-ethvl-1H-indazole-6-carboxylic acid hydroxycarbamoylmethyl5 methvl amide
This compound was prepared according to the method of Example 38, using 126 mg (0.290 mmol, 1.0 equiv) 1-cyclopentyl-3-ethyHH-indazole-6-carboxylic acid (benzyloxycarbamoyl-methyl)-methyl amide as starting material and 40 mg of Pd(OH)/C (Peariman’s catalyst) as catalyst, to give 78 mg (78%) of a light tan powder mp 63 °C (dec); HRMS calcd for CieH24N4O3 + H: 345.19285. Found: 345.1912.
EXAMPLE 49
1-Cyclopentyl-3-ethvl-lH-indazole-6-carboxvlic acid ffhydroxy-methylcarbamovD-methyfl-amide.
390 mg (16.9 mmol, 20 equiv) sodium, 3 to 8 mm spheres, were added to 10 15 mL of methanol portion wise for 30 minutes. A solution of 707 mg (8.47 mmol, 10 equiv) N-methylhydroxyiamine hydrochloride in 10 mL methanol was added dropwise, and the reaction mixture allowed to stir 10 min. A solution of 279 mg (0.847 mmol, 1.0 equiv) [(1-cydopentyl-3-ethyl-1H-indazole-6-carbonyI)-amino]-acetic acid methyl ester in 10 mL methanol was added drop wise, and the reaction allowed to stir 16 h at room temperature. The mixture was then concentrated to 1/2 of its initial volume, diluted with 150 mL HjO, acidified to pH = 2, and extracted 2 x 50 mL ethyl acetate. The organic extracts were combined, washed in 2 x 20 mL, HjO, 1 x 20 mL brine, and dried over Na2SO4. Filtration, concentration of filtrate and drying gave 0.33 g of a clear oil, which was purified on a silica gel column (10% CH3OH/CHjCL2, flash) to give 236 mg of a white foam. Trituration with pentane yielded 150 mg (51%) white amorphous solid: mp 60 eC (dec); Anal, calcd for Ο,,Η^ΝΑ^Ο: C, 59.65; H, 7.23; N, 15.46. Found: C, 62.04; H, 7.39: N, 15.86.
EXAMPLE 50 . 50A S-(1-Benzvloxvcarbamoyi-ethvD-carbamic add tert-butvl ester.
This compound was prepared according to the method of Example 44, using
500 mg (2.64 mmol, 1.0 equiv) N-(tert-butoxycartx)nyl)-L-alanine and 422 mg (2.64 mmol, 1.0 equiv) O-benzylhydroxylamine hydrochloride, to give 583 mg (75%) of a white oily solid: ’H NMR (300 MHz, CDClj) 6 9.02 (br s, 1H), 7.37 (m, 5H), 4.95 (m,
AP/P/ 9 7 / 0 1 0 80
AP . Ο Ο 7 9 5
-631Η),4.90 (s, 2Η), 4.03 (m, 1 Η), 1.41 (s, 9Η), 1.33 (d, 3Η, J=7.0 Hz); MS (Cl, NHJ m/z295 (M+H*, base).
50.B. S-2-Amino-N-benzyloxv-proprionamide hydrochloride.
HCI (g) was bubbled into a O’C solution of 561 mg (1.91 mmol, 1.0 equiv) S-(15 benzyloxycarbamoyl-ethyl)-carbamic acid tert-butyl ester in 10 mL anhydrous 1,4dioxane over 1-2 minutes. The reaction mixture was allowed to stir at room temperature for 45 min., then was concentrated on a rotary evaporator and dried at high vacuum, room temperature to give 492 mg (>100%) white hygroscopic amorphous solid: Ή NMR (300 MHz, DMSO-dJ δ 11.8 (s, 1H), 8.38 (br s, 3H), 7.38 (m, 5H),
4.82(m, 2H), 3.68 (m, 1H), 1.29 (d, 3H, J=6.9 Hz).
EXAMPLE 51
S-1-Cvclopentyl-3-ethvl-1H-indazole-6-carboxylic add (1-benzyloxycarbamoylethvD-amide
This compound was prepared according to the method of Example 37, using 15 200 mg (0.774 mmol, 1.0 equiv) 1 -cydopentyl-3-ethyH H-indazole-6-cartx>xylic acid and
180 mg (0.774 mmol, 1.0 equiv) S-2-amino-N-benzyioxy-propionamide hydrochloride as starting materials, to give 322 mg (96%) of a dear oil: HRMS calcd for C25H30N40J + H: 435.2396. Found: 435:2424.
EXAMPLE 52
S-1-CydopentYf-3-ethYl-1H-indazole-6-carboxYlic add (1 -hydroxvcarbamoytethvh-amide
This compound was prepared according to the method of Example 38, using 288 mg (0.663 mmol, 1.0 equiv) S-1-cydopentyl-3-ethyt-1H-indazole-6-carboxy6c add (1-benzyloxycarbamoyl-ethy1)-amide as starting material and 90 mg PdCOHj^/C as catalyst to give 170 mg (75%) tan powder mp 106’C (dec); HRMS calcd for C^H^Oj + H: 345.1927. Found: 345.1923.
EXAMPLE 53
R-(1-Benzyloxvcarbamovl-ethyfl-carbamic add tert-butyl ester.
This compound was prepared according to the method of Example 37, using
500 mg (2.64 mmol, 1.0 equiv) N-(tert-butoxycarbonyf)-D-alanine and 422 mg (2.64 mmol, 1.0 equiv) O-benzylhydroxylamine hydrochloride, to give 592 mg (76%) of a white oily solid: 1H NMR (300 MHz, CDCy δ 9.02 (br s, 1H), 7.37 (m, 5H), 4.95 (m,
8 0 I 9 > L 6 /d/dV
AR. θ θ 7 9 5
-641 Η),4.90 (s, 2Η), 4.03 (m, 1Η), 1.41 (s, 9Η), 1.33 (d, 3H, J=7.0 Hz); MS (Cl, NHJ m/z295 (M+H*, base).
EXAMPLE 54
R-1-Cvclopentvl-3-ethyl-1H-indazole-6-carboxvlic acid (1-hvdroxycartoamovl5 ethvD-amide
54A. R-2-Amino-N-benzyloxy-propionamide hydrochloride.
HCl (g) was bubbled into a O’C solution of 570 mg (1.94 mmol, 1.0 equiv) R-(1benzyloxycarbamoyl-ethyl)-carbamic add tert-butyl ester in 10 mL anhydrous 1,4dioxane over 1-2 minutes. The reaction mixture was allowed to stir at room temperature for 45 min., then was concentrated on a rotary evaporator and dried at high vacuum, room temperature to give 512 mg (>100%) white hygroscopic amorphous solid; 1H NMR (300 MHz, DMSO-d J δ 11.8 (s, 1H), 8.38 (br s, 3H), 7.38 (m, 5H), 4.82(m, 2H), 3.68 (m, 1H), 1.29 (d, 3H, J=6.9 Hz).
