NZ749999B2 - Amine compounds having anti-inflammatory, antifungal, antiparasitic and anticancer activity - Google Patents
Amine compounds having anti-inflammatory, antifungal, antiparasitic and anticancer activity Download PDFInfo
- Publication number
- NZ749999B2 NZ749999B2 NZ749999A NZ74999914A NZ749999B2 NZ 749999 B2 NZ749999 B2 NZ 749999B2 NZ 749999 A NZ749999 A NZ 749999A NZ 74999914 A NZ74999914 A NZ 74999914A NZ 749999 B2 NZ749999 B2 NZ 749999B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- mmol
- amine
- hexyloxy
- mixture
- compound
- Prior art date
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- -1 Amine compounds Chemical class 0.000 title claims description 135
- 230000000843 anti-fungal Effects 0.000 title description 15
- 230000001093 anti-cancer Effects 0.000 title description 7
- 230000002141 anti-parasite Effects 0.000 title description 6
- 230000003110 anti-inflammatory Effects 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 353
- 210000004027 cells Anatomy 0.000 claims abstract description 47
- 230000002378 acidificating Effects 0.000 claims abstract description 44
- 201000010099 disease Diseases 0.000 claims abstract description 43
- 210000003934 Vacuoles Anatomy 0.000 claims abstract description 40
- 241000233866 Fungi Species 0.000 claims abstract description 20
- 230000003071 parasitic Effects 0.000 claims abstract description 7
- 244000005700 microbiome Species 0.000 claims abstract 5
- 239000000203 mixture Substances 0.000 claims description 453
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 141
- 239000001257 hydrogen Substances 0.000 claims description 79
- 229910052739 hydrogen Inorganic materials 0.000 claims description 79
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 77
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 73
- 125000003545 alkoxy group Chemical group 0.000 claims description 69
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 35
- 239000008194 pharmaceutical composition Substances 0.000 claims description 21
- 239000003814 drug Substances 0.000 claims description 20
- 150000002500 ions Chemical class 0.000 claims description 19
- 239000011780 sodium chloride Substances 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 16
- 230000002401 inhibitory effect Effects 0.000 claims description 14
- 206010017533 Fungal infection Diseases 0.000 claims description 11
- 201000009910 diseases by infectious agent Diseases 0.000 claims description 11
- 230000000699 topical Effects 0.000 claims description 10
- 241001337994 Cryptococcus <scale insect> Species 0.000 claims description 8
- 229940035295 Ting Drugs 0.000 claims description 8
- 230000001613 neoplastic Effects 0.000 claims description 8
- 208000006551 Parasitic Disease Diseases 0.000 claims description 7
- 206010028980 Neoplasm Diseases 0.000 claims description 6
- 241000223238 Trichophyton Species 0.000 claims description 6
- 201000007336 cryptococcosis Diseases 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 241000222120 Candida <Saccharomycetales> Species 0.000 claims description 5
- 241000221204 Cryptococcus neoformans Species 0.000 claims description 5
- 241000228212 Aspergillus Species 0.000 claims description 4
- 241000235070 Saccharomyces Species 0.000 claims description 4
- 200000000018 inflammatory disease Diseases 0.000 claims description 4
- 229940095731 Candida albicans Drugs 0.000 claims description 3
- 241000222122 Candida albicans Species 0.000 claims description 3
- 241000192125 Firmicutes Species 0.000 claims description 3
- 235000003534 Saccharomyces carlsbergensis Nutrition 0.000 claims description 3
- 240000004808 Saccharomyces cerevisiae Species 0.000 claims description 3
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 claims description 3
- 229940081969 Saccharomyces cerevisiae Drugs 0.000 claims description 3
- 201000005787 hematologic cancer Diseases 0.000 claims description 3
- 238000007910 systemic administration Methods 0.000 claims description 3
- 201000008827 tuberculosis Diseases 0.000 claims description 3
- 241000222722 Leishmania <genus> Species 0.000 claims description 2
- 241000186781 Listeria Species 0.000 claims description 2
- 241000224016 Plasmodium Species 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 229940091771 Aspergillus fumigatus Drugs 0.000 claims 2
- 241001225321 Aspergillus fumigatus Species 0.000 claims 2
- 241000776296 Cryptococcus neoformans var. grubii Species 0.000 claims 2
- 241000223229 Trichophyton rubrum Species 0.000 claims 2
- 241000222126 [Candida] glabrata Species 0.000 claims 2
- 241000894006 Bacteria Species 0.000 claims 1
- 229940118765 Coxiella burnetii Drugs 0.000 claims 1
- 241000606678 Coxiella burnetii Species 0.000 claims 1
- 241000123365 Cryptococcus neoformans var. neoformans Species 0.000 claims 1
- 241000235527 Rhizopus Species 0.000 claims 1
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- 201000011510 cancer Diseases 0.000 abstract description 43
- 210000003712 Lysosomes Anatomy 0.000 abstract description 26
- 230000001868 lysosomic Effects 0.000 abstract description 26
- 230000001717 pathogenic Effects 0.000 abstract description 8
- 230000004075 alteration Effects 0.000 abstract description 6
- 238000009825 accumulation Methods 0.000 abstract description 5
- 230000002080 lysosomotropic Effects 0.000 abstract description 3
- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 abstract description 3
- 206010061218 Inflammation Diseases 0.000 abstract 1
- 230000004054 inflammatory process Effects 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 404
- 238000005160 1H NMR spectroscopy Methods 0.000 description 277
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 259
- 101700067048 CDC13 Proteins 0.000 description 216
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 164
- ZMANZCXQSJIPKH-UHFFFAOYSA-N N,N-Diethylethanamine Substances CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 160
- 239000012074 organic phase Substances 0.000 description 158
- 239000007787 solid Substances 0.000 description 157
- 229910001868 water Inorganic materials 0.000 description 144
- 239000012267 brine Substances 0.000 description 121
- 125000000217 alkyl group Chemical group 0.000 description 105
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 102
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Natural products CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 95
- 239000000047 product Substances 0.000 description 83
- 238000005406 washing Methods 0.000 description 78
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 76
- KNDOFJFSHZCKGT-UHFFFAOYSA-N 4-chloroquinoline Chemical compound C1=CC=C2C(Cl)=CC=NC2=C1 KNDOFJFSHZCKGT-UHFFFAOYSA-N 0.000 description 75
- SECXISVLQFMRJM-UHFFFAOYSA-N NMP Substances CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 71
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 70
- 239000003921 oil Substances 0.000 description 70
- 235000019198 oils Nutrition 0.000 description 70
- FQYRLEXKXQRZDH-UHFFFAOYSA-N 4-Aminoquinoline Chemical compound C1=CC=C2C(N)=CC=NC2=C1 FQYRLEXKXQRZDH-UHFFFAOYSA-N 0.000 description 66
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 65
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 65
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 56
- 238000006243 chemical reaction Methods 0.000 description 56
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 55
- 239000000741 silica gel Substances 0.000 description 52
- 229910002027 silica gel Inorganic materials 0.000 description 52
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 48
- 229910000029 sodium carbonate Inorganic materials 0.000 description 46
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M Sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 45
- 229910000027 potassium carbonate Inorganic materials 0.000 description 43
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 42
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Chemical compound [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 39
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 37
- 125000005843 halogen group Chemical group 0.000 description 37
- 238000004821 distillation Methods 0.000 description 36
- 239000000463 material Substances 0.000 description 35
- OKKJLVBELUTLKV-MZCSYVLQSA-N cd3od Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 32
- 239000002244 precipitate Substances 0.000 description 32
- 239000000727 fraction Substances 0.000 description 31
- 229910052799 carbon Inorganic materials 0.000 description 30
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 30
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 30
- 235000019341 magnesium sulphate Nutrition 0.000 description 30
- 238000002360 preparation method Methods 0.000 description 29
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 28
- 239000007788 liquid Substances 0.000 description 28
- AMQJEAYHLZJPGS-UHFFFAOYSA-N n-pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 28
- 239000002585 base Substances 0.000 description 27
- 239000003795 chemical substances by application Substances 0.000 description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 27
- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 26
- 239000000706 filtrate Substances 0.000 description 26
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 26
- FYRHIOVKTDQVFC-UHFFFAOYSA-M Potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 25
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 23
- 238000000746 purification Methods 0.000 description 23
- 150000002431 hydrogen Chemical class 0.000 description 22
- 239000002904 solvent Substances 0.000 description 20
- 230000000694 effects Effects 0.000 description 19
- 238000010438 heat treatment Methods 0.000 description 19
- GCMNJUJAKQGROZ-UHFFFAOYSA-N 2-Aminoquinoline Chemical compound C1=CC=CC2=NC(N)=CC=C21 GCMNJUJAKQGROZ-UHFFFAOYSA-N 0.000 description 18
- 210000002540 Macrophages Anatomy 0.000 description 18
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 18
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 18
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 18
- WHTVZRBIWZFKQO-UHFFFAOYSA-N Chloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 17
- 229960003677 Chloroquine Drugs 0.000 description 17
- 125000003118 aryl group Chemical group 0.000 description 17
- FEMOMIGRRWSMCU-UHFFFAOYSA-N Ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 16
- XKJCHHZQLQNZHY-UHFFFAOYSA-N Phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 16
- 229940079593 drugs Drugs 0.000 description 16
- SJRJJKPEHAURKC-UHFFFAOYSA-N n-methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 16
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 16
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 16
- 239000007832 Na2SO4 Substances 0.000 description 15
- 229940083599 Sodium Iodide Drugs 0.000 description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 15
- 125000002950 monocyclic group Chemical group 0.000 description 15
- 239000012071 phase Substances 0.000 description 15
- 235000009518 sodium iodide Nutrition 0.000 description 15
- 229910052938 sodium sulfate Inorganic materials 0.000 description 15
- 235000011152 sodium sulphate Nutrition 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- GVRRXASZZAKBMN-UHFFFAOYSA-N 4-chloroquinazoline Chemical compound C1=CC=C2C(Cl)=NC=NC2=C1 GVRRXASZZAKBMN-UHFFFAOYSA-N 0.000 description 14
- 239000008346 aqueous phase Substances 0.000 description 14
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 14
- 125000002619 bicyclic group Chemical group 0.000 description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- 239000008079 hexane Substances 0.000 description 14
- 238000001953 recrystallisation Methods 0.000 description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 14
- QARBMVPHQWIHKH-UHFFFAOYSA-N Methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 13
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 13
- 229910052786 argon Inorganic materials 0.000 description 13
- 239000012230 colorless oil Substances 0.000 description 13
- 238000001816 cooling Methods 0.000 description 13
- 230000002538 fungal Effects 0.000 description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 13
- 235000015320 potassium carbonate Nutrition 0.000 description 13
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 13
- 239000007858 starting material Substances 0.000 description 13
- MNDIARAMWBIKFW-UHFFFAOYSA-N 1-Bromohexane Chemical compound CCCCCCBr MNDIARAMWBIKFW-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
- 229920002892 amber Polymers 0.000 description 12
- 239000003430 antimalarial agent Substances 0.000 description 12
- LCGLNKUTAGEVQW-UHFFFAOYSA-N dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 12
- 238000001035 drying Methods 0.000 description 12
- 238000001704 evaporation Methods 0.000 description 12
- 230000012010 growth Effects 0.000 description 12
- 230000002132 lysosomal Effects 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- DKEGCUDAFWNSSO-UHFFFAOYSA-N 1,8-dibromooctane Chemical compound BrCCCCCCCCBr DKEGCUDAFWNSSO-UHFFFAOYSA-N 0.000 description 11
- 210000004379 Membranes Anatomy 0.000 description 11
- 150000001412 amines Chemical class 0.000 description 11
- 125000001309 chloro group Chemical group Cl* 0.000 description 11
- 239000012528 membrane Substances 0.000 description 11
- AEDRGUFWOIFSDY-UHFFFAOYSA-N N-[8-(3-ethoxypropoxy)octyl]quinolin-4-amine Chemical compound C1=CC=C2C(NCCCCCCCCOCCCOCC)=CC=NC2=C1 AEDRGUFWOIFSDY-UHFFFAOYSA-N 0.000 description 10
- 230000000078 anti-malarial Effects 0.000 description 10
- 235000020127 ayran Nutrition 0.000 description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 10
- 238000007796 conventional method Methods 0.000 description 10
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 10
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 10
- 101700037472 nhr-6 Proteins 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- 125000004433 nitrogen atoms Chemical group N* 0.000 description 10
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
- PWGJDPKCLMLPJW-UHFFFAOYSA-N 1,8-diaminooctane Chemical compound NCCCCCCCCN PWGJDPKCLMLPJW-UHFFFAOYSA-N 0.000 description 9
- WTAUMGJJFXKZLQ-UHFFFAOYSA-N 2-hexoxyphenol Chemical compound CCCCCCOC1=CC=CC=C1O WTAUMGJJFXKZLQ-UHFFFAOYSA-N 0.000 description 9
- KALRKHPOOAJAJB-UHFFFAOYSA-N 8-hexoxyoctan-1-amine Chemical compound CCCCCCOCCCCCCCCN KALRKHPOOAJAJB-UHFFFAOYSA-N 0.000 description 9
- 210000003491 Skin Anatomy 0.000 description 9
- 239000012298 atmosphere Substances 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 9
- 150000001768 cations Chemical class 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- JAFPUIBQSCCRFM-UHFFFAOYSA-N (3-hexoxyphenyl)methanamine Chemical compound CCCCCCOC1=CC=CC(CN)=C1 JAFPUIBQSCCRFM-UHFFFAOYSA-N 0.000 description 8
- YCIMNLLNPGFGHC-UHFFFAOYSA-N Catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 8
- 125000003277 amino group Chemical group 0.000 description 8
- VHUUQVKOLVNVRT-UHFFFAOYSA-N ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 8
- 235000011114 ammonium hydroxide Nutrition 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 8
- 230000005712 crystallization Effects 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
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- 201000004792 malaria Diseases 0.000 description 8
- DRYRBWIFRVMRPV-UHFFFAOYSA-N quinazolin-4-amine Chemical compound C1=CC=C2C(N)=NC=NC2=C1 DRYRBWIFRVMRPV-UHFFFAOYSA-N 0.000 description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N t-BuOH Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 8
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- SUOKINBZLAEKOU-UHFFFAOYSA-N 10-hexoxydecan-1-amine Chemical compound CCCCCCOCCCCCCCCCCN SUOKINBZLAEKOU-UHFFFAOYSA-N 0.000 description 7
- VKJCJJYNVIYVQR-UHFFFAOYSA-N 2-(3-bromopropyl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CCCBr)C(=O)C2=C1 VKJCJJYNVIYVQR-UHFFFAOYSA-N 0.000 description 7
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- FXHOOIRPVKKKFG-UHFFFAOYSA-N DMA Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 6
- 210000003463 Organelles Anatomy 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 238000005804 alkylation reaction Methods 0.000 description 6
- 239000003429 antifungal agent Substances 0.000 description 6
- 239000002246 antineoplastic agent Substances 0.000 description 6
- 230000006877 autophagy Effects 0.000 description 6
- 238000009835 boiling Methods 0.000 description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-M bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 6
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- 239000003054 catalyst Substances 0.000 description 6
- 239000006185 dispersion Substances 0.000 description 6
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- 229940011051 isopropyl acetate Drugs 0.000 description 6
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 6
- BAVYZALUXZFZLV-UHFFFAOYSA-N methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 6
- 230000002829 reduced Effects 0.000 description 6
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- 230000003827 upregulation Effects 0.000 description 1
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- 235000013343 vitamin Nutrition 0.000 description 1
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- 239000003039 volatile agent Substances 0.000 description 1
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Classifications
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Abstract
Quinazoline compounds of formula IB1 are described, along with their use as lysosomotropic agents against inflammation, fungi, unicellular parasitic microorganisms and cancer. The described compounds are useful for the treatment of diseases characterized by pathogenic cells featuring lysosomes or other acidic vacuoles with disease-related alterations predisposing them to accumulation of compounds of the invention, which then selectively inactivate or eliminate such pathogenic cells. her acidic vacuoles with disease-related alterations predisposing them to accumulation of compounds of the invention, which then selectively inactivate or eliminate such pathogenic cells.
Description
AMINE NDS HAVING ANTI—INFLAMMATORY, ANTIFUNGAL,
ANTIPARASITIC, AND ANTICANCER ACTIVITY
BACKGROUND OF THE INVENTION
Most nucleated otic cells, whether unicellular organisms or tuents of multicellular
organism including humans, contain acidified vacuoles that are critical for cellular maintenance
and function. In mammalian cells, these vacuoles comprise lysosomes and other mal
vesicular organelles. The pH of the interior of lysosomes is typically about 4.5 to 5, maintained
by vacuolar ATP—dependent proton pumps and also by Donnan equilibrium effects. mes
contribute to cytosolic pH buffering, ting the cell from acidic environments, and are also
primary sites for degrading and recycling the constituents of aging or damaged organelles such
as mitochondria, a process known as autophagy. There are several important pathological
conditions where lysosomal characteristics are altered and contribute to disease enesis,
presenting a potential target for pharmacological therapy.
A growing body of ce indicates that a common phenotypic change in invasive cancer cells
is a redirection of lysosomes to participate in destruction of surrounding cells via exocytosis of
acidic contents, including enzymes. Proteolytic enzymes normally found in lysosomes but
secreted by cancer cells, such as cathepsins, can degrade extracellular matrix proteins,
facilitating tumor invasion and metastasis. Furthermore, lysosomes and other acidic vacuolar
lles are often enlarged in cancer cells, which aids pH buffering; many solid tumors
generate an acidic extracellular environment, favoring on, which requires that cancer cells
adapt to both produce and tolerate a low extracellular pH. Cancer cells selected in vitro for
invasive potential have larger, more acidic lysosomes than do less aggressive cells. Cancer cells
exposed to ionizing radiation undergo a tive response involving enlargement and
acidification of lysosomes. A related tive response through cancer cells acquire survival
advantages is activation of autophagy, which involves fusion of autophagosomes containing
damamged organelles or other cell debris, with lysosomes; disruption of autophagy can impair
2014/013992
cancer cell viability. Some cancer cells also sequester chemotherapy agents in lysosomes, as a
mechanism of drug resistance. Chloroquine, an antimalarial drug that accumulates in
mammalian lysosomes, iates, or restores sensitivity to, anticancer ty of several
classes of chemotherapy agents and targeted small molecule and antibody cancer treatments.
Lysosomotropic ?uorescent dyes such as acridine orange can be used to visually differentiate
tumors in situ from surrounding tissues, indicating a potential sharp distinction for specific
lysosome—targeting cytotoxic agents to selectively kill cancer cells.
Lysosomal alterations are also important features of common in?ammatory diseases, especially
those involving activated macrophages, where exocytosis of lysosomal s, cytokines, and
some in?ammatory ors such as HMBGI that are processed and released via lysosomes
can participate in tissue damage and both local and ic in?ammation. orticoid
signaling is also linked to lysosomes, such that compromising lysosomal function can enhance
anti-in?ammatory pathways mediating glucocorticoid effects.
Most fungi have acidic vacuoles r to lysosomes. These acidic vacuoles are al for ion
and pH homeostasis, storage of amino acids, autophagy and for processing some proteins.
Vacuoles are acidified via a proton pump, the ar H+-ATPase, or ase”, and it is
known that fungi with inactivating mutations of subunits of V-ATPase that result in impaired
e acidification also lose virulence and grow poorly. Ergosterol, a fungal—specific steroid
analogous to cholesterol in mammalian cells as a major membrane component, is critical for
conformation and activity of the V—ATPase, and V—ATPase dysfunction appears to be a major
mechanism of antifungal activity of ergosterol synthesis inhibitors, which includes l
classes of existing ngal agents. Antifungal agents that act via binding to specific proteins,
e. g. enzyme inhibitors, are inherently vulnerable to development of drug ance via single
mutations in genes encoding target proteins. Agents that target fungi via adequately specific
targeting and disruption of fungal acidic vacuoles by cation trapping may be less susceptible to
development of resistance through point mutations than are drugs acting by binding to speci?c
protein targets, due to impaired viability and virulence when vacuolar acidification, is impaired.
Clinically ant larial drugs are known that accumulate in acidic es and
lysosomes and their biological activity is largely mediated through their concentration in acidic
vacuoles, not only in malaria but in atory diseases, some cancers and non—malarial
infections by fungi and unicellular and oal parasites. Quinoline analog antimalarial drugs
target malaria plasmodia via cation trapping in acidic digestive vacuoles, where they can
accumulate to concentrations several orders of magnitude higher than in extracellular spaces. A
large molar fraction of chloroquine, me?oquine, quinacrine and several of their congeners are
ged at the usual extracellular pH of about 7.4 and the cytoplasmic pH of 7.1, and can
thereby pass through cellular and organelle membranes. In an acidic environment such as the
interior of a lysosome or fungal acidic vacuole, these antimalarials are predominantly cationic
and are thereby restricted from free passage through the vacuolar membrane. Antimalarials such
as chloroquine impair processing of heme from hemoglobin ingested by malaria plasmodia after
accumulating in the feeding vacuoles, ting for much of their specific toxicity to
dia. However, chloroquine and similar quinoline-analog antimalarials can accumulate in
mammalian lysosomes and fungal acidic vacuoles and impair vacuolar function to a degree
sufficient to provide some clinical benefit, if only by partically deacidifying the vacuoles.
Chloroquine is used for treatment of in chronic autoimmune and in?ammatory diseases such as
ic lupus erythematosis or rheumatoid arthritis, with moderate efficacy. A degree of
antifungal activity has been reported for larials such as chloroquine or quinacrine, both as
single agents or in combination with other s of antifungal agents, such as ?uconazole,
notably in animal models of systemic cryptococcosis. However, their activity is suboptimal,
yielding incomplete fungal growth inhibition. Recent work has also demonstrated moderate
growth inhibitory activity of chloroquine, me?oquine and other weakly cationic drugs such as
siramesine in animal models of . Existing lysosomotropic agents such as antimalarial
quinolone compounds can thus display some eutically relevant activity in es in
which acidic vacuoles contribute to pathogenesis. However, the activity and potency of
antimalarials in such diseases are limited, as the target cells can te accumulation of
relatively high concentrations of the antimalarials; the specific lethal effect of ine
compounds in malaria is largely attributed to disruption of heme processing within plasmodial
feeding vacuoles, a ism of cytotoxicity not applicable in the areas of in?ammatory
disease, cancer or fungal infections. Despite the body of evidence indicating strong ial for
targeting lysosomes for treating cancers, existing agents have not shown adequate activity or
therapeutic index for effectively treating cancer in humans.
“Lyosomotropic detergents”, comprising weakly cationic heterocyclic moieties bearing a single
alkyl chain with approximately 10 to 14 carbon atoms, were reported be potently cytotoxic to
mammalian cells and to display broad spectrum antifungal activity in vitro. This class of agents
accumulate in lysosomes and acidic vacuoles via the same type of cation trapping process
through which antimalarials are trated, and when they reach a al micellar
tration in the vacuole, they behave as detergents, damaging vacuolar membranes. They
display a characteristic sigmoid dose—response curve, as a uence of their formation of
micellar micro ures. However, there is no information about ty or safety of this class
of agents in Vivo in animal models of relevant diseases.
Y OF THE INVENTION
This invention es a compound represented by Formula I or a pharmaceutically acceptable
2O salt thereof
G-NH-A-Q-X-Y-Z I
wherein
G is a monocyclic, bicyclic, or tricyclic aromatic ring having one, two, or three ring nitrogen
atoms. G can be unsubstituted, or it can substituted at a ring carbon by amino, dimethylamino,
hydroxy, halo, methyl, per?uoromethyl, or alkyl having from 1 to 16 carbon atoms which alkyl
is either unsubstituted or substituted by hydroxy or alkoxy having 1 to 12 carbon atoms or
acetoxy. Or it can be substituted at a ring en by alkyl having from 1 to 16 carbon atoms
which alkyl is either unsubstituted or substituted by hydroxy or alkoxy having from 1 to 8 carbon
atoms. N is nitrogen, H is hydrogen, and NH is absent or present. A is absent or present and is
alkyl having from 1 to 12 carbon atoms, provided that if A has 1 carbon atom Q must be absent;
Q is absent or present and is O, NHC(O), or NH, provided that if A is absent Q must be absent,
and if both X and Y are absent Q cannot be 0 or NH. X is absent or present and is alkyl having
from 1 to 5 carbon atoms, provided that if Y is absent and Z is alkoxy or phenoxy X must have
more than 1 carbon atom. Y is absent or present and is phenyl unsubstituted or substituted by
halo, or is a monocyclic or bicyclic aromatic ring having one or two en atoms. Z is absent
or present and is hydrogen, alkyl having from 1 to 12 carbon atoms either unsubstituted or
substituted by one phenyl or phenoxy group, alkoxy having from 1 to 12 carbon atoms either
unsubstituted or tuted by one phenyl or phenoxy group, phenyl, phenoxy, or NHC(O)R6 or
C(O)NHR6 or C(O)OR6 where R6 is alkyl having from 1 to 6 carbon atoms, provided that if all
of A, Q, X, and Y are absent then Z must be alkyl having 6 to 12 carbon atoms.
In a particular aspect, the present invention provides a compound represented by Formula IB1 or
a ceutically acceptable salt thereof
wherein n is 1;
Q is absent;
R1 is en or halo; and
R7 is phenyl substituted by alkoxy having from 6 to 10 carbon atoms or phenoxy.
This invention also provides a use or method for treating or preventing a condition in a
mammalian subject; the condition being selected from the group consisting of an inflammatory
disease, a fungal ion, a unicellular parasitic infection, and a neoplastic disease; comprising
administering to the t an effective amount of the compound or salt of the invention. It also
provides compositions comprising these compounds or salt. And it provides a method of
inhibiting a fungus ex vivo, comprising contacting a surface or the fungus with the compound or
salt.
[FOLLOWED BY PAGE 5a]
DETAILED DESCRIPTION OF THE INVENTION
Without wishing to be bound by theory, this ion provides compounds and their use for
treating diseases characterized by pathogenic cells featuring lysosomes or other acidic vacuoles
with disease-related alterations predisposing them to accumulation of nds of the
invention, which then selectively inactivate or eliminate such pathogenic cells. Compounds of
the ion, many of which are aminoquinoline and aminoquinazoline derivatives, feature
significant improvements in potency and activity over known aminoquinoline drugs such as
chloroquine, as a consequence of structural moieties that potently disrupt lysosomal or ar
membrane integrity when the compounds accumulate in acidic vacuoles in cells. Diseases that
are at least moderately sive to antimalarial quinoline derivatives and analogs are in l
more effectively d with compounds of the invention. Such diseases broadly comprise
inflammatory diseases, neoplastic diseases, including both hematologic cancers and solid tumors,
[FOLLOWED BY PAGE 6]
WO 20995
and infections by eukaryotic pathogens, including fungi and l classes of protozoal or other
unicellular parasites.
DEFINITIONS
As used herein the term “alkyl” means a linear or branched—chain or cyclic alkyl group. An alkyl
group identified as having a certain number of carbon atoms means any alkyl group having the
specified number of carbons. For example, an alkyl having three carbon atoms can be propyl or
isopropyl; and alkyl having four carbon atoms can be n—butyl, l—methylpropyl, 2—methylpropyl or
t-butyl.
As used herein the term “halo” refers to one or more of fluoro, chloro, bromo, and iodo.
As used herein the term “per?uoro” as in per?uoromethyl, means that the group in question has
?uorine atoms in place of all of the hydrogen atoms.
Certain chemical compounds are referred to herein by their chemical name or by the two-letter
code shown below. The following are compounds of this invention.
CH Hexyloxy)octy1]quinolin—4—amine
CI utoxyoctyl)quinolin—4—amine
CJ N—(8-Methoxyoctyl)quinolin—4—amine
CK N—[6-(Hexyloxy)hexyl]quinolin—4—amine
CL N—(6—Butoxyhexyl)quinolin—4—amine
AL N—[lO—(Hexyloxy)decyl] quinolin—4—amine
AM N—(lO—Butoxydecyl)quinolin—4—amine
CM N—(5—Methoxypentyl)quinolin—4—amine
WO 20995
AV N—[8—(Hexyloxy)octyl] —2—methy1quinolin—4—amine
AW 7—Ch10ro—N— [8—(hexy10xy)0ctyl]quinolin—4—amine
AX 8—Ch10r0—N—[8—(hexyloxy)octyl]quinolin—4—amine
AY N—[8—(Hexyloxy)octyl] —7—(tri?uoromethyl)quinolin—4—amine
CN N—[8—(Hexyloxy)octyl] —8—(tri?uoromethyl)quinolin—4—amine
BB N— { 5—[3—(Hexyloxy)propoxy]penty1}quin01in—4—amine
BC N— { 3—[5—(Hexy10xy)penty10xy]propy1}quinolin—4—amine
AJ 3—Eth0xypropoxy)octyl]quinolin—4—amine
BD N—[8—(2—Pr0p0xyethoxy)octyl]quinolin—4—amine
CO N—[8—(Benzyloxy)octyl]quinolin-4—amine
AR N-(6-Phenoxyhexyl)quinolinamine
AN N-(8-Phenoxyocty1)quinolinamine
CP N— { 2-[2-(Hexy10xy)phenoxy] ethyl } quinolinamine
CQ N— { 3-[2-(Hexyloxy)phenoxy]propyl } quinolinamine
CR N— { 4- [2- (Hexyloxy)phenoxy]butyl } quinolin—4-amine
CS 2-Ethoxyphenoxy)propy1]quinolin—4—amine
CT N—[3-(2-Methoxyphenoxy)propy1]quinolin—4—amine
CU N— { 3-[2— (Benyloxy)phenoxy]propy1}quinolinamine
BH N—[8-(3—Methoxyphenoxy)octyl]quinolin—4—amine
CV N— { 4—[3—(Hexyloxy)phenoxy]buty1}quin01in—4—amine
AZ N—{ 3—[3—(Hexyloxy)phenoxy]propy1}quin01in—4—arnine
CW N— { 2—[3—(Hexy10xy)phenoxy]ethy1}quin01in-4—amine
AD N—[8—(4—Meth0xyphenoxy)octyl]quinolin—4—amine
CX N—[6—(4—Methoxyphenoxy)hexyl]quinolin—4—amine
BA N— { 2—[4— (Hexyloxy)phen0xy]ethy1}quinolin—4—amine
CY N—{ 3—[4—(Hexyloxy)phenoxy]pr0py1}quinolin—4—amine
CZ N— { 4—[4— oxy)phenoxy]buty1}quinolin—4—amine
BE N—[8—(m—T01y10xy)0cty1]quinolin—4—amine
BF N—[8—(p—T01yloxy)octyl]quinolin—4—amine
BG N—[8—(0—T01y10xy)octyl]quinolin—4—amine
DA N—[8—(4—tert—Butylphenoxy)octyl]quinolin—4—amine
BJ N—[8—(4—F1u0r0phenoxy)octyl]quin01in—4—amine
BI N—[8—(3—F1u0r0phenoxy)octyl]quin01in—4—amine
DB N—[8—(2—F1u0r0phenoxy)octyl]quin01in—4—amine
DC N—(Bipheny1—4—y1)quinolin—4—amine
A0 N-(4-Hexylpheny1)quinolinamine
AP Hexyl 4-(quinolinylamino)benzoate
DD N-(4-Phenoxypheny1)quinolinamine
DE N—(3-Phenoxypheny1)quinolin—4—amine
DF N—(2-Phenoxypheny1)quinolin—4—amine
DG N—[4-(Quinolin—4—ylamino)pheny1]hexanamide
DH N—[3-(Quinolin—4—ylamino)pheny1]hexanamide
AQ N—Hexy1—4—(quinolin—4—y1amino)benzamide
BV N—Hexy1—3—(quinolin—4—y1amino)benzamide
DI N—(4—Methoxypheny1)quinolin—4—amine
DJ N—[4—(Benzyloxy)phenyl]quinolin—4—amine
DK utoxypheny1)quinolin—4—amine
DL N—[4—(Hexy10xy)phenyl]quinolin—4—amine
DM N—[3—(Benzy10xy)phenyl]quinolin—4—amine
DN N—[3—(Hexy10xy)phenyl]quinolin—4—amine
DO N—[2—(Benzy10xy)phenyl]quinolin—4—amine
DP N—[2—(Hexyloxy)phenyl]quinolin—4—amine
BL 1u0r0—4—(hexyloxy)phenyl]quinolin—4—amine
DQ N—Benzquuinolin—4—amine
DR N—Phenethquuinolin—4—amine
AA N—[4—(Hexy10xy)benzyl]quinolin—4-amine
AC N—[3—(Hexy10xy)benzyl]quinolin—4-amine
DS N—[2—(Hexy10xy)benzyl] quinolin—4—amine
BK N—[3—F1u0r0—4—(hexyloxy)benzy1]quinolin—4—amine
DT N-[4-(Decy10xy)benzy1]quinolinamine
DU N-[3-(Decy10xy)benzy1]quinolinamine
AF N-(3-Phenoxybenzyl)quinolinamine
BU N—[3-(Benzyloxy)bcnzyl]quinolin—4—amine
DV N—(3-Phenethoxybenzyl)quinolin—4—amine
DW N—[4-(Quinolin—4—ylamino)buty1]benzamide
DX N—[6-(Quinolin—4—ylamino)hexy1]benzamide
DY N—[8-(Quinolin—4—ylamin0)octy1]benzamide
DZ 3—Methoxy—N—[8—(quinolin—4—y1amino)0ctyl]benzamide
EA 4—Methoxy—N—[8—(quinolin—4—y1amino)octyl]benzamide
EB 2—(Hexy10xy)—N—[2—(quinolin—4—ylamin0)ethy1]benzamide
EC yloxy)—N—[3—(quinolin—4—y1amin0)pr0py1]benzamide
ED 2—(Hexyloxy)—N—[4—(quinolin—4—ylamin0)buty1]benzamide
EE N—[8—(Quinolin—4—ylamino)octyl]picolinamide
EF N—[8—(Quinolin—4—ylamino)octyl]nicotinamide
EG N—[8—(Quinolin—4—ylamino)octyl]isonicotinamide
BZ N—(Pyridin—4—ylmethyl)quinolin—4—amine
BY N—(Pyridin—3—ylmethyl)quinolin—4—amine
EH N—(Pyridin—Z—ylmethyl)quinolin—4—amine
EI N—Hexquuinolin—4—amine
AG y1)quin01in—4—amine
EJ N—(Dodecyl)quinolin—4—amine
AI N1,NS—Di(quinolin—4—y1)octane—1,8—diamine
EK N—[8—(Hexy10xy)0cty1]quinolin—6—amine
EL N-[8-(Hexy10xy)octy1]quinolinamine
EM N-[8-(Hexy10xy)octy1]quinolinamine
EN N-[8-(Hexyloxy)octy1] (tri?uoromethyl)quinolinamine
EO 7—Ch10r0-N—decquuinolin—4—amine
EP 7—Ch10ro-N—dodecquuinolin—4—amine
AH N—(Decyl)quinazolin—4—amine
EQ N—Dodecquuinazolin—4—amine
ER 1—7—?uoroquinazolin—4—amine
ES N—Dodecy1—7—?uor0quinazolin—4—amine
ET 7—Chlor0—N—decy1quinazolin—4—amine
EU 7—Chlor0—N—d0decy1quinazolin—4—amine
EV N—(6—But0xyhexy1)quinazOlin—4—amine
EW N—[8—(Hexyloxy)octyl]quinazolin—4—amine
AE N—[8—(4—Meth0xyphenoxy)octyl]quinazolin—4—amine
EX N— { 2— [2— (Hexyloxy)phen0xy] ethyl } quinazolin—4—amine
EY N—{ 3—[2—(Hexyloxy)phenoxy]pr0py1}quinazolin—4—amine
EZ N—{ 4—[2—(Hexyloxy)phen0xy]buty1}quinazolin—4—amine
FA N—[8—(Quinazolin—4—ylamin0)octyl]nicotinamide
AK N—[3—(Hexy10xy)benzyl] quinazolin—4—amine
CG N—[3—(Decy10xy)benzyl]quinazolin-4—amine
BM N—(3—Phenoxybenzyl)quinazolin—4—amine
BN Decy10xy)benzyl]quinazolin-4—amine
AB N—[4—(Hexy10xy)benzyl] quinazolin-4—amine
FB 1-[2-(Ethoxymethy1)-1H—imidazo[4,5-c]quinoliny1]methy1propanol
FC 1-(4-Aminoisobuty1—1H—imidazo[4,5-c]quinoliny1)penty1 acetate
FD 1-Isobutylpentadecy1— lH-imidazo[4,5-c]quinolin01
BP l-Octyl-1H-imidazo[4,5-c]quinoline
FE decyl— dazo[4,5—c]quin01ine
FF l—Hexadecyl— 1H—imidazo[4,5—c]quin01in—4—amine
PG 1—[2-(D0decy10xy)ethy1]—1H—imidazo[4,5—c]quinoline
PH 1—[2-(Dodecy10xy)ethy1]—N,N—dimethy1—lH—imidazo[4,5—c]quinolin—4—amine
F1 1—[6-(Octyloxy)hexy1]—1H—imidazo[4,5—c]quinoline
CD 1—(8—Ethoxy0cty1)—1H—imidazo[4,5—c]quinoline
CE 1—(8—Meth0xy0cty1)—1H—imidazo[4,5—c]quinoline
BQ 1—(8—Butoxyocty1)—1H—imidazo[4,5—c]quinoline
FJ 1—[9—(Hexy10xy)nonyl] — 1H—imidazo[4,5—c]quinoline
FK 1—(10—Butoxydecy1)—1H—imidazo[4,5—c]quinoline
BO 4—Amin0—1—[8—(hexyloxy)0cty1]pyridinium salts
FL ethoxyoctylamino)— 1 —methy1pyridinium iodide
AS 1—[8—(Hexy10xy)octyl] — 1H—imidazo[4,5—c]pyridine
FM l—Hexadecyl— dazo[4,5—c]pyridine
AT 1—( 1 0—But0xydecy1)— 1H—imidazo[4,5—c]pyridine
FN N—(8—Meth0xyocty1)pyridin—4—amine
F0 N—[8—(Hexyloxy)0cty1]pyridin—3—amine
FP N—[8—(Hexyloxy)0cty1]pyridin—2—amine
AU N—[8—(Hexyloxy)0cty1]pyrimidin—4—amine
FQ N—[8—Hexyloxy)octy1)pyrimidin—2—amine
FR 1—[8—(Hexy10xy)octy1]—4—pheny1—1H—imidazole
FS N-[8-(Hexy10xy)octy1]isoquinolinamine
FT N-[8-(Hexy10xy)octy1]isoquinolin-S-amine
FU N-[8-(Hexyloxy)octy1]quinoxalin-Z-amine
CC 1—[8—(Hexy10xy)octy1]—lH—benzimidazole
FV N—[8-(Hexyloxy)octy1]pyrazin—2—amine
1—[8—(Hexyloxy)octyl]—1H—indole
FX 3—[8-(Hexyloxy)0ctyl] —3H—imidazo[4,5—b]pyridine
FY cyl—1H—imidazo[4,5—c]quinoline
FZ 1—[3-(Decy10xy)propyl]—1H—imidazo[4,5—c]quinoline
GA 1—[4—(Decy10xy)butyl]—1H—imidazo[4,5—c]quinoline
GB 1—[8—(Hexyloxy)octyl]—1H—imidazo[4,5—c]quinoline
GC 1—{5—[3—(Hexyloxy)pr0poxy]penty1}—1H—imidazo[4,5—c]quinoline
GD 1—{3—[3—(Hexyloxy)phenoxy]pr0py1}—1H—imidazo[4,5—c]quinoline
The following compounds were less active in the biological activity example(s) in which they
were .
BR N—(2—Methoxyethyl)quinolin—4—amine
BS N—[2—(Morpholin—4—yl)ethyl]quinolin—4—amine
BT N—[3—(Quinolin—4—ylamino)propyl]benzamide
BW N—(2—Diethylaminoethyl)—4—(quinolin-4—y1amino)benzamide
BX N—(4—Dimethylaminobenzyl)quinolin—4—amine
CA N—(Pyridin—4—ylmethyl)—8—(hexyloxy)octanamide
CB N—(Quinolin—6—yl)—8—(hexyloxy)octanamide
CF l—{ 3— [(5—(Hexyloxy)pentoxy]propyl} lH—imidazo[4,5—c]quinoline
As used herein the transitional term “comprising” is nded. A claim utilizing this term can
contain elements in addition to those recited in such claim.
As used in the claims the word “or” means “and/or” unless such reading does not make sense in
context. So for example, when it is stated in connection with Formula I that variable G can be
tuted at a ring carbon “or” at a ring nitrogen, it may be substituted at a ring carbon, at a ring
nitrogen, or at both a ring carbon and a ring nitrogen.
The following iations are used in the chemical synthesis examples and elsewhere in this
description:
DCM dichloromethane
DIEA N,N—diisopropylethylamine
DMA N,N—dimethylacetamide
DMAP4—(N,N—dimethylamino)pyridine
DME 1,2-dimethoxyethane
DMF N,N—dimethylformamide
DMSOdimethyl sulfoxide
EA ethyl e
Et20 diethyl ether
EtOH ethanol
FC ?ash chromatography
Hex hexanes
IPA 2—propanol
LAH lithium ydridoaluminate
MeOH methanol
mp g point
NMP N—methylpyrrolidinone
NMR nuclear magnetic resonance spectrometry
SPE solid phase extraction
TEA triethylamine
THF tetrahydrofuran
TLC thin layer chromatography
COMPOUNDS
In an embodiment of the compound or salt of Formula I, G is selected from the group consisting
of substituted or unsubstituted quinolyl, substituted or tituted quinazolyl, unsubstituted
isoquinolyl, unsubstituted quinoxalyl, unsubstituted benzimidazolyl, unsubstituted pyridyl,
unsubstituted nyl, unsubstituted indolyl, substituted or unsubstituted imidazoquinolyl,
substituted pyridinium, unsubstituted imidazopyridine, unsubstituted pyrimidyl, and tuted
imidazolyl. In another embodiment of the compound or salt of Formula I Y—Z is selected
from the group consisting of alkoxyphenylalkyl, phenyl, alkoxyphenoxyalkyl,
alkoxyalkyl, alkoxyalkoxyalkyl, yphenyl, phenoxyphenylalkyl, phenylalkoxyphenylalkyl,
phenoxyalkyl, phenylalkoxyalkyl, alkylphenoxyalkyl, alkyl, (halophenoxy)alkyl, biphenyl,
alkylphenyl, alkoxycarbonylphenyl, N—alkylcarbamoylphenyl, alkoxy(halophenyl), phenylalkyl,
(halophenyl)alkyl, (alkoxybenzamido)alkyl, picolinamidoalkyl, nicotinamidoalkyl,
isonicotinamidoalkyl, N—(quinolylamino)alkyl, N—(quinazolylamino)alkyl,
phenylalkoxyphenoxyalkyl, alkylalkoxyphenyl, phenylalkoxyphenyl, pyridylalkyl and
hydroxyalkyl.
Some of the compounds of this inveniton in which G is unsubstituted or substituted quinolyl can
be represented by Formula IA
HN—A-Q-X-Y-Z
| / IA
wherein A is absent or present and is alkyl having from 1 to 12 carbon atoms, provided that if A
has 1 carbon atom Q must be absent. Q is absent or present and is O, NHC(O), or NH, ed
that if A is absent Q must be absent, and if both X and Y are absent Q cannot be 0 or NH.
X is absent or present and is alkyl having from 1 to 5 carbon atoms, provided that if Y is absent
and Z is alkoxy or phenoxy X must have more than 1 carbon atom. Y is absent or present and is
phenyl unsubstituted or substituted by halo, or is a monocyclic or bicyclic aromatic ring having
one or two nitrogen atoms. Z is absent or present and is hydrogen, alkyl having from 1 to 12
carbon atoms either unsubstituted or substituted by one phenyl or phenoxy group, alkoxy having
from 1 to 12 carbon atoms either tituted or substituted by one phenyl or phenoxy group,
phenyl, phenoxy, or NHC(O)R6 or C(O)NHR6 or C(O)OR6 where R6 is alkyl having from 1 to 6
carbon atoms, ed that if all of A, Q, X, and Y are absent then Z must be alkyl having 6 to
12 carbon atoms. One of R1 and R2 is hydrogen and the other is selected from the group
ting of hydrogen, halo, methyl, and per?uoromethyl. In an embodiment of this invention
both R1 and R2 are hydrogen. In an embodiment of Formula IA, A—Q—X—Y—Z is selected from the
group ting of alkoxyphenylalkyl, alkoxyphenyl, alkoxyphenoxyalkyl, alkyl,
alkoxyalkoxyalkyl, phenoxyphenyl, phenoxyphenylalkyl, phenylalkoxyphenylalkyl,
phenoxyalkyl, phenylalkoxyalkyl, alkylphenoxyalkyl, alkyl, (halophenoxy)alkyl, biphenyl,
alkylphenyl, alkoxycarbonylphenyl, lcarbamoylphenyl, alkoxy(halophenyl), phenylalkyl,
alkoxy(halophenyl)alkyl, (alkoxybenzamido)alkyl, picolinamidoalkyl, nicotinamidoalkyl,
otinamidoalkyl, phenylalkoxyphenoxyalkyl, alkylalkoxyphenyl, phenylalkoxyphenyl,
pyridylalkyl and N—(quinolylamino)alkyl.
A more ic embodiment of compounds in which G quinolyl can be represented by Formula
/(CH2)n(O)p(CH2)qR3
\ \ 1A1
wherein n is 0, 1,2, 3,4, 5, 6,7, 8, 9, 10, 11, or 12, provided that ifp is 1 then n must not be 0 or
1. p is 0 or 1; and q is 0 or 1. One of R1 and R2 is hydrogen and the other is selected from the
group consisting of hydrogen, halo, methyl, and per?uoromethyl. R3 can be alkyl having from 1
to 10 carbon atoms either unsubstituted or substituted by: a) a phenyl or monocyclic or bicyclic
aromatic ring having one or two nitrogen atoms or phenoxy either unsubstituted or substituted by
phenoxy or alkoxy having from 1 to 6 carbon atoms, or b) alkoxy having from 1 to 6 carbon
atoms, provided that if R3 is alkyl substituted by alkoxy then alkyl must have more than 1 carbon
atom. atively R3 can be phenyl unsubstituted or substituted by halo and unsubstituted or
substituted by: a) alkyl having from 1 to 6 carbon atoms unsubstituted or substituted by phenyl or
phenoxy, b) alkoxy having from 1 to 10 carbon atoms tituted or substituted by phenyl or
phenoxy, provided that when substituted by phenoxy the alkoxy must have more than one carbon
atom, c) phenyl, d) phenoxy, or e) C(O)OR6, C(O)NHR6, or NHC(O)R6, wherein R6 is alkyl
having from 1 to 6 carbon atoms.
In an embodiment of the compounds of Formula 1A1, R1 is hydrogen and R2 is en. In a
more specific embodiment n is 2, 3, 4, 5, 6, 7, 8, 9, or 10; p is l; and R3 is alkyl having from 1
to 6 carbon atoms. es of such compounds include N—[8—(Hexyloxy)octyl]quinolin—4—
amine, N—(8—Butoxyoctyl)quinolin—4—amine, ethoxyoctyl)quinolin—4—amine, N—[6—
(Hexyloxy)hexyl]quinolin—4—amine, N—(6—Butoxyhexyl)quinolin—4—amine, N—[lO—
(Hexyloxy)decyl]quinolin—4—amine, N—(l0—Butoxydecyl)quinolin—4—amine, N—(S—
Methoxypentyl)quinolin—4—amine.
In another embodiment of the compounds of Formula IAl, n is 2, 3, 4, 5, 6, 7, 8, 9, or 10; p is 1;
one of R1 and R2 is hydrogen and the other is selected from the group consisting of halo, methyl,
and per?uoromethyl; and R3 is alkyl haVing from 1 to 6 carbon atoms. es of such
compounds include N—[8—(Hexyloxy)octyl]—2-methquuinolin—4—amine, 7—Chloro—N—[8-
(hexyloxy)octyl]quinolin—4—amine, 8—Chloro—N—[8—(hexyloxy)octyl]quinolin—4—amine, N—[8—
(Hexyloxy)octyl]—7—(tri?uoromethyl)quinolin—4—amine, N—[8—(Hexyloxy)octyl]—8—
(tri?uoromethyl)quinolin—4—amine.
In another embodiment of the compounds of Formula 1A1 in which R1 is hydrogen and R2 is
hydrogen: n is 2, 3, 4, 5, 6, 7, 8, 9, or 10; p is 1; R3is alkyl having from 2 to 5 carbon atoms
substituted by alkoxy having from 1 to 6 carbon atoms. Examples of such compounds include
N-{ 5-[3-(Hexyloxy)propoxy]pentyl}quinolinamine, N- { 3-[5-(Hexyloxy)pentyloxy]propyl}
quinolinamine, N-[8-(3-Ethoxypropoxy)octyl]quinolinamine, N—[8—(2-
Propoxyethoxy)octyl]quinolin—4—amine.
A subset of nds of Formula 1A1 can be represented by Formula IAla
/(CH2)n(O)p(CH2)q
HN \
A IAla
\ \ /\R4
wherein n is 0, l, 2, 3, 4, 5, 6, 7, or 8; p is 0 or 1; q is 0 or 1, provided that ifp is 1 then n must
not be 0 or 1. One of R1 and R2 is hydrogen and the other is selected from the group consisting of
hydrogen, halo, methyl, and per?uoromethyl. R4 is hydrogen or halo. R5 is selected from the
group consisting of hydrogen; halo; unbranched or ed alkyl having from 1 to 6 carbon
atoms unsubstituted or substituted by phenyl or phenoxy; alkoxy having from 1 to 10 carbon
atoms unsubstituted or substituted by phenyl or phenoxy, provided that when substituted by
phenoxy the alkoxy must have more than one carbon atom; ; phenyl; phenoxy; C(O)OR6;
C(O)NHR6; or NHC(O)R6, wherein R6 is alkyl having from 1 to 6 carbon atoms. In ment
of Formula IAla R1 is hydrogen and R2 is hydrogen. In a more specific embodiment p is l and
R4 is hydrogen. In a still more specific embodiment R5 is en. Examples of such
compounds include N—[8—(Benzyloxy)octyl]quinolin—4—amine,
henoxyhexyl)quinolin—4—amine, N-(8—Phenoxyoctyl)quinolin—4—amine.
In another embodiment of Formula IAla, both R1 and R2 are en, q is 0, and R5 is alkoxy
having from 1 to 6 carbon atoms unsubstituted or substituted by phenyl. In a more specific
embodiment R5 is in the ortho position. Examples of such compounds include
N-{ 2-[2-(Hexyloxy)phenoxy]ethyl}quinolinamine, N- { 3-[2-(Hexyloxy)phenoxy]propyl}
quinolinamine, N-{4-[2-(Hexyloxy)phenoxy]butyl }quinolinamine, N—[3-(2-
Ethoxyphenoxy)propyl]quinolinamine, 2-Methoxyphenoxy)propyl] quinolinamine,
N—{ 3—[2—(Benyloxy)phenoxy]propy1}quinolin—4—amine. Alternatively R5 is in the meta position.
Examples of such compounds include N—[8—(3—Methoxyphenoxy)octyl]quinolin—4—amine, N—{4-
[3—(Hexyloxy)phenoxy]butyl}quinolin—4—amine, N—{ 3-[3-(Hexyloxy)phenoxy]propyl}quinolin
amine, N—{2-[3—(Hexyloxy)phenoxy]ethyl} quinolinamine. Alternatively R5 is in the para
position. Examples of such compounds include N—[8-(4—Methoxyphenoxy)octyl]quinolin—4—
amine, N—[6-(4—Methoxyphenoxy)hexyl]quinolin—4—amine, N— { 2—[4—(Hexyloxy)phenoxy]ethyl}
quinolin—4—amine, 4—(Hexyloxy)phenoxy] }quinolin—4—amine, N—{4—[4—
(Hexyloxy)phenoxy]butyl}quinolin—4—amine.
In another embodiment of Formula IAla, R1 is en and R2 is hydrogen, p is 1, R4 is
hydrogen, and R5 is unbranched or branched alkyl having from 1 to 6 carbon atoms. Examples of
such compounds e N—[8—(m—Tolyloxy)octyl]quinolin—4—amine, N—[8—(p—Tolyloxy)octyl]
quinolin—4—amine, N—[8—(0—Tolyloxy)octyl]quinolin—4—amine, N—[8—(4—tert—Butylphenoxy)octyl]
quinolin—4—amine. atively R5 is ?uoro. Examples of such compounds include
N—[8—(4—Fluorophenoxy)octyl]quinolin—4—amine, N—[8—(3—Fluorophenoxy)octyl]quinolin—4—amine,
N—[8—(2—Fluorophenoxy)octyl]quinolin—4—amine.
In r embodiment of Formula IAla, R1 is hydrogen and R2 is hydrogen, and p is 0. In a
more specific embodiment q is 0. In a still more specific embodiment n is 0. Examples of such
compound include N—(Biphenyl—4—yl)quinolin—4—amine, N—(4—Hexylphenyl)quinolin—4—amine,
Hexyl 4—(quinolin—4—ylamino)benzoate, henoxyphenyl)quinolin—4—amine,
N—(3—Phenoxyphenyl)quinolin—4—amine, N-(2—Phenoxyphenyl)quinolin—4—amine,
N—[4—(Quinolin—4—ylamino)phenyl]hexanamide, N—[3—(Quinolin—4—ylamino)phenyl]hexanamide,
N—Hexyl—4—(quinolin—4—ylamino)benzamide, N—Hexyl—3—(quinolin—4—ylamino)benzamide.
Alternatively R5 is alkoxy having from 1 to 10 carbon atoms unsubstituted or substituted by
phenyl. Examples of such compounds include N-(4-Methoxyphenyl)quinolinamine,
N-[4-(Benzyloxy)phenyl]quinolinamine, N-(4-Butoxyphenyl)quinolinamine,
N-[4-(Hexyloxy)phenyl]quinolinamine, N-[3-(Benzyloxy)phenyl]quinolinamine,
N-[3-(Hexyloxy)phenyl]quinolinamine, N-[2-(Benzyloxy)phenyl]quinolinamine,
N—[2—(Hexyloxy)phenyl]quinolin—4—amine, N—[2—Fluoro(hexyloxy)phenyl]quinolin—4—amine. In
another embodiment of a IAla, R1 is hydrogen and R2 is hydrogen, p is 0, q is 0, and n is
1 or 2. Examples of such compounds include N—Benzquuinolin—4—amine, and
N—Phenethquuinolin—4—amine.
In another embodiment of a IAla, R1 is hydrogen and R2 is hydrogen, p is 0, and q is 1. In
a more specific embodiment R5 is alkoxy having from 1 to 10 carbon atoms. Examples of such
compounds include N—[4—(Hexyloxy)benzyl]quinolin-4—amine, N—[3—(Hexyloxy)benzyl]quinolin—
4—amine, N—[2—(Hexyloxy)benzyl]quinolin—4—amine, N—[3—Fluoro—4—(hexyloxy)benzyl]quinolin—4—
amine, N—[4—(Decyloxy)benzyl]quinolin—4—amine, N—[3—(Decyloxy)benzyl]quinolin—4—amine.
atively R5 is y, or alkoxy having from 1 to 10 carbon atoms substituted by phenyl.
Examples of such compounds include N—(3—Phenoxybenzyl)quinolin—4—amine,
N— [3—(Benzyloxy)benzyl]quinolin—4—amine, N—(3—Phenethoxybenzyl)quinolin—4—amine.
Another more specific embodiment of compounds in which G quinolyl can be represented by
Formula 1A2
/(CH2)nN
HAR13
\ 1A2
wherein n is 2, 3, 4, 5, 6, 7, or 8. R13 is phenyl unsubstituted or substituted by alkoxy having from
1 to 6 carbon atoms; or 2-, 3-, or 4-pyridyl. In one embodiment R13 is unsubstituted phenyl.
Examples of such compounds include N—[4—(Quinolinylamino)butyl]benzamide,
N—[6—(Quinolinylamino)hexyl]benzamide, Quinolin—4—ylamino)octyl]benzamide. In
another embodiment R13 is phenyl substituted by alkoxy having from 1 to 6 carbon atoms.
Examples of such compounds include 3—Methoxy—N—[8-(quinolin—4—ylamino)octyl]benzamide,
4—Methoxy-N—[8—(quinolin—4—ylamino)octyl]benzamide, 2—(Hexyloxy)—N—[2—(quinolin—4—
ylamino)ethyl]benzamide, 2—(Hexyloxy)—N—[3—(quinolin—4—ylamino)propyl]benzamide,
2—(Hexyloxy)—N—[4—(quinolin—4—ylamino)butyl]benzamide. Alternatively R13 is 2—pyridyl, 3—
l, or 4—pyridyl. Examples of such compounds include N—[8—(Quinolin—4—
o)octyl]picolinamide, N—[8—(Quinolin—4—ylamino)octyl]nicotinamide,
N—[8—(Quinolin—4—ylamino)octyl]isonicotinamide.
Other examples of nds of a IA include N—(Pyridin—4—ylmethyl)quinolin—4—amine,
N—(Pyridin—3—ylmethyl)quinolin—4—amine, N—(Pyridin—2—ylmethyl)quinolin—4—amine,
N—Hexquuinolin—4—amine, N—(Decyl)quinolin—4—amine, N—(Dodecyl)quinolin—4—amine,
N1,NS—Di(quinolin—4—yl)octane—1,8—diamine. Other examples of compounds of Formula I in
which G is yl include N—[8—(Hexyloxy)octyl]quinolin—6—amine, N—[8—(Hexyloxy)octyl]
quinolin—3—amine, N—[8—(Hexyloxy)octyl]quinolin—8—amine, N—[8—(Hexyloxy)octyl]—2—
(tri?uoromethyl)quinolin—4—amine, 7—Chloro—N—decquuinolin—4—amine, 7—Chloro—N—
dodecquuinolin—4—amine.
Some of the compounds of this inveniton in which G is unsubstituted or substituted quinazolyl
can be represented by a IB
HN—A-Q-X-Y-Z
R,_|
l 2 IB
wherein A is absent or t and is alkyl having from 1 to 12 carbon atoms, provided that if A
has 1 carbon atom Q must be absent. Q is absent or present and is O, NHC(O), or NH, provided
that if A is absent Q must be absent, and if both X and Y are absent Q cannot be 0 or NH.
X is absent or present and is alkyl having from 1 to 5 carbon atoms, provided that if Y is absent
and Z is alkoxy or y X must have more than 1 carbon atom. Y is absent or present and is
phenyl unsubstituted or substituted by halo, or is a monocyclic or bicyclic aromatic ring having
one or two nitrogen atoms. Z is absent or present and is hydrogen, alkyl having from 1 to 12
carbon atoms either unsubstituted or substituted by one phenyl or phenoxy group, alkoxy having
from 1 to 12 carbon atoms either unsubstituted or substituted by one phenyl or phenoxy group,
phenyl, y, or R6 or C(O)NHR6 or C(O)OR6 where R6 is alkyl having from 1 to 6
carbon atoms, provided that if all of A, Q, X, and Y are absent then Z must be alkyl having 6 to
12 carbon atoms. R1 is selected from the group consisting of hydrogen, halo, methyl, and
perfluoromethyl.
In an embodiment of Formula IB, R1 is hydrogen. In another embodiment, Y—Z is
selected from the group ting of alkoxyphenylalkyl, alkoxyphenyl, alkoxyphenoxyalkyl,
alkoxyalkyl, alkoxyalkoxyalkyl, phenoxyphenyl, phenoxyphenylalkyl, phenylalkoxyphenylalkyl,
phenoxyalkyl, phenylalkoxyalkyl, alkylphenoxyalkyl, alkyl, (halophenoxy)alkyl, biphenyl,
henyl, alkoxycarbonylphenyl, N—alkylcarbamoylphenyl, alkoxy(halophenyl), phenylalkyl,
alkoxy(halophenyl)alkyl, (alkoxybenzamido)alkyl, picolinamidoalkyl, nicotinamidoalkyl,
isonicotinamidoalkyl, phenylalkoxyphenoxyalkyl, alkylalkoxyphenyl, phenylalkoxyphenyl,
lalkyl, N—(quinazolylamino)alkyl, and N—(quinolylamino)alkyl.
A subset of compounds of Formula IB can be represented by Formula IBl
2)nQR7
/ \N
R1_ | J
\ /
wherein n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; Q is absent or present and is O or NHC(O),
provided that if Q is present n cannot be 0 or 1; and provided that if Q is absent, then (CH2)nR7
must have more than 5 carbon atoms. R1 is hydrogen or halo. R7 is selected from the group
consisting of: hydrogen; alkyl having from 1 to 6 carbon atoms; and phenyl or monocyclic
aromatic ring having one nitrogen atom, unsubstituted or substituted by alkyl having from 1 to 6
carbon atoms or alkoxy haVing from 1 to 10 carbon atoms or phenyl or phenoxy. In an
embodiment Q is absent. Examples of such compounds include N—(Decyl)quinazolin—4—amine,
N—Dodecquuinazolin—4—amine, l—7—?uoroquinazolin—4—amine, N—Dodecyl—7—
?uoroquinazolin—4—amine, 7—Chloro—N—decquuinazolin—4—amine, 7—Chloro—N—dodecquuinazolin—
e. In r embodiment Q is O or NHC(O). Examples of such compounds include N—(6—
Butoxyhexyl)quinazolin—4—amine, N—[8—(Hexyloxy)octyl]quinazolin—4—amine,
N—[8—(4—Methoxyphenoxy)octyl]quinazolin—4—amine, N—{2—[2—(Hexyloxy)phenoxy]ethyl}
olin—4—amine, N— { 3— [2—(Hexyloxy)phenoxy]propyl zolin—4—amine,
N— { 4—[2—(Hexyloxy)phenoxy]butyl }quinazolin—4—amine, N— [8—(Quinazolin—4—
ylamino)octyl]nicotinamide. In an embodiment of Formula IB 1, n is 1, Q is , and R7 is
phenyl substituted by alkoxy having from 1 to 10 carbon atoms or phenoxy. Examples of such
compounds include N—[3—(Hexyloxy)benzyl]quinazolin—4—amine,
N— [3—(Decyloxy)benzyl]quinazolin—4—amine, N—(3—Phenoxybenzyl)quinazolin—4—amine,
N— [4—(Decyloxy)benzyl]quinazolin—4—amine, Hexyloxy)benzyl]quinazolin—4—amine.
Some of the compounds of this invention in which G is unsubstituted or substituted
imidazoquinolyl can be represented by Formula IC
|\ \ 1C
N R1
Wherein R1 is hydrogen, OH, NHz, or N(CH3)2; R2 is ed from the group consisting of
hydrogen, halo, methyl, and per?uoromethyl; R8 is hydrogen, or alkyl having from 1 to 15
carbon atoms tituted or substituted by alkoxy having 1 or 2 carbon atoms or acetoxy; and
R9 is a branched or unbranched alkyl having from 1 to 16 carbon atoms, unsubstituted or
substituted by hydroxy, or alkoxy having from 1 to 12 carbon atoms, provided that if substituted
by hydroxy or alkoxy R9 must have more than 1 carbon atom. In an embodiment R2 is hydrogen.
Examples of such compounds include l—[2—(Ethoxymethyl)—lH—imidazo[4,5—c]quinolin—l—yl]-2—
methylpropan—2—ol, l—(4—Amino—l—isobutyl—1H—imidazo[4,5—c]quinolin—2—yl)pentyl acetate,
1—Isobutyl—2—pentadecyl— lH—imidazo[4,5—c]quinolin—4—ol, l—Octyl— lH—imidazo[4,5—c]quinoline,
1—Hexadecyl— lH—imidazo[4,5—c]quinoline, 1—Hexadecyl— lH—imidazo[4,5—c]quinolin—4—amine,
l—Dodecyl— dazo[4,5—c]quinoline, l—{ 5—[3—(Hexyloxy)propoxy]pentyl } — lH—imidazo[4,5—
c]quinoline, 3—(Hexyloxy)phenoxy]propyl}—lH—imidazo[4,5—c]quinoline. In another
embodiment of Formula IC, R2 is hydrogen, and R9 is an unbranched alkyl having from 2 to 10
carbon atoms, substituted by alkoxy having from 1 to 12 carbon atoms. Examples of such
compounds include l—[2—(Dodecyloxy)ethyl]—lI-I—imidazo[4,5—c]quinoline,
Dodecyloxy)ethyl]—N,N—dimethyl—lH—imidazo[4,5—c]quinolin—4—amine, l—[6—
(Octyloxy)hexyl] — lH—imidazo[4,5—c]quinoline, l—(8—Ethoxyoctyl)— lH—imidazo[4,5—c]quinoline,
l-(8—Methoxyoctyl)— lH—imidazo[4,5—c]quinoline, l—(8—Butoxyoctyl)— lH—imidazo[4,5—
c]quinoline, l—[9—(Hexyloxy)nonyl] — lH—imidazo[4,5—c]quinoline, l—( l 0—Butoxydecyl)— 1H—
imidazo[4,5—c]quinoline, l—[3—(Decyloxy)propyl]—1H—imidazo[4,5—c]quinoline, l—[4—
(Decyloxy)butyl] — lH—imidazo[4,5—c]quinoline, 1—[8—(Hexyloxy)octyl] — lH—imidazo[4,5—
c]quinoline.
Some of the compounds of this invention in which G is substituted pyridinium can be
represented by Formula ID
wherein R10 is alkyl having from 1 to 8 carbon atoms, unsubstituted or substituted by alkoxy
having from 1 to 6 carbon atoms, provided that if tuted by alkoxy R10 must have more than
1 carbon atom. Rllis hydrogen; or alkyl having from 1 to 8 carbon atoms, unsubstituted or
substituted by alkoxy having from 1 to 3 carbon atoms, provided that if substituted by alkoxy R11
must have more than 1 carbon atom. X" is a rion. Examples of such compounds include
a 4—Amino-l—[8—(hexyloxy)octyl]pyridinium salt, and 4—(8—Methoxyoctylamino)— l—
pyridinium iodide.
WO 20995
In an embodiment of this invention G is lH—imidazo[4,5—c]pyridine. Some of those compounds
can be represented by Formula IE
/\\? IE
wherein R12 is alkyl having from 2 to 16 carbon atoms, unsubstituted or substituted by alkoxy
having from 4 to 6 carbon atoms. Examples of such compounds include l—[8—(Hexyloxy)octyl]—
lH—imidazo[4,5—c]pyn'dine, l—Hexadecyl—lH—imidazo[4,5—c]pyn'dine, l—(lO—Butoxydecyl)—1H—
imidazo[4,5—c]pyridine.
Examples of this invention in which G is pyridyl include N-(8-Methoxyoctyl)pyridineamine,
N—[8-(Hexyloxy)octyl]pyridinamine, and N-[8-(Hexyloxy)octyl]pyridin-2—amine.
Examples of this invention in which G is pyrimidyl include N-[8-(Hexyloxy)octyl]pyrimidin
amine, and N—[8-Hexyloxy)octyl)pyrimidin—2—amine. In an embodiment of this invention G is 5-
aryl dazolyl. Examples of such compounds include 1—[8—(Hexyloxy)octy1]—4—phenyl—1H-
imidazole. Examples of compounds of this invention in which G is isoquinolyl include N—[8—
(Hexyloxy)octyl]isoquinolin—l—amine, N—[8—(Hexyloxy)octyl]isoquinolin—S—amine. Examples of
compounds in which G is alyl include Hexyloxy)octyl]quinoxalin—Z—amine.
Examples of compounds in which G is benzimidazolyl include l—[8—(Hexyloxy)octyl]—1H—
benzimidazole. es of compounds in which G is pyrazinyl include N—[8—
(Hexyloxy)octyl]pyrazin—2—amine. Examples of compounds in which G is indolyl include l—[8—
(Hexyloxy)octyl]—lH—indole. In an embodiment of this invention G is 3H—imidazo[4,5—
b]pyridine. es of such compounds include Hexyloxy)octyl]—3H—imidazo[4,5—
b]pyridine.
In certain embodiments of this invention, one or more of the following compounds are excluded:
imiquimod; 4—(n—decylamino)quinoline [5891 ]; 4—decylaminoquinazoline [22754— 1 2—7].
In an embodiment of the compound of this invention, the compound is in substantially (at least
98%) pure form. This invention provides prodrugs of the compounds and salts bed above,
and their uses as described . Whenever a phenyl ring is substituted, the substitution may be
at the ortho—, meta—, or osition.
REACTION SCHEMES
The compounds of the present invention can be made in accordance with the following reaction
schemes.
The compound of formula I wherein G is a monocyclic or bicyclic aromatic ring having one
or two ring nitrogen atoms, either unsubstituted or substituted at a ring carbon by halo, methyl,
or per?uoromethyl;
N is nitrogen, H is en;
2O A is absent or present and is alkyl having from 1 to 12 carbon atoms, provided that if A has 1
carbon atom Q must be absent;
Q is absent or present and is O, NHC(O), or NH, provided that if A is absent Q must be
absent, and if both X and Y are absent Q cannot be 0 or NH;
X is absent or present and is alkyl having from 1 to 5 carbon atoms, provided that if Y is
absent and Z is alkoxy or phenoxy X must have more than 1 carbon atom;
Y is absent or present and is phenyl tituted or substituted by halo, or is a monocyclic or
bicyclic ic ring having one nitrogen atom;
Z is absent or present and is: a) hydrogen, b) alkyl having from 1 to 12 carbon atoms either
unsubstituted or tuted by one phenyl or phenoxy group, c) alkoxy having from 1 to 10
carbon atoms either unsubstituted or substituted by one phenyl or phenoxy group, d) phenyl, e)
phenoxy, or f) NHC(O)R6 or C(O)NHR6 or C(O)OR6 where R6 is alkyl with l to 6 carbon atoms
except if both X and Y are absent, provided that if all of A, Q, X, and Y are absent then Z must
be alkyl having 6 to 12 carbon atoms, can be prepared from the on of the compound of
formula 1 with the compound of formula 2 where LG is a leaving group such as a halogen, a
sulfonyloxy, a siloxy, or a borate via the reaction scheme in Scheme 1. If LG is located in a
position on the aromatic ring that is activated by a nitrogen atom, the reaction of step (a) can
proceed thermally without the use of a catalyst, and LG is halo is red, and LG is chloro is
most red. G is preferably selected from the group of compounds consisting of unsubstituted
or substituted 4—quinolyl, 4—quinazolyl, 2—quinolyl, azolyl, l—isoquinolyl, uinolyl, 2—
alyl, l—phthalazyl, 2—pyridyl, 4—pyridyl, 2—pyrimidyl, 4—pyrimidyl, and 2—pyrazinyl. The
compound of formula 1 and the compound of formula 2 and a suitable base such as
triethylamine, tripropylamine, N—methylmorpholine, or diisopropylethylamine are heated in a
suitable solvent such as l—pentanol, l—butanol, 2—propanol, dimethylformamide, N—
methylpyrrolidinone, or a mixture of suitable solvents. If LG is not located in a position on the
aromatic ring that is activated by a en atom, the reaction can proceed with the use of a
catalyst such as a transition metal complex catalyst such as a palladium complex or a nickel
complex.
Scheme 1.
HZN—A—Q—X—Y—Z G—NH—A—Q—x—Y—z
1 G—LG
The compound of formula 7 where T is CH and R2 is present or T is N and R2 is absent and
where either: a) n is 2—12 and p is l; or b) n is 0 or 1 and p is 0; and where q is 0 or 1, and one of
R1 and R2 is hydrogen and the other is ed from the group consisting of hydrogen, halo,
methyl, and per?uoromethyl, and R3 is alkyl having from 1 to 10 carbon atoms either
unsubstituted or tuted by: a) a monocyclic or bicyclic aromatic ring having one or two
en atoms or phenyl either unsubstituted or substituted by alkoxy having from 1 to 6 carbon
atoms, or b) alkoxy having from 1 to 6 carbons, provided that if R3 is alkyl substituted by alkoxy
2014/013992
then alkyl cannot have 1 carbon atom; phenyl unsubstituted or substituted by halo and
unsubstituted or substituted by: a) alkyl having from 1 to 6 carbon atoms, b) alkoxy having from
1 to 10 carbon atoms unsubstituted or substituted by phenyl or y ed that when
substituted by phenoxy the alkoxy must have more than one carbon atom, c) phenyl, d) phenoxy,
or e) C(O)OR6, C(O)NHR6, or NHC(O)R6 wherein R6 is alkyl having from 1 to 6 carbon atoms
can be prepared starting from the nd of a 3 or starting from the compound of
formula 6 via the reaction scheme in Scheme 2.
Some compounds of the formula 3 and some compounds of the formula 6 are commercially
available. The compound of formula 3 is reacted with the compound of formula 4 to give the
compound of formula 5 via reaction of step (a): the compound of formula 3 is treated with a
suitable base and then is reacted with the compound of formula 4. The selectivity of the reaction
for substitution of only one of the bromides of the compound of formula 4 can be increased by
using a stoichiometric excess of the compound of formula 3. If n is 1, any base that is commonly
used to convert an alcohol to an alkoxide is suitable, such as sodium hydride or a hindered alkali
metal de such as sodium isopropoxide. If n is 1, the base must be completely reacted with
the compound of formula 3 before the addition of the compound of formula 4 is performed. If n
is 0, any base that is ly used to convert a phenol to a phenoxide is suitable, such as
potassium carbonate or sodium carbonate. If n is 0, the compound of formula 4 may be present
when the base is reacted with the compound of formula 3.
The compound of formula 5 is converted to the compound of formula 6 via reactions of step
(b), the Gabriel synthesis of primary . The compound of formula 5 is d with
potassium phthalimide under conventionally used conditions to give the phthalimide
intermediate, which is converted to the compound of formula 6 under conventionally used
conditions such as hydrazine monohydrate in ethanol at re?ux. Any method for the cleavage of
phthalimides may be used.
The compound of formula 6 is converted to the compound of formula 7 via step (c): the
compound of a 6 reacts with the compound of a 7 in the presence of a tertiary
amine base such as triethylamine, diisopropylethylamine, or tripropylamine at elevated
temperature in a suitable solvent, such as anol heated at re?ux if T is N or 1—pentanol
heated at re?ux or dimethylformamide or N—methylpyrrolidinone at 130— 150 0C if T is CH.
Scheme 2.
HO—(CH2)q—R3 Br—(CH2)n—(O)p—(CH2)q—R3
Br—(CH2)n—Br
3 5
HN-(CH2)n—(O)p—(CH2)q-R3 (C)
R1_/ / ILRZ HzN-<CH2>,-<0>,,—(CH2)q-R3
\ \N) Cl 6
7 1_ L
R R
\ J \
The compound of formula 3 where q is 0 or 1 and R3 is alkyl having from 1 to 10 carbon
atoms substituted by alkoxy having from 1 to 12 carbon atoms, ed that if R3 is alkyl
substituted by alkoxy then alkyl cannot have one carbon, can be prepared via the reaction scheme
in Scheme 3. In step (a), the compound of formula 9 where n is 2—11 is treated with any base that
is commonly used to convert an alcohol to an de, such as sodium hydride or a hindered
alkali metal alkoxide such as sodium isopropoxide. Then, the compound of formula 10 where R6
is alkyl having from 1 to 12 carbon atoms is added. The selectivity of the reaction for alkylation
of only one of the hydroxyls of the compound of formula 9 can be increased by using a
stoichiometric excess of the compound of formula 9.
