CN100347151C - 新的氨基苯酰苯类化合物 - Google Patents
新的氨基苯酰苯类化合物 Download PDFInfo
- Publication number
- CN100347151C CN100347151C CNB028193571A CN02819357A CN100347151C CN 100347151 C CN100347151 C CN 100347151C CN B028193571 A CNB028193571 A CN B028193571A CN 02819357 A CN02819357 A CN 02819357A CN 100347151 C CN100347151 C CN 100347151C
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- China
- Prior art keywords
- phenyl
- amino
- chloro
- compound
- aminomethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- MAOBFOXLCJIFLV-UHFFFAOYSA-N (2-aminophenyl)-phenylmethanone Chemical class NC1=CC=CC=C1C(=O)C1=CC=CC=C1 MAOBFOXLCJIFLV-UHFFFAOYSA-N 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 674
- 238000002360 preparation method Methods 0.000 claims abstract description 194
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 424
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 306
- -1 2-(2-{[3-chloro-4-(2-methyl benzoyl) phenyl] amino } phenyl)-1-ethyl methyl acetic acid ester Chemical class 0.000 claims description 283
- 235000019439 ethyl acetate Nutrition 0.000 claims description 197
- PQOUBHREMAXTMZ-UHFFFAOYSA-N bis[2-(aminomethyl)phenyl]methanone Chemical compound NCC1=CC=CC=C1C(=O)C1=CC=CC=C1CN PQOUBHREMAXTMZ-UHFFFAOYSA-N 0.000 claims description 166
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 142
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 114
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 106
- 239000000203 mixture Substances 0.000 claims description 94
- 229910052760 oxygen Inorganic materials 0.000 claims description 92
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 91
- 239000001301 oxygen Substances 0.000 claims description 91
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 79
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 65
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 63
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 58
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 42
- 150000003839 salts Chemical class 0.000 claims description 41
- 125000000217 alkyl group Chemical group 0.000 claims description 38
- 229910052739 hydrogen Inorganic materials 0.000 claims description 37
- 239000001257 hydrogen Substances 0.000 claims description 37
- 150000002148 esters Chemical class 0.000 claims description 34
- 229910052736 halogen Inorganic materials 0.000 claims description 28
- 150000002367 halogens Chemical class 0.000 claims description 28
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 19
- 239000000460 chlorine Substances 0.000 claims description 18
- SNCZNSNPXMPCGN-UHFFFAOYSA-N butanediamide Chemical compound NC(=O)CCC(N)=O SNCZNSNPXMPCGN-UHFFFAOYSA-N 0.000 claims description 16
- 150000003851 azoles Chemical class 0.000 claims description 12
- 229910052794 bromium Inorganic materials 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 11
- 229960003328 benzoyl peroxide Drugs 0.000 claims description 10
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 10
- AIPRAPZUGUTQKX-UHFFFAOYSA-N diethoxyphosphorylmethylbenzene Chemical compound CCOP(=O)(OCC)CC1=CC=CC=C1 AIPRAPZUGUTQKX-UHFFFAOYSA-N 0.000 claims description 10
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 claims description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- 239000002777 nucleoside Substances 0.000 claims description 8
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 8
- DCCVVXOAXUMESS-UHFFFAOYSA-N diethoxy(propyl)phosphane Chemical compound CCCP(OCC)OCC DCCVVXOAXUMESS-UHFFFAOYSA-N 0.000 claims description 7
- 201000010099 disease Diseases 0.000 claims description 7
- SHZIWNPUGXLXDT-UHFFFAOYSA-N ethyl hexanoate Chemical compound CCCCCC(=O)OCC SHZIWNPUGXLXDT-UHFFFAOYSA-N 0.000 claims description 7
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 claims description 7
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 7
- HRDJRILDJWUGPM-UHFFFAOYSA-N 4-[2-[3-chloro-4-(2-methylbenzoyl)anilino]anilino]-4-oxobutanoic acid Chemical compound CC1=CC=CC=C1C(=O)C(C(=C1)Cl)=CC=C1NC1=CC=CC=C1NC(=O)CCC(O)=O HRDJRILDJWUGPM-UHFFFAOYSA-N 0.000 claims description 6
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 6
- 239000004202 carbamide Substances 0.000 claims description 6
- 235000013877 carbamide Nutrition 0.000 claims description 6
- 229960003082 galactose Drugs 0.000 claims description 6
- 229940124530 sulfonamide Drugs 0.000 claims description 6
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 5
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 claims description 5
- 230000002757 inflammatory effect Effects 0.000 claims description 5
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 4
- OGBVRMYSNSKIEF-UHFFFAOYSA-N Benzylphosphonic acid Chemical compound OP(O)(=O)CC1=CC=CC=C1 OGBVRMYSNSKIEF-UHFFFAOYSA-N 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 230000001684 chronic effect Effects 0.000 claims description 4
- 239000012453 solvate Substances 0.000 claims description 4
- AMOYMEBHYUTMKJ-UHFFFAOYSA-N 2-(2-phenylethoxy)ethylbenzene Chemical compound C=1C=CC=CC=1CCOCCC1=CC=CC=C1 AMOYMEBHYUTMKJ-UHFFFAOYSA-N 0.000 claims description 3
- 208000030507 AIDS Diseases 0.000 claims description 3
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 3
- 208000006673 asthma Diseases 0.000 claims description 3
- 201000008937 atopic dermatitis Diseases 0.000 claims description 3
- VXNZUUAINFGPBY-UHFFFAOYSA-N ethyl ethylene Natural products CCC=C VXNZUUAINFGPBY-UHFFFAOYSA-N 0.000 claims description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 3
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 claims description 3
- 230000001185 psoriatic effect Effects 0.000 claims description 3
- 201000003068 rheumatic fever Diseases 0.000 claims description 3
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 3
- OZNPMOURSIGSQF-UHFFFAOYSA-N 2-[2-[3-chloro-4-(2-methylbenzoyl)anilino]phenyl]ethyl-methylcarbamic acid Chemical compound OC(=O)N(C)CCC1=CC=CC=C1NC(C=C1Cl)=CC=C1C(=O)C1=CC=CC=C1C OZNPMOURSIGSQF-UHFFFAOYSA-N 0.000 claims description 2
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 2
- 208000002874 Acne Vulgaris Diseases 0.000 claims description 2
- NOTWWPLAOFJABP-UHFFFAOYSA-N C1=CC=C(C(=C1)CCCO)NC2=CC(=C(C=C2)C(=O)C3=CC=CC=C3CN)Cl Chemical compound C1=CC=C(C(=C1)CCCO)NC2=CC(=C(C=C2)C(=O)C3=CC=CC=C3CN)Cl NOTWWPLAOFJABP-UHFFFAOYSA-N 0.000 claims description 2
- DCMPPAGNPZBIFB-UHFFFAOYSA-N C1=CC=C(C(=C1)CN)C(=O)C2=C(C=C(C=C2)NC3=C(C=C(C=C3)Br)CCO)Cl Chemical compound C1=CC=C(C(=C1)CN)C(=O)C2=C(C=C(C=C2)NC3=C(C=C(C=C3)Br)CCO)Cl DCMPPAGNPZBIFB-UHFFFAOYSA-N 0.000 claims description 2
- YRHFQYULVONZRY-UHFFFAOYSA-N C1=CC=C(C(=C1)CN)C(=O)C2=C(C=C(C=C2)NC3=CC=CC=C3C(F)F)Cl Chemical compound C1=CC=C(C(=C1)CN)C(=O)C2=C(C=C(C=C2)NC3=CC=CC=C3C(F)F)Cl YRHFQYULVONZRY-UHFFFAOYSA-N 0.000 claims description 2
- KJMDKRXPWIHUDH-UHFFFAOYSA-N CC(CC1=CC=CC=C1NC2=CC(=C(C=C2)C(=O)C3=CC=CC=C3CN)Cl)O Chemical compound CC(CC1=CC=CC=C1NC2=CC(=C(C=C2)C(=O)C3=CC=CC=C3CN)Cl)O KJMDKRXPWIHUDH-UHFFFAOYSA-N 0.000 claims description 2
- WFYPYTFZKRAGDA-UHFFFAOYSA-N CC1(OCC(O1)CNCCC2=CC=CC=C2NC3=CC(=C(C=C3)C(=O)C4=CC=CC=C4CN)Cl)C Chemical compound CC1(OCC(O1)CNCCC2=CC=CC=C2NC3=CC(=C(C=C3)C(=O)C4=CC=CC=C4CN)Cl)C WFYPYTFZKRAGDA-UHFFFAOYSA-N 0.000 claims description 2
- NAZUAFGJJFAERP-UHFFFAOYSA-N CN(C)CCNCCC1=CC=CC=C1NC2=CC(=C(C=C2)C(=O)C3=CC=CC=C3CN)Cl Chemical compound CN(C)CCNCCC1=CC=CC=C1NC2=CC(=C(C=C2)C(=O)C3=CC=CC=C3CN)Cl NAZUAFGJJFAERP-UHFFFAOYSA-N 0.000 claims description 2
- 201000005569 Gout Diseases 0.000 claims description 2
- 206010020751 Hypersensitivity Diseases 0.000 claims description 2
- 208000001132 Osteoporosis Diseases 0.000 claims description 2
- 206010039361 Sacroiliitis Diseases 0.000 claims description 2
- 206010040070 Septic Shock Diseases 0.000 claims description 2
- 206010046851 Uveitis Diseases 0.000 claims description 2
- BKVKMFPQMKELKO-LJQANCHMSA-N [(2R)-4-[2-[3-chloro-4-(2-methylbenzoyl)anilino]phenyl]-1-hydroxybutan-2-yl]carbamic acid Chemical compound CC1=CC=CC=C1C(=O)C(C(=C1)Cl)=CC=C1NC1=CC=CC=C1CC[C@H](CO)NC(O)=O BKVKMFPQMKELKO-LJQANCHMSA-N 0.000 claims description 2
- 206010000496 acne Diseases 0.000 claims description 2
- 208000026935 allergic disease Diseases 0.000 claims description 2
- 230000007815 allergy Effects 0.000 claims description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
- 208000035475 disorder Diseases 0.000 claims description 2
- 125000004494 ethyl ester group Chemical group 0.000 claims description 2
- YKJSLQBDZJUASL-UHFFFAOYSA-N ethyl octan-2-yl hydrogen phosphate Chemical compound CCCCCCC(C)OP(O)(=O)OCC YKJSLQBDZJUASL-UHFFFAOYSA-N 0.000 claims description 2
- JUOXYWXXPHUSAI-UHFFFAOYSA-N ethylamino acetate Chemical compound CCNOC(C)=O JUOXYWXXPHUSAI-UHFFFAOYSA-N 0.000 claims description 2
- 206010020718 hyperplasia Diseases 0.000 claims description 2
- 208000028774 intestinal disease Diseases 0.000 claims description 2
- ANSUDRATXSJBLY-VKHMYHEASA-N methyl (2s)-2-amino-3-hydroxypropanoate Chemical compound COC(=O)[C@@H](N)CO ANSUDRATXSJBLY-VKHMYHEASA-N 0.000 claims description 2
- ITXSLCZPKOJHKM-UHFFFAOYSA-N n'-[2-[3-chloro-4-(2-methylbenzoyl)anilino]phenyl]-n-(6-hydroxyhexyl)butanediamide Chemical compound CC1=CC=CC=C1C(=O)C(C(=C1)Cl)=CC=C1NC1=CC=CC=C1NC(=O)CCC(=O)NCCCCCCO ITXSLCZPKOJHKM-UHFFFAOYSA-N 0.000 claims description 2
- XGXYMJHEYXZLMP-UHFFFAOYSA-N n'-[5-bromo-2-[3-chloro-4-(2-methylbenzoyl)anilino]phenyl]-n-(6-hydroxyhexyl)butanediamide Chemical compound CC1=CC=CC=C1C(=O)C(C(=C1)Cl)=CC=C1NC1=CC=C(Br)C=C1NC(=O)CCC(=O)NCCCCCCO XGXYMJHEYXZLMP-UHFFFAOYSA-N 0.000 claims description 2
- PNBZPYJGHSNMLZ-UHFFFAOYSA-N n-[2-[3-chloro-4-(2-methylbenzoyl)anilino]phenyl]-2-(1,3-dioxoisoindol-2-yl)acetamide Chemical compound CC1=CC=CC=C1C(=O)C(C(=C1)Cl)=CC=C1NC1=CC=CC=C1NC(=O)CN1C(=O)C2=CC=CC=C2C1=O PNBZPYJGHSNMLZ-UHFFFAOYSA-N 0.000 claims description 2
- 230000036303 septic shock Effects 0.000 claims description 2
- UIUJIQZEACWQSV-UHFFFAOYSA-N succinic semialdehyde Chemical compound OC(=O)CCC=O UIUJIQZEACWQSV-UHFFFAOYSA-N 0.000 claims description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical compound NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims 1
- 208000034189 Sclerosis Diseases 0.000 claims 1
- 210000001367 artery Anatomy 0.000 claims 1
- 229940043274 prophylactic drug Drugs 0.000 claims 1
- 208000011580 syndromic disease Diseases 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 63
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 239000003921 oil Substances 0.000 description 174
- 235000019198 oils Nutrition 0.000 description 174
- 238000003818 flash chromatography Methods 0.000 description 136
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 115
- 239000000047 product Substances 0.000 description 113
- 239000002585 base Substances 0.000 description 109
- 239000012043 crude product Substances 0.000 description 101
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 98
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 92
- 239000000243 solution Substances 0.000 description 71
- 239000011541 reaction mixture Substances 0.000 description 65
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 64
- 239000012044 organic layer Substances 0.000 description 58
- 150000001336 alkenes Chemical group 0.000 description 56
- 125000000753 cycloalkyl group Chemical group 0.000 description 54
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 51
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 40
- 239000000284 extract Substances 0.000 description 40
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 38
- 238000005406 washing Methods 0.000 description 38
- 238000001035 drying Methods 0.000 description 35
- 239000010410 layer Substances 0.000 description 34
- 239000007864 aqueous solution Substances 0.000 description 32
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 29
- 229910000080 stannane Inorganic materials 0.000 description 29
- KXCAEQNNTZANTK-UHFFFAOYSA-N stannane Chemical compound [SnH4] KXCAEQNNTZANTK-UHFFFAOYSA-N 0.000 description 28
- 238000003756 stirring Methods 0.000 description 28
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 25
- 239000006188 syrup Substances 0.000 description 24
- 235000020357 syrup Nutrition 0.000 description 24
- 125000003545 alkoxy group Chemical group 0.000 description 23
- 238000006243 chemical reaction Methods 0.000 description 23
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 22
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
- 238000011097 chromatography purification Methods 0.000 description 21
- 125000004093 cyano group Chemical group *C#N 0.000 description 21
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 20
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 20
- 239000007787 solid Substances 0.000 description 20
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 20
- 229910052786 argon Inorganic materials 0.000 description 19
- 239000007788 liquid Substances 0.000 description 19
- 125000003638 stannyl group Chemical group [H][Sn]([H])([H])* 0.000 description 19
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 18
- JKIHKXLJGQNTSH-UHFFFAOYSA-N NCC(C=CC=C1)=C1C(C(C=CC(N)=C1)=C1Cl)=O Chemical compound NCC(C=CC=C1)=C1C(C(C=CC(N)=C1)=C1Cl)=O JKIHKXLJGQNTSH-UHFFFAOYSA-N 0.000 description 18
- 239000002994 raw material Substances 0.000 description 18
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 17
- 150000001412 amines Chemical class 0.000 description 17
- 235000019441 ethanol Nutrition 0.000 description 17
- 125000006280 2-bromobenzyl group Chemical group [H]C1=C([H])C(Br)=C(C([H])=C1[H])C([H])([H])* 0.000 description 16
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 16
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 16
- 239000003795 chemical substances by application Substances 0.000 description 16
- 238000005859 coupling reaction Methods 0.000 description 16
- 150000002431 hydrogen Chemical class 0.000 description 16
- 150000001335 aliphatic alkanes Chemical class 0.000 description 15
- 229910000104 sodium hydride Inorganic materials 0.000 description 15
- 239000000725 suspension Substances 0.000 description 14
- 238000012545 processing Methods 0.000 description 13
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 12
- 230000008569 process Effects 0.000 description 12
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 12
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 12
- 239000003814 drug Substances 0.000 description 11
- 239000006260 foam Substances 0.000 description 11
- 239000011734 sodium Substances 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- 238000007738 vacuum evaporation Methods 0.000 description 11
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 10
- 150000001263 acyl chlorides Chemical class 0.000 description 10
- 229910052799 carbon Inorganic materials 0.000 description 10
- 230000008878 coupling Effects 0.000 description 10
- 238000010168 coupling process Methods 0.000 description 10
- 229910052740 iodine Inorganic materials 0.000 description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 10
- 229920006395 saturated elastomer Polymers 0.000 description 10
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 9
- 125000004455 (C1-C3) alkylthio group Chemical group 0.000 description 9