54.B. R-1-Cvclopentyl-3-ethyl-1 H-indazole-6-carboxvlic acid (115 benzvloxvcarbamovl-ethyl)-amide
This compound was prepared according to the method of Example 37, using
200mg (0.774 mmol, 1.0equiv)1-cydopentyl-3-ethyl-1H-indazqle-6-carboxylic addand 180 mg (0.774 mmol, 1.0 equiv) R-2-amino-N-benzyloxy-propionamide hydrochloride as starting materials, to give 330 mg (98%) of a dear oil: HRMS calcd for C^H^Oj + H: 435.2396. Found: 435.2414.
54.C. R-1-Cvclopentvl-3-ethyl-1H-indazole-6-carboxylic acid (1hydroxycarbamovl-ethyO-arnide
This compound was prepared according to the method of Example 30, using 295 mg (0.679 mmol, 1.0 equiv) R-1-cydopentyF3-ethyl-1H-indazole-6-carboxyiic add (1-benzyk>xycarbamoyl-ethyl)-amide as starting material and 90 mg PdiOHJj/C as catalyst, to give 201 mg (86%) tan powder, mp 102°C (dec); HRMS calcd for C^H^N.,0, + H; 345.1927. Found: 345.1927.
AP/P/ 9 7 / 0 1 0 8 0
AP.00795
-65EXAMPLE 55
-Cvclopentvl-3-ethvl-6-thiophen-2-vl-1 H-indazole
A solution of 76 mg (0.598 mmol, 1.2 equiv) thiophene-2-boronic acid in 0.5 mL methanol was added to a room temperature suspension of 146 mg (0.498 mmol, 1.0 equiv) 6-bromo-1-cydopentyl-3-ethyl-1 H-indazole and 17 mg (0.0149 mmol, 0.03 equiv) PdfPPhJJn 2 mL toluene and 0.5 mL 2M aqueous Na2CO5. The mixture was heated to reflux for 4 h, then cooled to room temperature. The reaction mixture was diluted with 50 mL ethyl acetate, washed 1 x 10 mL each H2O, brine, and dried over MgSO4. The crude product was purified on a silica gel column (3% ethylacetate/hexanes, flash) to give 81 mg (55%) of a clear oil, which crystallized onstanding: mp 60-64 “C; HRMS calcd for C^HJ^S + H: 297.1427. Found:297.1484.
EXAMPLE 56
-Cvclopentyl-3-ethvt-6-phenyl-1 H-indazole
This compound was prepared according to the method of Example 55, using 15 128 mg (0.437 mmol, 1.0 equiv) 6-bromo-1 -cydopentyl-3-ethyH H-indazole and 75 mg (0.612 mmol, 1.4 equiv) phenyl boronic add as starting materials, to give 98 mg (77%) of white crystals: mp 72-74 eC; Anal, calcd for C^H^N^ C, 82.77; H, 7.64; N, 9.65.
Found: C.81.95; H, 7.82; N, 9.75.
EXAMPLE 57
1-Cvdopentyi-3-ethvl-1H-indazole-6-carboxytic add (3,5-dichloro-pyridin-4-v0roethyt-amide
5.2 mg (0.130 mmol, 1.05 equiv) sodium hydride, 60% oil dispersion, were added to a room temperature solution of 50 mg (0.124 mmol, 1.0 equiv) 1-cydopentyl3-ethyl-1 H-indazote-6-carboxylic add (3,5-dichloro-pyridin-4-yl)-amide in 3 mL anhydrous DMF. After 30 min., 7.7 pL (0.124 mmol, I.Oequiv) iodomethane were added and the mixture stirred at room temperature for 4 h. The reaction mixture was diluted with 50mL HjO and extracted 2 x 20 mL ethyl acetate. The ethyl acetate extracts were combined, washed 2 x 5 mL K2O, 1x 5 mL brine, and dried over Na2SO4. Filtration, concentration of filtrate and drying gave a yellow oil, which was purified on a silica gel column (25% ethylacetate/hexanes, flash) to give 27 mg (52%) of a white crystalline solid: mp 118-119 *C; HRMS calcd for C^py^OCIj + H: 417.12519.
Found: 417.12270.
AP/P/ 9 7 / 0 1 0 8 0
AP.00795
-66EXAMPLE 58
1-Cyclopentvl-3-ethYl-1H-indazole-carboxylic acid dimethyl amide mg (0.246 mmol, 1.1. equiv) of 1-(3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride were added in one portion to a room temperature solution of 57.8 mg (0.224 mmoles, 1.0 equiv) 1-cyclopentyl-3-ethyl-1H-indazole-6carboxylic acid, 18 mg (0.224 mmole, 1.0 equiv) dimethylamine hydrochloride, 34 mg (0.224 mmol, 1.0 equiv) hydroxybenzotriazole hydrate and 66 /4 (0.470 mmol, 2.1 equiv) of triethylamine in 5.0 mL of anhydrous methylene chloride. After stirring the reaction mixture for 18 hours under a N2 atmosphere, the reaction mixture was diluted with 40 mL of ethylacetate, washed with 10 mL of 1N HCI, water, and brine, and dried over Na2SO4. The crude product was purified on a silica gel column. (50% EtOAc/50% CHjCIJ to give 55 mg (86%) of clear oil: HRMS calcd for C^H^NjO + H: 285.1843. Found: 285.1841.