Scheme 3.
HO—(CH2)n—OH 2)q—R3
Br—R6
9 3
The compound of formula 3 where q is 0 or 1 and R3 is phenyl tuted by halo, alkoxy
having from 1 to 10 carbon atoms unsubstituted or substituted by phenyl or phenoxy, can be
prepared from the compound of formula 11 where q is O or 1 and R4 is hydrogen or halo Via the
reaction scheme in Scheme 4. The compound of formula 11 is treated with a le base such
as potassium carbonate or sodium carbonate and reacted with the compound of formula 10,
where R6 is alkyl having from 1 to 10 carbon atoms unsubstituted or substituted by phenyl or
phenoxy. When using carbonate bases with the compound of formula 11 wherein q is 1, the
aromatic yl will react selectively with the compound of formula 10, despite the presence
of the aliphatic yl. If n is 0, the use of a stoichiometric excess of the compound of formula
11 will minimize the quantity of the dialkylated side product.
Scheme 4.
HO‘(CH2)q
\ (a)
’\J,—OH HO—(CHg) -R3q
Br—R6
R4 3
11
The compound of formula 6 where n is 0, p is 0, q is 0, and R3 is phenyl unsubstituted or
substituted by halo, 6 wherein R6 is alkyl having from 1 to 6 carbon atoms can be
prepared starting from the compound of formula 12 where R4 is hydrogen or halo and the
compound of formula 13 where R6 is alkyl having from 1 to 6 carbon atoms via the reaction
scheme in Scheme 5. The compound of formula 12 may be commercially available or can be
prepared from the carboxylic acid using conventional methods. The compound of formula 14
where R4 is hydrogen or halo and R5 is 6 wherein R6 is alkyl having from 1 to 6 carbon
atoms is ed from the reaction of the compound of a 12 with the compound of
formula 13 in the presence of a base such as pyridine or triethylamine via step (a). Any of the
conventional methods for the preparation of carboxylic esters from carboxylic acids or their
derivatives and alcohols may be used to prepare the compound of formula 14. If the compound
of a 13 is replaced by the amine , the reaction scheme will e the compound
of formula 6 where R3 is substituted by R6. The compound of formula 14 is reduced to
form the compound of formula 6 by catalytic reduction using hydrogen and a palladium on
charcoal catalyst via step (b). Any of the conventional methods for selective reduction of nitro
groups to amino groups in the presence of carboxylic ester groups can be used in step (b).
Scheme 5.
D (a)
C(O)C1 '\—R5
x) x)
02N \ HO—R6 02N
R4 R4
12 14
J (b)
HzN-(CH2>n-(O>p—(CH2)q-R3
The compound of formula 6 where n is O, p is 0, q is 0, and R3 is phenyl unsubstituted or
substituted by halo, NHC(O)R6 wherein R6 is alkyl having from 1 to 6 carbon atoms can be
prepared starting from the compound of formula 15 where R4 is hydrogen or halo and the
compound of formula 16 where R6 is alkyl having from 1 to 6 carbon atoms via the reaction
scheme in Scheme 5. The compound of a 15 and the compound of formula 16 can react to
produce the compound of formula 14 where R4 is hydrogen or halo and R5 is NHC(O)R6 n
R6 is alkyl having from 1 to 6 carbon atoms via the reaction of step (a) under any conventional
conditions for preparing carboxamides from the reaction of amines with carboxylic acid
chlorides. The compound of formula 14 is reduced to form the compound of formula 6 by
2014/013992
catalytic reduction using hydrogen and a palladium on charcoal st via step (b). Any of the
conventional methods for reduction of nitro groups to amino groups can be used in step (b).
Scheme 6.
n,a—NHz\ n,TRs
02N CIC(0>—R6 OZN \
R4 R4
14
j (b)
H2N—(CH2)n—(O)p—(CH2)q_R3
The compound of formula 6 where n is 0, p is 0, q is 0, and R3 is phenyl unsubstituted or
substituted by halo, alkoxy having from 1 to 12 carbon atoms either unsubstituted or substituted
by one phenyl or y group, can be prepared starting from the compound of formula 17
where R4 is hydrogen or halo and the compound of formula 10 where R6 is alkyl having from 1
to 12 carbon atoms either tituted or substituted by phenyl or phenoxy via the reaction
scheme in Scheme 7. A mixture of compound of formula 17 and compound of formula 10 is
reacted in the presence of a suitable base such as ium carbonate or sodium carbonate and a
suitable solvent such as dimethylformamide to give compound of formula 14 where R4 is
hydrogen or halo and R5 is alkoxy having from 1 to 12 carbon atoms either unsubstituted or
substituted by one phenyl or phenoxy group. The compound of formula 14 is reduced to form the
compound of formula 6 by catalytic reduction using hydrogen and a palladium on charcoal
catalyst via step (b). Any of the conventional s for reduction of nitro groups to amino
groups can be used in step (b).
Scheme 7.
n,70H\ n,TRs
02N Br—R6 OZN \
R4 R4
17 14
j (b)
H2N"(CHM—(0)1)—(CH2)q‘R3
The compound of formula 6 where n is 0, p is 0, q is l and R3 is either phenyl or a monocyclic
or bicyclic aromatic ring having one or two nitrogen atoms, that is unsubstituted or substituted by
halo and by: a) alkyl having from 1 to 12 carbon atoms, b) alkoxy having from 1 to 10 carbon
atoms either unsubstituted or substituted by one phenyl or phenoxy group, c) phenyl, d) phenoxy,
or e) NHC(O)R6 or C(O)NHR6 or C(O)OR6 where R6 is alkyl having from 1 to 6 carbon atoms
can be prepared starting from the compound of formula 3 where q is 1 and R3 is either phenyl or
a monocyclic or bicyclic aromatic ring having one or two nitrogen atoms, that is unsubstituted or
substituted by halo and by: a) alkyl having from 1 to 12 carbon atoms, b) alkoxy having from 1
to 10 carbon atoms either tituted or substituted by one phenyl or phenoxy group, c)
phenyl, d) phenoxy, or e) NHC(O)R6 or C(O)NHR6 or C(O)OR6 where R6 is alkyl having from 1
to 6 carbon atoms via the reaction scheme in Scheme 8. The compound of formula 3 is converted
to the compound of formula 18 Via the reaction of step (a) by treatment with thionyl de.
Any of the reagents and reactions that are used conventionally to convert an alcohol and
ularly a benzylic alcohol to a halide and ularly a ic halide can be used in step
(a). Alternatively, the compound of formula 3 is converted to the compound of formula 19 via
the reaction of step (b) by treatment with methanesulfonyl chloride and triethylamine. In step (b),
any sulfonylation reagent that is conventionally used to convert a hydroxyl to a leaving group
can be tuted for esulfonyl chloride, and any suitable base can be used in place of
triethylamine. The compound of a 18 or the compound of formula 19 is converted to the
compound of formula 6 via reactions of step (c), the Gabriel synthesis of primary amines. The
compound of formula 18 or the compound of a 19 is reacted with potassium phthalimide
under conventionally used ions to give the phthalimide ediate, which is converted to
the compound of formula 6 under conventionally used conditions such as hydrazine
monohydrate in ethanol at re?ux. Any method for the cleavage of phthalimides may be used.
Scheme 8.
Cl—(CH2)q—R3
HO—(CH2)q—R3 HZN—(CH2)n—(O)p—(CH2)q—R3
(b) (C) 6
\ /
O'(CH2)q-R3
The nd of formula 24 where T is CH and R2 is present or T is N and R2 is absent and
wherein n is 2, 3, 4, 5, 6, 7, or 8; R1 and R2 are hydrogen; and R13 is , 2—, 3—, or 4—pyridyl
unsubstituted or substituted by: a) alkyl having from 1 to 12 carbon atoms either unsubstituted or
substituted by one phenyl or phenoxy group, b) alkoxy having from 1 to 12 carbon atoms either
tituted or substituted by one phenyl or phenoxy group, c) phenyl, or d) phenoxy can be
prepared starting from the compound of formula 20 where R6 is alkyl of l to 6 carbon atoms or,
if commercially available, starting from the compound of formula 21 where R6 is alkyl of l to 6
carbon atoms and R13 is phenyl, 2—, 3—, or 4—pyridyl unsubstituted or substituted by: a) alkyl
having from 1 to 12 carbon atoms either unsubstituted or substituted by one phenyl or phenoxy
group, b) alkoxy having from 1 to 12 carbon atoms either unsubstituted or substituted by one
phenyl or phenoxy group, c) phenyl, or d) phenoxy via the reaction scheme in Scheme 9. The
nd of formula 20 is reacted with the compound of formula 10 where R6 is alkyl having
from 1 to 6 carbon atoms in the presence of a suitable base such as potassium carbonate via the
reaction of step (a). The benzoic acid derivative of the compound of formula 20 can be used as
the starting material, as well, if two equivalents of the compound of formula 10 and two
equivalents of a suitable base are used. The compound of formula 21 can be reacted with the
compound of a 22 where n is 2—8 to produce the nd of formula 23 via the reaction
of step (b). Step (b) can be d out in the absence of solvent at a temperature of 100—130 0C.
The selectivity of acylation of only one of the amino groups of the compound of formula 22 can
be increased by using a stoichiometric excess of the compound of formula 22. The compound of
a 23 can be reacted with the compound of formula 8 to give the compound of formula 24
via the on of step (c). A e of the compound of a 23 and the compound of
formula 7 where T is CH and R1 and R2 are hydrogen is heated inl—pentanol at re?ux or
dimethylformamide or N—methylpyrrolidinone or a e thereof at 130—160 0C in the presence
of a suitable base such as triethylamine, tripropylamine, N—methylmorpholine, or
diisopropylethylamine to give the compound of formula 24 where T is CH. A mixture of the
compound of formula 23 and the compound of formula 7 where T is N and R1 and R2 are
hydrogen is heated in 2-propanol at re?ux in the presence of a suitable base such as triethylamine
or diisopropylethylamine to give the compound of formula 24 where T is N. As an alternative
preparation of the compound of formula 24, compound of formula 8 where T is CH and R2 is
present or T is N and R2 is absent can be d with the compound of formula 22 to give the
compound of formula 25 where T is CH and R2 is present or T is N and R2 is absent via the
reaction of step (d). Step (d) is performed using the same t, ature, and base as
described for step (c). The compound of formula 21 can be converted to the compound of
formula 26 via the reactions of step (e). Any conventional method for the conversion of a
carboxylic ester to a carboxylic acid chloride can be used for step (e); e. g., basic saponification
and then reaction with thionyl chloride, oxalyl chloride, phosphoryl chloride, or phosphorus(V)
chloride. The compound of formula 25 where T is CH or N and where R1 and R2 are hydrogen
and the compound of formula 26 can be reacted to give the compound of formula 24 where T is
CH or N via the reaction of step (f) using any of the conventional methods for the formation of
carboxamides from ylic acid chlorides and amines.
Scheme 9.
O 0
R6O \ R6OJLR13
| —OH
Br—R6 21
10
HZN—(CH2)n-NH2
(c) JOL
HZN-(CH2)n—E R13
/ / 23
\ \ }_R2
(d) / / T
R—\1 2
\ J—R
HzN—(CH2)n—NH2 N
The compound of formula I wherein G is imidazoquinolyl unsubstituted or substituted at a
ring carbon by halo, methyl, or perfluoromethyl; NH is absent; R1 is hydrogen, OH, NH;, or
N(CH3)2; and either: a) AQXYZ is represented by R8, and R9 is a branched or ched alkyl
having from 1 to 16 carbon atoms, unsubstituted or substituted by hydroxy or alkoxy having
from 1 to 12 carbon atoms, provided that if substituted by hydroxy or alkoxy R9 cannot have 1
carbon atom, or b) AQXYZ is represented by R9, and R8 is hydrogen or alkyl having from 1 to
carbon atoms unsubstituted or substituted by alkoxy having 1 or 2 carbon atoms or acetoxy
can be prepared starting from the compound of formula 27 where R1 is hydrogen or hydroxy and
R2 is hydrogen, halo, methyl, or per?uoromethyl via the reaction scheme in Scheme 10. In step
(a), compound of the formula 27 where R1 is hydrogen or hydroxy is nitrated to produce the
nd of the formula 28 using nitric acid in hot acetic acid or propionic acid. In step (b), the
compound of formula 28 is treated with a chlorinating agent such as phosphoryl chloride, alone
or in combination with phosphorus(V) chloride, or with phenylphosphonic dichloride to produce
the compound of a 29, where R1 is chloro if the compound of formula 28 had hydroxy as
R1. In step (c), the compound of a 29 is reacted with the compound of formula 30 in the
ce of a tertiary amine base such as triethylamine in an inert solvent such as
dichoromethane, aided by gentle warming to produce the compound of formula 31. It is well-
established in the ture that the 4-chloro of the compound of formula 29 where R1 is chloro
is the more reactive with amines. Any of the amines described in the invention can be used in
step (c). It was discovered that if compound of formula 29 where R1 is chloro is d with the
compound of formula 30 in a mixture of dimethylformamide and dichloromethane initially, and
then the dichloromethane is replaced with toluene and the mixture is heated at re?ux, the
compound of formula 31 where R1 is N(CH3)2 is produced. In step (d), the nitro group of the
nd of a 31 is reduced by any of a number of methods. If R1 is hydrogen or chloro,
enation using 5% or 10% Pd—C or reduction using zinc dust and hydrochloric acid will
produce the compound of formula 32 where R1 is hydrogen. If R1 is chloro, hydrogenation using
% Pt—C will produce the compound of formula 32 where R1 is chloro. If R1 is dimethylamino,
all these s leave R1 unchanged. In step (e), the ortho—diamine of the compound of formula
32 is heated with the ylic acid compound of formula 33 or the compound of formula 34,
the ortho ester of the nd of 33, to produce the compound of formula 35. Any ortho ester
analog of the compound of formula 33 may be used. In step (f), if the compound of formula 35
where R1 is chloro is treated with hydrolytic conditions, the compound of formula 36 Where R1 is
hydroxy is produced. In step (f), if the compound of formula 35 Where R1 is chloro is d
with ammonia or a primary amine, the Rl—amino tive of the compound of formula 36 is
produced. In step (f), if the compound of formula 35 Where R1 is chloro is treated with zinc dust
and hydrochloric acid, the compound of formula 36 Where R1 is hydrogen is produced. The
compound of formula 35 Where R1 and R2 and R8 are hydrogen and R9 is stable to organolithium
bases can be reacted with an organolithium base and then alkylated by an halide or
aldehyde to give the compound of formula 36 where R8 contains the derivative of the tion
reagent.
REMAINDER OF PAGE INTENTIONALLY BLANK
Scheme 10.
R2 C61
N R1
NH NH
/ NH2 (d)
R—2 /|
N R1
(C) or
Rs—C(OCH3)3
R\9 R8
N’\<
/ / (f)
R—\2 I
N R1
WO 20995
If the compound of a 33, or the compound of formula 34, or the compound of formula
37 wherein n is 0—12, provided that ifp is 1 then n must not be 0 or 1; p is 0 or 1; q is 0 or 1; R3
is selected from the group consisting of: alkyl having from 1 to 10 carbon atoms either
unsubstituted or substituted by: a) a monocyclic or bicyclic aromatic ring having one or two
nitrogen atoms either unsubstituted or substituted by alkoxy having from 1 to 6 carbon atoms, or
b) alkoxy having from 1 to 6 carbon atoms, provided that if R3 is alkyl substituted by alkoxy then
alkyl must have more than 1 carbon atom; and phenyl unsubstituted or substituted by halo and
unsubstituted or substituted by: a) alkyl having from 1 to 6 carbon atoms, b) alkoxy having from
1 to 10 carbon atoms tituted or substituted by phenyl or phenoxy, provided that when
substituted by phenoxy the alkoxy must have more than one carbon atom, c) phenyl, d) phenoxy,
or e) C(O)OR6, C(O)NHR6, or NHC(O)R6, wherein R6 is alkyl having from 1 to 6 carbon atoms
is not available commercially or as a tic intermediate, the compound of formula 5 can be
converted to the compound of formula 37 and hence to the compound of formula 33, or the
compound of formula 5 can be converted to the compound of formula 34 via the Pinner reaction
by the scheme shown in Scheme 11. In step (a), the compound of formula 5 is d with the
alkali metal salt of acetic acid, such as potassium acetate or sodium acetate or lithium acetate, in
a suitable solvent such as dimethylformamide. Then, the acetate ester is hydrolyzed at
tely basic pH to produce the nd of formula 37. The nd of formula 37, a
primary l, can be oxidized to the ylic acid compound of the formula 33 via the
reaction of step (b) using any of the numerous suitable methods for the oxidation of alcohols to
acids, such as the Jones oxidation. Alternatively, the compound of formula 5 is reacted with an
alkali metal cyanide such as sodium cyanide or potassium cyanide in a suitable solvent such as
dimethylformamide to produce the nd of formula 38 via the reaction of step (c). In step
(d), the compound of formula 38 is treated with an alcohol such as methanol and an acid catalyst
such as hydrochloric acid to form the compound of formula 34.
Scheme 11.
Br—(CH2)n—(O)p—(CH2)q—R3 —> HO—(CH2)n—(O)p—(CH2)q—R3
37
j (c) (b)
NC—(CH2)n—(O)p—(CH2)q—R3 H0(0)C—R8
J (d)
3C—R8
The nd of formula ID wherein R10 is alkyl having from 1 to 8 carbon atoms,
unsubstituted or substituted by alkoxy having from 1 to 6 carbon atoms, provided that if
substituted by alkoxy R10 must have more than 1 carbon atom; R11 is hydrogen, or alkyl having
from 1 to 8 carbon atoms, unsubstituted or substituted by alkoxy having from 1 to 3 carbon
atoms, provided that if substituted by alkoxy R11 must have more than 1 carbon atom; and X‘ is a
counterion can be prepared by the scheme shown in Scheme 12. If the compound of formula 41
is not commercially available, compound 39, 4—chloropyridine hloride, can be used to
prepare it via the on of step (a). Compound 39 is heated at 0 0C in a hindered alcohol
such as 2—propanol in the presence of a tertiary amine base such as triethylamine with the
compound of formula 40 to give the compound of formula 41. Via the reaction of step (b), the
compound of formula 41 is reacted with an alkyl sulfonate such as the compound of formula 42
in a suitable solvent such as acetone to give the compound of formula ID, Where X" is a
counterion such as methanesulfonate, iodide, bromide, or de. Any alkyl iodide or alkyl
bromide or alkyl sulfonate derivative of R10 can be used in the reaction of step (b).
Scheme 12.
R11 R1\1
Cl \NH NH
/ (a) b < >
I d N \ a\
+ X_ N
HCl 1111—an RIO—0302CH3 If
40 41 42
The compound of formula 48, Where R12 is alkyl having from 2 to 16 carbon atoms,
unsubstituted or substituted by alkoxy having from 4 to 6 s, can be prepared starting from
compound 43, 4—hydroxy—3—nitropyridine, by the scheme shown in Scheme 13. Compound 43 is
reacted with a suitable halogenating agent such as phenylphosphonic ride to give
compound 44, 4-chloronitropyridine via the reaction of step (a). Compound 44 is reacted with
the compound of formula 45 in the presence of a suitable base such as triethylamine in a suitable
t such as pyridine to e the compound of formula 46 via the reaction of step (b). Any
of the amines described in the invention can be used in step (b). The nitro group of the
compound of formula 46 is reduced to the amino group of the compound of formula 47 by
catalytic hydrogenation via the reaction of step (c). The compound of formula 47 is heated in
yl orthoformate to e the compound of formula 48 via the reaction of step (d). Using
the same steps (b), (c), and (d), but starting from commercially available compound 49, 2—chloro-
3—nitropyridine, the compound of formula 52 is prepared.
REMAlNDER OF PAGE INTENTIONALLY BLANK
2014/013992
Scheme 13.
(FNOZ (b)
N Rlz—NHZ
43 44 45
R12—NH2
Any compound of formula 53 where G is a monocyclic, bicyclic, or tricyclic aromatic ring
having one, two, or three ring en atoms where a ring nitrogen atom is bonded to hydrogen
can react with the compound of formula 55 where Br—AQXYZ is a y alkyl bromide to
produce the compound of the formula 54, where AQXYZ is given by claim 1 for the compound
of formula I, by the scheme shown in Scheme 14. The compound of the formula 53 is treated
with a strong base such as sodium tert—butoxide in a suitable solvent such as dimethylformamide,
and the ing amide anion is treated with the compound of formula 55 to e the
compound of formula 54 via the reaction of step (a). If the amide anion is in resonance with a
neighboring en, the alkylation by the nd of formula 55 occurs at the less hindered
nitrogen ively. The primary alkyl iodide, chloride, alkanesulfonate, or arylsulfonate of
AQXYZ can be used in place of the compound of formula 55 for the reaction of step (a).
Scheme 14.
1'4 (a) 1?me
G G
Br—AQXYZ
53 55 54
Any compound of formula 58 where G is a monocyclic, bicyclic, or tricyclic aromatic ring
having one, two, or three ring nitrogen atoms as defined in Claim 1, where a ring carbon atom is
bonded to an NHZ group, can undergo an alkylation procedure to produce a compound with the
formula 59, where A, Q, X, Y, and Z are as defined in Claim 1, starting from the compound of
formula 56, where (AQXYZ) is a l that is terminated by a primary alcohol group, by the
scheme shown in Scheme 15. Many nds of the formula 58 are available commercially.
The compound of the formula 56, where the radical (AQXYZ) is terminated by a primary
alcohol function and where (AQXYZ) does not contain another alcohol group or an amino
group, can undergo oxidation by any of a variety of conventional methods such as the Swern
oxidation or oxidation by tetrapropylammonium perruthenate/N—methylmorpholine N—oxide to
produce the nd of formula 57 via the reaction of step (a). The compound of formula 58
2014/013992
can undergo reductive alkylation by the compound of formula 57 via the reaction of step (b)
using any conventional method for amine reductive alkylation such as by sodium
cyanoborohydride in tetrahydrofuran. Alternatively, the compound of formula 58 can undergo
acylation by the carboxylic acid radical of (AQXYZ) via the reaction of step (d) using any
conventional method for amide formation such as a carbodiimide sation or a mixed
anhydride acylation using isopropyl chloroformate. Also, step (d) can be carried out using the
acid chloride derivative of the compound of formula 60, Which can be ed using any
conventional reagent for the preparation of acid chlorides such as thionyl chloride or oxalyl
chloride. The nd of formula 60 can be produced from the compound of formula 56 via
the reaction of step (c) using any suitable tional t for the oxidation of alcohols such
as the Jones reagent. The amide group of the compound of formula 61, Where (AQXYZ) does
not contain an ester or another amide group, can be reduced to the amino group of the compound
of formula 59 via the reaction of step (e) using a suitable reducing agent such as lithium
aluminum hydride.
DER OF PAGE INTENTIONALLY BLANK
Scheme 15.
HOCHz—(AQXYZ) —> HOOC—(AQXYZ)
56 60
(3) G (d)
CHO—(AQXYZ) o
>—(AQXYZ)
57 HI‘II
ITIHz 61
(b) G <6)
uHAQXYz
Any compound of formula 58 where G is a monocyclic, bicyclic, or tricyclic aromatic ring
having one, two, or three ring nitrogen atoms as defined in Claim 1, where a ring carbon atom is
bonded to an NHZ group, can undergo an alkylation procedure to produce a compound with the
formula 59, where A, Q, X, Y, and Z are as defined in Claim 1, starting from the compound of
formula 56, where (AQXYZ) is a radical that is terminated by a primary alcohol group, by the
scheme shown in Scheme 16. Many nds of the a 58 are available commercially.
The compound of the formula 56, where the radical (AQXYZ) is terminated by a primary
alcohol on and where ) does not contain another alcohol or amino group, can
o a sulfonylation reaction using methanesulfonyl chloride and an amine base such as
pyridine or triethylamine to produce the compound of formula 62 Via the reaction of step (a). The
compound of formula 58 can undergo substitutive alkylation by the compound of formula 62 to
produce the compound of formula 59 via the reaction of step (b) using any conventional method
for amine alkylation, such as heating the mixture in tetrahydrofuran or dimethylformamide in the
absence or ce of a base such as ylamine, diisopropylamine, or N—methylmorpholine.
s of the compound of formula 62 where the methanesulfonate group is ed by a
conventional good leaving group such as iodide, bromide, chloride, or a different sulfonate group
can be used in step (b).
Scheme 16.
HOCHz—(AQXYZ) —’ CH3SOZOCH2—(AQXYZ)
56 62
G (b)
$HAQXYZ
USES AND METHODS OF TREATMENT
This invention provides certain compounds, described below, for treating diseases characterized
by pathogenic cells ing lysosomes or other acidic vacuoles with disease—related alterations
predisposing them to accumulation of compounds of the ion, which then selectively
vate or eliminate such pathogenic cells. Compounds of the invention, many of which are
aminoquinoline and aminoquinazoline derivatives, feature significant improvements in potency
2014/013992
and activity over known aminoquinoline drugs such as chloroquine, as a consequence of
structural moieties that ly disrupt lysosomal or vacuolar membrane integrity when the
compounds late in acidic vacuoles in cells. Diseases that are at least moderately
sive to antimalarial quinoline derivatives and analogs are in general more effectively
treated with compounds of the invention. Such diseases broadly comprise atory
diseases, neoplastic diseases, including both hematologic cancers and solid tumors, and
infections by eukaryotic ens, including fungi and several classes of protozoal or other
unicellular parasites.
ANTI—INFLAMMATORY USE
An important action of nds of the invention is anti—in?ammatory activity, providing
utility for treating or preventing diseases or symptoms related to excessive tissue in?ammation.
This invention also provides compositions containing a compound of this invention as well as the
use of a compound of this invention for the manufacture of a medicament for treatment or
prevention of in?ammatory diseases. Compounds of the invention y selectivity for
suppressing or inactivating macrophages that have been stimulated into a pro-in?ammatory state,
with less of an effect on non-stimulated macrophages. ted pro-in?ammatory hages
contribute to pathogenesis of a large variety of in?ammatory and autoimmune diseases.
Macrophages are both antigen presenting cells and effectors for tissue damage directed by
active T cells, and participate in tissue damage and dysfunction in diseases including but
not limited to rheumatoid arthritis, systemic lupus erythematosis, psoriasis, in?ammatory bowel
disease, and atopic dermatitis. In?ammatory macrophages participate in many systemic
diseases, including autoimmune diseases, cardiovascular and metabolic diseases, and
neurodegenerative conditions. Activated macrophages play a primary role in tissue damage in
instability of atherosclerotic plaques, with consequent risk of rupture and thrombotic vessel
ion. Activated macrophages in adipose tissue contribute to metabolic abnormalities
including n ance, type 2 diabetes and other consequences of obesity. Osteoclasts are
macrophage—like cells that mediate bone degeneration in osteoporosis and in participate in bone
destruction and “bone pain” in cancers arising in or metastasized to bones. Compositions of the
invention are useful for treating these and other disorders in which activated macrophages
contribute to in?ammatory disease pathogenesis.
Several s of topical agents are used for treatment of in?ammatory diseases of the skin, such
as atopic dermatitis, eczema or psoriasis. Corticosteroids are widely used, but have the potential
for both local and systemic toxicities, particularly with prolonged use. They can cause local skin
atrophy or thinning, which may lead to disruption of the skin, as well as telangiectasia.
Furthermore, topical corticosteroids can be absorbed systemically in amounts sufficient to cause
systemic side effects. A second class of agents for ent of atopic dermatitis is T cell
immunosuppressants, such as the calcineurin inhibitors tacrolimus and pimecrolimus. Their
local and systemic immunosuppressive effects have led to concerns about depressing
immunosurveillance of cancers, including melanomas and lymphomas.
Vitamin D analogs, y calcipotriene, are known for topical treatment of sis.
Calciptoriene acts by ting excessive proliferation of keratinocytes. Application to normal
skin is contra-indicated due to a bleaching effect and there is also a possibility of e events
from systemic absorption. Dermal irritation or g is known as a side effect of otriene.
Compounds of the invention are ularly active against macrophage precursors that have
been activated by exposure to n D3. It is possible that psoriasis ent with
calcipotriene, while providing some improvements by inhibiting keratinocyte proliferation, may
also direct local macrophages toward a pro—in?ammatory state, buting to known side
effects such as irritation, and limiting the net therapeutic effect. The y of compounds of the
invention to inactivate pro—in?ammatory vitamin D3-primed macrophage sors as shown in
several Examples below indicates that combination topical treatment with compounds of the
invention and vitamin D analogs may provide unexpected benefits in psoriasis and psoriatic
dermatitis, both in treating the in?ammatory epidermal hyperproliferation and in reducing
irritation or itching as side effects of vitamin D analogs.
Compounds of the invention are useful for treating ocular in?ammation, including keratitis,
whether caused by infection l, bacterial, amoebic) or by non—infectious triggers such as
corneal injury or contact lenses. Compounds of the invention are especially suitable for fungal
keratitis, counteracting both infectious fungi and concurrent in?ammatory damage. Compounds
of the invention t l enesis and other in?ammatory changes in response to
mechanical or chemical injury.
Compounds of the invention are useful for treating a variety of in?ammatory or
hyperproliferative skin conditions or lesions, including but not limited to eczema, atopic
dermatitis, psoriasis, and impetigo. Impetigo is a superficial bacterial skin infection with
atory damage to the mia; compounds of the invention both suppress in?ammation
and have direct inhibitory or bactericidal effects on gram positive bacteria, including but not
d to Staphylococcus aureus and Staphylococcus pyogenes, the primary organisms
responsible for go. nds of the invention also inhibit oplastic and neoplastic
skin alterations, which often exhibit characteristics of both in?ammation and neoplasia,
including but not limited to actinic keratosis, seborrheic keratoses and warts.
Examples E and F demonstrate efficacy of compounds of the invention for treating skin
in?ammation and psoriatic dermatitis in established mouse models of human skin disorders.
Macrophages and related cells types contribute to pathogenesis of autoimmune diseases
involving the adaptive immune system both as antigen presenting cells and as effectors
damaging tissues after inappropriate stimulation by T cells, which secrete interferon gamma and
other in?ammatory mediators that recruit and activate macrophages. Compounds of the
invention disrupt antigen presentation by hages and dendritic cells, and also inactivate
pro—in?ammatory effector macrophages that damage tissues. A general ce is that
compounds of the invention are useful for treating c or episodic autoimmune diseases
where chloroquine, hydroxychloroquine or other antimalarial ine analogs display activity
in humans or relevant animal models, and are generally more potent and active than the
larials in in?ammatory and non—malaria infectious diseases. Such diseases include but are
not limited to rheumatoid arthritis, systemic and discoid lupus erythematosis, psoriatic arthritis,
vasculitis, ns syndrome, scleroderma, autoimmune hepatitis, and multiple sclerosis.
Macrophage activation syndrome (MAS) is an acute cation of several autoimmune
diseases, especially in ood—onset conditions such as idiopathic juvenile arthritis where it
affects more than 10% of patients, and also in in?ammatory bowel diseases. In MAS,
macrophages are over—activated, causing damage to the hematopoietic system and systemic
in?ammation; MAS is sometimes lethal. Compounds of the invention are useful for treatment of
MAS, and are optionally delivered orally or by intravenous injection or infusion.
Example G shows beneficial activity of compounds of the invention when administered orally to
mice in a model of le sis, an autoimmune disease.
For treatment of chronic mune disorders, compounds of the invention are administered
systemically, preferably orally. For treatment of acute in?ammatory conditions, or ?ares of
autoimmune diseases, intravenous treatment with compounds of the invention is an optional
suitable delivery route.
For oral or intravenous treatment of autoimmune or in?ammatory diseases, compounds of the
invention are typically administered in doses ranging from 1 to 1000 rams per day,
advantageously 100 to 600 milligrams per day, in single doses or divided into two or three doses
per day.
ANTIFUNGAL AND ANTIPARASITIC USES
The compounds of this invention are useful in inhibiting fungal growth, both in viva and ex viva.
Accordingly this invention also provides methods and uses for ting the growth of a fungus
in a mammalian subject, for example a human. These methods can be used to treat and to prevent
fungal infection. Ex viva, it is useful to treat surfaces with a nd of this invention to t
or prevent fungal growth, or in agriculture or ulture to prevent or treat fungi that affect
valuable plants. This invention also provides compositions containing a compound of this
ion as well as the use of a compound of this invention for the manufacture of a
ment for inhibiting the growth of a fungus.
This invention is based, in part, on the finding that the compounds of this ion are effective
in inhibiting the growth of a variety of fungal species, as shown in the biological activity
examples below. Without wishing to be bound by theory, it is believed that compounds of this
disclosure exploit the ability of the fungal acidic vacuole. They are believed to
2014/013992
accumulate in acidic es via cation ng, and furthermore exert antifungal activity by
disrupting the structure and function of the acidic vacuoles.
In accordance with this invention, the growth of fungi generally is inhibited. Examples of fungi
that can be inhibited include but are not limited to Candida, Saccharomyces, Trichophyton,
Cryptococcns, Aspergillus, and Rhizopns. In more specific embodiments of this invention the
fungus is Candida albicans; a glabrata; Saccharomyces cerevisiae ; Trichophyton
rnbmm; Cryptococcus mans, for example Cryptococcns neoformans pes D and A;
and Aspergillns fumigatus.
This invention also provides methods of treating and preventing parasitic infections. Due to the
capability of compounds of the invention to enter and accumulate within acidic vacuoles in cells,
they are useful for treating infections due to parasitic rnicroorganisins that reside within acidic
vacuoles in macrophages and other cell types. 'l‘tiberculosis (mycobacteria‘), listeria or
staphylococcus (gram positive bacteria), coccus (fungus), and leishrnania and
trypanosornes (amoehae), Coxielia bzmzezii (gram negative ia), and Plasmodium (some of
which cause malaria) are nonlirniting examples of important such infectious organisms, in. which
nce within macrophages can protect the organisms from cellular or humoral immunity, or
reduce the efficacy of drug treatments.
Compounds of the invention, which bear lipophilic moieties and are generally partially neutral at
physiological pH (7.3), can pass freely into acidic vacuoles harboring parasites, and are
concentrated and tapped there due to ionization in the acidic environment (pH 4—6.5). These
compounds disrupt the structure and function of acidic vacuoles as hospitable sites for parasites
and also have direct antiparasitic activity, due to acidic vacuoles within many parasitic
organisms.
tes whose viability or virulence is dependent on ity and function of an acidic vacuole
are also vulnerable to compounds of the invention, r to the basis "or their antifungal
activity. The acidic vacuole of malaria plasn‘iodia provides an environment for concentration of
compounds of the invention. Similarly, trypanosomes have a large acidic vacuole which is
necessary for utilization of environmental nutrients. nds of the invention are useful for
treatment or prevention of malaria and trypanosonie in ‘ections. More hroadly, protozoal
parasites in general use acidified digestive vacuoles for acquisition and digestion of food, and are
therefore susceptible to antiparasitic actions of compounds of the invention.
The larial drug chloroquine is reported to have antiparasitic ty against a variety of
organisms harbored in acidic vacuoles in host cells, or which have acidic vacuoles lves,
including hut not limited to tuberculosis mycobacteria, cryptosporidium, leishmania and
cryptococcus. in general, chloroquine acts hy accumulating in acidic vacuoles via cation
trapping. Activity of chloroquine is thus an indicator of likely ty of compounds of the
inventions {many of which comprise an aminoquinoline or other cycle similar to that of
chloroquine for the purpose of targeting acidic vacuoles), with the difference that compounds of
the invention are substantially more potent and active than is chloroquine, as demonstrated in
Cryptomccas neaformans in Example K, where chlm‘oquine produced less than 50% growth
tion at a concentration of 100 micromolar, s many nds of the invention
produced lOt % growth tion at much lower concentrations. Chloroquine, despite
published s showing that it can improve survival in animal models of cryptococcosis,
displays a ceiling of about 40% inhibition of C. neoformans growth in vitro, whereas compounds
of the invention are substantially more potent than chloroquine and can cause .lll?‘ih inhibition of
coccus growth, due to superior disruption of the membranes of acidic vacuoles in which
the respective drugs are accumulated.
For treatment of fungal or parasitic infections, compounds of the invention are administered in
vehicles and by routes of administration appropriate for the nature and location of the infection.
For dermal or nail in ‘ections, compound of the invention are applied in a topical ation
which is optionally a lotion, ointment, solution, suspension, or spray. For ocular fungal
infections, compounds of the invention are ated in eyedrops. For ic infections,
compounds of the invention are administered orally in tablets, es, dragees, solutions or
suspensions, or administered systemically by injection in , lipid ons, liposomes or
other standard parenteral vehicles. Lung infections, especially involving organisms residing in
alveolar macrophages, are optionally treated via inhalational delivery of compounds of the
invention and suitable excipients known to be acceptable for inhalational drng delivery. For
intravenous or oral administration to treat systemic in ‘ections, compounds of the invention are
stered in doses ranging from If.) to 2000 milligrams per day, advantageously 200 to 100%
milligrams per day.
Other classes of antifungal agents in clinical use include inhibitors of ergosterol synthesis
(“azole” antifungals including but not limited to zole, ketoconazole, voriconazole, and
allylamines including but not limited to afine), polyene antifungals which act by binding to
fungal membrane constituents, especially erol (including but not limited to amphotericin B
or nystatin), echinocandin inhibtors of gluoan synthesis (including but not limited to
ungin), and other agents known as active antifungals in medical practice. Compounds of
the invention act via a distinct mechanism of action versus existing clinically important
antifungals and are optionally coadministered with one or more other antifungal agent to
improve l antifungal treatment. Compounds of the invention are coadministered as
separate pharmaceutical formulations, or are optionally formulated into a single combined-drug
product. A combination of compounds of the inventions with azole antifungals is particularly
advantageous as a completely oral regimen for use against cyptoccoccosis, which otherwise
generally requires amphotericin B injections or infusions for intial induction. Compounds of the
ion are also optionally coadministered with amphotericin B. One formulation of
amphotericin B involves its incorporation into lipids comprising the membranes of liposomes.
e many of the compounds of the ion bear lipophilic moieties that insert into lipid
membranes, they are advantageously orated into liposomes, either as single agents or in
combination with amphotericin B or other known polyene antifungal agents.
ANTICANCER USES
This invention provides compounds that are useful for ic treatment of cancer, based on
consistent lysosomal changes characterizing ve cancers. Lysosomal changes in cancer,
including their enlargement and acidification, facilitates survival of cancer cells in acidic
extracellular environments and also se the ability of cancer cells to invade surrounding
tissues, through exocytosis of lysosomal contents, including ses and polysaccharidases
which can degrade extracellular matrix components. However, these typed changes in
lysosomal properties can render cancer cells vulnerable to lysosome—disrupting agents with
appropriate physicochemical properties for selectively accumulating in and damaging lysosomes
in cancer cells versus normal tissues.
nds of the invention accumulate in lysosomes in cancer cells and disrupt their integrity,
thereby displaying potent selective cytotoxic activity against cancer cells in vivo and in vitro.
Because one major ism for cancer cell resistance to a variety of chemotherapy agents is
to sequester them in lysosomes and other acidic vesicular compartments, compounds of the
invention are able to restore or enhance sensitivity of cancer cells to a variety of classes of
anticancer agents, ing antimetabolites, tyrosine kinase inhibitors, anticancer antibodies
against growth factor receptors, anthracyclines, platinum nds, alkylating agents, and
antibodies. Compounds of the invention typically do not display toxicities overlapping dose
limiting toxicities of most ncer agents, permitting combination of compounds of the
invention with other classes of antineoplastic drugs with a net improvement in efficacy and
therapeutic index.
Cancer cells exposed to sublethal doses of ionizing radiation undergo a protective response that
increases their resistance to subsequent irradiation. A component of this protective response is
formation of enlarged mes or other ied vacuolar organelles; inhibition of the vacuolar
ATPase responsible for acidifying lysosomes with bafilomycin A prevents the protective
se in sublethally irradiated cells and sensitizes cancer cells to ionizing radiation
Lysosomal damage is a icant mediator of radiation-induced death in cancer cells. By
disrupting the integrity of lysosomal membranes, compounds of the invention are useful for
reducing resistance of cancer cells to therapeutic ionizing radiation and for potentiating
anticancer effectiveness of ionizing ion y. nds of the invention are
optionally administered prior to ionizing radiation therapy of cancer er with external
irradiation or stration of antibody—targeted radioisotopes) as radiosensitizers, or they may
be given after irradiation to attack surviving cancer cells undergoing protective responses to
nonlethal ation involving production or enlargement of acidic vacuoles.
One mechanism imparting selective survival and proliferation advantages in some cancers is
upregulation of autophagy, a process through which damaged organelles or other cell debris are
engulfed by autophagosomes, which fuse with lysosomes to digest and recycle constituent
les. By concentrating in and disrupting mes, compounds of the invention impair
autophagy in cancer cells, y reducing their viability and resistance to other anticancer
treatments.
For treatment of cancer, compounds of the invention are administered by oral or intravenous
stration in doses of 10 to 2000 milligrams per day. Compounds of the invention are
administered as single agents or in combination with other cancer treatments appropriate for a
particular type of cancer, and generally in doses when such agents are used alone, as compounds
of the invention will generally not have overlapping toxicities with other classes of anticancer
agents that would necessitate substantial dose reduction.
PHARMACEUTICAL COMPOSITIONS
This ion provides a ceutical composition comprising a biologically active agent as
described herein and a pharmaceutically acceptable carrier. Further embodiments of the
ceutical composition of this invention comprise any one of the embodiments of the
biologically active agents bed above. In the interest of avoiding unnecessary redundancy,
each such agent and group of agents is not being repeated, but they are incorporated into this
description of pharmaceutical compositions as if they were ed.
Preferably the ition is adapted for oral administration, e.g. in the form of a tablet, coated
tablet, dragee, hard or soft gelatin capsule, solution, emulsion or suspension. In general the oral
composition will comprise from 10 to 1000 mg of the compound of this invention. It is
convenient for the t to swallow one or two tablets, coated tablets, s, or gelatin
capsules per day. However the composition can also be adapted for administration by any other
conventional means of systemic administration including rectally, e. g. in the form of
suppositories, parenterally, e. g. in the form of injection solutions, or nasally.
The biologically active compounds can be processed with pharmaceutically inert, inorganic or
organic carriers for the production of ceutical itions. Lactose, corn starch or
derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such
carriers for tablets, coated tablets, dragees and hard n capsules. Suitable carriers for soft
gelatin capsules are, for example, vegetable oils, waxes, fats, semi—solid and liquid polyols and
the like. Depending on the nature of the active ingredient no carriers are, r, usually
required in the case of soft gelatin capsules, other than the soft gelatin itself. Suitable carriers for
the production of solutions and syrups are, for example, water, polyols, ol, ble oils
and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes,
fats, semi—liquid or liquid polyols and the like.
The pharmaceutical compositions can, moreover, contain preservatives, solubilizers, stabilizers,
g agents, emulsifiers, sweeteners, nts, ?avorants, salts for varying the osmotic
pressure, buffers, coating agents or idants. They can also contain still other therapeutically
le substances, particularly anti-in?ammatory or antifungal agents (depending on whether
an in?ammatory disease or a fungal infection or cancer are being addressed in a patient) that act
through mechanisms other than those underlying the effects of the compounds of the invention.
For treatment of cancer, preferred additional drugs that can advantageously be coadministered or
coformulated with a compound of the invention comprise orally active anticancer agents.
Because compounds of the ion act through a unique mechanism not shared by other
anticancer drugs, they are compatible with a large variety of concurrent therapies, including
antimetabolites, anthracyclines, tyrosine kinase tors, platinum drugs, or alkylating agents.
Such agents, when orally active, are administered or coformulated to deliver quantities of drugs
determined in previous clinical trials to be effective and adequately tolerated.
For systemic treatment of diseases, including some cancers, in?ammatory conditions and fungal
or oal infections, compounds of the invention are optionally administered by enous
injection or infusion. For intravenous administration, compounds of the invention are dissolved
in suitable intravenous formulations as ons or in lipid emulsions, using standard ents
known in the art as well—tolerated intravenous formulation ingredients and compositions.
Suitable volumes and concentrations are selected for delivery of 10 to 2000 miligrams of
compounds of the invention per day, depending on the specific ements for a compound,
and a disease condition as determined in clinical trials.
Compounds of the invention are optionally incorporated into liposomal formulations. The
ilic moieties of compounds of the invention permit their direct incorporation into lipid
layers of lipososomes. Liposomes are advantageous in some conditions for intravenous
administration due to improved efficacy and milder infusion reactions versus osomal
formulations. Liposomes are also le for inhalational delivery to treat fungal or parasitic
infections of the lungs, or in?ammation of the lungs and airways. In some embodiments,
compounds of the invention are incorporated into liposomal delivery formulations with other
drugs, including but not limited to ngal agents such as liposomal amphotericin B, or
anticancer agents such as liposomal doxorubicin.
For treatment of atory skin conditions or fungal infections of the skin or nails, or of
nasal es, compounds of the invention are applied topically in a pharmaceutically
acceptable ation. The l. composition can be in various forms, including, but not
limited. to, a on, spray, gel, hydrogel, lotion, cream, ointment, paste, or an emulsion in the
form of liquid suspension, lotion, or cream. ’l‘he composition can also be applied via a dermal
patch, or bandage which can he applied on the ed. area as needed, to provide an extended
exposure of the skin to the medication; in such tormulations, appropriate standard topical
medicament excipients and vehicles are suitable for deliverin(IQ compounds of the invention.
Standard constituents for topical formulations are known in the art and are suitable as vehciles
for compounds of the ion. {lintnient bases can comprise one or more of hydrocarbons
(paraffin wax, soft. paraffin, crystalline wax, or ceresine), absorption hases (wool fat or
beeswax}, macrogols (polyethylene glycol), or vegetable oils. Lotions and creams are water in
oil or oil in water emulsions; the oil components can comprise long chain fatty acids, alcohols or
esters, and al contain bioconipatihle nonionic surfactants. Compounds of the invention are
incorporated into topical vehicles in concentrations g from 0.01% to 5%, preferably 0.02
to 1%. Compounds of the invention are applied to skin lesions once to three times per day for
durations dependent on the rate of resolution of the condition.
For treatment of some lung ions, including fungal infections or parasites ng in
ar macrophages, inhalational as of compounds of the invention are suitable.
Excipients and inhalational drug delivery devices are known in the art and are useful for
delivering nds of the invention to treat lung infections, including cryptococcus and
tuberculosis.
Compounds of the invention are advantageously coformulated with other antifungal or anti—
atory agents for topical or systemic administration, particularly when both drugs are
appropriately administered via the same route and le. Compounds of the invention are
compatible with standard formulations and excipients used for other topical or systemic
ngal or anti—inflammatory agents, including but not limited to ointments and tablets or
capsules. Advantageous drug categories for combination in topical anti—in?ammatoty
formulations include corticosteroids, calcineurin inhibitors and vitamin D ues, and other
agents known to have independent therapeutic acitivity in in?ammatory skin conditions.
The invention will be better understood by reference to the following examples, which illustrate
but do not limit the invention described herein.
EXAMPLES
CHEMICAL SYNTHESIS EXAMPLES
Example 1: N—[8—(Hexyloxy)octyl]quinolin—4—amine
HN/\/\/\/\/O\/\/\/
CKE/
A mixture of 4—chloroquinoline (300 mg, 1.84 mmol), 8—(hexyloxy)octan—l—amine (558 mg, 2.44
mmol), and DMAP (260 mg, 2.13 mmol) was heated at 135 0C for 3 hr. The mixture was cooled
and partitioned between DCM and 5% N32C03. The organic phase was dried over NazSO4 and
concentrated. FC (10%, 12%, 14% MeOH/DCM step nt) gave 279 mg of product as a
W0 2014/120995
solid. Rf 0.26 (10% MeOH/DCM); mp 5.5 °C (from EA/Hex); 1H NMR ) 8 8.51
(d, 1H, J=5.2 Hz), 7.94 (d, 1H, J:8.4 Hz), 7.74 (d, 1H, J=8.4 Hz), 7.57 (m, 1H), 7.37 (m, 1H),
6.37 (d, 1H, J=5.5 Hz), 5.24 (br s, 1H, NH), 3.39—3.34 (m, 4H), 3.25 (m, 2H), 1.73—1.26 (m,
20H), 0.84 (m, 3H).
Example 2: N—(8—Butoxyoctyl)quinolin—4—amine
8—Butoxyoctan—1—ol 60% Sodium hydride in mineral oil (3.5 g, 87.5 mmol) was washed twice
with 20 mL of hexanes. Anhydrous DMF (300 mL) was added, the mixture was cooled with an
ice bath, and 1,8—octanediol (51.2 g, 351 mmol) was added. After 1.5 hr, obutane (6 g,
43.8 mmol) was added slowly. The mixture was warmed to room temperature. After 24 hr, the
mixture was concentrated. The residue was taken up in B20 (500 mL) and washed with
saturated NaHC03 and H20 (400 mL each). The aqueous phases were extracted with Et2O
(3x400 mL). The combined organic phases were dried over , filtered, and concentrated to
give 3.9 g colorless oil. Rf0.4 (30% EA/Hex); 1H NMR (CDC13) 5 3.6 (t, 2H), 3.4-3.3 (m, 4H),
1.6-1.4 (m, 6H), 1.4-1.2 (m, 10H), 0.9 (t, 3H).
8—Butoxyoctyl methanesulfonate A mixture of 8-butoxyoctan—1—ol (3.99 g, 20.2 mmol) and
TEA (3.4 mL, 24.2 mmol) in 70 mL of DCM was cooled using an ice bath. Then,
methanesulfonyl chloride (1.87 mL, 24.1 mmol) was added. After 2 hr, the mixture was washed
with H2O, saturated NaHC03, H2O, 1M HCl, and H20 (50 mL each). The organic phase was
dried over Na2SO4, filtered through a pad of silica gel, and concentrated to give 1.3 g of colorless
oil.
1—Butoxy—8—iodooctane A mixture of 8—butoxyoctyl esulfonate (1.3 g, 6.6 mmol)
and sodium iodide (1.0 g, 6.7 mmol) in 100 ml of e was heated at re?ux for 2 hr. The
mixture was cooled, filtered, and concentrated. The residue was taken up in EA (400 mL) and
washed with saturated NaHC03 and brine (100 mL each). The c phase was dried over
NaZSO4, filtered, and concentrated to give 1.3 g of yellow .
N—(8—Butoxyoctyl)phthalimide l—Butoxy—8—iodooctane (6.2 g, 20.2 mmol) and potassium
imide (3.73 g, 20.2 mmol) in 50 mL of DMF were mixed at 60—80 0C for 12 hr. The cooled
mixture was concentrated, and the residue was partitioned between EA (3x300 mL) and 5%
NaZSZOg, H20, and brine (100 mL each). The combined organic phases were dried over NaZSO4,
filtered, and concentrated to give 5.2 g of solid. 1H NMR (CDC13) 5 7.8 and 7.7 (m, 4H,
AA’BB’), 3.6 (t, 2H), 3.4-3.3 (m, 4H), 1.7-1.2 (m, 16H), 0.9 (t, 3H).
8-Butoxyoctan—1—amine Hydrazine monohydrate (0.92 mL, 19 mmol) was added to a
mixture of N—(8—butoxyocty1)phthalimide (5.2 g, 15.9 mmol) and 80 mL of EtOH. The mixture
was heated at re?ux for 2 hr. Then, the mixture was cooled with an ice bath and d
vigourously while 200 mL of EtZO were added. The precipitate was filtered and washed with
Et20, and the organic phases were concentrated to give 3.9 g of amber oil. 1H NMR (CDgOD)
3.5-3.4 (m, 4H), 2.9 (t, 2H), 1.7-1.3 (m, 16H), 0.9 (t, 3H).
N—(8-Butoxyoctyl)quinolinamine A mixture of 8-butoxyoctanamine (0.569 mg, 2.89
mmol), 4—chloroquinoline (710 mg, 4.33 mmol), TEA (5 mL, 36 mmol), and 0.5 mL of NMP
was sealed in a heavy walled glass tube and mixed at 130 0C for 4 days. The mixture was cooled
and partitioned between EA and 5% Na2C03 and brine, dried over Na2804, ed, and
concentrated. Purification by EC (60% EA/Hex + 2% TEA) gave 244 mg of oil. 1H NMR
(CDC13) 5 8.9 (m, 1H, NH), 8.7 (d, 1H), 8.2—8.1 (m, 2H), 7.6 (m, 1H), 7.4 (m, 1H), 6.4 (d, 1H),
3.5 (m, 2H), 3.4—3.3 (m, 4H), 1.8 (m, 2H), 3 (m, 14H), 0.9 (t, 3H).
Example 3: N—(8—Methoxyoctyl)quinolin—4—amine
HN/\/\/\/\/O\
:\J\T/
8—(Benzyloxy)octan—l—ol A 60% dispersion of sodium hydride in mineral oil (5.38 g, 134
mmol) was washed with hexanes to remove the oil. While cooling with an ice bath, a mixture of
l,8—octanediol (24.49 g, 168 mmol) in 300 mL of DMF was added slowly. The mixture was
allowed to warm to room temperature. After 1 hr, a mixture of benzyl chloride (7.70 mL, 66.7
mmol) in 30 mL of DME was added se. After 2 hr, additional benzyl chloride (1.00 mL,
8.7 mmol) was added, and the mixture was stirred overnight. Then, 2 mL of concentrated
NH4OH was added. After 1 hr, the volatile components were evaporated. The residue was taken
up in EtZO and thrice washed with 1M HCl and once with brine. The organic phase was dried
over ous MgSO4 and ated onto silica gel. SPE, washing with 5% EA/Hex and then
eluting with 20% EA/Hex gave 12.19 g of the product as a colorless oil. (Eluting with EA gave
12.19 g of recovered 1,8—octanediol after recrystallization from EA/Hex.) Rf 0.55 (20%
EA/Hex).
[(8-Methoxyoctyloxy)methyl]benzene A 60% dispersion of sodium hydride in mineral oil
(2.1 g, 52 mmol) was washed with hexanes to remove the oil. While g with an ice bath, a
mixture of 8-(benzyloxy)octanol (9.9 g, 42 mmol) in 25 mL of DMF was added . The
e was allowed to warm to room temperature. After 1 hr, dimethyl e (4.0 mL, 42
mmol) was added, and the mixture was stirred overnight. The mixture was d with Eth,
washed with 1 M HCl, twice with 0.1 M HCl, and brine, dried over MgSO4, and concentrated.
SPE, washing with 1% EA/Hex and then eluting with 10% EtzO/Hex gave 8.63 g of the product
as an oil. Rf0.62 (20% EA/Hex); 1H NMR (CDC13) 5 7.36—7.24 (m, 5H), 4.49 (s, 2H), 3.45 (t,
2H, J=6.7 Hz), 3.35 (t, 2H, J=6.7 Hz), 3.32 (s, 3H), 1.62-1.50 (m, 4H), 1.40—1.25 (m, 8H).
8—Methoxyoctan—1—ol A e of [(8—methoxyoctyloxy)methyl]benzene (8.60 g, 34.4 mmol)
and 860 mg of 5% Pd—C in 80 mL of THF was stirred under an atmosphere of hydrogen for 40
hr. The mixture was placed under an atmosphere of argon and filtered through a pad of Celite,
washing with additional THF. An aliquot was evaporated to dryness for spectroscopy. Rf 0.26
(30% EA/Hex); 1H NMR (CDCl3) 5 3.59 (t, 2H, J=6.7 Hz), 3.33 (t, 2H, J=6.4 Hz), 3.29 (s, 3H),
1.84 (s, 1H, OH), 1.60-1.45 (m, 4H), 1.40-1.25 (m, 8H).
WO 20995
8—Methoxyoctyl methanesulfonate A mixture of 8—methoxyoctan—l—ol (34.3 mmol) in 100 mL
of THF was cooled by an ice bath. Methanesulfonyl chloride (4.50 mL, 57.5 mmol) and TEA
(8.30 mL, 59.2 mmol) were added, and a white precipitate formed quickly. After 2 hr, the
mixture was diluted with EA and washed with H20, saturated NaHCOg, brine, 1M HCl, and
brine, and the organic phase was dried over MgSO4 and concentrated. SPE, washing with 10%
EA/Hex and then eluting with 30% EA/Hex gave 7.34 g of oil containing 8—methoxyocty1
methanesulfonate and 8—methoxyoctan—1—ol in a 9:1 mole ratio, as determined by NMR. 8—
Methoxyoctyl methanesulfonate had Rf 0.31 (30% EA/Hex); 1H NMR (CDC13) 5 4.19 (t, 2H,
J=6.7 Hz), 3.34 (t, 2H, J=6.5 Hz), 3.30 (s, 3H), 2.98 (s, 3H), 1.72 (m, 2H), 1.52 (m, 2H), 1.40—
1.25 (m, 8H).
N—(8—Methoxyoctyl)phthalimide A 9:1 e of 8—methoxyocty1 methanesulfonate and 8—
methoxyoctan—l—ol (4.10 g) was taken up in 80 mL of DMF and potassium phthalimide (4.4 g,
24 mmol) was added. The e was heated at 80-100 0C for 4 hr. Then, the mixture was
, diluted with EA, and washed with H20, twice with 0.1M HCl, and brine. The organic
phase was dried over MgSO4 and concentrated onto silica gel. SPE, eluting with 30% EA/Hex,
gave 4.32 g of the product as a solid. Rf 0.50 (30% EA/Hex); 1H NMR (CDClg) 8 7.81 and 7.67
(m, 4H, AA’BB’), 3.64 (t, 2H, J=7.3 Hz), 3.32 (t, 2H, J=6.7 Hz), 3.29 (s, 3H), 1.62 (m, 2H), 1.50
(m, 2H), 1.40-1.20 (m, 8H).
8—Methoxyoctan—1—amine Hydrazine monohydrate (1.00 mL, 20.6 mmol) was added to a
mixture of N—(8—methoxyoctyl)phthalimide (4.32 g, 14.9 mmol) in 100 mL of EtOH, and the
mixture was heated at re?ux for 6 hr, during which a white precipitate formed. Then, the mixture
was cooled, 4 mL of 6M HCl were added, most of the volatile components were evaporated, 100
mL of 0.1M HCl were added, and the mixture was allowed to stand for 30 min. The precipitate
was filtered and washed twice with 50 mL of 0.1M HCl. The combined filtrate was washed
thrice with 50 mL of EtzO. The pH of the filtrate was ed to greater than 10 by adding solid
NaOH while cooling with an ice bath. The filtrate was extracted with DCM (150 mL, 2x100
mL). The organic phases were dried over ous NaZSO4 and concentrated to give 2.17 g of
oil. 1H NMR(CDC13) 5 3.30 (t, 2H, J=6.6 Hz), 3.27 (s, 3H), 2.62 (m, 2H), 1.53—1.24 (m, 12H),
1.41 (s, 2H, N?z).
N—(8—Methoxyoctyl)quinolin—4—amine A mixture of 4—chloroquinoline (3.00 mmol), 8—
methoxyoctan—l—amine (233 mg, 1.46 mmol), DIEA (0.52 mL, 3.00), and 4 mL of IPA was
heated at 135 0C for 16 hr in a sealed tube. The mixture was treated with additional 8—
methoxyoctan—l—amine (343 mg, 2.16 mmol) and heated for an additional 64 hr. Then, the
mixture was treated with additional 8—methoxyoctan—l—amine (140 mg, 0.88 mmol) and heated
for an additional 48 hr. The mixture was cooled and the volatile components were evaporated.
The residue was partitioned between EA and 5% N32CO3, and the organic phases were washed
with brine, dried over anhydrous NaZSO4, and concentrated. The product was purified using PC,
eluting with 10% and then 15% MeOH/DCM. The product—containing fractions were
trated, and the residue was taken up in DCM, washed with 5% Na2C03, dried over
ous NaZSO4 and ated to give 694 mg of the product as a solid. Rf 0.26 (10%
MeOH/DCM); 1H NMR(CDC13) 8 8.41 (d, 1H, J=5.7 Hz), 7.93 (m, 1H), 7.52 (m, 1H), 7.30 (m,
1H), 6.33 (d, 1H, J=5.7 Hz), 6.09 (br s, 1H, NH), .23 (m, 7H), 1.65, (m, 2H), 1.48 (m, 2H),
1.33-1.25 (m, 8H).
Example 4: N-[6—(Hexyloxy)hexy1]quinolin—4—amine
HNW/OM
C(j/
6—(Hexyloxy)hexan—1—amine was made starting from xanediol following the method for
the preparation of 10—(hexyloxy)decan—1—amine.
6—(Hexyloxy)hexan—l—ol Rf0.16 (10% EA/Hex); 1H NMR (CDCl3) 5 3.59 (m, 2H), 3.36 (t,
2H, J=6.7 Hz), 3.35 (t, 2H, J=6.8 Hz), 1.87 (s, 1H, OH), 1.56—1.47 (m, 6H), 1.36—1.25 (m, 10H),
0.85 (m, 3H).
6—(Hexyloxy)hexyl methanesulfonate Rf0.16 (20% EA/Hex); 1H NMR (CDC13) 8 4.21 (t,
2H, J=6.6 Hz), 3.38 (t, 2H, 6.4 Hz), 3.37 (t, 2H, J=6.7 Hz), 2.98 (s, 3H), 1.74 (m, 2H), 1.61—1.46
(m, 4H), 1.40-1.37 (m, 4H), 1.35-1.24 (m, 6H), 0.87 (t, 3H, J=6.8 Hz).
N—[6—(Hexyloxy)hexyl]phthalimide Rf0.40 (20% EA/Hex).
6—(Hexyloxy)hexan—l—amine 1H NMR (CDClg) 5 3.36 (m, 2H), 3.35 (t, 2H, J=6.8 HZ), 2.67 (m,
2H), 2.10 (br s, 2H, N?z), 1.78-1.19 (m, 16H), 0.85 (t, 3H, J=6.8 Hz).
A mixture of 6—(hexyloxy)hexan—1—amine (234 mg, 1.16 mmol), 4—chloroquinoline (235 mg, 1.44
mmol) and TEA (0.50 mL, 3.56 mmol) in 1 mL of NMP was heated at 160 0C for 16 hr. The
mixture was cooled and partitioned between EA and 5% N212C03. The organic phases were
washed with brine, dried over NaZSO4, and concentrated. SPE, washing with 40% EA/Hex and
4% MeOH/DCM and eluting with 8% MeOH/DCM, gave 137 mg of product as a solid. Rf 0.42
(7.5% MeOH/DCM); mp 41-44 0C (from EA/Hex); 1H NMR (CDC13) 8 8.45 (d, 1H, J=5.5 Hz),
7.92 (d, 1H, J=8.4 Hz), 7.86 (d, 1H, J=8.4 Hz), 7.55 (ddd, 1H, J=1.2, 6.9, 8.4 Hz), 7.33 (ddd, 1H,
J=1.2, 6.9, 8.4 Hz), 6.35 (br s, 1H, NH), 3.37-3.22 (m, 6H), 1.72-1.19 (m, 16H), 0.83 (m, 3H).
Example 5: N-(6—Butoxyhexy1)quinolin—4—amine
HN/\/\/\/O\/\/
: \J\T/
6—Butoxyhexan—1—ol 60% Sodium hydride in mineral oil (3.56 g, 89 mmol) was washed twice
with 20 mL of hexanes. Anhydrous DMF (250 mL) was added, the e was cooled with an
ice bath, and 1,6—hexanediol (41.4 g, 351 mmol) was added. After 1.5 hr, l—bromobutane (4.71
mL, 43.7 mmol) was added . The e was warmed to room temperature. After 24 hr,
the e was trated. The residue was taken up in EtZO (500 mL) and washed with
saturated NaHC03 and H20 (400 mL each). The aqueous phases were extracted with Eth
(3x400 mL). The combined organic phases were dried over NaZSO4, filtered, and concentrated to
W0 2014/120995 2014/013992
give 6.55 g ess oil. Rf0.4 (30% EA/Hex); 1H NMR (CDC13) 5 3.6 (t, 2H), 3.4—3.3 (m, 4H),
1.6-1.4 (m, 6H), 1.4-1.2 (m, 6H), 0.8 (t, 3H).
6—Butoxyhexyl methanesulfonate A mixture of 6—butoxyhexan—l—ol (6.55 g, 37.6 mmol) and
TEA (5.51 mL, 39.5 mmol) in 100 mL of DCM was cooled using an ice bath. Then,
methanesulfonyl chloride (3.06 mL, 39.5 mmol) was added. After 1.5 hr, the mixture was
washed with H2O, saturated , H2O, 1M HCl, and H20 (50 mL each). The organic phase
was dried over Na2SO4, filtered through a pad of silica gel, and trated to give 9.24 g of
colorless oil. 1H NMR (CDC13) 8 4.2 (t, 2H), 3.4—3.3 (m, 4H), 2.9 (s, 3H), 1.7 (m, 2H), 1.6—1.2
(m, 10H), 0.8 (t, 3H).
1-Butoxy—6—iodohexane A mixture of 6-butoxyhexyl methanesulfonate (9.23 g, 36.6 mmol)
and sodium iodide (5.5 g, 36.6 mmol) in 300 ml of acetone was heated at re?ux for 3 hr. The
e was cooled, filtered, and concentrated. The residue was taken up in EA (400 mL) and
washed with saturated NaHC03 and brine (100 mL each). The organic phase was dried over
Na2SO4, ?ltered, and concentrated to give 10.4 g of yellow liquid.
utoxyhexyl)phthalimide 1-Butoxyiodohexane (10.4 g, 36.6 mmol) and potassium
phthalimide (6.78 g, 36.6 mmol) in 300 mL of DMF were mixed at 60—80 °C for 12 hr. The
cooled mixture was concentrated, and the residue was partitioned between EA (3x300 mL) and
5% Na2S203, H20, and brine (100 mL each). The combined organic phases were dried over
Na2SO4, ?ltered, and concentrated to give 7.2 g of solid. 1H NMR (CDC13) 5 7.8 and 7.7 (m, 4H,
AA’BB’), 3.6 (t, 2H), 3.4—3.3 (m, 4H), 2 (m, 12H), 0.8 (t, 3H).
6—Butoxyhexan—1—amine Hydrazine monohydrate (1.3 mL, 27 mmol) was added to a
mixture of N—(6—butoxyhexyl)phthalimide (6.72 g, 22.2 mmol) and 100 mL of EtOH. The
mixture was heated at re?ux for 16 hr. Then, the mixture was cooled with an ice bath and stirred
vigourously while 200 mL of Et2O were added. The precipitate was filtered and washed with
Et2O, and the organic phases were concentrated to give 4.2 g of amber oil. 1H NMR (CDgOD)
3.5—3.4 (m, 4H), 2.9 (t, 2H), 1.7-1.3 (m, 12H), 0.9 (t, 3H).
N—(6—Butoxyhexyl)quinolin—4—amine A mixture of 6—butoxyhexan—l—amine (0.5 g, 2.9 mmol), 4—
chloroquinoline (711 mg, 4.4 mmol), TEA (5 mL, 36 mmol), and 0.5 mL of NMP was sealed in
a heavy walled glass tube and mixed at 130 0C for 4 days. The mixture was cooled and
partitioned between EA and 5% Na2C03 and brine, dried over NaZSO4, filtered, and
concentrated. Purification by EC (60% EA/Hex + 2% TEA) gave 220 mg of amber oil. 1H NMR
(CDC13) 5 8.4 (d, 1H), 8.3-8.1 (m, 3H), 7.6 (m, 1H), 7.4 (m, 1H), 6.4 (d, 1H), 3.5 (m, 2H), 3.4—
3.3 (m, 4H), 1.8 (m, 2H), l.7-l.3 (m, 10H), 0.9 (t, 3H).
Alternative Synthesis
6-Butoxyhexan—1—ol 60% Dispersion of sodium hydride in mineral oil (14 g, 350 mmol) was
washed with two 50 mL portions of Hex, and then dried in vacuo. While cooling with an ice
bath, IPA (50 mL) and 1,6-hexanediol (200 g, 1700 mmol) were added cautiously, with gas
evolution observable. The mixture was allowed to warm to room ature, and 1-
bromobutane (25.0 mL, 234 mmol) was added. The mixture was warmed at 45 0C for 3 days.
Then, 6.6 mL of acetic acid were added, and distillation of volatile components was carried out
until bp 90 0C was attained. The residue was loaded onto silica gel. Two rounds of SPE (50%
EA/Hex) gave 36.7 g of pale yellow liquid. Rf 0.40 (50% EA/Hex).
6—Butoxyhexyl methanesulfonate 6—Butoxyhexanol (36.7 g, 211 mmol) was taken up in
600 mL of EtzO cooled by an ice bath. esulfonyl chloride (19.8 mL, 253 mmol) and TEA
(35.5 mL, 253 mmol) were added, anied by immediate precipitate formation. After 1.5
hr, 100 mL of H20 were added, and the phases were separated. The aqueous phase was extracted
with EA (2x150 mL), and the organic phases were washed with saturated NaHCOg, H20, 1M
HCl, H20, and brine (100 mL each). The organic phases were dried over anhydrous NaZSO4,
filtered through a pad of silica gel, and trated to 52.2 g of pale yellow liquid. Rf 0.55; 1H
NMR(CDC13) 5 4.19 (m, 2H), .34 (m, 4H), 2.97 (s, 3H), 1.72 (m, 2H), 1.56-1.50 (m, 4H),
1.50—1.30 (m, 6H), 0.88 (t, 3H); 13C NMR(CDC13)5 70.8, 70.7, 70.2, 37.4, 32.0, 29.7, 29.2,
.8, 25.4, 19.5, 14.0.
1—Butoxy—6—iodohexane A mixture of xyhexyl methanesulfonate (52.2 g, 207 mmol)
and sodium iodide (40 g, 267 mmol) in 400 ml of acetone was heated at re?ux for 1 hr. The
e was cooled, concentrated, and partitioned between EA (3x300 mL) and H20, 5%
N328203, H20, and brine (150 mL each). The organic phases were dried over NaZSO4 and
concentrated to give the product as a yellow liquid that ned 13 mol% of the starting
material. 1H NMR ) 5 .35 (m, 4H), 3.16 (t, 2H, J=7.0 Hz), 1.80 (m, 2H), .48
(m, 4H), 1.40-1.30 (m, 6H), 0.88 (t, 3H, J=7.3 Hz); 13C NMR (CDC13) 5 70.8, 70.7, 33.6, 32.0,
.5, 29.7, 25.3, 19.5, 14.1, 7.2.
N—(6—Butoxyhexyl)phthalimide Crude 1—butoxy—6—iodohexane and potassium phthalimide
(46 g, 249 mmol) in 300 mL of DMF were mixed at room temperature for 41 hr and at 60—80 0C
for 24 hr. The cooled mixture was concentrated, and the residue was partitioned between EA
(3x350 mL) and H20, 5% Na28203, H20, and brine (100 mL each). The combined organic
phases were dried over NaZSO4, ed through a pad of silica gel, and concentrated. SPE (10%
EA/Hex) gave 51.6 g of colorless liquid. Rf 0.38 (20% EA/Hex); 1H NMR (CDClg) 8 7.77 and
7.65 (m, 4H, AA’BB’), 3.62 (t, 2H, J=7.3 Hz), 3.34-3.31 (m, 4H), 1.63 (m, 2H), 1.52-1.44 (m,
4H), 1.35-1.25 (m, 6H), 0.85 (m, 3H); 13C NMR (CDC13) 5 168.5, 133.9, 132.3, 123.2, 70.8,
70.7, 38.0, 31.9, 29.7, 28.7, 26.8, 25.9, 19.4, 14.0.
6—Butoxyhexan-1—amine Hydrazine monohydrate (9.1 mL, 187 mmol) was added to a
mixture of N—(6—butoxyhexyl)phthalimide (51.6 g, 170 mmol) and 900 mL of EtOH. The mixture
was heated at re?ux for 12 hr, and allowed to stand at room temperature for 3 days. Then, 250
mL of volatile material was removed by distillation. 1M HCl (200 mL) was added to the still—
warm pot e. After cooling to room temperature, the precipitate was removed by filtration,
washing with three 200 mL portions of 50% aqueous EtOH. The filtrate was adjusted to pH 10
by adding NaOH pellets, concentrated, and taken up in 800 mL of DCM. The aqueous phase was
separated, and the organic phase was dried over anhydrous NaZSO4 and concentrated. SPE,
washing with DCM and 5% MeOH/DCM and eluting with 8% MeOH/DCM + 3% NH4OH,
gave ninhydrin (+) t fractions. The product fractions were concentrated and taken up in
DCM. The organic phase was separated, dried over anhydrous NaZSO4, and concentrated to give
29.1 g of yellow liquid. Rf 0.09 (10% MeOH/DCM); 1H NMR (CDCl3) 5 3.26 (t, 2H, J=6.6 Hz),
3.25 (t, 2H, J=6.6 Hz), 2.55 (t, 2H, J=6.9 Hz), 1.46—1.38 (m, 4H), 1.32 (m, 2H), 1.34 (br s, 2H,
N?z), 1.26-1.20 (m, 6H), 0.78 (t, 3H, J=7.4 Hz); 13C NMR (CDC13) 5 70.7, 70.6, 42.1, 33.6,
31.8, 29.7, 26.7, 26.0, 19.3, 13.8.
N—(6—Butoxyhexyl)quinolin—4—amine 6—Butoxyhexan—1—amine (6.05 g, 34.6 mmol) was taken up
in 150 mL of 1—pentanol, and 15 mL was removed by distillation. Tripropylamine (15.8 mL, 82.9
mmol) and 4—chloroquinoline (8.20 g, 50.3 mmol) were added, and the mixture was heated at
re?ux for 25 hr and allowed to stand at room temperature for 2 days. Then, most of the le
components were ated, and 30 mL of 1N NaOH and 60 mL of 5% Na2C03 were added.
The mixture was extracted with DCM (3x150 mL), and the organic phases were dried over
NaZSO4 and evaporated onto silica gel. SPE, washing with 50% EA/Hex and g with 5%
MeOH/DCM + 2% TEA, gave a brown oil. Upon cooling below 0 0C, the oil solidified. The
solid was washed with cold 10% EA/Hex and dried in vacuo to give 6.62 g of colorless solid. Rf
0.07 (50% EA/Hex) 0.35 (10% CM); mp 62.5-65.0 0C; 1H NMR (CDClg) 8 8.52 (d, 1H,
J=5.5 Hz), 7.99 (dd, 1H, J=0.7, 8.4 Hz), 7.77 (dd, 1H, J=0.7, 8.4 Hz), 7.62 (ddd, 1H, J=1.5, 7.0,
8.4 Hz), 7.42 (ddd, 1H, J=1.4, 6.9, 8.4 Hz), 6.42 (d, 1H, J=5.5 Hz), 5.26 (br s, 1H, NH), 3.41 (t,
2H, J=6.6 Hz), 3.40 (t, 2H, J=6.6 Hz), 3.33 (m, 2H), 1.78 (m, 2H), 1.64—1.31 (m, 10H), 0.91 (t,
3H, J=7.3 Hz); 13C NMR(CDC13)5150.5, 150.3, 147.8, 129.5, 129.4, 124.9, 119.6, 118.8, 98.9,
70.9, 70.8, 43.4, 32.0, 29.9, 29.1, 27.2, 26.2, 19.6, 14.1.