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 125000000304 alkynyl group Chemical group 0.000 description 9
- 150000002430 hydrocarbons Chemical group 0.000 description 9
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 description 8
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 239000012230 colorless oil Substances 0.000 description 8
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 8
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 8
- 125000002950 monocyclic group Chemical group 0.000 description 8
- 230000035484 reaction time Effects 0.000 description 8
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 description 7
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- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 239000004753 textile Substances 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 229950006828 timegadine Drugs 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- BWHOZHOGCMHOBV-BQYQJAHWSA-N trans-benzylideneacetone Chemical compound CC(=O)\C=C\C1=CC=CC=C1 BWHOZHOGCMHOBV-BQYQJAHWSA-N 0.000 description 1
- IAQRGUVFOMOMEM-ONEGZZNKSA-N trans-but-2-ene Chemical compound C\C=C\C IAQRGUVFOMOMEM-ONEGZZNKSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
- RRBYUSWBLVXTQN-UHFFFAOYSA-N tricyclene Chemical group C12CC3CC2C1(C)C3(C)C RRBYUSWBLVXTQN-UHFFFAOYSA-N 0.000 description 1
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- BPLUKJNHPBNVQL-UHFFFAOYSA-N triphenylarsine Chemical compound C1=CC=CC=C1[As](C=1C=CC=CC=1)C1=CC=CC=C1 BPLUKJNHPBNVQL-UHFFFAOYSA-N 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 150000003732 xanthenes Chemical class 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
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- C07C225/16—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
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- C07C225/22—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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- C07C229/40—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/44—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by unsaturated carbon chains
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- C07C233/40—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
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Abstract
本发明涉及新一类的氨基苯酰苯、含有所述化合物的药物制剂、这些药物制备的剂量单位、包括给予患者所述化合物进行治疗的方法以及所述化合物在药物制剂生产中的用途。
Description
发明领域
本发明涉及被称为氨基苯酰苯衍生物的一类新化合物、含有所述化合物的药物制剂、这些制剂的剂量单位、通过给予所述化合物进行治疗的方法以及所述化合物在药物制剂生产中的用途。
发明背景
以前的资料中已经描述了一系列密切相关的氨基苯酰苯类化合物(如4-(2-氨基-4-硝基苯基氨基)苯酰苯)(Hussein,F.A.等,Iraqi J.Sci.,22,54-66(1981))。然而,对它们的用途没有描述。WO 98/32730、WO 01/05744、WO 01/05746、WO 01/05749、WO 01/05751、WO 01/05745和W001/42189公开了体外抑制白细胞介素1β(IL-1β)和人肿瘤坏死因子α(TNF-α)分泌的的氨基苯酰苯类抑制剂,所述化合物在治疗细胞因子参与发病机理的炎性疾病(如哮喘、风湿性关节炎、银屑病、接触性皮炎和异位性皮炎)中具有潜在作用。另外,在12-O-十四烷酰佛波醇-13-乙酸酯(TPA)诱导的鼠慢性皮肤炎性模型中(De Young,L.M.等,Agents Actions,
26,335-341(1989);Carlson,R.P.等,Agents Actions,
17,197-204(1985);Alford,J.G.等,Agents Action,
37,(1992);Stanley,P.L.等,Skin Pharmacol,
4,262-271(1991)),测定了上述专利申请中的化合物的体内抗炎性质。在这些慢性皮肤炎性模型中,所述化合物具有与参照化合物氢化可的松相似的效能。在Man-Made Text.India(1987),30(6),275-6,Man-Made Text.India(1986),29(5),224-30和Man-Made Text.India(1985),28(11),425,427-9,431中公开了用于印染纺织品的结构上相关的氨基苯酰苯类化合物的制备方法;在JP 81-61259中公开了在制备荧烷印染前体过程中作为反应物的结构上相关的氨基苯酰苯。
本发明的目的是提供具有优异的物理化学特性、特别是具有较高的生物利用度的药理活性的苯酰苯衍生物。
发明概述
申请人出人意料地发现,通式I的新的氨基苯酰苯衍生物是体外白细胞介素1β(IL-1β)和人肿瘤坏死因子α(TNF-α)分泌的有效抑制剂,这使它们在治疗炎性疾病中具有潜在的作用,在这些炎性疾病中,细胞因子、特别是白细胞介素1β(IL-1β)和人肿瘤坏死因子α(TNF-α)的分泌和调节与这些疾病的发病机理有关。细胞因子的抑制或下调可能是由于对MAP激酶的抑制所致。
因此,本发明涉及通式I的化合物和其药学上可接受的盐、溶剂化物(如它们的水合物):
其中:
X代表氧、硫或N-ORc;
R1代表选自下列的取代基:卤素、羟基、巯基、三氟甲基、氨基、(C1-C3)烷基、(C2-C3)烯烃基团、(C1-C3)烷氧基、(C1-C3)烷硫基、(C1-C6)烷氨基、(C1-C3)烷氧基羰基、氰基、-CONH2、苯基和硝基;
R2代表一个或多个相同或不同的选自下列的取代基:氢、卤素、羟基、巯基、三氟甲基、氨基、(C1-C3)烷基、(C2-C3)烯烃基团、(C1-C3)烷氧基、(C1-C3)烷硫基、(C1-C6)烷氨基、(C1-C3)烷氧基羰基、氰基、-CONH2、苯基和硝基;
R3代表一个或多个相同或不同的选自下列的取代基:氢、卤素、羟基、巯基、三氟甲基、氰基、羧基、氨基甲酰基、硝基、(C1-C10)烷基、(C2-C10)烯烃基团、(C3-C12)环状烃基团、(C1-C10)烷氧基、(C1-C10)烷硫基、(C1-C10)烷氧基羰基和苯基;
R4代表氢、(C1-C6)烷基、(C2-C6)烯烃基团、(C3-C6)环状烃基团或-C(O)O-C(Rd)(Re)(-O-C(O)-R14);其中R14基团任选被一个或多个相同或不同的R8代表的取代基取代;
R5代表一个或多个相同或不同的选自下列的取代基:氢和R1;
R6代表(C1-C10)烷基-杂环基、(C1-C10)烷基(C3-C12)环状烃基团、(C1-C10)烷基、(C2-C10)烯烃基团、(C3-C12)环状烃基团、杂环基、(C2-C10)炔基、Y1R21、Y2R22或Y4R24;其中(C1-C10)烷基、(C2-C10)烯烃基团和(C3-C12)环状烃基团被一个或多个相同或不同的R7代表的取代基取代,其中(C1-C10)烷基-杂环基、(C1-C10)烷基-(C3-C12)环状烃基团、杂环基和(C2-C10)炔基任选被一个或多个相同或不同的R7代表的取代基取代;
R7代表R12、Y-H或Y-R14;其中R12和Y-R14基团任选被一个或多个相同或不同的R8代表的取代基取代;
R8代表R12、Y-H、Y-R14或R14;其中R12、Y-R14和R14基团任选被一个或多个相同或不同的R9代表的取代基取代;
R9代表R12、Y-H、Y-R14或R14;其中R12、Y-R14和R14基团任选被一个或多个相同或不同的R10代表的取代基取代;
R10代表R12、Y-H、Y-R14或R14;其中R12、Y-R14和R14基团任选被一个或多个相同或不同的R11代表的取代基取代;
R11代表R12或R14;其中R12和R14基团任选被一个或多个相同或不同的R12代表的取代基取代;
R12代表卤素、羟基、巯基、三氟甲基、氨基、(C1-C3)烷氧基、(C1-C3)烷硫基、(C1-C6)烷氨基、(C1-C3)烷氧基羰基、与阴离子相连的(C1-C9)三烷基铵离子、(C2-C10)二烷基次膦酰基(phosphinoyl)、(C1-C5)烷基(羟基)次膦酰基、(C2-C10)二烷基次膦酰基氧基、(C1-C5)烷基(羟基)膦酰基氧基、二羟基次膦酰基、二羟基次膦酰基氧基、氰基、叠氮基、硝基、-CHO、-COOH、-CONH2、-CONHR′或-CONRR′,其中R和R′代表(C1-C3)烷基;
Y代表-O-、-S-、-S(O)-、-S(O)2-、-NRa-、-NRaC(Z)NRb-、NRaC(Z)-、-C(Z)NRa-、-C(O)-、-C(S)-、-C(Z)-O-、-C(O)Z-、-C(S)S--OC(Z)-、-NRaC(Z)O-、-OC(Z)NRa-、-S(O)2O-、-OS(O)2-、-S(O)2NRa-、-NRaS(O)2-、-OC(Z)O-、-OC(Z)Z-、-OP(O)(ORa)O-、-P(O)(ORa)O-、-C(NRa)-、-C(NORa)-、-N=C(Ra)-、-N=C(ORa)-、-N(ORa)-、-ON(Ra)-、-N(Ra)O-、-N(Ra)C(=NRb)NRc-、-C(=NRa)NRb-或-N(Ra)C(=NRb)-;
Z代表氧或硫;
R14代表(C1-C6)烷基、(C2-C6)烯烃基团、(C3-C12)环状烃基团、杂环基或(C2-C6)炔基;
Y1代表-NRaC(S)NRb-、-C(O)-、-C(S)-、-C(S)O-、-C(O)S-、-C(S)S-、-OC(S)-、-OC(O)-、-NRaC(S)O-、-OC(Z)NRa-、-S(O)2O-、-OS(O)2-、-S(O)2NRa-、-NRaS(O)2-、-OC(Z)O-、-OC(Z)Z-、-OP(O)(ORa)O-、-P(O)(ORa)O-、-C(NRa)-、-C(NORa)-、-N=C(Ra)-、-N=C(ORa)-、-N(ORa)-、-ON(Ra)-、-N(Ra)O-、-N(Ra)C(=NRb)NRc-、-C(=NRa)NRb-或-N(Ra)C(=NRb)-;
R21代表(C1-C10)烷基-杂环基、(C1-C10)烷基-(C3-C12)环状烃基团、(C1-C10)烷基、(C2-C10)烯烃基团、(C3-C12)环状烃基团、杂环基或(C2-C10)炔基;它们中的任何一个均任选被一个或多个相同或不同的R7代表的取代基取代;
Y2代表-O-、-S-、-C(O)O-或-C(O)NRa-;
R22代表(C1-C10)烷基-杂环基、(C1-C10)烷基-(C3-C12)环状烃基团、杂环基、(C2-C10)炔基、(C1-C10)烷基、(C2-C10)烯烃基团或(C3-C8)单环烃基团;其中(C1-C10)烷基被一个或多个相同或不同的R7代表的取代基取代,其中(C1-C10)烷基-杂环基、(C1-C10)烷基-(C3-C12)环状烃基团、杂环基、(C2-C10)炔基、(C2-C10)烯烃基团和(C3-C12)单环烃基团任选被一个或多个相同或不同的R7代表的取代基取代;
Y4代表-NRaC(O)NRbCH(Rc)-、-NRaC(O)NRbS(O)2-、-NRa-、-NRaC(Z)-、-NRaC(O)OCH(Rc)-、-NRaC(O)NRbC(Rd)(Re)-OC(O)-或-NRaC(O)OC(Rd)(Re)-OC(O)-;
R24代表(C1-C10)烷基-杂环基、(C1-C10)烷基-(C3-C12)环状烃基团、杂环基、(C2-C10)炔基、(C1-C10)烷基、(C2-C10)烯烃基团或(C3-C12)环状烃基团;其中(C1-C10)烷基、(C2-C10)烯烃基团和(C3-C12)环状烃基团被一个或多个相同或不同的R15代表的取代基取代,其中(C1-C10)烷基、(C2-C10)烯烃基团、(C3-C12)环状烃基团、(C1-C10)烷基-杂环基、(C1-C10)烷基-(C3-C12)环状烃基团、杂环基和(C2-C10)炔基任选被一个或多个相同或不同的R7代表的取代基取代;
R15代表R12a、R12b或R12c;其中R12a、R12b和R12c任选被一个或多个相同或不同的R7代表的取代基取代;
R12a代表(C1-C3)烷氧基、(C1-C3)烷硫基、(C1-C6)烷氨基、(C1-C3)烷氧基羰基、-CONHR′或-CONRR′,其中R和R′代表(C1-C3)烷基;它们中的任何一个均可以被一个或多个相同或不同的R42代表的取代基取代;前提是当R12a或R15(包括进一步被R42取代的基团)代表下式基团时:-(Q-O)n-Q或-CH2(Q-O)n-Q,其中Q为(C1-C3)烷基且n为大于1的整数,那么所述基团包括具有至少16个碳原子的连续的线性序列;
R12b代表(C4-C10)烷氧基、(C4-C10)烷硫基、(C7-C12)烷氨基、(C4-C10)烷氧基羰基、-CONHR′或-CONRR′,其中R和R′代表(C4-C10)烷基;它们中的任何一个任选被一个或多个相同或不同的R7代表的取代基取代;
R12c代表-Y5(C1-C10)烷基、-Y-芳基、-Y-杂环基、-Y-(C3-C12)环状烃基团和-Y-(C2-C10)烯烃基团;它们中的任何一个任选被一个或多个相同或不同的R7代表的取代基取代;
Y5代表-S(O)-、-S(O)2-、-NRaC(Z)-、-NRaC(Z)NRb-、-C(S)NRa-、-C(O)-、-C(S)-、-C(S)O-、-C(O)S-、-C(S)S--OC(Z)-、-NRaC(Z)O-、-OC(Z)NRa-、-S(O)2O-、-OS(O)2-、-S(O)2NRa-、-NRaS(O)2-、-OC(Z)O-、-OC(Z)Z-、-OP(O)(ORa)O-、-P(O)(ORa)O-、-C(NRa)-、-C(NORa)-、-N=C(Ra)-、-N=C(ORa)-、-N(ORa)-、-ON(Ra)-、-N(Ra)O-、-N(Ra)C(=NRb)NRc-、-C(=NRa)NRb-或-N(Ra)C(=NRb)-;
R42代表-Y-H、Y-R14、R52、卤素、三氟甲基、氰基、叠氮基或硝基;其中,R52和-Y-R14任选被一个或多个相同或不同的R8代表的取代基取代;
R52代表(C6-C10)烷基、(C2-C6)烯烃基团、(C3-C12)环状烃基团、杂环基、(C2-C6)炔基或杂芳基;
Ra、Rb和Rc分别独立代表氢、(C1-C6)烷基、(C2-C6)烯烃基团、(C3-C12)环状烃基团、芳基、杂环基或(C2-C6)炔基;它们中的任何一个任选被一个或多个相同或不同的R12代表的取代基取代;
Rd和Re分别独立代表氢、(C1-C6)烷基、(C2-C6)烯烃基团或(C3-C12)环状烃基团;它们中的任何一个任选被一个或多个相同或不同的R12代表的取代基取代。
在另一方面,本发明涉及包含式I化合物或它们药学上可接受的盐的药物制剂,该制剂任选还含有药学上可接受的赋形剂或载体。
在另一方面,本发明还涉及治疗宿主炎症的方法,该方法包括给予所述宿主有效量的式I化合物。
在另一方面,本发明还涉及式I化合物在制备治疗炎症的药物中的用途,任选与药学上可接受的赋形剂或载体一起。
发明详述
众所周知,在许多(即使不是大部分)药物开发过程中,在体外筛选阶段似乎非常具有前景的化合物在体内测试时却不具有治疗作用。对这个结果有几种解释,如药物代谢机制过快或血浆稳定性不足,但是,十分常见的原因却是生物利用度不高。药物的生物利用度是由几种因素决定的,这些因素广义上指其物理化学性质。生物利用度的关键的物理化学性质为如水溶度和log P,定义为log(在辛烷中的溶度/在水中的溶度)。如果药物具有在1-5之间的log P值,那么大部分药物具有较理想的生物利用度。因此,在药物开发中,如果能够成功地将分子中的一个或多个不具有生物活性的可以被取代的基团的物理化学性质进行适当的处理,那么则能够提高该药物的生物利用度。本发明者出乎意料地发现,可以对R6代表的取代基进行处理以控制所述化合物的物理化学性质,同时在很大程度上可以保持式I化合物的生物活性。
因此,本发明优选的化合物为那些其中R1代表选自下列的取代基的化合物:卤素、羟基、三氟甲基、氨基、(C1-C3)烷基、(C2-C3)烯烃基团、(C1-C3)烷氧基和氰基。
在另一个优选的实施方案中,R2代表一个或多个独立选自下列基团的取代基:氢、卤素、羟基、三氟甲基、(C1-C3)烷基、(C2-C3)烯烃基团和(C1-C3)烷氧基。
在另一个优选的实施方案中,R3代表一个或多个独立选自下列基团的取代基:氢、卤素、羟基、三氟甲基、氰基、硝基、(C1-C6)烷基、(C2-C6)烯烃基团、(C3-C6)单环烃基团、(C1-C6)烷氧基和(C1-C6)烷氧基羰基。
在另一个优选的实施方案中,R4代表氢、(C1-C6)烷基或(C2-C6)烯烃基团。
在另一个优选的实施方案中,R5代表一个或多个独立选自下列基团的取代基:氢和卤素、羟基、三氟甲基、氨基、(C1-C3)烷基、(C2-C3)烯烃基团、(C1-C3)烷氧基、(C1-C3)烷氧基羰基和氰基。
在另一个优选的实施方案,X代表O或N-ORc。
在另一个优选的实施方案,R6代表(C1-C6)烷基-杂环基、(C1-C6)烷基-(C3-C9)环状烃基团、(C1-C6)烷基、(C2-C6)烯烃基团、(C3-C6)环状烃基团、杂环基、(C2-C6)炔基、Y1R21、Y2R22或Y4R24;其中(C1-C6)烷基、(C2-C6)烯烃基团和(C3-C6)环状烃基团可以被一个或多个相同或不同的R7代表的取代基取代,其中(C1-C6)烷基-杂环基、(C2-C6)烷基-(C3-C9)环状烃基团、杂环基和(C2-C6)炔基任选被一个或多个相同或不同的R7代表的取代基取代;
R7代表R12、Y-H或Y-R14;其中R12和Y-R14基团任选被一个或多个相同或不同的R8代表的取代基取代;
R8代表R12、Y-H、Y-R14或R14;其中R12、Y-R14和R14基团任选被一个或多个相同或不同的R9代表的取代基取代;
R9代表R12、Y-H、Y-R14或R14;其中R12、Y-R14和R14基团任选被一个或多个相同或不同的R10代表的取代基取代;
R10代表R12或R14;其中R12、Y-R14和R14基团任选被一个或多个相同或不同的R12代表的取代基取代;
R12代表卤素、羟基、巯基、三氟甲基、氨基、(C1-C3)烷氧基、(C1-C3)烷硫基、(C1-C6)烷氨基、(C1-C3)烷氧基羰基、与阴离子相连的(C1-C6)三烷基铵离子、(C2-C6)二烷基次膦酰基、(C1-C3)烷基(羟基)次膦酰基、(C2-C6)二烷基次膦酰基氧基、(C1-C3)烷基(羟基)次膦酰基氧基、二羟基次膦酰基、二羟基次膦酰基氧基、氰基、叠氮基、硝基、-CHO、-COOH、-CONH2、-CONHR′或-CONRR′;其中R和R′代表(C1-C3)烷基;
Y代表-O-、-S-、-S(O)-、-S(O)2-、-NRa-、-NRaC(Z)NRb-、-NRaC(Z)-、-C(Z)NRa-、-C(O)-、-C(Z)O-、-OC(Z)-、-NRaC(Z)O-、-OC(Z)NRa-、-S(O)2O-、-OS(O)2-、-S(O)2NRa-、-NRaS(O)2-、-OC(Z)Z-、-OP(O)(ORa)O-、-P(O)(ORa)O-、-C(NORa)-、-N(ORa)-、-ON(Ra)-、-N(Ra)O-、-N(Ra)C(=NRb)NRc-、-C(=NRa)NRb-或-N(Ra)C(=NRb)-;
Z代表氧;
R14代表(C1-C6)烷基、(C2-C6)烯烃基团、(C3-C9)环状烃基团、杂环基或(C2-C6)炔基;
Y1代表-NRaC(S)NRb-、-C(O)-、-OC(O)-、-NRaC(S)O-、-OC(Z)NRa-、-S(O)2NRa-、-NRaS(O)2-、-OC(Z)O-、-C(NRa)-、-C(NORa)-、-N(ORa)-、-ON(Ra)-、-N(Ra)O-、-N(Ra)C(=NRb)NRc-、-C(=NRa)NRb-或-N(Ra)C(=NRb)-;
R21代表(C1-C6)烷基-杂环基、(C1-C6)烷基-(C3-C9)环状烃基团、(C1-C6)烷基、(C2-C6)烯烃基团、(C3-C9)环状烃基团、杂环基或(C2-C6)炔基;它们中的任何一个任选被一个或多个相同或不同的R7代表的取代基取代;
Y2代表-O-、-S-、-C(O)O-或-C(O)NRa-;
R22代表(C1-C6)烷基-杂环基、(C1-C6)烷基-(C3-C9)环状烃基团、杂环基、(C2-C6)炔基、(C1-C6)烷基、(C2-C6)烯烃基团或(C3-C9)单环烃基团;其中(C1-C6)烷基可以被一个或多个相同或不同的R7代表的取代基取代,其中(C1-C6)烷基-杂环基、(C1-C6)烷基-(C3-C9)环状烃基团、杂环基、(C2-C6)炔基、(C2-C6)烯烃基团和(C3-C9)单环烃基团任选被一个或多个相同或不同的R7代表的取代基取代;
Y4代表-NRaC(O)NRbCH(Rc)-、-NRaC(O)NRbS(O)2-、-NRa-、-NRaC(Z)-、-NRaC(O)OCH(Rc)-、-NRaC(O)NRbC(Rd)(Re)-OC(O)-或-NRaC(O)OC(Rd)(Re)-OC(O)-;
R24代表(C1-C6)烷基-杂环基、(C1-C6)烷基-(C3-C9)环状烃基团、杂环基、(C2-C6)炔基、(C1-C6)烷基、(C2-C6)烯烃基团或(C3-C9)环状烃基团;其中(C1-C6)烷基、(C2-C6)烯烃基团和(C3-C9)环状烃基团可以被一个或多个相同或不同的R15代表的取代基取代,且其中(C1-C6)烷基、(C2-C6)烯烃基团、(C3-C9)环状烃基团、(C1-C6)烷基-杂环基、(C1-C6)烷基-(C3-C9)环状烃基团、杂环基和(C2-C6)炔基任选被一个或多个相同或不同的R7代表的取代基取代;
R15代表R12a、R12b或R12c;其中R12a、R12b和R12c任选被一个或多个相同或不同的R7代表的取代基取代;
R12a代表(C1-C3)烷氧基、(C1-C3)烷硫基、(C1-C6)烷氨基、(C1-C3)烷氧基羰基、-CONHR′或-CONRR′,其中R和R′代表(C1-C3)烷基;它们中的任何一个可以被一个或多个相同或不同的R42代表的取代基取代;前提是当R12a或R15(进一步包括R42取代基)代表下式基团时:-(Q-O)n-Q或-CH2(Q-O)n-Q,其中Q为(C1-C3)烷基,且n为大于1的整数,那么所述基团包括具有至少16个碳原子的连续的线性序列;
R12b代表(C4-C6)烷氧基、(C4-C6)烷硫基、(C7-C12)烷氨基、(C4-C8)烷氧基羰基、-CONHR′或-CONRR′;其中R和R′代表(C4-C8)烷基;它们中的任何一个任选被一个或多个相同或不同的R7代表的取代基取代;
R12c代表-Y5(C1-C6)烷基、-Y-芳基、-Y-杂环基、-Y-(C3-C9)环状烃基团和-Y-(C2-C6)烯烃基团;它们中的任何一个任选被一个或多个相同或不同的代表的取代基取代R7;
Y5代表-S(O)-、-S(O)2-、-NRaC(Z)-、-NRaC(Z)NRb-、-C(O)-、-OC(Z)-、-NRaC(Z)O-、-OC(Z)NRa-、-S(O)2NRa-、-NRaS(O)2-、-OC(Z)O-、-OP(O)(ORa)O-、-P(O)(ORa)O-、-C(NRa)-、-C(NORa)-、-N(ORa)-、-ON(Ra)-、-N(Ra)O-、-N(Ra)C(=NRb)NRc-、-C(=NRa)NRb-或-N(Ra)C(=NRb)-;
R42代表-Y-H、-Y-R14、R52、卤素、三氟甲基、氰基、叠氮基或硝基;其中R52和-Y-R14任选被一个或多个相同或不同的R8代表的取代基取代;
R52代表(C6-C8)烷基、(C2-C4)烯烃基团、(C3-C6)环状烃基团、杂环基、(C2-C4)炔基或杂芳基;
Ra、Rb和Rc独立代表氢、(C1-C4)烷基、(C2-C4)烯烃基团、(C3-C9)环状烃基团、芳基、杂环基或(C2-C4)炔基;它们中的任何一个任选被一个或多个相同或不同的R12代表的取代基取代;
Rd和Re独立代表氢、(C1-C4)烷基、(C2-C4)烯烃基团和(C3-C9)环状烃基团;它们中的任何一个任选被一个或多个相同或不同的R12代表的取代基取代。
在另一个优选的实施方案中,R1代表选自下列基团的取代基:卤素、羟基、三氟甲基、氨基、(C1-C3)烷基、(C2-C3)烯烃基团、(C1-C3)烷氧基和氰基;
R2代表一个或多个独立选自下列基团的取代基:氢、卤素、羟基、三氟甲基、(C1-C3)烷基、(C2-C3)烯烃基团和(C1-C3)烷氧基;
R3代表一个或多个独立选自下列基团的取代基:氢、卤素、羟基、三氟甲基、氰基、硝基、(C1-C6)烷基、(C2-C6)烯烃基团、(C3-C6)单环烃基团、(C1-C6)烷氧基和(C1-C6)烷氧基羰基;
R4代表氢、(C1-C6)烷基或(C2-C6)烯烃基团;
且R5代表一个或多个独立选自下列基团的取代基:氢和卤素、羟基、三氟甲基、氨基、(C1-C3)烷基、(C2-C3)烯烃基团、(C1-C3)烷氧基、(C1-C3)烷氧基羰基和氰基。
在更加优选的实施方案中,R1代表选自下列基团的取代基:卤素、氰基、甲基和甲氧基。
在更加优选的实施方案中,R2代表一个或多个独立选自下列基团的取代基:氢、卤素、氰基、甲基和甲氧基。
在更加优选的实施方案中,R3代表一个或多个独立选自下列基团的取代基:氢、卤素、羟基、甲基、甲氧基和氰基。
在更加优选的实施方案中,R4代表氢、甲基或乙基。
在更加优选的实施方案中,R5代表一个或多个独立选自下列基团的取代基:氢、卤素、羟基、三氟甲基、甲基、乙基和甲氧基。
在更加优选的实施方案中,X代表O。
在更加优选的实施方案中,R6代表(C1-C4)烷基-杂环基、(C1-C4)烷基-(C3-C6)环状烃基团、(C1-C6)烷基、(C2-C4)烯烃基团、杂环基、(C2-C4)炔基、Y1R21、Y2R22或Y4R24;其中(C1-C6)烷基和(C2-C4)烯烃基团可以被一个或多个相同或不同的R7代表的取代基取代,且其中(C1-C4)烷基-杂环基、(C1-C4)烷基-(C3-C6)环状烃基团、杂环基和(C2-C4)炔基任选被一个或多个相同或不同的R7代表的取代基取代;
R7代表R12、Y-H或Y-R14;其中R12和Y-R14基团任选被一个或多个相同或不同的R8代表的取代基进一步取代;
R8代表R12、Y-H、Y-R14或R14;其中R12、Y-R14和R14基团任选被一个或多个相同或不同的R9代表的取代基进一步取代;
R9代表R12、Y-R14或R14;其中R12、Y-R14和R14基团任选被一个或多个相同或不同的R12代表的取代基取代;
R12代表卤素、羟基、三氟甲基、氨基、(C1-C3)烷氧基、(C1-C3)烷硫基、(C1-C6)烷氨基、(C1-C3)烷氧基羰基、与阴离子相连的(C1-C6)三烷基铵离子、(C2-C6)二烷基次膦酰基、(C2-C6)二烷基次膦酰基、二羟基次膦酰基、二羟基次膦酰基氧基、氰基、-COOH、-CONH2、-CONHR′或-CONRR′;其中R和R′代表(C1-C3)烷基;
Y代表-O-、-S-、-S(O)-、-S(O)2-、-NRa-、-NRaC(Z)NRb-、-NRaC(Z)-、-C(Z)NRa-、-C(O)-、-C(Z)O-、-OC(Z)-、-NRaC(Z)O-、-OC(Z)NRa-、-S(O)2O-、-OS(O)2-、-S(O)2NRa-、-NRaS(O)2-、-OC(Z)Z-、-N(Ra)C(=NRb)NRc-、-C(=NRa)NRb-或-N(Ra)C(=NRb)-;
Z代表氧;
R14代表(C1-C4)烷基、(C2-C4)烯烃基团、(C3-C6)环状烃基团、杂环基或(C2-C3)炔基;
Y1代表-NRaC(S)NRb-、-C(O)-、-OC(O)-、-NRaC(S)O-、-OC(Z)NRa-、-S(O)2NRa-、-NRaS(O)2-或-OC(Z)O-;
R21代表(C1-C4)烷基-杂环基、(C1-C4)烷基-(C3-C6)环状烃基团、(C1-C6)烷基、(C2-C4)烯烃基团、(C3-C6)环状烃基团、杂环基或(C2-C6)炔基;它们中的任何一个任选被一个或多个相同或不同的R7代表的取代基取代;
Y2代表-O-、-S-、-C(O)O-或C(O)NRa-;
R22代表(C1-C4)烷基-杂环基、(C1-C4)烷基-(C3-C6)环状烃基团、杂环基、(C2-C4)炔基、(C1-C6)烷基、(C2-C4)烯烃基团或(C3-C6)单环烃基团;其中(C1-C6)烷基可以被一个或多个相同或不同的R7代表的取代基取代,且其中(C1-C4)烷基-杂环基、(C1-C4)烷基-(C3-C6)环状烃基团、杂环基、(C2-C4)炔基、(C2-C4)烯烃基团和(C3-C6)单环烃基团任选被一个或多个相同或不同的R7代表的取代基取代;
Y4代表-NRaC(O)NRbCH(Rc)-、-NRaC(O)NRbS(O)2-、-NRa-、-NRaC(Z)-、-NRaC(O)OCH(Rc)-、-NRaC(O)NRbC(Rd)(Re)-OC(O)-或-NRaC(O)OC(Rd)(Re)-OC-OC(O)-;
R24代表(C1-C4)烷基-杂环基、(C1-C4)烷基-(C3-C6)环状烃基团、杂环基、(C2-C4)炔基、(C1-C6)烷基、(C2-C4)烯烃基团或(C3-C9)环状烃基团;其中(C1-C6)烷基、(C2-C4)烯烃基团和(C3-C9)环状烃基团可以被一个或多个相同或不同的R15代表的取代基取代,且其中(C1-C6)烷基、(C2-C4)烯烃基团、(C3-C9)环状烃基团、(C1-C4)烷基-杂环基、(C-C4)烷基-(C3-C6)环状烃基团、杂环基和(C2-C4)炔基任选被一个或多个相同或不同的R7代表的取代基取代;
R15代表R12a、R12b或R12c;其中R12a、R12b和R12c任选被一个或多个相同或不同的R7代表的取代基取代;
R12a代表(C1-C3)烷氧基、(C1-C3)烷硫基、(C1-C6)烷氨基、(C1-C3)烷氧基羰基、-CONHR′或-CONRR′,其中R和R′代表(C1-C3)烷基;它们中的任何一个可以被一个或多个相同或不同的R42代表的取代基取代;前提是当R12a或R15(进一步包括R42取代基)代表下式基团时:-(Q-O)n-Q或-CH2(Q-O)n-Q,其中Q为(C1-C3)烷基,且n为大于1的整数,那么所述基团包括具有至少16个碳原子的连续的线性序列;
R12b代表(C4-C6)烷氧基、(C4-C6)烷硫基、(C7-C12)烷氨基、(C4-C8)烷氧基羰基、-CONHR′或-CONRR′,其中R和R′代表(C4-C8)烷基;它们中的任何一个任选被一个或多个相同或不同的R7代表的取代基取代;
R12c代表-Y5(C1-C6)烷基、-Y-芳基、-Y-杂环基、-Y-(C3-C9)环状烃基团和-Y-(C2-C6)烯烃基团;它们中的任何一个任选被一个或多个相同或不同的R7代表的取代基取代;
Y5代表-S(O)-、-S(O)2-、-NRaC(Z)-、-NRaC(Z)NRb-、-C(O)-、-OC(Z)-、-NRaC(Z)O-、-OC(Z)NRa-、-S(O)2NRa-、-NRaS(O)2-或OC(Z)O-;
R42代表-Y-H、Y-R14、R52、卤素、三氟甲基、氰基、叠氮基或硝基;其中R52和-Y-R14任选被一个或多个相同或不同的R8代表的取代基取代;
R52代表(C6-C8)烷基、(C2-C4)烯烃基团、(C3-C6)环状烃基团、杂环基、(C2-C4)炔基或杂芳基;
Ra、Rb和Rc独立代表氢、(C1-C2)烷基、(C2-C3)烯烃基团或(C2-C3)炔基;它们中的任何一个任选被一个或多个相同或不同的R12代表的取代基取代;
Rd和Re独立代表氢或(C1-C2)烷基。
在更加优选的实施方案中,R1代表选自下列基团的取代基:卤素、氰基、甲基和甲氧基;
R2代表一个或多个独立选自下列基团的取代基:氢、卤素、氰基、甲基和甲氧基;
R3代表一个或多个独立选自下列基团的取代基:氢、卤素、羟基、甲基、甲氧基和氰基;
R4代表氢、甲基或乙基;
R5代表一个或多个独立选自下列基团的取代基:氢、卤素、羟基、三氟甲基、甲基、乙基和甲氧基;
且X代表O。
在一个特别优选的实施方案中,X代表O;R1代表甲基;R2代表2-Cl;R3代表氢或4-Br,且R4和R5代表氢。
药物的生物利用度通常与所述药物的分子量成反比。也就是说,这意味着任何生物学活性结构都具有一个分子量上限,超过该上限,该药物将不再具有活性,这是由多种因素导致的,例如溶解性不足、不能通过细胞膜、药物与受体相互作用的空间位阻等。因此,在更加优选的实施方案中,本发明涉及分子量在1500Da以下或约1500Da的式I化合物,优选分子量在1200Da以下或约1200Da,且更优选在800Da以下或约800Da。
在更加优选的实施方案中,式I化合物选自下列化合物及它们药学上可接受的盐和溶剂合物(例如水合物):