Claims (2)
1. A compound of the formula I or a pharmaceutically acceptable salt thereof, wherein:
R is H, C,-Ce alkyl, -{CHJJS to 10 membered heterocyclyi) wherein m is 0 to 2, (Cq-Cg alkoxyJC^-Cg alkyl, C2-Ce alkenyl, or -{Z1)b(Z2)c(Ce-C10 aryl) wherein b and c are independently 0 or 1, Z, is C,-Ce alkylene or C2-Ce alkenylene, and Zj is O, S, SO2>
15 or NR12, and wherein said R groups are optionally, substituted by 1 to 3 substituents independently selected from the group consisting of halo, hydroxy, C,-C5 alkyl, C2-C5 alkenyl, C,-Ce alkoxy, trifluoromethyl, nitro, -CO2R12, -C(O)NR«R13l -NR12R13 and -SO2NR12R13;
R, is H, C,-C8 alkyl, C2·^ alkenyl, or phenyl, wherein said alkyl, alkenyl and
20 phenyl R, groups are optionally substituted by 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, trifluoromethyl, and halo;
R2 Is Rie, -C(O)NR12(CHR12)mC(O)NR12O(CH2),(C,-C10 aryl), -C(=NR32)NH(CH2)p(C,-C10 aryl), -C(O)NR8(CHR12)„C(O)NR12(CH2)pOR12, -C(O)NR12(CHR12)mS(C,-C4 alkyl), -C(=NOC(O)R2S)R2e, -CR17R„CHR2BNReSO2(CH2)pA,
25 ^RvRnCHR^NR^OXOR^OXCq-C, alkyl), -CR^^CHR^NRgPiOXC,^ alkoxy^, -Zs-Rt, or XCR^iLNR^CXOJXR^ wherein p is 0 to 2, m is 1 to 6, and q is 1 or 2;
AP/P/ 97.01080
AP.00795 (Ic) (Id) (Ie) (If)
NH I
AP/P/ 97.01080 (lg) < Ih>
(Ii)
AP. ϋ υ 7 9 5
-69wherein in said formulas (la>-(Ii), the structures of formulas (If) and (lg) are attached to formula I at carbons 5, 6, or 7 of said formulas (If) and (lg), the dashed line in formulas (Ic) and (Id) indicates a single bond or double bond, except R, is absent in formulas (Ic) and (Id) where said dashed line indicates a double bond, n is 0 to 2, p is
5 0 to 6, and m is 0 or 1;
Ra is -C(O)N(CHj)(OCH3) or -(CH2)nOH wherein n is 0 to 4;
R4 and Rj are independently selected from the group consisting of H, ethyl, -CO2H and -C(O)NHOH;
Re is H, cyano, hydroxy, 0,-0, alkyl, C5-Ce alkoxy, -00(0)(0,-0, alkyl) or 10 OC(O)(C,-C„ aryl);
R7 is C,-C,o aryl or 5 to 10 membered heterocyclyl, wherein said R7 groups are optionally substituted by 1 to 3 substituents independently selected from halo, trifluoromethyl, cyano, nitro, -OO2R,2, C,-C4 alkoxy, -OC(0)(C,-C4 alkyl), -NR,2C(O)(C,C4 alkyl), -C(O)NH2, -C(O)NHOH, -C(O)O(C,-C4 alkyl), C,-C4 alkyl, -S(O)nR,2 wherein
15 n is 0 to 2, benzoyl, -NR,2R,3i -OR,2, C,-C, alkanoyl, -Y,-(0,-0,, aryl), -C(O)O(C,-C„ aryl), -NH(C,-C„ aryl), -C(O)NH(C,-C,0 aryl), -0(0)^,,0(0^(0,-0,, aryl) wherein n is 1 to 3, and -SO2NH(C,-C10 aryl);
R, is H, C,-C, alkyl, or -(CH2)n(Ce-C„ aryl) wherein n is 0 to 4;
R, is H, -OR,2, -(CHjJhA or -Ch^OfCHJ^A wherein m is 0 to 2;
20 R„ is C,-C4 alkyl, -OR,2, -CR,2R,3OR,2i -CR,2R,3NR,2R,3i
-CR,2(OR13)CR,2R,3OR,2, 2,2-dimethyl-1,3-dioxolan-4-yl, -NR,2C(O)NR12R,3> -S(CR,2R,jJnCHj wherein n is 0 to 5, -NRj^CH^ipyridyl) wherein q is 0 or 1, -Ρ(θχθ,C4 alkoxy),, -NR,-NR,2OR,3, -NR^NR^R,,, -NR,2CH2R,4, -OCH2NR,2C(O)R,4, -OCH2C(0)NR,5R,„ -OCHR,2OC(0)(C,-C4 alkyl), -OCHR,2C(O)(C,-C3 alkoxy),
25 -OfCH^R,,. or -NR^CHy^R,, wherein m is 0 to 2;
R,, is H or A;
each R^ and R„ is independently H or C,-C4 alkyl;
R,4 is methyl or phenyl;
R„ is H, methyl, ethyl, or -ΟΗ,ΟΗ,ΟΗ;
30 R„ is H, methyl, ethyl, -CH^OJNHj, or -CHjCHjOH;
each R,7 is independently H, hydroxy, cyano, halo, 0,-0, alkyl, 0,-0^ alkoxy,
-NR,,R,3l -C(0)OR,2, -C(O)R12, -CH=CR12Ru, -C«CR,2i -CH,NR,2R,3, -CHjOR^,
AP/P/ 9 7.01080
AP . ύ U. 7 9 5
-70-C(O)NR12R13, -C(Ys)H, or -CH2NR12C(O)C(O)NR12R13, provided that when R17 is hydroxy then R18 is H or C,-C4 alkyl;
each R,a is independently H, fluoro, cyano, or C,-C4 alkyl, wherein said methyl is optionally substituted by 1 to 3 fluoro substituents;
5 or R17 and R18 are taken together to form an oxo (=0) moiety;
R,e is phenyi, naphthyl, pyrrolyl, furanyl, thienyl, oxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinolinyl, 5,6,7,8-tetrahydroquinolinyl, or 5,6,7,8tetrahydroisoquinoiinyl, wherein said Rie groups, except said phenyl, are optionally substituted by 1 to 3 R^ substituents, and wherein said phenyl R„ group is optionally
10 substituted by 1 to 3 substituents independently selected from and R24;
Rao is -C(O)R„. -C(O)C(O)R21, -C(O)C(Y2)C(O)R21 or
ΖΛ
R« fe H, -OR^, -NHR*, -NHOH, -NHNH2, -(CH^phenyl) or-(CH2)nY3(pyridyf) wherein n is 0 to 4;
20 Ra is H, 0,-0, alkyl, -{CH^^Cphenyl) or -<CH2)I1Y3(pyridyl) wherein n is 0 to 4;
each Rj, is independently halo, C,-C, alkyl, Ο,-Ογ alkoxy, C2-Ce alkylenedioxy, trifluoromethyl, -NR12R13, nitro, -CfNR^NR^R^, -C{O)NR12R13C(O)R12, -CtNORJR^, -C(NCN)NR,2R,3> -C(NCN)SR,2, -(CHjUCN) wherein m is 0 to 3, hydroxy, -C{0)R12, -C(O)NR12OR13, -C(O)NR12NR12R13, -OC(O)NR,2R,3> -NR12C(O)R12, -C(O)C(0)NR12R13,