Example 6: N—[10—(Hexyloxy)decyl]quinolin—4—amine
HN/\/\/\/\/\/O\/\/\/
C(i/N
10—(Hexyloxy)decan—1—ol 60% Sodium hydride dispersion in l oil (1.08 g, 27 mmol)
was washed with hexane. 2—Propanol (150 mL) was added, slowly at first. Then, 1,10—decanediol
(31.3 g, 180 mmol) was added, and the mixture was warmed slightly to attain homogeneity. l—
exane (2.50 mL, 17.9 mmol) was added dropwise. After being d at room
temperature overnight, the mixture was heated at re?ux for 2 hr and then 100 mL of volatile
components were removed by distillation. 1M HCl (10 mL) was added, and then the remainder
of the t was removed by distillation. Puri?cation by solid phase extraction, g with
12% EA/Hex, gave 1.20 g of 10—(hexyloxy)decan—l—ol as a colorless liquid. Rf 0.22 (20%
EA/Hex); 1H NMR (CDC13) 5 3.63 (m, 2H), 3.40—3.35 (m, 4H), 1.65-1.55 (m, 6H), 1.40—1.20 (m,
18H), 0.87 (m, 3H).
—(Hexyloxy)decan—l—amine Methanesulfonyl de (0.50 mL, 6.39 mmol) was added to a
mixture of 10—(hexyloxy)decan—1—ol (1.20 g, 4.65 mmol) and triethylamine (0.98 mL, 6.99
mmol) in 100 mL of DME cooled by an ice bath. After 1 hr, the mixture was partitioned between
EA (3x100 mL) and H20, saturated NaHCOg, H20, 0.1M HCl, and brine (50 mL each), and the
organic phases were dried over NaZSO4, filtered through a pad of silica gel, and concentrated.
The residue was taken up in 150 mL of acetone, sodium iodide (1.27 g, 8.47 mmol) was added,
and the mixture was heated at re?ux for 3 hr. Then, the mixture was , the solvent was
evaporated, and the residue was partitioned between EA (3x100 mL) and 5% NaZSZOg and H20
(50 mL of each), and the organic phases were dried over Na2804, filtered through a pad of silica
gel, and concentrated. The residue was taken up in 20 mL of NMP and potassium phthalimide
(1.66 g, 8.97 mmol) was added. After the iodide was consumed, as observed by TLC, the
mixture was partitioned between EA (3x100 mL) and 0.1M HCl and brine (50 mL of each), and
the organic phases were dried over NaZSO4, filtered through a pad of silica gel, and concentrated.
The e was taken up in 30 mL of ethanol, hydrazine monohydrate (0.60 mL, 12.5 mmol)
was added, and the mixture was heated at re?ux for 8 hr. Then, the volatile components were
ated, the residue was partitioned between DCM (3x60 mL) and 5% Na2C03 (50 mL), and
the organic phases were dried over NaZSO4 and concentrated to give 964 mg of 10—
(hexyloxy)decan—l—amine as an oil that solidified upon standing. 1H NMR ) 5 3.45—3.36
(m, 4H), 2.72 (m, 2H), 1.65-1.45 (m, 6H), 1.45—1.25 (m, 18H), 0.89 (m, 3H).
N—[10—(Hexyloxy)decyl]quinolin—4—amine A mixture of lO—(hexyloxy)decan—l—amine (256 mg,
1.00 mmol), 4—chloroquinoline (240 mg, 1.47 mmol), and a particle of prilled DMAP in 1.5 mL
of DIEA were heated at 150 0C in a sealed tube for 24 hr. The cooled mixture was partitioned
between DCM (3x60 mL) and 5% NazCO3 (50 mL), and the organic phases were dried over
NaZSO4 and concentrated. Purification by solid phase extraction, washing with 50% EA/Hex and
then eluting the product with 50% EA/Hex + 2% TEA, gave 175 mg of the product as a solid. Rf
0.42 (50% EA/Hex + 0.5% TEA); 1H NMR (CDC13) 5 8.51 (d, 1H, J=5.2 Hz), 7.94 (dd, 1H,
J=1.0, 8.4 Hz), 7.74 (d, 1H, J=8.2 Hz), 7.57 (ddd, 1H, J=l.5, 6.9, 8.4 Hz), 7.36 (ddd, 1H, J=1.2,
6.9, 8.1 Hz), 6.37 (d, 1H, J=5.4 Hz), 5.23 (br s, 1H, NH), 3.36 (t, 4H, J=6.7 Hz), 3.25 (m, 2H),
1.70 (m, 2H), 1.56-1.26 (m, 22H), 0.85 (m, 3H).
Example 7: N—(10—Butoxydecyl)quinolin-4—amine
HNWWVOW
CK?/N
1-Bromobutoxydecane 60% Sodium hydride dispersion in mineral oil (1.7 g, 42 mmol)
was washed with hexane. While cooling with an ice bath, a mixture of 1—butanol (10 mL, 109
mmol) and DMF (40 mL) was added, slowly at ?rst. After gas ion ceased, a e of
ibromodecane (47.1 g, 157 mmol) and 100 mL of DCM and 40 mL of DMF were added in
one portion. The mixture was d to come to room temperature ght. Then, the DCM
was evaporated, and the residue was partitioned between EA (3x250 mL) and 0.1M HCl and
brine (100 mL each), and the organic phases were dried over NaZSO4 and concentrated.
Purification by SPE, washing with Hex to recover excess dibromide and then eluting with 10%
EA/Hex gave 10.7 g of l—bromo—lO—butoxydecane contaminated with 1,10—dibutoxydecane. Rf
0.39 (10% EA/Hex); 1H NMR ) 5 3.40—3.36 (m, 6H), 1.82 (m, 2H), 1.57—1.47 (m, 4H),
1.41—1.26 (m, 14H), 0.89 (m, 3H).
lO—Butoxydecan—l—amine A e of 1—bromo—10—butoxydecane (21.1 g, 72 mmol) and
sodium azide (5.1 g, 78 mmol) in 30 mL of DMF was stirred at room temperature until the
bromide was consumed, as observed by TLC. The mixture was partitioned between EA (3x350
mL) and H20 (3x100 mL) and brine (100 mL), and the organic phases were dried over NaZSO4
and trated. Purification by SPE using 10% EA/Hex gave 19.6 g of the azide product. The
azide was taken up in 40 mL of EA and 40 mL of MeOH under a blanket of argon, 2.0 g of 5%
Pd/C were added, and the mixture was stirred under an atmosphere of hydrogen until the azide
was consumed, as ed by TLC. The catalyst was removed by filtration and the volatile
components were evaporated. Purification by SPE, washing with 50% EA/Hex and then eluting
with 15% MeOH/DCM + 2% TEA, gave 7.0 g of 10—butoxydecan—1—amine as a colorless solid.
1H NMR (CDCl3) 5 3.40-3.34 (m, 4H), 2.55 (m, 2H), 2.1 (br s, 2H, N?z), 1.58-1.26 (m, 20H),
0.90 (m, 3H).
N—(10-Butoxydecyl)quinolinamine A mixture of 10-butoxydecanamine (312 mg,
1.36 mmol), 4-chloroquinoline (375 mg, 2.30 mmol) and DIEA (0.50 mL, 2.87 mmol) in 3 mL
of 2-propanol was heated at 130 0C for 3 days and the 160 0C for 1 day. The volatile components
were ated. The mixture was partitioned between DCM (3x60 mL) and 5% N32C03 (50
mL), and the c phases were dried over Na2$O4 and concentrated. cation by long-
column FC (10% MeOH/DCM) gave N—(10—butoxydecy1)quinolin—4—amine. Rf 0.34 (10%
MeOH/DCM); 1H NMR (CDC13) 8 8.52 (d, 1H, J=5.4 Hz), 7.96 (d, 1H, J=8.4 Hz), 7.75 (d, 1H,
J=8.4 Hz), 7.60 (dd, 1H, J=7.0, 8.2 Hz), 7.39 (dd, 1H, J=6.9, 8.4 Hz), 6.39 (d, 1H, J=5.2 Hz),
.20 (br s, 1H, NH), 3.41-3.35 (m, 4H), 3.28 (m, 2H), 1.73 (m, 2H), 1.59—1.28 (m, 18H), 0.89 (m,
3H).
Example 8: N—(5—Methoxypentyl)quinolin—4—amine
/\/\/\
HN 00 H3
N
1—Bromo—5—methoxypentane MeOH (20 mL) was added drop—wise to hexane—washed sodium
hydride (61.8 mmol) while cooling with an ice bath. The mixture was added drop—wise to a
2014/013992
mixture of l,5—dibromopentane (99.44 g, 0.432 mol) and 100 mL of 1:1 MeOH and THF. After
42 hr, most of the solvent was removed by distillation at room pressure. Then, gentle vacuum
distillation gave approximately 20 mL of , which was comprised of a 1:1 mixture of 1,5—
dibromopentane and l—bromo—5—methoxypentane. The pot was partitioned between DCM and
H20, and the organic phase was dried over MgSO4 and concentrated by distillation at room
pressure to leave 96 g of a 21:1 mixture of 1,5—dibromopentane and DCM. The ide was
retreated with sodium methoxide. The crude 1—bromo—5—methoxypentane mixtures were
ed and separated by SPE, washing with pentane to recover l,5—dibromopentane and
eluting with 10% Eth/pentane to get 8.40 g of colorless liquid after concentration by distillation.
Rf0.53 (5% EA/Hex) 0.44 (10% EtZO/Hex); 1H NMR (CDC13) 5 3.4-3.3 (m, 4H), 3.31 (s, 3H),
1.86 (m, 2H), 1.6 (m, 2H), 1.3 (m, 2H).
1-Azido—5—methoxypentane A mixture of 1-bromo—5—methoxypentane 2.76 g, 15.2 mmol) and
sodium azide (1.14 g, 17.5 mmol) in 10 mL of DMF was stirred at room temperature for 16 hr.
Then, the mixture was partitioned between Et20 (3x70 mL) and H20 (3x50 mL) and brine. The
organic phases were dried over NaZSO4 and the mixture was carried on. Rf 0.36 (10% Eth/Hex).
-Methoxypentanamine A mixture of 1-azidomethoxypentane in Eth and 286 mg of
% Pd—C was stirred under a blanket of en for 24 hr. The mixture was blanketed with
argon and filtered through a pad of Celite. Most of the Et20 was removed by distillation at
atmospheric pressure. 1H NMR (CDC13) 8 3.35 (t, 2H), 3.3 (s, 3H), 2.6 (m, 2H), 3 (m, 6H).
ethoxypentyl)quinolin—4—amine A mixture of 5—methoxypentan—1—amine, 4—
chloroquinoline (900 mg, 5.52 mmol), and DIEA (0.50 mL, 2.87 mmol) was heated at 130 0C in
a sealed tube for 24 hr. The mixture was cooled and partitioned n EA and 5% N32C03 and
brine. The organic phases were dried over anhydrous NaZSO4 and concentrated. SPE, washing
with 40% EA/Hex + 2% TEA and eluting with 80% EA/Hex + 2% TEA, gave a solid. Rf0.20
(80% EA/Hex + 2% TEA); 1H NMR(CDC13)8 8.46 (d, 1H, J=5.2 Hz), 7.90 (dd, 1H, J=l.0, 8.4
Hz), 7.77 (m, 1H), 7.51 (ddd, lH, J=l.5, 6.9, 8.4 Hz), 7.28 (ddd, lH, J=l.2, 6.9, 8.1 Hz), 6.31 (d,
2014/013992
1H, J=5.4 HZ), 5.55 (m, 1H, NH), 3.30 (t, 2H, J=6.2 Hz), 3.25 (s, 3H), 3.20 (m, 2H), 1.65 (p, 2H,
J=7 Hz), 1.57—1.42 (m, 4H).
Example 9: N—[8—(Hexyloxy)octyl]—2—methquuinolin—4—amine
HN/VVWOM
m/N CH3
N—[8—(Hexyloxy)octyl]—2—methquuinolin—4—amine A mixture of 8—(hexyloxy)octan—1—amine
(479 mg, 2.09 mmol), 4—chloroquinaldine (575 mg, 3.25 mmol), and DIEA (1.00 mL, 5.74
mmol) was heated at 140 0C in a sealed tube for 4 days. Then, the volatile material was
evaporated, and the residue was purified by PC (7% CM) to give 217 mg of N—[8—
(hexyloxy)octyl]—2—methquuinolin—4—amine. 1H NMR (CDClg) 5 7.87 (d, 1H, J=8.4 Hz), 7.67 (d,
1H, J=8.0 Hz), 7.53 (m, 1H), 7.29 (m, 1H), 6.26 (s, 1H), 5.10 (m, 1H, NH), 3.35 (t, 4H, J=6.5
Hz), 3.21 (m, 2H), 2.57 (s, 3H), 1.73-1.21 (m, 20H), 0.85 (m, 3H).
Example 10: 7-Chloro-N—[8-(hexyloxy)octyl]quinolinamine
H NWOW
CIm/N
7—Chloro—N—[8-(hexyloxy)octy1]quinolin—4—amine A mixture of 8—(hexyloxy)octan—1—amine
(537 mg, 2.34 mmol), 4,7—dichloroquinoline (565 mg, 2.85 mmol), DIEA (0.50 mL, 287 mmol),
and 1 mL of NMP was heated at 140 °C in a sealed tube for 24 hr. Then, the volatile material
was evaporated, and the residue was ed by SPE (5% MeOH/DCM and then 30% EA/Hex +
2% TEA) to give 358 mg of 7—chloro—N—[8—(hexyloxy)octyl]quinolin—4—amine. Rf 0.20 (5%
MeOH/DCM), 0.31 (30% EA/Hex + 2% TEA); 1H NMR (CDClg) 8 8.43 (d, 1H, J=5.4 Hz), 7.87
(d, 1H, J=2.0 Hz), 7.68 (d, 1H, J=8.9 Hz), 7.22 (dd, 1H, J=2.2, 8.9 Hz), 6.30 d, 1H, J=5.4 Hz),
.46 (t, 1H, J=4.8 Hz, NH), 3.33 (t, 4H, J=6.7 Hz), 3.19 (m, 2H), 1.70—1.23 (m, 20H), 0.82 (m,
3H).
Example 11: 8—Chloro—N—[8—(hexyloxy)octyl]quinolin—4—amine
HN/\/\/\/\/O\/\/\/
8—Chloro—N—[8—(hexyloxy)octyl]quinolin—4—amine A mixture of 8—(hexyloxy)octan—1—amine
(456 mg, 1.99 mmol), 4,8—dichloroquinoline (480 mg, 2.42 mmol), DIEA (0.43 mL, 2.47 mmol),
and 1 mL of NMP was heated at 140 0C in a sealed tube for 24 hr. Then, the volatile material
was evaporated, and the residue was purified by SPE (5% MeOH/DCM and then 30% EA/Hex +
2% TEA) to give 338 mg of 8—chloro—N—[8—(hexyloxy)octyl]quinolin—4—amine. Rf 0.28 (5%
MeOH/DCM), 0.38 (30% EA/Hex + 2% TEA); 1H NMR (CDC13) 8 8.61 (d, 1H, J=5.5 Hz),
7.72—7.64 (m, 2H), 7.26 (m, 1H), 6.41 (d, 1H, J=5.4 Hz), 5.19 (t, 2H, J=4.7 Hz, NH), .33
(m, 4H), 3.26 (m, 2H), 1.76 (m, 20H), 0.85 (m, 3H).
Example 12: N-[8-(Hexyloxy)octyl] (tri?uoromethyl)quinolinamine
HNWOW
/ F3C’ : :N:
A mixture of 8-(hexyloxy)octan—1—amine (546 mg, 2.38 mmol), 4—chloro—7—
trifluoromethquuinoline (711 mg, 3.06 mmol), DIEA (0.50 mL, 2.87 mmol), and 1 mL of NMP
was heated at 0 0C in a sealed tube for 24 hr. Then, the residue was partitioned between
EA and 5% Na2C03 and brine, and the c phases were dried over NaZSO4 and concentrated.
Purification by SPE failed, but FC (25% EA/Hex) gave 626 mg of a yellow oil that solidi?ed
upon standing. Rf0.10 (20% EA/Hex); 1H NMR ) 5 8.53 (d, l, J=5.4 Hz), 8.19 (s, 1),
7.87 (d, 1, J=8.9 Hz), 7.47 (dd, 1,J=l.7, 8.9 Hz), 6.42 (d, 1, J=5.5 Hz), 5.47 (m, 1), 3.36—3.32 (m,
4), 3.25 (m, 2), 1.81—1.17 (m, 20), 0.83 (m, 3).
Example 13: N—[8—(Hexyloxy)octyl]—8—(tri?uoromethyl)quinolin—4—amine
HN/\/\/\/\/O\/\/\/
N—[8—(Hexyloxy)octyl]—8—(tri?uoromethyl)quinolin—4—amineA e of 8—(hexyloxy)octan—l—
amine (590 mg, 2.58 mmol), 4—chloro—8—(tri?uoromethyl)quinoline (780 mg, 3.36 mmol), and
DIEA (0.50 mL, 2.86 mmol) in 1 mL of NMP was heated in a heavy walled sealed tube at 140—
150 0C for 48 hr. Then, the residue was partitioned between EA and 5% Na2C03 and brine, and
the organic phases were dried over NaZSO4 and concentrated. FC (20% EA/Hex) gave 793 mg of
yellow oil. Rf0.28 (20% EA/Hex); 1H NMR (CDC13) 5 8.60 (d, 1, J=5.4 HZ), 7.94 (d, 1, J=8.6
Hz), 7.91 (d, 1, J=7.4 Hz), 7.35 (m, 1), 6.42 (d, 1, J=5.4 Hz), 5.23 (m, 1, NH), 3.36 (t, 4, J=6.6
Hz), 3.23 (m, 2), 1.74-1.25 (m, 20), 0.85 (m, 3).
Example 14: N-{ 5-[3-(Hexyloxy)propoxy]pentyl}quinolinamine
: \
yloxy)propan—1—ol One mole of sodium metal was added in portions to 250 g of 1,3-
ediol cooled by an ice bath and blanketed with argon. After the metal had dissolved, 0.466
mole of l—iodohexane mixed in 100 mL of DMF was added dropwise. The e was allowed
to warm to room temperature overnight. Then, the mixture was warmed to 60 °C for 2 hr. Then,
the mixture was cooled to room temperature and treated with 10 mL of concentrated NH4OH for
1 hr. Then, the mixture was partitioned between EA (3x250 mL) and 1.5 L H20 + H3PO4
(pH~10), H20, 1M HCl, 2x0.1M HCl, and brine. The organic phases were dried over MgSO4
and concentrated. Purification by SPE, washing with 10% EA/Hex and eluting with 30%
EA/Hex, gave 44.2 g of 3—(hexyloxy)propan—1—ol as a pale yellow liquid. Rf 0.28 (30% EA/Hex);
1H NMR(CDC13) 5 3.74 (t, 2H), 3.60 (t, 2H, J=5.7 Hz), 3.39 (t, 2H), 2.66 (s, 1H, OH), 1.80 (m,
2H), 1.53 (m, 2H), 1.56—1.20 (m, 6H), 0.85 (m, 3H).
WO 20995
3—(Hexyloxy)propyl methanesulfonate was prepared by the method used for the preparation of 3—
phenoxybenzyl esulfonate, using 44.2 g of 3—(hexyloxy)propan—l—ol, 43 mL of TEA, and
24 mL of methanesulfonyl chloride in 540 mL of DCM. The crude al was taken up in 450
mL of acetone and reacted with 55.7 g of sodium iodide at re?ux for 4 hr. Then, the mixture was
cooled and diluted with 1 volume of hexanes. The solid was filtered, and the filtrate was
concentrated. The residue was taken up in 350 mL of DCM and washed with 5% 3 (to
remove color) and H20. The organic phase was dried over NaZSO4 and concentrated to give
crude l—(3—iodopropoxy)hexane.
1,5—Pentanediol (230 mL) was ted with argon, and 22.6 g of potassium metal was added in
portions. The exothermic evolution of gas was ted by cooling with an ice bath. Then, at
room temperature, a mixture of the crude 1-(3—iodopropoxy)hexane and 100 mL of DMA was
added dropwise. After being stirred overnight, unreacted iodide was observed by TLC. Sodium
hydride (7.4 g) was added in 2-gram portions with cooling by an ice bath. The mixture was
allowed to stir at room temperature for 60 hr. Then, the mixture was cooled with an ice bath and
neutralized by the addition of concentrated HCl. The mixture was partitioned between EA and
H20, and the organic phases were washed with 5% N328203 (to remove color) and brine, dried
over Na2SO4, and concentrated. Purification by SPE, g with 5% EA/Hex and then eluting
with 30% EA/Hex, gave 39.0 g of 5—[3—(hexyloxy)propoxy]pentan—1—ol as a colorless oil. Rf 0.19
(30% ), 0.31 (40% EA/Hex); 1H NMR (CDC13) 5 3.60 (t, 2H, J=6.6 Hz), 3.48—3.34 (m,
8H), 1.8 (m, 2H), 1.6—1.5 (m, 4H), 1.5—1.2(m, 10H), 0.85 (t, 3H, J=6.7 Hz).
—[3—(Hexyloxy)propoxy]pentyl methanesulfonate (51.0 g) was prepared by the method used for
3—(hexyloxy)propyl methanesulfonate, using 39.0 g of 5—[3—(hexyloxy)propoxy]pentan—1—ol, 24.4
mL of TEA, 13.6 mL of esulfonyl chloride, and 420 mL of DCM. Rf 0.38 (40%
EA/Hex); 1H NMR (CDC13) 5 4.23 (t, 2H, J=6.4 Hz), 3.5-3.3 (m, 8H), 2.98 (s, 3H), 1.8—1.7 (m,
4H), 1.7—1.4 (m, 6H), 1.4-1.2 (m, 6H), 0.9 (t, 3H).
—Azidopentyl 3—(hexyloxy)propyl ether (29.3 g) was produced from the reaction of 5—[3—
(hexyloxy)propoxy]pentyl methanesulfonate (51 g) and sodium azide (11.3 g) in 80 mL of DMF
at room temperature following the method used for 8—(3—ethoxypropoxy)octan— l—amine. Rf0.20
(5% EA/Hex); 1H NMR (CDCl3) 5 3.4-3.3 (m, 8H), 3.22 (t, 2H), 1.7 (m, 2H), 1.6-1.2 (m, 14H),
0.84 (t, 3H).
—[3—(Hexyloxy)propoxy]pentan—l—amine (26.4 g) was prepared from 5—azidopentyl 3—
(hexyloxy)propyl ether using LAH by the method used to prepare [4—
(hexyloxy)phenyl]methanamine. 1H NMR (CDC13) 5 3 (m, 8H), 2.65 (t, 2H, J=6.4 Hz), 1.8
(m, 2H), 1.7—1.2 (m, 14H), 0.84 (t, 3, J=6.8 Hz).
N—{5—[3—(Hexyloxy)propoxy]pentyl}quinolin—4—amine A mixture of 5—[3—
(hexyloxy)propoxy]pentan—1—amine (482 mg, 1.97 mmol), 4—chloroquinoline (345 mg, 2.12
mmol), DIEA (0.80 mL, 4.59 mmol), and 2 mL of NMP were heated at 160 0C for 3 days in a
sealed tube. Then, the e was cooled, the le material was evaporated, the residue was
partitioned between DCM and 5% N32C03, and the organic phase was dried over Na2$O4 and
concentrated. SPE, washing with 50% EA/Hex and then eluting with 60% EA/Hex + 2% TEA,
gave 502 mg of N—{5-[3-(hexyloxy)propoxy]pentyl}quinolinamine as an amber oil. Rf 0.20
(60% EA/Hex + 2% TEA); 1H NMR (CDClg) 8 8.48 (d, 1H, J=5.4 Hz), 7.91 (dd, 1H, 1.2, 8.4
Hz), 7.76 (m, 1H), 7.54 (ddd, 1H, J=1.2, 6.9, 8.4 Hz), 7.32 (ddd, 1H, J=1.2, 6.9, 8.2 Hz), 6.34 (d,
1H, J=5.4 Hz), 5.42 (t, 1H, J=5.0 Hz), 3.46—3.20 (m, 10H), 1.83—1.39 (m, 10H), .15 (m,
6H), 0.81 (m, 3H).
Example 15: N—{ 3—[5—(Hexyloxy)pentyloxy]propyl }quinolin—4—amine
HN/\/\O/\/\/\O/\/\/\
—(Hexyloxy)pentyloxy]propyl}quinolin—4—amine (426 mg) was made by a method
analogous to that used for the preparation of N—{ 5—[3—(hexyloxy)propoxy]pentyl}quinolin—4—
amine but the two diols were reacted in the reverse sequence. Rf 0. 18 (60% EA/Hex + 2%
TEA); 1H NMR (CDC13) 5 8.47 (d, 1H, J=5.5 Hz), 7.90 (dd, 1H, J=0.7, 8.4 Hz), 7.70 (m, 1H),
7.54 (ddd, 1H, J=1.5, 6.9, 8.4 Hz), 7.32 (ddd, 1H, J=1.2, 6.9, 8.4 Hz), 6.30 (d, 1H, J=5.4 Hz),
6.19 (m, 1H), 3.57 (m, 2H), 3.44—3.24 (m, 8H), 1.96 (m, 2H), .16 (m, 14H), 0.81 (m, 3H).
Example 16: N—[8—(3—Ethoxypropoxy)octyl]quinolin—4—amine
/O\/\/O\/
d?/N
1—Bromo—8—(3—ethoxypropoxy)octane60% Dispersion of sodium hydride in mineral oil (1.4 g, 35
mmol) was washed twice with 20 mL of hexane. Anhydrous NMP (50 mL) and DME (50 mL)
were added, the mixture was cooled with an ice bath, and 3—ethoxy—1—propanol (2.00 mL, 17.4
mmol) was added. After evolution of gas ceased, 1,8—dibromooctane (25.7 mL, 139 mmol) was
added in one portion. After 16 hr at room ature, the mixture was heated at re?ux for 1.5
hr. Then, the volatile components were evaporated, and the residue was diluted with 150 mL of
H20 and extracted with DCM (2x25 mL). The combined organic phases were washed with
0.05M HCl, dried over ous MgSO4, and concentrated. SPE, washing with hexane to
recover 1,8-dibromooctane and then eluting with 10% EA/Hex, gave 4.15 g of o(3-
ethoxypropoxy)octane. Rf0.28 (10% EA/Hex); 1H NMR (CDCl3) 5 3.50-3.31 (m, 10H), 1.88-
1.77 (m, 4H), 1.56-1.38 (m, 10H), 1.17 (t, 3H, J=6.9 Hz).
1—Azido—8—(3-ethoxypropoxy)octane 1—Bromo—8—(3—ethoxypropoxy)octane (4.15 g, 14.1 mmol)
was taken up in 50 mL of DMF, and sodium azide (1.09 g, 16.8 mmol) and catalytic sodium
iodide were added. After 88 hr, the e was partitioned between EA (150 mL) and H20 (50
mL), and the organic phase was washed with brine (50 mL), dried over NaZSO4, and
concentrated. FC (5% EA/Hex) gave 2.55 g of colorless liquid. Rf 0.37 (10% EA/Hex); 1H NMR
(CDClg) 5 3.50—3.42 (m, 6H), 3.38 (t, 2H, J=6.7 Hz), 3.24 (t, 2H, J=6.9 Hz), 1.82 (m, 2H), 1.64-
1.49 (m, 4H), 1.31 (br m, 8H), 1.18 (t, 3H, J=6.9 Hz).
8—(3—Ethoxypropoxy)octan—1—amine 1—Azido-8—(3—ethoxypropoxy)octane (2.55 g, 9.84 mmol)
was taken up in 100 mL of EA. The mixture was placed under an atmosphere of argon, 10%
Pd/C (200 mg) was added, and the argon was replaced by hydrogen. When the starting material
was consumed, as observed by TLC, the hydrogen was ed by argon, and the mixture was
filtered through Celite, washing with EA. The filtrate was concentrated to give 1.0 g of yellow
oil. 1H NMR (CDC13) 5 3.6-3.3 (m, 8H), 2.6 (m, 1H), 2.4 (m, 1H), 1.8 (m, 2H), 1 (m, 15H).
N—[8—(3—Ethoxypropoxy)octyl]quinolin—4—amine A mixture of 8—(3—ethoxypropoxy)octan—1—
amine (1.0 g, 4.4 mmol), 4—chloroquinoline (1.46 g, 9.0 mmol), TEA (4.0 mL, 28 mmol), and 0.2
mL of NMP was sealed in a heavy walled glass tube and mixed at 130 0C for 4 days. The mixture
was cooled and partitioned between EA and 5% NaZCO3 and brine, dried over NaZSO4, ?ltered,
and concentrated. Purification by EC (60% EA/Hex + 2% TEA) gave 147 mg of amber oil. 1H
NMR(CDC13) 5 8.4 (d, 1H), 8.1-7.9 (m, 2H), 7.6 (m, 1H), 7.4 (m, 1H), 6.4 (d, 1H), 6.2 (br s, 1H,
NH), 3.6—3.3 (m, 10H), 7 (m, 6H), 2 (m, 8H), 1.2 (m, 3H).
Example 17: 2-Propoxyethoxy)octyl]quinolinamine
HN/W\/\/O\/\O/\/
: :kT/ N
N—[8-(2-Propoxyethoxy)octyl]quinolinamine (550 mg) was made using ethylene glycol
monopropyl ether (2.00 mL, 17.5 mmol), 1,8—dibromooctane (25.7 mL, 139 mmol), and 4—
chloroquinoline (1.42 g) using the method for the preparation of N—[8—(3—
ethoxypropoxy)octyl]quinolin—4—amine.
1—Bromo—8-(2—propoxyethoxy)octane: Rf 0.29 (10% EA/Hex); 3.55 (br s, 4H, Asz), 3.46—3.34
(m, 6H), 1.81 (m, 2H), 1.65-1.52 (m, 4H), 1.42—1.30 (m, 8H), 0.88 (t, 3H, J=7.4 Hz).
1—Azido—8-(2—propoxyethoxy)octane: Rf 0.37 (10% EA/Hex); 3.55 (br s, 4H, AZBZ), 3.43 (t, 2H,
J=6.7 Hz), 3.40 (t, 2H, J=6.8 HZ), 3.22 (m, 2H, J=6.9 Hz), 1.65—1.52 (m, 6H), 1.29—1.20 (m, 8H),
0.88 (t, 3H, J=7.4 Hz).
N—[8—(2—Propoxyethoxy)octyl]quinolin—4—amine: 1H NMR (CDCl3) 5 8.3 (m, 2H), 8.1 (d, 1H),
7.6 (m, 1H), 7.4 (m, 2H), 6.4 (d, 1H), 3.55 (br s, 4H, Ang), 3.45-3.35 (m, 6H), 1.8 (m, 2H), 1.6—
1.2 (m, 12H), 0.9 (t, 3H).
Example 18: N—[8—(Benzyloxy)octyl]quinolin—4—amine
HN/VWVOQ
CK?/N
8—(Benzyloxy)octan—l—amine (880 mg) was prepared from 8—(benzyloxy)octan—1—ol (4.23 g)
following the method used in the preparation of 10—(hexyloxy)decan—1—amine.
A mixture of zyloxy)octanamine (235 mg, 1.00 mmol), 4-chloroquinoline (201 mg,
1.23 mmol), DIEA (0.50 mL, 2.87 mmol), and 2 mL of IPA was heated in a heavy walled glass
tube at 150 0C for 4 days. The mixture was cooled and partitioned between DCM and 5%
N32CO3, and the organic phase was dried over N32SO4, and concentrated. SPE, washing with 3%
MeOH/DCM and g with 8% MeOH/DCM, gave 150 mg of the product as a yellow oil. Rf
0.13 (5% MeOH/DCM); 1H NMR (CDClg) 8 8.49 (d, 1H, J=5.4 Hz), 7.97 (d, 1H, J=8.4 Hz),
7.86 (d, 1H, J=8.4 Hz), 7.58 (ddd, 1H, J=1.2, 7.0, 8.5 Hz), .21 (m, 6H), 6.38 (d, 1H, J=5.4
Hz), 5.68 (m, 1H), 4.48 (s, 2H), 3.44 (t, 2H, J=6 Hz), 3.27 (m, 2H), 1.75-1.52 (m, 4H), 1.37—1.32
(m, 8H).
Example 19: N—(6—Phenoxyhexyl)quinolin—4—amine
(I5HN/W\/O\©/
N
N—(6—Phenoxyhexyl)quinolin—4—amine (188 mg) was prepared starting from 1,6—dibromohexane
(4.25 mL) and phenol (326 mg) ing the method used for the preparation of N—(8—
phenoxyoctyl)quinolin—4—amine.
(6—Bromohexyloxy)benzene (409 mg): Rf 0.46 (5% EA/Hex); 1H NMR (CDClg) 5 7.3 (m, 2H),
6.9 (m, 3H), 4.0 (m, 2H), 3.4 (m, 2H), 2.0-1.7 (m, 4H), 1.6-1.4 (m, 4H).
(6—Azidohexyloxy)benzene (344 mg): 1H NMR (CDC13) 8 7.3 (m, 2H), 6.9 (m, 3H), 4.0 (m, 2H),
3.28 (t, 2H, J=6.8 Hz), 1.8 (m, 2H), 1.7-1.4 (m, 6H).
6—Phenoxyhexan—l—amine (224 mg): 1H NMR (CDCl3) 5 7.3 (m, 2H), 6.9 (m, 3H), 3.91 (t, 2H,
J=6.4 Hz), 2.6 (m, 2H), 1.8-1.3 (m, 8H).
henoxyhexyl)quinolin—4—amine: Rf 0.15 (50% EA/Hex + 2% TEA); 1H NMR ) 5
8.53 (d, 1H, J=5.2 Hz), 7.97 (m, 1H), 7.75 (m, 1H), 7.60 (ddd, 1H, J=1.2, 6.9, 8.2 Hz), 7.38 (ddd,
1H, J=1.2, 6.9, 8.1 Hz), 7.30—7.22 (m, 2H), 6.95—6.86 (m, 3H), 6.39 (d, 1H, J=5.5 Hz), 5.22 (t,
1H, J=4.7 Hz), 3.94 (t, 2H, J=6 Hz), 3.29 (m, 2H), 1.81-1.44 (m, 8H).
Example 20: N-(8-Phenoxyoctyl)quinolinamine
HNWOQ : \J\T/ N
(8—Bromooctyloxy)benzene A mixture of phenol (321 mg, 3.41 mmol), 1,8—dibromooctane
(5.00 mL, 27.0 mmol), and K2C03 (1.41 g, 10.2 mmol) in 6 mL of DMF and 6 mL of 1,2—
oxyethane was heated at 90 °C for 24 hr. The mixture was cooled and partitioned between
ether (3x175 mL) and 0.1N NaOH (75 mL) and 1:1 0.1M HCl/brine (75 mL). The organic
phases were dried over MgSO4 and concentrated. Purification by PC (5% EA/Hex) gave 533 mg
of (8—bromooctyloxy)benzene as a colorless oil. Rf0.50 (5% EA/Hex); 1H NMR (CDClg) 8 7.31—
7.24 (m, 2H), 6.95—6.88 (m, 3H), 3.95 (t, 2H, J=6.5 Hz), 3.41 (t, 2H, J=6.8 Hz), 1.91-1.73 (m,
4H), 1.47—1.27 (m, 8H).
(8—Azidooctyloxy)benzene (460 mg of a colorless oil) and then oxyoctan—l—amine (339
mg of a colorless solid) were ed following the method for lO—butoxydecan—l—amine using
533 mg of (8—bromooctyloxy)benzene and 170 mg of sodium azide.
(8—Azidooctyloxy)benzene: 1H NMR (CDCl3) 8 .25 (m, 2H), 6.97—6.88 (m, 3H), 3.96 (m,
2H), 3.26 (t, 2H, J=7.0 Hz), 1.80 (m, 2H), 1.60 (m, 2H), 1.50—1.38 (m, 8H).
8—Phenoxyoctan—l—amine: 1H NMR (CDCl3) 5 7.26—7.20 (m, 2H), 6.91—6.84 (m, 3H), 3.90 (t, 2H,
J=6.4 Hz), 2.63 (m, 2H), 1.74 (m, 2H), 1.5-1.2 (m, 10H).
N—(8—Phenoxyoctyl)quinolin—4—amineA mixture of 8—phenoxyoctan—1—amine (339 mg, 1.53
mmol), 4—chloroquinoline (328 mg, 2.01 mmol) and TEA (0.50 mL, 3.56 mmol) in 1 mL of
NMP was heated at 160 °C for 24 hr. The mixture was cooled and partitioned between EA and
% N32C03. The organic phases were washed with brine, dried over NaZSO4, and concentrated.
Purification by EC (50% EA/Hex + 2% TEA) gave 431 mg of N-(8-phenoxyoctyl)quinolin
amine. Rf0.18 (50% EA/Hex + 2% TEA); 1H NMR (CDC13) 5 8.53 (d, 1H, J=5.4 Hz), 7.97 (dd,
1H, J=1.0, 8.4 Hz), 7.74 (m, 1H), 7.60 (ddd, 1H, J=1.5, 6.9, 8.4 Hz), 7.39 (ddd, 1H, J=1.5, 6.9,
8.4 Hz), 7.30-7.22 (m, 2H), 6.95-6.86 (m, 3H), 6.39 (d, 1H, J=5.4 Hz), 5.17 (br s, 1H, NH), 3.93
(t, 2H, J=6.5 Hz), 3.27 (m, 2H), 1.82—1.68 (m, 4H), 1.47-1.40 (m, 8H).
Example 21: N—{2—[2—(Hexyloxy)phenoxy]ethyl}quinolin—4—amine
€35/
Hexyloxy)phenoxy]ethanol A mixture of yloxy)phenol (9.10 g, 46.9 mmol),
ethylene carbonate (6.4 g, 72.7 mmol), and K2CO3 (10.0 g, 72.5 mmol) in 50 mL of DMF was
heated at 70—75 0C for 17 hr and then 90 °C for 6 hr. The mixture was cooled, partly neutralized
with 1M HCl, and partitioned between EA and 1M HCl, H20 (2x), and brine. The organic phases
were dried over Mg804, filtered through a pad of silica gel, and concentrated to a brown oil.
SPE, washing with 10% EA/HeX and then eluting with 37% EA/HeX, gave 10.73 g of pale
yellow . Rf0.15 (20% EA/HeX); 1H NMR (CDC13) 5 6.99-6.94 (m, 2H), 6.92—6.87 (m, 2H),
4.12 (m, 2H), 4.00 (t, 2H), 3.88 (m, 2H), 2.80 (s, 1H, OH), 1.82 (m, 2H), 1.46 (m, 2H), 1.38—1.31
(m, 4H), 0.90 (m, 3H); 13C NMR(CDC13)5150.2, 148.6, 122.8, 121.3, 117.2, 113.9, 72.5, 69.3,
61.5, 31.8, 29.4, 25.9, 22.8, 14.2.
2—[2—(Hexyloxy)phenoxy]ethyl methanesulfonate The crude 2—[2—(hexyloxy)phenoxy]ethanol
(10.73 g, 45.1 mmol) was taken up in 170 mL of 1,2—dimethoxyethane and cooled by an ice bath.
Methanesulfonyl chloride (4.90 mL, 62.6 mmol) and then TEA (9.40 mL 67.0 mmol) were
added. After 2 hr, 5 mL of H20 were added, and the volatile components were evaporated. The
residue was partitioned between EA and H20, saturated , H20, 1M HCl, H20 (2x), and
brine. The organic phases were dried over MgSO4 and concentrated to give 13.67 g of colorless
solid. Rf0.37 (30% EA/Hex); 1H NMR (CDClg) 8 6.99—6.86 (m, 4H), 4.60 (m, 2H), 4.25 (m,
2H), 3.98 (m, 2H), 3.16 (s, 3H), 1.78 (m, 2H), 1.46 (m, 2H), 1.38-1.30 (m, 4H), 0.90 (m, 3H);
13c NMR(CDC13)8149.7, 147.9. 122.8, 121.1, 115.5, 113.7, 69.1, 69.0, 67.6, 38.1, 31.8, 29.5,
25.9, 22.8, 14.2.
-[2-(Hexyloxy)ethy1]phthalimide A mixture of 2-[2-(hexyloxy)phenoxy]ethyl
methanesulfonate (13.67 g, 43.2 mmol), potassium phthalimide (15.5 g, 84 mmol), and sodium
iodide (610 mg) in 50 mL of DMF was heated at 90 0C for 24 hr. The cooled e was
partitioned between EA and 5% Na2C03 and brine. The organic phases were dried over Na2S04
and concentrated, and the residue was filtered through a pad of silica gel in 30% EA/Hex and
ated to give a solid. Recrystallization from EtOH gave 10.4 g of colorless solid. 1H NMR
(CDC13) 5 7.85 and 7.72 (m, 4H, AA’BB’), .82 (m, 4H), 4.26 and 4.12 (m, 4H, Asz),
3.88 (t, 2H), 1.71 (m, 2H), 1.42-1.27 (m, 6H), 0.90 (m, 3H); 13C NMR(CDC13) 5 168.3, 149.8,
148.6, 134.1, 132.4, 123.5, 122.3, 121.1, 115.6, 114.3, 69.3, 66.4, 37.7, 31.8, 29.4, 25.8, 22.8,
14.2.
2—[2—(Hexyloxy)phenoxy]ethanamineN—[2—(Hexyloxy)ethyl]phthalimide (10.4 g, 28.3 mmol) was
taken up in 130 mL of EtOH, and hydrazine monohydrate (2.0 mL, 41 mmol) was added. The
WO 20995
mixture was heated at re?ux for 16 hr. After heating was halted, 140 mL of 1M HCl was added
to the still—warm mixture, and the mixture was stirred vigorously during cooling. The itate
was ?ltered and washed with EtOH. The filtrate was concentrated. SPE, washing with 7%
MeOH/DCM and then 7% MeOH/DCM + 2% TEA gave fractions containing 6.80 g of oily—
solid ninhydrin (+) product. Rf 0.40 (5% MeOH/DCM + 2% TEA); 1H NMR (CDC13) 5 6.94—
6.82 (m, 4H), 4.00 (t, 2H, J=5.2 Hz), 3.97 (t, 2H, J=6.7 Hz), 3.05 (t, 2H, J=5.2 Hz), 1.80 (m, 2H),
1.54 (br s, 2H, N?z), 1.50—1.28 (m, 6H), 0.89 (m, 3H).
N- { 2—[2—(Hexyloxy)phenoxy] ethyl }quinolin—4—amine Crude 2— [2—
(hexyloxy)phenoxy]ethanamine (6.8 g, 28.7 mmol) was taken up in 30 mL of DMA, and 25 mL
was evaporated in vacuo. The residue was diluted with 5 mL of NMP, and 4—chloroquinoline
(4.20 g, 25.8 mmol) and DIEA (10.0 mL, mmol) were added. The mixture was heated in a sealed
tube at 160 0C for 24 hr. Then, the mixture was cooled, partitioned n EA and 5% N32C03
(3x) and brine. The organic phase was dried over NaZSO4 and trated to give a solid.
Trituration with Eth and drying gave 3.11 g of colorless solid. Rf 0.31 (10% CM); mp
1045-1060 0C; 1H NMR (CDC13) 8 8.55 (d, 1H, J=5.5 Hz), 8.04 (m, 1H), 7.85 (d, 1H, J=8.4
Hz), 7.66 (ddd, 1H, J=1.4, 6.9, 8.4 Hz), 7.44 (m, 1H), .97 (m, 2H), 6.95-6.89 (m, 2H), 6.50
(d, 1H, J=5.5 Hz), 6.00 (br s, 1H, NH), 4.37 (t, 2H, J=5.1 Hz), 4.02 (t, 2H, J=6.9 Hz), 3.71 (m,
2H), 1.79 (m, 2H), 1.40 (m, 2H), 1.28—1.20 (m, 4H), 0.83 (m, 3H).
Example 22: N—{ 3—[2—(Hexyloxy)phenoxy]propyl }quinolin—4—amine
HNMO/qj
C3) OM
2—(Hexyloxy)phenol A mixture of catechol (28.9 g, 263 mmol), K2C03 (37 g, 268 mmol), and
1—bromohexane (29.0 mL, 207 mmol) in 130 mL of DMA reacted at room temperature for 20 hr
with the aid of mechanical stirring. TLC of an aliquot showed the presence of a substantial
amount of catechol. The mixture was heated at 80 0C, and TLC of an aliquot showed good
reaction progress. l—Bromohexane (5.9 mL, 42 mmol) and K2C03 (6 g, 43 mmol) were added,
and heating ued for 10 hr. Then, the mixture was cooled, and most of the volatile
components were evaporated. The residue was partitioned between EA (3x250 mL) and H20,
%Na2C03 (2x), H20, 0.1M HCl, and brine (200 mL each). The combined organic phases were
dried over MgSO4 and concentrated. SPE (5% EA/Hex) gave 34.8 g of a 4:1 mixture of 2—
(hexyloxy)phenol and l,2—bis(hexyloxy)benzene as determined by 1H NMR. A sample was
purified by SPE, washing with Hex to obtain the diether, and then eluting yloxy)phenol
using 5% EA/Hex. Rf0.38 (5% EA/Hex); 1H NMR ) 8 7.0-6.8 (m, 4H), 5.7 (s, 1H), 4.0
(t, 2H), 1.9 (m, 2H), 1.5 (m, 2H), 1.4-1.3 (m, 4H), 1.9 (t, 3H).
N—{3—[2—(Hexyloxy)phenoxy]propyl}phthalimide A e of 2—(hexyloxy)phenol that
contained 1,2—bis(hexyloxy)benzene (90 mol % pure, 61.8 g), K2CO3 (43.6 g, 316 mmol), and N—
(3-bromopropyl)phthalimide (76.9 g, 287 mmol) in 150 mL of DMF was heated at 60 0C for 24
hr with the aid of ical stirring. TLC (5% BA, 45% toluene, 50% Hex) of an aliquot
showed that substantial bromide starting material ed, so the temperature was raised to 100
0C. After 16 hr, the reaction was completed, as shown by TLC. Then, the mixture was cooled,
and most of the volatile components were evaporated. The residue was partitioned between EA
(3x250 mL) and H20 neutralized using H3PO4, 0.1M HCl, H20, and brine (200 mL each). The
combined organic phases were dried over MgSO4 and concentrated to give 83 g of the product as
a light tan solid that contained 2—(hexyloxy)phenol and 1,2-bis(hexyloxy)benzene, as shown by
1H NMR. Rf 0.21 (19:10 uene/Hex) 0.19 (10% EA/Hex); 1H NMR (CDC13) 8 7.82 and
7.71 (m, 4H, AA’BB’), 6.93—6.82 (m, 4H), 4.06 (t, 2H), 3.96-3.88 (m, 4H), 2.19 (m, 2H), 1.76
(m, 2H), 1.46-1.24 (m, 6H), 0.87 (m, 3H).
3—[2—(Hexyloxy)phenoxy]propan—l—amine Crude N—{ 3—[2—
(hexyloxy)phenoxy]propyl}phthalimide was dissolved in 450 mL of warm IPA, and hydrazine
monohydrate (24.8 mL, 327 mmol) was added. The mixture was heated at 80 0C for 12 hr with
the aid of mechanical stirring, and then the mixture was allowed to stand at room temperature for
48 hr. The solid was broken up, diluted with 400 mL of EtZO, and stirred for 1 hr. The precipitate
was filtered and washed with 50% tzO (2x200 mL). The ed filtrates were
concentrated to give 73 g of amber liquid. The liquid was taken up in 400 mL of DCM and
washed with 1N NaOH and H20 (100 mL each). The organic phase was concentrated. The
e was separated by SPE. Elution with 1% MeOH/DCM gave 20 g of a mixture of 2—
(hexyloxy)phenol and 1,2—bis(hexyloxy)benzene. Then, elution with 7% MeOH/DCM + 2%
NH4OH gave the product. The partially concentrated fractions were washed with 200 mL of
H20, the water phase was extracted with 150 mL of DCM, and the combined organic phases
were dried over NaZSO4, filtered, and concentrated to give 33.6 g of an amber liquid. Rf 0.06
(5% CM, ninhydrin (+)); 1H NMR (CDC13) 5 6.91-6.87 (m, 4H), 4.09 (t, 2H), 3.98 (t,
2H, J=6.6 Hz), 2.93 (t, 2H), 1.95 (q, 2H), 1.80 (m, 2H), 1.50—1.31 (m, 6H), 0.90 (m, 3H); l3C
NMR(CDC13)8121.5, 121.2, 114.4, 114.1, 69.3, 67.9, 40.0, 33.4, 31.8, 29.5, 25.9, 22.8, 14.2.
N— { Hexyloxy)phenoxy]propyl}quinolin—4—amine 3—[2—(Hexyloxy)phenoxy]propan— 1—
amine (28.4 g, 113 mmol) was taken up in 230 mL of 1—pentanol, and 70 mL of le material
was removed by distillation in order to ensure anhydrous conditions. The mixture was allowed to
cool below re?ux temperature, and pylamine (43 mL, 226 mmol) and 4-chloroquinoline
(23.9 g, 147 mmol) were added. Heating at re?ux was resumed. After 15 hr, TLC of an aliquot
indicated no ninhydrin (+) starting al remained. After ng at room temperature for 48
hr, 120 mL of volatile material was removed by distillation. The cooled mixture was diluted with
350 mL of DCM and washed with 2N NaOH, H20, and 5% Na2C03 (100 mL each). The
aqueous phases were extracted in turn with 350 mL of DCM. The combined organic phases were
dried over Na2804, filtered, and concentrated. Purification by PC, eluting with a step gradient of
40, 50, and 60% EA/Hex + 2% TEA, gave pure product fractions, as shown by TLC and NMR.
The product e was trated, taken up in EA, washed with 5% N32C03 and brine,
dried over NaZSO4, filtered, and concentrated to give a yellow oil. Standing under Et20 and
cooling using an ice bath gave a colorless precipitate. The precipitate was collected by filtration
and washed with ice—cold EtZO to give 33.9 g of the product after drying in vacuo. mp 61.0—62.0
0C; 1H NMR (CDC13) 5 8.55 (d, 1H, J=5.1 Hz), 7.95 (dd, 1H, J=0.8, 8.5 Hz), 7.84 (dd, 1H, 121.1,
8.4 Hz), 7.60 (m, 1H), 7.35 (m, 1H), 6.98—6.87 (m, 4H), 6.44 (d, 1H, J=5.5 Hz), 5.98 (t, 1H,
J=4.4 Hz, NH), 4.21 (t, 1H, J=5.5 Hz), 4.02 (t, 2H), 3.58 (m, 2H), 2.27 (m, 2H), 1.75 (m, 2H),
1.40 (m, 2H), 1.27—1.21 (m, 4H), 0.84 (m, 3H); 13C NMR (CDC13) 8 151.2, 150.1, 149.6, 148.7,
148.6, 130.0, 129.0, 124.5, 122.3, 121.1, 120.2, 119.2, 115.2, 113.8, 98.7, 69.2, 69.2, 42.1, 31.6,
29.3, 28.5, 25.8, 22.7, 14.1.
Example 23: N— { 4— [2— (Hexyloxy)phenoxy]butyl lin—4—amine
C3?/N
N—(4—Bromobutyl)phthalimide A mixture of 1,4—dibromobutane (22 mL, 185 mmol) and
potassium phthalimide (11.35 g, 61.4 mmol) in 60 mL of DMF was mixed at room temperature
for 1 day. Then, the reaction mixture was extracted with hexane (3x150 mL). The hexane
fractions were dried over MgSO4, filtered, and concentrated to give 30 g of a 1:22 molar mixture
of recovered 1,4—dibromobutane and DMF. This mixture was d with 30 mL of DMF and
ted with potassium phthalimide (4.80 g, 26 mmol) at room temperature for 1 day. The two
reaction mixtures in DMF were partitioned between 1:1 EA/Hex (3x150 mL) and H20 (2x100
mL), 0.1M HCl (100 mL), and brine (100 mL).The organic phases were dried over MgSO4 and
concentrated. SPE, eluting with 0% and 10% EA/Hex, gave 17.3 g of colorless solid. Rf 0.55
(40% EA/Hex); 1H NMR (CDClg) 8 7.86-7.81 (m, 2H), 7.73-7.69 (m, 2H), 3.71 (t, 2H), 3.43 (t,
2H), .80 (m, 4H); 13C NMR (CDC13) 8 168.5, 134.2, 132.3, 123.5, 37.2, 32.9, 30.1, 27.4.
N—{4—[2—(Hexyloxy)phenoxy]butyl}phthalimide A mixture of N—(4—bromobutyl)phthalimide
(17.3 g, 61.3 mmol), 2—(hexyloxy)phenol (14.9 g, 61 mmol), and K2C03 (9.5 g, 69 mmol) in 80
mL of DMF was heated at 80 0C for 20 hr. Then, the mixture was cooled, partitioned between
40% EA/Hex (3x300 mL) and 0.25M HCl (340 mL), H20, 0.1M HCl, and brine (150 mL each),
dried over MgSO4, concentrated, filtered through a pad of silica gel with 40% EA/Hex, and
concentrated to give 25.7 g of pale yellow solid.
4—[2—(Hexyloxy)phenoxy]butan— l—amine Crude N— { 4— [2—
(hexyloxy)phenoxy]butyl}phthalimide was taken up in 400 mL of IPA, and ine
drate (4.40 mL, 91 mmol) was added. The mixture was heated at 80 0C for 12 hr. Then,
the mixture was cooled, resulting in precipitation. Eth (400 mL) was added, and the
heterogeneous mixture was stirred vigorously. The precipitate was removed by filtration h
Celite, and the precipitate was washed with Eth (4x150 mL). The volatile components were
evaporated to leave 14.2 g of colorless solid. 1H NMR ) 5 6.88—6.83 (m, 4H), 3.98 (t, 2H,
J=6.2 Hz), 3.96 (t, 2H, J=6.7 Hz), 2.77 (t, 2H, J=6.9 Hz), 2.17 (br s, 2H), 1.89-1.74 (m, 4H), 1.64
(m, 2H), 1.50-1.23 (m, 6H), 0.89 (m, 3H).
N— { 4—[2—(Hexyloxy)phenoxy]butyl }quinolin—4—amine Crude 4— [2—
(hexyloxy)phenoxy]butan—1—amine (14.2 g, 53.6 mmol) was taken up in 400 mL of 1—pentanol,
and 100 mL was removed by distillation. The mixture was cooled below boiling, and
tripropylamine (15 mL, 78.7 mmol) and 4-chloroquinoline (8.75 g, 53.7 mmol) were added.
Heating at re?ux was resumed for 18 hr. Then, the e was concentrated by distillation.
SPE, washing with 50% EA/Hex and then eluting with 10% MeOH/DCM gave a brown oil after
concentration. The oil was taken up in DCM and washed with 5% Na2C03, dried over ,
and concentrated. Purification by PC (60% EA/Hex + 2% TEA), evaporation of solvents from
the product fractions, and then ation of MeOH and drying gave 3.7 g of the product as a
ess solid. 1H NMR(CDC13) 8 8.53 (d, 1H, J=5.5 Hz), 7.95 (dd, 1H, J=0.7, 8.4 Hz), 7.74
(m, 1H), 7.59 (ddd, 1H, J=1.1, 7.0, 8.1 Hz), 7.33 (m, 1H), 6.97-6.88 (m, 4H), 6.43 (d, 1H, J=5.2
Hz), 5.63 (t, 1H, NH), 4.11 (t, 1H), 4.00 (t, 2H), 3.49 (m, 2H), 2.01—1.94 (m, 4H), 1.74 (m, 2H),
1.39 (m, 2H), 1.23—1.16 (m, 4H), 0.80 (m, 3H); 13C NMR(CDC13)5151.3, 150.0, 149.5, 148.8,
148.8, 130.1, 129.1, 124.6, 121.8, 121.1, 119.8, 119.1, 114.4, 113.7, 98.8, 69.2, 69.2, 42.8, 31.7,
29.4, 26.8, 25.9, 25.8, 22.8, 14.1.
Example 24: N—[3—(2—Ethoxyphenoxy)propyl]quinolin—4—amine
\ O\/
N—[3—(2—Ethoxyphenoxy)propyl]quinolin—4—amine (217 mg) was prepared ing the method
for the preparation of N—{3—[4—(hexyloxy)phenoxy]propyl}quinolin—4—amine, starting with 2—
ethoxyphenol (1.5 g) and N—(3—bromopropyl)phthalimide (2.91 g).
N—[3—(2—Ethoxyphenoxy)propyl]phthalimide (2.57 g): 1H NMR (CDC13) 5 7.85 and 7.75 (m, 4H,
AA’BB’), 6.95-6.80 (m, 4H), 4.1-4.0 (m, 4H), 3.9 (t, 2H), 2.2 (m, 2H), 1.4 (t, 3H).
3—(2—Ethoxyphenoxy)propan—l—amine (0.76 g): 1H NMR (CDC13) 5 6.9 (m, 4H), 4.1—4.0 (m, 4H),
2.95 (t, 2H), 1.95 (m, 2H), 1.5 (br s, 2H, NH;), 1.4 (t, 3H).
N—[3—(2—Ethoxyphenoxy)propyl]quinolin—4-amine: 1H NMR (CDC13) 5 8.8 (br s, 1H, NH), 8.5
(m, 1H), 8.4 (m, 1H), 8.2 (d, 1H), 7.7 (m, 1H), 7.5 (m, 1H), 7.0-6.8 (m, 4H), 6.6 (d, 1H), 4.2
(m,2H), 4.1 , 3.8 (q, 2H), 2.4 (m,2H), 1.4 (t, 3H).
Example 25: N-[3-(2-Methoxyphenoxy)propyl]quinolinamine
3—(2—Methoxyphenoxy)propan—1—amine was prepared ing the method for the preparation of
3—[4—(Hexyloxy)phenoxy]propan—1—amine, starting with 2—methoxyphenol (1.5 g) and N—(3—
bromopropyl)phthalimide (3.2 g).
N—[3—(2—Methoxyphenoxy)propyl]phthalimide (3.19 g): 1H NMR (CDC13) 5 7.8 and 7.7 (m, 4H,
AA’BB’), 6.9-6.8 (m, 4H), 4.1 (t, 2H), 3.9 (t, 2H), 3.7 (s, 3H), 2.2 (m, 2H).
3—(2—Methoxyphenoxy)propan—l—amine (770 mg): 1H NMR ) 5 6.9—6.8 (m, 4H), 4.1 (t,
2H), 3.8 (s, 3H), 2.9 (t, 2H), 2.0 (m, 2H), 1.5 (br s, 2H, N?z).
N—[3—(2—Methoxyphenoxy)propyl]quinolin—4—amine A mixture of 3—(2—
methoxyphenoxy)propan—l—amine (770 mg, 3.95 mmol), 4—chloroquinoline (777 mg, 4.77
mmol), 0.15 mL of NMP and 2 mL of TEA were heated at 130 0C in a sealed tube for 5 days.
Then, the mixture was cooled and concentrated in vacuo. Purification by preparative TLC (5%
MeOH/DCM) gave the product. 1H NMR (CDC13) 5 8.4 (d, 1H), 8.2 (d, 1H), 8.1 (d, 1H), 7.7 (m,
1H), 7.4 (m, 1H), 7.1 (br s, 1H, NH), 7.0-6.9 (m, 4H), 6.5 (d, 1H), 4.3 (t, 2H), 3.9 (s, 3H), 3.7 (m,
2H), 2.3 (m, 2H).
e 26: N—{ 3—[2—(Benyloxy)phenoxy]propyl }quinolin—4—amine
.NMOQ
$6 093
N—{3-[2-(Benyloxy)phenoxy]propyl}quinolinamine was prepared following the method for
the preparation of N—{3-[4-(hexyloxy)phenoxy]propyl}quinolinamine, starting with 2-
(benzyloxy)phenol (2.0 g) and N—(3-bromopropyl)phthalimide (2.68 g).
2-(Benzyloxy)phenoxy]propyl}phthalimide (3.6 g): 1H NMR (CDC13) 5 7.8 and 7.7 (m,
4H, AA’BB’), 7.5-7.3 (m, 4H), 7.0-6.8 (m, 5H), 5.1 (s, 2H), 4.1 (t, 2H), 3.9 (t, 2H), 2.2 (m, 2H).
3—[2—(Benzyloxy)phenoxy]propan—1—amine (1.92 g): 1H NMR ) 5 7.5—7.3 (m, 5H), 6.9—6.8
(m, 4H), 5.1 (s, 2H), 4.1 (t, 2H), 2.9 (t, 2H), 2.0 (m, 2H).
N—{3—[2—(Benyloxy)phenoxy]propyl}quinolin—4—amine: 1H NMR (CDC13) 5 8.5 (d, 1H), 7.9 (d,
1H), 7.8 (d, 1H), 7.5 (m, 1H), 7.4-7.2 (m, 6H), 7.0—6.9 (m, 4H), 6.4 (d, 1H), 6.0 (br s, 1H, NH),
.1 (s, 2H), 4.2 (t, 2H), 3.6 (m, 2H), 2.3 (m, 2H).
Example 27: N—[8—(3—Methoxyphenoxy)octyl]quinolin—4—amine
(>5/
1—(8—Bromooctyloxy)—3—methoxybenzene (1.28 g) was prepared by the same method used for 1—
(8—bromooctyloxy)—3—methylbenzene using 3—methoxyphenol (638 mg, 5.14 mmol), 1,8—
dibromooctane (14.3 g, 53 mmol), and K2C03 (852 mg, 6.17 mmol) in 14 mL of NMP and 7 mL
of DME heated for 24 hr. 1H NMR (CDC13) 5 7.2 (m, 1H), 6.46 (m, 3H), 3.9 (t, 2H), 3.4 (t, 2H,
J=6.9 Hz), 1.9—1.7 (m, 4H), 2 (m, 8H).
1-(8—Iodooctyloxy)—3—methoxybenzene (1.47 g) was prepared from 1—(8—bromooctyloxy)—3—
methoxybenzene (1.28 g, 6.78 mmol) and sodium iodide (601 mg) in 50 mL of acetone
following the method used in the preparation of 10—(hexyloxy)decan—1—amine.
N—[8-(3-Methoxyphenoxy)octyl]phthalimide (1.0 g) was prepared from 1-(8-iodooctyloxy)
methoxybenzene (1.47 g, 4.06 mmol) and potassium phthalimide (1.13 g) in 50 mL of DMF at
60-80 0C for 12 hr ing the method for N—[8-(hexyloxy)octyl]phthalimide. 1H NMR
(CDC13) 8 7.85 (m, 2H), 7.7 (m, 2H), 7.2 (m, 1H), 6.7-6.5 (m, 3H), 3.9 (m, 2H), 3.8 (s, 3H), 3.65
(m, 2H), 1.8-1.6 (m, 4H), 1.5—1.3 (m, 8H).
8—(3—Methoxyphenoxy)octan—1—amine (438 mg, 1.74 mmol) was prepared from 3—
methoxyphenoxy)octyl]phthalimide (1.0 g, 2.6 mmol) using hydrazine monohydrate (0.20 mL)
in EtOH (50 mL) following the method for [3—(hexyloxy)phenyl]methanamine. 1H NMR
(CDgOD) 5 7.1 (m, 1H), 4 (m, 3H), 3.9 (t, 2H), 3.7 (s, 3H), 2.7 (t, 2H), 1.8 (m, 2H), 1.6—1.4
(m, 10H).
N—[8—(3—Methoxyphenoxy)octyl]quinolin—4—amine (200 mg) was prepared from 8—(3—
methoxyphenoxy)octan—l—amine (438 mg, 1.74 mmol), 4—chloroquinoline (572 mg), TEA (2
mL), and NMP (0.2 mL) following the method for N—[8—(3—ethoxypropoxy)octyl]quinolin—4—
amine. 1H C13)5 8.5 (d, 1H), 8.0 (d, 1H), 7.75 (d, 1H), 7.6 (m, 1H), 7.4 (m, 1H), 7.15
(m, 1H), 6.5—6.4 (m, 4H), 5.1 (br s, 1H, NH), 3.9 (t, 2H), 3.3 (m, 2H), 1.8 (m, 4H), 3 (m,
8H).
Example 28: N—{4—[3—(Hexyloxy)phenoxy]butyl}quinolin—4—amine
HN/\/\/0
co 00\/\/\/
N/
1—(4—Bromobutoxy)—3—(hexyloxy)benzene A mixture of yloxy)phenol (1.21 g, 6.26
mmol), 1,4—dibromobutane (7.00 mL, 59 mmol), and K2C03 (950 mg, 6.88 mmol) in 14 mL of
1:1 NMP/1,2—dimethoxyethane was heated at gentle re?ux for 40 hr. The mixture was cooled and
partitioned between DCM and 1M HCl. The organic phase was dried over MgSO4 and
concentrated in vacuo with warming to remove excess dibromide. The residue was separated by
SPE, washing with Hex and then eluting the product with 5% EA/Hex to give 1-(4-
bromobutoxy)(hexyloxy)benzene (1.42 g). Rf0.40 (5% EA/Hex); 1H NMR (CDClg) 8 7.15
(m, 1H), 6.51-6.43 (m, 3H), 3.99-3.90 (m, 4H), 3.48 (t, 2H, J=6.6 Hz), 2.11 (m, 2H), 1.93 (m,
2H), 1.81 (m, 2H), 1.50—1.29 (m, 6H), 0.92 (m, 3H).
N— { 4—[3—(Hexyloxy)phenoxy]buty1}phtha1imide 1-(4-Bromobutoxy)—3—(hexyloxy)benzene
(1.40 g, 4.26 mmol), potassium phthalimide (1.18 g, 6.38 mmol), and DMF (5 mL) were mixed
at room temperature until the bromide was consumed, as observed by TLC of an aliquot. The
mixture was partitioned n EA and H20 and brine, and the organic phase was dried over
MgSO4 and concentrated. SPE (15% EA/Hex) gave 1.60 g of the product. Rf 0.40 (20%
EA/Hex); 1H NMR (CDC13) 8 7.83 and 7.70 (m, 4H, AA’BB’), 7.12 (m, 1H), 6.48—6.42 (m, 3H),
.88 (m, 4H), 3.76 (t, 2H, J=6.8 Hz), 1.92—1.70 (m, 6H), 1.49-1.25 (m, 6H), 0.89 (m, 3H).
4—[3-(Hexyloxy)phenoxy]butan—1—amine A mixture of the 3—
(hexyloxy)phenoxy]butyl}phthalimide (1.60 g, 4.05 mmol), hydrazine monohydrate (0.30 mL,
6.3 mmol), and 15 mL of EtOH were heated at re?ux for 8 hr. The mixture was cooled and
2014/013992
partitioned between EA and 5% K2C03 and brine, and the organic phases were dried over
NaZSO4 and concentrated. SPE, washing with 5% MeOH/DCM and eluting with 10%
MeOH/DCM + 2% TEA gave 1.05 g of the amine as a colorless solid. 1H NMR (CD30D +
CDC13) 8 7.01 (t, 1H, J=7.8 Hz), 6.37—6.32 (m, 3H), .76 (m, 4H), 2.66 (t, 2H), 1.74—1.50
(m, 6H), 1.34-1.17 (m, 6H), 0.77 (m, 3H).
3—(Hexyloxy)phenoxy]butyl}quinolin-4—amine A mixture of the 4—[3—
(hexyloxy)phenoxy]butan—l—amine (300 mg, 1.20 mmol), 4—chloroquinoline (283 mg, 1.74
mmol), DIEA (0.50 mL, 2.87 mmol), and 1.5 mL of IPA was sealed in a heavy walled glass tube
and mixed at 180 0C for 3 days. The mixture was cooled and partitioned between EA and 5%
Na2C03 and brine, dried over NaZSO4, and concentrated. SPE, washing with 3% MeOH/DCM
and eluting with 10% MeOH/DCM, gave 293 mg of the product as a solid. Rf 0.26 (10%
MeOH/DCM); 1H NMR (CDC13) 8 8.52 (d, 1, J=5.2 Hz), 7.97 (d, 1, J=8.4 Hz), 7.72 (d, 1, J=8.4
Hz), 7.61 (m, 1H), 7.37 (m, 1H), 7.17 (t, 1, J=8 Hz), 6.53-6.47 (m, 3), 6.42 (d, 1, J=5.5 Hz), 5.35
(br s, 1H, NH), 4.03 (m, 2H), 3.91 (m, 2H), 3.40 (m, 2H), 1.96-1.95 (m, 4), 1.75 (m, 2H), 1.46-
1.31 (m, 6), 0.89 (m, 3).
Example 29: N-{ 3-[3-(Hexyloxy)phenoxy]propyl linamine
HNMO
CED dam
3—(Hexyloxy)phenol A mixture of resorcinol (7.1 g), K2C03 (1.13 g), and 1—bromohexane (1.0
mL) in 60 mL of NMP reacted at 50—60 °C for 20 hr with the aid of mechanical stirring. Then,
the e was cooled, and most of the volatile components were evaporated. The residue was
partitioned between EA (3x250 mL) and H20, 5% Na2C03 (2x), H20, 0.1M HCl, and brine (200
mL each). The combined organic phases were dried over MgSO4 and concentrated. SPE (5%
EA/Hex) gave 1.29 g of 3—(hexyloxy)phenol. 1H NMR (CDC13) 5 7.10 (m, 1H), 6.48 (m, 1H),
6.42—6.38 (m, 2H), 3.91 (t, 2H, J=6.7 Hz), 1.75 (m, 2H), 1.48—1.31 (m, 6H), 0.89 (m, 3H).
W0 2014/120995
N—{3—[3—(Hexyloxy)phenoxy]propyl}phthalimide A mixture of yloxy)phenol (9.8 g),
K2C03 (9.8 g), and N—(3—bromopropyl)phthalimide (15.5 g) in 150 mL of 2—butanone was heated
at re?ux for 24 hr with the aid of mechanical ng. Then, the mixture was cooled, and most of
the volatile components were evaporated. The residue was ioned between EA (3x250 mL)
and H20 neutralized using H3PO4, 0.1M HCl, H20, and brine (200 mL each). The combined
organic phases were dried over MgSO4 and concentrated to give 7.58 g of the t. 1H NMR
(CDC13) 5 7.81 and 7.68 (m, 4H, AA’BB’), 7.09 (t, 1H, J=8.2 Hz), 6.45 (ddd, 1H, J=1.0, 2.5, 8.4
Hz), 6.39—6.32 (m, 2H), 3.99 (t, 2H, J=6.0 Hz), 3.91—3.83 (m, 4H), 2.16 (m, 2H), 1.73 (m, 2H),
1.45—1.21 (m, 6H), 0.90 (m, 3H).
3-[3—(Hexyloxy)phenoxy]propan—1—amine Crude N— { 3— [3—(hexyloxy)phenoxy]propyl}
phthalimide (1.20 g) was dissolved in 50 mL of EtOH, and ine monohydrate (0.22 mL)
was added. The mixture was heated at re?ux for 12 hr, and then the mixture was allowed to stand
at room temperature for 48 hr. The solid was broken up, diluted with 50 mL of ether, and stirred
for 1 hr. The precipitate was filtered and washed with 50% MeOH/ether (2x40 mL). The
combined filtrates were concentrated. The liquid was taken up in 100 mL of DCM and washed
with 1N NaOH and H20 (10 mL each). The organic phase was concentrated. SPE, washing with
1% MeOH/DCM and then eluting with 7% MeOH/DCM + 2% NH4OH, gave the product. The
partially concentrated fractions were washed with 20 mL of H20, the water phase was extracted
with 40 mL of DCM, and the combined organic phases were dried over Na2SO4 and concentrated
to give 763 mg of an amber . 1H NMR ) 5 7.13 (m, 1H), 6.49—6.43 (m, 3H), 4.00 (t,
2H, J=6.1 Hz), 3.90 (t, 2H), 2.89 (t, 2H, J=6.7 Hz), 1.96-1.84 (m, 4H), 1.74 (m, 2H), 1.48—1.28
(m, 6H), 0.89 (m, 3H).
N—{3—[3—(Hexyloxy)phenoxy]propyl}quinolin—4—amine A mixture of 3—[3—
oxy)phenoxy]propan—l—amine (763 mg, 3.04 mmol), 4—chloroquinoline (746 mg, 4.58
mmol), DIEA (1.0 mL, 5.74 mmol), and 0.1 mL of DMF was sealed in a heavy walled glass tube
and heated at 130 0C for 4 days. The mixture was cooled. SPE, washing with 50% EA/Hex and
eluting with 10% MeOH/DCM, gave the product contaminated by ninhydrin (+) material. FC
(8% to 9% MeOH/DCM) resulted in partial purification. SPE (60% EA/Hex + 1% TEA) gave
389 mg of product as an oil that solidified upon standing. Rf 0.25 (10% MeOH/DCM); 1H NMR
(CDC13) 8 8.52 (d, 1H, J=5.2 Hz), 7.96 (dd, 1H, J=0.8, 8.4 Hz), 7.77 (dd, 1H, J=1.0, 8.4 Hz),
7.61 (ddd, 1H, J=1.5, 6.9, 8.4 Hz), 7.40 (ddd, 1H, J=1.2, 6.9, 8.4 Hz), 7.17 (m, 1H), 6.53—6.48
(m, 3), 6.42 (d, 1H, J=5.4 Hz), 5.74 (br s, 1H, NH), 4.14 (m, 2H), 3.90 (m, 2H), 3.54 (m, 2H),
2.23 (m, 2H), 1.76 (m, 2H), 1.49-1.24 (m, 6), 0.89 (m, 3).
Example 30: N—{2—[3—(Hexyloxy)phenoxy]ethyl }quinolin—4—amine
@0H\©/N/\/OO\/\/\/
3-(Hexyloxy)phenol (2.5 g), N—(2—bromoethy1)phthalimide (3.27 g), and K2C03 (1.95 g) in
acetone (50 mL) at re?ux and uent treatment with hydrazine monohydrate (3.5 mL) in
EtOH (24 mL) at re?ux gave 226 mg of ninhydrin (+) 2—[3—(hexyloxy)phenoxy]ethan-1—amine.
1H NMR (CDC13) 5 7.10 (m, 1H), 6.55-6.40 (m, 3H), 4.00-3.80 (m, 4H), 3.00 (br s, 2H), 1.90-
1.70 (m, 4H), .30 (m, 6H), 0.90 (m. 3H).