[2-氯代-4-({2-[2-(四氢-2H-吡喃-2-基氧基)乙基]苯基}氨基)苯基](2-甲基苯基)甲酮;
(2-氯代-4-{[2-(2-(羟基乙基)苯基)氨基]苯基}(2-甲基苯基)甲酮;
2-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)乙基乙酸酯;
4-(2-{2-[(3-氯代-4-(2-甲基苯甲酰基)苯基)氨基]苯基}乙氧基)-4-氧代丁酸;
2-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)乙基己酸酯;
2-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-1-甲基乙基乙酸酯;
(2-氯代-4-{[2-(2-羟基丙基)苯基]氨基}苯基)(2-甲基苯基)甲酮;
[2-氯代-4-({2-[(1E)-3-羟基丙-1-烯基]苯基}氨基)苯基](2-甲基苯基)甲酮;
(2-氯代-4-{[2-(3-羟基丙基)苯基]氨基}苯基)(2-甲基苯基)甲酮;
[2-氯代-4-({2-[(1E)-4-羟基丁-1-烯基]苯基}氨基)苯基](2-甲基苯基)甲酮;
[4-({2-[(1E)-3-氨基丙-1-烯基]苯基}氨基)-2-氯代苯基](2-甲基苯基)甲酮;
(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基膦酸二乙酯;
[2-氯代-4-({2-[(1E)-3-羟基-3-甲基丁-1-烯基]苯基}氨基)苯基](2-甲基苯基)甲酮;
(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙烯酸乙酯;
(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙烯酸;
{2-氯代-4-[(2-{(1E)-3-[(2,2-二甲基-1,3-二氧戊环-4-基)甲氧基]丙-1-烯基}苯基)氨基]苯基}(2-甲基苯基)甲酮;
[2-氯代-4-({2-[(1E)-3-(2,3-二羟基丙氧基)丙-1-烯基]苯基}氨基)苯基](2-甲基苯基)甲酮;
(1R)-3-{[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]氨基}-1-(羟基甲基)-2-氧代乙基氨基甲酸叔-丁酯;
O-(叔-丁基)-N-({[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]氨基}羰基)-L-丝氨酸甲酯;
N-(叔-丁基)-N′-[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]硫脲;
N-[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]-4-氧代戊酰胺;
N-[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]-N′-乙基脲;
4-{[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]氨基}-4-氧代丁酸乙酯;
N-[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]-N′-环己脲;
N′-[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]-N,N-二甲基琥珀酰胺;
[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]丙二酸二甲酯;
[2-氯代-4-({2-[(1E)-3-吗啉-4-基丙-1-烯基]苯基}氨基)苯基](2-甲基苯基)甲酮;
6-O-[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]-1,2:3,4-二-O-(1-甲基亚乙基)-α-D-吡喃半乳糖;
甲基5-O-[(2)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]-2,3-O-(1-甲基亚乙基)-β-D-呋喃核苷;
甲基5-O-[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]-β-D-呋喃核苷;
(4E)-5-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-2-(甲基磺酰基)戊-4-烯酸甲酯;
{[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]硫代}乙酸乙酯;
[2-氯代-4-{[2-((1E)-3-{双[2-(乙酰氧基)乙基]氨基}丙-1-烯基)苯基]氨基}苯基](2-甲基苯基)甲酮;
[2-氯代-4-{[2-((1E)-3-{双[2-(羟基)乙基]氨基}丙-1-烯基)苯基]氨基}苯基](2-甲基苯基)甲酮;
(2-氯代-4-{[2-((1E)-3-{4-[2-(乙酰氧基)乙基]哌啶-1-基}丙-1-烯基)苯基]氨基}苯基)(2-甲基苯基)甲酮;
{2-氯代-4-[(2-{(1E)-3-[4-(2-羟基乙基)哌啶-1-基]丙-1-烯基}苯基)氨基]苯基}(2-甲基苯基)甲酮;
{2-氯代-4-[(2-{2-[(四氢呋喃-2-基甲基)氨基]乙基}苯基)氨基]苯基}(2-甲基苯基)甲酮;
[2-氯代-4-({2-[2-(4-甲基哌嗪-1-基)乙基]苯基}氨基)苯基](2-甲基苯基)甲酮;
{2-氯代-4-[(2-{2-[(3-吗啉-4-基丙基)氨基]乙基}苯基)氨基]苯基}(2-甲基苯基)甲酮;
(2-氯代-4-{[2-(2-{[2-(二甲基氨基)乙基]氨基}乙基)苯基]氨基}苯基)(2-甲基苯基)甲酮;
{2-氯代-4-[(2-{2-[(2-甲氧基乙基)氨基]乙基}苯基)氨基]苯基}(2-甲基苯基)甲酮;
1-[3-({2-[2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苯基]乙基}氨基)丙基]吡咯烷-2-酮;
{2-氯代-4-[(2-{2-[甲基(四氢呋喃-2-基甲基)氨基]乙基}苯基)氨基]苯基}(2-甲基苯基)甲酮;
(2-氯代-4-{[2-(2-{[(2,2-二甲基-1,3-二氧戊环-4-基)甲基]氨基}乙基)苯基]氨基}苯基)(2-甲基苯基)甲酮;
{2-氯代-4-[(2-{2-[4-(2-甲氧基乙基)哌嗪-1-基]乙基}苯基)氨基]苯基}(2-甲基苯基)甲酮;
(2-氯代-4-{[2-(2-吗啉-4-基乙基)苯基]氨基}苯基)(2-甲基苯基)甲酮;
{2-氯代-4-[(2-{2-[(2,3-二羟基丙基)氨基]乙基}苯基)氨基]苯基}(2-甲基苯基)甲酮;
(4-{[2-(氨基甲基)苯基]氨基}-2-氯苯基)(2-甲基苯基)甲酮;
(2-氯代-4-{[2-({2-[2-(四氢-2H-吡喃-2-基氧基)乙氧基]乙氧基}甲基)苯基]氨基}苯基)(2-甲基苯基)甲酮;
{2-氯代-4-[(2-{[(四氢-2H-吡喃-2-基氧基)乙氧基]甲基}苯基)氨基]苯基}(2-甲基苯基)甲酮;
[2-氯代-4-({2-[(2-{2-[2-(四氢-2H-吡喃-2-基氧基)乙氧基]乙氧基}乙氧基)甲基]苯基}氨基)苯基](2-甲基苯基)甲酮;
[2-氯代-4-({2-[(3,3,3-三氟丙氧基)甲基]苯基}氨基)苯基](2-甲基苯基)甲酮;
2-({3-氯代-4-[(2-甲基苯基)羰基]苯基)氨基)苄基膦酸二乙酯;
2-[2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]-1H-异吲哚-1,3(2H)-二酮;
{2-氯代-4-[(2-{[2-(2-羟基乙氧基)乙氧基]甲基}苯基)氨基]苯基}(2-甲基苯基)甲酮;
[2-氯代-4-({2-[(羟基乙氧基)甲基]苯基}氨基)苯基](2-甲基苯基)甲酮;
(2-氯代-4-{[2-({2-[2-(2-羟基乙氧基)乙氧基]乙氧基}甲基)苯基]氨基}苯基)(2-甲基苯基)甲酮;
[4-({4-溴代-2-[(2-羟基乙氧基)甲基]苯基}氨基)-2-氯苯基](2-甲基苯基)甲酮;
(4-{[4-溴代-2-({2-[2-(2-羟基乙氧基)乙氧基]乙氧基}甲基)苯基]氨基}-2-氯苯基)(2-甲基苯基)甲酮;
{4-[(4-溴代-2-{[2-(2-羟基乙氧基)乙氧基]甲基}苯基)氨基]-2-氯苯基}(2-甲基苯基)甲酮;
5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基膦酸二乙酯;
[4-({4-溴代-2-[(3,3,3-三氟丙氧基)甲基]苯基}氨基)-2-氯苯基](2-甲基苯基)甲酮;
2-{[2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙基4-甲基苯磺酸酯;
2-{[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙基4-甲基苯磺酸酯;
2-(2-{[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙氧基)乙基4-甲基苯磺酸酯;
2-[2-(2-{[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙氧基)乙氧基]乙基4-甲基苯磺酸酯;
[4-({4-溴代-2-[(2-碘代乙氧基)甲基]苯基}氨基)-2-氯苯基](2-甲基苯基)甲酮;
{4-[(4-溴代-2-{[2-(2-碘代乙氧基)乙氧基]甲基}苯基)氨基]-2-氯苯基}(2-甲基苯基)甲酮;
(4-{[4-溴代-2-({2-[2-(2-碘代乙氧基)乙氧基]乙氧基}甲基)苯基]氨基}-2-氯苯基)(2-甲基苯基)甲酮;
[2-氯代-4-({2-[(2-碘代乙氧基)甲基]苯基}氨基)苯基](2-甲基苯基)甲酮;
2-{[2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙基膦酸二乙酯;
2-{[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙基膦酸二乙酯;
2-({[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙氧基)乙基膦酸二乙酯;
2-[2-(2-{[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙氧基)乙氧基]乙基膦酸二乙酯;
2-{[2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氨基}-2-氧代乙基膦酸二乙酯;
2-{[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苯基]氨基}-2-氧代乙基膦酸二乙酯;
{[2-({5-溴代-3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙基(二乙氧基磷酰基)乙酸酯;
2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基膦酸;
N-[2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]-2,2,2-三氟乙烷磺酰胺;
N-[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苯基]-2,2,2-三氟乙烷磺酰胺;
{2-氯代-4-[(2-{[(四氢-2H-吡喃-2-基氧基)丙氧基]甲基}苯基)氨基]苯基}(2-甲基苯基)甲酮;
[2-氯代-4-({2-[(羟基丙氧基)甲基]苯基}氨基)苯基](2-甲基苯基)甲酮;
3-{[2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}丙基膦酸二乙酯;
2-[2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苯基]乙基膦酸二乙酯;
2-[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苯基]乙基膦酸二乙酯;
2-{[2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氨基}-2-氧代乙基膦酸;
(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-氨基甲酸苯乙基酯;
N-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-2-苯氧基-乙酰胺;
N-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}-苯基)-3-苯氧基-丙酰胺;
N-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-2-(1,3-二氧代-1,3-二氢-异吲哚-2-基)-乙酰胺;
N-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}-苯基)-琥珀酸2-(2-甲氧基-乙氧基)乙酯;
N-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-苯磺酰胺;
乙酸(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基氨基甲酰基)-甲酯;
1-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)吡咯烷-2,5-二酮;
2-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)乙基丙酸酯;
2,2-二甲基-丙酸2-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)乙酯;
[2-氯代-4-({2-[3-(四氢-2H-吡喃-2-基氧基)丙氧基]苯基}氨基)苯基](2-甲基苯基)甲酮;
(2-氯代-4-{[2-(3-羟基丙氧基)苯基]氨基}苯基)(2-甲基苯基)甲酮;
2-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)乙基碳酸叔-丁酯;
2-({[(5-溴代-2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)氨基]羰基}氨基)乙基2-甲基丙烯酸酯;
(4-{[4-溴代-2-(2-羟基乙基)苯基]氨基}-2-氯代-苯基)(2-甲基苯基)甲酮;
3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯氧基)丙基乙酸酯;
[2-氯代-4-({2-[3-(吗啉-4-基)丙氧基]苯基}氨基)苯基](2-甲基苯基)甲酮;
N-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-N′-(4-苯氧基丁基)琥珀酰胺;
N-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-N′-(6-羟基己基)琥珀酰胺;
N-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-N′-(2,3-二羟基丙基)琥珀酰胺;
(1R)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-1-(羟基甲基)丙基氨基甲酸叔-丁酯;
6-[3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基氨基甲酰基)丙酰基氨基]-己基磷酸二乙酯;
N-({[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)(丙-2-烯基)氨基]羰基}氨基乙酸乙酯;
2-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)乙基(甲基)氨基甲酸叔-丁酯;
N-(5-溴代-2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-N′-(6-羟基己基)琥珀酰胺;
N-(5-溴代-2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-N′-(2,3-二羟基丙基)琥珀酰胺;
(2Z)-N-[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]-2-(2,5-二氧代咪唑烷-4-叉)乙酰胺;
(2-氯代-4-{[2-(二氟甲基)苯基]氨基}苯基)(2-甲基苯基)甲酮;
3-{[2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苯基]乙基}-1-甲基咪唑烷-2,4-二酮;
3-{[2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苯基]乙基}-5,5-二甲基唑啉-2,4-二酮;
4-{[2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苯基]乙基}吗啉-3,5-二酮;
1-{[2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苯基]乙基}哌啶-2,6-二酮;
4-(2-{[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙基)吗啉-3,5-二酮;
1-(2-{[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙基)吡咯烷-2,5-二酮;
2-[3-(2-{5-溴代-[2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄氧基]乙基}-2,4,5-三氧代咪唑烷-1-基)乙酸乙酯;
3-(2-{[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙基)咪唑烷-2,4-二酮;
1-(2-{[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙基)-3,4-顺式-二乙酸基吡咯烷-2,5-二酮;
3-(2-{[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙基)噻唑啉-2,4-二酮;
3-(2-{[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙基)-1-甲基咪唑烷-2,4-二酮;
1-(2-{[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙基)咪唑烷-2,4,5-三酮;
(2-氯代-4-{[(2-羟基甲基)苯基]氨基}苯基)(2-甲基苯基)甲酮;
2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苄基乙酸酯。
式I化合物可能含有双键、环系和不对称碳原子,因此,可能存在异构体。可以理解,本发明也涉及通式I代表的所有的异构形式,包括纯形式和它们的混合物。
术语“药学上可接受的盐”意指将式I化合物与适当的无机或有机酸反应制备的盐,所述酸包括如氢氯酸、氢溴酸、硫酸、硝酸、乙酸、磷酸、乳酸、马来酸、苯二甲酸、柠檬酸、丙酸、苯甲酸、戊二酸、葡糖酸、甲磺酸、水杨酸、琥珀酸、酒石酸、甲苯磺酸、氨基磺酸或富马酸。式I化合物的药学上可接受的盐也可以通过使其与适当的碱例如氢氧化钠、氢氧化钾、氨等反应制备。
术语“溶剂”意指化合物(如式I化合物)和溶剂(如乙醇、丙三醇和水)的相互反应形成的物质,所述物质为固体形式。当溶剂为水时,所述物质是指水合物。
术语“碳原子的连续的线性序列”意指一个碳原子列,而不包括任何氢原子。因此,二乙基醚和二-1-丙基酮为分别具有5或7个原子的连续的线性序列。
术语“卤素”意指周期表中的第7主族的成员,即氟、氯、溴和碘。
术语“烷基”意指通过移除任何碳原子上的氢原子衍生的直链或支链一价烷基团,它包括伯、仲和叔烷基基团,包括例如(C1-C3)烷基、(C1-C10)烷基、甲基、乙基、n-丙基、异丙基、n-丁基、异丁基、仲-丁基、叔-丁基、戊基、己基、庚基、癸基等。
术语“烯烃基团”意指一个具有一个或多个碳-碳双键(可以为E或Z立体化学)的直链或支链无环烃。该术语包括,例如(C2-C10)烯烃基团、(C2-C3)烯烃基团、乙烯基、烯丙基、1-丁烯基、2-丁烯基和2-甲基-2-丙烯基、2,4-戊二烯基等。
术语“烷氧基”意指式-OR的基团,其中R为上文所定义的烷基,例如(C1-C10)烷氧基、(C1-C3)烷氧基、甲氧基、乙氧基、n-丙氧基、叔-丁氧基等。
术语“烷硫基”意指式-SR的基团,其中R为上文所定义的烷基,例如(C1-C10)烷硫基、(C1-C3)烷硫基、甲硫基、乙硫基、n-丙硫基、2-丙硫基等。
术语“烷氨基”意指式-NHR或-NR2的基团,其中R为上文所定义烷基,包括例如甲基氨基、二甲基氨基、二-(n-丙基)氨基、n-丁基(乙基)氨基等。
术语“烷氧基羰基”意指式-COOR的基团,其中R为上文所定义烷基,包括甲氧基羰基、乙氧基羰基、n-丙氧基羰基、i-丙氧基羰基等。
术语“环状烃基团”包括饱和的和不饱和的任选稠合的双环烃基团,例如(C3-C12)环烷基、环丙基、环戊基、环己基和环辛基、(C3-C12)环烯基团(例如环丙-2-烯基、环丁-2-烯基、环戊-2-烯基、环己-3-烯基、环辛-4-烯基、环己-3,5-二烯基、茚满基、茚基、1,4-二氢萘基、苯基和萘基。术语“环状烃基团”也包括上文定义的化合物,其中一个或多个环-CH2-部分可被-C(O)-部分和/或环外碳-碳双键替代,例如氧代环己基、氧代环戊基、4-氧代-1,2,3,4-四氢萘-1-基、1-氧代-1,2,3,4-四氢萘-1-基、2-氧代环己-3-烯-1-基和2-氧代环己-1-烯-1-基以及下式的基团:
术语“炔基”意指通过移除任何碳原子上的氢原子衍生的一个直链或支链炔的一价基团,它分别包括伯、仲和叔烷基基团,并且具有指定的碳原子的数量,包括例如(C1-C10)炔基、乙炔基、丙炔基、1,1-二甲基-3-丁炔基等。
术语“杂环基”意指饱和的或不饱和的任选稠合的碳环基团,该基团包括一个或多个选自O、N和S的杂原子,例如吡咯基、呋喃噻吩基、咪唑基、唑基、噻唑基、吡唑基、吡咯烷基、吡啶基、嘧啶基、四氢噻吩基、四氢呋喃基、四氢吡喃基、哌啶基、嘌呤基(putinyl)、喹啉基、异喹啉基、1,2-二氢喹啉基等。术语“杂环基”也包括上文所定义的化合物,其中一个或多个环-CH2-部分可以被一个-C(O)-部分和/或环外碳-碳双键所取代,例如二氧代哌啶基、1-氧代-3,4-二氢异喹啉-2(1H)-基和下式的基团:
本发明化合物在人类或兽类上均有效,且可以经过全身给药或局部给药用于预防、治疗和/或改善疾病的严重性、疾病症状和/或与抗炎或细胞因子调节***的功能紊乱相关的疾病的周期性复发。这些疾病或紊乱包括痤疮、哮喘、过敏、关节炎(包括风湿性关节炎和脊椎关节炎)、痛风、动脉硬化、慢性炎性肠疾病(克罗恩氏病)、增生性和炎性皮肤疾病(例如银屑病、异位性皮炎、葡萄膜炎、脓毒性休克、AIDS和骨质疏松症。
另一方面,本发明涉及式I化合物的药物制剂。可用作兽类和人类的本发明的制剂包括活性成分,任选还包括药学上可接受的载体和其他任选的治疗成分。从与制剂中的其他成分相容的意义上讲,该载体必须是“可接受”的,并且对它们的受体无害。
所述活性成分最好占0.1-100%的制剂的重量。制剂的剂量单位中最好包括0.07mg-1g的式I化合物。
术语“剂量单位”意指一个剂量单位,即可以给予患者的单一剂量,并且便于操作和包装,同时保持其物理和化学稳定,该剂量单位仅包含活性物质本身或者包括它们与固体或液体的药用稀释剂或载体的混合物。
该制剂包括下列适合的形式,例如口服(包括缓释或定时释放形式)、直肠、胃肠外(包括皮下、腹膜内、肌肉内、关节内和静脉内)、经皮、眼、局部、鼻或口腔给药。
该制剂最好以剂量单位的形式提供,并且可以通过制药领域已知的任何方法制备,如公开于Remington,The Science and Practice of Pharmacy,第20版,2000中的方法。所有方法均包括使活性成分与载体混合的步骤,所述载体包括一个或多个辅助成分。通常,该制剂可以通过均匀密切地使活性成分与液体载体或细分的固体载体或两者混和在一起来制备,然后,如果需要,将产物制成所需制剂。
适于口服给药的本发明制剂可以以独立的单位形式存在,如胶囊、小袋、片剂或锭剂,每一种单位中均包含预定量的活性成分;也可以以散剂或颗粒剂的形式存在;以在水性液体或非水液体中的溶液或悬浮液形式存在,如乙醇或丙三醇;或以水包油型的乳剂或水包油型的乳剂形式存在。这样的油可以为食用油,例如棉籽油、芝麻油、椰子油或花生油。适当的水悬浮液的分散剂或悬浮剂包括人造的或天然的胶质,如黄芪胶、藻酸盐、***树胶、葡聚糖、羧甲基纤维素钠、明胶、甲基纤维素、羟丙基甲基纤维素、羟丙基纤维素、卡波姆和聚乙烯吡咯烷酮。活性成分也可以以大药丸、药糖剂或糊剂的形式给药。
片剂可以通过压制或模塑活性成分(任选与一种或多种添加成分一起)制备。压制片剂可以通过在适当的机器中压制来制备,其中活性成分以自由流动的形式(如粉末或颗粒)存在,任选与粘合剂(例如乳糖、葡萄糖、淀粉、明胶、***树胶、黄蓍胶、藻酸钠、羧甲基纤维素、甲基纤维素、羟丙基甲基纤维素、聚乙二醇、石蜡等)、润滑剂(例如油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氯化钠等)、崩解剂(例如淀粉、甲基纤维素、琼脂、膨润土、交联羧甲基纤维素钠、羟乙酸淀粉钠、交联聚维酮等)或分散剂(例如聚山梨醇酯80)等混合。模制片剂可以通过在适当的机器中模压活性成分粉末和用惰性液体稀释剂润湿的适当的载体的混合物来制备。
直肠给药的制剂可以为栓剂形式,其中本发明的化合物与低熔点的水溶性或不溶性固体混合,例如可可油、氢化植物油、聚乙二醇或聚乙二醇的脂肪酸酯,而酏剂则可以采用棕榈酸十四烷酯制备。
适于胃肠外给药的制剂最好为包含活性成分的无菌油或水溶液制剂,优选与受体的血液等渗,如等渗盐水、等渗葡萄糖溶液或缓冲溶液。该制剂可以便利地例如通过细菌截留过滤器过滤、向制剂中加入灭菌剂、照射制剂或加热制剂来消毒。公开于例如Encyclopedia of PharmaceuticalTechnology,第9卷,1994中的脂质体制剂也适于胃肠外给药。
另外,式I化合物也可以以无菌固体制剂的形式提供,例如冻干粉剂,该粉剂可在使用前即刻容易地溶于无菌溶剂。
透皮制剂也可以以膏剂或贴剂的形式存在。
适于眼部给药的制剂可以以活性成分的无菌水溶液制剂的形式存在,可以为微晶形式,例如,以微晶的悬浮液的形式存在。如公开于Encyclopedia of Pharmaceutical Tehcnology,第2卷,1989中的脂质体制剂或生物可降解的聚合物***也可以用于传递眼部给药的活性成分。
适于局部或眼部给药的制剂包括液体或半液体制剂(例如搽剂、洗剂、凝胶剂、涂敷剂)、水包油或油包水型乳剂(例如霜剂、软膏或糊剂)或溶液或悬浮液(如滴剂)。
适于鼻或口给药的制剂包括散剂、自驱动(self-propelling)和喷雾剂,例如气雾剂和喷雾剂。
本发明的前药也可以采用单克隆抗体作为单独的载体来传递,其中化合物分子与载体偶联。
除了上述成分,式I化合物的制剂中也包括一种或多种添加成分,例如稀释剂、缓冲剂、矫味剂、着色剂、表面活性剂、增稠剂、防腐剂如羟基苯甲酸甲酯(包括抗-氧化剂)、乳化剂等。
在使用本发明的化合物进行全身治疗时,日剂量为0.001-500mg每公斤体重,优选0.002-100mg/kg哺乳动物体重,例如给予式I化合物0.003-20mg/kg,成人的典型的日剂量为0.01-37000mg。在皮肤紊乱的局部治疗中,给予含有0.1-750mg/g的式I化合物的软膏、霜剂或洗剂,优选含有0.1-500mg/g,例如0.1-200mg/g的式I化合物。在将眼药膏用于局部使用中,给予含有0.1-750mg/g的式I化合物的滴剂或凝胶剂,优选含有0.1-500mg/g,例如0.1-200mg/g的式I化合物。口服组合物优选以片剂、胶囊或滴剂的形式制备,每剂量单位含有0.07-1000mg,优选0.1-500mg的式I化合物。
本发明也包括与其他通常用于治疗上述疾病的药物活性成分联合用于本发明的制剂。这样的其他药物活性成分可以为(但不限于)糖皮质激素、维生素D类似物、抗组胺化合物、血小板活化因子(PAF)拮抗剂、抗胆碱药(anticolergenic agents)、甲基黄嘌呤、β-肾上腺素能药物、COX-2抑制剂、水杨酸酯、消炎痛、氟芬那酯、萘普生、替美加定、氯金酸钠、青霉胺、血清胆固醇还原剂、类维生素A、锌盐和柳氮磺吡啶(salicylazosulfapyridin)。
本发明人还发现了一组适于式I化合物制备的特定的化合物。因此,本发明也提供了选自下列的化合物:
2-(2-溴苯基)-1-甲基乙基乙酸酯(化合物402);
(3E)-2-甲基-4-(三丁基甲锡烷基)丁-3-烯-2-醇(化合物403);
三丁基{(1E)-3-[(2,2-二甲基-1,3-二氧戊环-4-基)甲氧基]丙-1-烯基}锡烷(化合物404);
[(2E)-3-(三丁基甲锡烷基)丙-1-烯基]丙二酸二甲酯(化合物405);
4-[(2E)-3-(三丁基甲锡烷基)丙-2-烯基]吗啉(化合物406);
1,2:3,4-二-O-(1-甲基亚乙基)-6-O-[(2E)-3-(三丁基甲锡烷基)丙-2-烯基]-α-D-吡喃半乳糖(化合物407);
甲基2,3-O-(1-甲基亚乙基)-5-O-[(2E)-3-(三丁基甲锡烷基)丙-2-烯基]-β-D-呋喃核苷(化合物408);
(4E)-2-(甲基磺酰基)-5-(三丁基甲锡烷基)戊-4-烯酸甲酯(化合物409);
{[(2E)-3-(三丁基甲锡烷基)丙-2-烯基]硫代}乙酸乙酯(化合物410);
三丁基{(1E)-3-[双(2-羟基乙基)氨基]丙-1-烯基}锡烷(化合物411);
三丁基((1E)-3-{双[2-(乙酰氧基)乙基]氨基}丙-1-烯基)锡烷(化合物412);
三丁基{(1E)-3-[4-(2-羟基乙基)哌啶-1-基]丙-1-烯基}锡烷(化合物413);
三丁基((1E)-3-{4-[2-(乙酰氧基)乙基]哌啶-1-基}丙-1-烯基)锡烷(化合物414);
2-(2-{(2-溴苄基)氧基}乙氧基)乙醇(化合物415);
2-(2-{2-[(2-溴苄基)氧基]乙氧基}乙氧基)乙醇(化合物416);
2-溴苄基3,3,3-三氟丙基醚(化合物419);
2-(2-{2-[(2-溴苯苄)氧基]乙氧基}乙氧基)四氢-2H-吡喃(化合物420);
2-[2-(2-{2-[(2-溴苄基)氧基]乙氧基}乙氧基)乙氧基]四氢-2H-吡喃(化合物421);
2-{2-[(2-溴苄基)氧基]乙氧基}四氢-2H-吡喃(化合物422);
2-{3-[(2-溴苄基)氧基]丙氧基}四氢-2H-吡喃(化合物425);
3-[(2-溴苄基)氧基]丙基4-甲基苯磺酸酯(化合物426);
1-溴代-2-(3-碘-丙氧基甲基)苯(化合物427);
3-[(2-溴苄基)氧基]丙基膦酸二乙酯(化合物428);
2-(2-溴苯基)乙基膦酸二乙酯(化合物431);
(2-氯代-4-碘苯基)(2-甲基苯基)甲酮(化合物432);
(4R)-4-[2-(2-氨基苯基)乙基]-2,2-二甲基-1,3-唑烷-3-甲酸叔-丁酯(化合物433);
(4R)-4-[2-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)乙基]-2,2-二甲基-唑烷-3-甲酸叔-丁酯(化合物434);
[2-(2-溴苯基)乙基](甲基)氨基甲酸叔-丁酯(化合物435);
3-[2-(2-溴苯基)乙基]-1-甲基咪唑烷-2,4-二酮(化合物436);
3-[2-(2-溴苯基)乙基]-5,5-二甲基唑烷-2,4-二酮(化合物437);
4-[2-(2-溴苯基)乙基]吗啉-3,5-二酮(化合物438);
1-[2-(2-溴苯基)乙基]哌啶-2,6-二酮(化合物439);
2-溴苄基(三异丙基)甲硅烷基醚(化合物440);
{2-氯代-4-[(2-{[(三异丙基)硅氧基]甲基}苯基)氨基]苯基}(2-甲基苯基)甲酮(化合物441)。
制备方法
本发明的化合物可以通过许多有机合成领域技术人员已知的方法制备。本发明化合物可以通过下文所述的方法以及合成有机化学领域已知的方法,或本领域技术人员能够理解的这些方法的变通方案来合成。优选的方法包括(但不限于)下文所述方法。
式I化合物可以采用这部分描述的反应和技术制备。该反应在溶剂中进行,这些溶剂对于所用试剂和物质而言是恰当的,并且适于转化的进行。另外,在下文所述的合成方法中,应该理解,所有提到的反应条件,包括溶剂的选择、反应环境、反应温度、试验时间和处理方法,均是进行该反应的标准条件,这些条件应该是本领域人员容易地认可的。有机合成领域的技术人员可以理解,离析分子的各部分中存在的官能团必须与所需的试剂和反应相符。可以理解,并不是所有的列入该类的式I化合物均能与所述的方法中的某些反应相符。对本领域技术人员来说,与反应条件相符的这些取代基的限制是显而易见的,因此,可使用其他方法。
本发明的化合物可以通过下述方法制备,该方法包括将式III的胺和式II的溴化物、碘化物、氟化物、氯化物或三氟甲磺酸化物偶合(如流程1所示),或将式IIa的胺与例如式IIIa的碘化物偶合(其中R1、R2、R3、R4、R5、R6和X如上文所定义)(如流程1所示),但是在偶合反应中可能发生反应活性的任何取代基或官能团可以在偶合反应前先被保护,然后脱除。
L:Br、I、OSO2CF3或F和Cl(在特定情况下)
W:Cl、Br、I、OSO2CF3或OTs
FGI:官能团互换
流程1
偶合反应可以采用有机合成技术领域技术人员已知的二苯基胺形成的任何方法进行。优选方法为钯催化的胺化方法,该方法包括将胺和芳基卤化物(或芳基三氟甲磺酸酯)在碱、适当的Pd源和适当的膦配体存在下、于惰性溶剂中偶合。不同的钯化合物均可以在下述方法中使用,这些钯化合物包括但不限于例如乙酸钯(II)、氯化钯(II)、溴化钯(II)、二氯双(三苯基膦)钯(II)、四(三苯基膦)钯(0)、三(二亚苄丙酮)二钯(0)。优选的膦配体包括但不限于外消旋或非-外消旋2,2′-双(二苯基膦基)-1,1′-联萘(下文中称BINAP)、三-o-甲苯基膦、三-叔-丁基膦、1,1′-双(二苯基膦基)-二茂铁、双[(2-二苯基膦基)苯基]醚(DPEphos)、2-二环己基磷烷基(phosphanyl)-2′-二甲基氨基联苯、2-(二-叔-丁基膦基)联苯和9,9-二甲基-4,6-双(二苯基膦基)呫吨(Xantphos)。在此方法中使用的钯和配体的量通常为相对于所使用的芳族卤化物(或三氟甲磺酸酯)的摩尔量的0.1-10%。
已经证实,叔-丁氧醇钠(NaOt-Bu)和碳酸铯(Cs2CO3)为此方法中特别优选的碱,但也可以采用其他的碱。