25 -SO^j, -SO2NR12R13, -CiOJNR^R,,, -NR^SO^,, or -NR12C(O)NR12R,3;
each R^ is independently imidazolyl, pyrazolyl, triazolyl, tetrazolyl oxazolyl, isoxazotyf, oxadiazolyi, thiadiazotyl, thiazolyl, oxazoRdinyl, thiazolidinyl, or imidazofidinyl, wherein each of the foregoing R24 substituents is optionally substituted by 1 to 3 R^ substituents;
30 R» »s -NR12R1J. -NH(C,-CW aryl), 0,-C, alkoxy, or Ce-C10 aryloxy;
Rae is H, C,-C, alkyl or -(CHj)mY4(phenyI) wherein m is 0 to 4 and the phenyl moiety of said ~{CH2)mY4(phenyl) R^, group is optionally substituted by halo, -OR,2, 0,Ce alkanoyloxy, Ce-C10 aryloxy, -NR12R,3, -NH(C,-C10 aryl), or -NHC(O)(C,-C4 alkyl);
AP/P/ 97.01080
AP.υ υ 7 9 5
ΑΡ/Ρ/9 7 / Ο ΓΟ β Ο
AP. υ υ 7 9 5
- 71(a)provided that:
(1) when Ri is H, R is other than phenyl or pyridyl substituted by halo or trifluoromethyl;
(2) when R2 is defined as -Z3-R7, where Z3 is -NHC(O)- and R7 is isoxazolyl optionally substituted by (C1-C4) alkyl or is unsubstituted benzimidazolyl, Ri must be ethyl; and (3) when R2 is defined as -Z3-R7, where Z3 is -C(0)NH(CH2)n. where n is 0 to 4, or as -NHC(O)O-, and R7 is optionally substituted phenyl, R is other than .(CTbk-tetrazolyl and the optional sustituent on the R group is other that CO2R1230 2. The compound of claim 1 wherein R2 is -Z3-R7 wherein Z3 is -C (Y1) NH-,
-C(O)CH2-, -NHC(Yi)-, -Y1-CH2-, OC(O)-, -CH=CH-, or -C(Yi)C(Yi)-, and R7 is an optionally substituted aryl or heteroaryl group selected from phenyl, pridyl, pyrazinyl,
AP/P/ 9 7/0 10 β 0
72/...
AP .00795
-7210 thienyl, pyrimidinyl, 2,4-dioxopyrimidin-5-yl, isoxazolyl, isothiazolyl, pyridazinyl, and 1,2,4-triazinyl.
3. The compound of claim 2 wherein R7 is substituted phenyl, 2,6-dihalosubstituted phenyl, or 3,5-dihalo-pyrid-4-yl.
4. The compound of claim 1 wherein R2 is -Zj-Ry wherein Zj is -C(O)NH(CH2)n- or -NHCCOXCHJ,,-, wherein n is 0 or 1, and R7 is phenyl or pyridyl optionally substituted by 1 to 3 substituents independently selected from halo, nitro, trifiuoromethyl, -COjCHj, methyl, methoxy, and -C(O)NH2.
5. The compound of claim 1 wherein R2 is -Zj-R7 wherein Zj is -C(O)NHand R7 is phenyl or pyridyl optionally substituted by 1 to 3 substituents independently selected from halo, C,-C4 alkyl, 0,-0, alkoxy, cyano, carboxy and -00(0)(0,-0, alkyl).
6. The compound of claim 1 wherein wherein R2 is R,e wherein R„ is optionally substituted pyrimidinyl or optionally substituted pyridazinyl.
7. The compound of claim 1 wherein R2 is a substituent of formula (lh) Wherein R^ is -0(0)!^,, -C(O)C(O)R2„ or
AP/P/ 8 7 '01080 wherein R^ '» -OR^, -NHR^, or -NHOH, and R^ is H, C,-C3 alkyl, benzyl or pyridyf methyl.
8. The compound of claim 1 wherein R2 is phenyl substituted by R24 wherein said R^ is oxadiazofyi, thiadiazolyl or tetrazofyl wherein said groups are optionally substituted by C,-C2 alkyl, or wherein Rj is phenyl substituted by cyanomethyt, hydroxy or formyl.
9. The compound of claim 1 wherein Rj is -Zj-Ry wherein Z, is -C(Y,)NH-, and R7 is phenyl, pyrazinyl, pyrimidinyl, isoxazotyl, or pyridyl, wherein each of said R7 groups is optionally substituted by 1 to 3 substituents independently selected from halo, methoxycarbonyl, trifiuoromethyl, benzoyl, acetyl, dimethylamino, hydroxy, nitro, methyl, cyano, methylsulphonyl, and methylthio.
AP . 0 0 7 9 5
-7310. The compound of claim 1 wherein R2 is -C(=NOC(O)R2f>)R2e wherein R25 is amino and R^ is Η, Ο,-€3 alkyl or -(CHJ^phenyl) wherein m is 1 to 4 and said phenyl moiety is optionally substituted by halo, hydroxy, acetoxy, amino or acetamido.
11. The compound of claim 1 wherein R2 is -{CR17R1i)mNRs(C(O))qR10 5 wherein m is 2, q is 2, each R„ is independently H, cyano or methyl, each R1S is independently H or methyl, R, is H or methyl, and R10 is amino, hydroxy, methoxy or hydroxyamino.
12. The compound of claim 1 wherein R2 is -{CRnR5JmNR^(C(O))qR10 wherein m is 2, q is 1, each R,7 is independently H, -C(O)NH2, -CCH, cyano, formyl,
10 hydroxymethyl, or trifluoromethyl, each R18 is independently H or cyano, and R,o is C,C4 alkyl.
13. The compound of claim 1 wherein Rj is a substituent of formula (Ic), (Id) or (le), wherein, in formulas (Ic) and (Id), R, is H, hydroxy, C,-C4 alkyl or C,-C4 alkoxy.
14. The compound of claim 1 wherein R2 is 15 -C(0)NRe(CHR12)tnC(0)NRl2(CH2)pOR,2 or -C(O)NR12(CHR12)mS(C,-C4 alkyl), wherein
R,, R12, m and p are as defined in claim 1.