N—{2-[3-(Hexyloxy)phenoxy]ethyl}quinolinamine A mixture of 2-[3-
(hexyloxy)phenoxy]ethan—1—amine (226 mg, 0.95 mmol), 4-chloroquinoline (233 mg, 1.43
mmol), DIEA (1.0 mL, 5 .74 mmol), and 0.15 mL of DMF was sealed in a heavy walled glass
tube and stirred at 140 OC and mixed for 5 days. The cooled mixture was concentrated and
separated by FC (7% MeOH/DCM) to give 150 mg of t as a pink solid. Rf 0.32 (10%
MeOH/DCM); 1H NMR ) 8 8.50 (d, 1H, J=5.5 Hz), 7.99 (d, 1H, J=8.2 Hz), 7.93 (d, 1H,
J=8.1 Hz), 7.62 (m, 1H), 7.42 (m, 1H), 7.16 (m, 1H), 6.54—6.47 (m, 4), 6.21 (br s, 1H, NH), 4.28
(t, 2H, J=5.2 Hz), 3.92 (m, 2H), 3.75 (m, 2H), 1.75 (m, 2H), 1.48—1.24 (m, 6), 0.88 (t, 3, J26?
Hz).
Example 31: N—[8—(4—Methoxyphenoxy)octyl]quinolin—4—amine
HNWOO
1—(8—Bromooctyloxy)—4—methoxybenzene A mixture of 4—methoxyphenol (5.08 g, 41.0 mmol)
and KZCO3 (6.12 g, 44.3 mmol) in 40 mL of DMF was stirred for 1.25 hr. Then, a mixture of
bromooctane (86.0 g, 316 mmol) in 40 mL of DMF was added. The mixture was stirred for
24 hr and then it was allowed to stand for 6 days. The mixture was partitioned between 1:1
EA/Hex and H20 (3x), 0.1M HCl, and brine, and the organic phases were dried over NaZSO4,
filtered, and concentrated. The e in 10% EA/Hex was filtered through a pad of silica gel,
and then most of the solvents were ated. Vacuum distillation was performed to remove
most of the excess dibromide, and the pot residue consisted of almost colorless solid and a small
amount of liquid. The pot was rinsed twice with Hex and the solid was dried in vacuo. Rf 0.42
(10% EA/Hex); 1H NMR (CDC13) 8 6.82 (s, 4H), 3.89 (t, 2H), 3.76 (s, 3H), 3.40 (t, 2H, J=6.8
Hz), .70 (m, 4H), 1.48-1.33 (m, 8H).
N—[8-(4-Methoxyphenoxy)octyl]phthalimide A mixture of crude 1-(8-bromooctyloxy)
methoxybenzene and potassium phthalimide (7.59 g, 41.0 mmol) in 60 mL of NMP was stirred
at room temperature until the bromide was consumed, as shown by TLC analysis of an aliquot.
Then, 30 mL of H20 was added, and much of the volatile material was evaporated in vacuo. The
residue was ioned n 1:1 EA/Hex and H20 and brine. The organic phases were dried
over N32SO4, filtered, and concentrated to give 14.88 g of a colorless solid. Rf 0.11 (10%
EA/Hex).
8—(4—Methoxyphenoxy)octan—l—amine Hydrazine monohydrate (4.00 mL, 84mmol) was
added to a e of N—[8—(4—methoxyphenoxy)octyl]phthalimide (14.8 g, 38.8 mmol) and 125
mL of denatured EtOH using mechanical stirring. The mixture was heated at re?ux for 15 hr,
during which time a colorless precipitate formed. The mixture was concentrated by evaporation,
and the residue was partitioned between pyl acetate (300, 2x125 mL) and 5% N212CO3
(200, 3x100 mL) and brine (100 mL). The combined organic phases were dried over NaZSO4,
filtered, and concentrated to give 8.63 g of white solid after drying in vacuo. 1H NMR (CDC13) 5
6.79 (s, 4H), 4.66 (s, 3H), 3.86 (t, 2H, J=6.4 Hz), 3.72 (s, 3H), 2.72 (t, 2H, J=7.4 Hz), 1.71 (m,
2H), 1.55—1.33 (m, 10H).
N—[8—(4—Methoxyphenoxy)octyl]quinolin—4—amine 8—(4—Methoxyphenoxy)octan—1—amine (4.60
g, 18.3 mmol) was taken up in 100 mL of 1—pentanol, and 30 mL of volatile material was
removed by distillation. The e was cooled below boiling, and tripropylamine (7.00 mL,
36.7 mmol) and 4—chloroquinoline (3.28 g, 20.1 mmol) were added. Heating at re?ux was
resumed. After 26.25 hr, the mixture was cooled, and 20 mL of 1N NaOH was added. Volatile
material was removed by ation. The mixture was diluted with DCM (350 mL) and washed
with 5% N32C03 (50 mL). The aqueous phase was extracted with DCM (100 mL). The
ed organic phases were dried over NaZSO4, filtered, and concentrated. SPE, washing with
50% EA/Hex and then g with 50% EA/Hex + 2% TEA, gave product fractions that were
combined and concentrated. The e was partitioned between DCM and 5% Na2C03. The
combined organic phases were dried over , filtered, and concentrated to afford a yellow
solid. The solid was triturated with ice-cold 20% EtzO/Hex and dried in vacuo. The solid had mp
1410-1440 0C. The solid was dissolved in minimal hot butanone and then the mixture was
allowed to cool to room temperature. After chilling in an ice bath for 2 hr, the precipitate was
collected and washed with ice—cold butanone to give 3.98 g of a tan solid. Rf 0.23 (5%
MeOH/DCM + 2% TEA); mp 455 0C; 1H NMR (CDC13) 5 8.56 (d, 1H, J=5.1 Hz), 7.98
(dd, 1H, J=0.7, 8.5 Hz), 7.72 (m, 1H), 7.62 (m, 1H), 7.42 (m, 1H), 6.85—6.80 (m, 4H, AA’BB’),
6.42 (d, 1H, J=5.5 Hz), 4.97 (br s, 1H, NH), 3.90 (t, 2H, J=6.6 Hz), 3.76 (s, 3H), 3.31 (m, 2H),
1.80—1.73 (m, 4H), 1.48—1.39 (m, 8H); 13C NMR(CDC13)5153.9, 153.5, 151.3, 149.8, 148.7,
130.3, 129.1, 124.8, 119.3, 118.9, 115.6, 114.8, 99.0, 68.8, 56.0, 43.4, 29.6, 29.5, 29.5, 29.2,
27.3, 26.2.
Example 32: N—[6—(4—Methoxyphenoxy)hexyl]quinolin—4—amine
1—(6—Bromohexyloxy)—4—methoxybenzene A mixture of bromohexane (2.4 mL, 15.7
mmol), 4—methoxyphenol (243 mg, 1.96 mmol), and K2CO3 (550 mg, 3.99 mmol) in 4 mL of
DMF and 3 mL of DME was d 16 hr at room temperature, 4 hr at 80 0C, and 64 hr at room
temperature. The mixture was diluted with EA and washed with H20, 5% Na2C03, H20, 0.1M
HCl, and brine. The organic phase was dried over anhydrous NaZSO4, filtered through a pad of
silica gel, and concentrated. SPE, washing with Hex and then eluting with 15% EA/Hex, gave
623 mg of the product as a colorless solid. Rf0.29 (5% ); 1H NMR (CDClg) 8 6.82 (s,
4H, AA’BB’), 3.90 (t, 2H, J=6.3 Hz), 3.76 (s, 3H), 3.41 (m, 2H, AB), 1.88 (m, 2H), 1.76 (m,
2H), 1.56—1.39 (m, 4H).
1-(6-Azidohexyloxy)methoxybenzene A mixture of 1-(6-bromohexyloxy)
methoxybenzene 623 mg, 2.17 mmol) and sodium azide (210 mg, 3.23 mmol) in 5 mL of DMF
was stirred at room temperature for 48 hr. Then, the mixture was diluted with EA and washed
with H20 and brine. The organic phase was dried over MgSO4 and concentrated to give 500 mg
of oily solid. Rf0.50 (15% Et20/Hex); 1H NMR (CDCl3) 5 6.82 (s, 4H, AA’BB’), 3.89 (t, 2H,
J=6.5 Hz), 3.74 (s, 3H), 3.25 (t, 2H, J=6.9 Hz), 1.76 (m, 2H), 1.62 (m, 2H), 1.55—1.36 (m, 4H).
6—(4—Methoxyphenoxy)hexan—l—amine A mixture of zidohexyloxy)—4—
methoxybenzene (500 mg) and 65 mg of 5% Pd—C in 25 mL of MeOH was stirred under a
blanket of hydrogen for 16 hr. The mixture was blanketed with argon and filtered through a pad
of Celite. The filtrate was concentrated to give 448 mg of oil. 1H NMR (CDClg) 8 6.77 (s, 4H,
), 3.84 (m, 2H), 3.70 (s, 3H), 2.64 and 2.56 (m, 2H, AB), 1.71 (m, 2H), 1.51-1.31 (m,
6H).
4—Methoxyphenoxy)hexyl]quinolin—4—amine Four mL of ne was evaporated from 6—
(4—methoxyphenoxy)hexan—l—amine (448 mg, 2.01 mmol). Then, a mixture of the amine, 4—
chloroquinoline (424 mg, 2.60 mmol), DIEA (0.80 mL, 4.59 mmol), and 1.5 mL of NMP was
heated at 160 0C in a sealed tube for 24 hr. The e was cooled and partitioned between
DCM and 5% N212CO3. The organic phase was dried over anhydrous NaZSO4 and concentrated.
FC (50% EA/Hex + 2% TEA) gave an oil that contained residual NMP, as observed by NMR.
Dilution with EtOH and evaporation under high vacuum was ed until NMP was
undetectable by NMR. Rf 0.12 (50% EA/Hex + 2% TEA); 1H NMR ) 8 8.52 (d, 1H,
J=5.2 Hz), 7.96 (d, 1H, J=8.4 Hz), 7.74 (d, 1H, J=8.4 Hz), 7.59 (ddd, lH, J=1.2, 6.9, 8.4 Hz),
7.37 (ddd, 1H, J=1.2, 6.9, 8.2 Hz), 6.82-6.80 (m, 4H), 6.39 (d, 1H, J=5.4 Hz), 5.20 (m, 1H, NH),
3.89 (t, 2H, J=6.3 Hz), 3.74 (s, 3H), 3.31 (m, 2H), 1.78—1.75 (m, 4H), 1.52-1.49 (m, 4H).
Example 33: N—{2—[4—(Hexyloxy)phenoxy]ethyl }quinolin—4—amine
(>290o/W\
4-(Hexyloxy)phenol was prepared by methods similar to that used for the preparation of 3-
(hexyloxy)phenol. 4-(Benzyloxy)phenol (11.45 g), K2CO3 (8.68 g), 1-bromohexane (10.4 mL),
and DMF (50 mL) at 80—100 °C gave 1—(benzyloxy)—4-(hexyloxy)benzene (12.97 g). Rf 0.68
(20% EA/Hex); 1H NMR (CDC13) 8 7.44—7.28 (m, 5H), 6.91—6.76 (m, 4H), 5.00 (s, 2H), 3.89 (t,
2H, J=6.6 Hz), 1.74 (m, 2H), 1.49—1.24 (m, 6H), 0.89 (m, 3H).
4—(Hexyloxy)phenol A mixture of 1—(benzyloxy)—4—(hexyloxy)benzene (12.97 g) and 5% Pd/C
(1.2 g) in 200 mL of 1:1 MeOH/EA was d under en for 16 hr. Starting material was
consumed, as seen by TLC analysis. The reaction mixture was filtered through Celite, the
solvents were exchanged to 12% EA/Hex, and the mixture was filtered through a pad of silica
gel and concentrated to give 8.84 g of 4—(hexyloxy)phenol. Rf 0.21 (10% EA/Hex); 1H NMR
(CDC13)5 6.80—6.72 (m, 4H), 3.88 (t, 2H, J=6.7 Hz), 1.79—1.68 (m, 2H), 1.48—1.30 (m, 6H), 0.91—
0.86 (m, 3H).
2—[4—(Hexyloxy)phenoxy]ethanol A mixture of 4—(hexyloxy)phenol (11.0 g, 56.7 mmol),
ethylene ate (7.5 g, 85 mmol), and K2C03 (11.7 g, 85 mmol) in 60 mL of DMF was
heated at 60 0C for 16 hr. The mixture was partitioned between EA and H20, 0.1M HCl, H20,
and brine. The organic phases were dried over MgSO4 and concentrated. SPE, washing with 10%
EA/Hex (which gave 5.8 g of recovered starting ) and eluting with 37% EA/Hex, gave the
t as colorless solid. The recovered ng material was retreated with the reagents. The
combined t yield was 11.4 g of colorless solid. Rf 0.20 (20% EA/Hex); 1H NMR (CDCl3)
8 6.83—6.81 (m, 4H, ), 4.03 and 3.93 (m, 4H, AZBZ), 3.90 (t, 2H, J=6.6 Hz), 1.79—1.72
(m, 2H), 1.45 (m, 2H), 1.36-1.30 (m, 4H), 0.90 (m, 3H); 13C NMR(CDC13) 5 153.9, 152.9,
115.8, 115.7, 70.2, 68.9, 61.8, 31.8, 29.6, 25.9, 22.8, 14.2.
2-[4—(Hexyloxy)phenoxy]ethanamine was prepared by the method used for the preparation of [3—
(hexyloxy)phenyl]methanamine.
2-[4-(Hexyloxy)phenoxy]ethanol (11.4 g), methanesulfonyl chloride (5.60 mL), TEA (11.0 mL),
and DCM (150 mL) at 0 OC gave 2-[4-(hexyloxy)phenoxy]ethyl methanesulfonate (13.9 g). 1H
NMR(CDC13) 5 6.85—6.81 (m, 4H, AA’BB’), 4.54 and 4.19 (m, 4H, A2B2), 3.90 (t, 2H, J=6.6
Hz), 3.08 (s, 3H), 1.76 (m, 2H), 1.44 (m, 2H), 1.36—1.30 (m, 4H), 0.90 (m, 3H); 13C NMR
(CDC13)5154.3, 152.2, 116.0, 115.8, 68.9, 68.4, 66.9, 38.0, 31.8, 29.5, 25.9, 22.8, 14.2.
2—[4—(Hexyloxy)phenoxy]ethyl methanesulfonate (13.9 g), potassium phthalimide (8.57 g), and
DMF (40 mL) at 60 OC gave N—{2—[4—(hexyloxy)phenoxy]ethyl}phthalimide (11.58 g after
recrystallization from EtOH/HZO). Rf 0.40 (30% EA/Hex); 1H NMR (CDCl3) 5 7.85 and 7.71
(m, 4H, AA’BB’), 6.79 (m, 4H, AA’BB’), 4.18 and 4.08 (m, 4H, Asz), 3.86 (t, 2H, J=6.6 Hz),
1.73 (m, 2H), 1.42 (m, 2H), 1.34-1.28 (m, 4H), 0.89 (m, 3H); 13C NMR(CDC13) 5 168.4, 153.9,
152.6, 134.2, 132.3, 123.5, 115.9, 115.6, 68.8, 65.7, 37.7, 31.8, 29.5 25.9, 22.8, 14.2.
2— [4—(Hexyloxy)phenoxy]ethanamine N—{ 2—[4—(Hexyloxy)phenoxy]ethyl }phthalimide
(11.6 g), hydrazine monohydrate (2.25 mL), IPA (125 mL), and EtOH (50 mL) at re?ux gave a
colorless solid (7.50 g). 1H NMR (CDC13) 5 6.73 (s, 4H, ), 3.80 (t, 2H, J=5.2 Hz), 3.79
(t, 2H, J=6.7 Hz), 2.93 (t, 2H), 1.66 (m, 2H), 1.41—1.21 (m, 6H), 0.85—0.80 (m, 3H).
N— { 2—[4—(Hexyloxy)phenoxy] ethyl }quinolin—4—amine Crude 2— [4—
(hexyloxy)phenoxy]ethanamine (7.40 g, 31.2 mmol) was taken up in 30 mL of DMA, and then
25 mL was evaporated. The residue was transferred to a heavy—walled sealed tube, and 5 mL of
NMP, 4—chloroquinoline (5.09 g, 31.2 mmol), and DIEA (10.8 mL, 62 mmol) were added. The
mixture was heated at 160 0C for 16 hr. After cooling, dilution of the mixture with 5% N32C03
resulted in the ion of a precipitate. The precipitate was filtered and washed with H20. The
precipitate was recrystallized from MeOH/HZO and then from MeOH to give 7.50 g of colorless
solid. Rf0.20 (5% MeOH/DCM); mp 1315-1320 0C; 1H NMR (CDC13) 5 8.58 (d, 1H. J=5.2
HZ), 8.00 (dd, 1H, J=0.8, 8.4 Hz), 7.79 (dd, 1H, J=0.8, 8.4 Hz), 7.66-7.62 (m, 1H), 7.44 (ddd,
1H, J=1.5, 7.0, 8.5 Hz), 6.86 (m, 4H, AA’BB’), 6.49 (d, 1H, J=5.5 Hz), 5.60 (br s, 1H, NH), 4.25
(t, 2H), 3.90 (t, 2H, J=6.6 Hz), 3.70 (m, 2H), 1.74 (m, 2H), 1.45 (m, 2H), 1.36-1.30 (m, 4H), 0.90
(m, 3H); 13C NMR(CDC13)8154.2, 1526,1510, 149.9, 148.5, 130.0, 129.4. 125.1. 119.7,
119.1, 115.9, 115.8, 99.2, 68.9, 66.9, 42.9, 31.8, 29.5, 25.9, 22.8, 14.2.
Example 34: N-{ Hexyloxy)phenoxy]propyl }quinolinamine
HN/\/\O00W
CK?/
N—{3—[4—(Hexyloxy)phenoxy]propyl}phthalimide A mixture of 4—(hexyloxy)phenol (1.04 g,
5.36 mmol), N—(3—bromopropyl)phthalimide (1.44 g, 5.37 mmol), K2C03 (1.12 g, 8.12 mmol),
and 10 mL of DMF was reacted for 26 hr. Then, the mixture was diluted with EA and washed
with H20, 0.1M HCl, and brine, dried over anhydrous NaZSO4, and concentrated. The residue
was filtered h a pad of silica gel using 20% EA/Hex, and the filtrate was concentrated to
give 1.96 g of a pale yellow solid. Rf 0.20 (15% EA/Hex), 0.38 20% EA/Hex + 2% DIEA); 1H
NMR(CDC13) 5 7.83 and 7.69 (m, 4H, AA’BB’), 6.79—6.71 (m, 4H, AA’BB’), 3.96 (t, 2H, J=6.2
Hz), 3.91—3.81 (m, 4H), 2.14 (m, 2H), 1.73 (m, 2H), .28 (m, 6H), 0.89 (m, 3H).
3—[4—(Hexyloxy)phenoxy]propan—l—amine A mixture of N—{ 3—[4—
(hexyloxy)phenoxy]propyl}phthalimide (1.96 g) and hydrazine drate (0.40 mL, 8.24
mmol) in 40 mL of EtOH was heated at re?ux for 20 hr. Then, the volatile components were
evaporated. SPE, washing with 5% MeOH/DCM and then g with 5% MeOH/DCM + 2%
TBA, gave 632 mg of colorless solid. Rf 0.21 (5% MeOH/DCM + 25 DIEA); 1H NMR (CDC13)
8 6.75 (br s, 4H), 3.92 (t, 2H, J=6.0 Hz), 3.83 (t, 2H, J=6.7 Hz), 3.00 (br m, 2H, NH;), 2.82 (t,
2H, J=6.8 Hz), 1.87 (m, 2H), 1.68 (m, 2H), 1.43—1.23 (m, 6H), 0.83 (m, 3H).
N—{3—[4—(Hexyloxy)phenoxy]propyl}quinolin—4—amine A mixture of 3—[4—
(hexyloxy)phenoxy]propan—1—amine (476 mg, 1.90 mmol), 4—chloroquinoline (416 mg, 2.55
mmol), and DIEA (0.50 mL, 2.86 mmol) in 1 mL of NMP was heated at 150 0C in a sealed tube
for 18 hr. Then, the e was cooled and partitioned between EA and 5% Na2C03 and brine.
The organic phase was dried over NaZSO4 and concentrated. SPE, washing with 2.5%
MeOH/DCM and then eluting with 7% MeOH/DCM, gave 633 mg of solid. Rf 0.28 (10%
CM); mp 84.5-86.0 °C (from EA/Hex); 1H NMR (CDC13) 5 8.51 (d, 1H, J=5.4 Hz),
7.95 (dd, 1H, 121.0, 8.5 Hz), 7.79 (m, 1H), 7.57 (ddd, 1H, 121.5, 6.9, 8.4 Hz), 7.35 (ddd, 1H,
J=1.2, 6.9, 8.1 Hz), 6.82 (br s, 4H, AA’BB’), 6.38 (d, 1H, J=5.4 Hz), 5.97 (m, 1H, NH), 4.03 (t,
2H, J=5.4 Hz), 3.86 (t, 2H, J=6.4 Hz), 3.47 (m, 2H), 2.15 (m, 2H), 1.73 (m, 2H), 1.47—1.25 (m,
6H), 0.88 (m, 3H).
Example 35 : N—{4—[4—(Hexyloxy)phenoxy]butyl }quinolin—4—amine
Q5?HN/\/\/O\©\0W/
1—(4—Bromobutoxy)—4—(hexyloxy)benzene 4—(Hexyloxy)phenol (1.52 g, 7.84 mmol), 1,4—
dibromobutane (7.4 mL, 62 mmol), and K2C03 (1.22 g, 8.84 mmol) in 8 mL of DMF was mixed
WO 20995
for 16 hr. The mixture was partitioned between EA and 0.1M HCl and brine, and the organic
phases were dried over MgSO4, filtered, and concentrated. SPE, washing with 1% EA/Hex and
then g with 5% EA/Hex gave 2.36 g of colorless solid. Rf 0.59 (15% EA/Hex); 1H NMR
(CDC13) 5 6.80 (br s, 4H, AA’BB’), 3.93 (t, 2H, J=6.0 Hz), 3.88 (t, 2H, J=6.7 Hz), 3.48 (m, 2H),
2.05 (m, 2H), 1.90 (m, 2H), 1.74 (m, 2H), 1.48—1.28 (m, 6H), 0.89 (m, 3H).
N— { 4—[4—(Hexyloxy)phenoxy]butyl limide 1—(4—Bromobutoxy)—4—(hexyloxy)benzene
(2.36 g, 7.17 mmol) and potassium phthalimide (2.0 g, 10.8 mmol) in 12 mL of DMF was mixed
for 60 hr. The mixture was partitioned between EA and 0.1M HCl and brine, and the organic
phases were dried over MgSO4, filtered, and trated. SPE, washing with 5% EA/Hex and
then g with 15% EA/Hex gave 2.64 g of colorless solid. Rf 0.31 (15% EA/Hex); 1H NMR
(CDC13) 5 7.83 and 7.70 (m, 4H, AA’BB’), 6.78 (br s, 4H, AA’BB’), 3.92 (t, 2H, J=6.1 Hz), 3.87
(t, 2H, J=6.7 Hz), 3.75 (t, 2H, J=7.0 Hz), 1.92—1.68 (m, 6H), 1.48-1.22 (m, 6H), 0.89 (m, 3H).
4-[4-(Hexyloxy)phenoxy]butanamine A mixture of N-{4-[4-
(hexyloxy)phenoxy]butyl}phthalimide (2.64 g, 6.68 mmol) and hydrazine monohydrate (0.65
mL, 13.4 mmol) in 60 mL of EtOH was heated at re?ux for 20 hr. The mixture was cooled,
concentrated, and partitioned between EA and 5% N32CO3 and brine. The organic phases were
dried over Na2804, filtered, and concentrated. SPE, washing with 4% MeOH/DM and then
eluting with 6% MeOH/DCM + 2% DIEA gave product-containing fractions. These fractions
were trated, taken up in DCM and washed with 5% Na2C03, dried over NaZSO4, filtered,
and concentrated to give 1.69 g of colorless solid. Rf 0.20 (5% MeOH/DCM + 2% DIEA,
ninhydrin (+)); 1H NMR(CDC13) 8 6.80 (br s, 4H, AA’BB’), 3.93—3.85 (m, 4H), 2.75 (t, 2H, 127
Hz), 1.87—1.26 (m, 14H), 0.89 (m, 3H).
N—{4—[4—(Hexyloxy)phenoxy]butyl}quinolin—4—amine A mixture of 4—[4—
(hexyloxy)phenoxy]butan—1—amine (499 mg, 1.88 mmol), 4—chloroquinoline (3999 mg, 2.45
mmol), and DIEA (0.50 mL, 2.86 mmol) in 1 mL of NMP was heated at 150 0C in a sealed tube
for 18 hr. Then, the e was cooled and partitioned between EA and 5% N32C03 and brine.
The organic phase was dried over NaZSO4 and concentrated. SPE, washing with 2.5%
MeOH/DCM and then eluting with 7% MeOH/DCM, gave 633 mg of solid. Rf 0.25 (10%
MeOH/DCM); mp 11301 14.0 0C (from EA/Hex); 1H NMR (CDCl3) 5 8.53 (d, 1H, J=5.2 Hz),
7.95 (m, 1H), 7.70 (d, 1H, J=7.6 Hz), 7.58 (ddd, 1H, J=1.5, 6.9, 8.4 Hz), 7.34 (ddd, 1H, J=l.2,
6.9, 8.2 Hz), 6.82 (br s, 4H, AA’BB’), 6.40 (d, 1H, J=5.4 Hz), 5.38 (br t, 1H, NH), 3.96 (t, 2H,
J=5.6 Hz), 3.88 (t, 2H, J=6.5 Hz), 3.36 (br m, 2H), 1.92-1.90 (m, 4H), 1.74 (m, 2H), 1.48—1.28
(m, 6H), 0.89 (m, 3H).
Example 36: N—[8—(m—Tolyloxy)octyl]quinolin—4—amine
HN/\/\/\/\/O CH3
(>5 0
1-(8—Bromooctyloxy)—3—methylbenzene A mixture of m—cresol (1.00 mL, 9.54 mmol), 1,8—
dibromooctane (15.0 mL, 81 mmol), and K2CO3 (2.6 g, 18.8 mmol) in 20 mL of NMP and 10
mL of DME was heated at re?ux for 66 hr. Then, the mixture was cooled, diluted with DCM (20
mL), and extracted with 0.05N NaOH (150, 100 mL) and 1M HCl (100 mL). The aqueous
phases were ted with DCM (20 mL), and the combined c phases were dried over
MgSO4 and concentrated. SPE, washing with Hex to r dibromide and then eluting with 3%
EA/Hex, gave 1.7 g of 1-(8-bromooctyloxy)methylbenzene. Rf 0.39 (5% ); 1H NMR
(CDC13) 5 7.15 (t, 1H), 68-665 (m, 3H), 3.95 (t, 2H), 3.4 (t, 2H), 3.3 (s, 3H), 1.9—1.7 (m, 4H),
1.5—1.2(m, 8H).
1—(8—Azidoocyloxy)—3—methylbenzene (1.7 g) was prepared from 1—(8—bromooctyloxy)—3—
methylbenzene (1.7 g, 5.69 mmol) and sodium azide (740 mg, 11.4 mmol) in 50 mL of DMF
following the method for the preparation of 10—butoxydecan—1—amine.
8—(m—Tolyloxy)octan—l—amine (0.6 g) was prepared from 1—(8—azidoocyloxy)—3—methylbenzene
(1.7 g) by the method used for the ation of lO-butoxydecan—l—amine. 1H NMR (CDCl3) 5
7.1 (m, 1H), 6.6 (m, 3H), 3.9 (m, 2H), 2.7 (t, 1H), 2.3 (m, 4H), 1.8-1.6 (m, 4H), 1.5-1.3 (m, 8H).
N—[8—(m—Tolyloxy)octyl]quinolin—4—amine (166 mg) was prepared from 8—(m—tolyloxy)octan—l—
amine (0.6 g), 4—chloroquinoline (840 mg), TEA (2 mL), and NMP (0.2 mL) following the
method for N—[8—(3—ethoxypropoxy)octyl]quinolin—4—amine. 1H NMR (CDClg) 5 8.6 (m, 2H),
8.05 (m, 2H), 7.6 (t, 1H), 7.4 (t, 1H), 7.1 (t, 1H), 6.8-6.6 (m, 3H), 6.4 (d, 1H), 3.9 (t, 2H), 3.5 (m,
2H), 2.3 (s, 3H), 1.9-1.7 (m, 4H), 1.5—1.3 (m, 8H).
Example 37: N—[8—(p—Tolyloxy)octyl]quinolin—4—amine
(if? C”3
1-(8—Bromooctyloxy)—4—methylbenzene (1.9 g) was prepared by the same method used for 1—(8—
bromooctyloxy)—3—methylbenzene using p-cresol (1.00 mL, 9.54 mmol), bromooctane
(15.0 mL, 51 mmol), and K2CO3 (2.6 g, 18.8 mmol) in 20 mL of NMP and 10 mL of DME
heated for 66 hr. 1H NMR (CDClg) 8 7.0 (d, 2H), 6.8 (d, 2H), 3.9 (t, 2H), 3.4 (t, 2H), 2.3 (s, 3H),
1.9-1.7 (m, 4H), 1.5-1.2 (m, 8H).
zidooctyloxy)methylbenzene (1.9 g) was prepared from 1-(8-bromooctyloxy)
methylbenzene (1.9 g, 6.36 mmol) and sodium azide (830 mg, 12.7 mmol) in 50 mL of DMF
following the method for the preparation of 10—butoxydecan—1—amine.
8—(p—Tolyloxy)octan—1—amine (0.6 g) was prepared 1-(8-azidooctyloxy)—4—methylbenzene (1.9 g)
by the method used for the preparation of 10—butoxydecan—1—amine. 1H NMR (CDClg) 8 7.05 (d,
2H), 6.75 (d, 2H), 3.9 (m, 2H), 2.7 (m, 1H), 2.35 (t, 1H), 2.3 (s, 3H), 1.8-1.2 (m, 12H).
N—[8—(p—Tolyloxy)octyl]quinolin—4—amine (161 mg) was prepared from olyloxy)octan—l—
amine (0.6 g), 4—chloroquinoline (840 mg), TEA (2 mL), and NMP
(0.2 mL) following the method for N—[8—(3—ethoxypropoxy)octyl]quinolin—4—amine. 1H NMR
(CDC13)5 8.5 (d, 1H), 8.0 (d, 1H), 7.85 (d, 1H), 7.6 (t, 1H), 7.4 (t, 1H), 7.1 (m, 3H), 6.8 (m, 3H),
6.4 (d, 1H), 3.9 (t, 2H), 3.4 (m, 2H), 2.3 (s, 3H), 7 (m, 4H), 1.5-1.3 (m, 8H).
Example 38: N—[8—(0—Tolyloxy)octyl]quinolin—4—amine
HNWOI)
1—(8—Bromooctyloxy)—2—methylbenzene (1.3 g) was prepared by the same method used for l—(8—
bromooctyloxy)—3—methylbenzene using 0—Cresol (696 mg, 6.44 mmol), 1,8—dibromooctane (14 g,
81 mmol), and K2CO3 (1.00 g, 7.25 mmol) in 12 mL of NMP and 12 mL of DME heated for 16
1-(8—Iodooctyloxy)—2—methylbenzene (1.3 g) was prepared from 1—(8—bromooctyloxy)-2—
methylbenzene (1.3 g, 4.35 mmol) and sodium iodide (652 mg, 4.35 mmol) in 50 mL of acetone
following the method used in the preparation of 10—(hexyloxy)decan—1—amine.
N—[8-(0-Tolyloxy)octyl]phthalimide (1.3 g) was prepared from 1-(8-iodooctyloxy)
benzene (1.3 g) and potassium phthalimide (1.0 g, 5.4 mmol) in 50 mL of DMF following
the method for N—[8-(hexyloxy)octyl]phthalimide. 1H NMR (CDClg) 5 7.85 (m, 2H), 7.7 (m,
2H), 7.15 (m, 2H), 6.8 (m, 2H), 3.95 (m, 2H), 3.7 (m, 2H), 2.2 (m, 3H), 1.9-1.6 (m, 4H), 16-125
(m, 8H).
8—(0—Tolyloxy)octan—l—amine (390 mg) was prepared from N—[8—(0—tolyloxy)octy1]phthalimide
(1.0 g, 2.74 mmol) using hydrazine monohydrate (0.2 mL) in EtOH (50 mL) following the
method for [3—(hexyloxy)phenyl]methanamine. 1H NMR (DMSO—d6) 5 7.1 (m, 2H), 6.9—6.75 (m,
2H), 3.9 (t, 2H), 2.5 (m, 2H), 2.15 (s, 3H), 1.75 (m, 2H), 1.5—1.2 (m, 10H).
0—Tolyloxy)octyl]quinolin—4—amine (300 mg) was prepared from olyloxy)octan—l—
amine (390 mg), 4-Chloroquinoline (544 mg), TEA (2 mL), and NMP (0.2 mL) following the
method for N—[8—(3—ethoxypropoxy)octyl]quinolin—4—amine. 1H NMR (CDCl3) 5 8.55 (d, 1H), 8.0
(d, 1H), 7.75 (d, 1H), 7.65 (m, 1H), 7.45 (m, 1H), 7.15 (m, 2H), 6.8 (m, 2H), 6.4 (d, 1H), 3.95 (t,
2H), 3.35 (m, 2H), 2.3 (s, 3H), 1.8 (m, 4H), 1.6—1.3 (m, 8H).
e 39: N—[8—(4—tert—Butylphenoxy)octyl]quinolin—4—amine
HNWOO
1—(8—Bromooctyloxy)—4—tert—butylbenzene (900 mg) was prepared by the same method used for
1—(8—bromooctyloxy)—3—methylbenzene using 4—tert—butylphenol (647 mg, 4.31 mmol), 1,8—
dibromooctane (11.7 g, 43 mmol), and K2C03 (714 mg, 5.17 mmol) in 12 mL of NMP and 6 mL
of DME heated for 24 hr. 1H NMR (CDClg) 5 7.28 and 6.82 (m, 4H, AA’BB’), 3.93 (m, 2H),
3.40 (t, 2H, J=6.8 Hz), 1.90-1.71 (m, 4H), .22 (m, 8H), 1.29 (s, 9H).
1-tert-Butyl(8-iodooctyloxy)benzene (900 mg) was prepared from 1-(8-bromooctyloxy)
tert-butylbenzene (900 mg) and sodium iodide (400 mg) in 50 mL of acetone ing the
method for the preparation of 10-(hexyloxy)decan-l-amine.
N—[8—(4—tert-Butylphenoxy)octyl]phthalimide (1.3 g) was prepared from 1—tert—butyl—4—(8—
iodooctyloxy)benzene (900 mg) and potassium phthalimide (860 mg) in 50 mL of DMF
following the method for the preparation of N—[8—(hexyloxy)octy1]phthalimide. 1H NMR (CDC13)
8 7.85 and 7.70 (m, 4H, AA’BB’), 7.3 and 6.8 (m, 4H, AA’BB’), 3.9 (t, 2H), 3.65 (m, 2H), 1.8-
1.6 (m, 4H), 1.6—1.3 (m, 17H).
8—(4—tert—Butylphenoxy)octan—1—amine (590 mg) was prepared from 4—tert—
butylphenoxy)octyl]phthalimide (900 mg) and hydrazine monohydrate (0.17 mL) in 50 mL of
EtOH following the method for the preparation of [3—(hexyloxy)phenyl]methanamine. 1H NMR
(DMSO—d6) 5 7.25 and 6.80 (m, 4H, AA’BB’), 3.9 (t, 2H), 2.5 (m, 2H), 1.68 (m, 2H), 1.5—1.2 (m,
19H).
4—tert—Butylphenoxy)octyl]quinolin—4—amine A mixture of 8—(4—tert—butylphenoxy)octan—
l—amine (510 mg, 1.84 mmol), 4—chloroquinoline (604 mg, 3.70 mmol), TEA (4.0 mL, 28
mmol), and 0.4 mL of NMP was heated in a heavy walled glass tube at 130 0C for 4 days. The
e was cooled and partitioned between EA and 5% N32CO3 and brine, dried over NaZSO4,
filtered, and concentrated. Purification by EC (60% EA/Hex + 2% TEA) gave 320 mg of solid.
Mp 108—110 0C (from MeOH); 1H NMR (CDC13) 5 8.4 (d, 1H), 8.0 (d, 1H), 7.8 (d, 1H), 7.6 (m,
1H), 7.4 (m, 1H), 7.3 and 6.8 (m, 4H, AA’BB’), 6.4 (d, 1H), 5.2 (br s, 1H, NH), 3.9 (m, 2H), 3.3
(m, 2H), 1.8—1.6 (m, 4H), 1.6-1.3 (m, 8H), 1.3 (s. 9H).
Example 40: N—[8—(4—Fluorophenoxy)octyl]quinolin—4—amine
()5HN/VWVOOF/
N
romooctyloxy)?uorobenzene (2.75 g) was prepared by the same method used for 1-(8-
bromooctyloxy)methylbenzene using 4-?uorophenol (1.33 g, 12.1 mmol), 1,8-dibromooctane
(20 mL, 108 mmol), and K2C03 (1.77 g, 14.3 mmol) in 20 mL of NMP and 10 mL of DME
heated for 24 hr. 1H NMR ) 8 7.0-6.9 (m, 2H), 6.8 (m, 2H), 3.89 (t, 2H, J=6.4 Hz), 3.40
(t, 2H. J=6.8 Hz), 1.9—1.7 (m, 4H), 1.6-1.2 (m, 8H).
1—F1uoro—4—(8-iodooctyloxy)benzene was prepared from 1(8—bromooctyloxy)—4—?uorobenzene
(2.75 g, 9.08 mmol) and sodium iodide (1.63 g, 10.9 mmol) in 70 mL of acetone following the
method used in the preparation of 10—(hexyloxy)decan-1—amine.
N—[8—(4—Fluorophenoxy)octyl]phthalimide (2.19 g) was prepared from l—?uoro—4—(8—
iodooctyloxy)benzene and potassium phthalimide (2.52 g, 13.6 mmol) in 50 mL of DMF at 60-
80 0C for 12 hr following the method for N—[8—(hexyloxy)octyl]phthalimide. 1H NMR (CDC13) 5
7.85 (m, 2H), 7.7 (m, 2H), 6.9 (m, 2H), 6.8 (m, 2H), 3.9 (t, 2H), 3.7 (t, 2H), 1.8-1.6 (m, 4H), 1.5-
1.3 (m, 8H).
WO 20995
8—(4—F1uorophenoxy)octan—l—amine (657 mg, 2.75 mmol) was prepared from N—[8—(4—
?uorophenoxy)octyl]phthalimide (2.19 g, 5.94 mmol) using hydrazine monohydrate (0.43 mL)
in EtOH (50 mL) ing the method for [3—(hexyloxy)phenyl]methanamine. 1H NMR
(CD3OD) 5 7.0—6.8 (m, 4H), 3.9 (t, 2H), 2.7 (t, 2H), 1.75 (m, 2H), 1.6—1.3 (m, 10H).
N—[8—(4—Fluorophenoxy)octyl]quinolin—4—amine was prepared from 8—(4—?uorophenoxy)octan—1—
amine (657 mg, 2.75 mmol), 4—chloroquinoline (676 mg), TEA (2 mL), and NMP (0.2 mL) at
130 0C in a sealed tube for 5 days following the method for N—[8—(3—
ethoxypropoxy)octyl]quinolin—4—amine. 1H NMR (CDC13) 5 8.5 (d, 1H), 8.0 (d, 1H), 7.9 (d, 1H),
7.65 (m, 1H), 7.4 (m, 1H), 7.1-6.8 (m, 4H), 6.4 (d, 1H), 5.6 (br s, 1H, NH), 4.0 (t, 2H), 3.35 (m,
2H), 1.8 (m, 2H), 1.7-1.2 (m, 10H).
Example 41: N—[8—(3—Fluorophenoxy)octyl]quinolin—4—amine
(>5HN/\/\/\/\/O\©/F/N
romooctyloxy)?uorobenzene (2.06 g) was prepared by the same method used for 1-(8-
bromooctyloxy)methylbenzene using 3-?uorophenol (1.60 g, 14.3 mmol), 1,8-dibromooctane
(25 mL, 135 mmol), and K2C03 (2.56 g, 18.5 mmol) in 25 mL of NMP and 12 mL of DME
heated for 24 hr. Rf 0.42 (5% EA/Hex); 1H NMR (CDC13) 5 7.2 (m, 1H), 6.7-6.6 (m, 3H), 3.9 (t,
2H), 3.4 (t, 2H), 7 (m, 4H), 1.6—1.2 (m, 8H).
1—Fluoro—3-(8—iodooctyloxy)benzene was prepared from 1—(8—bromooctyloxy)—3—fluorobenzene
(2.06 g, 6.78 mmol) and sodium iodide (1.22 g, 8.13 mmol) in 60 mL of acetone following the
method used in the preparation of lO—(hexyloxy)decan—1—amine.
N—[8—(3—Fluorophenoxy)octyl]phthalimide (1.85 g) was ed from l—?uoro—3—(8—
iodooctyloxy)benzene and potassium phthalimide (1.9 g, 10.3 mmol) in 50 mL of DMF at 60—80
°C for 12 hr following the method for N—[8—(hexyloxy)octyl]phthalimide. 1H NMR (CDClg) 5
7.85 (m, 2H), 7.7 (m, 2H), 7.2 (m, 1H), 6.7—6.5 (m, 3H), 3.9 (t, 2H), 3.7 (t, 2H), 1.8—1.6 (m, 4H),
1.5—1.3 (m, 8H).
8—(3—F1uorophenoxy)octan—l—amine (874 mg, 3.66 mmol) was prepared from N—[8—(3—
?uorophenoxy)octyl]phthalimide (1.85 g, 5.01 mmol) using hydrazine drate (0.36 mL)
in EtOH (50 mL) following the method for [3-(hexyloxy)phenyl]methanamine. 1H NMR
(CD3OD) 5 7.25 (m, 1H), 6 (m, 3H), 3.9 (t, 2H), 2.7 (t, 2H), 1.8 (m, 2H), 1.6—1.3 (m, 10H).
N—[8—(3—Fluorophenoxy)octyl]quinolin—4—amine was prepared from 8—(3—fluorophenoxy)octan—l—
amine (874 mg, 3.66 mmol), 4—chloroquinoline (900 mg), TEA (2 mL), and NMP (1 mL) at 130
0C in a sealed tube for 5 days following the method for N—[8—(3—ethoxypropoxy)octyl]quinolin—4—
amine. 1H NMR ) 8 8.5 (d, 1H), 8.0 (d, 1H), 7.85 (d, 1H), 7.65 (m, 1H), 7.4 (m, 1H), 7.15
(m, 1H), 6.7—6.5 (m, 3H), 6.5 (d, 1H), 5.6 (br s, 1H, NH), 3.9 (t, 2H), 3.35 (m, 2H), 1.8 (m, 4H),
1.6-1.3 (m, 8H).
Example 42: N-[8-(2-Fluorophenoxy)octyl]quinolinamine
CmHN/VWVO:©F/N
1—(8—Bromooctyloxy)—2—f1uorobenzene (2.97 g) was ed by the same method used for 1—(8-
bromooctyloxy)—3—methylbenzene using 2—?uorophenol (1.69 g, 15.1 mmol), 1,8—dibromooctane
(38.3 g, 141 mmol), and K2C03 (2.76 g, 20 mmol) in 25 mL of NMP and 20 mL of DME heated
for 24 hr. Rf0.33 (5% EA/Hex); 1H NMR (CDCl3) 5 7.10-6.83 (m, 4H), 4.0 (m, 2H), 3.38 (t, 2H,
J=6.9 Hz), 1.91-1.76 (m, 4H), 1.47-1.32 (m, 8H).
1—Fluoro—2-(8—iodooctyloxy)benzene (3.43 g) was prepared from l—(8—bromooctyloxy)—2—
fluorobenzene (2.97 g, 9.80 mmol) and sodium iodide (1.76 g, 11.7 mmol) in 70 mL of acetone
following the method used in the preparation of lO—(hexyloxy)decan—l—amine.
N—[8—(2—Fluorophenoxy)octyl]phthalimide (2.84 g) was ed from l—?uoro—2—(8—
iodooctyloxy)benzene (3.43 g) and potassium phthalimide (2.72 g, 14.7 mmol) in DMF at 60—80
0C for 12 hr ing the method for N—[8—(hexyloxy)octyl]phthalimide. 1H NMR (CDC13) 5
7.85 and 7.70 (m, 4H, AA’BB’), 7.10-6.80 (m, 4H), 4.00 (t, 2H), 3.70 (t, 2H), 1.90-1.60 (m, 4H),
1.55—1.25 (m, 8H).
8—(2—F1uorophenoxy)octan—l—amine (1.27 g, 5.32 mmol) was prepared from N—[8—(2—
?uorophenoxy)octyl]phthalimide (2.84 g, 7.70 mmol) using hydrazine monohydrate (0.50 mL)
in EtOH (50 mL) following the method for [3—(hexyloxy)phenyl]methanamine.
N—[8—(2—Fluorophenoxy)octyl]quinolin—4-amine (100 mg) was prepared from 8—(2-
?uorophenoxy)octan—1—amine (1.27 g, 5.32 mmol), 4—chloroquinoline (1.3 g, 7.98 mmol), TEA
(2 mL), and NMP (1 mL) at 130 0C in a sealed tube for 5 days ing the method for N—[8—(3—
ethoxypropoxy)octyl]quinolinamine. 1H NMR (CDClg) 5 8.4 (d, 1H), 8.0 (d, 1H), 7.9 (d, 1H),
7.6 (m, 1H), 7.4 (m, 1H), 7.0-6.7 (m, 4H), 6.4 (d, 1H), 5.9 (br s, 1H, NH), 3.9 (t, 2H), 3.3 (m,
2H), 1.9-1.2 (m, 12H).
Example 43: N-(Biphenylyl)quinolinamine
A e of 4—biphenylamine (200 mg, 1.18 mmol), roquinoline (228 mg, ), and DIEA
(0.25 mL, 1.43 mmol) in 1 mL of NMP was heated at 150 0C in a sealed tube for 24 hr. The
cooled mixture was diluted with EA, washed with 5% Na2C03 (2x) and brine, dried over
anhydrous Na2804, and concentrated. SPE, eluting with a step gradient of 1%, 3%, and 5%
MeOH/DCM, gave fractions that were concentrated to give a brown solid. The solid was washed
with MeOH and dried in vacuo. Rf 0.21 (5% MeOH/DCM); mp 222—226 0C; 1H NMR (20%
CDC13) 5 8.38 (d, 1H, J=5.7 HZ), 8.06 (m, 1H), 7.91 (m, 1H), 7.67-7.26 (m, 11H), 6.98
(d, 1H, J=5.5 HZ).
Example 44: exylphenyl)quinolin—4—amine
.NQW
A mixture of 4—hexylaniline (197 mg, 1.11 mmol), 4—chloroquinoline (210 mg) and DIEA (0.24
mL) in 1 mL of NMP was heated at 150 0C in a sealed tube for 24 hr. The mixture was cooled
and partitioned between EA and 5% . The organic phases were washed with brine, dried
over Na2S04, and concentrated. Purification by SPE (step gradient 1, 2, 3, 5, 6% CM)
gave fractions yielding a yellow solid. Recrystallization from MeOH gave 229 mg of a colorless
solid. Rf0.14 (5% MeOH/DCM); mp 132.5-133.0 0C; 1H NMR (CDCl3) 8 8.52 (d, 1H, J=5.7
Hz), 8.03 (dd, 1H, J=0.7, 8.4 Hz), 7.85 (d, 1H, J=7.6 Hz), 7.64 (ddd, 1H, J=1.5, 6.9, 8.4 Hz),
7.44 (ddd, 1H, J=1.2, 6.9, 8.1 Hz), 6.88-6.81 (m, 4H), 6.50 (d, 1H, J=5.7 Hz), 5.92 (br s, 1H,
NH), 4.26 (t, 2H, J=5 Hz), 3.89 (t, 2H, J=6 Hz), 3.73 (q, 2H, J=5.2 Hz), 1.74 (m, 2H), 1.48-1.28
(m, 6H), 0.89 (m, 3H).
Example 45: Hexyl 4—(quinolin—4—y1amino)benzoate
Hexyl 4—aminobenzoate (282 mg), prepared from l—hexanol and 4—nitrobenzoyl chloride in two
unremarkable steps, was reacted with 4—chloroquinoline (322 mg) and DIEA (0.50 mL) in 2 mL
of NMP heated at 160 0C in a sealed tube for 16 hr. The mixture was cooled and partitioned
between EA and 5% N32CO3. The organic phases were washed with brine, dried over NaZSO4,
and concentrated. Purification by SPE, washing with 20% EA/Hex and then eluting with 55%
EA/Hex, gave a yellow solid. Recrystallization from EA/Hex gave a colorless solid. Rf0. 14
(50% EA/Hex); 1H NMR (CDC13) 5 8.61 (d, 1H, J=5.2 Hz), 8.09-8.03 (m, 4H), 7.70 (ddd, 1H,
J=l.2, 6.9, 8.4 Hz), 7.52 (ddd, 1H,J=1.2, 6.9, 8.4 Hz), 7.34-7.31 (m, 2H), 7.19 (d, 1H, J=5.2 Hz),
4.30 (t, 2H, J=6.6 Hz), 1.76 (m, 2H), 1.47-1.24 (m, 6H), 0.89 (m, 3H).
Example 46: N—(4—Phenoxyphenyl)quinolin—4—amine
.Nooo
A mixture of 4—phenoxyaniline (182 mg, 0.98 mmol), 4—chloroquinoline (175 mg, 1.07 mmol),
and DIEA (0.50 mL, 2.87 mmol) in 1 mL of NMP was heated at 140—150 0C in a sealed tube for
24 hr. Then, the mixture was cooled and partitioned between DCM and 5% N32CO3. The organic
phase was dried over Na2804 and concentrated. SPE, washing with 50% EA/Hex and g
with 5% MeOH/DCM, gave a solid. Recrystallization from EA/Hex gave 111 mg of tan solid. A
second crop of 111 mg light tan solid was obtained from MeOH. The two crops had comparable
NMR spectra. Rf 0.19 (5% MeOH/DCM); mp 170-172 0C (from MeOH); 1H NMR (CDClg) 5
8.51 (d, 1H, J=5.5 Hz), 8.05 (d, 1H, J=8.7 Hz), 7.99 (d, 1H, J=8.4 Hz), 7.68 (ddd, 1H, J=1.3, 6.9,
8.2 Hz), 7.50 (ddd, 1H, J=1.3, 6.9, 8.2 Hz), .25 (m, 5H), 7.22—6.99 (m, 5H), 6.83 (d, 1H,
J=5.4 Hz).
Example 47: N—(3—Phenoxyphenyl)quinolin—4—amine
A mixture of 3—phenoxyaniline (307 mg, 1.66 mmol), 4—chloroquinoline (296 mg, 1.82 mmol),
and DIEA (0.32 mL, 1.84 mmol) in 1 mL of NMP was heated at 140—150 0C in a sealed tube for
24 hr. Then, the mixture was cooled and partitioned between DCM and 5% . The organic
phase was dried over NaZSO4 and concentrated. SPE, washing with 20% EA/Hex, 20% EA/Hex
+ 2% TEA, and 35% EA/Hex + 2% TEA, then eluting with 50% EA/Hex + 2% TEA, gave 208
mg of yellow solid. Rf0.26 (7.5% MeOH/DCM); mp 189—192 0C (from MeOH); 1H NMR
(CDC13) 5 8.40 (d, 1H, J=5.2 Hz), 7.98-7.91 (m, 2H), 7.62 (m, 1H), 7.45 (m, 1H), .26 (m,
3H), 7.10—6.98 (m, 6H), 6.90 (t, 1H, J=2.2 Hz), 6.75 (dd, 1H, J=2.5, 8.1 Hz).
e 48: N—(2—Phenoxyphenyl)quinolin—4—amine
Cd: 0o
A mixture of 2—phenoxyaniline (286 mg, 1.54 mmol), 4—chloroquinoline (278 mg, 1.70 mmol),
and 4—methylmorpholine (0.19 mL, 1.73 mmol) in 0.5 mL of NMP was heated in a heavy walled
sealed tube at 130 0C for 20 hr. The mixture was cooled and partitioned between EA and 5%
Na2C03 and brine. The organic phases were dried over NaZSO4 and trated. FC (7.5%
MeOH/DCM) gave a dark oil that contained residual 4-methylmorpholine. The oil was filtered
through a pad of silica gel using 30% EA/Hex + 2% TEA to give 402 mg of solid. Rf 0.10 (5%
MeOH/DCM); 1H NMR(CDC13) 8 8.61 (d, 1H, J=5.2 Hz), 8.03 (dd, 1H, J=0.7, 8.4 Hz), 7.85-
7.81 (m, 1H), 7.64 (ddd, 1H, J=1.5, 6.9, 8.4 Hz), 7.59 (m, 1H), 7.43 (m, 1H), 7.34—7.24 (m, 2H),
7.19—6.98 (m, 8H).
Example 49: Quinolin—4—ylamino)phenyl]hexanamide
N—(4—Nitrophenyl)hexanamide Hexanoyl chloride ((0.81 mL, 5.8 mmol) was added slowly
to a mixture of 4—nitroaniline ((800 mg, 5.79 mmol) in 5 mL of pyridine and 15 mL of DMF
cooled by an ice bath. After 30 min, the mixture was warmed to room temperature. After an
onal 2 hr, the volatile components were evaporated. The residue was taken up in EA (100
mL) and washed with ted NaHC03 (2x75 mL), H20 (2x50 mL), 0.1N HCl (2x25 mL), and
H20. The organic phase was concentrated in vacuo to give 1.50 g product. 1H NMR (CDC13) 5
8.2 (m, 2H), 7.7 (m, 2H), 7.4 (br s, 1H, NH), 2.4 (m, 2H), 1.8 (m, 2H), 1.4-1.3 (m, 4H), 0.9 (m,
3H).
N—(4—Aminophenyl)hexanamide A mixture of N—(4—nitrophenyl)hexanamide (1.50 g), 10%
Pd—C (200 mg), and 75 mL of MeOH was stirred under a blanket of hydrogen until the starting
material was consumed, as observed by analytical TLC. Then, the atmosphere was purged with
argon, and the mixture was ed through a pad of . Evaporation of the solvent gave 1.22
g of product. 1H NMR (CDC13) 8 7.2 (m,3H), 7.0 (br s, 1H, NH), 6.6 (m, 2H), 3.6 (br s, 2H,
N?z), 2.3 (m, 2H), 1.7 (m, 2H), 1.4-1.2 (m, 4H), 0.9 (m, 3H).
N—[4-(Quinolinylamino)phenyl]hexanamide A mixture of 4-chloroquinoline (358 mg,
2.20 mmol), N—(4-aminophenyl)hexanamide (300 mg, 1.46 mmol), and TEA (1 mL) was heated
at 130 0C in a sealed tube for 5 days. Then the volatile components were evaporated. The e
was purified by preparative TLC (10% MeOH/DCM) to give 329 mg of product. Rf 0.3 (10%
MeOH/DCM); 1H NMR (CDC13) 8 8.56 (d, 1H, J=5.5 Hz), 8.04 (d, 2H, J=8.9 Hz), 8.05-7.99 (m,
2H), 7.69 (ddd, 1H, J=1.2, 6.9, 8.2 Hz), 7.51 (ddd, 1H, 121.5, 6.9, 8.4 Hz), 7.30 (d, 2H, J=8.9
Hz), 7.18 (d, 1H, J=5.4 Hz), 4.35 (q, 2H, J=7 Hz), 1.38 (t, 3H, J=7 Hz).
Example 50: N—[3—(Quinolin—4—ylamino)phenyl]hexanamide
HNOHM
N—[3—(Quinolin—4—ylamino)phenyl]hexanamide was prepared following the method for N—[4—
(quinolin—4—ylamino)phenyl]hexanamide, starting with 3—nitroaniline (800 mg) and hexanoyl
de (0.81 mL) and using 4—chloroquinoline (358 mg).
N—(4—Nitrophenyl)hexanamide (1.50 g): 1H NMR (CDC13) 5 8.4 (m, 1H), 8.0—7.9 (m, 2H), 7.8 (br
s, 1H, NH), 7.5 (m, 1H), 2.4 (m, 2H), 1.8 (m, 2H), 1.4-1.2 (m, 4H), 0.9 (m, 3H).
N—(4—Aminophenyl)hexanamide (1.34 g): 1H NMR (CDC13) 5 7.4 (br s, 1H, NH), 7.2 (br s, 1H),
7.0 (t, 1H), 6.7 (d, 1H), 6.4 (d, 1H), 3.5 (br s, 2H, N?z), 2.3 (t, 2H), 1.7 (m, 2H), 2 (m, 4H),
0.9 (m, 3H).
N—[3—(Quinolin—4—ylamino)phenyl]hexanamide: Rf0.2 (10% MeOH/DCM); 1H NMR (CD3OD) 5
8.5 (d. 1H), 8.4 (d, 1H), 8.0-7.8 (m, 3H), 7.7 (m, 1H), 3 (m, 2H), 7.1 (m, 1H), 7.0 (d, 1H),
2.4 (t, 2H), 1.7 (m, 2H), 1.4-1.2 (m, 4H), 0.9 (m, 3H).
Example 51: N—Hexy1—4—(quinolin—4-ylamino)benzamide
HN@NWH
(:6?/N
N—Hexyl(quinolinylamino)benzamide 4-Amino-N-hexylbenzamide (220 mg), prepared
from l—aminohexane (0.70 mL) and 4—nitrobenzoyl de (450 mg) in two unremarkable steps,
was reacted with 4—chloroquinoline (239 mg) and DIEA (0.50 mL) in 1 mL of IPA heated at 130-
180 0C in a sealed tube for 8 days. The mixture was cooled and partitioned between DCM and
% . The organic phases were dried over NaZSO4, and concentrated. Purification by SPE,
washing with 3% MeOH/DCM and then eluting with 15% MeOH/DCM, gave 105 mg of a solid.
Rf0.08 (5% MeOH/DCM); 1H NMR (20% CD30D/CDC13) 5 8.39 (d, 1H, J=5.4 Hz), 8.15 (dd,
1H, 120.7, 8.4 Hz), 7.89 (dd, 1H, J=0.7, 8.4 Hz), 7.80—7.75 (m, 2H), 7.65 (ddd, 1H, J=1.5, 6.9,
8.4 Hz), 7.47 (ddd, 1H, J=1.2, 6.9, 8.4 Hz), 7.36—7.30 (m, 2H), 7.07 (d, 1H, J=5.5 Hz), 3.35 (m,
2H, AB), 1.57 (m, 2H), 1.32—1.21 (m, 6H), 0.84 (t, 3H, J=6 Hz).
N—Hexyl—4—nitrobenzamide (467 mg): 1H NMR (CDC13) 5 8.17 (d, 2H, J=8.7 Hz), 7.91 (d, 2H,
J=8.7 Hz), 7.00 (br s, 1H, NH), 3.39 (m, 2H), 1.56 (m, 2H), 1.4-1.1 (m, 6H), 0.81 (m, 3H).
o—N—hexylbenzamide: Rf 0.22 (5% MeOH/DCM); 1H NMR (CDCl3) 5 7.56 (m, 2H), 6.58
(m, 2H), 6.56 (br s, 1H, NH), 4.12 (br s, 2H, NH;), 3.57 (m, 2H), 1.53 (m, 2H), 1.47-1.22 (m,
6H), 0.84 (m, 3H).
Example 52: N—Hexyl—3—(quinolin—4—ylamino)benzamide
N—Hexyl—3—(quinolin—4—ylamino)benzamide (117 mg) was prepared following the method for N—
hexyl—4—(quinolin—4—ylamino)benzamide, starting from 3—nitrobenzoic acid (1.17 g) and 1—
hexylamine (1.02 mL) and using 4—chloroquinoline (225 mg).
N—Hexylnitrobenzamide: 1H NMR (CDClg) 8 8.56 (m, 1H), 8.28 (m, 1H), 8.13 (ddd, 1H,
J=1.2, 1.7, 7.7 Hz), 7.58 (t, 1H, J=7.9 Hz), 6.84 (br s, 1H, NH), 3.44 (m, 2H), 1.60 (m, 2H), 1.39-
1.23 (m, 6H), 0.84 (t, 3H, J=7.0 Hz).
3—Amino—N—hexylbenzamide (1.47 g): Rf 0.25 (5% MeOH/DCM); 1H NMR (CDC13) 8 7.14—7.00
(m, 3H), 6.71 (m, 1H), 6.42 (br s, 1H, NH), 3.80 (br s, 2H, N?z), 3.34 (m, 2H), 1.53 (m, 2H),
1.48—1.21 (m, 6H), 0.84 (m, 3H).
N—Hexyl—3—(quinolin—4—ylamino)benzamide: Rf 0.05 (5% MeOH/DCM); 1H NMR (20%
CD30D/CDC13) 5 8.34 (d, 1H, J=5.6 Hz), 8.18 (dd, 1H, J=0.7, 8.4 Hz), 7.91-7.88 (m, 1H), 7.70-
7.64 (m, 2H), 7.53—7.38 (m, 4H), 6.93 (d, 1H, J=5.7 Hz), 3.35 (m, 2H), 1.57 (m, 2H), 1.32—1.20
(m, 6H), 0.84 (m, 3H).
Example 53: ethoxyphenyl)quinolin—4—amine
CK?/
A mixture ofp—anisidine (138 mg, 1.12 mmol), 4—chloroquinoline (235 mg, 1.44 mmol), and
DIEA (0.50 mL, mmol) was heated at 130 0C in a sealed tube for 40 hr. The cooled mixture was
partitioned between EA (3x) and 5% N32C03 (3x) and brine, and the organic phases were dried
over anhydrous NaZSO4 and trated to give 385 mg of brown oil. Purification by
preparative TLC (10% MeOH/DCM) gave 294 mg of brown oil that fied upon standing. 1H
NMR(CDC13) 5 8.48 (d, 1H, J=5.4 Hz), 7.99 (d, 1H, J=8.4 Hz), 7.96 (d, 1H, J=8.4 Hz), 7.64
(ddd, 1H, J=1.3, 7.0, 8.5 Hz), 7.45 (m, 1H), 7.21 (m, 2H), 6.93 (m, 2H), 6.68 (d, 1H, J=5.2 Hz),
3.82 (s, 3H).
Example 54: N-[4-(Benzyloxy)phenyl]quinolinamine
00 V
CK)/
A mixture of 4-(benzyloxy)aniline (197 mg, 0.99 mmol), 4—chloroquinoline (169 mg, 1.04
mmol), and DIEA (0.18 mL, 1.03 mmol) in 1 mL of NMP was heated at 150 °C in a sealed tube
for 24 hr. Then, the mixture was cooled and partitioned between EA (2x) and 5% N32C03 (2x)
and brine. The organic phase was dried over Na2S04 and concentrated. SPE, washing with 1%
MeOH/DCM and eluting with 5% MeOH/DCM while cutting fractions, gave 152 mg of
colorless solid. Rf 0.18 (5% MeOH/DCM); mp 201—202 0C (from MeOH); 1H NMR (CDC13) 5
8.49 (d, 1H, J=5.4 Hz), 8.02 (dd, 1H, J=1.0, 8.6 Hz), 7.91 (dd, 1H, J=0.7, 8.4 Hz), 7.66 (ddd, 1H,
J=1.2, 6.9, 8.4 HZ), 7.51—7.31 (m, 6H), 7.26—7.20 (m, 2H), 7.06-6.98 (m, 2H), 6.71 (d, 2H, J=5.2
Hz), 5.09 (s, 2H).
Example 55: N—(4—Butoxyphenyl)quinolin—4—amine
A mixture of xyaniline (236 mg, 1.43 mmol), 4—chloroquinoline (236 mg, 1.45 mmol), and
DIEA (0.26 mL, 1.49 mmol) in 1 mL of NMP was heated at 150 0C in a sealed tube for 24 hr.
The cooled mixture was partitioned between EA (2x) and 5% N32CO3 (2x) and brine, and the
organic phases were dried over anhydrous NaZSO4 and concentrated to give a solid. SPE,
washing with 1% MeOH/DCM and eluting with 5% MeOH/DCM, gave fractions affording a
solid after concentration. tallization from MeOH gave 177 mg. Rf 0. 18 (5%
MeOH/DCM); mp 181—185 0C; 1H NMR (CDC13) 5 8.45 (d, 1H, J=5.4 Hz), 8.03 (dd, 1H, J=1.0,
8.7 Hz), 7.97 (d, 1H, J=8.4 Hz), 7.67 (ddd, 1H, J=1.2, 6.9, 8.1 Hz), 7.48 (ddd, 1H, J=1.5, 6.9, 8.4
Hz), 7.22 and 6.95 (m, 4H, ), 6.67 (d, 1H, J=5.4 Hz), 3.98 (t, 2H, J=6.5 Hz), 1.79 (m,
2H), 1.51 (m, 2H), 0.99 (t, 3H, J=7.3 Hz).
Example 56: N-[4—(Hexyloxy)pheny1]quinolin—4—amine
1—(Hexyloxy)—4—nitrobenzene A mixture of 4—nitrophenol (480 mg, 3.45 mmol), 1—bromohexane
(0.43 mL, 3.08 mmol), K2C03 (481 mg, 3.57 mmol), and 20 mg sodium iodide in 5 mL of DMF
was heated at 60 0C for 18 hr. The cooled mixture was diluted with EtZO and washed with 5%
N212C03 and brine, repetitively, until the aqueous phase was colorless. The organic phase was
dried over MgSO4 and concentrated to obtain 532 mg of yellow oil. Rf 0.21 (5% EA/Hex); 1H
NMR(CDC13) 5 8.19-8.13 (m, 2H, ), 6.94—6.88 (m, 2H, AA’BB’), 4.02 (t, 2H), 1.80 (m,
2H), 1.50—1.29 (m, 6H), 0.89 (m, 3H).
4—(Hexyloxy)aniline A mixture of 1—(hexyloxy)—4—nitrobenzene (532 mg, 2.38 mmol) and 5%
Pd/C (60 mg) in 20 mL of MeOH was stirred under a hydrogen atmosphere for 3 hr. Then, the
mixture was ed through a pad of Celite and concentrated to give 458 mg of oil. 1H NMR
(CDC13) 5 6.78—6.72 (m, 2H, AA’BB’), 6.65-6.59 (m, 2H, AA’BB’), 3.88 (t, 2H), 3.44 (br s, 2H,
NH;), 1.75 (m, 2H), 1.50-1.28 (m, 6H), 0.92 (m, 3H).
N—[4—(Hexyloxy)phenyl]quinolin—4—amine A mixture of 4—(hexyloxy)aniline (430 mg, 2.23
mmol), 4—chloroquinoline (431 mg, 2.64 mmol), and DIEA (1.0 mL, 5.74 mmol) in 1 mL of
NMP was heated in a heavy walled sealed tube at 160 0C for 24 hr. The e was cooled and
partitioned between EA and 5% Na2C03 and brine. The organic phases were dried over Na2S04
and concentrated to give a solid that was tallized from EtOH to give a colorless solid. 1H
NMR (CDC13) 5 8.49 (d, 1, J=5.2 Hz), 8.02 (dd, 1, J=0.7, 8.4 Hz), 7.91 (d, 1, J=8.4 Hz), 7.67
(ddd, 1, J=1.5, 6.9, 8.4 Hz), 7.48 (ddd, 1, J=1.5, 6.9, 8.4 Hz), 7.25-7.18 (m, 2H), 6.98-6.92 (m,
2H), 6.69 (d, 1, J=5.5 Hz), 6.64 (br s, 1H), 3.97 (t, 2H, J=6 Hz), 1.80 (m, 2H), 1.50-1.30 (m, 6),
0.92 (m, 3).
Example 57: N-[3-(Benzyloxy)phenyl]quinolinamine
A mixture of 3—(benzyloxy)aniline (312 mg, 1.57 mmol), 4—chloroquinoline (280 mg, 1.72
mmol), and DIEA (0.30 mL, 1.72 mmol) in 1 mL of NMP was heated at 150 °C in a sealed tube
for 24 hr. Then, the mixture was cooled and partitioned between DCM and 5% N32C03. The
organic phase was dried over NaZSO4 and concentrated. SPE, washing with 20% , 20%
EA/Hex + 2% TEA, and 35% EA/Hex + 2% TEA, then eluting with 50% EA/Hex + 2% TEA,
gave 528 mg of yellow solid. tallization from MeOH gave 390 mg of pale yellow solid. Rf
0.26 (7.5% MeOH/DCM); mp 77—80 0C (from MeOH); 1H NMR (CDC13) 5 8.45 (d, 1H, .1255
Hz), 8.04 (d, 1H, J=8.4 Hz), 7.98 (d, 1H, J=8.4 Hz), 7.67 (m, 1H), .24 (m, 8H), 6.94—6.79
(m, 4H), 5.08 (s, 2H).
Example 58: N—[3—(Hexyloxy)phenyl]quinolin—4—amine
1—(Hexyloxy)—3—nitrobenzene A mixture of 3—nitrophenol (553 mg, 3.98 mmol), 0hexane
(0.50 mL, 3.58 mmol), and K2C03 (618 mg, 4.48 mmol) in 5 mL of DMF was heated at 60—80
0C for 12 hr. The cooled mixture was diluted with EtZO and washed with 5% N32C03 and brine,
repetitively, until the aqueous phase was colorless, and then with 0.1M HCl and brine. The
organic phase was dried over MgSO4 and concentrated to obtain 756 mg of oil. 1H NMR
)8 7.78 (ddd, 1H, J=1.0, 2.0, 7.9 Hz), 7.70 (m, 1H), 7.39 (m, 1H), 7.19 (ddd, 1H, J=1.0,
2.4, 8.1 Hz), 4.01 (t, 2H, J=6.6 Hz), 1.80 (m, 2H), 1.58-1.30 (m, 6H), 0.89 (m, 3H).
3-(Hexyloxy)aniline A mixture of 1-(hexyloxy)nitrobenzene (756 mg, 3.39 mmol) and 5%
Pd/C (90 mg) in 20 mL of MeOH was stirred under a hydrogen atmosphere for 3 hr. Then, the
mixture was filtered through a pad of Celite and concentrated to give 660 mg of light orange oil.
1H NMR (CDC13) 5 7.04 (m, 1H), 6.34—6.23 (m, 3H), 3.90 (t, 2H), 3.62 (br s, 2H, N?z), 1.75 (m,
2H), 1.49—1.26 (m, 6H), 0.90 (m, 3H).
N—[3—(Hexyloxy)phenyl]quinolin—4—amine Anhydrous pyridine (4 mL) was evaporated from
the crude 3-(hexyloxy)aniline (406 mg, 2.10 mmol), then 4—chloroquinoline (420 mg, 2.58
mmol), DIEA (0.80 mL, 4.59 mmol), and 1.5 mL of NMP were added, and the mixture was
heated at 160 0C in a heavy walled sealed tube for 24 hr. The mixture was cooled and partitioned
n EA and 5% N32CO3 and brine. The organic phases were dried over NaZSO4 and
concentrated. SPE, washing with 20% EA/Hex and then g with 50% EA/Hex + 2% TEA,
gave the product as a brown oil that contained residual NMP. Crystallization from EA/Hex gave
410 mg of light tan solid. Rf0.32 (50% 50% EA/Hex + 2% TEA); 1H NMR (CDClg) 5 8.55 (d,
l, J=5.2 HZ), 8.03—7.96 (m, 2H), 7.63 (ddd, 1, J=l.2, 6.9, 8.4 Hz), 7.43 (ddd, l, J=l.2, 6.7, 8.2
Hz), 7.26 (m, 1H), 7.14 (br s, 1H), 7.04 (d, 1, J=5.5 HZ), 6.87-6.83 (m, 2H), 6.69 (m, 1H), 3.90
(t, 2H, J=6 Hz), 1.75 (m, 2H), .30 (m, 6), 0.89 (m, 3).
Example 59: N—[2—(Benzyloxy)phenyl]quinolin—4—amine
A mixture of 2—(benzyloxy)aniline (301 mg, 1.51 mmol), 4—chloroquinoline (268 mg, 1.64
mmol), and ylmorpholine (0.18 mL, 1.64 mmol) in 0.5 mL of NMP was heated in a heavy
walled sealed tube at 130 °C for 20 hr. The mixture was cooled and partitioned between EA and
% N32CO3 and brine. The organic phases were dried over NaZSO4 and concentrated. FC (7.5%
MeOH/DCM) gave a dark oil that contained residual 4-methylmorpholine. The oil was filtered
through a pad of silica gel using 30% EA/Hex + 2% TEA to give 268 mg of tan solid. Rf0.12
(5% MeOH/DCM); 1H NMR(CDC13) 8 8.60 (d, 1H, J=5.4 Hz), 8.05 (dd, 1H, 1.0, 8.4 Hz), 7.88
(dd, 1H, J=0.8, 8.4 Hz), 7.66 (ddd, 1H, J=1.2, 6.9, 8.4 Hz), .40 (m, 2H), 7.37-7.29 (m,
5H), 7.15 (d, 1H, J=5.2 Hz), 7.07-6.98 (m, 3H), 5.17-5.10 (m, 2H, AB).
Example 60: N-[2—(Hexyloxy)pheny1]quinolin—4—amine
HN ;
C6?OM/N
1—(Hexyloxy)—2—nitrobenzene 2—Nitrophenol (1.38 g, 9.93 mmol), l—bromohexane (1.30 mL, 9.30
mmol), and K2C03 (1.38 g, 10.0 mmol) in 6 mL of DMF was mixed at room temperature for 3
days. The mixture was diluted with EtzO and washed with 0.25N NaOH until the aqueous phase
was colorless, and then with brine. The organic phase was dried over MgS O4 and concentrated.
Rf0.39 (5% EA/Hex); 1H NMR (CDCl3) 5 7.78 (dd, 1H, J=l.7, 8.2 Hz), 7.48 (ddd, 1H, J=l.8,
7.3, 8.9 HZ), 7.04 (dd, 1H, J=l.0, 8.5 Hz), 6.97 (ddd, 1H, 1.2, 7.4, 8.2 Hz), 4.07 (t, 2H, J=6.4
Hz), 1.80 (m, 2H), 1.51—1.28 (m, 6H), 0.90 (m, 3H).
2—(Hexyloxy)aniline A mixture of the l—(hexyloxy)—2—nitrobenzene and 5% Pd/C (94 mg) in 15
mL of MeOH and 15 mL of EA was stirred under a hydrogen atmosphere for 5 hr. Then, the
mixture was filtered through a pad of Celite and concentrated. The residue was ed through
silica gel using 30% EA/Hex to give 1.51 g of brown oil that contained residual 1—bromohexane,
as shown by NMR is. SPE, washing with hexane and eluting with 30% EA/Hex gave 1.38
g of red—brown oil. Rf0.26 (5% EA/Hex); 1H NMR (CDC13) 8 6.81—6.68 (m, 4H), 3.98 (t, 2H,
J=6.4 Hz), 3.76 (br s, 2H, NH;), 1.81 (m, 2H), 1.53—1.23 (m, 6H), 0.91 (m, 3H).