该反应通常在升高的温度(80-120℃)下、于惰性溶剂中(例如1,4-二烷、甲苯、苯和四氢呋喃)中、在惰性气氛(如氩气或氮气)下进行。
R4不为氢的本发明化合物可以通过这样的方法制备,该方法包括将式I的胺(R4=H)和烷化剂偶合,如流程1所示,其中R1、R2、R3、R5、R6和X如通式I所定义,但是在偶合反应中可能发生反应的活性的任何取代基或官能团可以在偶合反应前先进行保护,随后进行脱除。典型的通式R4-W的烷化剂包括但不限于碘化物(W=I)、溴化物(W=Br)、氯化物(W=Cl)和磺酸酯(L=OSO2R′,其中R′代表甲基、三氟甲基或4-甲基苯基)。
在特定情况下,本发明的化合物可以通过简单的官能团互换(FGI)来制备,也就是有机合成领域技术人员已知的标准方法,其中通式I化合物中的官能团经过一个或多个合成步骤被转化为不同的官能团,由此得到通式I的新的化合物。这些方法的实例包括(但不限于)在碱条件下将酯水解得到酸,经如三溴化硼(BBR3)处理,使甲基醚脱保护得到酚,和将烯烃催化氢化得到饱和的烃。
具有通式I(其中X=S)的本发明化合物可以用酮(通式I,其中X=O)通过FGI方法,采用有机合成领域技术人员已知的多种硫代羰基化剂之一来制备。这样的硫代羰基烷化剂的实例包括但不限于,五硫化磷(P4S10)、Lawesson′s reagent(2,4-双(4-甲氧基苯基)-1,3,2,4-二硫杂二磷杂环丁烷-2,4-二硫化物)等。
通式I(其中X=N-ORc)的本发明的化合物可以通过将酮(通式I,其中X=O)用H2N-ORc或它们的保护的衍生物处理,随后在适当的溶剂(如吡啶或甲醇)中脱保护来制备。
通式III的本发明的化合物可以通过几种有机合成领域技术人员已知的方法制备。一个有用的方法如流程2所示。其关键步骤包括将通式VI的溴化物(或碘化物)与通式V的酰氯偶合,从而得到通式IV的苯酰苯。然后,将化合物IV经标准的还原剂处理,被还原为相应通式III的胺。这些还原剂的实例包括(但不限于)氯化锡二水合物;氢、甲酸铵或水合肼和催化量的披钯炭。该偶合反应是通过将溴化物(VI)转化为反应性有机金属中间体进行,如通过丁基锂处理得到锂衍生物或通过用镁处理得到镁衍生物。
Hal:Br、I
流程2
可以通过金属转移为例如锌对这些中间体的反应性进行调节,例如通过用ZnCl2、ZnBr2或ZnI2处理。然后在催化量的钯(0)复合物存在下,将该有机金属锌化合物与通式V的酰氯偶合。这样的催化剂的实例包括(但不限于)四(三苯基膦)钯(0)、四(三苯基胂)钯(0)、二氯双(三苯基膦)钯(II)或苄基氯化双(三苯基膦)钯(II)。
如流程2所示,通式IV的化合物(其中X=O)可以通过FGI方法被转化为上述的通式IV化合物(其中X=S或X=N-ORc)。这不仅说明了合成过程中的灵活性,而且还说明通常而言所述的流程仅是许多合成本发明的化合物的可能的方法之一。也就是说,在某些方法中,改变上文所述的操作次序可能更加有利。因此,所述的操作次序不应作为对本发明式I化合物的制备方法的限制,对有机合成领域的技术人员来讲,反应顺序的改变是显而易见的。
本发明的这一方法可以特别优选用于合成具有不同的R6基团取代基的化合物中。可以容易获得的中间体可以作为合成各种通式I化合物的合成中的起点。这样的化合物的实例在流程3和流程4中列出,在这些流程中,作为示例合成了通式I所包括的化合物(Ia-Ie)。可容易获得的中间体,如VIIa、VIIb和VIId本身也包括在通式I内。
流程3
通过有机合成领域技术人员已知的方法,使具有游离羟基的化合物(通式VIIa、VIIb)与羧酸(R-COOH)或它们活化的衍生物偶合,从而得到通式Ia和Ib的酯。
通过有机合成领域技术人员已知的方法,使具有游离氨基的化合物(通式VIIc、VIId)与羧酸(R-COOH)或它们活化的衍生物偶合,从而得到通式Ic和Id的酰胺。
流程4
通过有机合成领域技术人员已知的方法,使具有游离羧酸基团的化合物(通式VIIe)与胺(R-NH2)偶合,从而得到通式Ie的酰胺。
羧酸的适当的反应衍生物为,例如酰氯、混合酐或活性酯。该反应通常在惰性溶剂(例如***、四氢呋喃或二氯甲烷)中、在适当的碱(例如三乙胺、碳酸钾或吡啶)存在下进行。
如通式II、IIa、R-NH2和R-COOH的化合物的必要的起始原料可以通过文献中已知的方法或有机化学中的标准方法制备。起始原料的制备在制备部分有所描述。
常规步骤、制备及实施例
示例性化合物在表1中列出。
所有的溶点均未经校正。除特别指明外,1H核磁共振(NMR)波谱(300MHz)和13CNMR(75.6MHz)化学位移值(δ)(以ppm表示)是以相对于内标四甲基硅烷(δ=0.00)或氯仿(δ=7.25)或氘标氯仿(13C NMR的δ=76.81)在氘标氯仿溶液测定的。多重峰值(包括(双峰(d)、三峰(t)、四峰(q))或者非(m)是以近似中间点给出(除非给出一个范围)。采用无水有机溶剂。并在硅胶上进行快速层析。
全文使用了下列缩写词:
BOC 叔-丁氧基羰基
dba 二亚苄基丙酮
DCM 二氯甲烷
DMF N,N-二甲基甲酰胺
DMTMM 4-(4,6-二甲氧基-1,3,5-三嗪-2-基)-4-甲基吗啉氯化物
MS 质谱
NMM N-甲基吗啉
NMR 核磁共振
rac-BINAP 外消旋2,2′-双(二苯基膦基)-1,1′-联萘
RT 室温
TFA 三氟乙酸
THF 四氢呋喃
THP 四氢吡喃
表1中的编号是指下文通式中的编号:
表1.通式I的实例化合物(其中X=O;R1=甲基;R2=2-Cl;R3、R4和R5=H;除非另外指明)。
制备1:2-[2-(2-溴苯基)乙氧基]四氢-2H-吡喃(化合物401)。
于50℃,将2-溴苯乙醇(9.88g)、3,4-二氢-2H-吡喃(4.45mL)和4-甲苯磺酸(0.20g)的THF(20mL)溶液搅拌2小时,然后于室温下搅拌过夜。将反应混合物倾至冰水和EtOAc混合物中。水层用更多的EtOAc(x2)洗涤。合并的有机层用饱和的NaHCO3、盐水洗涤,干燥(MgSO4)、过滤并真空浓缩。粗品产物产物经层析纯化(洗脱液为石油醚/Et2O 4∶1),得到目标化合物,为无色油状物。
制备2:2-(2-溴苯基)-1-甲基乙基乙酸酯(化合物402)
于20℃,搅拌下,将乙酸酐(1.2mL)加入1-(2-溴苯基)-2-丙醇(529mg)的吡啶(1.0mL)溶液中。将反应混合物搅拌过夜,然后倾至水和EtOAc的混合物中。水层用更多的EtOAc(x2)提取。合并的有机层用水(x3)洗涤,干燥(MgSO4)、过滤并真空浓缩得到目标化合物,为糖浆状物。
制备3:(3E)-2-甲基-4-(三丁基甲锡烷基)丁-3-烯-2-醇(化合物403)
于搅拌下,将2-甲基丁-3-炔-2-醇(2.00g)、三丁基锡氢化物(10.5g)和αα′-偶氮二异丁腈(190mg)的混合物加热(纯的)至80℃。4小时后,将反应混合物冷却至室温。粗品产物经层析纯化(洗脱液为石油醚/Et2O 7∶1),得到目标化合物,为液体。
制备4:三丁基{(1E)-3-[(2,2-二甲基-1,3-二氧戊环-4-基)甲氧基]丙-1-烯基}锡烷(化合物404)
于0℃,将氢化钠(215mg)加至(2,2-二甲基-1,3-二氧戊环-4-基)甲醇(644mg)的无水DMF(25mL)溶液中。10分钟后,将[(1E)-3-溴丙-1-烯基](三丁基)锡烷(1.00g)加至反应混合物。
于20℃,将反应混合物搅拌20小时,然后用饱和的NH4Cl(水溶液)淬灭。用EtOAc提取并干燥(Na2SO4),真空浓缩后得到有机层的粗品产物。经层析纯化(洗脱液为石油醚/EtOAc 10∶1),得到目标化合物,为液体。
制备5:[(2E)-3-(三丁基甲锡烷基)丙-1-烯基]丙二酸二甲酯(化合物405)
于0℃,将氢化钠(75mg)加至丙二酸二甲酯(387mg)的无水DMF(5mL)溶液中。10分钟后,将[(1E)-3-溴丙-1-烯基](三丁基)锡烷(600mg)加至反应混合物中。于20℃,将反应混合物搅拌3小时,然后用饱和的NH4Cl(水溶液)淬灭。用EtOAc提取并干燥(MgSO4)有机层,真空浓缩后得到粗品产物。经层析纯化(洗脱液为石油醚/Et2O 12∶1),得到目标化合物,为液体。
制备6:4-[(2E)-3-(三丁基甲锡烷基)丙-2-烯基]吗啉(化合物406)
于20℃,将吗啉(637mg)和[(1E)-3-溴丙-1-烯基](三丁基)锡烷(1.00g)的无水DMF(8.0mL)溶液搅拌24小时。将反应混合物用饱和的Na2SO4(水溶液)淬灭。用Et2O提取,并干燥(MgSO4)有机层,真空浓缩后得到粗品产物。经层析纯化(洗脱液为石油醚/EtOAc 10∶1),得到目标化合物,为液体。
制备7:1,2:3,4-二-O-(1-甲基亚乙基)-6-O-[(2E)-3-(三丁基甲锡烷基)丙-2-烯基]-α-D-吡喃半乳糖(化合物407)
于0℃,将氢化钠(62mg)加至1,2:3,4-二-O-(1-甲基亚乙基)-α-D-吡喃半乳糖(635mg)的无水THF(8mL)溶液中。10分钟后,将[(1E)-3-溴丙-1-烯基](三丁基)锡烷(500mg)加至反应物中。于20℃,将反应混合物搅拌20小时,然后用饱和的NaHCO3(水溶液)淬灭。用Et2O提取并干燥(Na2SO4)有机层,真空浓缩后得到粗品产物。经层析纯化(洗脱液为石油醚/Et2O 9∶1),得到目标化合物,为液体。
制备8:甲基2,3-O-(1-甲基亚乙基)-5-O-[(2E)-3-(三丁基甲锡烷基)丙-2-烯基]-β-D-呋喃核苷(化合物408)
将反应于制备化合物407的条件下进行,采用2,3-O-(1-甲基亚乙基)-β-D-呋喃核糖(598mg)作为醇。经层析纯化(洗脱液为石油醚/EtOAc30∶1),得到目标化合物,为液体。
制备9:(4E)-2-(甲基磺酰基)-5-(三丁基甲锡烷基)戊-4-烯酸甲酯(化合物409)
将反应于制备化合物407的条件下进行,采用(甲基磺酰基)乙酸甲酯(446mg)作为亲核成分。经快速层析纯化(洗脱液为石油醚/Et2O 5∶1的混合物),得到目标化合物,为液体。
制备10:[(2E)-3-(三丁基甲锡烷基)丙-2-烯基]硫代}乙酸乙酯(化合物410)
将反应于制备化合物407的条件下进行,采用巯基乙酸乙酯(550mg)作为亲核成分。经快速层析纯化(洗脱液为石油醚/Et2O 100∶1的混合物),得到目标化合物,为液体。
制备11:三丁基{(1E)-3-[双(2-羟基乙基)氨基]丙-1-烯基}锡烷(化合物411)
于0℃,将N-乙基-N,N-二异丙基胺(315mg)加至二乙醇胺(256mg)的无水DMF(5mL)溶液中。10分钟后,将[(1E)-3-溴丙-1-烯基](三丁基)锡烷(600mg)加入反应物中。于20℃后,将反应混合物搅拌15小时,然后用饱和的NH4Cl(水溶液)淬灭。用Et2O提取并干燥(MgSO4)有机层,真空浓缩后得到粗品产物。经层析纯化(洗脱液为Et2O/MeOH 100∶4),得到目标化合物,为液体。
制备12:三丁基((1E)-3-{双[2-(乙酰氧基)乙基]氨基}丙-1-烯基)锡烷(化合物412)
将反应于制备化合物402的条件下进行,采用化合物411(575mg)作为醇。经快速层析纯化(洗脱液为石油醚/Et2O 4∶1的混合物),得到目标化合物。
制备13:三丁基{(1E)-3-[4-(2-羟基乙基)哌啶-1-基]丙-1-烯基}锡烷(化合物413)
将反应于制备化合物411的条件下进行,采用化合物2-哌啶-4-基乙醇(504mg)作为胺。经快速层析纯化(洗脱液为Et2O/MeOH 92∶8的混合物),得到目标化合物。
制备14:三丁基(1E)-3-{4-[2-(乙酰氧基)乙基]哌啶-1-基}丙-1-烯基)锡烷(化合物414)
将反应于制备化合物402的条件下进行,采用化合物413(510mg)作为醇。经快速层析纯化(洗脱液为石油醚/Et2O 1∶2混合物),得到目标化合物,为液体。
制备15:2-(2-{(2-溴苄基)氧基}乙氧基)乙醇(化合物415)
在氩气下,将NaH(0.53g,60%在油中,13mmol)悬浮于无水THF(80mL)的干燥的schlenk试管中。于搅拌下缓慢加入二甘醇(11.4mL,120mmol)。于室温下,搅拌悬浮液30分钟。将2-溴代-苄基溴化物(5.0g,20mmol)溶于5mL无水THF中,随后加入四丁基铵碘化物(74mg,0.2mmol)。加入水(50mL)后,将反应混合物回流18小时。用EtOAc提取水相2次,合并的有机层用水和盐水洗涤、干燥(MgSO4)、过滤并真空蒸发。将粗品产物经快速层析纯化(洗脱液为DCM/丙酮3∶1),得到目标化合物,为黄色油状物。
制备16:2-(2-{2-[(2-溴苄基)氧基]乙氧基}乙氧基)乙醇(化合物416)
用制备化合物415的方法制备和处理化合物,采用三甘醇(16.0mL,120mmol)代替二甘醇。粗品产物经快速层析纯化(洗脱液为DCM/丙酮6∶1-3∶1),得到目标化合物,为淡黄色油状物。
制备17:2-((2-溴苄基)氧基)乙醇(化合物417)
用制备化合物415的方法进行反应。起始原料为NaH(60%在油中,1.8g,44mmol)的THF(160mL)、乙二醇(13.4mL,240mmol)、溶于5mL无水THF的2-溴代-苄基溴化物(10g,40mmol)和四丁基铵碘化物(0.15g,0.4mmol)。将粗品产物经快速层析纯化(洗脱液DCM/丙酮30∶1),得到目标化合物,为淡黄色油状物。
制备18:2-溴苄基膦酸二乙酯(化合物418)
于氩气氛下,将亚磷酸二乙酯(0.77mL,6.0mmol)溶于无水THF(10mL)的干燥的schlenk试管中。在冰浴上,将溶液冷却,加入NaH(0.24g,60%在油中,6.0mmol)并搅拌5分钟。加入溶于2mL无水THF的2-溴代-苄基溴化物(1.0g,4.0mmol),并将反应混合物回流过夜。加入水(20mL),并将水层用EtOAc(3×10mL)提取。合并的有机层用盐水洗涤、干燥(MgSO4)、过滤并真空蒸发。粗品产物经快速层析纯化(洗脱液为EtOAc),得到目标化合物,为无色油状物。
制备19:2-溴苄基3,3,3-三氟丙基醚(化合物419)
在制备化合物415的条件下进行反应和处理。起始原料为NaH(60%在油中,0.08g,2mmol)的无水THF(10mL)、3,3,3-三氟丙-1-醇(0.23g,2mmol)、2-溴代-苄基溴化物(0.50g,2mmol)和四丁基铵碘化物(0.74g,0.2mmol)。粗品产物经快速层析纯化(洗脱液为EtOAc/石油醚1∶35),得到目标化合物,为淡黄色油状物。
制备20:2-(2-{2-[(2-溴苄基)氧基]乙氧基}乙氧基)四氢-2H-吡喃(化合物420)
于氩气氛下,将化合物415(2.78g,10.0mmol)溶于无水THF(6mL)中。加入3,4-二氢-2H-吡喃(1.03mL,11.3mmol),然后加入p-甲苯磺酸(43mg,0.23mmol)。加入水溶液NaHCO3(5%,30mL)后,于50℃,将反应混合物加热2小时。用EtOAc(3×15mL)提取水层,并将合并的有机层用水洗涤、干燥(Na2SO4)、过滤并真空蒸发。粗品产物经快速层析纯化(洗脱液为EtOAc/石油醚1∶3),得到目标化合物,为黄色油状物。
制备21:2-[2-(2-{2-[(2-溴苄基)氧基]乙氧基}乙氧基)乙氧基]四氢-2H-吡喃(化合物421)
在制备化合物420的条件下制备和处理来制备化合物。起始化合物为化合物416(2.82g,8.9mmol)的6mL无水THF、3,4-二氢-2H-吡喃(0.89mL,9.8mmol)和p-甲苯磺酸(37mg,0.19mmol)。粗品产物经快速层析纯化(洗脱液为EtOAc/石油醚1∶3),得到目标化合物,为淡黄色油状物。
制备22:2-{2-[(2-溴苄基)氧基]乙氧基}四氢-2H-吡喃(化合物422)
在制备化合物420的条件进行和处理反应。起始原料为化合物417(8.0g,34.9mmol)的20mL无水THF、3,4-二氢-2H-吡喃(3.2mL,34.9mmol)和p-甲苯磺酸(0.14g,0.76mmol),反应时间为4小时。粗品产物经快速层析纯化(洗脱液为EtOAc/石油醚1∶2),得到目标化合物,为无色油状物。
制备23:2-(2-溴苄基)-1H-异吲哚-1,3(2H)-二酮(化合物423)
将2-溴苄基溴化物(5.25g,21.0mmol)溶于无水DMF(200mL)并加入苯邻二甲酰亚胺钾(3.89g,21.0mmol)。于70℃,将悬浮液搅拌5小时。将混合物冷却至室温并倾至冰水(200mL)中。30分钟后,将混合物过滤并将晶体化合物干燥过夜。自DCM/石油醚重结晶,得到目标化合物,为无色晶体。
制备24:3-[(2-溴苄基)氧基]丙醇(化合物424)
在制备化合物415的条件下进行反应和处理。起始原料为NaH(60%在油中,0.86g,22mmol)的THF(80mL)、1,3-丙二醇(8.67mL,120mmol)、溶于4mL无水THF的2-溴苄基溴化物(5.0g,20mmol)和四丁基铵碘化物(0.07g,0.2mmol)。粗品产物经快速层析纯化(洗脱液为EtOAc/石油醚1∶1->2∶1),得到目标化合物,为淡黄色油状物。
制备25:2-3-[(2-溴苄基)氧基]丙氧基}四氢-2H-吡喃(化合物425)
在制备化合物420的条件下反应和处理。起始化合物为化合物424(2.41g,9.8mmol)的7mL无水THF、3,4-二氢-2H-吡喃(0.99mL,10.8mmol)和p-甲苯磺酸(37mg,0.19mmol)。粗品产物经快速层析纯化(洗脱液为EtOAc/石油醚1∶4),得到目标化合物,为淡黄色油状物。
制备26:3-[(2-溴苄基)氧基]丙基4-甲基苯磺酸酯(化合物426)
采用化合物424(2.50g,10.2mmol)的吡啶(3mL)和p-甲苯磺酰氯(2.14g,11.2mmol),在制备化合物163的条件下反应和处理。粗品产物经快速层析纯化(洗脱液为EtOAc/石油醚1∶3),得到目标化合物,为无色晶体化合物。
制备27:1-溴代-2-(3-碘-丙氧基甲基)苯(化合物427)
采用化合物426(3.04g,7.6mmol)的8mL丙酮和NaI(2.28g,15.2mmol),在制备化合物167的条件下反应和处理。粗品产物经快速层析纯化(洗脱液为EtOAc/石油醚1∶2),得到目标化合物,为无色油状物。
制备28:3-[(2-溴苄基)氧基]丙基膦酸二乙酯(化合物428)
采用NaH(0.036g,60%在油中,0.9mmol)的无水THF(2mL)和亚磷酸二乙酯(0.12mL,0.9mmol),在制备化合物171的条件下进行反应。加入溶于无水THF(1mL)的化合物427(0.20g,0.6mmol),于室温下搅拌48小时,根据化合物171制备中进行处理。粗品产物经快速层析纯化(洗脱液为EtOAc),得到目标化合物,为无色油状物。
制备29:2-(2-溴苯基)乙基4-甲基苯磺酸酯(化合物429)
采用2-溴苯乙基醇(5g,25mmol)的吡啶(12mL)和p-甲苯磺酰氯(5.2g,27.5mmol),在制备化合物163的条件下进行反应和处理。粗品产物经快速层析纯化(洗脱液为EtOAc/石油醚1∶4),得到目标化合物,为无色晶体化合物。
制备30:1-溴代-2-(2-碘乙基)苯(化合物430)
采用化合物429(7.98g,22.5mmol)的22mL丙酮和NaI(6.7g,44.9mmol),在制备化合物167的条件下反应和处理。粗品产物经快速层析(洗脱液为石油醚),得到目标化合物,为无色油状物。
制备31:2-(2-溴苯基)乙基膦酸二乙酯(化合物431)
采用NaH(0.19g,60%在油中,4.8mmol)的无水THF(10mL)和亚磷酸二乙酯(0.62mL,4.8mmol),在制备化合物171的条件下进行反应。加入化合物430(1.0g,3.2mmol),并于室温下搅拌18小时。在制备化合物171的条件下处理。粗品产物经快速层析纯化(洗脱液为EtOAc/石油醚0∶1->1∶0),得到目标化合物,为无色油状物。
制备32:(2-氯代-4-碘苯基)(2-甲基苯基)甲酮(化合物432)
于0℃,20分钟内,向搅拌的(4-氨基-2-氯苯基)(2-甲基苯基)甲酮(9.83g,40mmol)(公开于WO 01/42189 A1中)的HCl(37%,150mL)悬浮液中加入NaNO2(5.52g,80mmol)的水(40mL)溶液。将反应混合物搅拌15分钟,并于搅拌下,加入KI(36g,240mmol)的水(100mL)溶液。于室温下2小时后,将水层用***提取2次。合并的有机层用Na2CO3(10%)、NaHSO3(40%)提取2次,经Na2SO4干燥,并真空浓缩。残留物经快速层析纯化(洗脱液为石油醚/EtOAc 40∶1),得到目标化合物,为固体。
制备33:(4R)-4-[2-(2-氨基苯基)乙基]-2,2二甲基-1,3-唑烷-3-甲酸叔-丁酯(化合物433)
在氩气氛下,将叔-丁醇钾(498mg,4.44mmol)加入(2-硝基苄基)三苯基膦氯化物(2.04g,4.89mmol)的1,4-二烷(10mL)溶液中。于室温下,将混合物搅拌30分钟,然后于80℃搅拌40分钟。用注射器,加入(4S)-4-甲酰基-2,2-二甲基-恶唑烷-3-甲酸叔-丁酯(510mg,2.22mmol)的1,4-二烷(3.0mL)溶液。得到的混合物回流4小时,然后至室温过夜。将反应混合物倾至水中,并用EtOAc(x3)提取。合并有机层并用盐水洗涤,MgSO4干燥。粗品产物经快速层析纯化(洗脱液为石油醚/EtOAc 9∶1),得到(4R)-2,2-二甲基-4-[2-(2-硝基苯基)乙烯基]-1,3-唑烷-3-甲酸叔-丁酯的(Z)/(E)混合物,为黄色油状物。将288mg得到的产物溶于EtOAc(10ml),加入Pd/C(40mg,10%),然后于氢气氛(1atm)下,搅拌4小时。将反应混合物经decalite垫过滤并真空浓缩。粗品产物经快速层析纯化(洗脱液为石油醚/EtOAc 2∶1),得到目标化合物,为白色固体。
制备34:(4R)-4-[2-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)乙基]-2,2-二甲基-唑烷-3-甲酸叔-丁酯(化合物434)
采用化合物432(378mg,1.06mmol)和化合物433(340mg,1.06mmol),在制备化合物101的条件下反应和处理。经快速层析纯化(洗脱液为石油醚/EtOAc 9∶1),得到目标化合物,为泡沫状物。
制备35:[2-(2-溴苯基)乙基](甲基)氨基甲酸叔-丁酯(化合物435)
于氩气氛下,将[2-(2-溴苯基)乙基]氨基甲酸叔-丁酯(810mg,2.7mmol)的无水THF(2.0mL)转移至含有氢化钠(65mg,2.7mmol)的无水THF(2.0mL)的悬浮液烧瓶中。于室温下,将混合物搅拌15分钟,并于60℃,搅拌10分钟。用注射器,加入碘甲烷(0.19mL,2.97mmol)。4小时后,将反应混合物化倾至水中,并用EtOAc(x3)提取。合并有机层并用盐水洗涤,MgSO4干燥。粗品产物经层析纯化(洗脱液为石油醚/EtOAc 10∶1),得到目标化合物,为无色油状物。
制备36:3-[2-(2-溴苯基)乙基]-1-甲基咪唑烷-2,4-二酮(化合物436)
于室温下,向2-溴苯乙基醇(402mg,2.0mmol)、1-甲基乙内酰脲(320mg,2.8mmol)和三苯基膦(734mg,2.8mmol)的THF(20ml)的溶液中加入偶氮二甲酸二乙酯溶液(40%在甲苯中,1.22ml,2.8mmol)。在相同的温度下,将反应溶液搅拌3小时并真空浓缩。残留物经层析纯化(石油醚/乙酸乙酯1∶1),得到目标化合物,为无色固体。
13C NMR(CDCl3):δ169.6,156.7,137.6,132.9,130.9,128.5,127.6,124.6,51.6,38.6,34.4,29.6
制备37:3-[2-(2-溴苯基)乙基]-5,5-二甲基唑烷-2,4-二酮(化合物437)
在制备化合物436的条件下,处理2-溴苯乙基醇(402mg,2mmol)和5,5-二甲基-唑烷-2,4-二酮(361mg,2.8mmol)。经快速层析纯化(石油醚/乙酸乙酯4∶1),得到目标化合物,为无色固体。
13C NMR(CDCl3):175.7,154.4,136.6,133.1,131.1,128.8,127.5,124.7,83.6,39.2,33.7,23.5
制备38:4-[2-(2-溴苯基)乙基]吗啉-3,5-二酮(化合物438)
在制备化合物436的条件下,处理2-溴苯乙基醇(402mg,2mmol)和吗啉-3,5-二酮(322mg,2.8mmol)。经快速层析纯化(石油醚/乙酸乙酯4∶1),得到目标化合物,为无色固体。
13C NMR(CDCl3):δ168.9,137.7,132.9,131.0,128.5,127.5,124.7,67.7,38.2,34.0
制备39:1-[2-(2-溴苯基)乙基]哌啶-2,6-二酮(化合物439)
在制备化合物436的条件下,处理2-溴苯乙基醇(402mg,2mmol)和戊二酰亚胺(317mg,2.8mmol),经快速层析纯化(石油醚/乙酸乙酯2∶1),得到目标化合物,为无色固体。
13C NMR(CDCl3):172.3,138.3,132.7,131.0,128.2,127.4,124.7,39.0,34.1,32.8,17.1
制备40:2-溴苄基(三异丙基)甲硅烷基醚(化合物440)
室温下,向o-溴苄基醇(2.55g,13.6mmol)和咪唑(1.36g,20mmol)的CH2C12(20ml)溶液中加入三异丙基甲硅烷基氯化物(2.6ml,12mmol)。于相同温度下,搅拌得到的混合物1小时,然后溶于水。分离水层后,用石油醚提纯水层2次。合并的有机层经MgSO4干燥,真空浓缩。残留物通过硅胶短柱过滤纯化,得到目标化合物,为无色液体。
13C NMR(CDCl3):δ140.3,131.7,127.8,127.2,127.1,120.6,64.6,17.9,11.8
制备41:{2-氯代-4-[(2-{[(三异丙基)硅氧基]甲基}苯基)氨基]苯基}(2-甲基苯基)甲酮(化合物441)
在制备化合物215的条件下,处理(4-氨基-2-氯苯基)(2-甲基苯基)甲酮(2.15g,8.74mmol)(公开于WO 01/42189 A1)和化合物440(3.0g,8.74mmol)的混合物。经快速层析纯化(石油醚/乙酸乙酯20∶1),得到目标化合物,为红色油状物。
13C NMR(CDCl3):δ196.2,147.3,140.3,139.1,137.6,134.9,133.4,131.0,130.6,130.6,129.4,128.9,128.7,128.5,125.2,122.4,119.1,116.5,113.2,65.2,20.2,17.8,17.5
实施例1:[2-氯代-4-({2-[2-(四氢-2H-吡喃-2-基氧基)乙基]苯基}氨基)苯基](2-甲基苯基)甲酮(化合物101)。
将(4-氨基-2-氯苯基)(2-甲基苯基)甲酮(9.42g)(公开于WO 01/42189 A1)的1,4-二烷(60mL)、化合物401(12.0g)、Cs2CO3(17.5g)、Pd2(dba)3(440mg)和rac-BINAP(900mg)置入Schlenk试管。将试管用橡皮膜包住,使氩气流入5分钟,然后于100℃搅拌72小时。将反应混合物冷却至室温,然后倾入水和EtOAc的混合物中。用更多的EtOAc(x2)提取水层。合并的有机层用盐水洗涤、干燥(MgSO4)、过滤并真空浓缩。粗品产物经层析纯化(洗脱液为石油醚/醚2∶1),得到目标化合物,为橙色半固体。
13C NMR(CDCl3):δ196.3,149.0,139.6,139.5,137.6,135.3,133.9,133.5,131.1,130.6,129.4,127.8,127.4,125.3,124.4,122.3,115.8,112.1,99.3,70.2,62.3,32.8,30.6,25.2,20.3,19.6
实施例2:(2-氯代-4-{[2-(2-羟基乙基)苯基]氨基}苯基)(2-甲基苯基)甲酮(化合物102)
于室温下,将化合物101(4.00g)和4-甲苯磺酸(2.54g)的甲醇(25mL)溶液搅拌2小时。将反应混合物倾至1NNaOH和EtOAc的混合物中。水层用更多的EtOAc(x2)提取。合并的有机层用盐水洗涤、干燥(MgSO4)、过滤并真空浓缩。粗品产物经层析纯化(洗脱液为石油醚/醚2∶1,随后4∶1),得到目标化合物,为黄色糖浆状物。
13C NMR(CDCl3):δ196.6,149.0,139.5,137.6,135.3,133.8,133.4,131.2,131.2,130.6,129.5,127.8,127.5,125.3,124.6,122.7,115.9,112.2,65.0,34.6,20.3
实施例3:2-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)乙基乙酸酯(化合物103)
于0℃,搅拌下,将乙酸酐(0.12mL)加入化合物102(306mg)的吡啶(3.0mL)溶液。将反应混合物至室温过夜,然后倾至水和EtOAc混合物中。水层用更多的EtOAc(x2)提取。合并的有机层用盐水洗涤、干燥(MgSO4)、过滤并真空浓缩。粗品产物经层析纯化(洗脱液石油醚/Et2O 1∶1),得到目标化合物,为糖浆状物。
13C NMR(CDCl3):δ196.4,171.4,148.8,139.3,138.9,137.8,135.1,133.6,131.2,131.1,130.7,129.6,128.7,128.1,125.3,124.8,123.1,116.1,112.7,64.6,31.2,21.0,20.4
实施例4:4-(2-2-[(3-氯代-4-(2-甲基苯甲酰基)苯基)氨基]苯基)乙氧基)-4-氧代丁酸(化合物104)
采用化合物102(1.37g)作为醇和琥珀酸酐(0.56g),在制备化合物103的条件下进行反应。经快速层析纯化(洗脱液为石油醚/EtOAc 4∶1和5%乙酸混合物),得到目标化合物,为黄色糖浆状物。
13C NMR(CDCl3):δ196.6,176.3,172.7,149.0,148.6,139.3,138.8,137.8,135.1,133.6,131.2,131.0,130.7,129.6,128.4,128.1,125.3,125.1,123.8,115.9,112.5,64.8,31.0,29.0,28.8,20.4
实施例5:2-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)乙基己酸酯(化合物105)
采用化合物102(0.42g)作为醇和己酸酐(0.40mL),在制备化合物103的条件下进行。合并的有机层也用0.5N NaOH洗涤。经快速层析纯化,随后顺次用石油醚/EtOAc 9∶1和石油醚/EtOAc 4∶1洗脱,得到目标化合物,为黄色糖浆状物。
13C NMR(CDCl3):δ196.4,174.3,148.8,139.3,138.9,137.8,135.2,133.6,131.2,131.1,130.8,130.7,129.6,128.6,128.0,125.3,124.8,123.2,116.1,112.6,64.4,34.3,31.3,24.6,24.4,22.3,20.4,13.9
实施例6:2-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-1-甲基乙基乙酸酯(化合物106)
采用化合物402(304mg)作为溴化物,在制备化合物101的条件下反应。经快速层析纯化(洗脱液为石油醚/EtOAc 4∶1的混合物),得到目标化合物,为橙色糖浆状物。
13C NMR(CDCl3):δ196.5,171.7,148.5,139.4,139.3,137.8,135.1,133.6,131.7,131.2,130.7,129.6,129.0,128.8,127.9,125.3,123.7,121.5,116.4,113.2,71.6,39.0,21.4,20.4,19.1
实施例7:(2-氯代-4-{[2-(2-羟基丙基)苯基]氨基}苯基)(2-甲基苯基)甲酮(化合物107)
向化合物106(49mg)的THF(1.0mL)溶液中加入甲醇钠的甲醇(3.0mL,0.33M)溶液,并于20℃搅拌45分钟。将反应混合物倾至水和EtOAc的混合物中。水层用更多的EtOAc(x2)提取。合并的有机层用盐水洗涤、干燥(MgSO4)、过滤并真空浓缩,得到目标化合物,为黄色糖浆状物。
13C NMR(CDCl3):δ196.5,148.9,139.7,139.6,137.6,135.3,133.9,132.0,132.0,131.1,130.6,129.4,127.7,127.5,125.3,124.1,122.3,116.0,112.3,70.6,40.6,23.8,20.3
实施例8:[2-氯代-4-({2-[(1E)-3-羟基丙-1-烯基]苯基}氨基)苯基](2-甲基苯基)甲酮(化合物108)
在氩气氛下,将{2-氯代-4-[(2-溴苯基)氨基]苯基}(2-甲基苯基)甲酮(300mg)(公开于WO01/42189)的二烷(1.5mL)溶液和P-t-Bu3(18mg)的二烷(1.0mL)溶液依次加至含有Pd2(dba)3(21mg)和CsF(152mg)的Schienk试管中。然后注入(2E)-3-(三丁基甲锡烷基)丙-2-烯-1-醇(273mg),并将Schlenk试管密封,置于35-50℃的油浴中,搅拌48小时。然后将反应混合物冷却至室温,用乙腈洗脱,并经硅胶土垫过滤。将硅胶土垫用乙腈洗涤。合并的有机层彻底用石油醚洗涤,并真空浓缩。产物经快速层析纯化(洗脱液为石油醚/EtOAc 4∶1的混合物),得到目标化合物,为黄色糖浆状物。
13C NMR(CDCl3):δ196.8,149.0,139.2,137.7,137.2,135.1,133.6,131.9,131.5,131.2,130.8,129.6,128.6,128.4,127.4,126.0,125.4,125.4,124.0,116.1,112.5,63.4,20.4
实施例9:(2-氯代-4-{[2-(3-羟基丙基)苯基]氨基}苯基)(2-甲基苯基)甲酮(化合物109)
于氢气下,室温将化合物108(50mg)和10%Pd/C(7mg)的乙醇(1.0mL)混合物搅拌8小时。反应混合物真空浓缩,并经快速层析纯化(洗脱液为DCM/MeOH 97∶3的混合物),得到目标化合物,为黄色糖浆状物。
13C NMR(CDCl3):δ196.5,149.4,139.5,138.7,137.7,135.2,134.7,133.8,131.2,130.7,130.6,129.5,128.0,127.1,125.3,124.9,123.1,115.8,112.2,60.9,32.8,26.6,20.4
实施例10:[2-氯代-4-({2-[(1E)-4-羟基丁-1-烯基苯基}氨基)苯基](2-甲基苯基)甲酮(化合物110)
采用(2E)-4-(三丁基甲锡烷基)丁-3-烯-1-醇(304mg)作为锡烷,在制备化合物108的条件下进行反应。经快速层析纯化(洗脱液为石油醚/EtOAc 8∶1,随后1∶1的混合物),得到目标化合物,为黄色糖浆状物。
13C NMR(CDCl3):δ196.5,149.0,139.3,137.8,136.8,135.1,133.6,131.2,130.8,129.8,129.6,128.3,127.9,127.3,125.5,125.3,124.2,116.0,112.4,61.9,36.6,20.4