15. The compound of claim 1 selected from the group consisting of 1-Cyclopentyl-3-ethyi-1H-indazole-6-carboxyfic acid (3,5-dichloro-pyridin-4-yl)-amide; 1-Cydopentyl-3-ethyt-1 H-indazoie-6-carboxyiic add (2,6-dichloro-phenyl)-amide;
20 1-Cydobutyt-3-ethyi-1 H-indazole-6-carboxylic add (3,5-dichloro-pyridin-4-yl)-amide; 3-EthyH-isopropyl-1 H-indazote-6-carboxylic add (3,5-dichk>ro-pyridin-4-yf)-arn»de; 1-Cydopropylmethyl-3-ethyHH-indazole-6-carboxylic add (3,5-dichloro-pyridin-4-y{)amide;
1-Cydohexyl-3-ethyl-1H-indazofe-6-cart>oxyiic add (3,5-dichloro-pyridin-4-yf)25 amide;
3- EthyH-(4-fiuoro-phenyl)-1H-indazole-6-carboxylic add (3,5-dichloro-pyridin4- yl)-amide;
1-Cydopentyk3-ethyt-1H-indazole-6-cart>oxyiic add hydroxycarbamoylmethyl-amide; 1-Cydopentyk3-ethyR1H-indazole-6-carboxylic add (2-methylsulfanyl-ethyl)-am»de;
30 1-Cydopentyt-3-ethyP1H-indazole-6-carboxylic add hydroxycarbamoylmethyi-methyl amide;
5- 1-Cydopenty1-3-ethyl-1H-indazote-6-carboxylic add (1-benzyloxycarbamoyt-ethyf)amide;
AP/P/ 9 7 / 0 1 0 80
ΑΡ. Ο ϋ 79 5
-74R-1-Cyclopentyl-3-ethyl-1 H-indazole-6-carboxylic acid (1-hydroxycarbamoyl-ethyl)amide; 1-Cyclopentyl-3-ethyl-6-thiophen-2-yl-1 H-indazole; 1-Cyclopentyl-3-ethyl-6phenyH H-indazole; and the pharmaceutically acceptable salts of the foregoing compounds.
or a pharmaceutically acceptable salt thereof, wherein:
R is H, 0,-C, alkyl, -{CH2)m(5 to 10 membered heterocyclyl) wherein m is 0 to
15 2, (C,-Ce alkoxy)Cn-Ce alkyl, C2-Ce alkenyl, or -{Z^fZ^Ce-C,,, aryl) wherein b and c are independently 0 or 1, Z, is C,-Ce alkylene or C2-Ce alkenylene, and is O, S, SO2, or NR^, and wherein said R groups are optionally substituted by 1 to 3 substituents independently selected from the group consisting of halo, hydroxy, C.,-C5 alkyl, C2-C5 alkenyl, Ο,-Ce alkoxy, trifiuoromethyl, nitro, -CO2R,2, -C(O)NR12Rn, -NR12R13 and
20 -SOjNR^R^;
R1 is H, C,-Ce alkyi, Cj-C, alkenyl, or phenyl, wherein said alkyi, alkenyl and phenyl R, groups are optionally substituted by 1 to 3 substituents independently selected from the group consisting of methyl, ethyl, trifiuoromethyl, and halo;
each R12 and R13 is independently H or Ci-C4 alkyl; and,
25 X is -C(O)Cl.
17. A pharmaceutical composition for the inhibition of phosphodiesterase (PDE) type IV or the production of tumor necrosis factor (TNF) in a mammal comprising a therapeutically-effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier.
30 18. A method for the inhibition of phosphodiesterase (PDE) type IV or the production of tumor necrosis factor (TNF) in a mammal which comprises administering to said mammal a therapeutically-effective amount of the compound of claim 1.
AP/P/ 9 7 / 0 1 0 80
Λ Ρ. OO795
19. A pharmaceutical composition for the prevention or treatment of asthma, joint inflammation, rheumatoid arthritis, gouty arthritis, rheumatoid spondylitis, osteoarthritis, and other arthritic conditions; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, acute respiratory distress syndrome, cerebal
5 malaria, chronic pulmonary inflammatory disease, siiicosis, pulmonary sarcoidosis, bone resorption diseases, reperfusion injury, graft versus host reaction, allograft rejections, fever and myalgias due to infection, cachexia secondary to infection or malignancy, cachexia secondary to human acquired immune deficiency syndrome (AIDS), AIDS, HIV, ARC (AIDS related complex), keloid formation, scar tissue formation, Crohn’s
10 disease, ulcerative colitis, pyresis, multiple sclerosis, type 1 diabetes mellitus, autoimmune diabetes, diabetes insipidus, systemic lupus erythematosis, bronchitis, chronic obstructive airway disease, psoriasis, Bechet’s disease, anaphylactoid purpura nephritis, chronic glomerulonephritis, inflammatory bowel disease, leukemia, allergic rhinitis, depression, multi-infarct dementia or dermatitis, in a mammal, comprising a
15 therapeutically-effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier.
20. A method for treating asthma, joint inflammation, rheumatoid arthritis, gouty arthritis, rheumatoid spondylitis, osteoarthritis, and other arthritic conditions; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome,
20 acute respiratory distress syndrome, cerebal malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption diseases, reperfusion injury, graft vs. host reaction, allograft rejections, fever and myalgias due to infection, such as influenza, cachexia secondary to infection or malignancy, cachexia secondary to human acquired immune deficiency syndrome (AIDS), AIDS, HIV, ARC (AIDS related complex),
25 keloid formation, scar tissue formation, Crohn’s disease, ulcerative colitis, pyresis, multiple sclerosis, type 1 diabetes mellitus, diabetes insipidus, autoimmune diabetes, systemic lupus erythematosis, bronchitis, chronic obstructive airway disease, psoriasis, Bechet’s disease, anaphylactoid purpura nephritis, chronic glomerulonephritis, inflammatory bowel disease, leukemia, allergic rhinitis, depression, multi-infarct
30 dementia or dermatitis in a mammal which comprises administering to said mammal a therapeutically-effective amount of the compound
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US2544696P | 1996-09-04 | 1996-09-04 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AP9701080A0 AP9701080A0 (en) | 1997-10-31 |
| AP795A true AP795A (en) | 1999-12-28 |
Family
ID=21826124