N—[2—(Hexyloxy)phenyl]quinolin—4—amine A mixture of 2—(hexyloxy)aniline (282 mg, 1.46
mmol), 4—chloroquinoline (258 mg, 1.58 mmol), and 4—methylmorpholine (0.18 mL, 1.64 mmol)
in 0.5 mL of NMP was heated in a heavy walled sealed tube at 130 0C for 20 hr. The mixture
was cooled and ioned between EA and 5% Na2C03 and brine. The organic phases were
dried over NaQSO4 and concentrated. FC (7.5% MeOH/DCM) gave a dark oil that contained
residual 4-methylmorpholine. The oil was filtered through a pad of silica gel using 30% EA/Hex
+ 2% TEA to give 416 mg of tan solid. Rf0.13 (5% MeOH/DCM) 0.50 (10% MeOH/DCM); 1H
NMR(CDC13) 5 8.59 (dd, 1H, J=6.3, 11.5 Hz), 8.05 (m, 1H), 7.95 (m, 1H), 7.65 (ddd, 1H, J=1.3,
6.7, 9.7 Hz), 7.50—7.44 (m, 2H), 7.19-7.13 (m, 2H), .91 (m, 3H), 3.99 (t, 2H, J=6.4 Hz),
1.75 (m, 2H), 1.45—1.17 (m, 6H), 0.83 (m, 3H).
Example 61: N—[2—Fluoro—4—(hexyloxy)pheny1]quinolin—4—amine
2—Fluoro—4—(hexyloxy)—l—nitrobenzene (2.6 g) was prepared from o—4—nitrophenol (5.0 g,
31.5 mmol), 60% sodium hydride (1.9 g), l—bromohexane (4.75 mL), and 30 mL of DMF
2014/013992
following the method for romooctyloxy)—3—methylbenzene. 1H NMR (CDCl3) 5 8.05 (t,
1H), 6.7 (m, 2H), 4.0 (t, 2H), 1.8 (m, 2H), 161.3 (m, 6H), 0.9 (m, 3H).
2—Fluoro—4—(hexyloxy)aniline (1.6 g) was prepared from 2—?uoro—4—(hexyloxy)—l—nitrobenzene
(2.6 g) following the method for 8—(3—ethoxypropoxy)octan—l—amine. 1H NMR (CDCl3) 8 6.75—
6.5 (m, 3H), 3.85 (t, 2H), 3.4 (br s, 2H, NH;), 1.75 (m, 2H), 15-12 (m, 6H), 0.9 (m, 3H).
N—[2—Fluoro—4—(hexyloxy)phenyl]quinolin—4—amine (114 mg) was prepared from 2—?uoro—4—
(hexyloxy)aniline (1.6 g), roquinoline (1.33 g), TEA (5 mL), and NMP (0.5 mL) at 130 0C
in a sealed tube for 5 days following the method for N—[8—(3—ethoxypropoxy)octyl]quinolin—4—
amine. 1H NMR(CDC13)5 8.55 (d, 1H), 8.05 (d, 1H), 7.95 (d, 1H), 7.7 (m, 1H), 7.5 (m, 1H), 7.3
(m, 1H), 6.75 (m, 2H), 6.65 (d, 1H), 6.4 (br s, 1H, NH), 3.95 (t, 2H), 1.8 (m, 2H), 1.6-1.3 (m,
6H), 0.9 (m, 3H).
Example 62: N-Benzquuinolinamine
A mixture of benzylamine (166 mg, 1.55 mmol), 4—chloroquinoline (268 mg, 1.64 mmol), and
DIEA (0.50 mL, 2.87 mmol) was heated in a heavy walled sealed tube at 130 °C for 40 hr. The
mixture was cooled, a mixture of EtOH and H20 was added, and the sealed mixture was heated
for 16 hr. Then, the mixture was cooled and partitioned n EA (3x) and 5% N32C03 (3x)
and brine. The organic phases were dried over Na2S04 and concentrated to give 385 mg of oil.
Purification by preparative TLC (10% MeOH/DCM) gave 294 mg of brown oil. Rf 0.33 (10%
MeOH/DCM); 1H NMR (CDC13) 8 8.49 (d, 1H, J=5.2 Hz), 7.98 (dd, 1H, J=0.8, 8.4 Hz), 7.82 (d,
1H, J=8.4 Hz), 7.61 (ddd, 1H, J=l.2, 6.9, 8.4 Hz), 7.42—7.27 (m, 6H), 6.41 (d, 1H, J=5.4 Hz),
.76 (br s, 1H), 4.51 (m, 2H, AB).
e 63: N—Phenethquuinolin—4—amine
A mixture of 2—phenethylamine (177 mg, 1.46 mmol), 4—chloroquinoline (258 mg, 1.58 mmol),
and DIEA (0.50 mL, 2.87 mmol) was heated at 130 0C in a sealed tube for 40 hr. The cooled
mixture was partitioned between EA (3x) and 5% N32C03 (3x) and brine, and the organic phases
were dried over anhydrous NaZSO4 and trated to give a solid. Washing with EtZO gave
230 mg of red solid. 1H NMR (CDC13) 5 8.55 (d, 1H, J=5.4 Hz), 7.98 (m, 1H), 7.64-7.58 (m,
2H), 7.42—7.24 (m, 6H), 6.48 (d, 1H, J=5.4 Hz), 5.17 (br s, 1H, NH), 3.60 (m, 2H), 3.06 (t, 2H,
J=6.9 Hz).
Example 64: N—[4-(Hexyloxy)benzyl]quinolinamine
co“(10W/N
4-(Hexyloxy)benzonitrile A mixture of 4-cyanophenol (25.2 g, 212 mmol), K2CO3 (24.7 g,
233 mmol), and l-bromohexane (29.6 mL, 212 mmol) in 150 mL of DMF was d at room
temperature for 24 hr and then at 55 °C for 24 hr. 4—Cyanophenol remained, as shown by TLC.
Na2C03 (7.0 g, 66 mmol), and 1—bromohexane (3.0 mL, 21 mmol) were added, and, after 24 hr,
the temperature was lowered to 40 °C and additional Na2C03 (12.4 g, 117 mmol) and 1—
bromohexane (10.0 mL, 72 mmol) were added. r, after 24 hr, no consumption of the
ing 4-cyanophenol was apparent. The mixture was cooled to room temperature and 6 mL
of concentrated NH4OH was added. After standing for 3 days, the mixture was partitioned
between EA (3x250 mL) and H20 (300 and 200 mL), 1M HCl (100 mL), and brine (150 mL).
The combined organic phases were dried over MgSO4 and concentrated. SPE (10% EA/Hex)
gave 35.8 g of colorless oil that solidified upon standing. Rf 0.63 (20% EA/Hex); 1H NMR
(CDC13)5 7.55 and 6.92 (m, 4H, AA’BB’), 3.98 (t, 2H, J=6.6 Hz), 1.78 (m, 2H), 1.43 (m, 2H),
1.35—1.30 (m, 4H), 0.89 (m, 3H); 13C NMR ) 5 162.6, 134.1, 119.5, 115.4, 103.8, 68.6,
31.7, 29.1, 25.8, 22.7, 14.2.
[4—(Hexyloxy)phenyl]methanamine 4—(Hexyloxy)benzonitrile (35.8 g, 176 mmol) was taken up
in 350 mL of THF, and the mixture was cooled by an ice bath. LAH (7 g, 184 mmol) was added
cautiously in ns. After 1 hr, the mixture was heated at re?ux. After 15 hr, the mixture was
cooled with an ice bath. Cautiously, with thorough ng, in portions and in sequence, 7 mL of
H20, 7 mL of 15% NaOH, and 21 mL of H20 were added to the ice—cold mixture. The resultant
heterogenous mixture was diluted with 350 mL of IPA. The mixture was filtered through a bed
of Celite, and the solids were washed with 200 mL of IPA. The filtrate was trated to give
34.4 g of the product that contained residual IPA. Rf 0.25 (5% MeOH/DCM + 2% TEA,
ninhydrin (+)); 1H NMR (CDCl3) 8 7.17 and 6.83 (m, 4H, ), 3.90 (t, 2H, J=6.7 Hz), 3.74
(s, 2H), 2.00 (br s, 2H, N?z), 1.78 (m, 2H), 1.48—1.27 (m, 6H), 0.88 (m, 3H).
N—[4-(Hexyloxy)benzyl]quinolinamine [4-(Hexyloxy)phenyl]methanamine (166 mmol)
was taken up in 400 mL of 1-pentanol, and 150 mL of volatile material was removed by
distillation in order to ensure anhydrous conditions. The mixture was allowed to cool to 70 OC,
and tripropylamine (63 mL, 330 mmol) and 4-chloroquinoline (28 g, 172 mmol) were added.
Heating at re?ux was resumed. After 16 hr, TLC of an aliquot indicated very little ninhydrin (+)
ng material ed. Volatile material was removed by distillation and evaporation. The
cooled mixture was diluted with 1:2 DCM/EA and washed with 3N NaOH (60 mL), H20, and
brine. The combined organic phases were dried over NaZSO4, filtered, and concentrated. SPE,
eluting with 50% EA/Hex and then 15% EtOH/DCM, gave a brown oil. The oil was taken up in
EA and washed with 5% Na2C03 and brine. The organic phase was dried over Na2804, filtered,
and concentrated. EA (10 mL) and then s (20 mL) were added to the e. A
precipitate was obtained. The colorless precipitate was collected by filtration and washed with
100 mL of 50% EA/Hex and then 50 mL of 30% EA/Hex. A second crop was obtained from the
combined filtrates. The crops were combined and dried in vacuo to give 38.4 g. Rf 0.25 (5%
MeOH/DCM); mp 1035—1040 0C; 1H NMR(CDC13) 5 8.55 (d, 1H, J=5.5 Hz) 8.00 (d, 1H, J=0.7
Hz), 7.98 (d, 1H, J=0.7 Hz), 7.74 (m, 1H), 7.65—7.61 (m, 1H), 7.41 (m, 1H), 7.30 and 6.90 (m,
4H, AA’BB’), 6.46 (d, 1H, J=5.1 Hz), 5.33 (m, 1H), 4.43 (m, 2H, AB), 3.96 (t, 2H, J=6.6 Hz),
1.79 (m, 2H), 1.46 (m, 2H), 1.39—1.30 (m, 4H), 0.90 (m, 3H); 13C NMR(CDC13) 8 159.2, 151.4,
149.6, 148.7, 130.3, 129.5, 129.2, 129.1, 124.9, 119.5, 119.0, 115.2, 99.5, 68.4, 47.4, 31.8, 29.4,
.9, 22.8, 14.2.
Example 65: N—[3—(Hexyloxy)benzyl]quinolin—4—amine
3—(Hexyloxy)benzaldehyde A mixture of 3—hydroxybenzaldehyde (10.3 g, 84.4 mmol), K2C03
(13.9 g, 100.7 mmol), and 1—bromohexane (11.2 mL, 80.0 mmol) in 90 mL of DMF was heated
at 60 °C for 12 hr. The mixture was cooled to room temperature, poured into 30% , and
washed with H20, 5% Na2C03, H20, 0.1M HCl, and brine. The organic phases were dried over
NagSO4, filtered h a pad of silica gel, and concentrated to give 15.8 g of brown oil. Rf 0.56
(20% EA/Hex), 1H NMR (CDC13) 8 9.94 (s, 1H), 7.43-7.36 (m, 3H), 7.14 (m, 1H), 3.99 (t, 2H,
J=6.6 Hz), 1.79 (m, 2H), 1.45 (m, 2H), 1.37-1.28 (m, 4H), 0.89 (m, 3H); 13C NMR (CDC13) 8
192.4, 159.9, 137.9, 130.1, 123.4, 122.1, 113.0, 68.4, 31.7, 29.2, 25.8, 22.7, 14.2.
xyloxy)phenyl]methanol 3—(Hexyloxy)benzaldehyde was taken up in 160 mL of
MeOH, and the mixture was cooled using an ice bath. NaBH4 (3.17 g, 83 mmol) was added in
three portions, during which gas was evolved from the mixture. Three hours after the final
addition, 10 mL of acetone was added, and the mixture was allowed to stand for 3 days. Then,
the volatile material was evaporated, and the residue was partitioned between 1:1 EA/Hex and
H20, 5% Na2C03 (2x), H20, 0.1M HCl (2x), and brine. The c phases were dried over
Na2804, ?ltered through a pad of silica gel, and concentrated to give 15.3 g of light brown oil. Rf
0.28 (20% ); 1H NMR(CDC13) 8 8.16 (m, 1H), 7.83—7.81 (m, 2H), 7.73 (m, 1H), 5.55 (s,
2H), 4.86 (t, 2H, J=6.6 Hz), 2.86 (br s, 1H, OH), 2.69 (m, 2H), 2.37 (m, 2H), 2.27—2.23 (m, 4H),
1.82 (t, 3H, J=7.0 Hz); 13C NMR(CDC13)8159.6, 142.7, 129.7, 119.1, 114.0, 113.1, 69.2, 65.4,
31.8, 29.4, 25.9, 22.8, 14.2.
WO 20995
3—(Hexyloxy)benzyl methanesulfonate [3—(Hexyloxy)phenyl]methanol was taken up in 180
mL of THF and 100 mL of EA and cooled using an ice bath. TEA (12.4 mL, 88 mmol) and then
methanesulfonyl chloride (6.30 mL, 80 mmol) were added. A white precipitate formed y.
After 2 hr, 5 mL of H20 were added, and the volatile ents were evaporated. The residue
was partitioned between EA (3x300 mL) and H20, saturated NaHC03, H20, 0.1M HCl, and
brine (100 mL each). The combined organic phases were dried over Na2SO4, ed through a
pad of silica gel, and concentrated to give 20.75 g of light brown oil. Rf 0.50 (30% EA/Hex); 1H
NMR (CDC13) 8 7.3 (m, 1H), 6.9-6.8 (m, 3H), 5.2 (s, 2H), 4.0 (t, 2H, J=6.6 Hz), 2.9 (2s, 3H), 1.8
(m, 2H), 1.4 (m, 2H), 1.4-1.3 (m, 4H), 0.9 (m, 3H); 13C NMR(CDC13) 5 159.7, 134.9, 130.1,
120.9, 115.7, 114.9, 71.7, 68.3, 38.6, 31.7, 29.4, 25.9, 22.8, 14.2.
N—[3—(Hexyloxy)benzyl]phthalimide A mixture of 3—(hexyloxy)benzyl methanesulfonate and
potassium phthalimide (15.4 g, 83.2 mmol) in 200 mL of DMF was stirred using a mechanical
stirrer at room temperature for 4 hr and then at 50 0C for 4 hr. Then, H20 (100 mL) was added,
and the volatile material was evaporated. The residue was partitioned between EA and 5%
Na2C03 (2x), H2O, 0.1M HCl, and brine. The organic phases were dried over Na2SO4, filtered
through a pad of silica gel, and trated. Crystallization from IPA gave 20.74 g of colorless
solid. Rf0.56 (30% EA/Hex); 1H NMR (CDClg) 8 7.9 and 7.7 (m, 4H, AA’BB’), 7.2 (m, 1H),
7.0—6.9 (m, 2H), 6.8 (m, 1H), 4.8 (s, 2H), 3.9 (t, 2H, J=6.6 Hz), 1.8 (m, 2H), 1.5 (m, 2H), 1.3—1.2
(m, 4H), 0.9 (m, 3H); 13C NMR(CDC13) 8 168.2, 159.6, 138.0, 134.2, 132.3, 129.8, 123.6,
120.8, 114.8, 114.1, 68.1, 41.8, 31.8, 29.4, 25.9, 22.8, 14.2.
xyloxy)phenyl]methanamine Hydrazine drate (2.20 mL, 45.3 mmol) was added
to a mixture of N—[3—(hexyloxy)benzyl]phthalimide (10.1 g, 30.0 mmol) and 90 mL of denatured
EtOH with mechanical stirring. The mixture was heated at re?ux for 15 hr, during which time a
colorless precipitate formed. The mixture was concentrated by evaporation, and the residue was
partitioned between DCM (150, 2x80 mL) and 5% Na2C03 (2x100 mL). The combined organic
phases were dried over Na2SO4, filtered, and concentrated. SPE, washing with 50% isopropyl
acetate/Hex and then eluting with 3% MeOH/DCM + 2% TEA gave 4.40 g of the product as a
pale yellow liquid, which was carried on without additional drying. Rf 0.26 (10% MeOH/DCM,
ninhydrin (+)); 1H NMR (CDCl3) 5 7.22 (m, 1H), 6.87-6.84 (m, 2H), 6.76 (dd, 1H, J=2.4, 8.0
Hz), 3.94 (t, 2H, J=6.6 Hz), 3.82 (br s, 2H, AB), 1.76 (m, 2H), 1.59 (br s, 2H, N?z), 1.47—1.29
(m, 6H), 0.89 (t, 3H, J=6.8 Hz).
Hexyloxy)benzyl]quinolin—4—amine [3—(Hexyloxy)phenyl]methanamine (7.20 g, 34.8
mmol) was taken up in 100 mL of 1—pentanol, and then 25 mL of volatile material was removed
by distillation. The mixture was cooled below g, and tripropylamine (10.0 mL, 52.4 mmol)
and 4—chloroquinoline (5.67 g, 34.8 mmol) were added. Heating at re?ux was d. After 26
hr, volatile material was removed by evaporation. The mixture was diluted with DCM (350 mL)
and washed with 1N NaOH (50 mL) and 5% N32CO3 (50 mL). The aqueous phases were
ted with DCM (100 mL). The combined organic phases were dried over NaZSO4, ?ltered,
and concentrated. SPE, washing with 50% EA/Hex and then eluting with 50% EA/Hex + 2%
TEA, gave product fractions that were combined and concentrated. The residue was partitioned
between EA (400, 175 mL) and 5% Na2C03 and brine (50 mL each). The combined organic
phases were dried over Na2804, filtered, and concentrated to approximately 50 mL, pon
substantial precipitate formed. The precipitate was recrystallized by heating and cooling, at the
end of which 20 mL of hexanes was added. After standing overnight, the colorless precipitate
was collected by filtration and washed with 30% . (The mother liquor contained
imately 2.4 g of material, but it was not treated further.) Drying in vacuo gave 4.05 g. Rf
0.20 (10% MeOH/DCM); mp 1095—1100 0C; 1H NMR(CDC13) 5 8.55 (d, 1H, J=5.1 Hz), 8.00
(dd, 1H, 120.7, 8.4 Hz), 7.76 (dd, 1H, J=1.1, 8.5 Hz), 7.65 (ddd, 1H, J=1.4, 6.9, 8.4 Hz), 7.44 (m,
1H), 7.29 (t, 1H), 6.98—6.94 (m, 2H), 6.86 (dd, 1H, 121.8, 8.1 Hz), 6.46 (d, 1H, J=5.2 Hz), 5.34
(t, 1H, NH), 4.50 (m, 2H, AB), 3.94 (t, 2H, J=6.6 Hz), 1.80—1.73 (m, 2H), 1.46—1.40 (m, 2H),
1.35—1.30 (m, 4H), 0.91—0.87 (m, 3H); 13C NMR(CDC13)5160.0, 151.4, 149.6, 148.8, 139.4,
130.4, 130.2, 129.2, 125.0, 119.8, 119.5, 119.1, 114.2, 113.9, 99.7, 68.3, 47.9, 31.8, 29.5, 25.9,
22.8, 14.2.
W0 2014/120995
Example 66: N—[2—(Hexyloxy)benzyl]quinolin—4—amine
HN/\©
[2—(Hexyloxy)phenyl]methanol A mixture of 3—hydroxybenzyl alcohol (3.06 g, 24.7 mmol),
1—bromohexane (3.20 mL, 22.9 mmol), K2C03 (3.50 g, 25.4 mmol), and 10 mL of DMF was
reacted for 40 hr. The mixture was partitioned between EA and H20, 5% Na2C03, H2O, 0.1M
HCl, and brine. The organic phases were dried over anhydrous Na2SO4 and trated. SPE,
washing with 5% EA/Hex and eluting with 15% EA/Hex, gave 2.86 g of product. Rf 0.31 (15%
EA/Hex); 1H NMR ) 8 7.27—7.22 (m, 2H), 6.95-6.85 (m, 2H), 4.69 (s, 2H), 4.01 (t, 2H,
J=6.5 Hz), 2.45 (br s, 1H, 0H), 1.81 (m, 2H), 1.52—1.32 (m, 6H), 0.91 (m, 3H).
N—[2-(Hexyloxy)benzyl]phthalimide DIEA (4.90 mL, 28.1 mmol) was added to a mixture of [2-
(hexyloxy)phenyl]methanol (2.86 g, 13.8 mmol) and methanesulfonyl chloride (2.10 mL, 26.8
mmol) in 25 mL of dioxane and 10 mL of EA cooled by an ice bath. After 2 hr, the mixture was
partitioned between EA and H20, saturated NaHCOg, H2O, 0.1M HCl, and brine. The organic
phases were dried over anhydrous Na2SO4 and trated. The residue was filtered through a
pad of silica gel using 50% EA/Hex and the filtrate was concentrated to give crude 2—
(hexyloxy)benzyl methanesulfonate. The crude 2—(hexyloxy)benzyl methanesulfonate was taken
up in 150 mL of acetone, sodium iodide (3.1 g, 21 mmol) was added, and the mixture was heated
at re?ux for 1.5 hr. Then, the solvent was evaporated, and the solid residue was ioned
between EA and H20. The c phase was decolorized with aqueous Na2S203 and washed
with H20 and brine, dried over anhydrous MgSO4, and concentrated. The residue was ed
through a pad of silica gel using 25% EA/Hex and the filtrate was concentrated to give crude 1-
(hexyloxy)-2—(iodomethyl)benzene. A mixture of the crude 1—(hexyloxy)—2—(iodomethyl)benzene
and potassium phthalimide (3.8 g, 20 mmol) in 12 mL of DMF was reacted at room temperature
for 24 hr. The mixture was partitioned between EA and H20, aqueous Na2S203, H20, 5%
Na2C03, H2O, 0.1M HCl, and brine, and the c phases were dried over ous MgSO4
and concentrated. SPE, washing with 5% EA/Hex and eluting with 15% EA/Hex, gave 2.30 g of
oil. Careful TLC (avoiding overloading and using a longer plate) showed that the product
contained a nearly co—migratory impurity. Rf0.37 (15% EA/Hex); 1H NMR (CDClg) 5 7.84 and
7.71 (m, 4H, AA’BB’), 7.27-7.14 (m, 2H), .81 (m, 2H), 4.91 (s, 2H), 3.96 (t, 2H, J=6.5
Hz), 1.77 (p, 2H, J=6.7 Hz), 1.46-1.22 (m, 6H), 0.88 (m, 3H).
[2—(Hexyloxy)phenyl]methanamine Hydrazine monohydrate was added to a mixture of N—[2—
(hexyloxy)benzyl]phthalimide and 80 mL of EtOH, and the mixture was heated at re?ux for 20
hr. The e was cooled, and the volatile components were evaporated. The residue was
partitioned between EA and 5% Na2C03 and brine, dried over anhydrous NaZSO4, and
concentrated. SPE, g with 18% EA/Hex followed by 4% MeOH/DCM and eluting with
6% MeOH/DCM + 2% TEA, gave the ninhydrin (+) product. Rf 0.61 (5% MeOH/DCM + 2%
TEA).
N—[2-(Hexyloxy)benzyl]quinolinamine A mixture of [2-(hexyloxy)phenyl]methanamine
(417 mg, 2.01 mmol), 4-chloroquinoline (430 mg, 2.64 mmol), and DIEA (0.50 mL, 2.86 mmol)
in 1 mL of NMP was heated at 150 0C in a sealed tube for 18 hr. Then, the e was cooled
and partitioned between EA and 5% N32C03 and brine. The organic phase was dried over
N32804 and trated. SPE, washing with 2.5% MeOH/DCM and then eluting with 7%
MeOH/DCM, gave 545 mg of solid. Rf 0.20 (10% MeOH/DCM); mp 90—91°C (from EA/Hex);
1H NMR (CDC13) 5 1H NMR (CDC13) 8 8.52 (d, 1H, J=5.5 Hz), 7.98 (dd, 1H, J=0.7, 8.4 Hz),
7.77 (dd, 1H, 121.0, 8.4 Hz), 7.61 (ddd, 1H, J=1.5, 6.9, 8.4 Hz), 7.39 (ddd, 1H, J=1.2, 6.9, 8.1
Hz), 7.31—7.23 (m, 2H), 6.92-6.87 (m, 2H), 6.48 (d, 1H, J=5.2 Hz), 5.71 (bt, 1H, J=5.2 Hz, NH),
4.54 (m, 2H, AB), 4.02 (t, 2H, J=6.4 Hz), 1.84—1.74 (m, 2H), 1.50—1.17 (m, 6H), .81 (m,
3H).
Example 67: N—[3—Fluoro—4—(hexyloxy)benzyl]quinolin—4—amine
WO 20995
3—Fluoro—4—(hexyloxy)benzonitrile (721 mg) was prepared from 3—?uoro—4—hydroxybenzonitrile
(1.5 g, 10.9 mmol), 60% sodium e (654 mg), 1—bromohexane (1.30 mL), and 10 mL of
DMF following the method for 1—(8—bromooctyloxy)—3—methylbenzene. 1H NMR (CDCl3) 5 7.5
(t, 1H), 6.8-6.6 (m, 2H), 3.95 (t, 2H), 1.8 (m, 2H), 1.5—1.2 (m, 6H), 0.9 (m, 3H).
[3—Fluoro—4—(hexyloxy)phenyl]methanamine (212 mg, 0.9 mmol) was ed from 3—?uoro—(4—
hexyloxy)benzonitrile (721 mg, 3.3 mmol) and LAH (6.6 mmol) in THF (50 mL) at 0 0C for 4 hr
and room temperature for 12 hr following the method for [4—(hexyloxy)phenyl]methanamine. 1H
NMR (CDC13) 5 7.15 (t, 1H), 6.7-6.5 (m, 2H), 3.9 (t, 2H), 3.75 (s, 2H), 1.75 (m, 2H), 1.6—1.2 (m,
8H), 0.9 (m, 3H).
N—[3—Fluoro—4—(hexyloxy)benzyl]quinolinamine (325 mg) was prepared from [3-fluoro—4—
(hexyloxy)phenyl]methanamine (486 mg, 2.2 mmol), 4—chloroquinoline (541 mg, 3.3 mmol),
TEA (4 mL), and NMP (0.5 mL) at 130 0C in a sealed tube for 5 days following the method for
3-ethoxypropoxy)octyl]quinolinamine. 1H NMR (CDC13) 5 8.5 (d, 1H), 8.0 (d, 1H), 7.8
(d, 1H), 7.6 (m, 1H), 7.4 (m, 1H), 7.25 (t, 1H), 6.6 (m, 2H), 6.45 (d, 1H), 5.8 (br s, 1H, NH), 4.5
(m, 2H, AB), 3.9 (t, 2H), 1.8 (m, 2H), 1.6-1.2 (m, 6H), 0.9 (m, 3H).
Example 68: N-[4—(Decyloxy)benzy1]quinolin—4—amine
CK?HN/\©\OW/
4—(Decyloxy)benzonitrile A mixture of 4—hydroxybenzonitrile ( 4.32 g, 36.3 mmol), 1—
bromodecane (6.80 mL, 32.9 mmol), and K2C03 (6.61 g, 47.8 mmol) in 20 mL of DMF was
reacted for 2 days. The solvent was evaporated in vacuo. The e was partitioned between
50% EA/HeX (3X150 mL) and 5% N212C03 (3X80 mL), H20 (40 mL), 0.1M HCl (40 mL), and
brine (80 mL). The organic phases were dried over anhydrous NaZSO4 and concentrated to give
8.30 g of colorless oil that solidified upon standing. 1H NMR (CDCl3) 5 7.54 and 6.90 (m, 4H,
AA’BB’), 3.97 (t, 2H, J=6.6 Hz), 1.78 (m, 2H), 1.42 (m, 2H), 1.34-1.25 (m, 12H), 0.86 (m, 3H);
W0 20995
13C NMR(CDC13) 5 162.6, 134.0, 119.4, 115.3, 103.7, 68.5, 32.0, 29.6, 29.4, 29.4, 29.1, 26.0,
22.8, 14.2.
[4—(Decyloxy)phenyl]methanamine Lithium aluminum hydride (2.0 g, 53 mmol) was added in
ns to a mixture of 4—(decyloxy)benzonitrile (8.30 g, 32.0 mmol) and 80 mL of THF cooled
by an ice bath. Then, the mixture was allowed to warm to room temperature. After 2 hr, the
mixture was cooled by an ice bath, and 2 mL H20, 2 mL 15% NaOH, and 6 mL H20 were added
sequentially and cautiously. The resulting solids were ed, and the solids were washed with
% MeOH/DCM + 1% TBA. The te was concentrated, then taken up in DCM and washed
with 5% N32CO3. The organic phase was dried over anhydrous NaZSO4 and concentrated. SPE,
washing with 40% isopropyl acetate/Hex and eluting with 3% MeOH/DCM + 2% TEA, gave
ninhydrin (+) fractions. These fractions were concentrated, and the residue was taken up in
DCM, washed with 5% NaZC03, dried over anhydrous NaZSO4, and concentrated to give 7.61 g
of colorless solid. Rf 0.11 (10% CM); 1H NMR ) 8 7.18 and 6.83 (m, 4H,
AA’BB’), 3.90 (t, 2H, J=6.6 Hz), 3.76 (s, 2H), 1.75 (m, 2H), 1.56 (br s, 2H, N?z), 1.43 (m, 2H),
.26 (m, 12H), 0.87 (t, 3H, J=6.9 Hz); 13C NMR (CDC13) 5 158.1, 135.4. 128.2, 114.5,
68.0, 46.0, 32.0, 29.6, 29.6, 29.5, 29.4, 26.1, 22.7, 14.2.
N—[4—(Decyloxy)benzyl]quinolin—4—amine [4—(Decyloxy)phenyl]methanamine (5.90 g, 22.4
mmol) was taken up in 100 mL of 1—pentanol, and 25 mL was removed by distillation. The
mixture was cooled slightly, and tripropylamine (6.50 mL, 34.1 mmol) and 4—chloroquinoline
(3.63 g, 22.3 mmol) were added. Heating at re?ux was continued for 24 hr. Then, the volatile
components were evaporated, and the residue was partitioned between DCM and 5% NazCO3.
The organic phase was dried over anhydrous Na2S04 and concentrated onto silica gel. SPE,
washing with 50% EA/Hex and then eluting with 10% MeOH/DCM, gave a solid. The solid was
taken up in DCM, washed with 5% N32C03, dried over anhydrous NaZSO4, and concentrated to
give a solid. Recrystallization from EA/Hex gave 3.70 g colorless solid. Rf 0.13 (10%
MeOH/DCM); mp 96.5—97.0 0C; 1H NMR (CDC13) 5 8.55 (d, 1H, J=5.2 Hz), 7.99 (d, 1H, J=8.5
Hz), 7.74 (d, 1H, J=8.4 Hz), 7.63 (m, 1H), 7.42 (m, 1H), 7.30 and 6.90 (m, 4H, AA’BB’), 6.47
(d, 1H, J=5.1 Hz), 5.30 (br s, 1H, NH), 4.44 (m, 2H, AB), 3.95 (m, 2H), 1.79 (m, 2H), 1.46 (m,
2H), 1.32—1.27 (m, 10H), 0.88 (m, 3H); 13C NMR ) 5 159.1, 151.3, 149.6, 148.7, 130.2,
129.4, 129.2, 129.2, 124.9, 119.5, 118.9, 115.1, 99.5, 68.3, 47.3, 32.1, 29.8, 29.8, 29.6, 29.5,
29.5, 26.2, 22.9, 14.3.
e 69: N—[3—(Decyloxy)benzyl]quinolin—4—amine
\/\/
CK?/
N
3-(Decyloxy)benzaldehyde 1—Bromodecane (15.0 mL, 72.6 mmol) was added to a mixture of
3—hydroxybenzaldehyde (9.75 g, 79.9 mmol) and K2C03 (12.2 g, 88.4 mmol) in 80 mL of DMF
heated at 50 0C using mechanical stirring. After 22 hr, the mixture was diluted with H20 (100
mL) and extracted with EA (3x100 mL), and the organic phases were washed with 5% N32C03
and H20 (100 mL each), 0.1M HCl (2x100 mL), and brine (100 mL), and dried over anhydrous
NagSO4. Evaporation of the volatile components yielded 18.74 g of product as a brown oil. Rf
0.54 (10% EA/Hex); 1H NMR(CDC13) 8 9.96 (s, 1H), 7.44-7.37 (m, 3H), 7.18 (m, 1H), 4.00 (t,
2H, J=6.6 Hz), 1.80 (m, 2H), 1.46 (m, 2H), 1.36-1.23 (m, 12H), 0.88 (m, 3H); 13C NMR(CDC13)
8192.4, 159.9, 138.0, 130.2, 123.5, 122.2, 113.0, 68.5, 32.1, 29.8, 29.7, 29.6, 29.5, 29.3, 26.2,
22.9, 14.3.
cyloxy)phenyl]methanol Sodium borohydride (2.63 g, 69.2 mmol) was added to a
mixture of 3-(decyloxy)benzaldehyde (18.74 g) and 160 mL of MeOH cooled by an ice bath.
After 1 hr, residual hydride was quenched by adding H20, and 80 mL of 1M HCl was added
slowly, resulting in precipitation. The volatile components were evaporated, and the residue was
partitioned between 50% EA/Hex and H20, 5% N32C03 (2x), H20, and brine. The organic
phases were dried over anhydrous NaZSO4, filtered through a pad of silica gel, and concentrated
to give 21.05 g of product as a light brown solid. Rf0.11 (10% EA/Hex) 0.28 (1:4:5
EA/toluene/Hex); 1H NMR (CDCl3) 5 7.24 (m, 1H), 6.90-6.88 (m, 2H), 6.81 (m, 1H), 4.60 (br s,
2H, AB), 3.94 (t, 2H, J=6.6 Hz), 2.55 (br s, 1H, OH), 1.78 (m, 2H), 1.46 (m, 2H), 1.38-1.24 (m,
12H), 0.91 (m, 3H); 13C NMR(CDC13)5159.5, 142.7, 129.6, 119.0, 113.8, 113.0, 68.1, 65.2,
32.0, 29.8, 29.7, 29.6, 29.5, 29.4, 26.2, 22.8, 14.3.
3—(Decyloxy)benzyl methanesulfonate Triethylamine (11.8 mL, 84.4 mmol) was added to a
mixture of [3—(Decyloxy)phenyl]methanamine (21.05 g, mmol) and methanesulfonyl chloride
(6.60 mL, 84.4 mmol) in 120 mL of THF cooled by an ice bath. A precipitate formed rapidly.
After 1 hr, 5 mL of H20 was added, and the volatile components were ated. The residue
was partitioned between EA and H20, saturated NaHCOg, H20, 0.1M HCl, and brine. The
organic phases were dried over anhydrous NaZSO4, filtered through a pad of silica gel, and
trated to give 23.53 g of 3—(decyloxy)benzyl methanesulfonate as an amber oil that
solidified upon standing. Rf 0.45 (1:4:5 EA/toluene/Hex) 0.35 (20% ); 1H NMR (CDC13)
8 7.29 (m, 1H), 6.98-6.90 (m, 3H), 5.19 (m, 2H, AB), 3.95 (t, 2H, J=6.6 Hz), 2.90 (s, 3H), 1.78
(m, 2H), 1.43 (m, 2H), 1.36-1.28 (m, 12H), 0.88 (m, 3H); 13C NMR(CDC13) 5 159.6, 134.9,
130.1, 120.8, 115.6, 114.8, 71.7, 68.2, 38.4, 32.0, 29.7, 29.7, 29.5, 29.4, 29.4, 26.2, 22.8, 14.3.
N—[3-(Decyloxy)benzyl]phthalimide A mixture of 3-(decyloxy)benzyl esulfonate (23.53
g, 68.8 mmol) and potassium phthalimide (14.00 g, 75.7 mmol) in 90 mL of DMF was reacted at
room temperature for 16 hr and at 50-60 0C for 3 hr. The mixture was cooled, diluted with 350
mL H20, and ted with EA (3x400 mL). The c phases were washed with H20 (3x200
mL) and brine (2x200 mL), dried over anhydrous NazSO4, and concentrated to give a ess
solid. The solid was broken up and washed with 10% EA/Hex to give 11.40 g of solid as a
colorless solid. The washes were partially concentrated to give an additional 6.95 g of colorless
solid. Rf0.50 (20% EA/Hex); 1H NMR (CDClg) 8 7.84 and 7.70 (m, 4H, AA’BB’), 7.21 (m,
1H), 7.00—6.96 (m, 2H), 6.79 (m, 1H), 4.81 (s, 2H, AB), 3.92 (t, 2H, J=6.6 Hz), 1.74 (m, 2H),
1.43 (m, 2H), 1.30—1.26 (m, 12H), 0.88 (m, 3H); 13C NMR(CDC13) 5 168.2, 159.6, 137.9, 134.2,
132.4, 129.9, 123.6, 120.8, 114.8, 114.1, 68.2, 41.8, 32.1, 29.8, 29.8, 29.6, 29.5, 29.5, 29.5, 26.2,
22.9, 14.3.
[3—(Decyloxy)phenyl]methanamine Hydrazine monohydrate (3.90 mL, 80.3 mmol) was added
in three portions to a mixture of N—[3—(decyloxy)benzyl]phthalimide (5.12 g, 13.0 mmol) and
IPA heated at re?ux. After the starting material was consumed as observed by TLC (30 hr), the
mixture was cooled and concentrated. The residue was partitioned between pyl acetate and
% Na2C03 and brine, and the organic phases were dried over anhydrous NaZSO4 and
trated. SPE, washing with 50% isopropyl acetate/Hex and then eluting with 3%
MeOH/DCM + 2% TEA, gave ninhydrin (+) material. Partial tration and washing of the
te with 5% N32CO3 and drying over NaZSO4 gave 3.25 g of yellow oil after drying in vacuo.
N—[3—(Decyloxy)benzyl]quinolin—4—amine A mixture of [3—(decyloxy)phenyl]methanamine
(2.54 g, 9.66 mmol), 4—chloroquinoline (1.73 g, 10.62 mmol), and tripropylamine (4.00 mL, 21.0
mmol) in 65 mL of 1—pentanol was heated at re?ux for 16 hr. Analytical TLC ted a
substantial quantity of unreacted [3—(decyloxy)phenyl]methanamine. 4—Chloroquinoline (0.85 g,
.21 mmol) and tripropylamine (2.00 mL, 10.5 mmol) were added. After 24 hr, the mixture was
cooled and 15 mL of 1N NaOH were added. The volatile components were evaporated, the
residue was taken up in DCM and washed with 5% N32CO3, and the organic phase was dried
over anhydrous Na2804 and evaporated onto silica gel. SPE, washing with 70% EA/Hex and
eluting with 50% EA/Hex + 2% TEA, gave 2.62 g of white solid after crystallization from IPA.
Recrystallization from 30% EA/Hex gave 2.00 g of N-[3-(decyloxy)benzyl]quinolinamine as
a white powdery solid. Rf 0.24 (50% EA/Hex + 2% TEA) 0.40 (10% MeOH/DCM); mp 71.0-
72.0 0C; 1H NMR ) 5 8.55 (d, 1H, J=5.1 Hz), 8.00 (m, 1H), 7.77 (m, 1H), 7.64 (ddd, 1H,
J=1.5, 7.0, 8.5 Hz), 7.43 (ddd, 1H, J=1.5, 7.0, 8.5 Hz), 7.28 (m, 1H), 6.97—6.93 (m, 2H), 6.85 (dd,
1H, J=1.8, 8.1 Hz), 6.45 (d, 1H, J=5.5 Hz), 5.38 (m, 1H, NH), 4.49 (m, 2H, AB), 3.94 (m, 2H),
1.77 (m, 2H), 1.42 (m, 2H), 1.34—1.26 (m, 10H), 0.87 (m, 3H); 159.9, 151.4, 149.6, 148.7, 139.3,
130.3, 130.2, 129.2, 125.0, 119.7, 119.5, 18.95, 114.1, 113.8, 99.6, 68.3, 47.8, 32.1, 29.8, 29.8,
29.6, 29.5, 29.5, 26.3, 22.9, 14.3.
Example 70: N—(3—Phenoxybenzyl)quinolin—4—amine
2014/013992
3—Phenoxybenzyl methanesulfonate A mixture of 3—phenoxybenzyl alcohol (15.44 g, 77.2
mmol) and TEA (13.1 mL, 93.4 mmol) in 180 mL of THE and 100 mL of EA was cooled using
an ice bath. Then, methanesulfonyl chloride (6.60 mL, 84.4 mmol) was added. A white
precipitate formed rapidly. After 2 hr, 5 mL of H20 were added, and the volatile components
were evaporated. The residue was partitioned between EA (3x300 mL) and H20, saturated
NaHCOg, H20, 0.1M HCl, and brine (100 mL each). The combined organic phases were dried
over NaZSO4, filtered h a pad of silica gel, and concentrated to give 22.02 g of colorless
oil. Rf0.38 (30% EA/Hex); 1H NMR (CDC13) 8 7.4—7.3 (m, 3H), 7.2-7.1 (m, 2H), 7.1-7.0 (m,
4H), 5.2 (m, 2H, AB), 2.9 (s, 3H); 13C NMR (CDC13) 5 158.0, 156.7, 135.5, 130.4, 130.1, 124.0,
123.4,119.5,119.4,118.8, 71.0, 38.4.
N—(3—Phenoxybenzyl)phthalimide A mixture of 3—phenoxybenzyl methanesulfonate (22.5 g,
80.9 mmol) and potassium phthalimide (16.4 g, 88.6 mmol) in 200 mL of NMP was stirred at 50
0C for 17 hr using a mechanical stirrer. Then, H20 (100 mL) was added, and the volatile material
was ated. The residue was partitioned between EA and 5% Na2C03 (2x), H20, 0.1M HCl,
and brine. The c phases were dried over Na2SO4, filtered through a pad of silica gel, and
concentrated. Crystallization from IPA gave 23.55 g of colorless solid. Rf 0.53 (30% EA/Hex);
1H NMR(CDC13) 5 7.85 and 7.73 (m, 4H, AA’BB’), .24 (m, 3H), 7.15-7.07 (m, 3H),
6.99—6.97 (m, 2H), 6.88—6.85 (m, 1H), 4.82 (m, 2H, AB); 13C NMR(CDC13) 5 168.1, 157.6,
157.1, 138.4, 134.5, 134.2, 132.2, 130.2. 129.9, 123.8, 123.6, 123.6, 123.2, 119.1. 119.1, 118.1,
41.4.
noxyphenyl)methanamine Hydrazine drate (3.50 mL, 72.1 mmol) was added
to a mixture of N—(3—phenoxybenzyl)phthalimide (6.28 g, 19.1 mmol) and 200 mL of IPA while
using mechanical stirring. The mixture was heated at re?ux for 7 hr. After standing overnight, a
precipitate had formed. The mixture was concentrated by evaporation, and the residue was
partitioned between isopropyl acetate and 5% N32C03 and brine. The organic phases were dried
over NagSO4, filtered, and concentrated. SPE, washing with 50% isopropyl acetate/Hex and then
eluting with 3% CM + 2% TEA gave fractions that contained ninhydrin (+) t.
The combined product fractions were washed with 5% N32CO3, dried over NaZSO4, filtered, and
concentrated to give 3.25 g of yellow oil. Rf 0.28 (10% MeOH/DCM); 1H NMR (CDC13) 5 7.36—
7.25 (m, 3H), 7.12—6.95 (m, 5H), 6.87 (ddd, 1H, J=l.0, 2.5, 8.2 Hz), 3.82 (br s, 2H), 2.15 (br s,
2H, NH;).
N—(3—Phenoxybenzyl)quinolin—4—amine (3—Phenoxyphenyl)methanamine (2.02 g, 10.2
mmol) was taken up in 60 mL of l—pentanol, and then 15 mL of volatile material was removed
by distillation. The mixture was cooled below boiling, and tripropylamine (3.80 mL, 19.9 mmol)
and roquinoline (1.65 g, 10.2 mmol) were added. Heating at re?ux was d. After 66
hr, volatile material was removed by evaporation. The e was partitioned between DCM
(150, 100 mL) and 5% N32CO3 (80 mL). The combined organic phases were dried over Na2S04,
filtered, and concentrated to give a solid. Recrystallization from EA/Hex gave 2.08 g of colorless
solid. Rf0.34 (10% MeOH/DCM); mp 640 0C; 1H NMR (CDC13) 5 8.54 (d, 1H, J=5.5
Hz), 8.00 (m, 1H), 7.76 (d, 1H, J=8.1 Hz), 7.64 (m, 1H), 7.43 (m, 1H), 7.34-7.29 (m, 3H), 7.11
(m, 1H), 7.05 (s, 1H), 7.02-6.99 (m, 2H), 6.94 (dd, 1H, J=2.2, 8.0 Hz), 6.42 (d, 1H, J=5.5 Hz),
.46 (br s, 1H, NH) 4.51 (m, 2H, AB); 13C NMR(CDC13)5158.2, 156.9, 151.3, 149.5, 148.7,
139.9, 130.5, 130.3, 130.0, 129.3, 125.0, 123.8, 122.2, 119.5, 119.3, 118.9, 118.0, 117.8, 99.7,
47.4.
Example 71: N-[3—(Benzyloxy)benzy1]quinolin—4—amine
3—(Benzyloxy)benzonitrile A mixture of oxybenzonitrile (504 mg, 4.24 mmol), benzyl
chloride (607 mg, 4.78 mmol), and K2C03 (605 mg, 4.38 mmol) in 2 mL of DMF reacted for 42
hr. The mixture was diluted with 50% EA/Hex and washed with 5% N32CO3 (2x) and brine
made acidic with 1M HCl. The organic phase was dried over anhydrous MgSO4 and
concentrated. FC (15% EA/Hex) gave 780 mg of colorless oil. Rf 0.50 (20% EA/Hex); 1H NMR
(CDClg) 5 7.43—7.31 (m, 6H), 7.26—7.17 (m, 3H), 5.08 (m, 2H, AB).
WO 20995
[3—(Benzyloxy)phenyl]methanamine A mixture of 3—(benzyloxy)benzonitrile and 30 mL of THF
was cooled by an ice path. LAH (195 mg and then 190 mg) was added. The mixture was allowed
to warm to room temperature. After 24 hr, the mixture was cooled by an ice bath, and 0.40 mL
H20, 0.40 mL 15% NaOH, and 1.2 mL H20 were added in succession. The geneous
mixture was diluted with 5% MeOH/DCM and preloaded on silica gel. SPE, washing with 5%
MeOH and eluting with 10% MeOH/DCM + 2% TEA gave 672 mg of colorless oil that
solidified upon ng. 1H NMR (CDCl3) 5 7.48—7.23 (m, 6H), 6.98-6.83 (m, 3H), 5.07 (m, 2H,
AB), 3.83 (m, 2H, AB).
N—[3—(Benzyloxy)benzyl]quinolin—4—amine (600 mg) was prepared from [3—
(benzyloxy)phenyl]methanamine (670 mg, 3.14 mmol), roquinoline (767 mg, 4.70 mmol),
and DIEA (1.20 mL, 6.88 mmol) in 0.5 mL DMF heated in a sealed tube. FC (7% MeOH/DCM)
gave 600 mg of product. Rf 0.38 (10% MeOH/DCM); 1H NMR (CDCl3) 5 8.43 (d, 1H, J=5.4
Hz), 8.01-7.96 (m, 2H), 7.62-7.56 (m, 1H), 7.40-7.22 (m, 7H), 6.99-6.88 (m, 3), 6.53 (br s, 1H,
NH), 6.34 (d, 1H, J=5.5 Hz), 4.99 (s, 2H), 4.48 (m, 2H, AB).
Example 72: N-(3-Phenethoxybenzyl)quinolinamine
N—(3—Phenethoxybenzyl)quinolin—4—amine was prepared by the method for N—[3—
(benzyloxy)benzyl]quinolin—4—amine starting with 3-hydroxybenzonitrile (561 mg, 4.71 mmol),
2—bromoethylbenzene (1.34 g, 7.24 mmol), and K2C03 (1.00 g, 7.25 mmol) in 2 mL of DMF
heated at 60 OC.
3—(Phenethoxy)benzonitrile (454 mg): Rf 0.46 (20% EA/Hex): 1H NMR (CDC13) 8 7.38—7.20 (m,
7H), 7.10 (m, 2H), 4.18 (t, 2H, J=6.9 Hz), 3.11 (t, 2H, J=6.9 Hz).
(3—(Phenethoxyphenyl)methanamine (480 mg): 1H NMR (CDC13) 5 7.36—7.20 (m, 6H), 6.87 (m,
2H), 6.78 (m, 1H), 4.18 (t, 2H, J=7.2 Hz), 3.82 (m, 2H, AB), 3.10 (t, 2H, J=7.2 Hz), 2.16 (br s,
2H, NH;).
N—(3—Phenethoxybenzyl)quinolin—4—amine (358 mg): Rf 0.12 (5% MeOH/DCM); 1H NMR
(CDC13) 5 8.39 (d, 1H, J=5.4 Hz), 7.96 (d, 1H, J=8.4 Hz), 7.91 (d, 1H, J=8.4 Hz), 7.59 (m, 1H),
7.38 (m, 1H), 7.31—7.18 (m, 6H), 6.94—6.90 (m, 2H), 6.80 (dd, 1H, J=2.4, 8.1 Hz), 6.35 (d, 1H,
J=5.5 Hz), 6.26 (br s, 1H), 4.48 (m, 2H, AB), 4.12 (t, 2H, J=7.0 Hz), 3.05 (m, 2H).
Example 73: N—[4—(Quinolin—4—ylamino)butyl]benzamide
N
N1-(Quinolinyl)butane-1,4-diamine A mixture of 1,4-butanediamine (1.54 g, 17.5
mmol), 4-chloroquinoline (357 mg, 2.19 mmol), and DIEA (0.50 mL, 2.87 mmol) was heated at
130 0C in a sealed tube for 24 hr. The mixture was cooled, taken up in EA, and washed with 5%
Na2C03 (3x) and brine. The organic phase was dried over NaZSO4 and concentrated. 1H NMR
(20% CD3OD/CDC13) 5 8.33 (d, 1H, J=5.5 Hz), 7.86 (ddd, 1H, J=0.5, 1.5, 8.4 Hz), 7.81 (ddd,
1H, J=0.5, 1.2, 8.4 Hz), 7.53 (ddd, 1H, J=1.3, 6.7, 8.4 Hz), 7.33 (ddd, 1H, J=1.2, 6.9, 8.4 Hz),
6.29 (d, 1H, J=5.5 Hz), 3.20 (m, 2H), 2.66 (t, 2H, J=6.9 Hz), 1.69 (m, 2H), 1.51 (m, 2H).
N—[4—(Quinolin—4—ylamino)butyl]benzamide inolin—4—yl)butane—1,4—diamine (185 mg,
0.86 mmol) was taken up in 5 mL of pyridine, and the mixture was concentrated. The residue
was taken up in 10 mL of DCM, cooled by an ice bath, and TEA (0.49 mL, 3.5 mmol) and then
benzoyl chloride (0.40 mL, 3.43 mmol) were added. The mixture was allowed to warm to room
temperature. After 2 hr, 3.43 mL of 1N NaOH were added, and the le ents were
removed by distillation. The residue was partitioned between EA and 5% Na2C03 and brine. The
organic phases were dried over NaZSO4 and concentrated. SPE, washing with 5% MeOH/DCM
and eluting with 15% CM, gave an oily solid. Repurification by preparative TLC (15%
CM) gave the product as a solid. Rf 0.21 (15% MeOH/DCM); 1H NMR (CDC13) 8 8.31
(d, 1H, J=5.7 Hz), 8.10 (m, 1H), 7.80-7.77 (m, 3H), 7.62 (ddd, 1H, J=l.2, 6.6, 8.4 Hz), 7.55—7.39
(m, 4H), 6.51 (d, 1H, J=5.5 Hz), 3.45 (q, 2H, J=7 Hz), 1.86-1.76 (m, 4H).
Example 74: N—[6—(Quinolin—4—ylamino)hexyl]benzamide
/\/\/\/N
N
N1—(Quinolin—4—yl)hexane—1,6—diamine A mixture of 1,6—hexanediamine (2.05 g, 17.7
mmol) and 4—chloroquinoline (297 mg, 1.82 mmol) was heated at 130 0C in a sealed tube for 24
hr. The mixture was cooled, partitioned between EA (3x) and 5% Na2C03 (3x) and brine. The
organic phases were dried over NaZSO4 and concentrated. 1H NMR (20% CDC13) 5 8.39
(d, 1H, J=5.4 Hz), 7.87 (d, 1H, J=8.1 Hz), 7.75 (d, 1H, J=8.4 Hz), 7.56 (ddd, 1H, J=1.3, 6.9, 8.4
Hz), 7.36 (m, 1H), 6.35 (d, 1H, J=5.4 Hz), 3.26 (m, 2H), 2.63 (m, 2H), 1.71 (m, 2H), 1.49-1.38
(m, 6H).
N—[6-(Quinolinylamino)hexyl]benzamide N1-(Quinolinyl)hexane-1,6-diamine (230 mg,
0.946 mmol) was taken up in 5 mL of pyridine, and the mixture was concentrated. The residue
was taken up in 10 mL of DCM, cooled by an ice bath, and TEA (0.53 mL, 3.8 mmol) and then
benzoyl chloride (0.44 mL, 3.78 mmol) were added. The mixture was allowed to warm to room
temperature. After 2 hr, 3.78 mL of 1N NaOH were added. The e was partitioned between
DCM and 5% N212C03. The organic phase was dried over NaZSO4 and concentrated. cation
by preparative TLC (15% MeOH/DCM) gave the product. The residue from tration of the
eluate was taken up in DCM, washed with 5% N32C03, dried over NaZSO4 and concentrated to
give the product. Rf 0.23 (15% MeOH/DCM); 1H NMR (CDCl3) 5 8.30 (d, 1H, J=6.0 Hz), 8.09
(d, 1H, J=8.4 Hz), 7.91 (d, 1H, J=8.4 Hz), 7.82—7.78 (m, 2H), 7.55 (m, 1H), 7.45—7.30 (m, 4H),
6.94 (t, 1H, J=6 Hz), 6.81 (br s, 1H), 6.24 (d, 1H, J=6.2 Hz), 3.40 (m, 2H), 3.25 (m, 2H), 1.68—
1.54 (m, SH).
Example 75: N—[8—(Quinolin—4—ylamino)octyl]benzamide
HN/VW\/
C6? 0
N—(8—Aminooctyl)benzamide A mixture of 1,8—octanediamine (3.27 g, 22.7 mmol) and methyl
benzoate (0.40 mL, 3.20 mmol) was heated at 115 0C for 24 hr. The mixture was cooled and
ioned between EA and H20. The organic phase, which contained a 1:1 molar ratio of
diamine and monoamide, was concentrated. Reverse—phase SPE, washing with 20% MeOH/HZO
and eluting with MeOH, gave the product fraction, which was concentrated, taken up in DCM,
washed with 5% N32CO3, dried over NaZSO4, and concentrated to give 698 mg of product. 1H
NMR (20% CD3OD/CDC13) 5 7.64-7.59 (m, 2H), 7.43 (br s, 1H, NH), .18 (m, 3H), 3.19
(m, 2H), 2.45 (m, 2H), 1.42 (m, 2H), 1.27-1.04 (m, 10H).
N—[8-(Quinolinylamino)octyl]benzamide A mixture of N-(8-aminooctyl)benzamide (357 mg,
1.44 mmol), 4-chloroquinoline (312 mg, 1.91 mmol), and DIEA (0.50 mL, 2.87 mmol) in 1 mL
of NMP was heated at 160 °C in a sealed tube for 24 hr. The mixture was cooled, diluted with
DCM, and washed with 5% . The organic phase was dried over NaZSO4 and
concentrated. SPE, washing with 5% MeOH/DCM and eluting with 2.5% MeOH/DCM + 2%
TEA, gave the product as an oil, which was crystallized from EtOH. Rf 0.33 (50% EA/Hex + 2%
TEA); lH NMR(CDC13)5 8.33 (d, 1H, J=5.7 Hz), 7.87 (dd, 1H, J=0.7, 8.4 Hz), 7.80 (d, 1H,
J=8.7 Hz), 7.74—7.71 (m, 2H), 7.58 (ddd, 1H, J=1.5, 6.9, 8.4 Hz), 7.48-7.34 (m, 4H), 6.38 (d, 1H,
J=5.7 Hz), 3.38—3.26 (m, 4H), .35 (m, 12H).
Example 76: 3—Methoxy—N—[8—(quinolin—4—ylamino)octyl]benzamide
HNW OCH3
C09 0
N—(8—Aminooctyl)—3—methoxybenzamide A mixture of methyl 3—methoxybenzoate (863 mg,
.20 mmol) and l,8—octanediamine (6.90 g) was heated at 110—120 0C for 24 hr. The mixture was
cooled and ioned between EA (3x60 mL) and H20, 2.5% N32CO3 (3x), and brine (60 mL
each). The organic phases were dried over anhydrous NaZSO4 and concentrated. NMR showed
the residue consisted of 2.3:1 ratio of amide and diamine. Reverse—phase SPE (ODS—silica gel),
washing with 20% MeOH/HZO and then eluting with MeOH, gave 1.43 g yellow oil. NMR
showed the oil consisted of 7.3:1 ratio of amide and diamine.
3—Methoxy—N—[8—(quinolin—4—ylamino)octyl]benzamide A mixture of N—(8—aminooctyl)—3—
ybenzamide (540 mg, 1.94 mmol), 4—chloroquinoline (340 mg, 2.08 mmol), and DIEA
(0.80 mL, 4.59 mmol) in 2.5 mL of NMP was heated at 160 0C in a sealed tube for 3 days. The
e was cooled, diluted with EA, washed with 5% N32C03 and brine, dried over NaZSO4,
and trated. SPE, washing with 1% MeOH/DCM and then eluting with 7.5% MeOH/DCM
+ 2% TEA, gave the product as a solid. Rf 0.19 (EA + 2% TEA); mp 162-165 0C (from MeOH);
1H NMR (20% CD3OD/CDC13) 8 8.38 (d, 1H, J=5.7 Hz), 8.04 (d, 1H, J=8.4 Hz), 7.92 (d, 1H,
J=8.4 Hz), 7.57 (m, 1H), 7.40-7.21 (m, 4H), 6.95 (ddd, 1H, J=1.2, 2.7, 8.1 Hz), 6.85 (m, 1H),
6.36 (d, 1H, J=5.7 Hz), 6.31 (br s, 1H, NH), 3.75 (s, 3H), 3.41-3.25 (m, 4H), 1.72-1.16 (m, 12H).
Example 77: 4-Methoxy—N—[8—(quinolin—4—ylamino)octy1]benzamide
HNWNYO/OCH3H
Cd 0
N—(8—Aminooctyl)—4—methoxybenzamide A mixture of methyl 4—methoxybenzoate (874 mg,
.26 mmol) and 1,8—octanediamine (6.18 g) was heated at 110—120 0C for 4 days. The mixture
was cooled and partitioned between EA (3x60 mL) and H20, 2.5% N32CO3 (3x), and brine (60
mL each). The c phases were dried over anhydrous NaZSO4 and trated. Reverse—
phase SPE (ODS—silica gel), washing with 20% MeOH/HZO and then eluting with MeOH, gave
an oil. The oil was taken up in DCM and washed with 5% N32CO3, dried over Na2804, and
concentrated to give 533 mg of sticky yellow solid. 1H NMR (CD3OD) 5 7.77 and 6.96 (m, 4H,
AA’BB’), 4.88 (s, 3H), 3.34 (m, 2H), 3.13 (m, 1H, NH), 2.60 (m, 2H), 1.91 (2xs, 2H, N?z),
1.62—1.33 (m, 12H).
4—Methoxy—N—[8—(quinolin—4—ylamino)octyl]benzamide A mixture of N—(8—aminooctyl)—4—
methoxybenzamide (533 mg, 1.92 mmol) and 7.5 mL of anhydrous ne was evaporated to
dryness. Then, roquinoline (335 mg, 2.08 mmol) and DIEA (0.80 mL, 4.59 mmol) in 2.5
mL of NMP was added and the mixture was heated at 160 0C in a sealed tube for 3 days. The
mixture was cooled, diluted with EA, washed with 5% N32C03 and brine, dried over NaZSO4,
and concentrated. SPE, g with 1% MeOH/DCM and then g with 7.5% MeOH/DCM
+ 2% TEA, gave the product as a solid. Rf 0.00 (5% MeOH/DCM) 0.20 (EA + 2% TEA) ; 1H
NMR (20% CD3OD/CDC13) 5 8.30 (d, 1H, J=5.7), 7.82—7.76 (m, 2H), 7.65 and 6.82 (m, 4H,
AA’BB’), 7.53 (ddd, 1H, J=1.5, 6.9, 8.4 Hz), 7.33 (ddd, 1H, 121.2, 6.9, 8.4 Hz), 6.32 (d, 1H,
J=5.5 Hz), 3.74 (s, 3H), 3.32-3.19 (m, 4H), .25 (m, 12H).
Example 78: 2-(Hexyloxy)-N—[2-(quinolinylamino)ethyl]benzamide
\ OO\/\/\/
Methyl 2—(hexyloxy)benzoateA mixture of methyl salicylate (7.76 g, 51.1 mmol), K2C03 (8.8 g,
64 mmol), and 1—bromohexane (8.60 mL, 61.5 mmol) in 30 mL of DMF was heated at 50 0C for
.5 hr. The e was partitioned between 1:1 EA/Hex (3x150 mL) and 0.2M HCl, 0.1M
HCl, and brine (50 mL of each). The organic phases were dried over NaZSO4 and concentrated.
SPE, washing with Hex and eluting with 20% EA/Hex, gave 11.7 g colorless liquid.
N—(2—Aminoethyl)—2—(hexyloxy)benzamide A mixture of methyl 2—(hexyloxy)benzoate (2.11 g,
8.94 mmol) and 1,2—ethanediamine (5.40 mL, 81.0 mmol) was heated at 115 0C in a sealed tube
for 72 hr. Then, the volatile components were evaporated in vacuo. The residue was taken up in
mL of MeOH and evaporated in vacuo to give 2.34 g amber liquid. 1H NMR (CDgOD) 8 7.84
(m, 1H), 7.45 (ddd, lH, J=1.9, 7.4, 9.2 Hz), 7.09 (d, 1H, J=8.1Hz), 7.02 (m, 1H), 4.13 (t, 2H,
J=6.5 Hz), 3.47 (m, 2H), 2.84 (m, 2H), 1.86 (m, 2H), 1.49 (m, 2H), 1.39—1.34 (m, 4H), 0.93 (m,
3H); 13C NMR (CD3OD) 5 169.0, 158.5, 134.1, 132.0, 123.7, 122.0, 114.0, 70.4, 43.5, 42.3,
32.9, 30.4, 27.2, 23.9, 14.6.
2—(Hexyloxy)—N—[2—(quinolin—4—ylamino)ethyl]benzamide N—(2—Aminoethyl)—2—
(hexyloxy)benzamide (2.34 g, 8.86 mmol) was taken up in 65 mL of l—pentanol, and 15 mL was
removed by distillation. The mixture was cooled slightly, and tripropylamine 3.40 mL, 17.8
mmol) and 4—chloroquinoline (1.60 g, 9.82 mmol) were added. The mixture was heated at re?ux
for 63 hr. Then, the mixture was concentrated in vacuo. The residue was partitioned between
DCM and 5% N212CO3, and the organic phase was dried over NaZSO4 and concentrated. FC (5%
MeOH/DCM + 2% TBA) gave 1.84 g of brown syrup, which solidified upon standing. The solid
was rinsed with 20%, 33%, and 50% EtzO/Hex and dried in vacuo to give 1.67 g of solid. Rf0.30
(5% MeOH/DCM + 2% TEA); 1H NMR (CDC13)8 8.56-8.51 (m, 2H), 8.28 (dd, 1H, J=1.8, 8.1
Hz), 7.92 (d, 1H, J=8.8 Hz), 7.60 (m, 1H), 7.46-7.41 (m, 2H), 7.08 (m, 1H), 6.93 (d, 1H, J=8.0
Hz), 6.77 (br s, 1H, NH), 6.33 (d, 1H, J=5.1 Hz), 4.06 (t, 2H, J=6.6 Hz), 3.90 (m, 2H), 3.50 (m,
2H), 1.77 (m, 2H), 1.42—1.23 (m, 6H), 0.87 (t, 3H, J=7 Hz); 13C NMR(CDC13) 8 168.1, 157.3,
151.2, 150.3, 148.6, 133.5, 132.5, 129.8, 129.1, 124.9, 121.5, 120.9, 120.6, 119.1, 112.5, 98.1,
69.3, 46.1, 39.1, 31.5, 29.2, 26.0, 22.7, 14.2.
Example 79: 2—(Hexyloxy)—N—[3—(quinolin—4—ylamino)propyl]benzamide
HNMH%O\
yloxy)—N—[3—(quinolin—4—ylamino)propyl]benzamide (1.6 g) was prepared by the method
for yloxy)—N—[4—(quinolin—4—ylamino)butyl]benzamide, ng with methyl 2—
oxy)benzoate (2.13 g) and l,3—diaminopropane (6.00 mL) and using 4—chloroquinoline
(1.70 g).
minopropyl)—2—(hexyloxy)benzamide: 1H NMR (CDC13) 5 7.85 (dd, 1H, J=1.8, 7.7 Hz),
7.44 (ddd, 1H, J=1.8, 7.3, 9.2 Hz), 7.10 (d, 1H, J=8.4 Hz), 7.02 (m, 1H), 4.14 (m, 2H), 3.48 (m,
2H), 3.30 (m, 2H), 2.72 (m, 2H), 1.86 (m, 2H), 1.75 (m, 2H), 1.40-1.35 (m, 4H), 0.93 (m, 3H);
13C NMR (CDC13) 5 168.8, 158.5, 134.1, 132.0, 123.6, 122.0, 114.0, 70.4, 40.0, 38.2, 33.9, 32.9,
.4, 27.2, 23.9, 14.6.
2—(Hexyloxy)—N—[3—(quinolin—4—ylamino)propyl]benzamide: Rf 0.08 (5% MeOH/DCM); 1H
NMR ) 5 8.50 (d, 1H, J=5.5 Hz), 8.25 (dd, 1H, J=1.8, 7.7 Hz), 8.24-8.20 (m, 1H), 8.01—
7.98 (m, 1H), 7.93 (dd, 1H, J=0.7, 8.4 Hz), 7.58 (ddd, 1H, J=1.1, 7.0, 8.1 Hz), 7.44-7.36 (m, 2H),
7.10—7.06 (m, 1H), 6.92 (d, 1H, J=8.1 Hz), 6.49—6.46 (t, 1H, J=6 Hz, NH), 6.39 (d, 1H, J=5.5
Hz), 4.03 (t, 2H), 3.63-3.59 (m, 2H), 3.46-3.42 (m, 2H), 2.64 (br s, 1H, NH), 1.95-1.89 (m, 2H),
.74 (m, 2H), 1.45-1.27 (m, 6H), 0.89-0.86 (m, 3H); 13C NMR(CDC13) 5 166.8, 157.2,
151.0, 150.0, 148.7, 133.1, 132.4, 129.7, 129.1, 124.7, 121.4, 21.3, 120.4, 119.3, 112.4, 98.3,
69.2, 39.6, 39.6, 36.8, 31.6, 29.3, 28.7, 26.0, 22.7, 14.1.
Example 80: 2-(Hexyloxy)-N-[4-(quinolinylamino)buty1]benzamide
HNWNWKQH
\ OO\/\/\/
N—(4—Aminobutyl)—2—(hexyloxy)benzamide A mixture of 1,4—diaminobutane (5.37 g, 61 mmol)
and methyl 2-(hexyloxy)benzoate (1.80 g, 7.63 mmol) was heated at 110 0C in a sealed tube for
48 hr. The mixture was partitioned between isopropyl acetate (3x125 mL) and H20 (100 mL),
5% N32C03 (2x100 mL), and brine (100 mL). The organic phases were dried over anhydrous
Na2804 and trated to give 2.10 g of colorless syrup. 1H NMR (CDC13) 5 8.15 (dd, 1H,
J=7.7, 1.8 Hz), 8.01 (br s, 1H), 7.33 (ddd, 1H, J=9.2, 7.3, 1.8 Hz), 6.98 (m, 1H), 6.88 (d, 1H,
J=8.4 Hz), 4.04 (m, 2H), 3.41 (m, 2H), 2.68 (m, 2H), 1.80 (m, 2H), 1.59 (m, 2H), 1.52-1.40 (m,
4H), 1.32—1.25 (m, 4H), 1.12 (br, s, 2H), 0.86 (m, 3H); 13C NMR (CDC13) 5 165.3, 157.0, 132.6,
132.2, 121.6, 121.1, 112.2, 69.0, 42.0, 39.6, 31.6, 31.3, 29.3, 27.1, 26.0, 22.6, 14.0.
yloxy)—N—[4—(quinolin—4—ylamino)butyl]benzamide N—(4—Aminobutyl)—2—
(hexyloxy)benzamide was taken up in 60 mL of 1—pentanol, and 15 mL of volatile liquid was
removed by distillation. The mixture was cooled slightly, and tripropylamine (2.70 mL, 14.2
mmol) and 4—chloroquinoline (1.29 g, 7.91 mmol) were added. Heating at re?ux was resumed for
42 hr. The cooled mixture was concentrated and partitioned n DCM and 5% N212CO3, and
the organic phase was dried over anhydrous NaZSO4 and concentrated. The residue was taken up
in EA and then concentrated again. The resulting oil solidified upon standing. The solid was
broken up and washed with 20%, 50%, and 100% x. Drying in vacuo gave 1.53 g of
yellow—gray solid. Rf 0.21 (5% MeOH/DCM + 2% TEA); 1H NMR (CD3OD) 8 8.53 (d, 1H,
J=5.5 Hz), 8.24 (dd, 1H, J=1.9, 7.7 Hz), 8.16 (m, 1H, NH), 7.95 (d, 1H, J=8.4 Hz), 7.85 (d, 1H,
J=8.4 Hz), 7.61 (m, 1H), 7.44-7.38 (m, 2H), 7.07 (m, 1H), 6.94 (d, 1H, J=8.4 Hz), 6.41 (d, 1H,
J=5.1 Hz), 5.44 (br s, 1H, NH), 4.08 (m, 2H), 3.57 (m, 2H), 3.39 (m, 2H), 1.91-1.75 (m, 6H),
1.44 (m, 2H), 1.34-1.27 (m, 4H), 0.86 (m, 3H); 13C NMR (CDC13) 5 165.9, 157.2, 151.2, 149.9,
148.7, 133.0, 132.5, 130.1, 129.1, 124.8, 121.5, 121.4, 119.8, 119.0, 112.4, 98.9, 69.2, 43.2, 39.3,
31.7, 29.4, 28.0, 26.2, 26.1, 22.8, 14.2.
Example 81: N-[8-(Quinolinylamino)octyl]picolinamide
H |
/\/\/\/\/N \
HN \n/(Nj
cm 0
N—(8—Aminooctyl)picolinamide A e of 1,8-octanediamine (8.19 g, 56.9 mmol) and
methyl picolinate (970 mg, 7.08 mmol) was heated at 130 0C for 60 hr. The mixture was cooled,
taken up in methanol, and evaporated onto silica gel. The pre—loaded silica gel was loaded on top
of a ?ash column and eluted using 15% MeOH/DCM + 2% TEA. Concentration of the product—
containing fractions gave 1.28 g of liquid. Rf 0.23 (15% MeOH/DCM + 2% TEA); 1H NMR
(20% CD3OD/CDC13) 5 8.5 (ddd, 1H, J=1.0, 1.7, 4.9 Hz), 8.2 (m, 1H), 8.0 (br s, 1H, NH), 7.8
(m, 1H), 7.4 (ddd, 1H, J=1.5, 4.9, 7.7 Hz), 3.43 (m, 2H), 2.66 (m, 2H), 2.17 (br s, 2H,NH2), 1.65-
1.28 (m, 12H).
N—[8—(Quinolin—4—ylamino)octyl]picolinamide A mixture of minooctyl)picolinamide
(557 mg, 2.24 mmol), 4—chloroquinoline (544 mg, 3.34 mmol), DlEA (1 mL, 6 mmol) and 0.5
mL of DMF was heated at 140 0C in a sealed tube for 89 hr. Then, the volatile components were
evaporated, and the residue was purified by EC (8% MeOH/DCM) to give 520 mg of product. Rf
0.38 (10% MeOH/DCM); 1H NMR (CDC13) 5 8.6 (d, 1H), 8.4 (d, 1H), 8.1 (d, 1H), 9 (m,
3H), 7.7 (m, 1H), 7.5 (m, 1H), 7.30 (m, 1H), 6.3 (d, 1H), 3.4-3.3 (m, 4H), 1.7 (m, 2H), 1.5 (m,
2H), 1.3—1.0 (m, 8H).
Example 82: N—[8—(Quinolin—4—ylamino)octyl]nicotinamide
WWH \ IN
CKE O
N
N—(8-Aminooctyl)nicotinamide A mixture of 1,8-diaminooctane (9.78 g, 67.0 mmol) and
methyl nicotinate (1.50 g, 10.9 mmol) was heated at 84 0C for 16 hr and 110-120 0C for an
additional 56 hr. The cooled mixture was ted by SPE, washing with 5% MeOH/DCM +
2% TEA to remove the octane-1,8-bis(amide) and residual methyl nicotinate and then with 15%
MeOH/DCM + 2% TEA to elute ninhydrin (+) product fractions. The product fractions were
concentrated, taken up in DCM, washed with 5% N212C03, dried over Na2804, filtered, and dried
to give 2.07 g of pale yellow solid. Rf 0.10 (15% MeOH/DCM + 2% TEA); 1H NMR (CD3OD) 5
8.95 (dd, 1H, J=0.8, 2.2 Hz), 8.67 (m, 1H), 8.23 (m, 1H), 7.53 (m, 1H), 3.38 (t, 2H, J=7.3 Hz),
2.60 (t, 2H), 1.61 (m, 2H), 1.47—1.33 (m, 10H); 13C NMR (CD3OD) 8 167.8, 152.7, 149.2, 137.1,
132.4, 125.3, 42.8, 41.3, 34.1, 30.7, 30.6, 28.2, 28.2, 22.2.