实施例11:[4-({2-[(1E)-3-氨基丙-1-烯基]苯基}氨基)-2-氯苯基](2-甲基苯基)甲酮(化合物111)
采用(2E)-3-(三丁基甲锡烷基)丙-2-烯-1-胺(273mg)作为锡烷,在制备化合物108的条件下进行反应。经快速层析纯化(洗脱液为DCM/MeOH/Et3N90∶5∶5的混合物),得到目标化合物,为黄色泡沫。
13C NMR(CDCl3):δ196.5,149.0,139.3,137.8,137.1,135.1,133.6,132.2,131.2,130.8,129.6,128.5,128.4,127.4,125.4,125.3,125.2,123.9,116.2,112.5,44.2,20.4
实施例12:(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基膦酸二乙酯(化合物112)
采用(2E)-3-(三丁基甲锡烷基)丙-2-烯基膦酸二乙酯(219mg)作为锡烷,在制备化合物108的条件下进行反应。经快速层析纯化(洗脱液为石油醚/EtOAc 1∶1),得到目标化合物。
13C NMR(CDCl3):δ196.4,148.9,139.3,137.8,137.1,135.1,133.6,132.0,131.2,130.8,130.3,130.1,129.6,128.7,127.4,125.3,123.9,122.2,122.0,116.1,112.5,62.1,31.3,20.4,16.5
实施例13:[2-氯代-4-({2-[(1E)-3-羟基-3-甲基丁-1-烯基]苯基}氨基)苯基](2-甲基苯基)甲酮(化合物113)
采用化合物403(295mg)作为锡烷,在制备化合物108的条件下进行反应。经快速层析纯化(洗脱液为:石油醚/EtOAc 2∶1的混合物),得到目标化合物,为糖浆状物。
13C NMR(CDCl3):δ196.5,148.8,140.5,139.3,137.8,137.2,135.0,133.5,132.1,131.2,130.8,129.6,128.7,128.5,127.4,125.5,125.3,124.1,121.8,116.2,112.7,71.2,30.0,20.4
实施例14:(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙烯酸乙脂(化合物114)
采用(2E)-3-(三丁基甲锡烷基)丙烯酸二乙酯(295mg)作为锡烷,在制备化合物108的条件下进行反应。经快速层析纯化(洗脱液为石油醚/EtOAc6∶1的混合物),得到目标化合物,为黄色糖浆状物。
13C NMR(CDCl3):δ196.5,167.2,148.2,139.7,139.3,139.0,138.0,135.0,133.4,131.3,130.9,129.8,129.6,129.0,128.0,125.4,125.3,123.9,119.9,116.8,113.3,51.8,20.5
实施例15:(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙烯酸(化合物115)
将化合物114(190mg)的THF(2.0mL)溶液加至氢氧化锂(22mg)的MeOH/H2O(3:4;3.5mL)的混合物溶液中,然后于20℃,搅拌72小时。将反应混合物倾至1N的HCl(水溶液)和DCM的混合物中。用更多的DCM(x3)提取水层。合并的有机层用盐水洗涤、干燥(Na2SO4)、过滤并真空浓缩,得到粗品产物,为固体。自EtOAc结晶得到目标化合物,为黄色结晶。
13C NMR(DMSO-d6):δ195.2,167.5,149.8,139.3,139.2,139.1,136.5,133.5,131.2,131.0,130.7,128.9,128.9,127.7,126.7,125.6,125.2,124.8,120.0,115.1,112.1,19.7
实施例16:{2-氯代-4-[(2-{(1E)-3-[(2,2-二甲基-1,3-二氧戊环-4-基)甲氧基]丙-1-烯基}苯基)氨基]苯基}(2-甲基苯基)甲酮(化合物116)
采用化合物404(351mg)作为锡烷,在制备化合物108的条件下进行反应。经快速层析纯化(洗脱液为:石油醚/EtOAc 2∶1的混合物),得到目标化合物,为黄色糖浆状物。
13C NMR(CDCl3):δ196.4,148.8,139.3,137.9,137.2,135.1,133.5,131.9,131.3,130.8,129.6,128.9,128.8,127.5,125.5,125.4,124.1,116.2,112.6,109.5,74.8,72.1,71.4,66.7,26.8,25.4,20.4
实施例17:[2-氯代-4-({2-[(1E)-3-(2,3-二羟基丙氧基)丙-1-烯基]苯基}氨基)苯基](2-甲基苯基)甲酮(化合物117)
于20℃,将化合物116(70mg)的THF(1.0mL)和HCl(1.0mL,1N)混合物溶液搅拌24小时。将反应混合物倾至水和EtOAc的混合物中。将有机层干燥(MgSO4)、过滤并真空浓缩。粗品产物经层析纯化(洗脱液为:DCM/MeOH 95∶5的混合物),得到目标化合物,为黄色糖浆状物。
13C NMR(CDCl3):δ196.9,149.2,139.1,137.9,137.3,135.0,133.5,131.9,131.3,130.9,129.7,128.8,128.4,128.1,127.9,127.3,125.6,125.4,124.5,116.0,112.4,71.8,71.7,70.7,63.9,20.4
实施例18:(1R)-3-{[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]氨基}-1-(羟基甲基)-2-氧代乙基氨基甲酸叔-丁酯(化合物118)
于20℃,将N-(叔-丁氧基羰基)-L-丝氨酸(30mg)和化合物111(50mg)的THF(1.0mL)混合物搅拌10分钟。将DMTMM(40mg)加至混合物中并于20℃搅拌20小时。将反应混合物倾至水中并用EtOAc(x3)提取。合并有机层并用盐水洗涤并经MgSO4干燥。粗品产物经层析纯化(洗脱液EtOAc/三氟乙酸99∶1),得到目标化合物,为黄色泡沫。
13C NMR(CDCl3):δ196.8,171.4,156.2,149.0,139.2,137.9,137.3,135.0,133.5,131.3,131.2,130.9,129.7,128.7,128.4,127.6,127.2,126.8,125.4,125.1,123.7,116.2,112.6,80.7,62.8,55.5,41.5,28.3,20.4
实施例19:O-(叔-丁基)-N-({[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]氨基}羰基)-L-丝氨酸甲酯(化合物119)
于20℃,将O-(叔-丁基)-N-(氧代亚甲基)-L-丝氨酸甲酯(40mg)和化合物111(50mg)的DCM(3.0mL)的混合物搅拌1小时。加入乙胺(20mg),并将反应混合物搅拌2小时。真空浓缩,随后层析(洗脱液为石油醚/EtOAc2∶1),得到目标化合物,为黄色泡沫。
13C NMR(CDCl3):δ196.5,172.9,158.1,149.3,139.5,137.7,137.6,134.9,133.6,131.2,131.1,130.6,129.5,129.0,128.3,127.9,127.2,126.3,125.3,124.5,123.0,116.6,112.7,73.5,62.4,54.0,52.4,46.1,27.3,20.4
实施例20:N-(叔-丁基)-N′-[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]硫脲(化合物120)
于20℃,将异硫氰酸叔-丁酯(19mg)和化合物111(50mg)的DCM(3.0mL)混合物搅拌1.5小时。加入乙胺(20mg)并将反应混合物搅拌24小时。真空浓缩,随后层析(洗脱液为石油醚/EtOAc 3∶1),得到目标化合物。
13C NMR(CDCl3):δ196.6,181.4,149.0,139.2,137.8,137.2,135.0,133.6,131.9,131.3,130.8,129.6,128.8,128.5,127.9,127.8,127.4,125.5,125.4,124.0,116.1,112.5,53.0,47.5,29.5,20.4
实施例21:N-[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]-4-氧戊酰胺(化合物121)
采用4-氧代戊酸(25mg)作为羧酸,在制备化合物118的条件下进行反应。经快速层析纯化(洗脱液为石油醚/EtOAc 2∶3的混合物),得到目标化合物。
13C NMR(CDCl3):δ208.5,196.5,172.0,149.1,139.4,137.8,137.3,135.0,133.6,131.2,131.0,130.7,129.6,128.4,128.4,128.2,127.1,125.7,125.3,124.9,123.4,116.5,112.6,41.3,38.6,29.9,20.4
实施例22:N-[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]-N′-乙基脲(化合物122)
于20℃,将异氰酸乙酯(28mg)和化合物111(100mg)的DCM(1.0mL)混合物搅拌2.5小时。将反应混合物倾至水中并用DCM(x3)提取。合并有机层并用盐水洗涤,MgSO4干燥。粗品产物经层析纯化(洗脱液为石油醚/EtOAc 2∶3),得到目标化合物,为黄色糖浆状物。
13C NMR(CDCl3):δ197.0,158.7,149.5,139.2,137.7,137.1,134.9,133.6,132.1,131.3,130.9,129.9,129.6,128.4,127.8,127.3,126.5,125.4,125.4,124.2,116.2,112.3,42.5,35.2,20.4,15.5
实施例23:4-{[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]氨基}-4-氧代丁酸乙酯(化合物123)
采用琥珀酸氢乙酯(32mg)作为羧酸,在制备化合物118的条件下进行反应。经快速层析纯化(洗脱液为DCM/MeOH 95∶5混合物),得到目标化合物,为糖浆状物。
13C NMR(CDCl3):δ196.6,173.3,171.7,149.2,139.3,137.7,137.3,135.0,133.6,131.4,131.2,130.8,129.6,128.5,128.3,128.2,127.2,126.5,125.4,125.2,123.8,116.2,112.5,60.9,41.6,30.9,29.5,20.4,14.1
实施例24:N-[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]-N′-环己脲(化合物124)
采用异氰酸环己酯(40mg),在制备化合物122的条件下进行反应。经快速层析纯化(洗脱液为石油醚/EtOAc 1∶1的混合物),得到目标化合物,为糖浆状物。
13C NMR(CDCl3):δ196.8,157.8,149.2,139.2,137.8,137.1,134.9,133.5,132.0,131.3,130.9,130.0,129.7,128.5,128.1,127.4,126.7,125.4,125.3,124.0,116.3,112.5,49.1,42.6,33.9,25.6,25.0,20.4
实施例25:N′-[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]-N,N-二甲基琥珀酰胺(化合物125)
采用N,N-二甲基琥珀酰胺酸(32mg)作为羧酸,在制备化合物118的条件下进行反应。经快速层析纯化(洗脱液为EtOAc/MeOH 95∶5混合物),得到目标化合物,为糖浆状物。
13C NMR(CDCl3):δ196.5,172.7,172.1,149.6,139.6,137.6,137.5,135.1,133.7,131.1,130.6,129.4,128.2,127.8,126.9,125.6,125.3,124.7,123.5,116.1,112.3,41.4,37.1,35.7,31.2,28.6,20.3
实施例26:[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]丙二酸二甲酯(化合物126)
采用化合物405(300mg)作为锡烷,在制备化合物108的条件下进行反应。经快速层析纯化(洗脱液为石油醚/EtOAc 6∶1混合物),得到目标化合物,为黄色糖浆状物。
13C NMR(CDCl3):δ196.4,169.2,148.6,139.3,137.8,137.1,135.1,133.6,131.8,131.2,130.8,129.6,129.0,128.7,128.5,127.7,125.3,125.0,123.1,116.2,112.6,52.6,51.6,32.4,20.4
实施例27:[2-氯代-4-(2-[(1E)-3-吗啉-4-基丙-1-烯基]苯基)氨基]苯基](2-甲基苯基)甲酮(化合物127)
采用化合物406(466mg)作为锡烷,在制备化合物108的条件下进行反应。经快速层析纯化(洗脱液为EtOAc),得到目标化合物,为黄色泡沫。
13C NMR(CDCl3):δ196.4,149.0,139.3,137.8,136.9,135.1,133.5,132.4,131.3,130.8,129.6,128.9,128.7,128.7,127.3,125.8,125.4,124.6,115.9,112.5,66.9,61.5,53.7,20.4
实施例28:6-O-[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]-1,2:3,4-二-O-(1-甲基亚乙基)-α-D-吡喃半乳糖(化合物128)
采用化合物407(400mg)作为锡烷,在制备化合物108的条件下进行反应。经快速层析纯化(洗脱液为石油醚/EtOAc 5∶1的混合物),得到目标化合物,为黄色糖浆状物。
13C NMR(CDCl3):δ196.4,148.7,139.3,137.8,137.3,135.1,133.6,131.6,131.2,130.7,129.6,129.3,128.7,128.6,127.6,127.3,125.3,125.1,123.5,116.3,112.6,109.4,108.6,96.4,71.8,71.3,70.7,70.5,69.4,67.1,26.1,26.0,24.9,24.5,20.4
实施例29:甲基5-O-[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]-2,3-O-(1-甲基亚乙基)-β-D-呋喃核苷(化合物129)
采用化合物408(427mg)作为锡烷,在制备化合物108的条件下进行反应。经快速层析纯化(洗脱液为石油醚/EtOAc 6∶1的混合物),得到目标化合物,为黄色糖浆状物。
13C NMR(CDCl3):δ196.4,148.8,139.3,137.8,137.2,135.1,133.6,131.7,131.2,130.8,129.6,129.0,128.8,127.5,127.4,125.4,125.3,123.9,116.2,112.6,112.5,109.4,85.2,82.1,71.8,71.5,54.9,26.5,25.0,20.4
实施例30:甲基5-O-[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]-β-D-呋喃核苷(化合物130)
将化合物129(50mg)溶于80%的乙酸溶液(1.0mL),并于50℃搅拌混合物7天。将反应混合物倾至饱和的Na2CO3(10mL)水溶液,并将水层用EtOAc(3×10mL)提取。干燥合并的有机层(Na2SO4)、过滤并真空蒸发。经快速层析纯化(洗脱液为石油醚/EtOAc 1∶4混合物),得到目标化合物,为黄色泡沫。
13C NMR(CDCl3):δ197.4,149.2,138.8,138.2,137.0,134.9,133.3,132.4,131.4,131.1,130.1,128.8,128.7,127.4,127.3,125.9,125.4,124.8,116.0,112.4,108.4,81.7,75.1,72.4,71.9,71.7,55.3,20.6
实施例31:(4E)-5-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-2-(甲基磺酰基)戊-4-烯酸甲酯(化合物131)
采用化合物409(250mg)作为锡烷,在制备化合物108的条件下进行反应。经快速层析纯化(洗脱液为石油醚/EtOAc 3∶1的混合物),得到目标化合物,为糖浆状物。
13C NMR(CDCl3):δ196.4,166.5,148.6,139.2,137.9,137.3,135.0,133.5,131.5,131.3,130.8,130.2,129.7,128.9,128.9,127.6,126.1,125.4,125.3,123.8,116.1,112.6,68.8,53.5,39.4,30.4,20.4
实施例32:{[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]硫代}乙酸乙酯(化合物132)
采用化合物410(300mg)作为锡烷,在制备化合物108的条件下进行反应。经快速层析纯化(洗脱液为石油醚/EtOAc 10∶1的混合物),得到目标化合物,为糖浆状物。
13C NMR(CDCl3):δ196.4,171.0,148.6,139.3,137.8,137.5,135.1,133.6,131.2,131.0,130.7,129.6,129.3,128.7,127.5,127.0,125.3,124.8,122.9,116.4,112.6,61.6,35.2,32.4,20.4,14.1
实施例33:[2-氯代-4-{[2-((1E)-3-{双[2-(乙酰氧基)乙基]氨基}丙-1-烯基)苯基]氨基}苯基](2-甲基苯基)甲酮(化合物133)
采用化合物412(454mg)作为锡烷,在制备化合物108的条件下进行反应。经快速层析纯化(洗脱液为石油醚/EtOAc 1∶2的混合物),得到目标化合物,为泡沫状物。
13C NMR(CDCl3):δ196.4,171.2,149.0,139.4,137.8,137.4,135.1,133.6,131.9,131.2,130.7,129.7,129.6,128.5,128.3,127.5,125.3,125.1,123.5,116.4,112.6,62.4,57.6,52.8,21.0,20.4
实施例34:[2-氯代-4-{[2-((1E)-3-{双[2-(羟基)乙基]氨基}丙-1-烯基)苯基]氨基}苯基](2-甲基苯基)甲酮(化合物134)
采用化合物133(172mg)作为酯,在制备的化合物107的条件下进行反应。经快速层析纯化(洗脱液为DCM/MeOH 10∶1的混合物),得到目标化合物,为黄色糖浆状物。
13C NMR(CDCl3):δ196.6,149.1,139.2,137.9,137.1,135.0,133.5,132.0,131.3,130.8,129.7,129.2,128.6,128.6,128.5,127.4,125.4,125.3,124.0,116.1,112.6,59.6,57.0,56.0,20.4
实施例35:(2-氯代-4-{[2-((1E)-3-{4-[2-(乙酰氧基)乙基]哌啶-1-基}丙-1-烯基)苯基]氨基}苯基)(2-甲基苯基)甲酮(化合物135)
采用化合物413(280mg)作为锡烷,在制备化合物108的条件下进行反应。经快速层析纯化(洗脱液为EtOAc),得到目标化合物,为泡沫状物。
13C NMR(CDCl3):δ196.5,171.1,149.0,139.3,137.8,137.0,135.1,133.5,132.3,131.2,130.8,129.6,129.1,128.7,128.6,127.3,125.6,125.3,124.4,116.0,112.5,62.4,61.3,53.8,35.1,32.5,31.9,21.0,20.4
实施例36:{2-氯代-4-[(2-{(1E)-3-[4-(2-羟基乙基)哌啶-1-基]丙-1-烯基}苯基)氨基]苯基}(2-甲基苯基)甲酮(化合物136)
采用化合物135(170mg)作为酯,在制备化合物107的条件下进行反应。经快速层析纯化(洗脱液为DCM/MeOH 17∶3的混合物),得到目标化合物,为黄色固体。
13C NMR(CDCl3):δ196.6,149.0,139.3,137.8,137.5,135.0,133.5,131.4,131.2,130.8,129.6,128.9,128.5,127.3,125.3,125.2,123.9,116.1,112.7,60.6,60.1,53.5,38.8,31.7,31.1,20.4
实施例37:{2-氯代-4-[(2-{2-[(四氢呋喃-2-基甲基)氨基]乙基}苯基)氨基]苯基}(2-甲基苯基)甲酮(化合物137)
于0℃,将化合物102(0.15g,0.41mmol)溶于吡啶(0.2mL),并加入p-甲苯磺酰氯(0.086g,0.45mmol)。于0℃,将悬浮液搅拌45分钟后加入胺(四氢-糠基胺,0.127mL,1.23mmol)。于室温下,搅拌反应混合物18小时。加入水(10mL),并将水层用EtOAc(5×10mL)提取。合并的有机层用盐水洗涤、干燥(MgSO4)、过滤并真空蒸发。粗品产物经快速层析纯化(洗脱剂为EtOAc/MeOH/Et3N 10∶1∶0.1),得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.4,149.3,139.9,137.5,135.3,134.4,134.0,131.2,131.1,130.4,129.3,127.3,127.2,125.3,123.8,121.8,116.2,112.1,78.0,68.0,54.6,51.7,33.5,29.4,25.7,20.3
实施例38:[2-氯代-4-({2-[2-(4-甲基哌嗪-1-基)乙基]苯基}氨基)苯基](2-甲基苯基)甲酮(化合物138)
采用1-甲基哌嗪(0.137mL,1.23mmol)作为胺,在制备化合物137的条件下进行反应。在制备化合物137的条件下进行处理,并将粗品产物经快速层析纯化(洗脱液为EtOAc/EtOH/Et3N 7∶1∶0.5),得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.3,149.1,139.8,139.6,137.7,135.3,134.7,133.8,131.2,130.6,129.4,128.0,127.2,125.3,123.8,121.4,116.8,112.8,60.8,55.2,54.0,46.1,30.9,20.4
实施例39:{2-氯代-4-[(2-{2-[(3-吗啉-4-基丙基)氨基]乙基}苯基)氨基]苯基}(2-甲基苯基)甲酮(化合物139)
采用1-吗啉基-3-氨基丙烷(0.18mL,1.23mmol)作为胺,在制备化合物137的条件下进行反应。并在制备化合物137的条件下进行处理。粗品产物经快速层析纯化(洗脱液为EtOAc/EtOH/Et3N 5∶1∶0.5),得到目标化合物,为橙色油状物。
13C NMR(CDCl3):δ196.7,149.6,140.2,140.0,137.9,135.7,134.3,133.9,131.5,131.4,130.9,129.8,127.9,127.8,125.7,124.4,122.6,116.4,112.6,67.2,57.9,54.2,51.4,49.5,33.0,26.1,20.7
实施例40:(2-氯代-4-{[2-(2-{[2-(二甲基氨基)乙基]氨基}乙基)苯基]氨基}苯基)(2-甲基苯基)甲酮(化合物140)
采用2-二甲基氨基-乙基胺(0.13mL,1.23mmol)作为胺,在制备化合物137的条件下进行反应。并在制备化合物137的条件下进行处理。粗品产物经快速层析纯化(洗脱液为EtOAc/EtOH/Et3N 4∶1∶0.5)。得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.4,149.4,139.8,139.8,137.5,135.3,133.9,131.1,131.1,130.5,129.4,127.4,125.3,123.9,121.9,116.2,112.1,58.2,51.2,47.0,45.3,33.0,20.3
实施例41:{2-氯代-4-[(2-{2-[(2-甲氧基乙基)氨基]乙基}苯基)氨基]苯基}(2-甲基苯基)甲酮(化合物141)
采用2-甲氧基-乙基胺(0.11mL,1.23mmol)作为胺,在制备化合物137的条件下进行反应。并在制备化合物137的条件下进行处理。粗品产物经快速层析纯化(洗脱液为EtOAc/MeOH/Et3N 4∶1∶0.5),得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.4,149.2,139.8,139.8,137.5,135.3,134.2,133.9,131.2,131.1,130.5,129.4,127.4,127.3,125.3,123.8,121.7,116.2,112.1,71.5,58.9,51.4,49.4,33.3,20.3
实施例42:1-[3-({2-[2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苯基]乙基}氨基)丙基]吡咯烷-2-酮(化合物142)
于3℃将化合物102(0.15g,0.41mmol)溶于吡啶(0.2mL),加入p-甲苯磺酰氯(0.086g,0.45mmol)。于3℃,搅拌悬浮液45分钟,随后加入胺(1-(3-氨基丙基)-2-吡咯烷酮(0.18mL,1.23mmol)。于3℃,搅拌反应混合物3天。在制备化合物137的条件下进行处理,粗品产物经快速层析纯化(洗脱液为:EtOAc/EtOH/Et3N 4∶1∶0.5的混合物),得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.4,175.5,149.3,139.7,139.6,137.5,135.2,134.0,134.0,131.2,131.1,130.5,129.4,127.4,127.3,125.3,124.0,122.0,116.0,112.2,51.0,47.2,46.6,39.9,33.0,30.9,27.0,20.3,17.9
实施例43:{2-氯代-4-[(2-{2-[甲基(四氢呋喃-2-基甲基)氨基]乙基}苯基)氨基]苯基}(2-甲基苯基)甲酮(化合物143)
采用N-甲基-四氢糠基胺(0.14g,1.23mmol)作为胺,在制备化合物142的条件下进行反应。在制备化合物137的条件下进行处理,粗品产物经快速层析纯化(洗脱液为:EtOAc/MeOH/Et3N 20∶1∶0.1的混合物),得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.4,155.8,149.5,140.0,139.9,137.5,135.3,134.7,134.0,131.2,131.1,130.4,129.3,127.1,125.3,123.6,121.4,116.4,112.3,76.8,67.9,63.2,60.9,42.9,31.5,30.2,25.3,20.3
实施例44:(2-氯代-4-{[2-(2-{[(2,2-二甲基-1,3-二氧戊环-4-基)甲基]氨基}乙基)苯基]氨基}苯基)(2-甲基苯基)甲酮(化合物144)
采用2,2-二甲基-1,3-二氧戊环-4-甲胺(0.16mL,1.23mmol)作为胺,在制备化合物142的条件下进行反应。在制备化合物137的条件下进行处理,粗品产物经快速层析纯化(洗脱液为:EtOAc/EtOH/Et3N 15∶1∶0.1的混合物)。得到目标化合物,为黄色油状物。
13C NMR(Cl3):δ196.4,149.2,139.7,137.6,135.3,134.4,133.9,131.2,131.1,130.5,129.4,127.5,127.3,125.3,124.1,122.1,116.1,112.1,109.5,75.0,67.3,53.1,51.8,33.6,26.9,25.2,20.3
实施例45:{2-氯代-4-[(2-{2-[4-(2-甲氧基乙基)哌嗪-1-基]乙基}苯基)氨基]苯基}(2-甲基苯基)甲酮(化合物145)
采用1-(2-甲氧基乙基)-哌嗪(0.18mL,1.23mmol)作为胺,在制备化合物142的条件下进行反应。在制备化合物137的条件下进行处理,粗品产物经快速层析纯化(洗脱液为:EtOAc/EtOH/Et3N 15∶1∶0.1的混合物)。得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.3,149.1,139.8,139.6,137.6,135.3,134.7,133.8,131.2,130.6,129.4,127.9,127.2,125.3,123.7,121.3,116.8,112.8,70.0,60.9,58.9,57.9,54.0,53.6,30.9,20.3
实施例46:(2-氯代-4-{[2-(2-吗啉-4-基乙基)苯基]氨基}苯基)(2-甲基苯基)甲酮(化合物146)
在制备化合物142的条件下进行反应。起始原料为化合物102(2.0g,5.45mmol)的吡啶(2.7mL)溶液、p-甲苯磺酰氯(1.15g,6.0mmol)和吗啉(1.43mL,16.4mmol)作为胺。在制备化合物137的条件下进行处理,粗品产物经快速层析纯化(洗脱液为:EtOAc/石油醚1∶2-1∶0的混合物)。得到目标化合物,为黄色晶体化合物。
13C NMR(CDCl3):δ196.3,149.1,139.5,139.5,137.7,135.3,134.7,133.8,131.2,131.1,130.6,129.5,128.1,127.4,125.3,124.1,122.0,116.3,112.7,67.1,61.3,54.4,30.4,20.4
实施例47:{2-氯代-4-[(2-{2-[(2,3-二羟基丙基)氨基]乙基}苯基)氨基]苯基}(2-甲基苯基)甲酮(化合物147)
将化合物144溶于1M的HCl/THF 1∶1(1.2mL),并于室温下将混合物搅拌18小时。将反应混合物倾至10%的NaHCO3水溶液(10mL),用EtOAc(3×10mL)提取水层。将合并的有机层干燥(MgSO4),过滤并真空蒸发。得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.7,149.6,139.4,139.0,137.7,135.2,134.2,133.8,131.2,131.0,130.7,129.5,127.8,127.6,125.3,125.1,123.8,115.8,112.1,70.1,65.3,52.1,50.7,32.3,20.4
实施例48:(4-{[2-(氨基甲基)苯基]氨基}-2-氯苯基)(2-甲基苯基)甲酮(化合物148)
将化合物154(2.17g,4.51mmol)溶于DCM(50mL)和EtOH(10mL)。加入水合肼(0.44mL,9.0mmol),并于室温下将反应混合物搅拌4天。过滤悬浮液并将滤液真空浓缩。粗品产物经快速层析纯化(洗脱液为:EtOAc/MeOH/Et3N 10∶1∶0.1的混合物)。得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.4,147.8,141.1,139.5,137.7,135.1,133.7,131.2,130.7,130.0,129.5,128.4,128.4,125.3,122.4,119.2,116.8,113.1,45.4.20.4
实施例49:(2-氯代-4-{[2-({2-[2-(四氢-2H-吡喃-2-基氧基)乙氧基]乙氧基}甲基)苯基]氨基}苯基)(2-甲基苯基)甲酮(化合物149)
于氩气氛下,将化合物420(3.39g,10.3mmol)溶于15mL无水1,4-二烷的schlenk试管中。加入(4-氨基-2-氯苯基)(2-甲基苯基)甲酮(公开于WO01/42189),并溶于溶剂。加入rac-BINAP(0.26g,0.42mmol)、Pd2(dba)3(0.19g,0.20mmol)和Cs2CO3(4.7g,14.4mmol),于100℃、氩气下,将反应混合物搅拌18小时。用水和EtOAc稀释反应混合物,水层用EtOAc提取2次。合并的有机层用盐水洗涤、干燥(MgSO4)并真空蒸发。粗品产物经快速层析纯化(洗脱液为DCM/丙酮100∶1),得到目标化合物,为油状物。
13C NMR(CDCl3):δ196.4,147.9,140.9,139.4,137.8,135.0,133.6,131.2,130.7,130.4,129.6,129.3,128.7,128.5,125.3,122.8,120.1,116.9,113.3,99.1,72.3,70.6,70.3,69.4,66.6,62.3,30.6,25.4,20.4,19.5
实施例50:{2-氯代-4-[(2-{[(四氢-2H-吡喃-2-基氧基)乙氧基]甲基}苯基)氨基]苯基}(2-甲基苯基)甲酮(化合物150)
在制备化合物149的条件下进行反应和处理。起始原料为化合物422(8.3g,26.3mmol)的38mL无水1,4-二烷、(4-氨基-2-氯苯基)(2-甲基苯基)甲酮(6.47g,26.3mmol)(公开于WO 01/42189)、rac-BINAP(0.67g,1.07mmol)、Pd2(dba)3(0.48g,0.52mmol)和Cs2CO3(11.98g,36.8mmol)。粗品产物经快速层析纯化(洗脱液为EtOAc/石油醚1∶2,得到目标化合物,为油状物。
13C NMR(CDCl3):δ196.4,147.7,140.9,139.3,137.8,135.0,133.5,131.2,130.7,130.5,129.6,129.2,128.9,128.3,125.3,122.7,119.8,117.1,113.2,99.4,72.3,69.4,66.6,62.7,30.7,25.3,20.4,19.8
实施例51:[2-氯代-4-({2-[(2-{2-[2-(四氢-2H-吡喃-2-基氧基)乙氧基]乙氧基}乙氧基)甲基]苯基}氨基)苯基](2-甲基苯基)甲酮(化合物151)