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| APAP/P/1997/001080A AP795A (en) | 1996-09-04 | 1997-09-04 | Indazole derivatives. |
Country Status (35)
| Country | Link |
|---|---|
| US (1) | US6262040B1 (en) |
| EP (1) | EP0931075A1 (en) |
| JP (2) | JP3554337B2 (en) |
| KR (1) | KR100338610B1 (en) |
| CN (1) | CN1234031A (en) |
| AP (1) | AP795A (en) |
| AR (1) | AR008162A1 (en) |
| AU (1) | AU724549B2 (en) |
| BG (1) | BG64447B1 (en) |
| BR (1) | BR9712005A (en) |
| CA (1) | CA2264798A1 (en) |
| CO (1) | CO4600636A1 (en) |
| DZ (1) | DZ2303A1 (en) |
| EA (1) | EA002113B1 (en) |
| GT (1) | GT199700102A (en) |
| HN (1) | HN1997000126A (en) |
| HR (1) | HRP970478B1 (en) |
| HU (1) | HUP9903248A3 (en) |
| ID (1) | ID18157A (en) |
| IL (1) | IL128642A0 (en) |
| IS (1) | IS4979A (en) |
| MA (1) | MA26439A1 (en) |
| NO (1) | NO991048L (en) |
| NZ (1) | NZ334213A (en) |
| OA (1) | OA10985A (en) |
| PA (1) | PA8437301A1 (en) |
| PE (1) | PE107998A1 (en) |
| PL (1) | PL332187A1 (en) |
| SK (1) | SK27299A3 (en) |
| TN (1) | TNSN97148A1 (en) |
| TR (1) | TR199900481T2 (en) |
| TW (1) | TW402595B (en) |
| WO (1) | WO1998009961A1 (en) |
| YU (1) | YU11299A (en) |
| ZA (1) | ZA977903B (en) |
Families Citing this family (62)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997048697A1 (en) | 1996-06-19 | 1997-12-24 | Rhone-Poulenc Rorer Limited | Substituted azabicylic compounds and their use as inhibitors of the production of tnf and cyclic amp phosphodiesterase |
| HUP0004150A3 (en) * | 1997-11-04 | 2001-08-28 | Pfizer Prod Inc | Indazole derivatives as tyrosine kinase receptor antagonists and pharmaceutical compositions containing them |
| CA2309175A1 (en) * | 1997-11-04 | 1999-05-14 | Pfizer Products Inc. | Therapeutically active compounds based on indazole bioisostere replacement of catechol in pde4 inhibitors |
| JP2000198734A (en) * | 1998-12-30 | 2000-07-18 | Pfizer Inc | Motility enhancers for the treatment of gastric motility impairment and related disorders |
| US6191300B1 (en) | 1999-04-16 | 2001-02-20 | Eastman Chemical Company | Process for the preparation of cyclopropylacetonitrile |
| UA71971C2 (en) | 1999-06-04 | 2005-01-17 | Agoron Pharmaceuticals Inc | Diaminothiazoles, composition based thereon, a method for modulation of protein kinases activity, a method for the treatment of diseases mediated by protein kinases |
| US7141581B2 (en) | 1999-07-02 | 2006-11-28 | Agouron Pharmaceuticals, Inc. | Indazole compounds and pharmaceutical compositions for inhibiting protein kinases, and methods for their use |
| PE20010306A1 (en) * | 1999-07-02 | 2001-03-29 | Agouron Pharma | INDAZOLE COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM USEFUL FOR THE INHIBITION OF PROTEIN KINASE |
| TWI262914B (en) | 1999-07-02 | 2006-10-01 | Agouron Pharma | Compounds and pharmaceutical compositions for inhibiting protein kinases |
| HU229439B1 (en) | 1999-08-21 | 2013-12-30 | Takeda Gmbh | Synergistic combination roflumilast and salmeterol |
| US6362213B1 (en) | 1999-12-23 | 2002-03-26 | Icos Corporation | Cyclic AMP-specific phosphodiesterase inhibitors |
| ATE290002T1 (en) * | 1999-12-23 | 2005-03-15 | Icos Corp | CYCLIC AMP SPECIFIC PHOSPHODIESTERASE INHIBITORS |
| US7217722B2 (en) | 2000-02-01 | 2007-05-15 | Kirin Beer Kabushiki Kaisha | Nitrogen-containing compounds having kinase inhibitory activity and drugs containing the same |
| BR0110302A (en) | 2000-04-18 | 2003-01-14 | Agouron Pharma | Pyrazole compounds for protein kinase inhibition, pharmaceutically acceptable salt and prodrug, pharmaceutically active metabolite or pharmaceutically acceptable salt of metabolite, pharmaceutical composition, method of treating disease in mammals mediated by protein kinase activity, modulation or inhibition method of the activity of a protein kinase receptor |
| US7153871B2 (en) * | 2001-01-22 | 2006-12-26 | Memory Pharmaceuticals Corporation | Phosphodiesterase 4 inhibitors, including aminoindazole and aminobenzofuran analogs |
| US7205320B2 (en) | 2001-01-22 | 2007-04-17 | Memory Pharmaceuticals Corp. | Phosphodiesterase 4 inhibitors |
| WO2002094321A1 (en) * | 2001-05-23 | 2002-11-28 | Tanabe Seiyaku Co., Ltd. | Compositions for promoting healing of bone fracture |
| EP1389467B1 (en) * | 2001-05-23 | 2013-07-03 | Mitsubishi Tanabe Pharma Corporation | Therapeutic composition for the regenerative treatment of cartilage diseases |
| TWI221838B (en) | 2001-08-09 | 2004-10-11 | Tanabe Seiyaku Co | Pyrazinoisoquinoline compound or naphthalene compound |
| PE20030701A1 (en) | 2001-12-20 | 2003-08-21 | Schering Corp | COMPOUNDS FOR THE TREATMENT OF INFLAMMATORY DISORDERS |
| MY140561A (en) | 2002-02-20 | 2009-12-31 | Nycomed Gmbh | Dosage form containing pde 4 inhibitor as active ingredient |
| AU2003262187A1 (en) * | 2002-04-12 | 2003-10-27 | Celgene Corporation | Modulation of stem and progenitor cell differentiation, assays, and uses thereof |
| JP2005528105A (en) * | 2002-05-30 | 2005-09-22 | セルジーン・コーポレーション | Methods of using JNK or MKK inhibitors to modulate cell differentiation and to treat myeloproliferative diseases and myelodysplastic syndromes |
| BR0313000A (en) * | 2002-07-19 | 2005-07-12 | Memory Pharm Corp | Compounds, pharmaceutical composition and method for inhibiting pde4 enzyme, enhancing cognition and / or treating psychosis in a patient |
| EP1539697A1 (en) | 2002-07-19 | 2005-06-15 | Memory Pharmaceutical Corporation | Phosphodiesterase 4 inhibitors, including n-substituted aniline and diphenylamine analogs |