N—[8—(Quinolin—4—ylamino)octyl]nicotinamide N—(8—aminooctyl)nicotinamide (5.66 g, 22.7
mmol) was taken up in 100 mL of 1—pentanol, and then 50 mL of le material was d
by lation. The mixture was cooled below boiling, and tripropylamine (9.50 mL, 49.8 mmol)
and 4—chloroquinoline (4.08 g, 25.0 mmol) were added. Heating at re?ux was resumed. After 22
hr, volatile material was removed by evaporation. The mixture was partitioned between DCM
(175, 2x100 mL) and a combination of 25 mL of 1N NaOH and 25 mL of 5% N32CO3. The
combined organic phases were dried over , filtered, and concentrated to give a dark
syrup. Two crystallizations from MeOH/HZO and drying in vacuo over P205 gave 2.31 g of tan
solid. Rf0.56 (15% MeOH/DCM + 2% TEA); mp 1395-1410 0C; 1H NMR (DMSO-dg) 5 8.97
(m, 1H), 8.66 (m, 1H), 8.61 (t, 1H, J=5.5 Hz), 8.35 (d, 1H, J=5.1 Hz), 8.19 (d, 1H, J=8.8 Hz),
8.14 (ddd, 1H, J=1.4, 2.2, 7.7 Hz), 7.74 (dd, 1H, J=1.1, 8.5 Hz), 7.57 (m, 1H), 7.46 (m, 1H), 7.38
(ddd, 1H, J=1.4, 7.0, 8.4 Hz), 7.16 (t, 1H, J=5 Hz), 6.40 (d, 1H, J=5.5 Hz), 3.27-3.22 (m, 4H),
1.65 (m, 2H), 1.44 (m, 2H), 1.30 (m, 8H); 13C NMR (DMSO-d6) 5 164.6, 151.6, 150.4, 150.2,
148.3, 148.0, 134.8, 130.1, 128.7, 123.7, 123.4, 121.7, 118.8, 98.0, 42.4, 39.2, 29.0, 28.8, 28.7,
27.8, 26.6, 26.4.
Example 83: N—[8—(Quinolin—4—ylamino)octyl]isonicotinamide
/ WH\I“
N—(8-Aminooctyl)isonicotinamide A mixture of 1,8-diaminooctane (7.66 g, 53 mmol) and
methyl isonicotinate (910 mg, 6.64 mmol) was heated at 130 0C for 60 hr. The cooled mixture
was partitioned between DCM and 5% N32C03, and the organic phase was dried over ous
NazSO4 and concentrated. FC (15% MeOH/DCM + 2% TEA) gave 539 mg of oily solid. Rf0.15
(15% CM + 2% TEA); 1H NMR (20% CD3OD/CDC13) 5 8.59 and 7.66 (m, 4H,
AA’BB’), 3.33 (m, 2H), 3.10 (m, 1H, NH), 278 (m, 2H), 1.85 (s, 2H, N?z), 1.57—1.24 (m, 12H).
N—[8—(Quinolin—4—ylamino)octyl]isonicotinamide A mixture of N—(8—
ctyl)isonicotinamide (539 mg, 2.16 mmol), 4—chloroquinoline (536 mg, 3.29 mmol),
DIEA (2 mL, 12 mmol) and 0.5 mL of DMF was heated at 140 0C in a sealed tube for 89 hr.
Then, the volatile components were evaporated, and the residue was purified by EC (8%
MeOH/DCM) to give 113 mg of product. Rf 0.13 (10% MeOH/DCM); 1H NMR (20%
CD30D/CDC13) 5 8.58 and 7.62 (m, 4H, AA’BB’), 8.35 (d, 1H, J=5.4 Hz), 7.83 (dd, 1H, 120.7,
2014/013992
8.4 Hz), 7.71 (m, 1H), 7.55 (ddd, 1H, J=1.3, 7.0, 8.2 Hz), 7.35 (ddd, 1H, J=1.2, 6.9, 8.4 HZ), 6.34
(d, 1H, J=5.5 Hz), 3.37—3.21 (m, 4H), 1.70—1.22 (m, 12H).
Example 84: N—(Pyridin—4—ylmethyl)quinolin—4—amine
HN /|
/|\N
N—(Pyridin—4—ylmethyl)quinolin—4—amine was prepared following the method for idin—2—
ylmethyl)quinolin—4—amine. Rf 0.29 (5% MeOH/DCM + 2% TEA);1H NMR (CDCl3) 5 8.51—8.47
(m, 2H), 8.39 (d, 1H, J=5.4 Hz), 8.03-8.00 (m, 1H), 7.95 (dd, 1H, J=1.0, 8.4 Hz), 7.59 (ddd, 1,
J=1.2, 6.9, 8.4 Hz), 7.40 (ddd, 1H, J=1.5, 6.9, 8.4 Hz), 7.28-7.22 (m, 2H), 6.61 (br s, 1H), 6.19
(d, 1H, J=5.4 Hz), 4.56 (br s, 2H).
Example 85: N—(Pyridinylmethyl)quinolinamine
HN /|
/|\N
N—(Pyridinylmethyl)quinolinamine was prepared following the method for N—(pyridin
ylmethyl)quinolin-4—amine. Rf 0.36 (5% MeOH/DCM + 2% TEA);1H NMR (CDC13) 8 8.56 (d,
1H, J=2.0 Hz), 8.45 (dd, 1H, J=1.7, 5.0 Hz), 8.41 (d, 1H, J=5.2 Hz), 7.98 (d, 1H, J=8.4 Hz), 7.91
(dd, 1H, J=1.0, 8.4 Hz), 7.61 (ddd, 1H, J=1.7, 2.0, 7.9 Hz), 7.54 (ddd, 1H, J=1.2, 6.9, 8.2 Hz),
7.33 (ddd, 1H, J=1.2, 6.9, 8.4 Hz), 7.17 (dd, 1H, 125.0, 7.9 Hz), 6.61 (br s, 1H), 6.29 (d, 1H,
J=5.5 Hz), 4.50 (m, 2H, AB).
Example 86: N—(Pyridin—2—ylmethyl)quinolin—4—amine
HN /|
A mixture of 4—chloroquinoline (228 mg, 1.40 mmol), 2—(aminomethyl)pyridine (144 mg, 1.33
mmol), and DIEA (0.50 mL) was heated at 130 0C in a sealed tube for 48 hr. Then, the mixture
was cooled, partitioned between EA and 5% Na2C03 and brine, dried over NaZSO4, and
concentrated. FC (3% MeOH/DCM + 2% TEA) gave product—containing fractions, which were
concentrated. The residue was taken up in DCM and washed with 5% N32CO3, dried over
NaZSO4, and trated to give the product. Rf0.54 (5% MeOH/DCM + 2% TEA); 1H NMR
(CDC13) 5 .54 (m, 1H), 8.46 (d, 1H, J=5.4 Hz), 7.99-7.91 (m, 2H), .52 (m, 2H), 7.37
(ddd, 1H, J=1.2, 6.9, 8.1 Hz), 7.26-7.23 (m, 1H), .13 (m, 1H), 7.03 (br s, 1H), 6.32 (d, 1H,
J=5.4 Hz), 4.52 (m, 2H, AB).
Example 87: N—Hexquuinolin—4—amine
@j/N
A mixture of 4-chloroquinoline (248 mg, 1.52 mmol) and 1-hexylamine (2 mL, 15 mmol) was
heated in a sealed tube at 100 °C for 2 days, 120-130 0C for 2 days, and 150 0C for 1 day. The
mixture was cooled and partitioned between EA and 5% Na2C03 and brine, and the organic
phase was dried over Na2804 and concentrated in vacuo. SPE, washing with 25% EA/Hex and
eluting with 12% MeOH/DCM, followed by repurification by preparative TLC (10%
MeOH/DCM), gave the product as an oil. Rf 0.16 (5% MeOH/DCM); 1H NMR (CDC13) 8 8.48
(d, 1H, J=5.4 Hz), 7.97 (dd, 1H, J=1.0, 8.4 Hz), 7.8? (d, 1H, J=8.4 Hz), 7.60 (ddd, 1H, 121.5,
6.9, 8.4 Hz), 7.40 (ddd, 1H, J=1.2, 6.9, 8.4 Hz), 6.40 (d, 1H, J=5.7 Hz), 5.66 (br s, 1H, NH), 3.32
(m, 2H), 1.75 (m, 2H), 1.46—1.26 (m, 6H), 0.89 (m, 3H).
Example 88: N—(Decyl)quinolin—4—amine
:jkT/
A mixture of 1—aminodecane (4.36 g, 27.8 mmol), tripropylamine (8.00 mL, 42.0 mmol), and 4—
chloroquinoline (4.55 g, 27.9 mmol) in 25 mL of l—pentanol was heated at re?ux for 3 days.
2014/013992
Then, the volatile components were evaporated. The e was take up in DCM (150 mL) and
washed with 5% N32CO3 (100 mL). The aqueous phase was extracted with DCM (100 mL), and
the combined organic phases were dried over , filtered, and concentrated to give a dark
. SPE, eluting with 1% and then 5% MeOH/DCM + 2% TEA, gave product fractions that
were concentrated, ioned between DCM (150, 100 mL) and 5% N32CO3 (100 mL), dried
over NagSO4, filtered, and concentrated. Recrystallization from EA/Hex gave 4.14 g colorless
solid. Rf0.30 (5% MeOH/DCM + 2% TEA); mp 79.0-80.0 0C; 1H NMR (CDCl3) 5 8.56 (d, 1H,
J=5.5 Hz), 7.97 (dd, 1H, J=1.1, 8.4 Hz), 7.72 (m, 1H), 7.62 (ddd, 1H, J=l.4, 7.0, 8.4 Hz), 7.41
(m, 1H), 6.43 (d, 1H, J=5.5 Hz), 4.97 (br s, 1H, NH), 3.31 (m, 2H), 1.76 (m, 2H), 1.46 (m, 2H),
1.39—1.27 (m, 12H), 0.88 (m, 3H); 13C NMR (CDC13) 5 152.2, 149.9, 149.6, 129.2, 128.2, 125.0,
122.7, 121.0, 102.4, 62.0, 51.8, 32.6, 28.0, 25.7, 22.4, 14.0.
Example 89: N—(Dodecyl)quinolin—4-amine
A mixture of 4-chloroquinoline (3.25 g, 19.9 mmol), l-dodecylamine (3.80 g, 20.5 mmol), and
tripropylamine (5.90 mL, 30.9 mmol) in 30 mL of l-pentanol was heated at re?ux for 16.5 hr.
Then, the volatile components were evaporated in vacuo. The residue was partitioned between
DCM (150, 100 mL) and a mixture of 1N NaOH and 5% Na2C03 (20 mL each). The organic
phases were dried over NaZSO4 and concentrated. Crystallization from ice—cold 10% EA/Hex,
washing the collected solid with ice—cold 20% EtzO/Hex, gave 4.95 g colorless solid (mp 81.5-
82.0 0C). LC/MS (230 nm) indicated the presence of 5-10% impurity. SPE (1% TEA/EA)
ted an impurity with predominantly aryl hydrogens by NMR. The product was
tallized from ice—cold 10% EA/Hex to give 4.70 g colorless solid. Rf 0.12 (10%
MeOH/DCM); mp 80.5—81.5 0C; 1H NMR(CDC13)5 8.56 (d, 1H, J=5.1 Hz), 7.97 (dd, 1H,
J=1.1, 8.4 Hz), 7.72 (m, 1H), 7.62 (ddd, 1H, J=1.5, 7.0, 8.5 Hz), 7.42 (ddd, 1H, J=1.5, 7.0, 8.5
Hz), 6.42 (d, 1H, J=5.5 Hz), 4.98 (br s, 1H, NH), 3.31 (m, 2H), 1.76 (p, 2H, J=7.3 Hz), 1.47 (m,
2H), 1.38—1.26 (m, 16H), 0.88 (t, 3H, J=6.8 Hz);13C NMR (CDC13) 5 151.3, 149.8, 148.7, 130.3,
2014/013992
129.1, 124.7, 119.3, 118.9, 99.0, 43.5, 32.1, 29.8, 29.8, 29.8, 29.8, 29.6, 29.5, 29.2, 27.4, 22.9,
14.3.
Example 90: N1,NS—Di(quinolin—4—yl)octane—1,8—diamine
HN \
CE? I”
A mixture of 1,8—octanediamine and excess 4—chloroquinoline and DIEA in NMP was heated at
160 0C in a sealed tube for 3 days. The mixture was cooled and purified by SPE, washing with
1% MeOH/DCM and then eluting with 7.5% MeOH/DCM + 2% TEA to give the product as a
solid. Rf0.05 (EA + 2% TEA); 1H NMR (20% CD3OD/CDC13) 5 8.32 (d, 2H, J=5.7 Hz), 7.85—
7.80 (m, 4), 7.58 (ddd, 2H, J=1.2, 6.9, 8.2 Hz), 7.38 (ddd, 2H, J=1.2, 6.9, 8.4 Hz), 6.37 (d, 2H,
J=5.7 Hz), 3.38-3.25 (m, 4H), 1.73-1.24 (m, 12H).
Example 91: N-[8-(Hexyloxy)octyl]quinolinamine
8—(Hexyloxy)octanoic acid imately 6.0 mL of Jones reagent was added to a mixture of
8—(hexyloxy)octan—1—ol (2.1 g, 9.1 mmol) and 50 mL of DCM cooled by an ice bath, after which
the green color of the mixture did not persist. Then, the mixture was washed with H20 and 0.1M
HCl, and the organic phase was dried over MgSO4, d with 5 mL of MeOH, filtered through
a pad of silica gel, washing the pad with 5% MeOH/DCM, and concentrated. EC (5%
MeOH/DCM) gave 1.6 g of product. Rf 0.3 (5% MeOH/DCM); 1H NMR (CDClg) 8 3.4 (t, 4H),
2.3 (m, 2H), 1.7—1.4 (m, 6H), 1.4—1.2 (m, 12H), 0.9 (m, 3H).
8—(Hexyloxy)—N—(quinolin—6—yl)octanamide A mixture of 6—aminoquinoline (0.5 g, 3.5 mmol),
8—(hexyloxy)octanoic acid (847 mg, 3.47 mmol), l—hydroxybenzotriazole (469 mg, 3.47 mmol),
4—dimethylaminopyridine (42 mg, 0.3 mmol), and EDC (663 mg, 3.47 mmol) in 20 mL of DCM
was reacted until the starting material was consumed, as ed by TLC. Then, the volatile
ents were evaporated, and the residue was ioned between EA and H20, 5%
N32CO3, H20, and brine, and the organic phases were dried over NaZSO4 and concentrated. FC
(50% EA/Hex) gave 225 mg of the t. Rf 0.4 (50% EA/Hex); 1H NMR (CDC13) 5 8.8 (m,
1H), 8.4 (m, 1H), 8.15 (m, 1H), 8.05 (m, 1H), 7.9 (br s, 1H, NH), 7.6 (m, 1H), 7.4 (m, 1H), 3.4
(t, 4H), 2.4 (t, 2H), 1.7 (m, 2H), 1.6-1.4 (m, 4H), 1.4—1.2 (m, 12H), 0.85 (m, 3H).
N—[8—(Hexyloxy)octyl]quinolin—6—amine A mixture of 8—(hexyloxy)—N—(quinolin—6—
yl)octanamide (171 mg, 0.46 mmol) and 20 mL of THF was cooled by an ice bath before 70 mg
of lithium aluminum hydride was added. The mixture was allowed to warm slowly to room
temperature overnight. Then, the mixture was recooled, and 0.7 mL of H20, 0.7 mL of 15%
NaOH, and 2.1 mL of H20 were added cautiously. The mixture was filtered through a pad of
Celite, washing with 5% MeOH/DCM, and the filtrate was concentrated. The residue was
partitioned between EA and 5% Na2C03 and brine, and the organic phase was dried over Na2$O4
and concentrated. FC (50% EA/Hex) gave 100 mg of the product. Rf 0.3 (50% EA/Hex); 1H
NMR(CDC13) 5 8.6 (m, 1H), 7.95-7.85 (m, 2H), 7.3 (m, 1H), 7.1 (m, 1H), 7.7 (m, 1H), 3.4 (t,
4H), 3.2 (t, 2H), 2 (m, 20H), 0.85 (t, 3H).
Example 92: N-[8—(Hexyloxy)octy1]quinolin—3—amine
\ N\/\/\/\/\O/\/\/\
N—[8—(Hexyloxy)octyl]quinolin—3—amine (66 mg) was prepared following the method for N—[8-
(hexyloxy)octyl]quinolin—6—amine starting with 3—aminoquinoline (728 mg).
8—(Hexyloxy)—N—(quinolin—3—yl)octanamide: 1H NMR (CDClg) 5 9.05 (br s, 1H), 8.95 (br, s, 1H),
8.5 (br s, 1H, NH), 8.1 (d, 1H), 7.8 (d, 1H), 5 (m, 2H), 3.4 (m, 4H), 2.5 (t, 2H), 1.8 (m,
2H), 1.7—1.2 (m, 16H), 0.85 (t, 3H).
206—181 N—[8—(Hexyloxy)octyl]quinolin—3—amine 1H NMR ) 5 8.6 (d, 1H), 8.0
(d, 1H), 7.6 (d, 1H), 7.5-7.3 (m, 2H), 7.0 (m, 1H), 4.3 (br s, 1H, NH), 3.5-3.3 (m, 4H), 3.2 (m,
2H), 1.8—1.2 (m, 20H), 0.9 (m, 3H).
Example 93: N—[8—(Hexyloxy)octyl]quinolin—8—amine
/\/O\/\/\/
\
N—[8—(Hexyloxy)octyl]quinolin—8—amine (58 mg) was prepared following the method for N—[8—
(hexyloxy)octyl]quinolin—6—amine ng with 8—aminoquinoline (472 mg).
8—(Hexyloxy)—N—(quinolin—8—yl)octanamide: Rf 0.7 (10% EA/Hex); 1H NMR (CDC13) 5 9.8 (br s,
1H, NH), 8.85—8.75 (m, 2H), 8.2 (m, 1H), 7.6—7.4 (m, 3H), 3.4 (m, 4H), 2.6 (t, 2H), 1.8 (m, 2H),
1.7-1.2 (m, 16H), 0.9 (m, 3H).
Hexyloxy)octyl]quinolinamine: Rf 0.6 (50% EA/Hex); 1H NMR (CDClg) 8 8.7 (d, 1H),
8.1 (br s, 1H), 7.5-7.3 (m, 2H), 7.0 (d, 1H), 6.7 (d, 1H), 3.5-3.3 (m, 4H), 3.3 (m, 2H), 1.8 (m,
2H), 1.7-1.2 (m, 18H), 0.9 (m, 3H).
Example 94: N—[8—(Hexyloxy)octy1]—2—(trifluoromethyl)quinolin—4—amine
/\/\/\/\/ \/\/\/O
N CF3
A mixture of 8—(hexyloxy)octan—1—amine (350 mg, 1.53 mmol), 4—chloro—2—
trifluoromethquuinoline (420 mg, 1.81 mmol) and TEA (0.32 mL, 1.84 mmol) in 1 mL of NMP
was heated at 150 0C for 16 hr. The mixture was cooled and partitioned between EA and 5%
NaZCO3. The organic phases were washed with brine, dried over NaZSO4, and concentrated.
Purification by preparative TLC gave the product. Rf 0.38 (20% EA/Hex); 1H NMR (CDC13) 5
8.01 (m, 1H), 7.75 (d, 1H, J=8.4 Hz), 7.62 (ddd, 1H, J=1.2, 6.9, 8.4 Hz), 7.42 (ddd, 1H, J=1.2,
7.0, 8.4 HZ), 6.65 (s, 1H), 5.45 (m, 1H, NH), 3.38—3.34 (m, 4H), 3.27 (m, 2H), 1.76—1.18 (m,
20H), 0.85 (m, 3H).
Example 95: 7—Chloro—N—decquuinolin—4—amine
HN/\/\/\/\/\
CI N/
7—Chloro—N—decquuinolin—4—amine (8.10 g) was prepared following the method for 7—chloro—N—
dodecquuinolin—4—amine, starting with 5.18 g of l—decylamine and 6.53 g of 4,7—
dichloroquinoline. Mp 1025-1030 0C x); 1H NMR (CDC13) 5 88.5 (d, 1H, J=5.5 Hz), 7.9
(d, 1H, J=1.9 Hz), 7.6 (d, 1H, J=8.8 Hz), 7.3 (m, 1H), 6.4 (d, 1H, J=5.5 Hz), 5.1 (br m, 1H, NH),
3.3 (m, 2H), 1.7 (m, 2H), 1.5-1.3 (m, 14H), 0.8 (m, 3H); 13C NMR(CDC13) 5 152.2, 149.9,
149.4, 134.9, 129.0, 125.4, 121.1, 117.3, 99.2, 43.5, 32.1, 29.7, 29.7, 29.6, 29.5, 29.1, 27.3, 22.9,
14.3.
Example 96: 7-Chloro-N—dodecquuinolinamine
CI N
A mixture of l-dodecylamine (4.57 g, 24.7 mmol), tripropylamine (9.4 mL, 49 mmol), 4,7—
roquinoline (4.89 g, 24.7 mmol) and 50 mL of l-pentanol were heated at re?ux for 22 hr.
Then, the volatile components were ated. The residue was partitioned between EA and 5%
N32C03 and brine, and the organic phase was dried over NaZSO4 and concentrated. SPE (50%
EA/Hex) gave the product as a yellow solid. The t was taken up in DCM, washed with 5%
N32C03, dried over NaZSO4, and concentrated. The product was crystallized from ice—cold 20%
EA/Hex to give 7.50 g colorless solid. Rf 0.30 (50% EA/Hex); mp 95.0—97.0 0C; 1H NMR
(CDC13)5 8.5 (d, 1H, J=5.1 Hz), 7.9 (d, 1H, J=1.9 Hz), 7.6 (d, 1H, J=8.8 Hz), 7.3 (m, 1H), 6.39
(d, 1H, J=5.5 Hz), 5.0 (br m, 1H, NH), 3.3 (m, 2H), 1.8 (m, 2H), 1.5-1.2 (m, 20H, 0.9 (m, 3H);
WO 20995 2014/013992
13C NMR(CDCl3)5152.3, 149.9, 149.4, 135.0, 129.1, 125.4, 121.0, 117.3, 99.3, 43.5, 32.1,
29.8, 29.8, 29.8, 29.7, 29.6, 29.5, 29.1, 27.3, 22.9, 14.3.
Example 97: N—(Decyl)quinazolin—4—amine
HN/V\/\/\/\
A mixture of 4—chloroquinazoline (6.90 g, 42.1 mmol), l—decylamine (10.8 mL, 54.3 mmol), and
TEA (8.90 mL, 62.7 mmol) in 50 mL of IPA was heated at re?ux for 6 hr, then d to stand
overnight. Then, the volatile components were evaporated, and the residue was taken up in DCM
and washed with a mixture of 20 mL of 1N NaOH and 20 mL of 5% Na2C03. The organic phase
was dried over ous NaZSO4 and filtered through a pad of silica gel, washing with 5%
MeOH/DCM. The filtrate was concentrated to give a solid. The solid was washed with 25 mL
and 10 mL portions of 20% EtZO/Hex, then dried in vacuo to give 11.22 g of colorless solid. Rf
0.41 (10% MeOH/DCM); mp 72.5-73.0 0C; 1H NMR (CDCl3) 5 8.66 (s, 1H), 7.82 (dd, 1H,
J=1.1, 8.8 Hz), 7.73-7.69 (m, 2H), 7.44 (m, 1H), 5.83 (br s, 1H, NH), 3.65 (m, 2H), 1.72 (m,
2H), 1.46-1.25 (m, 14H), 0.86 (t, 3H, J=7.0 Hz); 13C NMR(CDC13) 8 159.7, 155.7, 149.6, 132.7,
128.8, 126.1, 120.6, 115.2, 41.6, 32.1, 29.8, 29.7, 29.6, 29.5, 27.6, 22.9, 14.3.
Example 98: cquuinazolin—4—amine
/\/\/\/\/\/\
1—Dodecylamine (4.20 g, 22.7 mmol) was taken up in 45 mL of IPA, and 10 mL was removed by
distillation. Then, the mixture was cooled slightly, and TEA (6.5 mL, 46 mmol) and 4—
chloroquinazoline (3.72 g, 22.7 mmol) were added. The mixture was heated at reflux for 7 hr.
Then, most of the volatile components were removed by distillation. The residue was partitioned
between DCM (150, 100 mL) and a mixture of 1N NaOH and 5% N32CO3 (20 mL each). The
organic phases were dried over NaZSO4 and concentrated. SPE (30, 50, and 60% EA/Hex step
gradient) gave product—containing fractions that were concentrated, taken up in DCM, washed
with 5% N32CO3, dried over NaZSO4, and concentrated to a syrup. Crystallization from ice—cold
% EA/Hex gave 6.05 g colorless solid. Rf 0.20 (50% EA/Hex); mp 74.0—75.0 0C; 1H NMR
(CDC13) 5 866 (s, 1H), 7.82 (m, 1H), 7.74-7.69 (m, 2H), 7.45 (m, 1H), 5.76 (br s, 1H, NH), 3.65
(m, 2H), 1.72 (m, 2H), 1.46-1.25 (m, 18H), 0.87 (m, 3H); 13C NMR (CDC13) 5 159.6, 155.7,
149.6, 132.7, 128.9, 126.1, 120.6, 115.1, 41.6, 32.1, 29.8, 29.8, 29.8, 29.8, 29.6, 29.6, 29.5, 27.3,
22.9, 14.3.
Example 99: N—Decyl—7—?uoroquinazolin—4—amine
/W\/\/\
F N
A mixture of 1—decylamine (1.2 mL, 6.0 mmol), 4—chloro—7—?uoroquinazoline (1.1 g, 6.0 mmol),
and TEA (1.3 mL, 9.3 mmol) in 10 mL of IPA was heated at re?ux for 6 hr. Then, the volatile
components were evaporated, and the residue was partitioned between DCM (400, 300 mL) and
% N32C03 (400 mL). The organic phases were dried over anhydrous NaZSO4, filtered through a
pad of silica gel, g with 10% MeOH/DCM, and concentrated. The t was
crystallized from EA/Hex.
e 100: N—Dodecy1—7—f1uoroquinazolinamine
/\/\/\/\/\/\
F N
cyl-7—?uoroquinazolin—4—amine was made from 1—dodecylamine (1.2 mL, 5.2 mmol), 4-
chloro—7—?uoroquinazoline (1.0 g, 5.5 mmol), and TEA (1.2 mL, 8.6 mmol) in 10 mL of IPA
following the method for the preparation of N—decyl-7—?uoroquinazolin—4—amine.
e 101: 7—Chloro—N—decquuinazolin—4—amine
HN/\/\/\/\/\
130”A
CI N
7—Chloro— N—decquuinazolin—4—amine was made from 1—decylamine (1.5 mL, 7.0 mmol), 4,7—
dichloroquinazoline (1.4 g, 7.0 mmol), and TEA (2.0 mL, 14 mmol) in 15 mL of IPA following
the method for the preparation of N—decyl—7—?uoroquinazolin—4—amine.
Example 102: 7—Chloro—N—dodecquuinazolin—4—amine
/\/\/\/\/\/\
D?”A
Cl N
7-Chloro— cquuinazolin—4—amine was made from 1—dodecylamine (1.3 g, 7.0 mmol), 4,7—
dichloroquinazoline (1.4 g, 7.0 mmol), and TEA (2.0 mL, 14 mmol) in 15 mL of IPA following
the method for the preparation of N-decyl?uoroquinazolinamine.
Example 103: N-(6-Butoxyhexyl)quinazolinamine
/\/\/\/
6—Butoxyhexan-1—amine (7.20 g, 41.1 mmol) was taken up in 200 mL, and 50 mL was removed
by distillation. The mixture was cooled ly, and TEA (17.4 mL, 124 mmol) and 4—
chloroquinazoline (11.11 g, 67.7 mmol) were added. The e was heated at reflux for 38 hr,
then allowed to stand at room temperature for 3 days. The volatile components were evaporated.
The residue was partitioned n DCM (150, 2x50 mL) and a mixture of 40 mL 1N NaOH
and 40 mL of 5% Na2C03. The organic phases were dried over anhydrous NaZSO4 and
evaporated onto silica gel. SPE, washing with 30% EA/Hex and eluting with 60% EA/Hex, gave
a yellow syrup that crystallized from 10% EA/Hex at —20 0C to give 4.64 g of colorless solid. Rf
0.25 (50% EA/Hex); mp 40—46 0C; 1H NMR (CDClg) 5 8.64 (s, 1H), 7.84 (d, 1H, J=8.4 Hz),
7.78-7.70 (m, 2H), 7.46 (ddd, 1H, J=1.4, 7.3, 8.4 Hz), 6.12 (br s, 1H, NH), 3.66 (m, 2H), 3.41-
3.37 (m, 4H), 1.74 (m, 2H), 1.62-1.30 (m, 10H), 0.90 (t, 3H, J=7.3 C NMR (CDC13) 5
159.8, 155.2, 148.6, 133.0, 128.1, 126.3, 120.9, 115.0, 70.9, 70.9, 41.6, 32.0, 29.8, 29.4, 27.1,
26.2, 19.6, 14.1.
e 104: N—[8—(Hexyloxy)octyl]quinazolin—4—amine
HN/\/\/\/\/O\/\/\/
8—(Hexyloxy)octan—l—ol tanediol (201.4 g, 1.38 mol) was taken up in 1.3 L of IPA,
and 250 mL of volatile material was removed by distillation. The mixture was allowed to cool
below boiling, and sodium metal (6.9 g, 0.30 mol) was added in portions while maintaining a
blanket of argon. After the addition was completed, the mixture was boiled for one hour, and
then it was d to stir at room temperature overnight. l-Bromohexane (32.2 mL, 0.23 mol)
was added in a slow stream. After 25 hr, the mixture was warmed gently. Precipitate began to
form. After 2 days of warming, the mixture was heated to distill 400 mL of volatile material.
Then, heating was halted, and 16 g of NH4Cl in 48 mL of H20 was added. After 1 hr, the
distillation was resumed and 450 mL of distillate was collected. Heating was halted, and 214 g of
silica gel was added to the hot e. The warm mixture was d well and cooled. The
excess diol was removed by SPE using 30% EA/Hex, which afforded 25.9 g of light yellow oil
containing the desired product. Rf 0.19 (20% EA/Hex); 1H NMR (CDCl3) 5 3.63-3.58 (m, 2H),
3.37 (t, 4H, J=6.7 Hz), 1.66 (br s, 1H, OH), 1.57—1.50 (m, 6H), 1.30—1.28 (m, 14H), 0.87 (t, 3H,
J26.6 Hz). 1,8—Octanediol was recovered by eluting with 5% MeOH/DCM, evaporation of
solvent, and crystallization of three crops from , which afforded 182.4 g of colorless
solid.
8—(Hexyloxy)octyl methanesulfonate 8—(Hexyloxy)octan—1—ol was taken up in 250 mL of DCM
and cooled using an ice bath. TEA (21.0 mL, 150 mmol) and methanesulfonyl chloride (10.5
mL, 134 mmol) were added in turn. After 1.25 hr, 20 g of ice chips were added. Most of the
volatile material was evaporated. The residue was partitioned between 1:1 EA/Hex (3x300 mL)
and H20, saturated NaHCOg, H2O, 1M HCl, H20, and brine (100 mL each). The combined
organic phases were dried over Na2SO4, filtered through a pad of silica gel, and trated. Rf
0.28 (20% ); 1H NMR (CDCl3) 8 4.21 (t, 2H, J=6.6 Hz), 3.38 (t, 2H, J=6.4 Hz), 3.37 (t,
2H, J=6.7 Hz), 2.98 (s, 3H), 1.72 (m, 2H), 1.61—1.46 (m, 4H), 1.40-1.24 (m, 14H), 0.87 (t, 3H,
J=6.8 Hz).
N—[8—(Hexyloxy)octyl]phthalimide Toluene (100 mL) was mixed with the crude 8—
(hexyloxy)octyl methanesulfonate and then was evaporated. The residue was taken up in 120 mL
of DMF and 60 mL of NMP. Potassium phthalimide (25.0 g, 135 mmol) was added. After
mixing for 21.5 hr, 50 mL of H20 was added, and the volatile material was evaporated. The
residue was partitioned between EA (3x300 mL) and H20 (150 mL), saturated NaHC03 (150
mL), and brine (2x150 mL). The ed organic phases were dried over Na2SO4, filtered
through a pad of silica gel, and concentrated. Rf 0.50 (10% EA/Hex); 1H NMR (CDClg) 8 7.81
and 7.68 (m, 4H, AA’BB’), 3.65 (t, 2H, J=7.3 Hz), 3.36 (t, 2H, J=6.7 Hz), 3.35 (t, 2H, J=6.7 Hz),
.48 (m, 6H), 1.29-1.22 (m, 14H), 0.86 (t, 3H, J=6.8 Hz).
8-(Hexyloxy)octanamine IPA (100 mL) was mixed with the crude N—[8-
(hexyloxy)octy1]phthalimide and then was evaporated. The residue was taken up in 450 mL of
EtOH, hydrazine drate (6.60 mL, 136 mmol) was added, and the mixture was heated at
re?ux overnight. The mixture was concentrated by lation of 300 mL of volatile material.
Heating was halted, 150 mL of 1M HCl was added to the hot mixture, and the mixture was
allowed to cool. The itate was removed by ?ltration, and it was washed with 1:1
EtOH/H2O (2x100 mL). The filtrate was concentrated to 100 mL, and the pH was adjusted to
>10 using NaOH pellets. The mixture was extracted with DCM (3x250 mL), and the combined
c phases were dried over Na2SO4, filtered, and concentrated to give 27.6 g of cloudy
liquid. 1H NMR (CDC13) 5 3.36 (t, 4H, J=6.7 Hz), 2.66 (t, 2H, J=6.9 Hz), 1.52 (m, 2H), 1.44—
1.28 (m, 18H), 0.86 (m, 3H).
N—[8—(Hexyloxy)octyl]quinazolin—4—amine Crude 8—(hexyloxy)octan—l—amine was taken up in
400 mL of IPA, and 250 mL of volatile material was removed by distillation. The mixture was
cooled, and TEA (16.8 mL, 120 mmol) and 4—chloroquinazoline (9.8 g, 60 mmol) were added.
The mixture was heated at re?ux for 4 hr. TLC of an aliquot indicated a substantial ty of
ninhydrin (+) material remained. TEA (11.2 mL, 80 mmol) and 4—chloroquinazoline (6.5 g, 38
mmol) were added. After 5 hr additional heating the mixture was allowed to cool and d 12
hr. Then, the volatile components were evaporated, and the e was partitioned between
DCM (300, 2x150 mL) and 1N NaOH and 5% N32C03 (100 mL each). The combined organic
phases were dried over NaZSO4, filtered, and concentrated. SPE, eluting with 20%, 30%, and
50% EA/Hex, gave product fractions that were combined and concentrated. The residue was
taken up in 300 mL of EA, filtered, and concentrated. The resulting yellow solid was
recrystallized twice from 10% EA/Hex to give 30.3 g of pale yellow solid. Rf 0.11 (40%
EA/Hex); mp 67.0—67.5 °C; 1H NMR(CDC13)8 8.66 (s, 1H), 7.83 (d, 1H, J=7.8 Hz), 7.75—7.70
(m, 2H), 7.46 (m, 1H), 5.81 (br s, 1H, NH), 3.65 (dt, 2H, J=5.5, 7.4 Hz), 3.38 (t, 4H), 1.73 (m,
2H), 1.59-1.52 (m, 4H), 1.46-1.24 (m, 14H), 0.87 (t, 3H, J=6.9 Hz); 13C C13)8 159.7,
155.6, 149.4, 132.8, 128.7, 126.2, 120.6, 115.1, 71.2, 71.1, 41.7, 41.5, 31.9, 30.0, 29.6, 29.6,
29.5, 27.2, 26.4, 26.1, 22.8, 14.3.
Example 105: N-[8—(4—Methoxyphenoxy)octyl]quinazolin—4—amine
HN/\/\/\/\/O\©\\
N OCH3
ethoxyphenoxy)octan—l—amine (4.03 g, 16.1 mm) was taken up in 125 mL of IPA, and 50
mL of volatile components were removed by distillation. The mixture was cooled slightly, and
TEA (4.50 mL, 32.1 mmol) and roquinazoline (2.92 g, 17.7 mmol) were added. Heating at
re?ux was d. After 24 hr, the mixture was allowed to cool, and 15 mL of 1N NaOH were
added. The volatile components were evaporated. The residue was diluted with DCM, washed
with 5% N32CO3, dried over anhydrous NaZSO4, and concentrated onto silica gel. SPE, washing
with 50% EA/Hex and eluting with 40% EA/Hex + 2% TEA, gave product—containing fractions,
which were concentrated, taken up in DCM, washed with 5% N32CO3, dried over anhydrous
NaZSO4, and concentrated to give a yellow solid. Recrystallization form EA/Hex gave 3.93 g of
white solid. Rf0.41 (50% EA/Hex + 2% TEA); mp 97.0—98.0 0C; 1H NMR (CDC13) 5 8.66 (s,
1H), 7.81 (dd, 1H, J=0.7, 8.4 Hz), 7.51 (m, 1H), 7.69 (ddd, 1H, J=l.5, 7.0, 8.5 Hz), 7.41 (ddd,
1H,J=1.5, 7.0, 8.4 Hz), 6.83—6.78 (m, 4H, AA’BB’), 6.09 (m, 1H, NH), 3.87 (t, 2H, J=6.6 Hz),
3.74 (s, 3H), 3.67 (m, 2H), 1.76-1.66 (m, 4H), 1.46—1.33 (m, 8H); 13C NMR ) 5 159.7,
155.6, 153.8, 153.4, 149.5, 132.6, 128.6, 126.0, 120.8, 115.6, 115.2, 114.8, 68.7, 55.9, 41.5, 29.5,
29.4, 29.4, 27.1, 26.1.
Example 106: N— { 2—[2— (Hexyloxy)phenoxy]ethyl}quinazolin—4—amine
HN/\/0
N/
2-[2-(Hexyloxy)phenoxy]ethanamine (15.32 g, 64.6 mmol) was taken up in 350 mL of IPA, and
50 mL was removed by distillation. The mixture was cooled slightly, and TEA (18.0 mL, 128
mmol) and 4-chloroquinazoline (11.0 g, 67.1 mmol) were added. The e was heated at
re?ux for 16 hr. Then, the volatile components were ated and the residue was partitioned
between DCM and 5% N32CO3 (500 mL of each). The organic phase was dried over N32804 and
concentrated. The solid was recrystallized from EA/Hex to give 16.0 g of solid. 1H NMR
(CDC13) 5 8.6 (s, 1H), 7.9—7.7 (m, 3H), 7.4 (m, 1H), 8 (m, 4H), 6.6 (br s, 1H, NH), 4.3 (m,
2H), 4.1—4.0 (m, 4H), 1.8 (m, 2H), 1.4 (m, 2H), 1.3—1.2 (m, 4H), 0.8 (m, 3H).
Example 107: N—{ 3—[2—(Hexyloxy)phenoxy]propyl}quinazolin—4—amine
HNMO/g
\ WV
2—(Hexyloxy)phenol A mixture of catechol (47.5 g, 432 mmol), l—bromohexane (71.2 g, 432
mmol), and K2C03 (71.5 g, 518 mmol) in 120 mL of NMP and 240 mL of DMF was heated at
60 0C for 24 hr. Then, the volatile components were evaporated, and the slurry was partitioned
between EA (600, 2x250 mL) and H20, 5% NaZCO3 (2x), H20, 0.1M HCl, and brine (150 mL
each). The organic phases were dried over NaZSO4 and evaporated onto silica gel. SPE (10%
EA/Hex) gave 75.5 g of a colorless liquid that contained a 25:1 mole ratio of 2—
oxy)phenol and l,2—bis(hexyloxy)benzene, as ated from the NMR spectrum. The
reaction was repeated using catechol (71.68 g, 652 mmol), l—bromohexane (91.0 mL, 651
mmol), and K2CO3 (108 g, 783 mmol) in 240 mL of DMF at room temperature. The reaction
gave 96.3 g pale yellow liquid that contained a 1:1 mole ratio of 2—(hexyloxy)phenol and 1,2—
bis(hexyloxy)benzene.
N—{3—[2—(Hexyloxy)phenoxy]propyl}phthalimide A 1:1 mixture of 2—(hexyloxy)phenol and
1,2-bis(hexyloxy)benzene (47.2 g, 100 mmol of phenol), K2C03 (18.7 g, 136 mmol), and N-(3-
bromopropyl)phthalimide (26.8 g, 100 mmol) in 100 mL of DMF was heated at 55 0C for 24 hr.
Then, the mixture was , and most of the le components were evaporated. The residue
was partitioned between EA (3x250 mL) and H20 (3x200 mL), 0.05M HCl (2x150 mL), and
brine (150 mL). The combined organic phases were dried over Na2804 and concentrated. SPE,
washing with 5% EA/Hex to elute residual starting materials and then eluting the product with
% EA/Hex, gave 29.8 g of white solid. Rf 0.41 (20% EA/Hex).
3—[2—(Hexyloxy)phenoxy]propan—1—amine A e of N—{3—[2—
(hexyloxy)phenoxy]propyl}phthalimide (29.8 g, 78.2 mmol) and ine monohydrate (4.80
mL, 101 mmol) in 300 mL of EtOH was heated at re?ux for 16 hr. Then, heating was stopped,
and 50 mL of 2M HCl was added. The slurry was mixed for 2 hr, then filtered through a pad of
Celite, washing with 100 mL of 10% aqueous EtOH. The filtrate was adjusted to pH 10 using
NaOH pellets and concentrated. SPE, washing with 3% MeOH/DCM and eluting with 8%
MeOH/DCM + 2% TEA, gave 15.5 g of yellow oil.
WO 20995
3—[2—(Hexyloxy)phenoxy]propan—l—amine (15.5 g, 61.8 mmol) was taken up in 250 mL of IPA,
and 50 mL was removed by distillation. The mixture was cooled slightly, and TEA (10.5 mL,
74.8 mmol) and 4—chloroquinazoline (l 1.1 g, 67.6 mmol) were added. The mixture was heated at
re?ux for 16 hr. Then, most of the volatile components were evaporated, and the residue was
partitioned between EA (300, 2x250 mL) and 5% N212CO3 and brine (150 mL each). The c
phases were dried over anhydrous NaZSO4 and concentrated to a dark liquid. Trituration with two
portions of ice—cold 50% EtzO/Hex gave 14.9 g of light tan solid. Rf 0.20 (50% EA/Hex + 2%
TEA) 0.28 (5% MeOH/DCM + 2% TEA); mp 67.0—67.5 0C; 1H NMR (CDC13) 8 8.65 (s, 1H),
7.85—7.81 (m, 2H), 7.70 (ddd, 1H, J=1.5, 7.0, 8.4 Hz), 7.38 (ddd, lH, J=1.1, 6.9, 8.0 Hz), 7.11 (br
s, 1H, NH), .89 (m, 4H), 4.24 (m, 2H), 4.04 (m, 2H), 3.93 (m, 2H), 2.24 (m, 2H), 1.71 (m,
2H), 1.37 (m, 2H), 1.23-1.17 (m, 4H), 0.81 (m, 3H); 13C NMR(CDC13)5159.7, 155.5, 149.5,
149.2, 148.6, 132.6, 128.3, 126.0, 122.5, 121.6, 121.3, 115.5, 115.3, 113.8, 70.5, 69.2, 40.9, 31.6,
29.2, 28.5, 25.8, 22.7, 14.1.
Example 108: N- { 4-[2-(Hexyloxy)phenoxy]butyl }quinazolinamine
won\
N
4—[2—(Hexyloxy)phenoxy]butan—1—amine (13.82 g, 52.2 mmol) was taken up in 300 mL of IPA,
and 50 mL was removed by distillation. Then, the mixture was cooled slightly, and TEA (15 mL,
107 mmol) and 4—chloroquinazoline (8.6 g, 52 mmol) were added. The mixture was heated at
reflux for16 hr. Then, the volatile components were evaporated and the residue was partitioned
between DCM and 5% N32CO3 (500 mL of each). The organic phase was dried over Na2$O4 and
trated. The solid was recrystallized from EA/Hex to give 8.3 g of colorless solid.
2014/013992
Example 109: N—[8—(Quinazolin—4—ylamino)octyl]nicotinamide
H |
/\/\/\/\/N \ N
N—(8—Aminooctyl)nicotinamide (2.60 g, 10.4 mmol) was taken up in 65 mL of IPA, and 30 mL of
volatile components were removed by distillation. The mixture was cooled, and TEA (2.90 mL,
.7 mmol) and 4—chloroquinazoline (1.88 g, 11.5 mmol) were added. The mixture was heated at
re?ux for 6 hr. Then, the volatile components were evaporated, and the residue was partitioned
between DCM and a mixture of 20 mL of 1N NaOH and 20 mL of 5% Na2C03. The dark
aqueous phase was extracted with 40 mL of 1—butanol. The combined organic phases were
concentrated. The residue was taken up in 10% MeOH/DCM + 2% TEA and filtered through a
pad of silica gel. The filtrate was concentrated to give a dark solid. The solid was recrystallized
from 10% aqueous MeOH, which removed some of the color. tallization from EtOH gave
two crops of light tan solid with comparable 1H NMR spectra; the crops were combined to give
2.08 g with mp 173-176 °C and 67% purity by LC (230 nm). FC (10% to 12% CM step
gradient) and recrystallization from IPA/H20 gave 1.52 g of pale yellow solid, 89% purity by LC
(230 nm). Trituration with ice-cold Eth and then 30% EA/Hex at room temperature gave a solid
with mp 1725-1760 °C and 90% purity by LC (230 nm). 1H NMR (40 oC, DMSO—dé) 8 8.96 (d,
1H, J=1.5 Hz), 8.66 (d, 1H, J=3.3 Hz), 8.56 (br s, 1H), 8.42 (s, 1H), 8.21—8.13 (m, 3H), 7.72 (m,
1H), 7.63 (m, 1H), 7.48—7.44 (m, 2H), 3.51 (m, 2H), 3.23 (m, 2H), 1.62 (m, 2H), 1.51 (m, 2H),
2 (m, 8H); 13C NMR (DMSO—d6) 8 164.6, 159.3, 155.1, 151.6, 149.0, 148.3, 134.8, 132.3,
130.1, 127.4, 125.4, 123.4, 122.6, 114.9, 40.4, 39.2, 29.0, 28.8, 28.7, 28.5, 26.5, 26.4.
Example 1 10: Hexyloxy)benzyl]quinazolin—4—amine
CELEUOVWN/
xyloxy)phenyl]methanamine (18.5 g 89.3 mmol) was taken up in 300 mL of IPA, and 100
mL of volatile material was removed by lation. The mixture was cooled, and TEA (25.3
mL, 180 mmol) and 4—chloroquinazoline (16.1 g, 98.3 mmol) were added. The mixture was
heated at re?ux for 5 hr, and then stirred at room temperature overnight. Then, the volatile
ents were evaporated, and the residue was taken up in DCM (200 mL) and washed with
1N NaOH (100 mL). The aqueous phase was extracted with DCM (100 mL). The combined
organic phases were dried over NaZSO4, filtered, and concentrated to give a red—brown solid.
SPE, eluting with 20%, 30%, and 50% EA/Hex, gave product fractions that were combined and
concentrated to yield a brown solid. Recrystallization from EA/Hex gave 21.8 g of the product as
a colorless solid. Rf0.2l (50% EA/Hex); mp 1060—1070 0C; 1H NMR (CDC13) 5 8.69 (s, 1H),
7.84 (d, 1H), 7.74-7.71 (m, 2H), 7.44 (m, 1H), 7.25 (m, 1H), 6.96-6.93 (m, 2H), 6.83 (dd, 1H,
J=2.2, 8.5 Hz), 6.18 (br s, 1H), 4.83 (m, 2H, AB), 3.92 (t, 2H, J=6.6 Hz), 1.75 (m, 2H), 1.42 (m,
2H), 1.33—1.28 (m, 4H), 0.89 (m, 3H); 13C NMR (CDC13) 5 159.8, 159.5, 155.8, 149.6, 139.7,
132.9, 130.1, 128.8, 126.3, 120.8, 120.2, 115.0, 114.5, 113.8, 68.2, 45.5, 31.8, 29.4, 25.9, 22.8,
14.2.
e 1 1 1: N-[3-(Decyloxy)benzyl]quinazolinamine
HNUOWWV
(3—(Decyloxy)phenyl)methanol A mixture of 3-hydroxybenzyl alcohol (36.2 g, 292 mmol),
1—bromodecane (55.5 mL, 269 mmol), and K2CO3 (44.3 g, 321 mmol) in 60 mL of NMP and 120
mL of DMF was mixed at 60 0C for 2 days with the aid of a mechanical r. Then, the volatile
components were removed in vacuo. The resulting slurry was partitioned between 50% EA/Hex
(300, 2x250 mL) and H20 (400 mL), 0.2N NaOH (150 mL), H20 (150 mL), 2M HCl (150 mL),
H20 (150 mL), and brine (150 mL). The organic phases were dried over anhydrous NaZSO4,
filtered through a pad of silica gel, and concentrated to 67.8 g of amber oil. The oil solidified
exothermically. NMR indicated the presence of residual odecane and EA. 1H NMR
(CDC13)5 7.2 (m, 1H), 6.9 (m, 2H), 6.8 (m, 1H), 3.9 (br s, 2H, AB), 3.9 (t, 2H, J=6.6 HZ), 2.6
(br s, 1H, OH), 1.8 (m, 2H), 1.5 (m, 2H), 1.4—1.2 (m, 12H), 0.9 (m, 3H); 13C NMR ) 5
159.5, 142.7, 129.6, 119.0, 113.8, 113.0, 68.1, 65.2, 32.0, 29.8, 29.7, 29.6, 29.5, 29.4, 26.2, 22.8,
14.3.
1—(Chloromethyl)—3—(decyloxy)benzene A mixture of [3—(decyloxy)phenyl]methanol (58.4
g, 221 mmol) and 150 mL of toluene was added dropwise to a mixture of thionyl de (19.4
mL, 266 mmol) and 50 mL of toluene. During the addition, gas evolution was observed. After 16
hr, the mixture was heated at re?ux. After 1 hr, 150 mL of volatile al was removed by
distillation. Then, the remaining volatiles were evaporated in vacuo.
N—[3—(Decyloxy)benzyl]phthalimide The residue was taken up in 120 mL of DMF and 60 mL of
NMP, potassium phthalimide (49.2 g, 266 mmol) was added, and the mixture was heated at 60
0C for 24 hr. Then, the mixture was cooled and partitioned between 50% EA/Hex and H20 (2x),
0.1M HCl, and brine. The organic phases were dried over Na2804, filtered through a pad of silica
gel, and concentrated to 90.4 g of amber oil. 1H NMR (CDCl3) 5 7.8 and 7.7 (m, 4H, ),
7.2 (m, 1H), 7.0 (m, 2H), 6.8 (m, 1H), 4.8 (s, 2H), 3.9 (t, 2H, J=6.6 Hz), 1.7 (m, 2H), 1.4 (m,
2H), 2 (m, 12H), 0.9 (m, 3H); 13C NMR(CDC13) 5 168.2, 159.6, 137.9, 134.2, 132.3,
129.9, 123.6, 120.8, 114.8, 114.1, 68.2, 41.8, 32.1, 29.8, 29.8, 29.6, 29.5, 29.5, 26.2, 22.9, 14.3.
[3—(Decyloxy)phenyl]methanamine IPA (50 mL) was mixed with the residue and then
evaporated to remove residual EA. The residue was taken up in 400 mL of EtOH, ine
monohydrate (14.5 mL, 299 mmol) was added, and the mixture was heated at re?ux. After 6 hr,
the mixture was cooled, and 150 mL of 2M HCl was added. The solid precipitate was broken up
to form a slurry, which was filtered and washed with 20% aqueous IPA. The filtrate was adjusted
to pH 10 by adding NaOH pellets. Then, the e was concentrated. The resulting liquid was
partitioned between DCM and 5% N212C03, and the organic phase was dried over anhydrous
Na2804 and concentrated.
N—[3-(Decyloxy)benzyl]quinazolin—4—amine Crude [3—(decyloxy)phenyl]methanamine was taken
up in 400 mL of IPA, and 100 mL of volatile components were removed by distillation. The
WO 20995
mixture was allowed to cool slightly. TEA (39 mL, 278 mmol) and 4—chloroquinazoline 22.4 g,
136 mmol) were added. The mixture was heated at re?ux for 20 hr. Then, the mixture was
allowed to cool, and the volatile components were evaporated. The mixture was partitioned
between DCM (350, 2x100 mL) and 2N NaOH (150 mL). The organic phases were dried over
anhydrous NaZSO4, 150 mL of MeOH were added, and the mixture was ed through a pad of
silica gel. The filtrate was concentrated to give a pink solid. The solid was tallized from
EA/Hex to give a lightly colored solid. The solid was recrystallized from IPA to give 43.4 g of
colorless solid. Rf0.47 (10% MeOH/DCM); mp 93.0—95.5 0C; 1H NMR (CDCI3) 5 8.71 (s, 1H),
7.86 (d, 1H, J=8.4 Hz), 7.76-7.68 (m, 2H), 7.46 (m, 1H), 7.27 (m, 1H), 6.98-6.94 (m, 2H), 6.84
(m, 1H), 5.95 (br s, 1H, NH), 4.84 (m, 2H, AB), 3.94 (t, 2H, J=6.6 Hz), 1.77 (m, 2H), 1.43 (m,
2H), 1.29—1.26 (m, 12H), 0.87 (m, 3H); 13C NMR(CDC13) 5 159.8, 159.4, 155.6, 149.8, 139.8,
132.9, 130.1, 128.9, 126.3, 120.7, 120.2, 115.0, 114.6, 113.8, 68.3, 45.6, 32.1, 29.8, 29.8, 29.6,
29.5, 29.5, 26.3, 22.9, 14.3.
Example 1 12: N-(3-Phenoxybenzyl)quinazolinamine
HN/\©/O\©\ N
| N/)
noxyphenyl)methanamine (1.55 g, 7.79 mmol) was taken up in 60 mL of IPA, and 15 mL
of volatile material was removed by distillation. The mixture was cooled, and TEA (1.50 mL,
.7 mmol) and 4—chloroquinazoline (1.20 g, 7.32 mmol) in 15 mL of IPA were added. The
mixture was heated at re?ux for 5.5 hr, and then stirred at room temperature overnight. Then, the
volatile components were evaporated, and the residue was partitioned between DCM (3x70 mL)
and 5% N32CO3 (40 mL). The combined organic phases were dried over NaZSO4, filtered, and
concentrated. SPE, eluting with 25% and then 55% EA/Hex, gave product ons that were
combined and trated to yield an orange solid. Recrystallization from EA/Hex gave a pink
solid, and then from MeOH gave 1.29 g of a light pink solid. Rf 0.19 (50% EA/Hex); mp 146.5—
148.0 0C; 1H NMR (CDC13) 5 8.66 (s, 1H), 7.83 (d, 1H, J=8.5 Hz), 7.77 (d, 1H, J=8.1 Hz), 7.71
(m, 1H), 7.42 (m, 1H), 7.30 (m, 3H), 7.10 (m, 2H), 7.04 (br s, 1H), 6.99 (m, 2H), 6.90 (m, 1H),
6.44 (m, 1H, NH), 4.84 (m, 2H, AB); 13C NMR (CDC13) 8 159.5, 157.9, 157.0, 155.5, 149.6,
140.4, 132.9, 130.3, 130.0, 128.7, 126.3, 123.7, 122.6, 120.9, 119.2, 118.3, 117.9, 115.1, 45.1.
Example 1 13: N—[4—(Decyloxy)benzyl]quinazolin—4—amine
d)!HN/\©\O/\/\/\/\/\N
4-(Decyloxy)benzonitrile A e of oxybenzonitrile ( 4.32 g, 36.3 mmol), l—
bromodecane (6.80 mL, 32.9 mmol), and K2C03 (6.61 g, 47.8 mmol) in 20 mL of DMF was
reacted for 2 days. The solvent was evaporated in vacuo. The residue was partitioned between
50% EA/Hex (3X150 mL) and 5% Na2C03 (3x80 mL), H20 (40 mL), 0.1M HCl (40 mL), and
brine (80 mL). The organic phases were dried over anhydrous NaZSO4 and concentrated to give
8.30 g of colorless oil that solidified upon standing. 1H NMR (CDC13) 8 7.54 and 6.90 (m, 4H,
AA’BB’), 3.97 (t, 2H, J=6.6 Hz), 1.78 (m, 2H), 1.42 (m, 2H), 1.34-1.25 (m, 12H), 0.86 (m, 3H);
13’C NMR(CDC13) 8 162.6, 134.0, 119.4, 115.3, 103.7, 68.5, 32.0, 29.6, 29.4, 29.4, 29.1, 26.0,
22.8, 14.2.
[4-(Decyloxy)phenyl]methanamine (7.61 g) was prepared as a colorless solid by the method for
[4—(hexyloxy)phenyl]methanamine by treating 4—(decyloxy)benzonitile with 2 g of LAH. 1H
NMR (CDC13) 8 7.2 (m, 2H), 6.8 (m, 2H), 3.90 (t, 2H, J=6.6 Hz), 3.76 (s, 2H), 1.75 (m, 2H),
1.55 (m, 2H), 1.43 (m, 2H), 1.4—1.2 (m, 10H), 0.87 (m, 3H); 13C NMR (CDC13) 8 158.1, 135.4,
128.3, 114.5, 68.0, 46.0, 32.0, 29.6, 29.6, 29.5, 29.4, 29.4, 28.1, 26.1, 22.7, 14.2.
N—[4—(Decyloxy)benzyl]quinazolin—4—amine (3.77 g) was prepared from[4—
(decyloxy)phenyl]methanamine (3.04 g, 11.6 mmol), 4—chloroquinazoline (2.60 g, 15.8 mmol),
TEA (3.40 mL, 24.2 mmol), and IPA (50 mL) using the method for N—(3—
phenoxybenzyl)quinazolin—4—amine. The product was recrystallized from 30% EA/Hex. Rf0.24
(5% CM); mp 1030—1045 0C; 1H NMR(CDC13) 8 8.71 (s, 1H), 7.85 (dd, 1H, 120.7,
8.4 Hz), 7.74 (dd, 1H, J=l.5, 6.9 Hz), 7.69 (m, 1H), 7.44 (ddd, 1H, J=l.l, 7.0, 8.1 Hz), 7.31 (m,
2H), 6.88 (m, 2H), 5.90 (br s, 1H, NH), 4.78 (m, 2H, AB), 3.95 (t, 2H, J=6.6 Hz), 1.77 (m, 2H),
1.45 (m, 2H), 1.4—1.2 (m, 12H), 0.88 (m, 3H); 13C NMR(CDC13)5159.6, 159.1, 155.7, 149.7,
132.8, 130.0, 129.7, 128.9, 126.2, 120.8, 115.0, 68.3, 45.2, 32.1, 29.8, 29.8, 29.6, 29.5, 29.4,
26.2, 22.9, 14.3.
Example 114: N—[4—(Hexyloxy)benzyl]quinazolin—4—amine
Cb?m
N—[—4(Hexyloxy)benzyl] quinazolin—4—amine (31.9 g) was prepared from [4—
(hexyloxy)phenyl]methanamine (32 g), 4-chloroquinazoline (19 g), TEA (32.5 mL), and IPA
(250 mL) following the method for the preparation of N—(3—phenoxybenzyl)quinazolin-4—amine.
Mp 1090—1110 0C (from IPA); 1H NMR (CDC13) 5 8.68 (s, 1H), 7.82 (m, 1H), 7.71 (m, 2H),
7.41 (m, 1H), 7.29 (m, 2H, J=2.9, 4.8, 9.5 Hz, ), 6.87 (m, 2H, J=2.9, 5.1, 9.5 Hz,
AA’BB’), 6.11 (br s, 1H, NH), 4.77 (m, 2H, AB), 3.93 (t, 2H, J=6.6 Hz), 1.76 (m, 2H), 1.5 (m,
2H), 1.4—1.3 (m, 4H), 0.89 (m, 3H); 13C C13) 5 159.4, 150.0, 155.6, 149.6, 132.8,
130.0, 129.6, 128.7, 126.2, 120.8, 115.0, 115.0, 68.3, 45.1, 31.8, 29.4, 25.9, 22.8, 14.2.
Example 115: 1-[2—(Ethoxymethy1)—1H—imidazo[4,5-c]quinolin—1—y1]—2—methy1propan—2—ol
23fN
3—Nitroquinolin—4—ol 70% Aqueous nitric acid (6.1 mL) was added dropwise to a mixture of 4-
yquinoline (10 g, 69 mmol) and 100 mL of acetic acid heated at re?ux. After 15 min, the
mixture was allowed to cool to room temperature. Dilution with EtOH resulted in the formation
of a precipitate, which was filtered and washed sequentially with EtOH, H20, and EtOH. Drying
of the filtrate in vacuo gave 4.62 g of a light yellow powder. 1H NMR (DMSO—d6) 8 9.2 (s, 1H),
8.3 (d, 1H), 7.9-7.7 (m, 2H), 7.5 (m, 1H).
4—Chloro—3—nitroquinoline orus oxychloride (2.5 mL, 27 mmol) was added dropwise to
a mixture of 3—nitroquinolin—4—ol (4.6 g, 24 mmol) and 100 mL of DMF. The mixture was heated
at 100 0C for 15 min, and then poured onto stirred ice. The slurry was neutralized with solid
NaHCOg, and the precipitate was filtered and washed with saturated NaHC03 and H20. The
filtrate was taken up in DCM, dried over anhydrous NaZSO4, and concentrated to give 2.3 g of
solid.
yl—l—(3—nitroquinolin—4—yl)propan—2—ol A mixture of 4—chloro—3—nitroquinoline (2.3
g, 11 mmol), 1—amino—2—methylpropan—2—ol (1.0 g, 11 mmol), TEA (9.3 mL), and 100 mL of
DCM was heated at re?ux until the starting material was consumed. The mixture was allowed to
cool, washed with saturated NaHC03 and H20, dried over anhydrous , and concentrated
to give 1.01 g of product. 1H NMR (DMSO-d6) 8 9.9 (br s, 1H, NH), 9.2 (s, 1H), 8.5 (d, 1H), 7.9—
7.8 (m, 2H), 7.6 (m, 1H), 5.1 (s, 1H, OH), 3.8 (m, 2H, ABX), 1.2 (s, 6H).
1-(3-Aminoquinolinylamino)methylpropanol 2-Methyl(3-nitroquinolin
yl)propanol (1.01 g, mmol), 10% Pd-C (200 mg), and 20 mL of toluene were stirred under an
atmosphere of hydrogen until the starting material was consumed. The en was replaced by
argon, and the mixture was filtered through a pad of Celite and concentrated by ation to
give 586 mg of product. 1H NMR (CD3OD) 8 8.3 (s, 1H), 8.1 (m, 1H), 7.8 (m, 1H), 7.5—7.4 (m,
2H), 7.2—7.0 (m, 2H, ABX), 1.2 (s, 6H).
1—[2—(Ethoxymethyl)—1H—imidazo[4,5—c]quinolin—1—yl]-2—methylpropan—2—ol A mixture of
1—(3—aminoquinolin—4—ylamino)—2—methylpropan—2—ol (586 mg, 2.54 mmol) and 0.4 mL of
ethoxyacetic acid was heated at 130 °C for 3 hr. The cooled e was poured into 5 mL of
H20 and made basic with 6N NaOH. The resulting solid was collected by filtration, washed with
H20, and dried in vacuo to give 655 mg of product. 1H NMR (CDC13) 5 9.1 (s, 1H), 8.3 (m, 1H),
8.1 (m, 1H), 7.7-7.5 (m, 2H), 4.9 (br s, 2H), 4.8 (br s, 2H), 3.6 (q, 2H), 1.3 (s, 6H), 1.2 (t, 3H).
Example 1 16: l—(4—Amino— l—isobutyl— 1H—imidazo[4,5—c] quinolin—2—yl)pentyl acetate
>—CH.
CdN\/
N NH2
N—Isobutyl—3—nitroquinolin—4—amine 4—Chloro—3—nitroquinoline was prepared from 3—
nitroquinolin—4—ol (5.5 g, 28.8 mmol). Isobutylamine (3.2 mL, 32 mmol) was added slowly to a
e of the 4—chloro—3—nitroquinoline, TBA (24 mL, 170 mmol), and 40 mL of DCM. The
mixture was heated at re?ux for 30 min. Then, the volatile components were evaporated, and the
residue was taken up in aqueous acid and filtered. The filtrate was adjusted to pH 8-9 by adding
concentrated NH4OH, and the resulting solid was filtered and washed with H20. Drying in vacuo
gave 6.49 g of product. 1H NMR(CDC13) 5 9.8 (br s, 1H, NH), 9.3 (s, 1H), 8.3 (m, 1H), 8.0 (m,
1H), 7.8 (m, 1H), 7.4 (m, 1H), 3.8 (m, 2H), 2.1 (m, 1H), 1.1 (d, 6H).
N4-Isobutquuinoline-3,4-diamine A mixture of N-isobutylnitroquinolinamine (19.0 g,
77.6 mmol) and 10% Pd-C (700 mg) in 200 mL of EA was reacted under an here of
hydrogen at 42 psi until the starting material was consumed. Then, the hydrogen was replaced by
argon, and the mixture was filtered through a pad of Celite. The filtrate was concentrated to give
15.2 g of product. 1H NMR (CDC13) 5 8.4 (s, 1H), 7.9 (m, 1H), 7.8 (m, 1H), 4 (m, 2H), 3.9-
3.6 (br m, 3H, NH), 3.0 (d, 2H), 1.9 (m, 1H), 1.0 (d, 6H).
1—Isobutyl—lH—imidazo[4,5—c]quinoline A mixture of butquuinoline—3,4—diamine
(2.33 g, 10.8 mmol) and 17 mL of formic acid was heated at 100 0C for 3 hr. The volatile
components were evaporated in vacuo. The residue was diluted with H20, made basic using
trated NH4OH, and extracted with DCM. The organic solvent was replaced with EtZO,
treated with activated charcoal, ed through a pad of Celite, and concentrated. NMR
indicated the presence of starting material. The crude was mixed with triethyl orthoformate,
heated at 100 0C for 3 hr, and processed as before to give 1.4 g of t. 1H NMR (CDClg) 5
9.3 (s, 1H), 8.3 (m, 1H), 8.1 (m, 1H), 7.9 (s, 1H), 7.7—7.5 (m, 2H), 4.3 (d, 2H), 2.3 (m, 1H), 1.0
(d, 6H).
1—(1—Isobutyl—lH—imidazo[4,5—c]quinolin—2—yl)pentan—l—ol n—Butyllithium (1.5M in hexanes, 3.6
mL) was added to a mixture of l—isobutyl—1H—imidazo[4,5—c]quinoline (1.4 g, 4.9 mmol) and 25
mL of THE cooled by a dry ice/IPA bath. After 15 min, valeraldehyde (0.80 mL, 7.5 mmol) was
added. The mixture was allowed to warm to room temperature. After 3 hr, H20 and EtZO were
added, and the organic phase was separated, dried over anhydrous MgSO4, and concentrated. EC,
eluting with EA, gave 990 mg of the product. 1H NMR (CDC13) 5 9.2 (s, 1H), 8.1 (m, 1H), 7.9
(m, 1H), 7.7—7.5 (m, 2H), 4.95 (m, 1H), 4.5 (m, 1H), 4.3 (m, 1H), 2.3 (m, 2H), 1.6-1.3 (m, 4H),
1.1 (d, 3H), 1.0—0.8 (m, 6H).
1-(1—Isobutyl—1H—imidazo[4,5—c]quinolinyl)pentyl acetate Acetic anhydride (0.400 mL,
4.24 mmol) and TEA (0.510 mL, 3.64 mmol) were added sequentially to a mixture of 1-(1-
yl-1H—imidazo[4,5-c]quinolinyl)pentan-l-ol (818 mg, 2.75 mmol) and 20 mL of DCM.
After 16 hr, the mixture was diluted with 1 volume of DCM and washed with H20 and saturated
NaHCOg. The organic phase was dried over anhydrous MgSO4 and concentrated to give 1.00 g
of product. 1H NMR(CDC13) 8 9.3 (s, 1H), 8.25 (m, 1H), 8.1 (m, 1H), 7.75-7.55 (m, 2H), 6.1
(m, 1H), 4.5 (m, 2H, ABX), 2.3 (m, 2H), 2.1 (s, 3H), 1.5-1.3 (m, 4H), 1.1 (d, 3H), 1.0—0.8 (m,
6H).
2—(1—Acetoxypentyl)—1—isobutyl—1H—imidazo[4,5—c]quinoline 5—oxide A mixture of l—(l—
isobutyl—lH—imidazo[4,5—c]quinolin—2—yl)penty1 e (980 mg, 2.91 mmol) and 32% peracetic
acid (0.22 mL, 3.2 mmol) in 20 mL of EA was heated at re?ux for 1 hr and stirred at room
temperature overnight. The volatile components were evaporated in vacuo, and the e was
ioned between DCM and saturated NaHC03 and H20. The c phase was dried over
anhydrous NaZSO4 and concentrated to give a solid. The solid was slurried with cold acetone,
filtered, and dried to give 750 mg of product. 1H NMR ) 5 9.3 (s, 1H), 9.0 (m, 1H), 8.5
(br s, 2H, N?z), 8.15 (m, 1H), 7.85-7.75 (m, 2H), 6.0 (dd, 1H), 4.5 (m, 2H, ABX), 2.3 (m, 2H),
2.1 (s, 3H), 1.5-1.3 (m, 4H), 1.1 (d, 3H), 0.95 (d, 3H), 0.9 (m, 3H).
1—(4—Amino—1—isobutyl—1H—imidazo[4,5—c]quinolin—2—yl)pentyl acetate A mixture of 4—
toluenesulfonyl chloride (447 mg, 2.34 mmol) and 15 mL of DCM was added slowly to a
mixture of 2—(1—acetoxypentyl)—1—isobutyl—1H—imidazo[4,5—c]quinoline 5—oxide (750 mg, 2.13
mmol) and 8 mL of concentrated NH4OH cooled by an ice bath. The mixture was allowed to
warm to room temperature overnight. The e was diluted with DCM and washed with
saturated NaHCOg, and the c phase was dried over anhydrous NaZSO4 and concentrated to
give 650 mg of colorless solid. 1H NMR (CDC13) 5 7.9 (d, 1H), 7.7 (d, 1H), 7.5 (m, 1H), 7.3 (m,
1H), 6.1 (dd, 1H), 5.5 (br s, 2H, N?z), 4.4 (m, 2H, ABX), 2.3 (m, 2H), 2.15 (m, 1H), 2.1 (s, 3),
1.5-1.3 (m, 4H), 1.1 (d, 3H), 1.0-0.8 (m, 6H).
Example 117: 1—Isobutyl—2—pentadecyl-1H-imidazo[4,5—c]quinolin—4—ol
V\N,\(\/WVW\/
N OH
2-Chloro-N-isobutylnitroquinolinamine A e of isobutylamine (10.0 mL, 101
mmol) and TEA (15.6 mL, 111 mmol) in 10 mL of 1:1 DMF/DCM was added slowly to 2,4-
dichloro—3—nitroquinoline (26.94 g, 111 mmol) in 100 mL of 4:1 DMF/DCM cooled with an ice
bath. The mixture was allowed to warm to room temperature overnight. Then, the le
components were evaporated, and the residue was partitioned between EA and saturated
NaHC03 and brine, dried over NaZSO4, and trated. FC (15% EA/Hex) gave the product as
an orange solid. Recrystallization from EA/Hex gave 3 crops of the t (17.97 g) as a light
orange solid.
2—Chloro—N4—isobutquuinoline—3,4—diamine A mixture of 2—chloro—N—isobutyl—3—nitroquinolin-4—
amine (996 mg, 3.57 mmol) and 35 mg of 5% Pt—C in 15 mL of MeOH was stirred under 2
atmospheres of hydrogen for 90 min. Then, the mixture was blanketed with argon, filtered
through a pad of Celite and concentrated to dryness.
WO 20995
4—Chloro—l—isobutyl—2—pentadecyl— 1H—imidazo[4,5—c]quinoline A mixture of the crude 2—
chloro—N4—isobutquuinoline—3,4—diamine and palmitic acid (3.66 g, 14.3 mmol) was heated at
180 0C for 4 hr. Then, the mixture was partially cooled and, while mixing, diluted with 400 mL
of EA and 10 mL of 1M NaOH and 40 mL of 5% N32C03. The warm mixture was cooled with
an ice bath, and a solid (presumably sodium palmitate) formed. The liquid was decanted from the
solid, the layers were separated, and the aqueous layer was extracted with EA (2x150 mL). The
organic phases were washed with 5% N32C03 (3x50 mL) and brine, dried over NaZSO4, and
concentrated. FC (4% MeOH/DCM) gave fractions that ned the product, observed by TLC.
The fractions were concentrated, and two crops of the product (1.14 g) were crystallized from
DCM/Hex. Rf 0.27 (5% MeOH/DCM); 1H NMR (CDC13) 5 7.8 (m, 2H), 7.4 (m, 1H), 7.3 (m,
1H), 4.2 (d, 2H, ABX), 2.9 (m, 2H), 2.3 (m, 1H), 1.9 (m, 2H), 1.5-1.2 (m, 24H), 1.0 (d, 6H). 0.85
(t, 3H).
utylpentadecyl-1H-imidazo[4,5-c]quinolinol A e of 4-chloroisobutyl
pentadecyl-1H—imidazo[4,5-c]quinoline (165 mg, 0.35 mmol) in 5 mL of 50% concentrated
NH4OH/MeOH was heated at 160 0C for 72 hr. Then, the mixture was cooled and evaporated to
a solid. The solid was washed with saturated NaHC03 and H20 and dried in vacuo to give 160
mg light gray solid. Rf0.29 (10% CM); 1H NMR (CDCl3) 5 12.1 (br s, 1H, OH), 7.8
(m, 2H), 7.4 (m, 1H), 7.3 (m, 1H), 4.2 (d, 2H, ABX), 2.9 (m, 2H), 2.3 (m, 1H), 1.9 (m, 2H), 1.5-
1.2 (m, 24H), 1.0 (d, 6H), 0.85 (t, 3H).
e 1 18: 1—Octyl— lH—imidazo[4,5—c]quinoline
N’\\
:jkfx/ N
2,4—Dihydroxy—3—nitroquinoline Concentrated nitric acid (12.4 mL) was added to a
mechanically—stirred mixture of 2,4—dihydroxyquinoline (20.2 g, 125 mmol) in 160 mL of acetic
acid at re?ux. After 20 min, heating was stopped. After a further 15 min, 3 volumes of ice chips
were added, and the mixture was stirred 30 min. The precipitate was filtered and washed with
four times with 1 volume of ice—cold H20. After drying in vacuo, 23.0 g of orange solid was
obtained.
2,4—Dichloro—3—nitroquinolineA mixture of 2,4—dihydroxy—3—nitroquinoline (5.08 g, 24.7 mmol)
and phenylphosphonic dichloride (13.9 mL, 98.4 mmol) was heated at 140 0C for 3 hr. After the
mixture had cooled at, it was added to 18.5 g of NaHC03 in 150 mL ice—cold H20. The
pH was at least 6. The solid was filtered and washed twice with H20. After drying in vacuo, 5.09
g of a tan solid was obtained.
2—Chloro—3—nitro—N—octquuinolin—4—amine A mixture of 2,4—dichloro—3—nitroquinoline (1.0 g,
4.1 mmol), lamine (0.75 mL), TEA (3.5 mL), and 20 mL of DCM were heated at re?ux
for 1 hr. Then, the volatile material was evaporated, the residue was taken up in H20, and the pH
was adjusted to 8—9 with concentrated HCl and concentrated NH4OH. The precipitate was
collected and washed with H2O. After drying in vacuo, 1.65 g of a solid was obtained.