在制备化合物149的条件下进行反应和处理。起始原料为化合物421(3.12g,7.74mmol)的15ml无水1,4-二烷、(4-氨基-2-氯苯基)(2-甲基苯基)甲酮(2.06g,8.37mmol)(公开于WO 01/42189)、rac-BINAP(0.21g,0.34mmol)、Pd2(dba)3(0.15g,0.17mmol)和Cs2CO3(3.8g,11.7mmol)。粗品产物经快速层析纯化(洗脱液为EtOAc/石油醚1∶2-1∶1-1∶0),得到目标化合物,为油状物。
13C NMR(CDCl3):δ196.4,147.9,140.8,139.4,137.8,135.0,133.6,131.2,130.7,130.5,129.6,129.3,128.7,128.5,125.3,122.8,120.1,117.0,113.2,99.0,72.2,70.6,70.6,70.4,69.4,66.6,62.2,30.6,25.4,20.4,19.5
实施例52:[2-氯代-4-({2-[(3,3,3-三氟丙氧基)甲基]苯基}氨基)苯基](2-甲基苯基)甲酮(化合物152)
在制备化合物149的条件下进行反应和处理。起始原料为化合物419(0.22g,0.79mmol)和(4-氨基-2-氯苯基)(2-甲基苯基)甲酮(0.19g,0.79mmol)(公开于WO 01/42189 A1)的4mL无水1,4-二烷、rac-BINAP(20.0mg,0.03mmol)、Pd2(dba)3(14mg,0.016mmol)和Cs2CO3(0.36g,1.1mmol)。粗品产物经快速层析纯化(洗脱液为EtOAc/石油醚1∶2),得到目标化合物,为油状物。
13C NMR(CDCl3):δ196.4,147.3,140.6,139.2,137.9,135.0,133.5,131.3,130.8,130.6,129.7,129.6,129.4,127.6,126.3,125.4,122.9,120.0,117.0,113.6,72.3,63.0,34.4,20.5
实施例53:2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基膦酸二乙酯(化合物153)
在制备化合物149的条件下进行反应。起始原料为化合物418(0.55g,1.79mmol)和(4-氨基-2-氯苯基)(2-甲基苯基)甲酮(0.44g,1.79mmol)(公开于WO 01/42189 A1)的15mL无水1,4-二烷、rac-BINAP(44mg,0.07mmol)、Pd2(dba)3(33mg,0.04mmol)和Cs2CO3(0.82g,2.51mmol)。16小时后,于100℃,加入更多的rac-BINAP(44mg,0.07mmol)和Pd2(dba)3(33mg,0.04mmol),并于100℃,继续搅拌7小时。在制备化合物149的条件下进行处理。粗品产物经快速层析纯化(洗脱剂为EtOAc/石油醚1∶1),得到目标化合物,为棕色油状物。
13C NMR(CDCl3):δ195.7,148.0,139.4,138.8,137.0,134.5,133.0,131.4,130.5,129.9,128.8,127.6,127.4,124.6,124.0,123.7,122.3,115.6,112.1,62.1,30.4,19.7,15.7
实施例54:2-[2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]-1H-异吲哚-1,3(2H)-二酮(化合物154)
在制备化合物149的条件下进行反应。起始原料为化合物423(4.0g,12.65mmol)和(4-氨基-2-氯苯基)(2-甲基苯基)甲酮(3.1g,12.7mmol)(公开于WO 01/42189 A1)的125mL的无水甲苯、rac-BINAP(0.47g,0.76mmol)、Pd2(dba)3(0.35g,0.38mmol)和Cs2CO3(5.77g,17.7mmol)。于100℃,搅拌18小时,加入更多的rac-BINAP(0.24g,0.38mmol)和Pd2(dba)3(0.17g,0.19mmol),于100℃,将反应混合物再搅拌8小时。加入更多的rac-BINAP(0.24g,0.38mmol)和Pd2(dba)3(0.17g,0.19mmol),并于100℃,将反应搅拌18小时。在制备化合物149的条件下进行处理。粗品产物经快速层析纯化(洗脱液为EtOAc/石油醚1∶3),得到目标化合物,为黄色晶体化合物。
13C NMR(CDCl3):δ196.4,168.9,148.4,139.4,137.8,135.2,134.4,133.6,132.7,131.9,131.2,130.7,129.6,129.5,128.7,128.2,125.3,124.2,123.6,122.2,116.5,112.9,37.9,20.4
实施例55:{2-氯代-4-[(2-{[2-(2-羟基乙氧基)乙氧基]甲基}苯基)氨基]苯基}(2-甲基苯基)甲酮(化合物155)
将化合物149(5.68g,10.8mmol)溶于MeOH(100mL)并加入p-甲苯磺酸(3.09g,16.3mmol)。于室温下,将溶液搅拌2小时。加入NaHCO3(5%,100mL)水溶液并将水层用EtOAc(3×50mL)提取。合并的有机层用盐水(50mL)洗涤、干燥(MgSO4)并真空蒸发。粗品产物经快速层析纯化(洗脱液为EtOAc/石油醚1∶1-3∶2),得到目标化合物,为橙色油状物。
13C NMR(CDCl3):δ196.4,147.7,140.7,139.3,137.9,135.0,133.5,131.2,130.8,130.5,129.7,129.4,129.0,128.3,125.4,122.9,120.1,117.0,113.3,72.5,72.2,70.3,69.2,61.8,20.4
实施例56:[2-氯代-4-({2-[(羟基乙氧基)甲基]苯基}氨基)苯基](2-甲基苯基)甲酮(化合物156)
在制备化合物155的条件下进行反应和处理。起始化合物为化合物150(13g,27mmol)的290mLMeOH和p-甲苯磺酸(7.6g,40.4mmol)。粗品产物经快速层析纯化(洗脱液为EtOAc/石油醚1∶2-1∶1),得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.6,147.7,140.7,139.3,137.8,135.0,133.5,131.2,130.8,130.5,129.6,129.4,128.9,128.3,125.4,122.9,120.0,117.0,113.4,72.1,71.3,61.7,20.4
实施例57:(2-氯代-4-{[2-({2-[2-(2-羟基乙氧基)乙氧基]乙氧基}甲基)苯基]氨基}苯基)(2-甲基苯基)甲酮(化合物157)
在制备化合物155的条件下进行反应和处理。起始化合物为化合物151(4.4g,7.75mmol)的100mLMeOH和p-甲苯磺酸(2.2g,11.6mmol)。粗品产物经快速层析纯化(洗脱液为EtOAc/石油醚3∶1),得到目标化合物,为橙色油状物。
13C NMR(CDCl3):δ196.4,148.1,140.7,139.4,137.8,135.0,133.6,131.2,130.7,130.7,129.6,129.4,128.8,128.6,125.3,123.1,120.7,116.9,113.0,72.5,72.1,70.5,70.3,70.3,69.3,61.7,20.4
实施例58:[4-({4-溴代-2-[(2-羟基乙氧基)甲基]苯基}氨基)-2-氯苯基](2-甲基苯基)甲酮(化合物158)
将化合物156(3.8g,9.6mmol)溶于DMSO(115mL)。冰浴冷却溶液,缓慢加入48%HBr(32mL,285mmol)水溶液。于室温下,将溶液在密封的试管中搅拌5天。冰浴冷却反应混合物并加入27%NaOH(30mL)水溶液,得到碱溶液。用EtOAc提取水层3次,合并的有机层用盐水洗涤、干燥(MgSO4)、过滤并真空蒸发。粗品产物经快速层析纯化(洗脱液为EtOAc/石油醚1∶1),得到目标化合物,为淡色晶体化合物。
13C NMR(CDCl3):δ196.5,147.0,140.0,139.0,138.0,134.9,133.3,133.1,132.1,131.3,130.9,130.1,129.8,129.6,125.4,121.1,117.4,114.8,113.8,71.5,71.4,61.7,20.5
实施例59:(4-{[4-溴代-2-({2-[2-(2-羟基乙氧基)乙氧基]乙氧基}甲基)苯基]氨基}-2-氯苯基)(2-甲基苯基)甲酮(化合物159)
在制备化合物158的条件下进行反应和处理。起始原料为化合物157(2.14g,2.56mmol)的36mLDMSO和48%HBr(8.6mL,76.8mmol)水溶液。反应时间为8天。粗品产物经快速层析纯化(洗脱液为EtOAc/石油醚3∶1),得到目标化合物,为黄色油状物。
1H NMR(CDCl3):δ7.48(1H,bs),7.24-7.45(7H,m),7.20(1H,t),7.04(1H,d),6.90(1H,dd),4.51(2H,s),3.55-3.75(12H,m),2.45(3H,s)
实施例60:{4-[(4-溴代-2-{[2-(2羟基乙氧基)乙氧基]甲基}苯基)氨基]-2-氯苯基}(2-甲基苯基)甲酮(化合物160)
在制备化合物158的条件下进行反应和处理。起始原料为化合物155(1.19g,2.70mmol)的36mL DMSO和48%HBr(9.1mL,81.1mmol)水溶液。反应时间为8天。粗品产物经快速层析纯化(洗脱液为EtOAc/石油醚3∶1),得到目标化合物。为橙色油状物。
13C NMR(CDCl3):δ196.4,147.0,140.0,139.0,138.0,134.9,133.4,133.2,132.2,131.3,130.9,130.1,129.8,129.7,125.4,121.2,117.4,114.8,113.6,72.5,71.6,70.2,69.3,61.8,20.5
实施例61:5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基膦酸二乙酯(化合物161)
采用化合物153(0.11g,0.23mmol)的DMSO(3mL)和48%HBr(0.77mL,6.9mmol)水溶液,在制备化合物158的条件下进行反应。反应时间为11天。用NaHCO3(10%,10mL)水溶液淬灭反应。水层用EtOAc提取,合并的有机层用水和盐水洗涤、干燥(MgSO4)、过滤并真空浓缩。粗品产物经快速层析纯化(洗脱液为EtOAc/石油醚1∶1),得到目标化合物,为淡色油状物。
13C NMR(CDCl3):δ196.4,148.0,139.4,139.3,137.8,135.1,134.6,133.5,131.2,130.8,129.6,128.8,126.7,125.3,124.0,124.0,116.6,116.4,113.1,63.0,30.9,20.4,16.4
实施例62:[4-({4-溴代-2-[(3,3,3-三氟丙氧基)甲基]苯基}氨基)-2-氯苯基](2-甲基苯基)甲酮(化合物162)
采用化合物152(0.10g,0.22mmol)的DMSO(2.65mL)和48%HBr(0.75mL,6.70mmol)水溶液,在制备化合物158的条件下进行反应和处理。反应时间为6天。粗品产物经快速层析纯化(洗脱液EtOAc/石油醚1∶4),得到目标化合物,为黄色油状物。
1H NMR(CDCl3):δ7.5-7.25(7H,m),7.20(1H,t),7.00(1H,d),6.92(1H,bs),6.84(1H,dd),4.51(2H,s),3.71(2H,t),2.55-2.35(2H,m),2.46(3H,s)
实施例63:2-{[2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙基4-甲基苯磺酸酯(化合物163)
在氩气氛下,将化合物156(1.0g,2.55mmol)溶于吡啶(1.3mL)。冰浴冷却溶液并加入p-甲苯磺酰氯(0.56g,2.9mmol)。于室温下,搅拌悬浮液3小时。用水淬灭反应并用EtOAc提取水层2次。合并的有机层用盐水洗涤、干燥(Na2SO4)、过滤并真空蒸发。粗品产物经快速层析纯化(洗脱液为EtOAc/石油醚1∶2)。得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.5,147.4,145.1,140.7,139.2,137.9,134.9,133.5,132.9,131.3,130.8,130.6,129.9,129.7,129.6,129.2,127.9,127.6,125.4,122.8,120.0,117.0,113.8,72.2,68.9,67.5,21.6,20.5
实施例64:2-{[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙基4-甲基苯磺酸酯(化合物164)
采用化合物158(1.99g,4.19mmol)的吡啶(4mL)和p-甲苯磺酰氯(0.92g,4.19mmol),在制备化合物163的条件下进行反应和处理。粗品产物经快速层析纯化(洗脱液为EtOAc/石油醚1∶2),得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.5,146.7,145.2,140.0,139.0,138.1,134.8,133.3,133.2,132.8,132.3,131.3,131.0,130.0,129.8,129.5,127.9,125.4,121.3,117.4,114.8,114.2,71.5,68.8,67.6,21.7,20.5
实施例65:2-(2-{[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙氧基)乙基4-甲基苯磺酸酯(化合物165)
采用化合物160(1.10g,2.12mmol)和吡啶(2mL)和p-甲苯磺酰氯(0.47g,2.44mmol),在制备化合物163的条件下进行反应和处理。粗品产物经快速层析纯化(洗脱液为EtOAc/石油醚1∶2)。得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.4,146.9,144.9,140.0,139.0,138.0,134.8,133.4,133.1,132.9,132.1,131.3,130.9,130.1,129.9,129.8,129.6,127.9,125.4,121.0,117.3,114.7,113.7,71.5,70.5,69.2,69.0,68.8,21.6,20.5
实施例66:2-[2-(2-{[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙氧基)乙氧基]乙基4-甲基苯磺酸酯(化合物166)
采用化合物159(1.15g,2.04mmol)的吡啶(2mL)和p-甲苯磺酰氯(0.45g,2.35mmol),在制备化合物163的条件下进行反应和处理。粗品产物经快速层析纯化(洗脱液为EtOAc/石油醚2∶3),得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.4,149.5,147.1,144.8,140.0,139.1,138.0,134.8,133.4,133.1,132.0,131.3,130.9,130.3,129.8,129.7,129.5,127.9,125.4,121.2,117.4,114.8,113.4,71.5,70.8,70.4,70.4,69.4,69.2,68.7,21.6,20.5
实施例67:[4-({4-溴代-2-[(2-碘乙氧基)甲基]苯基}氨基)-2-氯苯基](2-甲基苯基)甲酮(化合物167)
将化合物164(1.72g,2.73mmol)溶于无水丙酮(2.7mL),加入无水NaI(0.82g,5.47mmol)。于室温下,将悬浮液在光保护的烧瓶内搅拌20小时,之后用水稀释反应混合物并将水层用EtOAc提取3次。合并的有机层用盐水洗涤、干燥(MgSO4)、过滤并真空蒸发,得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.8,147.1,140.4,139.3,138.5,135.2,133.7,132.8,131.7,131.4,130.4,130.2,130.0,125.8,121.6,118.0,115.2,114.6,71.6,70.8,20.9,4.1
实施例68:{4-[(4-溴代-2-{[2-(2-碘乙氧基)乙氧基]甲基}苯基)氨基]-2-氯苯基}(2-甲基苯基)甲酮(化合物168)
采用化合物165(0.87g,1.29mmol)的1.3mL丙酮和NaI(0.39g,2.59mmol),在制备化合物167的条件下进行处理和反应。处理后得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.4,146.9,140.1,139.0,138.0,134.9,133.4,133.1,132.1,131.3,130.9,130.0,129.8,129.7,125.4,121.0,117.5,114.7,113.7,72.0,71.7,69.9,69.3,20.5,2.4
实施例69:(4-{[4-溴代-2-({2-[2-(2-碘乙氧基)乙氧基]乙氧基}甲基]苯基)氨基}-2-氯苯基)(2-甲基苯基)甲酮(化合物169)
采用化合物166(1.07g,1.49mmol)的1.5mL丙酮和NaI(0.45g,2.98mmol),在制备化合物167的条件下进行反应和处理。处理后得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.4,147.1,140.1,139.1,138.0,134.9,133.4,133.1,132.0,131.3,130.9,130.2,129.7,129.5,125.4,121.1,117.4,114.7,113.5,71.9,71.6,70.5,70.4,70.2,69.4,20.5,2.7
实施例70:[2-氯代-4-({2-[(2-碘乙氧基)甲基]苯基}氨基)苯基](2-甲基苯基)甲酮(化合物170)
采用化合物163(0.26g,0.48mmol)的1.5mL丙酮和NaI(0.14g,0.96mmol),在制备化合物167的条件下进行反应和处理。粗品产物经快速层析纯化(洗脱液为EtOAc/石油醚1∶2),得到目标化合物,为淡黄色油状物。
13C NMR(CDCl3):δ196.4,147.4,140.7,139.2,137.9,135.0,133.4,131.3,130.8,130.7,129.7,129.6,129.3,127.8,125.4,122.9,120.0,117.2,113.8,71.9,70.3,20.5,3.9
实施例71:2-{[2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙基膦酸二乙酯(化合物171)
于氩气氛下,在干燥的schlenk试管中,将NaH(0.01g,60%在油中,0.24mmol)悬浮于无水THF(0.2mL)中,加入亚磷酸二乙酯(0.031mL,0.24mmol)。10分钟后,加入溶于无水THF(0.3mL)的化合物170(0.10g,0.20mmol),于回流温度下,加热反应混合物15小时。将反应混合物用水稀释,水层用EtOAc提取2次。合并的有机层用盐水洗涤、干燥(MgSO4)、过滤并真空浓缩。粗品产物经快速层析纯化(洗脱液为EtOAc/石油醚1∶2),得到目标化合物,为淡色油状物。
13C NMR(CDCl3):δ196.3,148.7,140.7,139.4,137.4,134.8,133.4,130.9,130.7,130.3,129.3,129.2,129.1,127.9,125.1,123.1,121.6,116.5,112.8,71.6,63.9,61.6,26.5,20.1,16.1
实施例72:2-{[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙基膦酸二乙酯(化合物172)
采用NaH(0.036g,60%在油中,0.9mmol)的无水THF(0.5mL)和亚磷酸二乙酯(0.13mL,1.0mmol),在制备化合物171的条件下进行反应。加入溶于无水THF(0.8mL)的化合物167(0.48g,0.82mmol),并回流18小时。在制备化合物171的条件下进行处理。粗品产物经快速层析纯化(洗脱液为EtOAc/石油醚1∶2-4∶1),得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.5,148.4,140.2,139.4,137.8,134.9,133.6,133.5,132.2,131.3,131.2,130.7,129.6,128.7,125.3,123.2,117.1,115.3,113.3,71.1,64.3,61.8,26.6,20.4,16.4
实施例73:2-({[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙氧基)乙基膦酸二乙酯(化合物173)
采用NaH(0.023g,60%在油中,0.6mmol)的无水THF(0.3mL)和亚磷酸二乙酯(0.078mL,0.6mmol),在制备化合物171的条件下进行反应。加入溶于无水THF(1.0mL)的化合物168(0.34g,0.55mmol),并回流18小时。在制备化合物171的条件下进行处理。粗品产物经快速层析纯化(洗脱液为EtOAc/石油醚1∶2-1∶0),得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.3,147.2,139.8,139.1,137.9,134.9,133.4,132.9,131.9,131.3,130.9,130.4,129.7,129.5,125.4,121.2,117.4,114.9,113.4,71.4,70.0,69.3,65.3,61.7,27.0,20.5,16.4
实施例74:2-[2-(2-{[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙氧基)乙氧基]乙基膦酸二乙酯(化合物174)
采用NaH(0.03g,60%在油中,0.76mmol)的无水THF(0.3mL)和亚磷酸二乙酯(0.098mL,0.76mmol),在制备化合物171的条件下进行反应。加入溶于无水THF(1.0mL)的化合物169(0.47g,0.69mmol),回流18小时。在制备化合物171的条件下进行处理。粗品产物经快速层析纯化(洗脱液为EtOAc/石油醚1∶1-EtOAc/MeOH 20∶1),得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.3,147.3,139.9,139.1,137.9,134.9,133.4,133.0,132.0,131.3,130.9,130.6,129.7,129.3,125.4,121.5,117.3,114.9,113.4,71.4,70.4,70.3,70.1,69.4,65.1,61.6,27.0,20.4,16.4
实施例75:2-{[2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氨基}-2-氧代乙基膦酸二乙酯(化合物175)
于氩气氛下,将化合物148(0.20g,0.56mmol)溶于恒温器中干燥的玻璃器皿中的无水DCM(1mL)。加入二乙基膦酰基乙酸(0.09mL,0.56mmol),随后滴加入二环己基碳化二亚胺(0.13g,0.61mmol,溶于1mL无水DCM)。于室温下,搅拌悬浮液7小时,随后将其过滤。用5mL DCM稀释滤液,并用10%NaHCO3、水和盐水洗涤。干燥有机层(MgSO4)、过滤并真空浓缩。粗品产物经快速层析纯化(洗脱液为EtOAc),得到目标化合物,为淡色油状物。
13C NMR(DMSO-D6):δ195.1,164.5,149.8,139.3,137.8,136.4,133.6,132.8,131.0,130.6,129.0,128.7,128.0,126.3,125.5,124.6,123.5,114.9,111.7,61.6,54.8,34.5,19.7,16.1
实施例76:2-{[5-溴代-2-({3-氯代-4-[(2甲基苯基)羰基]苯基}氨基)苯基]氨基}-2-氧代乙基膦酸二乙酯(化合物176)
于氩气氛下,在恒温器中干燥的玻璃器皿中进行反应。将二乙基膦酰基乙酸(0.085mL,0.53mmol)溶于无水甲苯(1mL),并加入亚硫酰氯(0.044mL,0.61mmol)。将反应混合物回流1小时后真空浓缩。将{4-[(2-氨基-4-溴苯基)氨基]-2-氯苯基(2-甲基苯基)甲酮(0.28g,0.48mmol)(公开于WO 01/05744)溶于无水DCM(1mL),加入N,N-二异丙基乙基胺(0.16mL,0.96mmol),随后滴加入上述溶于无水DCM(2.5mL)的酰氯。于室温下,搅拌反应混合物22小时,然后用DCM稀释。有机层用10%的NaHCO3水溶液、水和盐水洗涤、干燥(MgSO4)、过滤并真空浓缩。粗品产物经快速层析纯化(洗脱液为EtOAc/石油醚3∶1),得到目标化合物,为油状物。
13C NMR(CDCl3):δ196.5,163.2,148.0,139.0,138.0,134.9,133.3,131.9,131.8,131.3,130.9,129.7,129.4,129.2,126.9,125.4,124.5,117.2,116.6,113.0,63.4,36.1,20.5,16.3
实施例77:{[2-({5-溴代-3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙基(二乙氧基磷酰基)乙酸酯(化合物177)
于氩气氛下,在恒温器干燥的玻璃器皿中进行反应。将二乙基膦酰基乙酸(0.053mL,0.33mmol)溶于无水甲苯(2mL),加入亚硫酰氯(0.065mL,0.9mmol)。将反应混合物回流2小时,然后真空浓缩。将化合物158(0.14g,0.3mmol)溶于无水THF(1.5mL)。加入4-N,N-二甲基氨基吡啶(0.073g,0.6mmol),随后加入上述溶于THF(1.5mL)的酰氯。于回流温度下,加热反应混合物20小时。将反应混合物用EtOAc和NaHCO3水溶液稀释,有机层用水和盐水洗涤,合并的水层用EtOAc提取。将合并的有机层干燥(MgSO4),过滤并真空浓缩。粗品产物经快速层析纯化(洗脱液为EtOAc/石油醚2∶1),得到目标化合物,为淡色油状物。
13C NMR(CDCl3):δ196.4,165.7,147.5,139.4,139.1,138.0,134.9,133.4,133.0,132.0,131.3,130.9,129.7,129.5,125.4,122.1,117.3,115.5,113.4,70.9,68.1,64.8,62.9,34.4,20.5,16.3
实施例78:2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基膦酸(化合物178)
在氩气氛下,将化合物153(0.27g,0.56mmol)溶于无水DCM(5mL)。加入三甲基甲硅烷基溴化物(0.37mL,2.8mmol)并将溶液于室温下搅拌20小时。将溶液真空浓缩并与MeOH一起浓缩3次。粗品产物溶于MeOH并用活性炭处理、过滤并真空浓缩,得到目标化合物,为橙色油状物。
13C NMR(DMSO-D6):δ195.0,149.2,139.3,138.9,136.3,133.8,133.7,132.0,130.9,130.6,128.7,127.8,127.2,126.2,125.5,124.3,122.6,114.7,111.9,32.3,19.7
实施例79:N-[2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]-2,2,2-三氟乙磺酰胺(化合物179)
将化合物148(0.18g,0.71mmol)溶于无水吡啶(0.9mL),并加入2,2,2-三氟乙磺酰氯(0.12mL,1.1mmol)。于室温下搅拌溶液1小时,然后真空浓缩。用水稀释油状物,水层用EtOAc提取3次。用10%NaHCO3溶液洗涤合并的有机层、干燥(MgSO4)、过滤并真空浓缩。粗品产物经快速层析纯化(洗脱液为EtOAc/石油醚1∶2),得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.8,148.1,139.3,139.0,137.9,135.0,133.5,131.3,131.0,130.1,129.8,129.3,128.5,125.4,124.8,123.2,121.5,116.5,113.2,54.6,44.5,20.4
实施例80:N-[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苯基]-2,2,2-三氟乙磺酰胺(化合物180)
采用{4-[(2-氨基-4-溴苯基)氨基]-2-氯苯基}(2-甲基苯基)甲酮(0.15g,0.35mmol)(公开于WO 01/05744)的吡啶(0.47mL)和三氟乙磺酰氯(0.059mL,0.53mmol),在制备化合物179的条件下进行反应。反应时间为4小时。在制备化合物179的条件下进行处理,得到目标化合物,为棕色晶体。
13C NMR(CDCl3):δ196.8,149.2,147.3,138.5,138.3,134.9,134.0,133.2,131.5,131.3,131.0,130.2,130.0,127.1,125.7,125.5,121.3,118.0,117.1,113.7,53.1,20.6
实施例81:{2-氯代-4-[(2-{[(四氢-2H-吡喃-2-基氧基)丙氧基]甲基}苯基)氨基]苯基}(2-甲基苯基)甲酮(化合物181)
在制备化合物149的条件下进行反应和处理。起始原料为化合物425(2.6g,7.9mmol)的15mL无水1,4-二烷、(4-氨基-2-氯苯基)(2-甲基苯基)甲酮(2.14g,8.7mmol)(公开于WO 01/42189 A1)、rac-BINAP(0.22g,0.35mmol)、Pd2(dba)3(0.16g,0.17mmol)和Cs2CO3(3.9g,12.0mmol)。粗品产物经快速层析纯化(洗脱液为EtOAc/石油醚1∶3),得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.4,147.5,140.6,139.3,137.9,135.0,133.5,131.3,130.8,130.5,129.7,129.2,129.1,128.5,125.4,122.8,119.7,117.0,113.4,99.1,72.0,67.4,64.3,62.6,30.7,30.0,25.4,20.4,19.8
实施例82:[2-氯代-4-({2-[(羟基丙氧基)甲基]苯基}氨基)苯基](2-甲基苯基)甲酮(化合物182)
在制备化合物155的条件下进行反应和处理。起始化合物为化合物181(3.89g,7.9mmol)的100mL MeOH和p-甲苯磺酸(2.25g,11.82mol)。粗品产物经快速层析纯化(洗脱液为EtOAc/石油醚1∶1),得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.5,147.6,140.5,139.2,137.9,135.0,133.5,131.3,130.8,130.6,129.7,129.3,129.1,128.4,125.4,123.0,120.1,116.9,113.4,72.0,68.5,61.1,32.2,20.4
实施例83:3-{[2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}丙基膦酸二乙酯(化合物183)
在制备化合物149的条件下进行反应和处理。起始原料为化合物428(0.14g,0.4mmol)的3mL无水1,4-二烷、(4-氨基-2-氯苯基)(2-甲基苯基)甲酮(0.098g,0.4mmol)(公开于WO 01/42189 A1)、rac-BINAP(0.01g,0.016mol)、Pd2(dba)3(0.008g,0.009mmol)和Cs2CO3(0.18g,0.56mol)。粗品产物经快速层析纯化(洗脱液为EtOAc/石油醚1∶2->4∶1),得到目标化合物,为淡黄色油状物。
13C NMR(CDCl3):δ196.4,147.6,140.5,139.3,137.9,135.0,133.5,131.3,130.8,130.7,129.7,129.3,129.1,128.4,125.4,122.9,120.0,117.1,113.5,71.8,69.6,61.6,23.4,23.0,20.4,16.5
实施例84:2-[2-({3-氯代-4-[(2-甲基苯基)羰基]苯基})氨基]苯基]乙基膦酸二乙酯(化合物184)
在制备化合物149的条件下进行反应和处理。起始原料为化合物431(0.73g,2.3mmol)的19mL无水1,4-二烷、(4-氨基-2-氯苯基)(2-甲基苯基)甲酮(0.55g,2.3mmol)(公开于WO 01/42189 A1)、rac-BINAP(0.06g,0.08mmol)、Pd2(dba)3(0.046g,0.05mmol)和Cs2CO3(1.04g,3.18mmol)。粗品产物经快速层析纯化(洗脱液为EtOAc),得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.4,149.7,139.7,138.5,137.6,135.3,134.9,134.7,133.8,131.1,130.6,130.5,129.4,127.6,125.3,125.2,124.4,115.6,112.2,61.7,26.6,23.9,20.3,16.3
实施例85:2-[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苯基]乙基膦酸二乙酯(化合物185)
在制备化合物158的条件下进行反应和处理。起始原料为化合物184(0.37g,0.8mmol)的11mL的DMSO和48%的HBr(2.6mL,23mol)水溶液。反应时间为5天。粗品产物经快速层析纯化(洗脱液为EtOAc/石油醚1∶2->1∶0),得到目标化合物,为无色晶体化合物。
13C NMR(CDCl3):δ196.4,149.0,139.4,138.0,137.8,136.7,136.6,135.2,133.7,133.4,131.2,130.7,129.5,128.3,125.5,125.3,117.4,115.9,112.5,61.9,26.4,23.7,20.4,16.3
实施例86:2-{[2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氨基}-2-氧代乙基膦酸(化合物186)