| CN100513397C (en) * | 2002-11-19 | 2009-07-15 | 记忆药物公司 | Pyridine n-oxide compounds as phosphodiesterase 4 inhibitors |
| US7109337B2 (en) | 2002-12-20 | 2006-09-19 | Pfizer Inc | Pyrimidine derivatives for the treatment of abnormal cell growth |
| WO2004056807A1 (en) | 2002-12-20 | 2004-07-08 | Pfizer Products Inc. | Pyrimidine derivatives for the treatment of abnormal cell growth |
| US7135575B2 (en) | 2003-03-03 | 2006-11-14 | Array Biopharma, Inc. | P38 inhibitors and methods of use thereof |
| WO2004087211A2 (en) | 2003-04-01 | 2004-10-14 | Applied Research Systems Ars Holding N.V. | Inhibitors of phosphodiesterases in infertility |
| US7297709B2 (en) * | 2003-05-22 | 2007-11-20 | Abbott Laboratories | Indazole, benzisoxazole, and benzisothiazole kinase inhibitors |
| US20090048255A1 (en) * | 2003-07-21 | 2009-02-19 | Schumacher Richard A | Phosphodiesterase 4 inhibitors, including n-substituted aniline and diphenylamine analogs |
| JP2005089457A (en) * | 2003-09-03 | 2005-04-07 | Yung Shin Pharmaceutical Industry Co Ltd | Pharmaceutical composition for promoting bone growth or inhibiting bone resorption |
| MY141255A (en) * | 2003-12-11 | 2010-03-31 | Memory Pharm Corp | Phosphodiesterase 4 inhibitors, including n-substituted diarylamine analogs |
| CA2557268A1 (en) | 2004-02-27 | 2005-09-15 | F. Hoffmann-La Roche Ag | Indazole derivatives and pharmaceutical compositions containing them |
| BRPI0508220A (en) | 2004-02-27 | 2007-07-17 | Hoffmann La Roche | fused heteroaryl pyrazole derivatives |
| KR100843526B1 (en) | 2004-02-27 | 2008-07-03 | 에프. 호프만-라 로슈 아게 | Fused derivatives of pyrazole |
| CA2564199A1 (en) | 2004-05-14 | 2005-11-24 | Pfizer Products Inc. | Pyrimidine derivatives for the treatment of abnormal cell growth |
| WO2005111024A1 (en) | 2004-05-14 | 2005-11-24 | Pfizer Products Inc. | Pyrimidine derivatives for the treatment of abnormal cell growth |
| MXPA06013164A (en) | 2004-05-14 | 2007-02-13 | Pfizer Prod Inc | Pyrimidines derivatives for the treatment of abnormal cell growth. |
| WO2006017214A2 (en) * | 2004-07-12 | 2006-02-16 | Merck & Co., Inc. | Inhibitors of histone deacetylase |
| US7601847B2 (en) | 2004-10-26 | 2009-10-13 | Wyeth | Preparation and purification of 4-(indazol-3-yl)phenols |
| TW200621237A (en) | 2004-11-01 | 2006-07-01 | Wyeth Corp | [(1-h-indazol-3-yl)methyl]phenols and (hydroxyphenyl)(1h-indazol-3-yl)methanones |
| WO2006129158A2 (en) * | 2005-05-30 | 2006-12-07 | Ranbaxy Laboratories Limited | 3 - indazolyl - isoxazoline derivatives as inhibitors of phosphodiesterase type - i |
| AU2006283941A1 (en) | 2005-08-25 | 2007-03-01 | F. Hoffmann-La Roche Ag | P38 MAP kinase inhibitors and methods for using the same |
| EP1928866A1 (en) | 2005-09-05 | 2008-06-11 | Ranbaxy Laboratories Limited | Substituted indazoles as inhibitors of phosphodiesterase type-iv |
| EP1934219A1 (en) | 2005-09-16 | 2008-06-25 | Ranbaxy Laboratories Limited | Substituted pyrazolo [3,4-b] pyridines as phosphodiesterase inhibitors |
| RU2442777C2 (en) | 2006-01-31 | 2012-02-20 | Эррэй Биофарма Инк. | Kinase inactivators and methods of their application |
| US20100056791A1 (en) * | 2006-09-01 | 2010-03-04 | Yasushi Kohno | Pyrazolopyridine carboxamide derivative and phosphodiesterase (pde) inhibitor containing the same |
| US7825261B2 (en) * | 2006-12-05 | 2010-11-02 | National Taiwan University | Indazole compounds |
| ATE545417T1 (en) | 2007-03-14 | 2012-03-15 | Ranbaxy Lab Ltd | PYRAZOLOA3,4-BUPYRIDINE DERIVATIVES AS PHOSPHODIESTERASE INHIBITORS |
| WO2010003084A2 (en) * | 2008-07-02 | 2010-01-07 | Memory Pharmaceuticals Corporation | Phosphodiesterase 4 inhibitors |
| AU2010229144B2 (en) * | 2009-03-23 | 2012-07-12 | Merck Sharp & Dohme Corp. | P2X3, receptor antagonists for treatment of pain |
| JP2013525370A (en) * | 2010-04-22 | 2013-06-20 | ヤンセン ファーマシューティカ エヌ．ベー． | Indazole compounds useful as keto hexokinase inhibitors |
| EP3323820B1 (en) | 2011-02-28 | 2023-05-10 | Epizyme, Inc. | Substituted 6,5-fused bicyclic heteroaryl compounds |
| WO2015166370A1 (en) | 2014-04-28 | 2015-11-05 | Pfizer Inc. | Heteroaromatic compounds and their use as dopamine d1 ligands |
| AU2017360939B2 (en) * | 2016-11-18 | 2022-03-03 | Merck Sharp & Dohme Corp. | Indazole derivatives useful as inhibitors of diacylglyceride O-acyltransferase 2 |
| US11427558B1 (en) | 2019-07-11 | 2022-08-30 | ESCAPE Bio, Inc. | Indazoles and azaindazoles as LRRK2 inhibitors |
| GB201910608D0 (en) * | 2019-07-24 | 2019-09-04 | Enterprise Therapeutics Ltd | Compounds |
| CN112694474B (en) * | 2019-10-23 | 2022-03-18 | 四川大学 | Indazole derivative and preparation method and application thereof |
| WO2022256303A1 (en) * | 2021-05-31 | 2022-12-08 | Genscript Usa Inc. | Electrografted films for dna synthesis |
| CN116003325B (en) * | 2023-01-09 | 2025-04-25 | 南方医科大学 | Indazole compound or pharmaceutically acceptable salt thereof and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0381422A1 (en) * | 1989-02-02 | 1990-08-08 | Yamanouchi Pharmaceutical Co. Ltd. | Tetrahydrobenzimidazole derivatives |
| WO1991017748A1 (en) * | 1990-05-18 | 1991-11-28 | Hoechst Aktiengesellschaft | Isoxazole-4-carboxamides and hydroxyalkylidene-cyanoacetamides, drugs containing these compounds and use of such drugs |