N4-Octquuinoline-3,4-diamine (515 mg) was obtained by treating 2-chloronitro-N-
octquuinolinamine (1.33 g) with the conditions used to prepare N—[8-
oxy)octyl]pyrimidinamine. 1H NMR (CDClg) 5 8.5 (s, 1H), 8.05 (d, 1H), 7.9 (d, 1H),
7.5 (m, 1H), 7.35 (m, 1H), 4.1 (br s, 2H, N?2), 3.5 (m, 2H), 1.75 (m, 2H), 1.6—1.1 (m, 10H), 0.85
(m, 3H).
1—0ctyl—lH—imidazo[4,5—c]quinoline (400 mg) was obtained by ng N4—octquuinoline—3,4-
diamine (515 mg) with the conditions used to prepare 1—[8—(hexyloxy)octyl]—1H—imidazo[4,5—
c]pyridine. 1H NMR(CDC13) 5 9.35 (s, 1H), 8.6 (m, 1H), 8.2 (d, 1H), 8.0 (s, 1H), 7.75 (m, 2H),
4.6 (t, 2H), 2.0 (m, 2H), 1.5-1.1 (m, 10H), 0.9 (m, 3H).
e 1 19: l —Hexadecyl— 1H—imidazo[4,5—c]quinoline
N’\\
2—Chloro—3—nitro—N—octquuinolin—4—amine A mixture of 2,4—dichloro—3—nitroquinoline (1.0 g,
4.1 mmol), 1—octylamine (0.75 mL), TEA (3.5 mL), and 20 mL of DCM were heated at re?ux
for 1 hr. Then, the volatile material was evaporated, the residue was taken up in H20, and the pH
was adjusted to 8—9 with concentrated HCl and concentrated NH4OH. The precipitate was
collected and washed with H20. After drying in vacuo, 1.65 g of a solid was obtained.
N4—Octquuinoline—3,4—diamine (515 mg) was obtained by treating 2—chloro—3—nitro—N—
octquuinolin—4—amine (1.33 g) with the conditions used to e N—[8—
(hexyloxy)octyl]pyrimidin—4—amine. 1H NMR (CDCl3) 5 8.5 (s, 1H), 8.05 (d, 1H), 7.9 (d, 1H),
7.5 (m, 1H), 7.35 (m, 1H), 4.1 (br s, 2H, NH;), 3.5 (m, 2H), 1.75 (m, 2H), 1.6-1.1 (m, 10H), 0.85
(m, 3H).
l—1H—imidazo[4,5—c]quinoline (400 mg) was obtained by treating N4—octquuinoline—3,4—
diamine (515 mg) with the conditions used to prepare 1-[8-(hexyloxy)octyl]—1H—imidazo[4,5-
c]pyridine. 1H NMR (CDC13) 8 9.35 (s, 1H), 8.6 (m, 1H), 8.2 (d, 1H), 8.0 (s, 1H), 7.75 (m, 2H),
4.6 (t, 2H), 2.0 (m, 2H), 1.5-1.1 (m, 10H), 0.9 (m, 3H).
Example 120: 1-Hexadecyl-1H—imidazo[4,5-c]quinolinamine
N’\\
CCKN\
N NH2
1—Hexadecyl-1H—imidazo[4,5—c]quinolin—4—amine was made following the method for the
ation of utyl—2—pentadecyl—1H—imidazo[4,5—c]quinolin—4—ol, using 2,4—dichloro—3—
uinoline (1.00 g), 1—hexadecylamine (1.00 g), 8 mL of triethyl orthoforrnate at re?ux for
imidazole ring formation, and a solution of 1 mL of anhydrous NH3 in 8 mL of anhydrous IPA in
the final reaction. Final purification used FC (5% MeOH/DCM, Rf0. 17). 1H NMR (CDClg) 5 7.9
(m, 1H), 7.8 (m, 1H), 7.75 (s, 1H), 7.5 (m, 1H), 7.3 (m, 1H), 5.6 (br s, 1H, NH), 4.5 (t, 2H), 2.0
(m, 2H), 1.5-1.2 (m, 26H), 0.85 (t, 3H).
Example 121: l—[2— (Dodecyloxy)ethyl]— lH—imidazo[4,5—c]quinoline
W0\/\N’\\
©ij/
2—(Dodecyloxy)ethanol 60% Dispersion of sodium hydride in mineral oil (8.3 g, 208
mmol) was washed in Hex (2x). Then, a e of ethylene glycol (17.4 mL, 312 mmol) in 250
mL of DMF and 25 mL of DCM was added slowly while g with an ice bath. After 1 hr, 1—
iodododecane (104 mmol) was added. The mixture was allowed to warm to room temberature.
After 24 hr, the volatile components were ated, and the residue was partitioned between
EA and 100 mL of 1M HCl, then 0.1M HCl and 5% Na28203, then 0.1M HCl, then brine, and
the organic phases were dried over MgSO4 and concentrated. SPE, g with 5% EA/Hex
and eluting with 40% EA/Hex, gave 10.15 g of product. Rf 0.48 (40% EA/Hex); 1H NMR
(CDC13) 53.7 (m, 2H), 3.55—3.40 (m, 4H), 2.1 (br s, 1H, OH), 1.6 (m, 2H), 1.4-1.2 (m, 18H),
0.85 (t, 3H).
2-(Dodecyloxy)ethyl methanesulfonate as a crude material was prepared from 2-
(dodecyloxy)ethanol (10.15 g, 44.1 mmol), methanesulfonyl chloride (4.3 mL, 53 mmol), and
triethylamine (7.5 mL, 53 mmol) in 200 mL of THF, and carried on. Rf 0.56 (40% EA/Hex).
1—(2—Iodoethoxy)dodecane (14.9 g) was prepared from 2-(dodecyloxy)ethy1 methanesulfonate
and 12.9 g of sodium iodide by the Finkelstein reaction. Rf 0.94 (40% EA/Hex) 0.46 (5%
);1H NMR (CDClg) 5 3.7 (t, 2H), 3.45 (t, 2H), 3.25 (t, 2H), 1.6 (m, 2H), 1.4—1.2 (m,
18H), 0.85 (t, 3H).
1—(2—Azidoethoxy)dodecane as a crude was prepared from 1—(2—iodoethoxy)dodecane (14.9 g,
43.8 mmol) and sodium azide (2.85g, 43.8 mmol) in 33 mL of DMF. Rf 0.28 (5% ); 1H
NMR(CDC13) 5 3.6 (t, 2H), 3.45 (t, 2H), 3.35 (t, 2H), 1.6 (m, 2H), 1.4—1.2 (m, 18H), 0.85 (t,
3H).
2—(Dodecyloxy)ethanamine was prepared by the catalytic hydrogenation of the crude 1—(2—
azidoethoxy)dodecane using 1.5 g of 5% Pd—C in 150 mL of MeOH. SPE, washing with 50%
EA/Hex and eluting with 15% MeOH/DCM + 2% TEA, gave 8.0 g of t.
1—[2—(Dodecyloxy)ethyl]—lH—imidazo[4,5—c]quinoline (103 mg) was prepared by the method for
the preparation of l—hexadecyl—lH—imidazo[4,5—c]quinolin—4—amine ng with 2—
(dodecyloxy)ethanamine (2.73 g, 11.9 mmol) and 2,4—dichloro—3—nitroquinoline (2.94 g, 12.1
mmol), using reduction of both nitro and aryl chloride by zinc/HCl, and formation of the
ole ring using 7 mL of triethyl orthoformate at re?ux. Final cation was by EC (5%
MeOH/DCM, Rf0.10). 1H NMR (CDC13) 8 9.3 (s, 1H), 8.2 (d, 1H), 8.1 (d, 1H), 7.95 (s, 1H),
7.7-7.5 (m, 2H), 4.7 (m, 2H), 3.85 (m, 2H), 3.3 (m, 2H), 1.4 (m, 2H), 1.3-1.1 (m, 18H), 0.8 (m,
3H).
Example 122: 1-[2-(Dodecyloxy)ethyl]-N,N-dimethyl-1H—imidazo[4,5-c]quinolinamine
\/\/\/\/\/\/O\/\
N’\\
N4—[2—(Dodecyloxy)ethyl]—N2,N2—dimethyl—3—nitroquinoline-2,4—diamine Astoichiometric
excess of 2-(dodecyloxy)ethanamine and 2,4—dichloronitroquinoline (486 mg, 2.0 mmol) and
DIEA (0.38 mL, 2.18 mmol) in 10 m1 of DMF and 10 mL of DCM was mixed at room
temperature for 2 days. No on was observed by TLC. The DCM was evaporated and
replaced by toluene, and the mixture was heated at re?ux for 6 hr. Then, the reaction was cooled,
partitioned between EA and saturated NaHC03 and brine, and the organic phase was dried over
Na2804 and concentrated. FC (10% to 20% EA/Hex step gradient) gave 306 mg of N4—[2—
(Dodecyloxy)ethyl]—N2,N2—dimethyl—3—nitroquinoline—2,4—diamine as orange oil, as well as 376
mg of N2,N4—bis[2—(dodecyloxy)ethyl]—3—nitroquinoline—2,4—diamine as orange oil. 1H NMR
(CDClg) 57.9 (m, 2H), 7.6—7.55 (m, 2H), 7.1 (m, 1H), 3.8 (m, 2H), 3.5—3.4 (m, 4H), 3.0 (s, 6H),
1.6 (m, 2H), 1.4—1.2 (m, 18H), 0.85 (t, 3H).
l—[2—(Dodecyloxy)ethyl]—N,N—dimethyl— lH—imidazo[4,5—c]quinolin—4—amine The nitro group of
N4—[2—(dodecyloxy)ethyl]—N2,N2—dimethyl—3—nitroquinoline—2,4—diamine (306 mg, 0.70 mmol)
was reduced using zinc/HCl, and the ortho diamine was reacted with triethyl orthoformate at
re?ux to give 197 mg of the product after FC (5%MeOH/DCM). Rf 0.15 (5% CM); 1H
NMR(CDC13) 8 7.9 (m, 2H), 7.8 (s, 1H), 7.45 (m, 1H), 7.2 (m, 1H), 4.6 (t, 2H), 3.85 (t, 2H), 3.6
(s, 6H), 3.3 (t, 2H), 1.5 (m, 2H), 1.3—1.1 (m, 18H), 0.85 (t, 3H).
Example 123: l—[6—(Octyloxy)hexyl]-1H—imidazo[4,5—c]quinoline
\/\/\/\/O\/\/\/\
(:07N,\\NN/
6-(Octyloxy)hexan—1—ol Sodium hydride (6.38 g, 266 mmol) was added cautiously to a
mixture of 1,6—hexanediol (47.2 g, 400 mmol) and 120 mL of DMF cooled by an ice bath. After
min, a mixture of octane (31.9 g, 133 mmol) in 120 mL of DCM was added. The
mixture was allowed to warm to room temperature overnight. Then, the volatile components
were evaporated, and the residue was ioned between EA and 0.1M HCl, 5% Nagsgog, H20,
and brine. The organic phases were dried over anhydrous MgSO4 and concentrated. SPE,
washing with 2% EA/Hex and eluting with 40% EA/Hex, gave 13.0 g of colorless oil. Rf0.40
(50% ); 1H NMR (CDC13) 8 3.59 (t, 2H, J=6.7 Hz), 3.36 (t, 2H, J=6.7 Hz), 3.35 (t, 2H,
J=6.7 Hz), 2.02 (br s, 1H, CH), 1.56—1.47 (m, 6H), 1.40-1.20 (m, 14H), 0.84 (m, 3H).
2—Chloro—3-nitro—N—[6—(octyloxy)hexyl]quinolin—4—amine TEA (8.40 mL, 59.9 mmol) was
added to a mixture of 6—(octyloxy)hexan—1—ol (7.60 g, 33.0 mmol) and methanesulfonyl chloride
(4.56 mL, 58.3 mmol) in 190 mL of DME cooled by an ice bath. The mixture was allowed to
warm to room temperature. After 4 hr, 5 mL of H20 were added and the volatile components
were evaporated. The residue was partitioned n EA (3x150 mL) and H20, saturated
NaHCOg, H20, 1M HCl, H20, and brine (100 mL each). The organic phases were dried over
MgSO4 and concentrated to a colorless oil. The oil was taken up in 250 mL of acetone, sodium
iodide (9.9 g, 66 mmol) was added, and the mixture was heated at re?ux for 2 hr. The volatile
components were ated, and the e was partitioned between EA and H20, 5%
WO 20995
NaZSZOg, H20, and brine. The c phases were dried over MgSO4 and concentrated. SPE
(5% EA/Hex) gave a purple oil. The oil was taken up in 25 mL of DMF and 10 mL of toluene,
potassium phthalimide (5.55 g, 30 mmol) was added, and the mixture was heated at re?ux for 4
hr. Then, the mixture was cooled and partitioned between EA and 0.1M HCl, 5% Na28203, H20,
and brine. The organic phases were dried over MgSO4 and concentrated. SPE, washing with 5%
EA/Hex and eluting with 7.5% EA/Hex, gave 10.05 g colorless oil. The oil was taken up in 500
mL of 5% IPA/EtOH, hydrazine monohydrate (2.0 mL, 41 mmol) was added, and the mixture
was heated at reflux for 4 hr. The mixture was cooled and concentrated. The residue was
partitioned between DCM and 5% N32CO3. The organic phase was dried over anhydrous NaZSO4
and concentrated. SPE, washing with 50% EA/Hex and eluting with 15% MeOH/DCM + 2%
TEA, gave 1.91 g of colorless oil. The oil was taken up in a mixture of 9 mL of DMA and 9 mL
of toluene, and 2,4—dichloro—3—nitroquinoline (2.16 g, 8.87 mmol) and DIEA (1.45 mL, 8.32
mmol) were added. The mixture was reacted at room temperature for 88 hr and at re?ux for 2
days. The mixture was cooled, the volatile ents were evaporated, and the residue was
partitioned between EA and 5% Na2C03 and brine. The organic phases were dried over Na2S04
and concentrated. SPE (20% EA/Hex) gave product-containing fractions with impurities. FC
(20% EA/Hex) gave 2.06 g of yellow oil that solidified upon standing. The solid was
tallized from EA/Hex to give 1.70 g of yellow solid. Rf 0.22 (20% EA/Hex); 1H NMR
(CDC13) 8 7.84 (d, 1H, J=7.9 Hz), 7.76 (dd, 1H, J=1.2, 8.4 Hz), 7.63 (ddd, 1H, J=1.2, 6.9, 8.1
Hz), 7.42 (ddd, 1H, J=1.3, 7.0, 8.4 Hz), 5.98 (t, 1H, J=4.7 Hz, NH), 3.38—3.29 (m, 6H), 1.66 (m,
2H), 1.56—1.42 (m, 4H), 1.36—1.34 (m, 4H), 1.2—1.1 (m, 10H), 0.8 (m, 3H).
Octyloxy)hexyl]—lH—imidazo[4,5—c]quinoline Four mL of a 1:3 mixture of concentrated
HCl and MeOH was added slowly to a mixture of 2—chloro—3—nitro—N—[6—
oxy)hexyl]quinolin—4—amine (357 mg, 0.82 mmol), zinc dust (320 mg), and 20 mL of DCM
cooled by an ice bath. The mixture was allowed to warm to room temperature. After 16 hr, the
volatile components were evaporated, the residue was diluted with 75 mL of DCM, and the pH
was adjusted to >8 using 5% Na2C03. The organic phase was separated, dried over anhydrous
NaZSO4, and concentrated. Triethyl ormate (5 mL) was added to the crude product, and the
mixture was heated at 130 0C for 6 hr. Then, the mixture was cooled and concentrated. The
WO 20995
residue was partitioned between DCM and 5% N32CO3. The organic phase was dried over
NaZSO4 and concentrated. FC (3% and 5% MeOH/DCM step gradient) gave 101 mg of brown
oil. Rf0.2l (5% MeOH/DCM); 1H NMR (CDC13) 5 9.31 (s, 1H), 8.26 (m, 1H), 8.12 (m, 1H),
7.92 (s, 1H), 7.70-7.58 (m, 2H), 4.54 (t, 2H, J=7.2 Hz), 3.34 (t, 2H, J=6.2 Hz), 3.33 (t, 2H, J=6.7
Hz), 2.00 (m, 2H), 1.56-1.39 (m, 6H), 1.3—1.1 (m, 12H), 0.83 (m, 3H).
Example 124: l—(8—Ethoxyoctyl)— 1H—imidazo[4,5—c]quinoline
\/O\/\/\/\/\
N,\\
CGN\
1-(8—Ethoxyoctyl)—1H—imidazo[4,5—c]quinoline was made by the method used for the preparation
of 1—octyl—1H—imidazo[4,5—c]quinoline, substituting 8—ethoxyoctan—1—amine for 1-octylamine. 8—
Ethoxyoctan— l—amine was made by the method used for the preparation of 8—(hexyloxy)octan—1—
amine, using iodoethane and 1,8-octanediol as starting materials.
Example 125: ethoxyoctyl)-1H—imidazo[4,5-c]quinoline
N’\\
1—(8—Methoxyoctyl)—1H—imidazo[4,5—c]quinoline was made by the method used for the
preparation of 1—octyl—1H—imidazo[4,5—c]quinoline, substituting oxyoctan—1—amine for 1-
octylamine.
Example 126: l—(8—Butoxyoctyl)— 1H—imidazo[4,5—c]quinoline
WO\/\/\/\/\
N’\\N
N
1—(8—Butoxyoctyl)— lH—imidazo[4,5—c]quinoline was made by the method used for the preparation
of 1—octyl—1H—imidazo[4,5—c]quinoline, tuting 8—butoxyoctan—l—amine for l—octylamine. 8—
Butoxyoctan—l—amine was made by the method used for the preparation of lO—(hexyloxy)decan—
l—amine, using l—bromobutane and l,8—octanediol as starting als.
e 127: l—[9—(Hexyloxy)nonyl]—1H—imidazo[4,5—c]quinoline
/\/\/\O/\/\/\/\/\N’\\
m“N/
9—(Benzyloxy)nonan—l—ol, as 8.79 g of colorless oil, was made by the method used for the
preparation of 8—(benzyloxy)octan—1—ol, using 27.1 g of 1,9—nonanediol, 7.85 mL of benzyl
chloride in 20 mL of DME, 1.80 g of sodium hydride, 60% dispersion in mineral oil, and 300 mL
of DMF. Rf0.12 (20% EA/Hex); 1H NMR (CDC13) 5 7.37-7.22 (m, 5H), 4.49 (s, 2H), 3.61 (t,
2H, J=6.6 Hz), 3.45 (t, 2H, J=6.7 Hz), 1.65-1.49 (m, 4H), 1.36-1.21 (m, 10H).
{[9-(Hexyloxy)nonyloxy]methyl}benzene Sodium hydride (920 mg, 38.3 mmol) was added to
a mixture of 9-(benzyloxy)nonanol (8.79 g, 35.2 mmol) and 200 mL of DME. After 1 hr, 1-
iodohexane (10.6 g, 50 mmol) was added. After 40 hr, analysis by TLC indicated little
conversion. Another portion of sodium hydride was added. After 8 hr, another portion of sodium
hydride and l-bromohexane (7.0 mL, 50 mmol) were added. The mixture was stirred 48 hr, then
allowed to stand for several weeks. Then, 6 mL of concentrated NH4OH were added usly.
After 16 hr, the volatile components were evaporated. The residue was partitioned between EA
(3x250 mL) and H20 (100 mL), 5% Na28203 (100 mL), H20 (100 mL), 0.1M HCl (2x100 mL),
and brine (100 mL). The c phases were dried over anhydrous NaZSO4 and concentrated.
SPE (5% EA/Hex) gave 8.47 g of colorless oil. Rf0.75 (20% EA/Hex); 1H NMR (CDClg) 8 7.34—
7.23 (m, 5H), 4.49 (s, 2H), 3.48—3.36 (m, 6H), 1.68—1.51 (m, 6H), 1.5—1.2 (m, 16H), 0.88 (t, 3H,
J+6.8 Hz).
1—(Hexyloxy)—9—iodononane A e of {[9—(hexyloxy)nonyloxy]methyl}benzene (8.47 g,
25.4 mmol), trimethylsilane ( 20 mL, 158 mmol), and sodium iodide (23.7 g, 158 mmol)
in 150 mL of DCM was heated at re?ux for 60 hr, then mixed at room temperature for 48 hr.
Then, the le components were evaporated. The residue was partitioned between EA (3x250
mL) and saturated NaHC03 (100 mL), 5% Na2S203 (100 mL), H20 (100 mL), and brine (100
mL). The organic phases were dried over anhydrous MgSO4 and concentrated. Analysis by TLC
ted the presence of 9—(hexyloxy)nonan—1—ol with low Rf. The mixture was taken up in 25
mL of toluene and then concentrated. The purple oil was taken up in another 25 mL of toluene, 5
mL of phosphorus oxychloride was added, and the mixture was heated at re?ux until the
suspected alcohol was consumed, as observed by TLC analysis. The mixture was cooled with an
ice bath, and saturated NaHC03 was added slowly, accompanied by gas evolution. The mixture
was extracted with EA (3x250 mL), and the organic phases were washed with H20, 0.1M HCl,
and brine (100 mL each), dried over MgSO4, and concentrated. SPE (2% EA/Hex), discarding
early fractions that ned benzyl halides, gave 3.76 g of product as amber oil. Rf 0.53 (5%
EA/Hex); 1H NMR(CDC13) 8 3.37 (t, 4H, J=6.7 Hz), 3.16 (m, 2H), 1.80 (m, 2H), 1.57—1.49 (m,
4H), 1.4—1.2 (m, 16H), 0.87 (m, 3H).
N—[9-(Hexyloxy)nonyl]phthalimide A e of 1-(hexyloxy)iodononane (3.80 g, 14.4
mmol), and ium phthalimide (2.70 g, 14.6 mmol) in 8 mL of DMF was heated at 100 0C
for 5 hr. The mixture was cooled and partitioned between EA (3x250 mL) and 5% Na2C03, H20,
% Na2S203, H20, 0.1M HCl, and brine (100 mL each). The organic phases were dried over
anhydrous MgSO4 and concentrated. SPE, washing with 5% EA/Hex and eluting with 7.5%
EA/Hex, gave 3.30 g of product as a solid. Rf 0.26 (10% EA/Hex); 1H NMR (CDC13) 8 7.80 and
7.67 (m, 4H, AA’BB’), 3.64 (m, 2H), 3.35 (t, 2H, J=6.7 Hz), 3.34 (t, 2H, J=6.7 Hz), 1.77—1.47
(m, 6H), 1.28-1.22 (m, 16H), 0.86 (m, 3H).
9—(Hexyloxy)nonan—1—amine A mixture of N—[9—(hexyloxy)nonyl]phthalimide (3.05 g, 8.18
mmol) and hydrazine monohydrate (0.58 mL, 12 mmol) in 50 mL of 5% OH was heated
at re?ux for 4 hr. The mixture was cooled and concentrated. The residue was partitioned between
DCM and 5% . The c phase was dried over ous NaZSO4 and concentrated.
SPE, washing with 50% EA/Hex and eluting with 15% MeOH/DCM + 2% TEA, gave 1.08 g of
a mixture of 9—(hexyloxy)nonan—l—amine and phthalhydrazide. Rf 0. ll (15% MeOH/DCM + 2%
TEA); 1H NMR (CDCl3) 5 4.6 (br s, 2H, N?z), 3.4—3.3 (m, 4H), 2.7 (t, 2H), 1.7-1.1 (m, 22H),
0.8 (m, 3H).
2—Chloro—N—[9—(hexyloxy)nonyl]—3—nitroquinolin—4—amine The mixture of 9—(hexyloxy)nonan—l—
amine and phthalhydrazide was reacted with 2,4—dichloro—3—nitroquinoline (1.11 g, 4.56 mmol)
and TEA (0.63 mL, 4.49 mmol) in 9 mL of DMF and 16 mL of toluene heated at re?ux. After 24
hr, the mixture was cooled, partitioned between EA and H20, 5% N32CO3, and brine, dried over
anhydrous NaZSO4, and concentrated. FC, g with 15% and then 20% EA/Hex, gave 1.35 g
of yellow product as an oil that solidified upon standing. Recrystallization from cold EA/Hex
gave 650 mg of yellow solid. Rf0.18 (20% EA/Hex); 1H NMR (CDClg) 5 7.87 (d, 1H, J=8.6
Hz), 7.78 (dd, 1H, J=l.3, 9.5 Hz), 7.67.65 (m, 1H), 7.45 (m, 1H), 5.99 (t, 1H, J=4.7 Hz, NH),
3.39—3.31 (m, 6H), 1.66 (m, 2H), .45 (m, 4H), 1 (m, 16H), 0.82 (m, 3H).
1-[9—(Hexyloxy)nonyl]—1H—imidazo[4,5-c]quinoline Six mL of a 1:3 mixture of concentrated HCl
and MeOH was added slowly to a mixture of 2—chloro—N—[9—(hexyloxy)nonyl]—3-nitroquinolin—4—
amine (674 mg, 1.50 mmol), zinc dust (585 mg), and 25 mL of DCM cooled by an ice bath. The
mixture was allowed to warm to room temperature. After 1 hr, the volatile components were
evaporated, the residue was diluted with 75 mL of DCM, and the pH was adjusted to >8 using
% N32C03. The organic phase was separated, dried over anhydrous NaZSO4, and concentrated.
Rf 0.41 (15% MeOH/DCM) Triethyl ormate (4 mL) was added to the crude t, and
the mixture was heated at 130 0C for 6 hr. Then, the mixture was cooled and concentrated. FC
(3% and 5% MeOH/DCM step gradient) gave 273 mg of brown oil. Rf 0.27 (5% MeOH/DCM);
1H NMR ) 5 9.22 (s, 1H), 8.16 (m, 1H),7.98 (m, 1H), 7.60—7.47 (m, 2H), 4.38 (t, 2H,
J=7.1 Hz), 3.27 (t, 2H, J=6.7 Hz), 3.26 (t, 2H, J=6.7 Hz), 1.86 (m, 2H), 1.45—1.41 (m, 4H), 1.4-
1.1 (m, 16H), 0.78 (m, 3H).
Example 128: l—(lO—Butoxydecyl)—1H—imidazo[4,5—c]quinoline
O\/\/\/\/\/\
N
1—(10—Butoxydecyl)—1H—imidazo[4,5—c]quinoline was made by the method used for the
preparation of 1—octyl—1H—imidazo[4,5—c]quinoline, substituting 10—butoxydecan—1—amine for 1—
octylamine. 10—Butoxydecan—1—amine was made by the method used for the preparation of 10—
(hexyloxy)decan—1—amine, using 1—bromobutane and 1,10—decanediol as starting materials. Rf
0.23 (5% MeOH/DCM); 1H NMR(CDC13) 5 9.32 (s, 1H), 8.27 (m, 1H), 8.12 (m, 1H), 7.93 (s,
1H), 7.66 (m, 2H), 4.54 (t, 2H, J=7.2 Hz), 3.36 (t, 2H, J=6.5 Hz), 3.35 (t, 2H, J=6.5 HZ), 1.99 (m,
2H), 1.57—1.13 (m, 18H), 0.88 (t, 3H, J=7.3 Hz).
Example 129: 4—Amino—1—[8—(hexyloxy)octyl]pyridinium salts
N: X
A mixture of 8-(hexyloxy)octyl methanesulfonate (0.5 g, 1.62 mmol) and opyridine (450
mg) in 20 mL of THF was heated at re?ux for 18 hr. The e was concentrated and purified
by PC (5% MeOH/DCM) to give 396 mg of an oily solid. Recrystallization from MeOH gave a
solid. Mp 108-110 0C; 1H NMR(CDC13) 8 8.4 (br s, 1.4H), 7.8 (d, 2H), 7.2 (d, 2H), 4.1 (m, 2H),
3.35 (m, 4H), 2.4 (br s, 4.5H), 1.8 (m, 2H), 1.6 (m, 4H), 2 (m, 14H), 0.8 (m, 3H).
Example 130: 4—(8—Methoxyocty1amino)— 1 —methylpyridinium iodide
N\/\/\/\/\
I. |\ OCH3
H3C’
A mixture of N—(8—methoxyoctyl)pyridin—4—amine (176 mg, 0.74 mmol) and iodomethane (0.5
mL, 8 mmol) in 4 mL of acetone was heated at 80 0C in a sealed tube for 1.5 hr, then allowed to
stand at room temperature for 2 days, during which a precipitate formed. The volatile
components were evaporated from the precipitated product. 1H NMR (CDCl3) 5 8.47 (m, 1H),
7.99 (m, 2H), 7.57 (m, 1H), 6.59 (m, 1H), 4.04 (s, 3H), 3.35-3.21 (m, 4H), 3.29 (s, 3H), 1.71 (m,
2H), 1.54—1.28 (m, 10H).
Example 131: l—[8—(Hexyloxy)octyl] — 1H—imidazo[4,5—c]pyridine
\/\/\/O\/\/\/\/\
N’\\
N—[8—(Hexyloxy)octyl]—3—nitropyridin—4—amine A mixture of 3—nitropyridin—4—ol (510 mg,
3.64 mol) in 1 mL of phenylphosphonic dichloride was heated at 170—140 0C for 3 hr. Then, the
mixture was cooled and partitioned between EA and saturated . The organic phase was
washed with brine, dried over NaZSO4, filtered h a pad of silica gel, and concentrated to
give crude 4—chloro—3—nitropyridine. 8—(Hexyloxy)octan—1—amine was taken up in 10 mL of
pyridine, and 5 mL of volatile material was evaporated from the mixture. The e was
cooled with an ice bath, TEA (0.44 mL, 3.14 mol) was added, and then a mixture of the
chloropyridine prepared above and 10 mL of DCM was added. The mixture was allowed to
warm to room ature overnight. Then, the reaction was concentrated by evaporation, and
the residue was partitioned between EA and saturated NaHCOg. The organic phases were washed
with brine, dried over NaZSO4, and concentrated. cation by EC (50% ) gave 405 mg
of N—[8-(hexyloxy)octyl]nitropyridinamine as a yellow oil. Rf 0.28 (50% EA/Hex); 1H
NMR(CDC13) 5 9.16 (s, 1H), 8.24 d, 1H, J=6.2 Hz), 8.12 (br s, 1H), 6.66 (d, 1H, J=6.2 Hz),
3.38-3.25 (m, 6H), 1.70 (m, 2H), 1.52-1.47 (m, 4H), 1.39-1.18 (m, 14H), 0.84 (t, 3H, J=6.7 Hz).
N4—[8—(Hexyloxy)octyl]pyridine—3,4—diamine A mixture of N—[8—(hexyloxy)octyl]—3—
nitropyridinamine (405 mg, 1.15 mol) and 45 mg of 10% Pd/C in 30 mL of MeOH was d
under an atmosphere of hydrogen for 5 hr. Then, the catalyst was removed by filtration through
Celite, and the filtrate was concentrated. Purification by SPE, washing with 10% MeOH/DCM
and then eluting with 15% MeOH/DCM + 2% TEA, gave 216 mg of N4—[8—
(hexyloxy)octyl]pyridine—3,4—diamine. Rf 0.05 (15% CM, ninhydrin (+)); 1H NMR
(CDC13)5 7.86 (d, 1H, J=5.4 Hz), 7.79 (s, 1H), 6.38 (d, 1H, J=5.4 Hz), 4.53 (br s, 1H), 3.62 (br
s, 2H), 3.34 (t, 4H, J=6.7 Hz), 3.08 (m, 2H), 1.62—1.46 (m, 6H), 1.27—1.24 (m, 14H), 0.83 (t, 3H,
J=6.8 Hz).
1—[8—(Hexyloxy)octyl]—1H—imidazo[4,5—c]pyridine A e of N4—[8—
(hexyloxy)octyl]pyridine—3,4—diamine (216 mg, 0.67 mol) in 2 mL of triethyl orthoformate was
heated at re?ux for 6 hr. Then, volatile material was removed by evaporation, and the residue
was partitioned between EA and saturated NaHCO3. The organic phases were washed with brine,
dried over NaZSO4, and concentrated. Purification by EC (7% MeOH/DCM) gave 217 mg of 1—
[8—(hexyloxy)octyl]—1H—imidazo[4,5—c]pyridine as an amber oil. Rf 0.11 (5% MeOH/DCM); 1H
NMR (CDC13) 5 9.02 (s, 1H), 8.34 (d, 1H, J=5.7 Hz), 7.86 (s, 1H), 7.25 (m, 1H), 4.08 (t, 2H,
J=7.0 Hz), 3.30-3.25 (m, 4H), 1.78 (m, 2H), 1.45—1.43 (m, 4H), 1.22-1.19 (m, 14H), 0.78 (t, 3H,
J=6.7 Hz).
Example 132: l—Hexadecyl—1H—imidazo[4,5—c]pyridine
[$1\
N—Hexadecylnitropyridinamine 1-Hexadecylamine was taken up in 10 mL of pyridine, and
6 mL of volatile components were removed by distillation. The mixture was cooled, and a
mixture of 4-chloronitropyridine in 10 mL of DCM and 10 mL of DMF was added. Then,
TEA (0.46 mL, 3.28 mmol) was added and the e was heated at gentle re?ux. After 16 hr,
the cooled mixture was taken up in EA and washed with saturated NaHCOg, H20, and brine. The
c phase was dried over anhydrous Na2$O4 and concentrated. SPE, washing with 10%
EA/Hex and eluting with 20% EA/Hex, gave 626 mg of solid. Rf 0.34 (50% EA/Hex); 1H NMR
(CDC13) 5 9.19 (s, 1H), 8.26 (d, 1H, J=6.1 Hz), 8.15 (br s, 1H, NH), 6.68 (d, 1H, J=6.2 Hz), 3.30
(m, 2H), 1.72 (m, 2H), .17 (m, 26H), 0.86 (m, 3H).
1—Hexadecyl—1H—imidazo[4,5—c]pyridine A mixture of decyl—3—nitropyridin—4—amine
(626 mg, 1.79 mmol) and 65 mg of 10% Pd—C in 25 mL of 1:1 EA/MeOH was stirred under a
blanket of en for 40 hr. The hydrogen atmosphere was replaced by argon, and the mixture
was filtered through a pad of Celite and trated. SPE, washing with 10% MeOH/DCM and
eluting with 10% MeOH/DCM + 2% TEA, gave 540 mg of colorless solid. The solid was taken
up in 8 mL of triethyl orthoformate and heated at re?ux for 4 hr. Then, the volatile components
were evaporated. The residue was taken up in a fresh 8—mL portion of yl orthoformate and
heated at re?ux for 6 hr. The volatile components were ated. PC of the residue (5%
MeOH/DCM) gave 375 mg of tan solid. Rf 0.10 (5% MeOH/DCM); 1H NMR (CDC13) 5 9.06 (s,
1H), 8.39 (d, 1H, J=5.7 Hz), 7.92 (s, 1H), 7.31 (dd, 1H, J=l.0, 5.7 Hz), 4.12 (m, 2H), 1.82 (m,
2H), 1.26—1.18 (m, 26H), 0.81 (t, 3H, J=6.6 Hz).
e 133: l—( l 0—Butoxydecyl)— 1H—imidazo[4,5—c]pyridine
O\/\/\/\/\/\
1-(10—Butoxydecyl)—1H—imidazo[4,5—c]pyridine (231 mg) as an amber oil was prepared
following the method for 1—[8—(hexyloxy)octyl]—1H—imidazo[4,5—c]pyridine, using 492 mg of 4—
hydroxy—3—nitropyridine and 535 mg of 10-butoxydecan—1—amine.
N—(10-Butoxydecyl)nitropyridinamine: Rf0.30 (50% EA/Hex); 1H NMR (CDClg) 8 9.18
(s, 1H), 8.25 (d, 1H, J=6.0 Hz), 8.14 (br s, 1H, NH), 6.68 (d, 1H, J=6.2 Hz), 3.39-3.26 (m, 6H),
1.71 (m, 2H), 1.57-1.47 (m, 4H), 1.40-1.27 (m, 14H), 0.88 (t, 3H, J=7.2 Hz).
N4—(10—Butoxydecyl)pyridine—3,4—diamine: Rf 0.08 (15% MeOH/DCM); 1H NMR (CDC13) 5
7.89 (d, 1H, J=6.4 Hz), 7.83 (s, 1H), 6.41 (d, 1H, J=6.4 Hz), 4.41 (br s, 1H, NH), 3.58 (br s, 2H,
N?z), 3.39-3.33 (m, 4H), 3.11—3.10 (br m, 2H), 1.66-1.47 (m, 6H), 1.40—1.26 (m, 14H), 0.88 (t,
3H, J=7.2 Hz).
Butoxydecyl)—1H—imidazo[4,5—c]pyridine: RfO. 15 (5% MeOH/DCM); 1H NMR (CDClg) 5
9.06 (s, 1H), 8.38 (d, 1H, J=5.7 Hz), 7.88 (d, 1H), 7.28 (d, 1H, J=5.4 Hz), 4.12 (m, 2H), 3.35—
3.29 (m, 4H), 1.82 (m, 2H), 1.53—1.43 (m, 4H), 1.36-1.20 (m, 14H), 0.84 (m, 3H).
Example 134: N—(8—Methoxyoctyl)pyridin—4—amine
\ N\/\/\/\/\
I OCH3
A mixture of 4—chloropyridine hydrochloride (1.50 g, 10.0 mmol), 8—methoxyoctan—1—amine (894
mg, 5.62 mmol), TEA (1.80 mL, 10.4 mmol), and 4 mL of IPA was heated at 0 0C in a
sealed tube for 48 hr. Then, the mixture was cooled and the volatile components were
evaporated. The residue was partitioned n DCM and 5% N32CO3, and the organic phase
was dried over NaZSO4 and concentrated. FC (1% TEA + 0%, 2%, 3% MeOH/DCM step
gradient) gave 176 mg of solid. Rf 0.13 (10% MeOH/DCM); 1H NMR (CDCl3) 5 8.6 (m, 1H),
7.8 (m, 2H), 6.9 (m, 2H), 3.3 (m, 5H), 3.2 (m, 2H), 1.7 (m, 2H), 1.5 (m, 2H), 1.4-1.2 (m, 8H).
Example 135: N—[8—(Hexyloxy)octyl]pyridin—3—amine
(j/NWOWl/
8-(Hexyloxy)octanal (1.12 g, 4.91 mmol), prepared by the Swem oxidation of 8-
(hexyloxy)octanol, was mixed with 3-aminopyridine (500 mg, 5.32 mmol) in 5 mL of
acetontrile and 0.4 mL of 1M HCl. Then, 0.37 mL of 1M sodium cyanoborohydride in THF was
added. After 20 hr, the e was ioned between EA and 5% Na2C03 and brine, and the
organic phase was dried over Na2$O4 and concentrated. FC (70% EA/Hex) gave 160 mg of the
product. 1H NMR (CDC13) 5 8.0 (m, 1H), 7.9 (m, 1H), 7.1 (m, 1H), 6.9 (m, 1H), 3.4 (t, 4H), 3.1
(t, 2H), 1.7-1.5 (m, 6H), 1.5—1.2 (m, 14H), 0.85 (m, 3H).
Example 136: N—[8—(Hexyloxy)octyl]pyridin-2—amine
\ N\/\/\/\/\O/\/\/\
A e of 2—aminopyridine (458 mg, 4.8 mmol) and 8—(hexyloxy)octyl methanesulfonate (0.5
g, 1.6 mmol) in 20 mL of THF was heated at re?ux for 3 hr. Then, the reaction was cooled and
worked up following the procedure for N—[8—(hexyloxy)octyl]pyridin—3—amine to give 100 mg of
product. 1H NMR(CDC13) 5 8.0 (m, 1H), 7.4 (m, 1H), 6.55 (m, 1H), 6.35 (m, 1H), 4.6 (br s, 1H,
NH), 3.4 (t, 4H), 3.2 (m, 2H), 5 (m, 6H), 1.5—1.2 (m, 14H), 0.85 (m, 3H).
Example 137: Hexyloxy)octyl]pyrimidin—4—amine
HN/\/\/\/\/O\/\/\/
0”| N/)
6—Chloro—N—[8—(Hexyloxy)octyl]pyrimidin—4—amine 8—(Hexyloxy)octan—1—amine (636 mg, 2.78
mmol) was taken up in 15 mL of pyridine, and then 10 mL of le material was removed by
distillation. The mixture was cooled to room temperature, and 15 mL of DCM, 4,6-
dichloropyrimidine (621 mg, 4.17 mmol), and TEA (0.47 mL, 3.35 mmol) were added
sequentially. After being stirred overnight, TLC indicated the presence of the amine starting
material, so a second quantity of 4,6-dichloropyrimidine was added and the mixture was heated
at re?ux for 3 hr. Then, the mixture was cooled, the volatile al was evaporated, and the
residue was partitioned between EA and 5% N32CO3. The organic phases were washed with
brine, dried over Na2804, filtered through a pad of silica gel, and concentrated. Purification by
PC (30% EA/Hex) gave 767 mg of 6-chloro-N-[8-(hexyloxy)octyl]pyrimidinamine as a tan
solid. Rf0.18 (20% EA/Hex); 1H C13)8 8.30 (s, 1H), 6.30 (d, 1H, J=1.0 Hz), 5.36 (br
s, 1H, NH), 3.37 (t, 4H, J=6.9 Hz), 3.24 (m, 2H, AB), 1.6-1.5 (m, 6H), 1.3—1.2(m, 14H), 0.8?
(m, 3H).
N—[8—(Hexyloxy)octyl]pyrimidin—4—amine A mixture of 6—chloro—N—[8—(hexyloxy)octyl]
pyrimidin—4-amine (767 mg, 2.25 mmol) in 30 mL of DCM and 6.8 mL of 2M HCl/IPA was
cooled using an ice bath. Then, 876 mg of zinc dust was added. After 45 min, the e was
allowed to warm to room temperature. After being stirred overnight, the mixture was partitioned
between DCM and 5% Na2C03. The organic phase was dried over NaZSO4 and concentrated.
Purification by PC H/DCM) gave 229 mg of N—[8—(hexyloxy)octyl]pyrimidin—4—amine
as a colorless solid. Rf0.2l (5% MeOH/DCM); 1H NMR (CDCl3) 5 8.46 (s, 1H), 8.08 (d, 1H,
J=5.7 Hz), 6.25 (dd, 1H, J=1.2, 5.9 Hz), 5.59 (br s, 1H), 3.33 (t, 4H, J=6.7 Hz), 3.21 (m, 2H,
AB), 1.58—1.45 (m, 6H), .17 (m, 14H), 0.83 (m, 3H).
Example 138: N—[8—Hexyloxy)octyl)pyrimidin—2—amine
N m
A mixture of 2—chloropyrimidine (272 mg, 2.39 mmol), 8—(hexyloxy)octan—l—amine (548 mg,
2.39 mmol), and TEA (0.34 mL, 2.42 mmol) in 10 mL of DMF was heated at 80—90 0C for 2 hr.
Then, the mixture was partitioned between EA and 5% N32C03 (2x) and brine, and the organic
phase was dried over NaZSO4 and concentrated. FC (50% EA/Hex) gave 227 mg of product as a
yellow solid. 1H NMR (CDClg) 8 8.2 (d, 2H), 6.4 (d, 2H), 5.6 (br s, 1H, NH), 3.3 (m, 4H), 1.6—
1.4 (m, 6H), 1.4—1.2 (m, 14H), 0.8 (m, 3H).
Example 139: 1-[8-(Hexyloxy)octyl]phenyl-1H—imidazole
WWN‘ /\/\/\
4-Phenylimidazole (1.0 g, 6.9 mmol) was added to a mixture of sodium tert-butoxide (7.9 mmol)
in 20 mL of DMF cooled by an ice bath. After 30 min, 8-(hexyloxy)octyl methanesulfonate (2.14
g, 6.95 mmol) was added, and the mixture was allowed to come to room ature. After 6 hr,
volatile components were evaporated. The residue was taken up in EA and washed with
saturated NaHC03, 0.1M HCl, and H20. The organic phase was dried over anhydrous Na2S04
and trated. FC (70% EA/Hex) gave 2.5 g of 1-[8—(hexyloxy)octyl]—4—phenyl—1H—
ole.1H NMR (CDClg) 5 7.8 (m, 2H), 7.6 (s, 1H), 7.4 (m, 2H), 7.2 (m, 2H), 3.9 (t, 2H), 3.4
(m, 4H), 1.8 (m, 2H), 1.6—1.5 (m, 4H), 1.4—1.2 (m, 14H), 0.9 (m, 3H).
Example 140: N—[8—(Hexyloxy)octyl]isoquinolin— 1 —amine
HN/\/\/\/\/O\/\/\/
l—Chloroisoquinoline (390 mg, 2.38 mmol), 8—(hexyloxy)octan—l—amine (360 mg, 1.57 mmol),
and triethylamine (0.22 mL, 1.57 mmol) in 2 mL of DMA was heated at 80 0C for 24 hr. Then
the mixture was cooled and partitioned between EA and 5% N32CO3 and brine, and the c
phase was dried over NaZSO4 and concentrated. EC (20% EA/Hex) gave 87 mg of the product.
Rf0.25 (20% EA/Hex); 1H NMR (CDC13) 8 7.97 (d, l, J=6.0 Hz), .73 (m, l), 7.67—7.64
(m, 1), 7.59-7.53 (m, l), 7.47-7.41 (m, 1), 6.89 (d, 1, J=5.9 Hz), 5.25 (br s, l), 3.62—3.55 (m, 2),
3.38 (t, 4, J=6.7 Hz), 1.77—1.67 (m, 2), 1.58—1.24 (m, 18), 0.89—0.84 (m, 4).
Example 141: N—[8—(Hexyloxy)octyl]isoquinolin—5—amine
/\/\/\/\/O\/\/\/
N—[8—(Hexyloxy)octyl]isoquinolin—S-amine (123 mg) was prepared following the method for N—
[8-(hexyloxy)octyl]quinolinamine starting with 8-(hexyloxy)octanoic acid (300 mg, 123
mmol) and 5-aminoisoquinoline (174 mg, 1.21 mmol). 1H NMR (CDClg) 8 9.14 (d, 1, J=0.7 Hz),
8.44 (d, 1, J=6.1 Hz), 7.57-7.54 (m, 1), 7.45 (t, 1, J=7.9 Hz), 7.30-7.25 (m, 1), 6.74 (dd, 1, J=0.7,
7.7 Hz), 4.35 (br s, 1), 3.41-3.35 (m, 4), 3.27-3.22 (m, 2), 1.80-1.70 (m, 2), 1.57-1.21 (m, 18),
0.89-0.84 (m, 3).
e 142: N—[8—(Hexyloxy)octyl]quinoxalin-2—amine
(I TN N\/\/\/\/\WO/
N—[8—(Hexyloxy)octyl]quinoxalin—2—amine (238 mg) was ed following the method for N-
[8—(hexyloxy)octyl]isoquinolin—l—amine starting with 8—(hexyloxy)octan—l—amine (380 mg, 1.66
mmol) and 2—chloroquinoxaline (413 mg, 2.50 mmol), but the reaction proceeded at room
temperature over 4 days. Rf0.20 (20% ); 1H NMR (CDC13) 5 8.14 (s, l), 7.80 (dd, 1,
J=1.2, 8.1 Hz), 7.64 (m, l), 7.50 (m, l), 7.29 (m, l), 5.24 (br t, l), 3.46 (m, 2), 3.37—3.32 (m, 4),
1.66—1.47 (m, 6), 1.31—1.25 (m, 14), 0.84 (m, 3).
Example 143: l—[8—(Hexyloxy)octyl]—1H—benzimidazole
QN/VWVOWV,4
8—(Hexyloxy)octyl methanesulfonate (9.4 g, 31 mmol) was added to a mixture of benzimidazole
(4.0 g, 31 mmol) and sodium tert—butoxide (31 mmol) in 100 mL of DMF. After 6 hr, the volatile
components were evaporated, and the residue was partitioned between EA and ted
NaHCOg, 0.1M HCl, and H20, and the c phases were dried over NaZSO4 and concentrated.
FC (70% EA/Hex) gave 7.4 g of the t. 1H NMR (CDC13) 5 7.9 (s, 1H), 7.8 (m, 1H), 7.4
(m, 1H), 7.2 (m, 2H), 4.1 (t, 2H), 3.3 (m, 4H), 1.9 (m, 2H), 1.7-1.5 (m, 4H), 1.4-1.2 (m, 14H),
0.9 (m, 3H).
Example 144: N—[8—(Hexyloxy)octyl]pyrazin—2—amine
NWN\/\/\/\/\O/\/\/\
N—[8-(Hexyloxy)octyl]pyrazinamine (102 mg) was prepared following the method for N—[8-
(hexyloxy)octyl]isoquinolinamine starting with 8-(hexyloxy)octanamine (583 mg, 2.54
mmol) and 2-chloropyrazine (0.25 mL, 2.81 mmol) and heating at 70 °C for 5 days. Rf0.26
(40% EA/Hex); 1H NMR (CDC13) 8 7.9 (m, 1H), 7.8 (m, 1H), 7.7 (m, 1H), 4.8 (br s, 1H, NH),
3.4—3.2 (m, 6H), 1.6—1.4 (m, 6H), 1.4—1.2 (m, 14H), 0.8 (m, 3H).
e 145: 1—[8—(Hexyloxy)octyl]—1H—indole
Q]/\/\/\/\/O\/\/\/
1— [8—(Hexyloxy)octyl]—]—l—Hindole (1.0 g) was prepared following the method for 1— [8—
(hexyloxy)octyl]—lH—benzimidazole starting with indole (836 mg, 7.1 mmol), 8—(hexyloxy)octyl
methanesulfonate (1.1 g, 3.6 mmol), and 7.1 mmol of sodium tert—butoxide. 1H NMR (CDC13) 5
7.6 (d, 1H), 7.3 (d, 1H), 7.2 (m, 1H), 7.1 (m, 2H), 6.5 (d, 1H), 4.1 (t, 2H), 3.4 (m, 4H), 1.8 (m,
2H), 1.7—1.5 (m, 4H), 1.4-1.2 (m, 14H), 0.9 (m, 3H).
e 146: 3—[8—(Hexyloxy)octyl]—3H—imidazo[4,5—b]pyridine
\ / N/\/\/\/\/O\/\/\/
3—[8—(Hexyloxy)octyl]—3H—imidazo[4,5—b]pyridine was ed following the method for l—[8—
(hexyloxy)octyl]—lH—imidazo[4,5—c]pyridine starting from 2—chloro—3—nitropyridine (479 mg, 3.0
mmol) and 8—(hexyloxy)octan—l—amine (0.69 g, 3.0 mmol). Since 2—chloro—3—nitropyridine was
commercially available, the first step in the l—[8—(hexyloxy)octyl]—lH—imidazo[4,5—c]pyridine
preparation (chlorination using phenylphosphonic dichloride) was not med. Rf 0.31 (5%
MeOH/DCCM); 1H C13) 8 8.21 (dd, 1, J=1.5, 4.7 Hz), 7.89 (s, 1), 7.87 (m, 1), 7.02
(dd, 1, J=4.7, 7.9 Hz), 4.09 (m, 2), 3.21-3.15 (m, 4), 1.74 (m, 2), 1.36-1.32 (m, 4), 1.14—1.10 (m,
14), 0.69 (m, 3).
Example 147: 1-Dodecyl-1H—imidazo[4,5-c]quinoline
N’\\
1—Dodecyl—1H—imidazo[4,5—c]quinoline (510 mg) was prepared following the method for the
preparation of l-octyl—1H—imidazo[4,5—c]quinoline, starting with 2,4—dichloro—3—nitroquinoline
(1.0 g, 4.1 mmol) and 1—dodecy1amine (1.0 g, 4.5 mmol). 1H NMR (CDC13) 5 8.5 (s, 1H), 8.15
(d, 1H), 8.05 (d, 1H), 7.5 (m, 1H), 7.3 (m, 1H), 3.7 (t, 2H), 1.8 (m, 2H), 1.5—1.1 (m, 18H), 0.8
(m, 3H).
Example 148: l—[3—(Decyloxy)propyl]— lH—imidazo[4,5—c]quinoline
WO/\/\
N’\\
yloxy)propan—1—amine (7.17 g of a solid) was ed following the method for the
preparation of 8—butoxyoctan—1—amine, starting from 1,3—propanediol (26.3 mL, 363 mmol) and
1—iododecane (121 mmol) mixed in 240 mL of 1:1 DCM/DMF.
1—[3—(Decyloxy)propyl]—1H—imidazo[4,5—c]quinoline (127 mg) was prepared following the
method for the preparation of 1—octyl—1H—imidazo[4,5—c]quinoline, starting with 2,4—dichloro—3—
nitroquinoline (1.94 g, 7.99 mmol) and 3—(decyloxy)propan—1—amine (1.72 g, 7.99 mmol). 1H
NMR(CDC13) 5 8.9.3 (s, 1H), 8.3 (m, 2H), 7.95 (s, 1H), 7.7-7.5 (m 2H), 4.7 (t, 2H), 3.5—3.3 (m,
4H), 2.2 (m, 2H), 1.6 (m, 2H), 2 (m, 14H), 0.8 (t, 3H).
Example 149: Decyloxy)butyl]-1H—imidazo[4,5—c]quinoline
4-(Decyloxy)butanamine (2.42 g, 7.28 mmol) was prepared by lithium aluminum hydride
reduction of 4-(decyloxy)butyronitrile, which was prepared in poor yield from the sodium
alkoxide of l-decanol and 4-bromobutyronitrile.
Decyloxy)butyl]—1H—imidazo[4,5—c]quinoline (78 mg) was prepared following the method
for the preparation of 1—octyl—1H—imidazo[4,5—c]quinoline, starting with 2,4—dichloro—3—
nitroquinoline (1.77 g, 7.28 mmol) and 4—(decyloxy)butan—1—amine (2.42 g, 7.28 mmol). 1H
NMR(CDC13) 5 9.3 (s, 1H), 8.25 (m, 1H), 8.15 (m, 1H), 7.95 (s, 1H), 7.7—7.5 (m, 2H), 4.6 (t,
2H), 3.5—3.3 (m, 4H), 2.1 (m, 2H), 1.7 (m, 2H), 1.5 (m, 2H), 1.4—1.1 (m, 14H), 0.8 (t, 3H).
Example 150: 1—[8—(Hexyloxy)octyl]—1H—imidazo[4,5—c]quinoline
\/\/\/O\/\/\/\/\
N’\\
2014/013992
1—[8—(Hexyloxy)octy1]—1H—imidazo[4,5—c]quinoline was made by the method used for the
preparation of 1—octy1—1H—imidazo[4,5—c]quinoline, substituting 8—(hexyloxy)octan—1—amine for
1—octylamine.
Example 151: 1—{ 5 — [3—(Hexyloxy)propoxy]pentyl } — 1H—imidazo[4,5—c]quinoline
/\/\/\OMOW
N’\\
on?“/
N
1—{5—[3—(Hexyloxy)propoxy]penty1}—1H—imidazo[4,5—c]quinoline (2.75 g of brown oil) was made
by the method used for the preparation of 1—octy1—1H—imidazo[4,5—c]quinoline, starting with 2,4—
dichloro—3—nitroquinoline (5.35 g, 22 mmol) and 5—[3—(hexyloxy)propoxy]pentanamine (4.90
g, 20 mmol).1H NMR (CDC13) 5 9.3 (s, 1H), 8.25 (m, 1H), 8.1 (m, 1H), 7.9 (s, 1H), 7.7—7.5 (m,
2H), 4.5 (t, 2H), 3.5—3.3 (m, 8H), 2.0 (m, 2H), 1.8 (m, 2H), 1.7—1.4 (m, 6H), 1.4—1.2 (m, 6H), 0.8
(m, 3H).
Example 152: 1-{3-[3-(Hexyloxy)phenoxy]propyl}-1H—imidazo[4,5-c]quinoline
O ,\\
1—{3—[3—(Hexyloxy)phenoxy]propyl}—1H—imidazo[4,5-c]quinoline (1.33 g of brown oil) was
made by the method used for the preparation of 1—octy1—1H—imidazo[4,5—c]quinoline, starting
with 2,4—dichloro—3—nitroquinoline (4.33 g, 17.8 mmol) and 3—[2—(hexyloxy)phenoxy]propan—1-
amine (4.37 g, 17.8 mmol).1H C13)8 9.3 (s, 1H), 8.3—8.1 (m, 2H), 7.9 (s, 1H), 7.7—7.5
(m, 2H), 7.1 (m, 1H), 6.6-6.4 (m, 3H), 4.7 (t, 2H), 3.95-3.80 (m, 4H), 2.4 (m, 2H), 1.7 (m, 2H),
1.5—1.2 (m, 6H), 0.8 (m, 3H).
ICAL ACTIVITY EXAMPLES
ANTI—INFLAMMATORY EXAMPLES
EXAMPLE A: Selective killing of tivated in?ammatory hages by Compound AC.
Summary: THP—l is a human AML cell line that can be d into a macrophage—like cell by
treatment with 0.2 uM vitamin—D3 (vit—D3) for 3—5 days. In the absence of an atory
activator (LPS; bacterial endotoxin), AC exerted little effect on cell viability in THP—1 cells over
a 6 hour period. Similarly, LPS in the absence of AC induced only a low level of cell death. In
contrast, when both components, LPS and AC were added to vit—D3 activated THP-1 cells,
massive cytotoxicity was observed within 6 hours. These observations te that stimulated
macrophages participating in an in?ammatory reaction may be specifically targeted for
deactivation with AC.
Experiment Overview:
1. Vit-D3 activated THP-1 cells were transferred to the wells of a 24-well dish
2. Compound AC, LPS from E.coli 0111:B4 or both components were added
3. After 6 hours at 37C the wells viable cell counts were performed by FACS
Experimental procedures
Cell culture:
THP—1 cells (ATCC) treated with 0.2 uM vitamin—D3 (EMD Biosciences) for 4 days prior to day
0 were transferred to the wells of 24—well dishes (1x106 cells in lml cRPMI [RPMI (ATCC) +
% AFBS (ATCC)]. LPS from E.coli 01 l 1:B4 (Sigma—Aldrich) and compound AC were added
to appropriate wells and the plates placed in a 37C incubator. After 6 hours the wells were
sed for Annexin V apoptosis assay.
2014/013992
FACS cell count and viability assay:
After 6 hours, 500 pl of the cell suspension from each well was transferred to 3ml FACS tubes
and 50 ul CountBright beads (Invitrogen) were added to each tube. Samples were vortexed, 2 ul
propidium iodide (150 MM) (Sigma—Aldrich) added then acquired on the FACSCalibur.
Results:
As shown in Table l, in the e of a second pro—inflammatory signal (LPS), AC exerted
little effect on cell viability in THP—1 cells over a 6 hour period. Similarly, LPS in the absence
of AC induced only a low level of cell death. In marked contrast, when both LPS and AC were
added to vit—D3 activated THP—1 cells, e cytotoxicity was observed within 6 hours.
Cytotoxicity increased in a AC dose—dependent manner.
Table 1: Dose—dependent acute cell death in AC—treated THP—1 cells primed with LPS
(Viable cell t change from 0 hours)
Compound AC No LPS Plus LPS
concentration (100ng/ml)
0 (0.1%
DMSO)
0.5 ”M AC
1.0 uM AC
2.0 uM AC -10.63 —77.43
As shown in Table 2, in the absence of a second signal (LPS), AC, in a concentration range of
0.1 to 2 pM, exerted little effect on cell viability in THP—1 cells over a 6 hour period. Similarly,
LPS in the absence of AC induced a low level of cell death that increased in a dose dependent
manner. In st, when both components, LPS and AC, were added to vit—D3 activated THP—
1 cells, e cytotoxicity was observed within 6 hours. Cytotoxicity appeared to have
reached maximal level with the lowest dose of LPS used (1 ng/ml).
Table 2: Titration of LPS in the THP—l acute/5—hour AC + LPS—induced cell death model
(Viable cell t change from 0 hours)
LPS THP—l viable cell % from 0 hours
concentration 5 hours treatment
Conclusion:
AC selectively reduces viability of pro—in?ammatory LPS-activated macrophages, with relative
g of nonstimulated macrophages. A very low dose of LPS (1 ng/ml) ed suf?cient
activation of macrophages to make them susceptible to AC.
EXAMPLE B: Relative potency of Compound AC and chloroquine for inactivation of
in?ammatory macrophages
Background: THP—l is a human AML cell line that can be induced into a macrophage—like cell
with vitamin—D3 (vit—D3) then activated into an in?ammatory state by stimulation with LPS
(bacterial xin). In the macrophage, LPS binding to toll—like receptor 4 (TLR—4) leads to
WO 20995
NF-KB activation and ion of in?ammatory cytokines which can lead to tissue damage in
in?ammatory diseases.
Compounds of the invention inactivate in?ammatory macrophages by accumulating in acidic
vacuoles and disrupting their ure and function, inhibiting release of vesicular in?ammatory
mediators and inducing cytosolic changes that r macrophage death or dysfunction,
including inhibition of autophagy; autophagy is important for differentiation of monocytes into
macrophages. The aim of this study was to compare relative potency of a compound of the
invention, AC, with chloroquine. Both AC and chloroquine are 4—aminoquinoline derivatives,
and chloroquine is known to be useful for treatment of several al in?ammatory diseases.
In this experiment, cell viability was monitored and uptake and accumulation of acridine orange,
a lysosomotropic ?uorescent dye, was used to assess lysosomal acidification and ity. JC—l
dye was used to measure s of test compounds on mitochondrial membrane potential
(MMP); reduction of MMP is a feature of apoptotic cell death.
Experimental procedures:
1. Vit-D3 activated THP-1 cells (0.5x106 cells in 2 ml) were transferred to the wells of a 24-
well dish
Compound AC was added at a concentration of 0.5 uM, 1.0 uM or 5.0 uM
Chloroquine was added at a concentration of 25.0 uM, 50.0 uM or 100.0 uM
LPS from E.coli 0111:B4 (1 ng/ml final tration) was added to some wells
99>.WN After 5 hours viable cell count, ne Orange (A.O.) uptake and JC—1 mitochondrial
loading were determined by ?uorescence—activated cell sorting (FACS)
Cell line information:
THP—l: ATCC TIB—202 Organism: Human, male, one—year infant
Organ: eral blood Disease: Acute Monocytic Leukemia (AML)
Cell type: Monocyte Growth properties: Suspension in RPMI plus 10% FBS
Test Compounds:
Compound Conc. Supplier Batch
info.
Alfa Aesar 43998 E26X026
AC N/A 073 1 12DZ
Chloroquine diphosphate SIGMA C6628 JR
(C-Q-)
Bafilomycin A1 (Baf A1) SIGMA B1793 040912JR
Crude—LPS E.c0110111:B4 SIGMA L4391 111611JR
Acridine Orange (A.O.) Invitrogen A3568 092311JR
JC-1 Invitrogen T3168 JR
CCCP Invitrogen 818978
M34152
Sterile water HyClone AXF3933
SH30529.03 5
Sterile DPBS N/A e AW]2125
SH30529.03 3
Cell e:
THP—1 cells (p39) treated with 0.1 uM Vit—D3 (100 uM) in DMSO] for 3 days were counted,
spun down, ended in serum—free RPMI (Lonza 12—115F) and transferred to the wells of
two 24—well dishes (0.5X106 cells in 2ml). Compound AC was added (in triplicate) at 0.1 uM,
0.5 uM and 1.0 uM, Chloroquine diphosphate was added (in triplicate) at 10.0 uM, 50.0 uM and
100.0 uM. Crude—LPS from E.coli 0111:B4 was added to some wells (1ng/ml final conc) and
the plates placed in a 37C incubator. lul of Baf A1 (50 nM final conc) was added to one well
(no LPS) at T=4 hours to serve as a compensation control for Acridine Orange loading. After 5
hours, 500ul aliquots of cells were transferred to FACS tubes and Viable cell counts, A.O.
loading and JC—1 accumulation determined by FACS.
Acridine Orange (A.O.) uptake and viability cell count assay — 5 hour time point:
s were ed, 2 ul of 50 ug/ml A.O. stock solution was added (200 ng/ml final) and
the tubes incubated at 37C for 15 minutes. The tubes were washed twice in DPBS, ended
in 500p] DPBS and acquired on the FACSCalibur. Acridine Orange exhibits strong ?uorescence
in both FL—l (green — RNA binding) and FL—3 (far red — acidic lysosomes).
Results:
As shown in Table 3 below, in the absence of LPS, low doses of AC had low direct cytotoxic
effects that increased in a concentration ent manner at the acute/ (5 —hour) time point.
Chloroquine followed a similar trend though this required 100—fold more drug versus AC;
100uM quine was approximately equivalent to luM AC.
In the presence of a low dose of LPS (1 ng/ml), cytotoxicity was increased with addition of
0.1uM (lOOnM) AC. Addition of 10 uM, 50 uM or 100 uM Chloroquine had a smaller effect on
LPS-induced cell death than did 1 uM AC, indicating approximately 100x higher potency of AC
than chloroquine for inactivating LPS-stimulated as well as basal THP-1 cells.
Both AC and chloroquine reduced acridine orange ?uorescence in THP-1 cells primed with
Vitamin D3 and activated with 0.1 ng/ml LPS (Table 4), ting deacidification or disruption
of lysosomal integrity. AC was approximately 50x more potent than chloroquine for ng
acridine orange ?uorescence.
AC treatment led to a dose—dependent reduction in mitochondrial depolarization, resulting in a
decrease mitochondrial accumulation of red JC—l dimers.
LPS alone (1 ng/ml) had no effect on mitochondrial integrity but potentiated AC—induced
mitochondrial depolarization. In contrast Chloroquine had little or no direct effect on
mitochondrial integrity at concentrations up to 100uM in the absence or presence of LPS.
Table 3: Effect of AC and chloroquine on cell Viability after 5 hours +/—LPS in Vit—D3 activated
THP—1 cells
THP—l Viable cell count/well
Test compound percent change from 0 hrs
concentration
lng/ml LPS
Mean i SE Mean 1 SE
DMSO
(Vehicle) 0.00 i 2.37 —10.20 i 6.47
0.1 uM AC —l7.46i2.84 -32.77 i 1.98
0.5 “M AC J_r 2.27 -40.99 i 5.01
—31.20 i 2.71 -49.63 i 0.96
.0 M C.Q. -7.34 i 0.53 -17.38 i 4.44
50.0 M C.Q. -17.11 i 2.70 -30.13 i 1.23
100.0 M C.Q. —31.44 i 1.37 -43.98 i 1.73
REMAINDER OF PAGE INTENTIONALLY BLANK
Table 4: Effect of AC and chloroquine on acridine orange cence after 5 hours +/—LPS in
Vit—D3 activated THP—l cells
A.O. FL—3 ?uorescence (MFI)
Treatment percent change from DMSO no
No LPS lng/ml LPS
Mean i SE Mean 1 SE
0.00 i 3.89 —2l.06 i 0.45
0.1uM AC —27.64 i 9.68 -54.72 i 2.74
0.5uM AC -54.59 i 4.05 -68.24 i 2.39
1.0uM AC -69.52 i 2.05 -81.11 i 2.65
.0uM C.Q. —49.37 i 6.16 -64.76 i 3.01
50.0uM C.Q. -63.45 i 2.36 -72.28 i 0.78
100.0uM C.Q. -91.25 i 0.60 -88.28 i 1.60
REMAINDER OF PAGE INTENTIONALLY BLANK
Table 5: Effect of AC and chloroquine on JC—l accumulation in mitochondria after 5 hours +/—
LPS in Vit—D3 activated THP—1 cells
JC—l Red cells (functional
mitochondria) percent change from
Treatment DMSO (no LPS)
No LPS 1 ng/ml LPS
Mean i SE Mean 1 SE
0.00 i 1.59 -0.33 i 0.69
.91 -1.66i0.96
—4.39 i 1.40 -7.19 i 1.52
1.0 uM AC -10.40 i 2.08 -16.41i 2.60
.0 uM C.Q. 2.58 i 0.81 4.39 i 0.81
50.0 uM C.Q. -0.70 i 1.24 2.21 i 0.63
100.0 uM C.Q. -1.40 i 0.67 1.07 i 0.39
Conclusion:
AC displays selectivity for inactivating LPS—activated macrophages versus unstimulated cells.
AC also attenuated acridine orange accumulation in lysosomes, ting that it caused
lysosomal tion. AC was approximately 100 fold more potent than quine for
inactivating macrophages, and about 50 times more potent than chloroquine for disrupting
lysosomal integrity as measured by acridine orange accumulation.
E C: Screen of compounds of the invention for anti—in?ammatory activity in vitro
Background: THP—l is a human acute myeloid leukemia (AML) cell line that can be induced
into a macrophage—like cell with Vitamin—D3 (vit—D3). In the macrophage, LPS
(lipopolysaccharide; endotoxin) stimulation of toll—like receptor 4 ) leads to NF-KB
activation and secretion of atory cytokines but also the priming of programmed death
pathways through RIP and Caspase 8. The e of this complex regulatory network is
dependent on highly specific kinases, enzymes that e ATP. Disruption of either cytosolic
pH or ATP availability/energy level uncouples this control network and the can macrophage shift
away from production of in?ammatory cytokines towards a mmed death event, which has
the net effect of limiting in?ammatory damage.
Compounds of the invention have been shown to inactivate macrophages rapidly (within 5 to 6
hours) when the macrophages have been put into a ?ammatory state activated with LPS.
More than 200 compounds of the invention were screened for anti—in?ammatory activity in the
THP—l system to assess their relative potency and activity in vitro.
Summary:
Addition of LPS to compound-treated macrophages resulted in acute/5-hour cell death; this
activity sed in a concentration dependent manner. Treatment with test nds alone
exhibited only a low level of acute cytotoxicity.
The majority of compounds tested displayed signi?cant y to inactivate pro—in?ammatory
THP—1 cells in accord with the proposed mechanism of action involving lysosome disruption,
which is not dependent upon binding to a specific protein target. Of the compounds tested, seven
demonstrated higher activity than the active benchmark compound AC: CJ, AM, AG, CX, AF,
BM and AH.
At the lowest tration tested (0.1 uM), all seven tested compounds were more active than
AC in causing death of cells treated with LPS. At concentrations of 0.5 uM and above all
compounds, including AC, reached a maximum activity threshold.
Results:
Addition of LPS to test compound—treated macrophages resulted in massive 5—hour cell
death; this activity sed in a concentration dependent manner (Table 6). Treatment with
compounds alone without pro—in?ammatory activation of the macrophages with LPS exhibited
only a low level of acute cytotoxicity.
At the lowest concentration tested (0.1 uM), seven compounds were more active than AC in
conditioning the cells for LPS—induced cell death. At concentrations of 0.5 uM and above, all
eight compounds, including AC, reached a maximum activity threshold.
Compound CX was the most effective cytotoxic nd at the acute/5—hour time point,
ed by a te activity group including CJ, AF, 30006 and BM. AG and AM exerted
the lowest effect on cytoplasmic conditioning, albeit still greater than that shown by AC.
Table 6: Compound screen: Reduction in viable THP-l cell count (percent change) from 0
hours after treatment with test compounds for 5 hours
Comound (0.1uM) Comound (1.0 uM)
Compound Plus LPS Plus LPS
Mean i SE Mean 1 SE Mean i SE Mean 1 SE
Vehicle -7.42 i 3.07 0.00 i 4.71 -7.42 i 3.07 0.00 i 4.71
AC —15.14i2.06 —7.48 i 5.82 -44.25 i 2.53 —9.60 i 1.96
C] -30.15 i441 -5.53 i 3.89 -41.62 i 1.80 —6.99 i 1.55
-19.80 i196 -5.57 i 2.67 -44.05 i 1.38 —8.47 i 3.31
—21.28 i 1.52 —6.24 i 0.69 -38.58 i 0.73 —4.02 i 2.83
—38.09 i 0.41 —8.00 i 1.41 —49.57 i 2.44 —9.20 i 3.09
—27.32 i 4.69 —8.99 i 2.00 -44.82 i 2.46 -6.02 i 2.31
—25.80 i 3.26 —3.96 i 0.82 —39.17 i 2.18 —4.18 i 2.46
AH —26.55 i 0.95 —9.66 i 1.34 —35.51 i 3.90 —7.87 i 0.98
2014/013992
EXAMPLE D: Anti—in?ammatory activity of compounds of the invention
Compounds of the invention have been shown to directly inhibit NF-KB, damage ellular
acidic lysosomes leading to proton leakage and acidification of the cytoplasm and also damage
mitochondria reducing the cellular energy level. Together these actions result in direct cell death
in some vulnerable cell types, over a period of about 48 hours. Additionally in the macrophage,
cytoplasmic acidification and energy depletion by compounds of the invention prime the cell for
inactivation when exposed to low concentrations of LPS, leading to an acute (5—hour) cell death
event through a combination of Caspase—driven apoptosis and RIP—driven necrosis.
Compounds of the invention were tested at 0.1 uM versus AC in the LPS—triggered THP—l cell
death assay. Both acute/S—hour and chronic/48—hour phases of cell death were assessed.
Compounds were ed in s with DMSO as the negative control and AC as the high
activity control. Compounds were tested at the low concentration of 0.1 uM with a View toward
identifying agents more potent than the benchmark agent AC; at higher concentrations, e.g. 1
uM, most compounds of the ion are active in inducing cell death in this assay, which
makes entiation from AC less clear than at a 10 fold lower drug concentration.
Results/Summary:
Seven of the compounds not only demonstrated equivalent activity to AC at the acute/S—hour
time point (cell conditioning) but were also more active than AC at the chronic/48—hour time
point (retention): CJ, AM, AG, CX, AF, BM and AH.
A further 15 tested compounds demonstrated equivalent activity to AC at both the 5—hour and
48—hour time : CI, CL, AL, AR, AN, AD, BH, CV, AJ, BD, BU, BK, EW, AK and AB.
The remaining 187 compounds exhibited lower anti—in?ammatory activity than AC at the tested
concentraction of 0.1 uM. However, this screen was conducted at a suboptimal concentration to
detect the most potent nds in the y; low activity at a concentration of 0.1 mM in the
t of this assay is still consistent with significant and potent anti—in?ammatory activity
when compared to chloroquine or other antimalarials.