在氩气氛下,将化合物175(0.04g,0.075mmol)溶于无水CH2Cl2(0.5mL)。加入三甲基甲硅烷基溴化物(0.1mL,0.75mmol),于室温下,放置溶液45小时。真空浓缩溶液,然后与MeOH一起浓缩3次,得到目标化合物,为橙色油状物。
13C NMR(DMSO d-6):δ195.6,166.3,150.3,139.7,138.2,136.7,134.1,133.9,133.6,131.4,131.0,129.6,129.1,128.3,126.5,126.0,125.1,124.0,115.2,112.1,37.5,20.1
实施例87:(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-氨基甲酸苯乙酯(化合物187)
于氩气氛下进行反应。将2-苯基乙醇(0.108mL)的DCM(2.5mL,0.90mmol)溶液冷却至0℃。于搅拌下,缓慢加入双(三氯代甲基)碳酸酯(0.097g,0.33mmol)和吡啶(0.07mL,0.90mmol)的DCM(2.5mL)的混合物。于室温下,将反应混合物搅拌2小时,然后过滤,并真空浓缩。残留物溶于DCM(2.5mL),加入{2-氯代-4-[(2-氨基苯基)氨基]苯基}(2-甲基苯基)甲酮(0.150g,0.45mmol)(公开于WO 98/32730)和碳酸钾(0.25g,1.78mmol)。于室温下,搅拌反应混合物48小时,之后倾至水和Et2O的混合物中。水层经更多的Et2O提取。用水、盐水洗涤合并的有机层、干燥(MgSO4)、过滤并真空浓缩。粗品产物经快速层析纯化(洗脱液为EtOAc/石油醚1∶3),得到目标化合物。
13C NMR(CDCl3):δ196.6,154.0,149.1,139.1,137.9,137.5,135.0,133.5,133.1,131.3,130.9,130.6,129.7,129.0,128.9,128.6,126.8,126.7,125.8,125.4,125.0,121.9,116.1,112.4,66.1,35.3,20.4
实施例88:N-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-2-苯氧基-乙酰胺(化合物188)
将2-苯氧基乙酸(75mg,0.49mmol)、亚硫酰氯(72μL,1.0mm0l)和一滴DMF的甲苯(2.0mL)溶液回流30分钟。将反应混合物真空浓缩,得到的粗品酰氯溶于无水DCM(2.0ml)。向冷却的(0℃){2-氯代-4-[(2-氨基苯基)氨基]苯基}(2-甲基苯基)甲酮(0.150g,0.45mmol)(公开于WO 98/32730)和三乙基胺(135mg,1.33mmol)的无水DCM(5.0ml)溶液中缓慢加入该溶液。冷却溶液至室温。搅拌反应混合物3小时,然后倾至NaHCO3(水溶液)和EtOAc中。水层用更多的EtOAc(x2)提取。合并的有机层用盐水洗涤、干燥(MgSO4)、过滤并真空浓缩。粗品产物经快速层析纯化(洗脱液为DCM),得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.5,166.9,156.7,148.8,139.0,137.8,135.1,133.6,131.8,131.4,131.2,130.8,129.9,129.6,128.9,126.6,126.3,125.7,125.3,122.9,122.4,116.0,114.5,112.1,67.3,20.4
实施例89:N-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-3-苯氧基-丙酰胺(化合物189)
采用3-苯氧基丙酸(81mg,0.49mmol)作为羧酸,在制备化合物188的条件下进行反应和处理。经快速层析纯化(洗脱液为石油醚/EtOAc 1∶1),得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.7,170.0,157.9,148.8,139.2,137.7,134.9,133.5,132.4,132.0,131.2,130.8,129.6,129.5,128.5,126.1,125.9,125.4,124.9,123.8,121.5,116.2,114.5,112.4,63.9,37.2,20.4
实施例90:N-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-2-(1,3-二氧代-1,3-二氢-异吲哚-2-基)-乙酰胺(化合物190)
采用(1,3-二氧代-1,3-二氢-异吲哚-2-基)乙酰氯(219mg,0.98mmol)作为酰氯。在制备化合物188的条件下进行反应和处理。经快速层析纯化(洗脱液为DCM/EtOAc 10∶1),得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.5,167.8,165.2,148.9,139.1,137.9,134.9,134.6,133.5,132.1,131.7,131.3,130.9,129.7,128.9,126.4,126.2,125.4,123.8,123.0,116.1,112.3,41.6,20.5
实施例91:N-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-琥珀酰胺酸2-(2-甲氧基乙氧基)乙酯(化合物191)
将偶氮二甲酸二乙酯(40%在甲苯中,229μL,0.5mmol)溶液缓慢加至N-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-琥珀酰胺酸(200mg,0.46mmol)(公开于WO 01/05746)、三苯基膦(132mg,0.50mmol)和2-(2-甲氧基乙氧基)乙醇(55mg,0.46mmol)的无水甲苯(2.5ml)中。搅拌反应混合物48小时,然后倾至水和EtOAc的混合物中。水层用更多EtOAc(x2)提取。合并的有机层用盐水洗涤、干燥(MgSO4)、过滤并真空浓缩。粗品产物经快速层析纯化(洗脱液为EtOAc),得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.6,173.0,171.1,148.7,139.3,137.7,135.0,133.6,133.4,131.2,130.9,130.8,129.5,128.4,126.4,125.4,125.1,124.7,123.7,116.4,112.5,71.8,70.4,68.9,63.9,59.0,31.7,29.7,20.4
实施例92:N-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-苯磺酰胺(化合物192)
向冷却的(冰/水){2-氯代-4-[(2-氨基苯基)氨基]苯基}(2-甲基苯基)甲酮(0.67g,2.0mmol)(公开于WO 98/32730)的吡啶(10mL)溶液中加入苯磺酰氯(0.32mL,2.5mmol)。将反应混合物温热至室温。搅拌48小时,将反应混合物倾至冰水中。过滤沉淀,用水和***洗涤,得到粗品产物。自乙酸结晶得到目标化合物,为固体。
M.p:211-215℃
13C NMR(DMSO-d6):δ195.2,148.6,139.4,139.2,136.4,134.0,133.2,133.2,132.3,131.0,130.6,129.7,128.7,126.7,126.6,126.4,126.2,125.6,124.6,123.8,114.6,112.1,19.7
实施例93:乙酸(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基氨基甲酰基)-甲酯(化合物193)
采用乙酰氧基乙酰氯(62μL,0.58mmol)作为酰氯,在制备化合物188的条件下进行反应和处理。经快速层析纯化(洗脱液为石油醚/EtOAc1∶1),得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.5,169.3,165.8,148.6,138.9,138.0,135.0,133.5,131.7,131.6,131.4,131.0,129.7,129.3,126.6,125.6,125.4,123.2,116.0,112.4,63.2,20.5
实施例94:1-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)吡咯烷-2,5-二酮(化合物194)
于-15℃,将氯甲酸异-丁酯(60μL,0.46mmol)加至搅拌的N-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-琥珀酰胺酸(200mg,0.46mmol)(公开于WO 01/05746)和4-甲基吗啉(51μL,0.46mmol)的THF(5.0mL)溶液中。5分钟后,于0℃,将反应混合物冷却至-15℃,加入乙基二异丙基胺(65μL,0.46mmol)的THF(5.0mL)溶液。于0℃,将得到的反应混合物放置1小时。于室温下,搅拌反应混合物16小时,然后倾至1MHCl(水溶液)和EtOAc的混合物中。有机层用更多的HCl(水溶液)(x2)中。有机层用盐水洗涤、干燥(MgSO4)、过滤并真空浓缩。粗品产物经快速层析纯化(洗脱液为石油醚/EtOAc 1∶2),得到目标化合物,为油状物。
13C NMR(CDCl3):δ196.5,176.2,147.8,138.9,138.0,137.0,134.8,133.3,131.3,131.0,130.3,129.7,129.5,129.1,126.3,125.6,125.4,125.2,116.9,113.1,28.6,20.5
实施例95:2-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)乙基丙酸酯(化合物195)
采用丙酰氯(63mg,0.68mmol)为酰氯,在制备化合物188的条件下进行反应和处理。经快速层析纯化(洗脱液为DCM),得到目标化合物,为油状物。
13C NMR(CDCl3):δ196.4,174.8,148.8,139.3,138.9,137.8,135.1,133.7,131.2,131.1,130.9,130.7,129.6,128.6,128.0,125.3,124.8,123.2,116.0,112.7,64.5,31.2,27.6,20.4,9.0
实施例96:2,2-二甲基-丙酸2-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)乙酯(化合物196)
采用新戊酰氯(32mg,0.27mmol)作为酰氯,在制备化合物188的条件下进行反应和处理。经快速层析纯化(洗脱液为石油醚/EtOAc 10∶1),得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.5,179.2,148.9,139.4,138.8,137.8,135.2,133.6,131.2,131.1,130.8,130.7,129.6,128.6,128.0,125.3,124.8,123.3,116.0,112.6,64.1,38.8,31.2,27.2,20.4
实施例97:[2-氯代-4-({2-[3-(四氢-2H-吡喃-2-基氧基)丙氧基]苯基}氨基)苯基](2-甲基苯基)甲酮(化合物197)
采用2-[3-(2-溴苯氧基)丙氧基]四氢-2H-吡喃(4.10g)作为溴化物,在制备化合物101的条件下进行反应和处理。经快速层析纯化(洗脱液为石油醚/EtOAc 4∶1),得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.4,149.2,147.4,139.2,137.9,134.9,133.4,131.3,130.8,130.1,129.7,129.3,125.4,123.0,120.9,118.6,117.1,113.5,112.4,99.1,65.8,64.0,62.6,30.7,29.6,25.4,20.4,19.7
实施例98:(2-氯代-4-{[2-(3-羟基丙氧基)苯基]氨基}苯基)(2-甲基苯基)甲酮(化合物198)
在制备化合物102的条件下进行反应和处理。起始化合物为化合物197(2.56g)的MeOH(5.0mL)和4-甲苯磺酸(1.52g)。经快速层析纯化(洗脱液为石油醚/EtOAc 4∶1),得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.5,149.5,147.4,139.2,137.9,134.9,133.4,131.3,130.8,130.1,129.7,129.3,125.4,123.3,121.2,119.1,117.0,113.5,112.8,66.4,60.1,32.0,20.5
实施例99:2-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)乙基碳酸叔-丁酯(化合物199)
将化合物102(200mg)溶于无水三乙胺(3.0mL),加入{[(叔-丁氧基羰基)氧基]氨基}(苯基)乙腈(148mg)。于70℃,搅拌溶液5小时。将反应混合物冷却至室温,然后倾至水和EtOAc的混合物中。用更多的EtOAc(x2)提取水层。合并的有机层用盐水洗涤、干燥(MgSO4)、过滤和真空浓缩。粗品产物经快速层析纯化(洗脱液为石油醚/***8∶1),得到目标化合物。
13C NMR(CDCl3):δ196.5,153.5,148.8,139.4,139.2,137.8,135.2,133.7,131.3,131.2,130.8,130.7,129.6,128.5,128.0,125.3,124.6,122.6,116.4,112.6,82.9,67.5,31.7,27.8,20.4
实施例100:2-({[(5-溴代-2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)氨基]羰基}氨基)乙基2-甲基丙烯酸酯(化合物200)
将2-异氰酸根合乙基2-甲基丙烯酸酯(0.31g,2.2mmol)缓慢加至{4-[(2-氨基-4-溴苯基)氨基]-2-氯苯基}(2-甲基苯基)甲酮(0.60g,1.44mmol)(公开于WO 01/05744)的无水吡啶(3.00mL)溶液中。于室温下,搅拌溶液6小时,然后倾至水和EtOAc的混合物中。水层用更多的EtOAc(x2)提取。合并的有机层用盐水洗涤、干燥(MgSO4)、过滤并真空浓缩。粗品产物经快速层析纯化(洗脱液为石油醚/EtOAc 4∶1),得到目标化合物,为淡棕色固体。
13C NMR(CDCl3):δ197.4,167.6,155.7,149.0,138.8,137.8,135.8,135.0,134.8,133.6,131.4,131.2,130.1,129.8,128.5,127.3,126.3,126.1,125.5,125.4,118.7,116.3,112.5,63.7,39.6,20.5,18.3
实施例101:(4-{[4-溴代-2-(2-羟基乙基)苯基]氨基}-2-氯代-苯基)(2-甲基苯基)甲酮(化合物201)
采用化合物102(0.10g,0.22mmol)的DMSO(3.0mL)和48%HBr(0.4mL,6.70mmol)水溶液,在制备化合物158的条件下进行反应和处理。反应时间为2天。粗品产物经快速层析纯化(洗脱液为EtOAc/石油醚1∶4),得到目标化合物,为黄色油状物。
13C NMR(CDCl3):196.6,148.3,139.3,139.0,137.8,135.5,135.2,133.9,133.7,131.2,130.8,130.4,129.6,128.4,125.3,123.7,116.7,116.2,112.5,64.9,34.4,20.4
实施例102:3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯氧基)丙基乙酸酯(化合物202)
于20℃,搅拌下将乙酸酐(72μL,0.77mmol)加至化合物198(121mg,0.31mmol)的100%乙酸(1.0mL)溶液中。于80℃,将反应混合物搅拌过夜,然后倾至水和EtOAc的混合物中。水层用更多的EtOAc(x2)提取。用水洗涤合并的有机层、干燥(MgSO4)、过滤并真空浓缩。粗品产物经快速层析纯化(洗脱液为石油醚/EtOAc 4∶1),得到目标化合物。
13C NMR(CDCl3):δ196.8,171.5,149.5,147.8,139.6,138.3,135.3,133.8,131.7,131.2,130.5,130.1,129.6,125.8,123.5,121.5,119.3,117.5,114.0,112.8,65.4,61.4,29.0,21.4,20.8
实施例103:[2-氯代-4-({2-[3-(吗啉-4-基)丙氧基]苯基}氨基)苯基](2-甲基苯基)甲酮(化合物203)
于氩气氛下,将化合物198(100mg,0.25mmol)溶于无水吡啶(130μL)。将溶液在冰浴上冷却并加入4-甲苯磺酰氯(48mg,0.25mmol)。45分钟后,于室温下,用水淬灭反应混合物。水层用EtOAc提取2次。用盐水洗涤合并的有机层、干燥(MgSO4)、过滤并真空浓缩。粗品产物经快速层析纯化(洗脱液为石油醚/EtOAc 4∶1)。将甲苯磺酸酯溶于无水DMF(2.0mL)并加入吗啉(17μL,0.19mmol)。于室温下,搅拌反应混合物48小时,然后倾至水和EtOAc的混合物中。水层用更多的EtOAc(x2)提取。用水洗涤合并的有机层、干燥(MgSO4)、过滤并真空浓缩。粗品产物经快速层析纯化(洗脱液为DCM/MeOH 100:4),得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.4,149.4,147.4,139.2,137.9,134.9,133.4,131.3,130.8,129.9,129.7,129.3,125.4,123.2,120.9,119.0,117.1,113.6,112.3,66.9,66.9,55.5,53.8,26.4,20.5
实施例104:N-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-N′-(4-苯氧基丁基)琥珀酰胺(化合物204)
将4-(4,6-二甲氧基-1,3,5-三嗪-2-基)-4-甲基吗啉-4-氯化物(DMTMM)(69mg,0.25mmol)加至N-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-琥珀酰胺酸(100mg,0.23mmol)(公开于WO 01/05746)和4-苯氧基丁基胺(30mg,0.25mmol)的甲醇(2.0mL)溶液。于室温下,搅拌反应混合物18小时。将反应混合物倾至1NHCl(水溶液)中,用EtOAc(x2)提取。用水洗涤合并的有机层、干燥(MgSO4)、过滤并真空浓缩。粗品产物经快速层析纯化(洗脱液为DCM/MeOH/NH3(水溶液)95∶5∶0.5),得到目标化合物,为黄色固体。
13C NMR(CDCl3):δ196.6,172.4,171.8,158.8,148.6,139.2,137.8,134.9,133.5,133.4,131.2,130.8,130.6,129.7,129.5,128.6,126.3,125.4,124.9,124.7,123.2,120.8,116.6,114.5,112.4,67.2,39.5,32.4,31.5,26.7,26.3,20.4
实施例105:N-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-N′-(6-羟基己基)琥珀酰胺(化合物205)
将4-(4,6-二甲氧基-1,3,5-三嗪-2-基)-4-甲基吗啉-4-氯化物(DMTMM)(138mg,0.50mmol)加至N-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-琥珀酰胺酸(200mg,0.46mmol)(公开于WO 01/05746)和6-氨基己醇(60mg,0.51mmol)的THF(4.0mL)溶液中。于室温下,搅拌反应混合物18小时。将反应混合物倾至1NHCl(水溶液)中,用EtOAc(x2)提取。用水洗涤合并的有机层、干燥(MgSO4)、过滤并真空浓缩。粗品产物经快速层析纯化(洗脱液为DCM/MeOH/NH3(水溶液)95∶5∶0.5),得到目标化合物,为黄色固体。
13C NMR(CDCl3):δ196.7,172.5,171.8,148.6,139.2,137.8,134.9,133.5,133.4,131.3,130.8,130.5,129.7,128.6,126.2,125.4,124.9,124.7,123.0,116.6,112.5,62.4,39.6,32.5,32.3,31.5,29.4,26.2,25.1,20.4
实施例106:N-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-N′-(2,3-二羟基丙基)琥珀酰胺(化合物206)
在制备化合物204的条件下进行反应和处理。起始化合物为N-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-琥珀酰胺酸(100mg,0.46mmol)(公开于WO 01/05746)和3-氨基丙烷-1,2-二醇(23mg,0.25mmol)。粗品产物经快速层析纯化(洗脱液为DCM/MeOH/NH3(水溶液)90∶10∶0.5),得到目标化合物,为黄色固体。
13C NMR(CDCl3):δ197.1,173.8,172.2,148.8,138.9,137.9,134.7,133.4,133.3,131.3,131.1,130.7,129.8,128.4,126.4,125.4,124.9,123.5,70.9,63.9,42.3,32.0,31.0,20.5
实施例107:(1R)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-1-(羟基甲基)丙基氨基甲酸叔-丁酯(化合物207)
将三氟乙酸(78μL,0.78mmol)加至化合物434(213mg,0.39mmol)的湿润的MeOH(2.50mL)溶液中。回流反应混合物10小时,然后倾至饱和的NaHCO3和EtOAc的混合物中。用盐水洗涤有机层、干燥(MgSO4)、过滤并真空浓缩。粗品产物经快速层析纯化(洗脱液为石油醚/EtOAc 2∶1),得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.5,156.7,149.8,139.5,138.2,137.7,136.0,135.2,133.8,131.2,130.6,130.5,129.5,127.9,127.3,125.5,125.3,124.6,115.9,112.1,80.1,65.4,52.2,32.6,28.4,27.5,20.4
实施例108:6-[3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基氨基甲酰基)丙酰氨基]-己基磷酸二乙酯(化合物208)
于0℃,将一定量的碘(53mg,0.21mmol)加至亚磷酸三乙酯(36L,0.21mmol)的无水DCM(0.50mL)溶液中。于0℃,搅拌15分钟,再于室温下搅拌5分钟,将溶液通过导管加至化合物205(101mg,0.19mmol)的无水吡啶(61uL,0.75mmol)溶液中。于0℃,搅拌90分钟后,再于室温下搅拌90分钟,将反应混合物倾至水和DCM中。用水洗涤有机层、干燥(MgSO4)、过滤并真空浓缩。粗品产物经快速层析纯化(洗脱液为DCM/MeOH 97∶3),得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.6,172.5,171.9,148.7,139.3,137.8,134.9,133.5,133.4,131.2,130.8,129.6,128.5,126.1,125.4,124.9,124.6,123.1,116.6,112.4,67.3,63.8,39.3,32.7,31.6,29.9,29.2,25.9,24.7,20.4,16.1
实施例109:N-({[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]氨基}羰基)氨基乙酸乙酯(化合物209)
将异氰酸根合乙酸乙酯(45mg,0.35mmol)加至化合物111(100mg,0.27mmol)的无水DCM(1.0mL)溶液中。于室温下,搅拌溶液5小时,然后倾至水和DCM的混合物中。用更多的DCM(x2)提取有机层。用盐水洗涤合并的有机层、干燥(MgSO4)、过滤并真空浓缩。粗品产物经快速层析纯化(洗脱液为石油醚/EtOAc 4∶1),得到目标化合物。
13C NMR(CDCl3):δ196.8,172.0,158.6,149.4,139.4,137.6,137.5,135.0,133.6,131.3,131.2,130.8,129.5,129.2,128.4,127.8,127.2,126.1,125.4,124.9,123.4,116.5,112.5,61.5,42.6,42.2,20.4,14.1
实施例110:2-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)乙基(甲基)氨基甲酸叔-丁酯(化合物210)
在制备化合物101的条件下进行反应和处理。起始化合物为(4-氨基-2-氯苯基)(2-甲基苯基)甲酮(211mg,0.86mmol)(公开于WO 01/42189 A1)和化合物435(324mg,1.03mmol)。粗品产物经快速层析纯化(洗脱液为石油醚/EtOAc 6∶1),得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.5,149.3,139.7,139.4,137.7,135.2,133.7,131.1,130.5,129.5,127.5,125.3,123.5,122.0,116.4,112.2,80.4,50.0,35.1,31.1,28.5,20.3
实施例111:N-(5-溴代-2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-N′-(6-羟基己基)琥珀酰胺(化合物211)
在制备化合物205的条件下进行反应和处理。起始化合物为N-(5-溴2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-琥珀酰胺酸(600mg,1.16mmol)(与WO 01/05746中所述的制备方法类似)和6-氨基己醇(151mg,1.28mmol)。粗品产物经快速层析纯化(洗脱液为EtOAc),得到目标化合物,为黄色固体。
13C NMR(CDCl3):δ196.7,172.6,171.8,148.2,139.0,138.0,134.9,133.3,132.1,131.4,131.0,129.8,129.2,128.9,127.2,125.4,124.3,117.0,116.8,112.7,62.4,39.7,32.5,32.3,31.4,29.4,26.3,25.1,20.5
实施例112:N-(5-溴代-2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-N′-(2,3-二羟基丙基)琥珀酰胺(化合物212)
在制备化合物211的条件下进行反应和处理。起始化合物为N-(5-溴2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-琥珀酰胺酸(600mg,1.16mmol)(根据WO 01/05746中所述的方法制备)和3-氨基-1,2-丙二醇(117mg,1.28mmol)。粗品产物经快速层析纯化(洗脱液为EtOAc,随后EtOAc/MeOH 95∶5),得到目标化合物,为固体。
13C NMR(CDCl3):δ197.2,173.9,172.2,148.4,138.7,138.1,134.6,133.3,132.3,132.0,131.4,131.3,130.0,129.0,127.2,125.5,124.9,117.3,116.8,112.7,70.9,64.0,42.4,32.1,31.6,20.6
实施例113:(2Z)-N-[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]-2-(2,5-二氧代咪唑烷-4-叉)乙酰胺(化合物213)
于20℃,将(2Z)-(2,5-二氧代咪唑烷-4-叉)乙酸(35mg,0.22mmol)和化合物111(75mg,0.20)的THF(1.5mL)混合物搅拌10分钟。将DMTMM(40mg)加至混合物并于20℃搅拌20小时。将反应混合物倾至水中,并用EtOAc(x3)提取。合并有机层并用盐水洗涤,经MgSO4干燥。粗品产物经层析纯化(洗脱液为石油醚/EtOAc 2∶3,随后EtOAc),得到目标化合物,为黄色泡沫。
13C NMR(DMSO-d6):δ195.1,164.7,164.4,154.6,150.4,139.3,137.3,137.1,136.3,133.6,131.8,130.9,130.5,128.7,128.5,127.9,126.5,126.2,125.9,125.5,125.4,125.1,114.7,111.5,97.6,40.8,19.7
实施例114:(2-氯代-4-{[2-(二氟甲基)苯基]氨基}苯基)(2-甲基苯基)甲酮(化合物214)
在制备化合物101的条件下进行反应和处理。起始化合物为(4-氨基-2-氯苯基)(2-甲基苯基)甲酮(270mg,1.10mmol)(公开于WO 01/42189 A1)和化合物1-溴代-2-(二氟甲氧基)苯(324mg,1.03mmol)。粗品产物经快速层析纯化(洗脱液为石油醚/EtOAc 9∶1),得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.4,146.2,141.6,138.8,138.2,134.8,133.1,132.9,131.4,131.1,130.7,130.0,126.3,125.4,123.1,120.3,119.7,117.8,116.3,114.4,20.6
实施例115:3-{[2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苯基]乙基}-1-甲基咪唑烷-2,4-二酮(化合物215)
于搅拌下,将(4-氨基-2-氯苯基)(2-甲基苯基)甲酮(61mg,0.25mmol)(公开于WO 01/42189 A1)、化合物436(89mg,0.30mmol)、BINAP(5mg)、Pd2(dba)3(5mg)和Cs2CO3(114mg,0.35mmol)的1,4-二烷(5ml)混合物加热至120℃3天。过滤反应混合物。将得到的溶液真空浓缩。残留物经层析纯化(洗脱液为石油醚/乙酸乙酯1∶1),得到所需的不纯的产物。该不纯的产物进一步经制备性TLC纯化(石油醚/乙酸乙酯2∶1),得到纯净的目标化合物,为褐色油状物。
1H NMR(CDCl3):δ7.53(d,1H),7.4-7.0(m,9H),6.95(bs,1H),6.89(dd,1H),3.80(s,2H),3.79(m,2H),3.08(m,2H),2.91(s,3H),2.44(s,3H)
实施例116:3-{[2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苯基]乙基}-5,5二甲基唑啉-2,4-二酮(化合物216)
将(4-氨基-2-氯苯基)(2-甲基苯基)甲酮(31mg,0.13mmol)(公开于WO01/42189 A1)和化合物437(47mg,0.15mmol)如制备化合物215的方法处理。经快速层析纯化(石油醚/乙酸乙酯4∶1),得到目标化合物,为褐色油状物。
13C NMR(CDCl3):δ196.5,176.1,154.6,149.0,139.3,139.0,137.9,135.1,133.6,131.4,131.2,131.0,130.7,129.6,128.8,128.6,125.4,125.3,124.7,116.0,112.6,84.0,39.0,29.8,23.4,20.4
实施例117:4-{[2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苯基]乙基}吗啉-3,5二酮(化合物217)
将(4-氨基-2-氯苯基)(2-甲基苯基)甲酮(61mg,0.25mmol)(公开于WO01/42189 A1)和化合物438(89mg,0.30mmol)的混合物如制备化合物215的方法处理。经快速层析纯化(石油醚/乙酸乙酯4∶1),得到目标化合物,为褐色油状物。
13C NMR(CDCl3):δ196.5,169.5,148.5,139.3,139.0,137.8,135.1,133.6,131.2,131.2,130.7,129.8,129.6,128.8,128.2,125.3,124.1,122.2,116.3,113.0,77.2,67.6,38.6,30.3,20.4
实施例118:1-{[2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苯基]乙基}哌啶-2,6-二酮(化合物218)
将(4-氨基-2-氯苯基)(2-甲基苯基)甲酮(61mg,0.25mmol)(公开于WO01/42189 A1)和化合物439(89mg,0.30mmol)的混合物如制备化合物215的方法处理。经快速层析纯化(石油醚/乙酸乙酯2∶1),得到目标化合物,为褐色油状物。
13C NMR(CDCl3):δ196.5,172.9,148.6,139.4,139.1,137.8,135.0,133.6,131.2,130.7,130.2,129.7,129.6,128.5,127.9,125.3,123.6,121.4,116.4,113.1,39.6,32.7,30.6,20.4,17.1
实施例119:4-(2-{[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙基)吗啉-3,5-二酮(化合物219)
于室温下,向化合物158(47mg,0.1mmol)、吗啉-3,5-二酮(16mg,0.14mmol)和三苯基膦(37mg,0.14mmol)的THF(5ml)溶液中加入偶氮二甲酸二乙酯溶液(40%在甲苯中,0.1ml,0.23mmol)。于相同温度下,搅拌反应溶液18小时,并真空浓缩。残留物经层析纯化(石油醚/乙酸乙酯1∶1),得到不纯目标化合物。产物经制备性TLC进一步纯化(石油醚/乙酸乙酯1∶1),得到纯净的目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.5,169.4,147.0,140.0,139.1,138.0,134.9,133.4,132.2,131.3,130.9,129.9,129.8,125.4,121.4,117.4,114.8,113.9,71.1,67.7,66.8,38.1,20.5