| US5444038A (en) * | 1992-03-09 | 1995-08-22 | Zeneca Limited | Arylindazoles and their use as herbicides |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE531433A (en) | 1953-06-17 | |||
| US4665397A (en) | 1983-11-01 | 1987-05-12 | Universal Photonics, Inc. | Apparatus and method for a universal electronic locking system |
| GB8524157D0 (en) * | 1984-10-19 | 1985-11-06 | Ici America Inc | Heterocyclic amides |
| JPH061350B2 (en) * | 1985-07-26 | 1994-01-05 | コニカ株式会社 | Silver halide photographic light-sensitive material |
| JPS6250751A (en) * | 1985-08-29 | 1987-03-05 | Konishiroku Photo Ind Co Ltd | Silver halide photographic sensitive material |
| GB8609175D0 (en) * | 1986-04-15 | 1986-05-21 | Ici America Inc | Heterocyclic carboxamides |
| EP0707585A1 (en) * | 1993-07-06 | 1996-04-24 | Pfizer Inc. | Bicyclic tetrahydro pyrazolopyridines |
| GB9401460D0 (en) | 1994-01-26 | 1994-03-23 | Rhone Poulenc Rorer Ltd | Compositions of matter |
| HUT74611A (en) * | 1994-02-17 | 1997-01-28 | American Home Prod | Biphenyl derivatives with phosphodiesterase inhibitor activity and pharmaceutical compns. contg. them |
| WO1995027692A1 (en) * | 1994-04-08 | 1995-10-19 | Smithkline Beecham Corporation | Subtituted biphenyl tnf inhibitors |
| JPH08143525A (en) * | 1994-11-21 | 1996-06-04 | Banyu Pharmaceut Co Ltd | Prophylactic / therapeutic agent for bone diseases containing a hydroxybenzoic acid amide derivative as an active ingredient |
| ES2201299T3 (en) * | 1996-06-25 | 2004-03-16 | Pfizer Inc. | INDAZOL SUBSTITUTED DERIVATIVES AND ITS USE AS TYPE IV PHOSPHODIESTERASE (PDE) INHIBITORS AND TUMOR NECROSIS FACTOR (TNF) `. |
| ES2168581T3 (en) * | 1996-06-27 | 2002-06-16 | Pfizer | INDAZOL DERIVATIVES REPLACED. |
-
1997
- 1997-08-25 PL PL97332187A patent/PL332187A1/en unknown
- 1997-08-25 US US09/254,346 patent/US6262040B1/en not_active Expired - Fee Related
- 1997-08-25 AU AU37813/97A patent/AU724549B2/en not_active Ceased
- 1997-08-25 KR KR1019997001779A patent/KR100338610B1/en not_active Expired - Fee Related
- 1997-08-25 SK SK272-99A patent/SK27299A3/en unknown
- 1997-08-25 WO PCT/IB1997/001023 patent/WO1998009961A1/en not_active Ceased
- 1997-08-25 BR BR9712005A patent/BR9712005A/en not_active Application Discontinuation
- 1997-08-25 CN CN97199022A patent/CN1234031A/en active Pending
- 1997-08-25 TR TR1999/00481T patent/TR199900481T2/en unknown
- 1997-08-25 EA EA199900183A patent/EA002113B1/en not_active IP Right Cessation
- 1997-08-25 JP JP51240998A patent/JP3554337B2/en not_active Expired - Fee Related
- 1997-08-25 YU YU11299A patent/YU11299A/en unknown
- 1997-08-25 HU HU9903248A patent/HUP9903248A3/en unknown
- 1997-08-25 EP EP97934678A patent/EP0931075A1/en not_active Withdrawn
- 1997-08-25 IL IL12864297A patent/IL128642A0/en unknown
- 1997-08-25 NZ NZ334213A patent/NZ334213A/en unknown
- 1997-08-25 CA CA002264798A patent/CA2264798A1/en not_active Abandoned
- 1997-08-29 HN HN1997000126A patent/HN1997000126A/en unknown
- 1997-09-01 TW TW086112518A patent/TW402595B/en not_active IP Right Cessation
- 1997-09-02 AR ARP970104001A patent/AR008162A1/en unknown
- 1997-09-02 PE PE1997000777A patent/PE107998A1/en not_active Application Discontinuation
- 1997-09-03 PA PA19978437301A patent/PA8437301A1/en unknown
- 1997-09-03 DZ DZ970153A patent/DZ2303A1/en active
- 1997-09-03 MA MA24783A patent/MA26439A1/en unknown
- 1997-09-03 ID IDP973065A patent/ID18157A/en unknown
- 1997-09-03 GT GT199700102A patent/GT199700102A/en unknown
- 1997-09-03 TN TNTNSN97148A patent/TNSN97148A1/en unknown
- 1997-09-03 ZA ZA977903A patent/ZA977903B/en unknown
- 1997-09-04 AP APAP/P/1997/001080A patent/AP795A/en active
- 1997-09-04 CO CO97051473A patent/CO4600636A1/en unknown
- 1997-09-04 HR HR970478A patent/HRP970478B1/en not_active IP Right Cessation
-
1999
- 1999-02-16 IS IS4979A patent/IS4979A/en unknown
- 1999-02-22 BG BG103195A patent/BG64447B1/en unknown
- 1999-03-01 OA OA9900046A patent/OA10985A/en unknown
- 1999-03-03 NO NO991048A patent/NO991048L/en unknown
-
2004
- 2004-03-23 JP JP2004083812A patent/JP2004217668A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0381422A1 (en) * | 1989-02-02 | 1990-08-08 | Yamanouchi Pharmaceutical Co. Ltd. | Tetrahydrobenzimidazole derivatives |
| WO1991017748A1 (en) * | 1990-05-18 | 1991-11-28 | Hoechst Aktiengesellschaft | Isoxazole-4-carboxamides and hydroxyalkylidene-cyanoacetamides, drugs containing these compounds and use of such drugs |
| US5444038A (en) * | 1992-03-09 | 1995-08-22 | Zeneca Limited | Arylindazoles and their use as herbicides |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AP795A (en) | Indazole derivatives. | |
| AP1025A (en) | The invention relates to compounds of the formula | |
| AP1146A (en) | Substituted Indazole derivatives and related compounds. | |
| CA2469821C (en) | Heteroaryl substituted triazole modulators of metabotropic glutamate receptor-5 | |
| JP4732354B2 (en) | Bicyclic [3.1.0] derivatives as glycine transport inhibitors | |
| US5958953A (en) | Substituted indazole derivatives | |
| JP2007008816A (en) | New isoquinoline derivatives | |
| MXPA06013593A (en) | Pyridazin-3(2h)-one derivatives and their use as pde4 inhibitors. | |
| CA2545710A1 (en) | Indazol-3-ones and analogues and derivatives thereof which modulate the function of the vanilloid-1 receptor (vr1) | |
| CZ71099A3 (en) | Indazole derivatives, pharmaceutical compositions based thereon, intermediates and methods of treating diseases |