Summary Table 7: Compound screen: Viable cell percent change after 5 and 48 hours in the
THP—l cell death assay (10 ng/ml LPS 0.1uM test compound)
Cell death time point
Compound Acute/S—hour Chronic/48—hour
Mean SE Mean SE
DMSO —l9.09 6.46 52.22 6.74
AC 3.83 4.12 27.70
CH —23.58 1.41- 53.55 7.24
ON 1 WU] 28.46 1.27
CJ —39.08 . 6 15.44 4.55
CK 4. 7
CL 086
.34
1.43
50.12 1.11
cw 43.71 2.34
DA 2597 2.71 43.55 6.40
DB 2573 0.25 20.47 3.28
BA —20.15 1.07 41.79 6.41
CY -29.18 1.70 47.86 2.06
CZ 53.70 1.63
CP —21.87 1.68 49.81 4.04
.49
BG —26.46 3.81 38.39 10.97
Summary Table 8: Compound screen: Viable cell percent change after 5 and 48 hours in the
THP—l cell death assay (10 ng/ml LPS 0.1uM test compound)
Cell death time point
Compound 5—hour Chronic/48—hour
Mean SE SE
.05
7.90
4.64
2.63
0.81
3.73
17.34
8.29
4.16
9.59
3.39
7.17
4.54
7.16
7.09
3.87
3.12
1.13
2.15
2.81
AE —37.73 3.86 4.11 2.24
AB —20.14 0.71 56.56 5.96
REMAlNDER OF PAGE INTENTIONALLY BLANK
Summary Table 9: Compound screen: Viable cell percent change after 5 and 48 hours in the
THP—l cell death assay (10 ng/ml LPS 0.1 uM test compound)
Cell death time point
Compound Acute/S—hour c/48—hour
Mean SE SE
0.40 35.66 3.27
1.94 14.24 1.47
2.17 19.14 4.63
1.18 39.53 5.09
2.45 33.86 1.63
2.14 31.64 4.04
2.07 31.07 8.11
4.07 18.03 3.64
2.14 27.30 8.06
3.87 34.36 2.98
1.56 41.84 3.25
2.45 28.60 12.70
2.80 2.74
1.15 24.32 3.49
4.94 2.24
0.73 47.40 8.60
REMAINDER OF PAGE INTENTIONALLY BLANK
Summary Table 10: Compound screen: Viable cell percent change after 5 and 48 hours in the
THP—l cell death assay (10 ng/ml LPS 0.1 uM test compound)
Cell death time point
Compound 5—hour Chronic/48—hour
Mean SE SE
0.95 28.09 5.15
0.31 11.13 3.65
0.91 25.19 0.81
2.78 42.36 6.73
2.99 37.38 8.16
4.26 44.34 4.25
3.02 25.65 6.11
3.09 39.26 1.86
1.57 22.32 6.35
3.09 34.67 10.04
3.36 36.46 8.92
7.00 5.64
6.72 4.28
2.44 2.50
0.16 2.29
1.42 5.20
3.02 16.12 2.95
3.16 2.36
2.48 15.96 2.96
2.26 38.76 3.70
1.73 18.20 4.10
REMAlNDER OF PAGE INTENTIONALLY BLANK
Summary Table 11: Compound screen: Viable cell percent change after 5 and 48 hours in the
THP—l cell death assay (10 ng/ml LPS 0.1 uM test compound)
Cell death time point
Compound Acute/5—hour Chronic/48—hour
Mean SE SE
0.94 1.11
2.33 —23.17 2.92
2.85 —5 .72 1.19
4.75 -6.80 3.16
2.07 0.65 3.12
1.94 6.40 11.50
0.36 -l7.21 4.61
BS —17.29 1.13 -6.51 2.77
y Table 12: Compound screen: Viable cell percent change after 5 and 48 hours in the
THP-l cell death assay (10 ng/ml LPS 0.1 uM test compound)
Cell death time point
Compound Acute/S-hour Chronic/48-hour
SE Mean SE
13 2.21
—24.59 1.48
FD —34.27 2.34 —3.68 4.14
FB —43.02 2.59 —10.18 3.14
FC —34.17 7.15 —20.85 1.63
FH —29.93 1.60 -5.12 4.01
FF —25.50 0.78 -4.74 0.92
FE —28.83 3.01 —11.23 1.97
FY —35.57 2.74 -1.84 3.24
BP —26.04 1.33 -3.39 7.15
FG —24.92 3.17 1.15 3.75
FZ —23.87 1.56 —5.31 3.01
y Table 13: Compound screen: Viable cell percent change after 5 and 48 hours in the
THP—l cell death assay (10 ng/ml LPS 0.1 uM test compound)
Cell death time point
Compound Acute/5—hour Chronic/48—hour
AC —36.91 0.49 3.97
GA —22.33 1.00 4.55
FI -23.79 2.33 1.85
GB —25.77 0.93 4.19
CE —30.76 3.40 2.96
F] -31.23 2.21 2.43
GC -27.62 3.64 7.07
1.80 3-66
1.51 2.47
2.59 4-50
0-86 3-30
3-48 3.41
—31.34 0.29 2.28
-22.83 2.09 2.40
REMAINDER OF PAGE INTENTIONALLY BLANK
Summary Table 14: Compound screen: Viable cell percent change after 5 and 48 hours in the
THP—l cell death assay (10 ng/ml LPS 0.1 uM test compound)
Cell death time point
Compound 5—hour Chronic/48—hour
Mean SE
DMSO 9.11 9.96
AC —16.35 2.21
1.57 —3.09 6.02
1.15 —0.47 2.36
1.22 —1.83 3.18
1.21 3.59 3.14
1.79 -2.75 1.97
1.69 10.62 5.40
1.04 -1.09 0.38
1.96 1.27 3.15
2.66 -3.62 2.06
3.71 3.86 1.52
2.48 6.64 2.20
1.27
2.34
2.71
2.64
REMAINDER OF PAGE INTENTIONALLY BLANK
y Table 15: Compound : Viable cell percent change after 5 and 48 hours in the
THP—l cell death assay (10 ng/ml LPS 0.1 uM test compound)
Cell death time point
Compound Acute/5—hour Chronic/48—
hour
Mean SE SE
DMSO 40.68 6.03
AC —41.20 2.33 16.40 3.98
DG —25.02 0.28 37.90 7.88
—27.53 1.35 50.89 5.57
—26.78 1.89 24.71 1.45
42.14 2.90
36.08 4.32
.10 6.23
—29.46 3.65 32.85 4.45
—29.40 1.20 39.64 5.24
.72 2.28
—32.45 1.49 30.34 2.30
28.35 4.70
38.59 1.87
EXAMPLE E: Anti-in?ammatory properties of Compound AC in a model of skin in?ammation
Objective: To evaluate the n?ammatory properties of compounds of the invention in a 12-
O—tetradecanoylphorbol—13—acetate (TPA) induced c skin in?ammation mouse model.
Topically applied phorbol esters such as TPA induce skin in?ammation involving edema,
macrophage and T cell infiltration and epidermal hyperplasia (Alford et al., 1992), and this
system has been used as an animal model for dermatitis, mimicking aspects of human
in?ammatory skin disorders. TPA is also known as a tumor promoter, so that agents which
inhibit hyperproliferative or angiogenic actions of TPA may inhibit tumor promotion.
s
Drug formulations: Compound AC was dissolved in isopropyl ate:propylene glycol (1:1)
+ 0.9% DMSO at the indicated concentrations. TPA was dissolved in acetone:water (99:1).
Dexamethasone (0.06%) was dissolved in normal saline.
Mice: HSD—ICR(CD—1R) female mice at 8—10 weeks of age were used in this experiment.
Experimental Design: Mice were placed into six groups of 10 mice each. 20 ML of 0.01% TPA
was administered to each ear on days 0, 2, 4, 7, 9, ll, 13, 15, 18, 20, and 22. 20 ML of AC at
various concentrations or 20 ML of thasone solution was applied to the ears daily
beginning on day 7, after in?ammatory changes in ear thickness were established. Ear thickness
was measured with calipers every three days.
Results
Compound AC treatment prevented in?ammatory thickening of mouse ears treated with TPA.
ogy indicated that both TPA—induced edema and epidermal hyperplasia were reduced by
AC, as was angiogenesis. The potency of AC was able to that of dexamethasone, with
signi?cant activity ed at the lowest dose of 12.5 micrograms of AC per ear per day.
Table 16. Ear thickness of vehicle and compound-treated mice: day 22
Treatment Ear thickness (mm)
Vehicle 0.646 1 0.1161
Dexamethasone, 0.05 mg/ear 0.301 + 0 0722
AC, 0.0125 mg/ear 0.362 i 0.0394
AC, 0.025 mg/ear 0.390 i 0 0319
AC, 0.05 mg/ear 0.391 i 0.0334
AC, 0.075 mg/ear 0.395 i 0.0438
Reference
Alford JG, Stanley PL, Todderud G, sch KM. (1992) Temporal infiltration of leukocyte
subsets into mouse skin d with phorbol ester. Agents Actions. 37(3—4):260—7
EXAMPLE F: Anti—in?ammatory effects of compounds of the invention on psoriasiform
dermatitis in mice
WO 20995
Topical imiquimod (IMQ), a toll—like receptor t, has been established as a model of
In?ammatory skin diseases including psoriasis and atopic dermatitis. Dermal in?ammatory
changes and gene expression in mice treated with l imiquimod mimic human sis and
dermatitis (van der Fits et al., 2009; Swindell et al., 2011). The effect of a set of compounds of
the invention were tested in a mouse model of imiquimod—induced dermatitis, with topical
tacrolimus and dexamethasone as comparators for assessing safety and efficacy relative to
standard agents used to treat dermatitis in humans.
Compounds to be tested for anti—in?ammatory activity were individually dissolved in ethanol at
a concentration of 0.6% and then mixed with 9 volumes of petrolatum (melted on a heated water
bath at 50 degrees C), yielding ointments containing 0.06% active drug. Dexamethasone
nt was prepared similarly, though at a final concentration of 0.03%, e 0.06%
dexamethasone applied topically in preliminary experiments had caused significant weight loss
due to systemic absorption. Commercial 0.1% tacrolimus ointment (ProTopicTM; Novartis) was
also used as an active comparator. Petrolatum containing 10% ethanol was used as a control
ent.
Female Balb/C mice (8 weeks old) were randomized and divided into groups of 5 animals each.
Polyethylene collars were affixed to the mice to prevent them from easily scratching their ears.
% mod was applied to both ears of each mouse (20 iters per ear) daily for 5 days,
and then every other day for the full duration of the study. In?ammatory changes, including a
doubling of ear thickness were apparent by day 5. On day 7 after initiation of imiquimod,
treatment with topical agents was started. Both ears of each mouse were treated with test
ointments, with one compound per mouse.
Ear thickness and PASI assessments (Psoriasis Area and ty Index, a standard psoriasis
scoring system) were recorded twice per week throughout the study. The PASI score comprises
the sum of evaluations of swelling, erythema and g on scales from 0 to 4; the maximum
PASI score is 12, and the minimum, in unaffected skin, is 0).
Results
Imiquimod treatment resulted in significant in?ammatory changes, including an increase in ear
thickness and a change in PASI scores; control ears reached the maximum possible value in the
PASI g system, with severe thickening, erythema and scaling. Compounds of the
invention, d topically in an nt base, reduced imiquimod—induced in?ammatory
damage to mouse ears, as assessed by caliper measurements of thickness and PASI scoring of
appearance. The ator drugs tacrolimus and dexamethasone also reduced ear thickness
and PASI scores. Notably, AF was superior to the commercial clinical form of topical 0.1%
tacrolimus (Protopic nt) in reducing ear thickness and PASI score. The anti—in?ammatory
activity of dexamethasone was accompanied by significant loss of body weight, indicating
systemic toxicity due to dexamethasone absorption. Neither compounds of the invention nor
tacrolimus affected body weight. In addition to inducing in?ammation of the ears imiquimod
transfer from the ears to the scalps of mice resulted in loss of hair and psoriasiform dermatitis on
the head, from n the ears, forward to the nose. In dexamethasone—treated mice, this area
remained hairless after treatment at the end of the experiment; in contrast, hair growth was
ined in this area during daily ent with AF, indicating that AF inhibited ogic
in?ammation without also impairing tissue normal tissue maintenance. A known side effect of
treatment with dexamethasone and other topical corticosteroids is thinning and weakening of the
treated areas; the lack of hair th may re?ect the clinical problem of skin atrophy known as
a side effect of topical dexamethasone. AF was equally effective at 0.06% and 0.6%
concentrations in the ointment base, indicating a wide therapeutic window. All of the tested
compounds of the invention reduced IMQ—induced changes in ear thickness, thus demonstrating
their anti—in?ammatory ty in vivo.
REMAINDER OF PAGE INTENTIONALLY BLANK
Table 17: Ear thickness in mice with imiquimod—induced dermatitis
ent Mean i SEM
Untreated (no IMQ) 0220 i 0.004
Control 1.355 i 0.004
AF 0.06% 0.355 i 0.005 *
AF 0.6% 0.390 i 0.008 *
0.577+0.019*
0.613 i 0.010 *
0.589+0.018*
*=1ess than control ear thickness, p<.05
REMAINDER OF PAGE INTENTIONALLY BLANK
Table 18: PASI Scores in mice with imiquimod-induced psoriasiform dermatitis
Treatment Mean ± SEM
Untreated (no IMQ) 0.000 ± 0.000
Control 12.000 ± 0.000
AF 0.06% 3.575 ± 0.158 *
AF 0.6% 4.875 ± 0.155 *
AC 7.150 ± 0.221 *
BM 9.250 ± 0.183 *
EF 7.275 ± 0.199 *
DD 7.450 ± 0.322*
DU 7.975 ± 0.621 *
DE 7.250 ± 0.183 *
AE 11.550 ± 0.281
Dexamethasone 4.525 ± 0.375 *
Tacrolimus 0.1% 6.075 ± 0.0990 *
*=less than control PASI score, p<.05
DER OF PAGE INTENTIONALLY BLANK
Table 19: Body weights of mice with imiquimod-induced psoriasiform dermatitis
Treatment Body Weight (mean ± SEM)
Initial (g) Final (g) D BW (g)
Control 21.2 ± 0.8 21.9 ± 0.7 + 0.7
AF 0.06% 20.5 ± 0.8 20.9 ± 0.6 + 0.4
AF 0.6% 20.8 ± 0.6 20.4 ± 0.6 - 0.4
AC 21.1 ± 0.7 21.3 ± 0.6 + 0.2
BM 20.8 ± 0.7 20.9 ± 0.6 + 0.1
EF 21.5 ± 0.6 21.3 ± 0.2 - 0.2
DD 20.9 ± 0.8 20.7 ± 0.6 - 0.2
DU 20.4 ± 0.7 20.9 ± 0.5 + 0.5
DE 20.6 ± 0.5 20.5 ± 0.5 - 0.1
AE 20.9 ± 0.5 21.3 ± 0.4 + 0.4
Dexamethasone 20.5 ± 0.6 18.1 ± 0.5 * -2.4 *
Tacrolimus 0.1% 20.9 ± 0.7 20.4 ± 0.6 -0.5
* Less than initial body weight, P<.02
References
ll WR, Johnston A, Carbajal S, Han G, Wohn C, Lu J, Xing X, Nair RP,
Voorhees JJ, Elder JT, Wang XJ, Sano S, Prens EP, DiGiovanni J, Pittelkow MR,
Ward NL, Gudjonsson JE. (2011) Genome-wide sion profiling of five mouse models
identifies similarities and differences with human psoriasis. PLoS One. 6(4):e18266
van der Fits L, s S, Voerman JS, Kant M, Boon L, Laman JD, Cornelissen
F, Mus AM, Florencia E, Prens EP, Lubberts E. (2009) Imiquimod-induced psoriasis-like skin
inflammation in mice is mediated via the IL-23/IL-17 axis. J Immunol. 182(9):5836-45
EXAMPLE G: Effects of compounds of the invention in a mouse model of multiple sclerosis
Multiple sclerosis (MS) is an autoimmune disease mediated ing destruction by the immune
system of myelin sheaths surrounding neuron axons in the brain. An established animal model
for this e is Experimental Autoiimune Encephalitis (EAE), induced by immunization of
mice with proteins or peptides that induce an immune se to myelin—specific proteins.
In this experiment, EAE was induced by immunization of mice with a peptide from proteolipid
protein (PLP), a known antigenic target in MS. Several compounds of the invention were
administered orally to assess their effect on the course of EAE, with quantitative evaluation of
disease symptoms as an endpoint. Linomide, a small molecule immunomodulator with known
activity in EAE models was used as a comparator drug.
Materials and Methods
41 mice received subcutaneous injections of 90 ug PLP139-151 in 200 uL of PBS on Day 0.
The PLP was ed in incomplete Freund’s adjuvant (IFA) by mixing 10 mL IFA with 40 mg
M. tuberculosis H37Ra (final concentration 4 mg/ml M. ulosis). The resulting mixture is
complete Freund’s adjuvant (CFA).
For injection, an emulsion of PLPl39—15 l and CPA was prepared by mixing 1 mL of stock
solution with 1 mL of CFA while vortexing for 15 minutes to form an emulsion.
Mice received vehicle or a test compound (60 g; suspended in 1% aqueous
ypropylmethylcellulose) by oral gavage, three times per week for 2 weeks followed by
once daily ent for 4 onal weeks, beginning on Day 14. Vials with vehicle and with
compounds were coded by letters (A—E) in order to obtain blind readings of disease severity.
Group 1 (n=7) Vehicle
Group 2 (n=6): AZ
Group 3 (n=7): CZ
Group 4 (n=7): CP
Group 5 (n=7): CQ
Group 6 (n=7) Linomide
Mice were monitored every other day for the pment of clinical symptoms according to the
grading system below.
Grading System for Clinical Assessment of EAE
Score Clinical Signs
0 Normal mouse, no overt signs of disease
1 Lim tail21 and hind limb weaknessb, but not both
2 Lim tail21 and hind limb weakness'
3 Partial hind limb aral sisC
4 e hind limb inaral sis'
Moribund state; death by EAE; sacrifice for humane reasons
“Limp tail: complete ?accidity of the tail, and absence of curling at the tip of the tail when mouse
is picked up.
bHind limb ss: observed as a waddling gait, the objective sign being that, in walking,
mouse’s hind limbs fall through the wire cage tops.
al hind limb paralysis: mouse can no longer use hind limbs to maintain rump posture or
walk but can still move one or both limbs to some .
dComplete hind limb paralysis: total loss of movement in hind limbs; mouse drags itself only on
its forelimbs. Mice at this stage are given food on the cage ?oor, long sipper tubes, and daily
subcutaneous saline injections to prevent death by ation.
Results:
Mice in all groups were displaying comparable mild EAE disease symptoms by day 14 after PLP
ion, at which time oral treatment with the test agents was initiated. At the termination of
the study, on Day 46, Vehicle—treated mice displayed more severe disease symptom scores than
did the treatment groups. Compounds of the invention displayed protective activity comparable
to the positive control compound linomide.
Table 20
Treatment EAE Score on Day 14 EAE Score on Day 46
(Before Treatment)
Vehicle 0.71 i 0.18 3.57 i 0.48
Linomide 0.93 i 0.19 2.29 i 0.48
AZ 0.83 i 0.41 2.50 i 0.29
CZ 1.00 i 0.00 2.29 i 0.20
CP 0.86 i 0.14 1.86 i 0.34
ANTIFUNGAL AND ANTIPARASITIC EXAMPLES
EXAMPLE H2Anti—Candida Activity of Compounds of the Invention
Reagents Manufacturer/Catalog # Lot #
Candida albicans strain 3153 ATCC 28367 61794
YPD Broth KD Medical YLF-3260 032111-03
Sabouraud Dextrose Agar KD Medical #YPL-1050 C21-03
Sterile PBS, pH7.4 Quality Biological Inc; #114131
DMSO Sigma; cat#D2650
Experiment overview:
A single colony of Candida Albicans was grown in 50 ml YPD broth overnight (19 hr). The cells
were washed with PBS and 4 CFU/ml of C. AZbicans (144 ul/well) in YPD medium were
plated in 96 well . Test compounds were then added to each well with concentration ranged
from 5 to 40 MM as final concentrations. The plates were ted at 30°C ght (24 hrs)
and OD at 600nm was read at the end of incubation as an index of yeast cell y.
Results:
Most of the compounds tested showed inhibition of Candida growth.. Based on inhibition curves,
IC50 (50% inhibition of fungal growth) and MIC (99% of inhibition of fungal growth) values of
compounds were calculated using XLfit and listed in the following table. The compounds with
higher antifungal activity have the lower numerical values.
Table 21: 50% Inhibition (ICSO) and m Inhibition Concentration (MIC) Value
I050 (uM) MIC (uM)
AL BR
* The MIC cannot be calculated for these compounds due to insufficient data points.
Procedure:
: Preparation of Candida albicans Cells
1. One day prior to the inoculum preparation, pick a single colony of a albicans
strain 3153 (lot# 61794) from the Sabouraud Dextrose Agar plate using the inoculum
loop and inoculate into a 250 mL ?ask containing 50ml of YPD growth medium
Incubate at 30 0C with shaking at 150rpm for at least 18 hours with ed lid to allow
air in and facilitate growth.
Examine an aliquot of the culture under a microscope for Candida cell morphology and
lack of bacterial contamination; >95% of Candida cells should be blastoconidia.
Transfer 25ml the overnight culture into a 50—ml plastic able centrifuge tube, and
centrifuge at 1000Xg for 20min.
d the supernatant and wash the pellet with 4ml of PBS at three times. Vortex and
centrifuge, 1000xg for 10min.
After the third wash, se the pellet with 2ml PBS and vortex.
Make three 1:10 serial dilutions in sterile PBS (10*, 102, 103) from the 2 ml cell
suspension using 15ml culture tubes. The ?nal volume in each tube is 5 m1.
Count the number of cells in cell suspension from the 10'3 dilution tube on the
hemocytometer.
To calculate cell concentration per ml:
Average number of cells in one large square x dilution factor x 104
104 2 conversion factor to convert 10'4ml to 1 ml
The cell number in 50—fold dilution of 10‘3 was: 14x104 CFU/ml
9. Make a 1:4 dilution in YPD medium from the 50—fold dilution of 10'3 cell suspension for
testing compounds.
The final C. albicans cell tration for the test: 3.5X104CFU/1’1’ll
. Plated l44ul/well of the above dilution of cell on 96—well plates.
Part—II: C. ns Growth Inhibition Testing with Compounds
1. From 10 mM DMSO stock solutions, make serial dilutions of compounds to 0.13, 0.25,
0.40, 0.55, 0.75 and l.0mM ons
2. Add 6ul each of diluted compound ons per well in duplicates. The final
concentrations were 0, 5, 10, 16, 22, 30 and 40 micromolar.
3. Incubated all plates at 30C for overnight (~24 hours).
4. Read ance at OD600 for each plate.
6. Calculate the % inhibition of each compound against the DMSO treated cell.
EXAMPLE 1: Evaluation of ty of Compounds against Saccharomyces cerevisiae
Reagents Manufacturer/Catalog # Lot #
Baker’s yeast Red Star
YPD Broth KD Medical YLF-3260 032111—03
Sabouraud Dextrose Agar KD Medical #YPL-1050 C21—03
Sterile PBS, pH7.4 Quality Biological Inc; #1 14—058—131
DMSO Sigma; cat#D2650
Experiment overview:
An overnight culture of S. seae was dilution in YPD broth to concentration of 40,000/ml
40 and 150ul/well was plated in 96 well plates. Compounds were then added to each well with
concentration ranged from 4 to 50 MM as final concentration. The plates were inoculated at 30°C
overnight with shaking at 220 rpm and absorbance at 600 nm was read after 18 hour incubation.
2014/013992
Results:
Among all the effect compounds against S. cerevisiae, compounds AL, BG, and AW were the
most effective ones. Compound AI generated lower IC50 from XLfit calculation, even though it
could not reach near 100% kill at high concentration like other compounds did. Chloroquine
(C.Q.) did not show any inhibition of yeast growth up to 50uM. ing listed IC50 (50%
inhibition of fungal ) and MIC (99% of inhibition of fungal growth) values of compounds
(calculated using XLfit) based on inhibition curves.
Table 22: Anti—S. cerevisiae — 50% Inhibition (IC50) and Maximum Inhibition
Concentration (MIC) Value
Com pou nd inactive co mp0 und
AL BA
AM BT
AG AC
AN CA
AZ CB
BE Chloroquine
*The MIC cannot be calculated for these compounds due to insufficient data points.
Procedure:
Part—I: Preparation of Yeast Cells
1. One days prior to the inoculum preparation, pick a single colony of S. cereViseae from
the Sabouraud Dextrose Agar plate using the inoculum loop and inoculate into a 50 mL
tube containing 10ml of YPD growth medium
Incubate at 30 0C with shaking at 220rpm for 24 hours with loosen lid to allow air in and
facilitates growth.
Examine an aliquot of the culture under a microscope for yeast cell morphology and lack of
bacterial contamination.
Dilute the overnight culture with YPD medium at 1:30 dilution (70ul to 2.1ml) and count
the number of cells as 4,230,000/ml.
Mix 620 pl of 1:30 dilution and 64.4 ml YPD to make final concentration of 40,000/ml
cells
6. Plated 144 ul/well in four l plates.
Part—II: Yeast Growth tion Testing
1. From 10 mM DMSO stock solutions, make serial dilutions of compounds to
0.1, 0.2, 0.3, 0.63 and 1.25 mM solutions
Add 6 ul each of diluted compound solutions per well in duplicates. The final
concentrations were 0, 4, 8, 12, 25 and 50 micromolar.
Incubated all plates at 30C for overnight (~18 hours) with 220 rpm shaking.
Read absorbance at OD600 for each plate on Spectra Max Plus plate .
ate the % inhibition of each compound against the DMSO treated cell and plotted.
EXAMPLE J: Anti—Trichophyton Activity of Compounds of the Invention
Tricophyton rubrum is one of the primary fungi responsible for persistent, treatment—resistant
l infections.
Reagents Manufacturer/Catalog # Lot #
Trichophyton rubrum ACTT, MYA—4438 59404737
PDB (potato dextrose broth) VWR 61000— 102 0000130316
PDA (potato dextrose agar) VWR 90008—416 1
Sterile PBS, pH7.4 Quality Biological Inc; #1 14—058—131
DMSO Sigma; cat#D2650
ell plate VWR 29442— 120 04709006
(Costar 3422, 24well with 8pm)
Experiment overview:
Trichophyton grown on two agar plates were collected by scraping into 10 ml saline and filtered
h 8 um filters. The filtered solution was diluted (1:75) and plated in 96 well plates and
treated with selected compounds of the invention.
Results:
This ment included some active compounds from previous experiment and added several
untested compounds. Culture treated by compounds AW, AX, AT, AE or AH showed no visible
fungal grow with even the lowest concentration (6uM) tested, representing their est
inhibitory effect against trichophyton growth. Most of rest compounds also inhibited fungal
growth with higher concentration (12—18 uM). AO, AP, AF, BL, AQ and B0 showed only
partial or no inhibition on fungal grow with highest concentration (40uM) . Following
table listed the maximum inhibition concentration (MIC) based on scoring by eye.
Table 23
Compound MIC, Compound MIC, HM Compound MIC, MM
AL 12 AO >40 AX 6
AM 12 AP ~40 AT 6
AG 18 AC 18 BO >40
AN 18 AF >40 BP 12
AZ 18 BL >40 AK 18
BE 12 AC) >40 BM 18
BF 18 AU 12 AE 6
BG 12 AS 25 AH 6
B] 18 AV 25 AB 18
BI 18 AW 6 C12-Im 18
Procedure:
Part—I: Preparation of Trichophyton rubrum Cells
Scrape frozen Trichophyton culture from ATCC vial and suspended in 100 pl PDB, and then
plate on a PDA plate. Incubate plate at 30 C for 4 days.
The plate was covered almost full. Scrap colonies from two plates in 10ml saline and filter
through 8pm filter in a 24 well transwell plate (used 2 wells). Take OD of collected solution at
52 0nm and 600 nm:
A 520 nm = 0.13; A 600 nm = 0.092 1x without on
A 520 nm 2 0.061; A 600 nm 2 0.037 1:25 dilution
Make 90ml of 1:75 dilution in PDB broth from the filtered cell sion by mixing 1.2 ml of
cell solution with 88.8ml PDB and t 144 ul/well in 5 X 96 well plates.
Part—II: Trichoph?on Growth Inhibition Testing with Compounds
1. From 10 mM DMSO stock solutions, make serial dilutions of compounds to 0.15,
0.3, 0.45, 0.63 and 1 mM solutions
2. Add 6 111 each of diluted compound solutions per well in triplicates. The final
trations were 0, 6, 12, 18, 25 and 40 micromolar.
3. Wrap the plates with parafilms and incubate all plates at 30°C for 6 days.
Take picture of the plates on KODAK imager with 17 captures of 1.5 sec/capture for total
of 25.5 second exposure.
EXAMPLE K:Anti—Cryptococcus Activity of Compounds of the Invention
Reagents Manufacturer/Catalog # Lot #
coccus neoformans Stain ID 52 ATCC 24067 4282211
YM Broth TEKNOVA #Y073l Y073105J 1101
Sabouraud Dextrose Agar KD Medical #YPL— 1050 C21—03
e PBS, pH7.4 Quality Biological Inc; #114—058—131
DMSO Sigma; cat#D2650
Experiment ew:
Cryptococcus mans (serotype D) were plated in 96 well plates with 144 til/well of 8 x10e5
CFU/ml in YM growth medium. Diluted compounds were then added to each well with
concentration ranged from 4 to 60 uM as final concentration in ates. The plates were
inoculated at 37°C for total of 48 hours. Two readings of OD at 600nm were measured after 30
and 48 hour treatments.
Results:
Most compounds tested in this assay inhibited the growth of coccus, with compounds AL,
AG, AW, AX, AA, AE, AH, AK, BM, and EN as the most ive ones. It is noteworthy that
compounds AA and AC were quite active against Cryptococcus, comparing with their relative
weak ties against Candida and S. cereviseae. Overall it seems that Cryptococcus is more
susceptible to compounds of the invention than the other fungi tested. Chloroquine had very
weak activity against Cryptococcus, with a maximum growth inhibition of 40% at a
concentration of 100 micromolar, so that its IC50 is greater than this concentration. IC50
(concentration for 50% of inhibition) and MIC (concentration for maximum—99% of inhibition)
were calculated using XLfit based on OD of 48 hour reading are listed in the following table.
Table 24
I050 I050
ure:
Part-I: Preparation of fungal Cells
1. Pick a single colony of Cryptococcus from the YM agar plate using the inoculum loop
and inoculate into a 125 ml ?ask containing 25 ml of YM growth medium.
2. Incubate at 37 °C with shaking at 220 rpm for 24 hours with loosen lid to allow air in and
facilitates .
3. Examine an aliquot of the culture under a microscope for yeast cell morphology and lack
of bacterial contamination.
4. Dilute the overnight culture with YM medium at 1:100 dilution and count the number of
cells as 1X106cfu/ml.
5. Make a final concentration of cells suspension at 8X105 cfu /ml in YM medium.
6. Plate 144 ul/well of 8X105 cfu /ml cell suspension on 96—well plates.
Part—II: Cryptococcus Growth tion Testing with Compounds
1. From 10mM DMSO stock solutions, make serial dilutions of compounds to 0.1, 0.2, 0.3,
0.5, 1.0 and 1.5 mM solution
2. Add 6ul each of diluted nd solutions per well in duplicates. The final
concentrations were 0, 4, 8, 12, 20, 40 and 60 micromolar.
3. Incubated all plates at 37°C overnight (30 hours) with 150 rpm shaking.
4. Read absorbance at OD600 for each plate.
5. Leave plates in 37°C incubator for another day and read absorbance at OD600 again at 48
hours to ensure the inhibitory effect of the compounds.
6. Calculated the % inhibition and IC50 of each compound against untreated cells.
EXAMPLE L: Anti-Cryptococcus (serotype A) Activity of Compounds of the Invention
Reagents Manufacturer/Catalog # Lot #
Cryptococcus neaformans serotype A ATCC MYA-1017 58178990
YPD Broth KD Medical 60 090712-04
aud Dextrose Agar KD Medical #YPL—1050 C21—03
Sterile PBS, pH7.4 y Biological Inc; #1 14—058—131
DMSO Sigma; cat#D2650
Experiment overview:
Cryptococcus neoformans (serotype A) were plated in 96 well plates with 144 til/well of 5 X10e5
CFU/ml in YPD growth medium. Diluted compounds were then added to each well with
concentration ranged from 0.05 to 10 uM as final concentration in duplicates. The plates were
ated at 30°C. Two readings of OD at 600nm were measured after 18hr and 48 hour
treatments.
Results:
Most compounds tested in this assay ted the growth of Cryptococcus (serotype A), with
AX, AK, BM, AE and AH as the most effective ones. Cl2—imidazol had relative weak activity
against Cryptococcus serotype A at low concentration. Data plotted was based on 26 hour
reading because 18 hour reading was too low. IC50 (concentration for 50% of inhibition) and
MIC (concentration for maximum — 99% of inhibition) were calculated using XLfit based on OD
of 26 hour reading are listed in the ing table.
Table 25: 50% Inhibition (IC50) and m Inhibition Concentration (MIC) Value
|C50, uM MIC, uM
It is worthy of note that C. neoformans (serotype A) is the most sensitive fungus to the
compounds compared to the other tested species, including C. Albicans, S. siae,
Trichophyton , and Cryptococcus serotype D
Procedure:
Part—I: Preparation of fungal cells
1. Pick a single colony of Cryptococcus from the Sabouraud Dextrose agar plate using the
inoculum loop and inoculate into a l25ml ?ask containing 25ml of YPD growth medium
2. Incubate at 30 0C with shaking at 220 rpm for 24 hours with loosen lid to allow air in and
facilitates growth.
3. Examine an aliquot of the culture under a microscope for yeast cell morphology and lack
of bacterial contamination.
4. Dilute the overnight culture with YPD medium at 1:100 dilution and count the number of
cells as 8X106cfu/ml.
. Make a final concentration of cells suspension at 5x105 cfu /ml in YPD medium after the
stock e had been stored at 4°C for 3 days.
6. Plate 144 ul/well of 5X105 cfu /ml cell suspension on 96—well plates.
Part—II: Cryptococcus Growth Inhibition Testing with Compounds
1. From 10mM DMSO stock ons, make serial dilutions of compounds to 0.0013,
0.0025, , 0.025, 0.05, 0.125 and 0.25 mM solution
2. Add 6ul each of diluted compound solutions per well in duplicates. The final
trations were 0, 0.05, 0.1, 0.5, 1.0, 2.0, 5.0 and 10 micromolar.
3. Incubated all plates at 30°C overnight with 175rpm shaking.
4. Read absorbance at OD600 after 18 and 26 hours for each plate.
. Calculated the %inhibition and 1C50 of each compound against the ted cell.
EXAMPLE M: Effects of compounds of the Invention on THP—l—derived macrophage
antifungal activity; pment of a phagocytosed Cryptococcus neoformans antifungal screen
Background: In the preceding examples compounds have been shown to possess direct anti—
fungal activity t coccus neoformans at concentrations less than 5 uM. The
compounds, being weak bases, are lysosomotropic, concentrating in the acidic lysosomal
compartment of macrophages. Some pathogenic fungi, such as Cryptococcus neoformans, reside
in acidic lysosomes of macrophages in an effort to avoid the host immune system (Srikanta et al.,
2011.
2014/013992
Another lysosomotropic drug, chloroquine, which has some direct anti—fungal activity at the
much higher tration of lOOuM in C. mans, has been shown to enhance anti—fungal
activity of macrophages against C. neoformans when tested at only 10 uM. This effect was
shown to be due to the drug concentrating in lysosomes housing the yeast (Harrison et a1., 2000)
The potential therefore exists for compounds of the invention to behave in a manner similar to
chloroquine for attacking Cryptococcus or other organisms residing in macrophages, but at much
lower concentrations.
Results/Summary:
The compounds tested (AM, BM, AH and AC) all showed clear dose dependent inhibition of
fungal growth after phagocytosis and lysis. AH showed the highest potency with near 100%
inhibition of the fungal growth at 2uM.
The IC50 values after macrophage phagocytosis were comparable to the IC50 values for direct
inhibition of fungal growth, in the absence of macrophages reported in an earlier study.
The compounds were capable of killing C. neoformans (serotype A) even when the fungus was
d within live macrophages.
References:
1: A sensitive high—throughput assay for evaluating host-pathogen interactions in Cryptococcus
neofomans infection Srikanta, D et a1 (2011) PLoS ONE 6(7): 622773
2: Conditional ity of the diprotic weak bases Chloroquine and Quinacrine against
Cryptococcus neoformans Harrison, T. S et al (2000) J Infect Disease 182: p283—289
Results:
Two concentrations of hages (1X105 and 2x105/well) and a high concentration of C.
neoformans (4X106/well) (MOI values of 40 and 20 respectively) were tested in this experiment.
WO 20995
All of the compounds tested showed clear dose ent inhibition of fungal growth after
phagocytosis and lysis. Phagocytosis by macrophages did not protect the fungus cells from
antifungal activity of compounds of the invention.
The IC50 values after macrophage phagocytosis were comparable to the IC50 values for direct
inhibition of fungal growth, in the absence of macrophages.
Table 26: IC50 for inhibition of fungal growth by compounds directly or after macrophage
ytosis
Compound IC50 value (uM)
No macrophages 1x10 macrophages 2X10 macrophages
1.57 1. 13 0.85
0.69 1.31
0.39 0.25
AC 1.15 1.29 1.35
Experimental procedures:
Experiment ew for assay development plate #4:
THP-1 cells were adjusted to 5x105/ml or ml in cRPMI + PMA
200 pl was transferred to a ?at-bottomed 96-well dish (1x105 and well) (48hrs at 37C)
Media was removed and fresh cRPMI + PMA added (further 24hrs at 37C)
C. neoformans cells in DPBS were opsonized with human serum (60mins at 30C)
The opsonized yeast was washed (DPBS) and resuspended at 1X107/m1 or 2X107/m1 in cRPMI.
100ul added to macrophage plate (1x106 and 2x106/well) (4hrs at 37C) washed X4 with DPBS
100p] of cRPMI was added to each well (18hrs at 37C) Compound AC was added to some wells.
Media was removed, no wash, 25ul 0.05% Triton X—100 added to lyse cells (3 mins RT rocking)
125p] YPD broth was added and the plate incubated (24hrs at 30C then 24hrs at 37C)
C. neoformans growth was determined on a Spectrophotometer (600nm) after 24 and 48 hours
Cell line information:
THP—l: ATCC TIB—202 Organism: Human, male, one—year old infant
Organ: Peripheral blood e: Acute Monocytic Leukemia (AML)
Cell type: Monocyte Growth properties: Suspension in RPMI plus 10% FBS
THP— l—derived macrophage entiation protocol (PMA):
THP—1 cells (p15) grown in cRPMI [RPMI (Lonza 12—115F) plus 10% AFBS (Lonza DE14—
701F)] were counted on a hemacytometer. Cells were spun at 1,800 rpm, RT for 5 mins,
supernatant aspirated, pellet bed then adjusted to 5.0X105/1’1’ll and 1.0X106/1'1'll in cRPMI
supplemented with 0.2ug/ml phorbol 12—myristate 13—acetate (PMA) (1 mg/ml in DMSO Sigma
P8139). 200ul aliquots of each cell concentration were transferred to 42 wells (half a plate) of a
?at-bottomed 96—well dish (1X105 and 2X105/we11) and placed in a 37C incubator for 48 hours,
media was then d and 200 pl of fresh cRPMI + PMA added. The plate was incubated for
an additional 24 hours at 37 C then processed for yeast uptake.
Yeast strain information:
C?gtococcus neotormans: ATCC MYA-1017 Designation: CDC21
Isolation: Derived from strain H99 from patient with Hodgkin’s disease, New York
Antigenic properties: pe-A Growth properties: Suspension in YEPD broth 25C
Opsonization of Cryptococcus neoformans cells (human serum only):
In parallel to hage preparation, C. neoformans cells were grown from a single colony in
20ml YPD broth at 30C ght. Absorbance of 1:10 dilution of the overnight (ON) culture
gave 0.89 OD at 600nm. Estimated tration of this stock was 4X108 cells/ml (2x108
cells/ml gave an OD 600nm of 0.426 in an r study Cryptococcus macrophage development
plate 3 12). The cells were washed with DPBS once and resuspended in 2ml DPBS. 230
pl of this stock (~60x107 cells) was brought up to 500 pl with DPBS in an Eppendorf tube. For
Opsonization, 500 pl of human serum (SIGMA S7023) was added and the tube incubated at 30 C
for 60 mins with orbital shaking. The opsonized fungal cells were washed three times with 800ul
DPBS (1,100g for 2 min) and resuspended in 800p] DPBS. A 1:200 dilution of cells was counted
(4.25X106/ml), equivalent to 8.5X108/l’1’11 for the 1X stock. 470 pl of the 1X stock was brought up
tolOml with cRPMI for a final concentration of 4x107/ml.
Macrophage mediated anti—fungal activity assay:
Media was aspirated from the prepared macrophage plate and 100ul of the opsonized fungal cell
suspension added to the wells. Media without yeast was added to triplicate wells for each
macrophage concentration to provide background readings. Three empty wells (no macrophages)
were seeded with fungus to serve as the wash control. The plates were then ted at 37 C for
4 hours then washed 4 times with DPBS (plates were shakes brie?y after addition of DPBS to
se wash efficiency). 144 pl of cRPMI was added to each well and 6ul of 12.5 uM, 25 uM
and 50 uM stocks of compounds AM, BM, AH, and AC added in triplicate for final
concentrations of 0.5 uM, luM or 2 uM. The plate was incubated at 37 C, 5% CO2 for 18 hours.
Media was removed, 25ul of 0.05% Triton X—100 (SIGMA T—9284) in DPBS was added to each
well and the plate rocked at RT for 3 min, to lyse the cells. 125 pl YPD broth (KD Medical
YLF—3260) was then added to each well and the plate placed in a 30C incubator. C. neoformans
cell growth was determined by measuring absorbance at 600nm on a Spectrophotometer ra
Max Plus using program x Pro) after 30 hours.
EXAMPLE N: Antifungal Activity as Determined by Minimum tory and Fungicidal
Concentrations
OBJECTIVE
The objective of this study was to determine the antifungal activity of eight experimental
compounds against a representative panel of fungal isolates, including Candida ns, C.
glabrata, Cryptococcus neoformans, Trichophyton rubrum, Aspergillus fumigatus, and us
spp. Antifungal activity was measured by minimum inhibitory concentration (MIC) and
minimum fungicidal concentration (MFC).
MATERIALS
Isolates
Three recent clinical strains of each species, taken from the culture collection at the Center for
Medical Mycology, Case Western University, were tested.
Antifungal Agents
Compounds in powder form were dissolved in DMSO. Serial dilutions of each compound were
then prepared in RPMI—l640 in a range of 0125—64 ug/ml.
MIC testing was performed according to the CLSI M27—A3 and M38—A2 rds for the
susceptibility testing of yeasts and filamentous fungi, respectively (1, 2). Test isolates were
subcultured from frozen slants onto potato dextrose agar plates (Trichophyton rubmm was
subcultured onto oatmeal plates for conidia production) and checked for purity. Inocula were
then prepared in RPMI—1640 (YNB for Cryptococcus) to a concentration of 0.5 — 2.5 x 103
colony—forming units (CFU)/ml or 0.4 - 5 x 104 conidia/ml for yeast and filamentous fungi,
respectively. MIC endpoints were read at 50% and 100% inhibition, as compared to the growth
control, at both 24 and 48 hrs (C. neoformans were incubated for 72 hrs and T. rubmm strains
were incubated for 96 hrs).
MFC determinations were performed according to the modifications previously described by
Canton et al. and Ghannoum and Isham. (3, 4) Specifically, the total contents of each clear well
from the MIC assay were tured onto potato dextrose agar. To avoid antifungal carryover,
the aliquots were allowed to soak into the agar and then were streaked for isolation once dry,
thus ng the cells from the drug source. Fungicidal activity was defined as a 2 99.9%
reduction in the number of colony forming units (CFU)/ml from the ng inoculum count,
with compounds being determined as cidal if the MFC fell within 4 dilutions of the MIC.
The data shows that all eight compounds demonstrated antifungal activity against the strains
tested, although MIC and MFC results were strain specific. As can be seen in Table 27,
compound AC showed the lowest MIC values t the C. albicans strains at both the 50% and
100% inhibition at 24 hrs (<0. 12—025 and <0. 12—1 ug/ml, respectively) and 48 hrs (<0.l2—l
and 0.5—2 ug/ml, respectively). Importantly, compound AC was cidal against 2 of the 3 C.
albicans strains tested. nd AG demonstrated similar MIC and MFC values against the C.
albicans strains.
Table 28 shows that compounds AG and AC were also the most active against the C. ta
strains tested. After 24 hrs, the MIC at 50% for compound AG was 0.25—l ug/ml and 0.5—2 at
100%. After 48 hrs, the corresponding compound AG values were both 0.5—2 ug/ml. After 24
hrs, the MIC at 50% for compound AC was 0.5—1 ug/ml and l—2 at 100%. After 48 hrs, the
corresponding compound AC values were 1—2 (50%) and 2—4 ug/ml (100%). Both compounds
AG and AC were cidal against all of the C. glabrata strains .
As can be seen in Table 29, compounds AX and AH demonstrated the st antifungal activity
against the Cryptococcus neoformans strains tested. Compound AX had MIC values of 0.12—2
and 0.5-4 ug/ml at 50% and 100% inhibition, respectively, while compound AH had
corresponding values of 0004-2 and 025-2 ug/ml. Both compounds were cidal against all 3
neoformans isolates.
Table 30 shows the MIC and MFC values of the eight compounds t the Aspergillus
fumigatus strains. Compounds AE, AH, and AC showed equivalent inhibitory activity, with
compound AE demonstrating MIC values of <0.12—0.5 and <0.12—1 ug/ml at 50% and 100%
inhibition, respectively, after 24 hrs. After 48 hrs, the corresponding values for compound AE
were 0.5—2 and 1—4 ug/ml. Compound AH demonstrated MIC values of <0. 12 and 0.25—0.5 ug/ml
at 50% and 100% inhibition, respectively, after 24 hrs. After 48 hrs, the corresponding values for
compound AH were 025—1 and 0.25—4 ug/ml. For compound AC, the MIC values at 24 hrs were
<0. 12 and 0.25—0.5 ug/ml for 50% and 100% tion, respectively, while the corresponding
values at 48 hrs were 0.5 —l and l ug/ml. r, only nds AL, AM, and AG were cidal
against one of the A. fumigatus strains (MRL 28397).
In Table 31, it can be seen that compounds AE, AH, and AC were the most active against the
Rhizopus strains. At 24 hrs, compound AE showed MIC values of <0. 12 and l—2 ug/ml for 50%
and 100% inhibition, respectively, with corresponding 48 hr values of l—2 and l—4 ug/ml.
Compound AH showed MIC values of 025—05 and 2 ug/ml for 50% and 100% inhibition,
tively, at 24 hrs and 2 ug/ml for both endpoint readings at 48 hrs. At 24 hrs, compound AC
showed MIC values of <0.l2—0.25 and 0.5 ug/ml for 50% and 100% inhibition, respectively,
with corresponding 48 hr values of 0.5 and 0.5—1 ug/ml. Generally, no cidal activity was
demonstrated against the Rhizopus strains tested.
Finally, Table 32 shows the MIC and MFC values of the eight compound against T. rubrum. At
the 50% inhibition endpoint, compounds AG, AX, AE, AH, and AC showed lent activity
(<0. 12—4 ug/ml overall). At the 100% inhibition endpoint, compounds AG, AH, and AC were
equivalent (0.25—4 ug/ml overall), with compounds AX and AE g slightly higher (0.25—16
ug/ml). Within the definition of cidality (MFC within 4 dilutions of the MIC) all compounds
were considered cidal against the T. rubrum strains, though the MFC were high in some strains
(8-16 ug/ml).
Overall, nds AE, AH, and AC appeared to demonstrate the greatest inhibitory activity
t the most fungal strains tested.
References for Example N
1. CLSI. Reference Methodfor Broth Dilution Antifungal Susceptibility Testing of Yeasts;
Approved Standard — Second n. CLSI document M27—A2 (ISBN 1—56238—469—4).
CLSI, 940 West Valley Road, Suite 1400, Wayne, PA 19087—1898 USA, 2002.
2. CLSI. Reference Methodfor Broth Dilution ngal Susceptibility Testing of
Filamentous Fungi; Approved Standard— Second Edition. CLSI document M38—A2
[ISBN 89]. CLSI, 940 West Valley Road, Suite 1400, Wayne, PA 19087—
1898 USA, 2008.
3. Canton E, Peman J, Viudes A, Quindos G, Gobemado M, Espinel—Ingroff A. 2003.
Minimum fungicidal concentrations of amphotericin B for bloodstream Candida s.
Diagn Microbiol Infect Dis. 45:203—6.
4. Ghannoum MA, Isham N. 2007. nazole and Caspofungin Cidality Against Non—
Albicans Candida Species. Infectious Diseases in Clinical Practice. l5(4):250—253.
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ANTICANCER EXAMPLES
EXAMPLE 0: Compounds of the invention inhibit eic breast cancer growth in mice
Cancer models in mice generally either involve syngeneic murine tumors in immunocompetent
mice or xenografts of human tumors in immunocompromised mice. An important aspect of
using murine tumors in mice is that the tumor and host have much closer c similarity than
do human xenografts in mice and therefore can be a very rigorous test of selectivity of agents for
inhibiting proliferation of cancer cells versus normal tissues. 4T1 is breast cancer cell line
commonly used as a syngeneic cancer model. Test compounds were chosen based upon their
ability to selectively to kill 4T1 mouse mammary breast cancer cells relative to a normal mouse
mammary cell line in vitro.
Female Balb/C mice were randomized into treatment groups anle3 4T1 cells were ed into
into the mammary fat pad of each mouse in 0.1mL PBS on 4/28/10 (day 0). Mice received test
compounds by oral gavage in 1% hydroxypropylmethylcellulose from day 2 until day 30. Tumor
growth was ed by caliper measurements twice per week and tumor weight after necropsy,
and body weight was also monitored.
Treatment groups were:
TJQMPP’N?‘ Vehicle (1% hydroxypropylmethylcellulose; HPMC)
CI (lZOumol/kg/day)
BA (lZOumol/kg/day)
CP (lZOumol/kg/day)
CQ (lZOumol/kg/day)
AA (lZOumol/kg/day)
AC (lZOumol/kg/day)
Table 33: Results
Treatment Final Tumor l Body Final Body A BW %
Volume (mm3) Weight (g) Weight
Vehicle 906 i 316 22.2 i1.1 21.8 :r 0.7
CI 702 i 244 21.8 i 0.8 20.6 i 0.6 -5.5 %
BA 641 i 159 25.5 i 1.5 24.8 i 2.0 —2.7 %
352i114 24.1:r0.9 24.1J_r1.3
CQ 140 i 60 24.9 i 0.6 24.4 i' 0.9 —2.0 %
AA 563 i 175 21.4 i1.0 20.3 i' 1.3 —5.1 %
AC 723i 185 21.5i 1.0 1971- 1.1 -8.4%
Compounds of the invention reduced tumor growth versus vehicle—treated mice after daily oral
administration at a dose of 120 uM/kg/day for 33 days, with acceptable toxicity (less than 10%
body weight loss). CQ was the most active of the compounds tested in this experiment in the
4T1 breast cancer model. Compounds were chosen for in vivo g based upon their ability to
selectively to kill 4T1 mouse mammary breast cancer cells relative to a normal mouse mammary
cell line in vitro, indicating a correspondence between in vitro cancer cell line cytotoxicity in
vivo ncer activity of compounds of the invention.
EXAMPLE P: Effects of Compound AC in mice g xenografts of human hormone-
independent prostate cancer
Experimental ure
Standard models for prostate cancer use subcutaneous xenografts of human prostate cancer cell
line. Local measurable tumors are produced at the site of injection of the cells, and they
asize to critical tissues such as the bones, lungs and liver. Mortality in this model is due to
ases impairing tissue function. Compounds of the invention were assessed for inhibition
of tumor growth and reduction or delay of mortality in the PC—3 prostate cancer model, which
mimics an advanced, androgen—independent stage of prostate cancer.
female nude mice (female Hsdzathymic nude—Foxnlnu) received PC—3 cells (5X106 per mouse
in 0.1mL PBS) by subcutaneous ion into the right hind ?ank. After 8 days tumors were
palpable and mice were divided into two groups with approximately equal mean tumor sizes.
Mice received AC or vehicle (saline) via intraperitoneal (i.p.) injection once daily until day 79.
1. Vehicle (0.9 % saline): Mean pretreatment tumor volume 55.7 mm3; body weight 26.6 i
0.9 g)
2. Compound AC: 120 umol/kg/day. Mean pretreatment tumor volume 59.6 mm}; body
weight 26.8 i 0.5 g)
Tumors were ed with rs twice per week, and body weights and mortality were also
monitored.
Results
All 5 vehicle-treated mice died by day 35 (Individual days of death 20, 24, 24, 26, and 35). One
mouse in the AC-treated group died on day 65 and the remaining 4 ed until the study was
terminated on day 79.
In the longest-surviving vehicle—treated mouse, the tumor volume was 3007% larger at time of
death on day 35 than at initiation of treatment; all other e—treated animals died of
metastatic disease with smaller primary tumor sizes. Among mice treated with AC, tumors had
enlarged to an average of 949 % of initial size at day 77; two of the mice surviving to the end of
the study had no detectable tumors at that time and were deemed complete regressions, and one
regressed more than 50% from the initial tumor size. AC—treated mice had a mean body weight
of 28.9 i 1.3 g at end of study; a weight gain rather than a weight loss from the initial group
body weight of 26.8 i 0.5 g indicates that the treatment was well tolerated. Daily injections of
AC therefore ly improved survival and decreased tumor size, including producing
complete and partial regressions, in mice bearing hormone—independent prostate cancers.
EXAMPLE Q: Effects of compounds of the invention in a mouse model of liver ases of
human colorectal cancer
A major cause of morbidity and mortality in patients with colorectal cancer is metastasis of the
tumor into the liver; colorectal cancer can often be successfully resected from the y site,
but metastases to the liver are much less accessible to surgical treatment. A mouse model of
colorectal cancer metastasis to the liver has been established, using HCT—l l6 colon
adenocarcinoma cells ed into the spleen of athymic (nude) mice. The HCT—l 16 cancer
cells spontaneously spread from the spleen into the liver via the circulation, and they form
tumors in the liver (Ishizu, K., , N., Yamazaki, K., Tsuruo, T., Sadahiro, S., Makuuchi,
H., and Yamori, T. Development and Characterization of a Model of Liver asis Using
Human Colon Cancer HCT—116. Biol. Pharm. Bull. 2007, 30(9): 1779-1783).
Compounds CQ and AA were tested for antitumor activity in the HCT—l 16 model of metastatic
colorectal cancer.
Methods:
Mice (female Hsdzathymic nude-Foxnlnu) were anesthetized with xylazine/ketamine
intraperitoneal injection, followed by incision approximately 10mm on the left subcostal region
(area disinfected with ethanol) to expose the peritoneum. The peritoneum was opened for about
8mm near the spleen, and 2.5X106 cells in 50 uL PBS were ed into the spleen using a 30G
. The spleen was repositioned, and the surgical area was closed using sutures and clips.
N Treatment Dose (umol/kg) Dose Volume (per mouse)
Vehicle N/A 0.4mL
CQ 240 0.4mL
AA 240 0.4mL
2014/013992
The day after receiving cells, mice were randomized into groups of five based upon body weight
to provide groups with approximately equivalent mean body weight. Mice received a single,
daily oral dose of test e or vehicle (1% hydroxypropylmethylcellulose) beginning 48 hours
ing cell injection into the spleen.
At study termination 28 days after HCT—l 16 cell injection, body weights were recorded, and
spleens and livers were removed, weighed and ?xed in 10% formalin. Livers were sectioned and
stained; the relative areas of normal and tumor tissue were quantified in histology sections with
quantitative planimetry software.
Results:
Tumors in the Vehicle control group occupied 14% of the liver as assessed by tative
planimetry in histology sections. Both compounds CQ and AC markedly reduced the area of
liver invaded by metastatic cancer cells. The Vehicle group had a 12% higher liver weight/body
weight ratio than the groups treated with either CQ or AC, corroborating the histology
planimetry measurements indicating that tumors increased the total liver mass in the Vehicle
group. Body weights were not icantly different between groups of mice treated with
vehicle-treated versus test compounds, ting that the compounds of the invention were well
tolerated at a dose of 240 umol/kg/day for 28 days.
Table 34
Tumor Area Tumor Area Liver Weight
Final Body Weight
Treatment
% of Total Liver % of Vehicle % of Body Weight
Grams
Group
e 14 i 5.6 % 100 % 6.1 i 0.3 % 27.4 i 0.9
CQ 0.02 i 0.01% * 0.15% * 5.3 i 0.1% 26.2 i 0.9 NS
AA 0.2 i 0.26 % * 1.5% * 5.3 i 0.2 % 28.2 i 1.5 NS
= less than Vehicle group, P< .02
EXAMPLE R: Effects of compounds of the ion, sorafenib, and combinations in a mouse
model of human hepatocellular carcinoma
Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers ide,
generally developing as a uence of chronic infection with hepatitis B or C viruses. The
tyrosine kinase inhibitor sorafenib is a multikinase inhibitor used for treatment of advanced
HCC, and has both direct antitumor and antiangiogenic properties. Compounds of the invention
act via a different mechanism of action than does sorafenib or other kinase inhibitors; therefore it
is possible that compounds of the invention, in addition to displaying single agent activity, may
also e the efficacy of sorafenib or other standard treatments in HCC and other cancers.
The Hep3B hepatocellular carcinoma cell line is human in origin, contains genetic traces of
hepatitis B virus, and can be injected into the livers of athymic immunocompromised mice as a
model of primary HCC. Oral sorafenib is active in this model and was used as both a positive
control treatment and as a partner for combination therapy with a selection of compounds of the
invention. The test compounds were all administered orally.
The test compounds of the invention were ded in 1% hydroxypropylmethylcellulose
(HPMC) using a sonicator equipped with a microtip to ze particle size and maximize
uniformity of the suspension. Sorafenib was dissolved in a 1:1 mixture of Cremophor EL and
ethanol by heating to 60°C for 1 minute and then sonicating for 10 minutes to fully suspend.
Female nude mice (Hsdzathymic nude—Foxnln") weighing approximately 25 g were anesthetized
with ketamine/xylazine, laid on their backs, and a l—cm erse on made through the
skin and peritoneum of the left upper abdomen. The mediant lobe of the liver was exposed by
applying gentle pressure on the abdomen. 1.5—2x106 Hep3B cells in a ZOML volume of
eleMEM serum free (lzl) were slowly ted by subserosal injection into the liver
using a 27—gauge needle on a Hamilton syringe. The liver was allowed to slip back into place,
and the peritoneum was closed with sutures and wound clips.
Mice were divided into 8 groups of mice each following injection of cells; the vehicle/vehicle
group comprised 12 mice and the other groups comprised 8 or 9. Mice began receiving oral
testdrug treatments 48hr post cell injection.
Table 35
Daily Dose
Group No. of
Treatment
No. Animals
1% HPMC vehicle; cremophor
1 12 N/A
veh1cle
Sorafenib;
30mg/kg/day
1% HPMC vehicle
180um01/kg/day
cremophor vehicle
180umol/kg/day;20mg/kg/day
360umol/kg/day
cremophor vehicle
360Mmol/kg/day; 20mg/kg/day
7 8 360pmol/kg/day
cremophor vehicle
8 9 AB + sorafenib 360umol/kg/day; 20mg/kg/day
The test nds, sorafenib, and vehicles were administered by oral gavage. Sorafenib or its
cremophor—containing vehicle were given in the morning and compounds of the invention or
their HPMC e was administered in the afternoon each day; all animals ed two gavage
treatments of drugs or appropriate vehicles daily. In the group with sorafenib as the only active
test agent, the daily dose was 30 mg/kg; when ed with compounds of the invention, the
sorafenib dose was reduced to 20 mg/kg because the tolerability of the combination was
n, and also because possible improved anticancer activity of compounds of the invention
combined with a lower dose of sorafenib over a higher dose of sorafenib alone would more
clearly demonstrate advantageous activity of compounds of the invention.
Mice were sacrificed at day 35 after 2 of the initial 12 vehicle—treated mice had died from tumor
progression; livers were removed and photographed, and tumors were dissected out for
measurement and weighing.
Results
All vehicle—treated mice developed tumors, with a mean weight of about 2 grams at the time of
sacri?ce. Sorafenib (30 mg/kg/day) as a single agent reduced the tumor size by more than 50%.
nds AC and AB alone also reduced tumor size by more than 50%; AK alone produced a
cally but not statistically significant ion in tumor size versus vehicle. on of
sorafenib (20 mg/kg/day) to compounds of the ion resulted in better inhibition of tumor
growth than was achieved with sorafenib alone at 30 mg/kg/day. The combinations of DD or
AB with sorafenib produced more complete regressions (no viable tumor detected at necropsy)
than single-agent treatments. All treatments including combinations were well-tolerated as
indicated by maintenance of body weight throughout the entire duration of the study.
Table 36. Effects of compounds of the invention alone and in combination with sorafenib on
growth of cellular carcinoma in nude mice
Tumor Weight Complete Body Weight (g) Mean i
Treatment (g) Regression SEM
Mean i SEM Initial Final
e 2.03 i 0.37 26.0 i 0.4 26.4 i 0.5
Sorafenib 0.81 i' 0.20 * 25.9 i' 0.7 24.9 i 0.4
AC 0.49 i- 0.17 * 25.4 i- 0.5 25.6 i 0.7
AC + Sorafenib 0.17 i 0.07 *+ 24.9 i 0.5 25.2 i 0.9
AK 1.56 i 0.39 25.9 i 0.7 24.9 i 0.9
AK+ Sorafenib 0.48 + 0.22 * 25.1 i 0.7 25.1i 1.3
_E0.88 + 033 * 2 26.2 i- 0.7 26.0 :r 0.9
_n0.38 6 25-3 i 0-7
:r 0.18 * 25.7 i- 0.8
= less than Vehicle group, P<.02 + = less than Sorafenib group, p<.02
EXAMPLE S: In vitro screen for anticancer activity against 4T1 murine breast cancer and PC-3
human prostate cancer
Compounds of the invention were screened for ability to kill or inhibit proliferation of cancer
cell lines in vitro, as a complement to in vivo studies on subsets of compounds demonstrating
anticancer efficacy in vivo, at doses that were well tolerated after either oral or intraperitoneal
administration.
Anticancer activity against 4T1 murine breast cancer cells cancer cells was assessed in vitro by
seeding 1x104 cells/well in ?at bottom culture plates, then treating with ed 1 uM or 5 uM
trations of nds for 18hr after plating. Then 10 ML of Wstl dye reagent, a
tetrazolium dye indicator for cell death, was added/well and incubated approximately 2hr before
being assayed on the Biotek EL800 Universal microplate reader (450nm, nce 630nm).
Activity against PC3 human prostate cancer cells in vitro was assessed by a similar method.
PC—3 prostate cancer cells were plated at 2x104 cells/well in 96 well ?at bottom tissue culture
plates, and ted for approximately 20 hours with vehicle or test compounds at
trations of 0.4, 0.5 or 2.5 MM as ted for specific compounds in the right—hand column
of Table 37. A 1/10th volume of Wstl dye was added/well and incubated for two hours in the cell
culture incubator. Samples were analyzed in triplicate on an EL800 Universal Microplate Reader
at 450nm, reference wavelength 630nm.
Numerical values in the Table 37 represent percent of cancer cell survival relative to vehicle
treated cells at the indicated trations, with values under 100 indicating anticancer cytotoxic
activity at the drugs concentrations tested.
Table 37
_———
BH 19.3 98.5 0.4ttM
WO 20995
0.5 M
0.4MM
0.4MM
0.4MM
0.4MM
0.4 M
0.4MM
0.4MM
0.4 M
E____0.4MM
2.5 M
————2.5 M
————WM
————Wm
I3____
———m-WM
0.4 M
I3____0.4m
————
————
————
————
0.4 M
0.4 M
————Wm
————Wm
————
0.4 M
—_——
—_——
2.5 M
—_——
E____
2.5 M
“mm25W
m-_——25W
E__——2.5 M
1.5 M
0.4 M
————WM
————WM
————
"rm-—
————
————
————
————
————
————BZ
————
————
————
——m_—
————
————
EL 108 39.4 41.8 2.5},LM
2014/013992
————
—_——
14.1 0MM
—_——
—_——
—_——
——_—MM
—_m-—
——_—2.MM
2.MM
0.4 M
18 0MM
—_——
2.MM
————OMM
————
————
Iz_———OMM
———m_2.5 M
————
———E-s M
2.5 M
IB-_-_o.MM
0.5 M
————2.MM
———-2.5 M
m———2.MM
38.1 24.5 0.5MM
0.5 M
2.5“
2.5m
GD 24.3 2.5uM
EXAMPLE T: Effects of compounds of the invention of ance of human te cancer
cells to cytotoxic chemotherapy agents in vitro
Cancer therapy is ed by inherent or acquired resistance of tumor to single cytotoxic
anticancer agents. One mechanism of cancer cell resistance to chemotherapy agents such as
anthracylines, platinum compounds, vinca alkaloids, taxanes, and some tyrosine kinase
inhibitors, is to ter anticancer agents in lysosomes or related acidic vacuoles. Compounds
of the invention were tested in vitro for their ability to increase sensitivity to several other classes
of anticancer agents to which PC—3 prostate cancer cells are relatively resitant in vitro and in
vivo.
PC-3 prostate cancer cells were plated at 2x104 cells/well in 96 well ?at bottom tissue culture
plates, and incubated imately 20 hours. Cells were treated with an anticipated suboptimal
concentration of test compounds for cell killing as a single agent for imately 30 minutes.
Chemotherapeutic agents (doxorubicin, oxaliplatin, paclitaxel or vincristine at concentrations
suboptimal for PC—3 cell killing) were added and PC-3 cells were incubated for an onal 72
hours before being assayed using Wstl reagent. A 1/ 10th volume of Wstl dye was added/well
and incubated for two hours in the cell culture incubator. Samples were analyzed in triplicate on
an EL800 Universal Microplate Reader at 450nm, reference wavelength 630 nm.
In Table 38, numerical values in the column headed “No Chemo” represent percent cell survival
after exposure to the compounds of the invention at concentrations indicated to the left of that
column. In the columns headed by the names of the four chemotherapeutic agents, values lower
than the corresponding “No Chemo” values indicate better anticancer activity of the ic
combination of the cytotoxic agent in combination with a compound of the invention than was
obtained with either class of compound alone. At the trations ted, the minimal
activity of the chemotherapy agents alone during 72 hours of exposure was normalized to 100%
for y in discerning synergistic or additive effects of compounds of the invention. The
results indicate that, at the concentrations tested, a broad range of compounds of the invention
increase sensitivity of cancer cells to one or more of the tested cytotoxic herapy agents
doxorubicin, oxaliplatin, paclitaxel or vincristine.
Table 38: Cytotoxicity of suboptimal concentrations of compounds of the invention alone and
combined With cytotoxic herapy agents
Compound [HM] No Doxorubicin Oxaliplatin Paclitaxel Vincristine
Chemo 3.50M 100uM 50uM 100nM
Vehicle (100) (100) (100) (100) (100)
84-6 67-4
CJ 04uM 53.7 18. 9 19.7 51.7 16.9
642 138.2
503 27.7
51-8 28.1
54-8 26
50-1 69.5
21- 8 17-1
51-6 32-8
AR 0.4uM 57 22.4 24.1 54.1 24.2
54.7 23. 9 23.1 46.1 46.7
45.9 21.7 22.2 48.2 38.1
98.5 35.7 30.6 61 71.6
73.8 36.2 30.6 21.4 36.1
95.4 33.6 26.9 54.1 71.2
98.5 31.9 26.6 55.9 69.4
99.1 44.1 41.2 64 74.9
92.8 40.9 37.2 57.1 74.1
99.1 40.1 36.2 59.2 71.1
95.7 82.8 91.3 100.8 19.1
23.9 56.8 64.1 50.2 50.8
110.9 76.6 84.3 71.7 81.7
24.7 56 62.3 40.3 29.6
WO 20995
145-7 148-7
CY 0.40M 40.5 76.6 84.3 71.7 81.7
74-5 48-2
CQ 2.50M 95.8 86.5 93.8 34.8 47.1
69-7 82-8
CT 2.50M 34.5 63.2 71.9 46.3 46.3
CM 5 M 74-8 81-3
BB 2.50M 16.3 20.4 24.7 25 17.2
-8 20-1
BD 0.40M 29.3 66.1 61.3 28.4 33.3
DY 5M 23-3 18-3
DZ 0.40M 84.8 85.6 86.7 71.8 89
EA 0.461735 84.5
BE 04 45-3 47.1
24-3 23.4
EG 049M 95-3 88.5
EB 2-5 143-3 982
136-8 91-6
93-1 91-1
164-8 164-9
DN 2.50M 31.7 64.1 78 64.7 72.3
68-6 74
DF 0.40M 101.9 88.7 96.5 89.4 95.4
45.6 79.2 91.1 105.4 92.1
59.2 79.9 89.9 93.4 90.1
31.5 59.9 68.7 49.2 35.5
82.6 38.6 31 22.2 43
61.5 32.8 30 14 34.1
70 86.4 97 97.1 98.6
19.1 35 32.4 25.2 22.6
24 48.1 57.2 31 26.7
31.6 76.7 61.9 23.3 32.2
BK 0.40M 29.2 32.1 27.3 20.6 28.3
WO 20995
120 141-4 111-2
BY 2.50M 96.6 98.4 101.1 99.9 94.1
86-1 70-8
FT 2.50M 41.1 74.4 94.2 85.2 78.3
128-5 1046
AS 2.50M 31.1 51.1 555 36.8 30.8
344 37-2
AW 0.40M 382 59.5 51.3 33.6
90-1 78-7
AT 040M 34.6 65.4 768 57.4 32.9
928 69-7
FB 250M 97.7 89.1 955 93.2 98.6
___E-—1318 114.9 FF 51M 1361 1101
FE 511M 113-7 373
91 80.1
95-1 93
47-2 41
F2 5 M 1148 38-5
GA 1.5M 41. 3 82.2 91.8 109.2 84.2
762 38-8
CD 2.50M 16.6 19.5 201 23.2 17.1
2.5M 21.4 48.5 251 26.9 21.4
0.50M 38.6 75.1 97.3 82.2
0.50M 35.5 47.4 62 18 39
19.8 59.5 63.2 30.3 26.4
126.4 68.8 83.5 70.3 75.3
2.50M 24.3 39.5 26.? 27 23.5
Claims (34)
1. A compound represented by Formula IB1 or a pharmaceutically acceptable salt thereof wherein n is 1; Q is absent; R1 is hydrogen or halo; and R7 is phenyl substituted by alkoxy having from 6 to 10 carbon atoms or phenoxy.
2. The nd or salt of claim 1, wherein the nd is selected from the group consisting of: N-[3-(Hexyloxy)benzyl]quinazolinamine, N-[3-(Decyloxy)benzyl]quinazolinamine, N-[4-(Decyloxy)benzyl]quinazolinamine, N-[4-(Hexyloxy)benzyl]quinazolinamine.
3. The compound or salt of claim 1, wherein the compound is N-(3- Phenoxybenzyl)quinazolinamine.
4. Use of the compound or pharmaceutically acceptable salt of any one of claims 1 to 3 in the manufacture of a medicament for treating or preventing a condition in a mammalian subject; the ion being ed from the group consisting of an inflammatory disease, a fungal infection, a unicellular parasitic infection, and a neoplastic disease.
5. A pharmaceutical composition adapted for use in ng or preventing a condition in a mammalian subject; the condition being selected from the group consisting of an inflammatory disease, a fungal infection, a unicellular parasitic infection, and a stic disease, the pharmaceutical ition comprising the compound or pharmaceutically acceptable salt of any one of claims 1 to 3 and a pharmaceutically acceptable carrier.
6. The use according to claim 4 or pharmaceutical composition according to claim 5, wherein the mammalian subject is a human subject.
7. The use according to claim 4 or pharmaceutical composition according to claim 5, wherein the condition is an matory disease.
8. The use according to claim 4 or pharmaceutical composition according to claim 5, wherein the condition is a fungal infection.
9. The use or pharmaceutical composition of claim 8, wherein the fungus is selected from the group consisting of Candida, Saccharomyces, Trichophyton, Cryptococcus, Aspergillus, and
10. The use or pharmaceutical composition of claim 9, wherein the Candida is Candida albicans or Candida glabrata.
11. The use or ceutical composition of claim 9, n the Saccharomyces is Saccharomyces cerevisiae.
12. The use or pharmaceutical composition of claim 9, wherein the Trichophyton is Trichophyton rubrum.
13. The use or pharmaceutical composition of claim 9, wherein the Cryptococcus is Cryptococcus mans.
14. The, use or pharmaceutical composition of claim 13, wherein the Cryptococcus neoformans is Cryptococcus neoformans pe D or Cryptococcus neoformans serotype A.
15. The use or pharmaceutical composition of claim 9, wherein the Aspergillus is Aspergillus fumigatus.
16. The use ing to claim 4 or pharmaceutical ition according to claim 5, wherein the condition is infection with a unicellular parasitic microorganism.
17. The use or ceutical composition of claim 16, wherein the parasitic infection is infection with a parasitic microorganism that resides within acidic vacuoles in cells of the subject.
18. The use or pharmaceutical composition of claim 16, wherein the parasitic microorganism is ed from the group consisting of mycobacteria, gram positive bacteria, amoebae, and gram negative bacteria.
19. The use or pharmaceutical composition of claim 16, wherein the parasitic microorganism is selected from the group consisting of tuberculosis, listeria, leishmania, a trypanosome, Coxiella burnetii, and a Plasmodium.
20. The use according to claim 4 or ceutical composition ing to claim 5, wherein the condition is a neoplastic disease.
21. The use or pharmaceutical composition of claim 20, wherein the neoplastic disease is a hematologic cancer.
22. The use or pharmaceutical composition of claim 20, wherein the neoplastic disease is a solid tumor.
23. The use ing to claim 4 or pharmaceutical composition according to claim 5, wherein the compound or composition is adapted for topical administration to the subject.
24. The use according to claim 4 or pharmaceutical composition according to claim 5, wherein the compound or composition is adapted for systemic administration to the t.
25. The use or pharmaceutical composition of claim 24, wherein the compound or composition is adapted for oral, rectal, parenteral or nasal administration.
26. A method of inhibiting a fungus ex vivo, sing ting a surface or the fungus with the compound or pharmaceutically acceptable salt of any one of claims 1 to 3.
27. The method of claim 26, n the fungus is ed from the group consisting of Candida, Saccharomyces, Trichophyton, Cryptococcus, illus, and Rhizopus.
28. The method of claim 27, wherein the Candida is Candida albicans or Candida glabrata.
29. The method of claim 27, wherein the romyces is Saccharomyces cerevisiae.
30. The method of claim 27, wherein the Trichophyton is Trichophyton rubrum.
31. The method of claim 27, wherein the Cryptococcus is Cryptococcus neoformans.
32. The method of claim 31, wherein the Cryptococcus neoformans is Cryptococcus neoformans serotype D or Cryptococcus neoformans serotype A.
33. The method of claim 27, wherein the Aspergillus is Aspergillus fumigatus.
34. The compound of any one of claims 1 to 3, substantially as described herein with reference to any one of the Examples or
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201361759512P | 2013-02-01 | 2013-02-01 | |
US61/759,512 | 2013-02-01 | ||
NZ709885A NZ709885A (en) | 2013-02-01 | 2014-01-31 | Amine compounds having anti-inflammatory, antifungal, antiparasitic and anticancer activity |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ749999A NZ749999A (en) | 2020-09-25 |
NZ749999B2 true NZ749999B2 (en) | 2021-01-06 |
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