实施例120:1-(2-{[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙基)吡咯烷-2,5-二酮(化合物220)
将化合物158(47mg,0.1mmol)、琥珀酰亚胺(14mg,0.14mmol)如制备化合物219的方法制备。经快速层析纯化(石油醚/乙酸乙酯1∶1),得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.5,177.4,147.2,139.9,139.0,138.0,134.9,133.5,133.4,132.2,131.3,130.9,130.0,129.8,129.6,125.4,121.7,117.3,114.9,113.8,70.8,66.6,38.5,28.2,20.5
实施例121:2-[3-(2-{5-溴代-[2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄(bezoyl)氧基}乙基)-2,4,5-三氧代咪唑烷-1-基]乙酸乙酯(化合物221)
将化合物158(47mg,0.1mmol)和2,4,5-三氧代咪唑烷-1-乙酸乙酯(28mg,0.14mmol)如制备化合物219的方法处理。经快速层析纯化(石油醚/醚1∶1),得到不纯目标化合物。产物进一步经层析纯化(CH2Cl2/乙酸乙酯15∶1),得到目标化合物,为黄色泡沫。
13C NMR(CDCl3):δ165.8,153.1,146.9,139.9,139.0,138.1,134.8,133.4,133.3,132.4,131.4,131.0,130.0,129.8,129.7,125.4,121.7,117.4,115.0,114.0,71.1,66.1,62.6,39.8,39.3,20.5,14.0
实施例122:3-(2-{[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙基}咪唑烷-2,4-二酮(化合物222)
将化合物158(47mg,0.1mmol)、乙内酰脲(14mg,0.14mmol)如制备化合物219的方法处理。经快速层析纯化(石油醚/乙酸乙酯1∶1),得到不纯目标化合物。产物进一步经制备性TLC纯化(石油醚/乙酸乙酯1∶1),得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.5,171.3,157.8,147.4,139.9,139.1,138.0,134.9,133.5,133.4,132.2,131.3,130.9,130.2,129.8,129.5,125.4,121.9,117.3,115.0,113.7,70.9,66.9,46.4,38.5,20.5
实施例123:1-(2-{[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙基)-3,4-顺式-二乙酰氧基吡咯烷-2,5-二酮(化合物223)
将化合物158(67mg,0.1mmol)和2,3-顺式-二乙酰氧基琥珀酰亚胺(30mg,0.14mmol)如制备化合物219的方法处理。经快速层析纯化(CH2Cl2/乙酸乙酯1∶20),得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.5,169.9,169.5,147.1,139.9,139.0,138.0,134.8,133.5,133.3,132.3,131.3,130.9,130.0,129.8,125.4,121.7,117.5,115.0,113.9,72.7,71.0,66.1,39.2,20.5,20.3
实施例124:3-(2-{[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙基)噻唑啉-2,4-二酮(化合物224)
将化合物158(47mg,0.1mmol)和2,4-噻唑啉二酮(16mg,0.14mmol)如制备化合物219的方法处理。经快速层析纯化(石油醚/乙酸乙酯3∶1),得到不纯目标化合物。产物经制备性TLC进一步纯化(石油醚/乙酸乙酯3∶1),得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.5,172.0,171.6,147.0,139.9,139.0,138.0,134.9,133.4,133.4,132.3,131.3,130.9,129.8,125.4,121.6,117.4,114.9,114.0,71.0,66.3,41.5,33.8,20.5
实施例125:3-(2-{[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙基)-1-甲基咪唑烷-2,4-二酮(化合物225)
将化合物158(47mg,0.1mmol)和甲基乙内酰脲(16mg,0.14mmol)如制备化合物219的方法处理。经快速层析纯化(石油醚/乙酸乙酯1∶1),得到不纯目标化合物。产物经制备性TLC进一步纯化(石油醚/乙酸乙酯1∶1),得到纯的目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.5,170.0,156.7,147.4,140.0,139.1,137.9,134.9,133.6,133.4,132.2,131.3,130.9,130.3,129.7,129.5,125.4,121.9,117.4,115.0,113.7,70.8,67.2,51.7,38.7,29.7,20.5
实施例126:1-(2-{[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙基)咪唑烷-2,4,5-三酮(化合物226)
将化合物158(47mg,0.1mmol)和乙二酰脲(16mg,0.14mmol)如制备化合物219的方法处理。经快速层析纯化(CH2Cl2/乙酸乙酯4∶1),得到不纯目标化合物。产物经制备性TLC进一步纯化(CH2Cl2/乙酸乙酯20∶1),得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.4,156.4,153.8,146.8,139.7,138.9,138.1,134.8,133.3,132.4,131.4,131.0,130.0,129.9,129.8,125.4,121.8,117.4,115.1,113.9,70.9,66.1,39.2,20.5
实施例127:(2-氯代-4-{[2-(羟基甲基)苯基]氨基}苯基)(2-甲基苯基)甲酮(化合物227)
将化合物441(3.21g,6.32mmol)和TBAF·3H2O(2.99g,6.32mmol)溶于THF(20ml)。于室温下,将得到的反应溶液搅拌0.5h。反应后,真空浓缩溶液。残留物再溶于CH2Cl2并用水洗涤。水层用CH2Cl2提取2次。经MgSO4干燥合并的有机层并真空浓缩。粗品产物经层析纯化(石油醚/乙酸乙酯2∶1),得到目标化合物,为红色泡沫。
13C NMR(CDCl3):δ196.7,147.5,140.4,139.1,137.9,135.0,133.5,131.3,130.9,130.8,129.7,129.7,129.2,129.0,125.4,123.1,120.1,117.0,113.4,64.3,20.4
实施例128:2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苄基乙酸酯(化合物228)
于室温下,向化合物227(50mg,0.14mmol)、Et3N(0.1ml)和DMAP(3mg)的溶液中加入Ac2O(0.05ml)。于相同温度下,将反应溶液搅拌1小时。反应后,真空浓缩溶液。残留物再溶于CH2Cl2,用饱和的碳酸氢钠水溶液洗涤。水层用CH2Cl2提取2次。合并的有机层经MgSO4干燥并真空浓缩。残留物经硅胶短柱过滤(乙酸乙酯/石油醚1∶2),得到目标化合物,为黄色油状物。
13C NMR(CDCl3):δ196.4,171.8,148.1,139.7,139.2,137.8,135.1,133.5,132.3,131.2,130.8,130.1,129.6,128.9,128.0,125.3,124.2,122.1,116.5,113.0,63.6,21.0,20.4。
Claims (10)
2.权利要求1的化合物,其中R1代表甲基。
3.权利要求1的化合物,其中R2代表2-氯。
4.权利要求1-3中任一项的化合物,其中R3代表氢或4-溴。
5.权利要求1的化合物,其中所述化合物的分子量在约800Da以下。
6.权利要求1的化合物,它们选自下列化合物及其药学上可接受的盐、溶剂合物和水合物:
[2-氯代-4-({2-[2-(四氢-2H-吡喃-2-基氧基)乙基]苯基}氨基)苯基](2-甲基苯基)甲酮;
(2-氯代-4-{[2-(2-(羟基乙基)苯基)氨基}苯基)(2-甲基苯基)甲酮;
2-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)乙基乙酸酯;
4-(2-{2-[(3-氯代-4-(2-甲基苯甲酰基)苯基)氨基]苯基}乙氧基)-4-氧代丁酸;
2-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)乙基己酸酯;
2-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-1-甲基乙基乙酸酯;
(2-氯代-4-{[2-(2-羟基丙基)苯基]氨基}苯基)(2-甲基苯基)甲酮;
[2-氯代-4-({2-[(1E)-3-羟基丙-1-烯基]苯基}氨基)苯基](2-甲基苯基)甲酮;
(2-氯代-4-{[2-(3-羟基丙基)苯基]氨基}苯基)(2-甲基苯基)甲酮;
[2-氯代-4-({2-[(1E)-4-羟基丁-1-烯基]苯基}氨基)苯基](2-甲基苯基)甲酮;
[4-({2-[(1E)-3-氨基丙-1-烯基]苯基}氨基)-2-氯代苯基](2-甲基苯基)甲酮;
(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基膦酸二乙酯;
[2-氯代-4-({2-[(1E)-3-羟基-3-甲基丁-1-烯基]苯基}氨基)苯基](2-甲基苯基)甲酮;
(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙烯酸乙酯;
(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙烯酸;
{2-氯代-4-[(2-{(1E)-3-[(2,2-二甲基-1,3-二氧戊环-4-基)甲氧基]丙-1-烯基}苯基)氨基]苯基}(2-甲基苯基)甲酮;
[2-氯代-4-({2-[(1E)-3-(2,3-二羟基丙氧基)丙-1-烯基]苯基}氨基)苯基](2-甲基苯基)甲酮;
(1R)-3-{[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]氨基}-1-(羟基甲基)-2-氧代乙基氨基甲酸叔-丁酯;
O-(叔-丁基)-N-({[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]氨基}羰基)-L-丝氨酸甲酯;
N-(叔-丁基)-N′-[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]硫脲;
N-[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]-4-氧代戊酰胺;
N-[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]-N′-乙基脲;
4-{[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]氨基}-4-氧代丁酸乙酯;
N-[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]-N′-环己脲;
N′-[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]-N,N-二甲基琥珀酰胺;
[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]丙二酸二甲酯;
[2-氯代-4-({2-[(1E)-3-吗啉-4-基丙-1-烯基]苯基}氨基)苯基](2-甲基苯基)甲酮;
6-O-[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]-1,2:3,4-二-O-(1-甲基亚乙基)-α-D-吡喃半乳糖;
甲基5-O-[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]-2,3-O-(1-甲基亚乙基)-β-D-呋喃核苷;
甲基5-O-[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]-β-D-呋喃核苷;
(4E)-5-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-2-(甲基磺酰基)戊-4-烯酸甲酯;
{[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]硫代}乙酸乙酯;
[2-氯代-4-{[2-((1E)-3-{双[2-(乙酰氧基)乙基]氨基}丙-1-烯基)苯基]氨基}苯基](2-甲基苯基)甲酮;
[2-氯代-4-{[2-((1E)-3-{双[2-(羟基)乙基]氨基}丙-1-烯基)苯基]氨基}苯基](2-甲基苯基)甲酮;
(2-氯代-4-{[2-((1E)-3-{4-[2-(乙酰氧基)乙基]哌啶-1-基}丙-1-烯基)苯基]氨基}苯基)(2-甲基苯基)甲酮;
{2-氯代-4-[(2-{(1E)-3-[4-(2-羟基乙基)哌啶-1-基]丙-1-烯基}苯基)氨基]苯基}(2-甲基苯基)甲酮;
{2-氯代-4-[(2-{2-[(四氢呋喃-2-基甲基)氨基]乙基}苯基)氨基]苯基}(2-甲基苯基)甲酮;
[2-氯代-4-({2-[2-(4-甲基哌嗪-1-基)乙基]苯基}氨基)苯基](2-甲基苯基)甲酮;
{2-氯代-4-[(2-{2-[(3-吗啉-4-基丙基)氨基]乙基}苯基)氨基]苯基}(2-甲基苯基)甲酮;
(2-氯代-4-{[2-(2-{[2-(二甲基氨基)乙基]氨基}乙基)苯基]氨基}苯基)(2-甲基苯基)甲酮;
{2-氯代-4-[(2-{2-[(2-甲氧基乙基)氨基]乙基}苯基)氨基]苯基}(2-甲基苯基)甲酮;
1-[3-({2-[2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苯基]乙基}氨基)丙基]吡咯烷-2-酮;
{2-氯代-4-[(2-{2-[甲基(四氢呋喃-2-基甲基)氨基]乙基}苯基)氨基]苯基}(2-甲基苯基)甲酮;
(2-氯代-4-{[2-(2-{[(2,2-二甲基-1,3-二氧戊环-4-基)甲基]氨基}乙基)苯基]氨基}苯基)(2-甲基苯基)甲酮;
{2-氯代-4-[(2-{2-[4-(2-甲氧基乙基)哌嗪-1-基]乙基}苯基)氨基]苯基}(2-甲基苯基)甲酮;
(2-氯代-4-{[2-(2-吗啉-4-基乙基)苯基]氨基}苯基)(2-甲基苯基)甲酮;
{2-氯代-4-[(2-{2-[(2,3-二羟基丙基)氨基]乙基}苯基)氨基]苯基}(2-甲基苯基)甲酮;
(4-{[2-(氨基甲基)苯基]氨基}-2-氯苯基)(2-甲基苯基)甲酮;
(2-氯代-4-{[2-({2-[2-(四氢-2H-吡喃-2-基氧基)乙氧基]乙氧基}甲基)苯基]氨基}苯基)(2-甲基苯基)甲酮;
{2-氯代-4-[(2-{[(四氢-2H-吡喃-2-基氧基)乙氧基]甲基}苯基)氨基]苯基}(2-甲基苯基)甲酮;
[2-氯代-4-({2-[(2-{2-[2-(四氢-2H-吡喃-2-基氧基)乙氧基]乙氧基}乙氧基)甲基]苯基}氨基)苯基](2-甲基苯基)甲酮;
[2-氯代-4-({2-[(3,3,3-三氟丙氧基)甲基]苯基}氨基)苯基](2-甲基苯基)甲酮;
2-({3-氯代-4-[(2-甲基苯基)羰基]苯基)氨基)苄基膦酸二乙酯;
2-[2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]-1H-异吲哚-1,3(2H)-二酮;
{2-氯代-4-[(2-{[2-(2-羟基乙氧基)乙氧基]甲基}苯基)氨基]苯基}(2-甲基苯基)甲酮;
[2-氯代-4-({2-[(羟基乙氧基)甲基]苯基}氨基)苯基](2-甲基苯基)甲酮;
(2-氯代-4-{[2-({2-[2-(2-羟基乙氧基)乙氧基]乙氧基}甲基)苯基]氨基}苯基)(2-甲基苯基)甲酮;
[4-({4-溴代-2-[(2-羟基乙氧基)甲基]苯基}氨基)-2-氯苯基](2-甲基苯基)甲酮;
(4-{[4-溴代-2-({2-[2-(2-羟基乙氧基)乙氧基]乙氧基}甲基)苯基]氨基}-2-氯苯基)(2-甲基苯基)甲酮;
{4-[(4-溴代-2-{[2-(2-羟基乙氧基)乙氧基]甲基}苯基)氨基]-2-氯苯基}(2-甲基苯基)甲酮;
5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基膦酸二乙酯;
[4-({4-溴代-2-[(3,3,3-三氟丙氧基)甲基]苯基}氨基)-2-氯苯基](2-甲基苯基)甲酮;
2-{[2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙基4-甲基苯磺酸酯;
2-{[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙基4-甲基苯磺酸酯;
2-(2-{[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙氧基)乙基4-甲基苯磺酸酯;
2-[2-(2-{[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙氧基)乙氧基]乙基4-甲基苯磺酸酯;
[4-({4-溴代-2-[(2-碘代乙氧基)甲基]苯基}氨基)-2-氯苯基](2-甲基苯基)甲酮;
{4-[(4-溴代-2-{[2-(2-碘代乙氧基)乙氧基]甲基}苯基)氨基]-2-氯苯基}(2-甲基苯基)甲酮;
(4-{[4-溴代-2-({2-[2-(2-碘代乙氧基)乙氧基]乙氧基}甲基)苯基]氨基}-2-氯苯基)(2-甲基苯基)甲酮;
[2-氯代-4-({2-[(2-碘代乙氧基)甲基]苯基}氨基)苯基](2-甲基苯基)甲酮;
2-{[2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙基膦酸二乙酯;
2-{[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙基膦酸二乙酯;
2-({[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙氧基)乙基膦酸二乙酯;
2-[2-(2-{[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙氧基)乙氧基]乙基膦酸二乙酯;
2-{[2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氨基}-2-氧代乙基膦酸二乙酯;
2-{[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苯基]氨基}-2-氧代乙基膦酸二乙酯;
{[2-({5-溴代-3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙基(二乙氧基磷酰基)乙酸酯;
2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基膦酸;
N-[2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]-2,2,2-三氟乙磺酰胺;
N-[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苯基]-2,2,2-三氟乙磺酰胺;
{2-氯代-4-[(2-{[(四氢-2H-吡喃-2-基氧基)丙氧基]甲基}苯基)氨基]苯基}(2-甲基苯基)甲酮;
[2-氯代-4-({2-[(羟基丙氧基)甲基]苯基}氨基)苯基](2-甲基苯基)甲酮;
3-{[2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}丙基膦酸二乙酯;
2-[2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苯基]乙基膦酸二乙酯;
2-[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苯基]乙基膦酸二乙酯;
2-{[2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氨基}-2-氧代乙基膦酸;
(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-氨基甲酸苯乙酯;
N-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-2-苯氧基-乙酰胺;
N-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}-苯基)-3-苯氧基-丙酰胺;
N-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-2-(1,3-二氧代-1,3-二氢-异吲哚-2-基)-乙酰胺;
N-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}-苯基)-琥珀酰胺酸2-(2-甲氧基-乙氧基)乙酯;
N-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-苯磺酰胺;
乙酸(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基氨基甲酰基)-甲酯;
1-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)吡咯烷-2,5-二酮;
2-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)乙基丙酸酯;
2,2-二甲基-丙酸2-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)乙酯;
[2-氯代-4-({2-[3-(四氢-2H-吡喃-2-基氧基)丙氧基]苯基}氨基)苯基](2-甲基苯基)甲酮;
(2-氯代-4-{[2-(3-羟基丙氧基)苯基]氨基}苯基)(2-甲基苯基)甲酮;
2-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)乙基碳酸叔-丁酯;
2-({[(5-溴代-2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)氨基]羰基}氨基)乙基2-甲基丙烯酸酯;
(4-{[4-溴代-2-(2-羟基乙基)苯基]氨基}-2-氯代-苯基)(2-甲基苯基)甲酮;
3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯氧基)丙基乙酸酯;
[2-氯代-4-({2-[3-(吗啉-4-基)丙氧基]苯基}氨基)苯基](2-甲基苯基)甲酮;
N-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-N′-(4-苯氧基丁基)琥珀酰胺;
N-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-N′-(6-羟基己基)琥珀酰胺;
N-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-N′-(2,3-二羟基丙基)琥珀酰胺;
(1R)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-1-(羟基甲基)丙基氨基甲酸叔-丁酯;
6-[3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基氨基甲酰基)丙酰基氨基]-己基磷酸二乙酯;
N-({[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]氨基}羰基)氨基乙酸乙酯;
2-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)乙基(甲基)氨基甲酸叔-丁酯;
N-(5-溴代-2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-N′-(6-羟基己基)琥珀酰胺;
N-(5-溴代-2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)-N′-(2,3-二羟基丙基)琥珀酰胺;
(2Z)-N-[(2E)-3-(2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苯基)丙-2-烯基]-2-(2,5-二氧代咪唑烷-4-叉)乙酰胺;
(2-氯代-4-{[2-(二氟甲基)苯基]氨基}苯基)(2-甲基苯基)甲酮;
3-{[2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苯基]乙基}-1-甲基咪唑烷-2,4-二酮;
3-{[2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苯基]乙基}-5,5-二甲基唑啉-2,4-二酮;
4-{[2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苯基]乙基}吗啉-3,5-二酮;
1-{[2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苯基]乙基}哌啶-2,6-二酮;
4-(2-{[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙基)吗啉-3,5-二酮;
1-(2-{[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙基)吡咯烷-2,5-二酮;
2-[3-(2-{5-溴代-[2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄氧基]乙基}-2,4,5-三氧代咪唑烷-1-基)乙酸乙酯;
3-(2-{[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙基)咪唑烷-2,4-二酮;
1-(2-{[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙基)-3,4-顺式-二乙酰氧基吡咯烷-2,5-二酮;
3-(2-{[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙基)噻唑啉-2,4-二酮;
3-(2-{[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙基)-1-甲基咪唑烷-2,4-二酮;
1-(2-{[5-溴代-2-({3-氯代-4-[(2-甲基苯基)羰基]苯基}氨基)苄基]氧基}乙基)咪唑烷-2,4,5-三酮;
(2-氯代-4-{[(2-羟基甲基)苯基]氨基}苯基)(2-甲基苯基)甲酮;
2-{[3-氯代-4-(2-甲基苯甲酰基)苯基]氨基}苄基乙酸酯。
7.药用组合物,该组合物包含权利要求1-6中任何一项的化合物。
8.权利要求7的药用组合物,其中所述组合物包含基于组合物的重量计0.1%-100%的式I化合物。
9.权利要求7的药用组合物,其中制剂的剂量单位中含有0.07mg至1g的式I化合物。
10.权利要求1-6中任何一项的化合物在制备治疗或预防疾病的药物中的用途,其中所述疾病选自:哮喘、过敏、关节炎、风湿性关节炎、痛风、动脉粥性硬化、慢性炎性肠疾病、增生性和炎性皮肤紊乱、银屑病、异位性皮炎、葡萄膜炎、脓毒性休克、艾滋病、骨质疏松症和痤疮。
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WO2001005751A1 (en) * | 1999-07-16 | 2001-01-25 | Leo Pharmaceutical Products Ltd. A/S (Løvens Kemiske Fabrik Produktionsaktieselskab) | AMINOBENZOPHENONES AS INHIBITORS OF IL-1β AND TNF-$g(a) |
WO2001005749A1 (en) * | 1999-07-16 | 2001-01-25 | Leo Pharmaceutical Products Ltd. A/S (Løvens Kemiske Fabrik Produktionsaktieselskab) | AMINOBENZOPHENONES AS INHIBITORS OF IL-1β AND TNF-$g(a) |
WO2001042189A1 (en) * | 1999-12-06 | 2001-06-14 | Leo Pharma A/S | AMINOBENZOPHENONES AS INHIBITORS OF IL-1β AND TNF-$g(a) |
WO2002045752A2 (en) * | 2000-12-08 | 2002-06-13 | Leo Pharma A/S | Dermal anti-inflammatory composition |
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ATE251117T1 (de) | 1999-07-16 | 2003-10-15 | Leo Pharma As | Neue aminobenzophenone |
RU2270194C2 (ru) * | 2000-05-22 | 2006-02-20 | Лео Фарма А/С | Бензофеноны как ингибиторы il-1бета и tnf-альфа, фармацевтическая композиция и способ лечения |
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- 2002-08-26 BR BR0212249-9A patent/BR0212249A/pt active Search and Examination
- 2002-08-26 IL IL16044202A patent/IL160442A0/xx unknown
- 2002-08-26 RU RU2004109142/04A patent/RU2361855C2/ru not_active IP Right Cessation
- 2002-08-26 EP EP02767145A patent/EP1423356A2/en not_active Withdrawn
- 2002-08-26 MX MXPA04001912A patent/MXPA04001912A/es active IP Right Grant
- 2002-08-26 AU AU2002331310A patent/AU2002331310B2/en not_active Ceased
- 2002-08-26 CN CNB028193571A patent/CN100347151C/zh not_active Expired - Fee Related
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- 2002-08-26 WO PCT/DK2002/000557 patent/WO2003018535A2/en active Application Filing
- 2002-08-26 PL PL368686A patent/PL207487B1/pl not_active IP Right Cessation
- 2002-08-26 HU HU0401644A patent/HUP0401644A3/hu unknown
- 2002-08-28 US US10/228,954 patent/US7034015B2/en not_active Expired - Fee Related
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- 2004-02-17 IL IL160442A patent/IL160442A/en not_active IP Right Cessation
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2005
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WO1998032730A1 (en) * | 1997-01-24 | 1998-07-30 | Leo Pharmaceutical Products Ltd. A/S (Løvens Kemiske Fabrik Produktionsaktieselskab) | Aminobenzophenones as inhibitors of interleukin and tnf |
WO2001005746A1 (en) * | 1999-07-16 | 2001-01-25 | Leo Pharmaceutical Products Ltd. A/S (Løvens Kemiske Fabrik Produktionsaktieselskab) | AMINOBENZOPHENONES AS INHIBITORS OF IL-1β AND TNF-$g(a) |
WO2001005751A1 (en) * | 1999-07-16 | 2001-01-25 | Leo Pharmaceutical Products Ltd. A/S (Løvens Kemiske Fabrik Produktionsaktieselskab) | AMINOBENZOPHENONES AS INHIBITORS OF IL-1β AND TNF-$g(a) |
WO2001005749A1 (en) * | 1999-07-16 | 2001-01-25 | Leo Pharmaceutical Products Ltd. A/S (Løvens Kemiske Fabrik Produktionsaktieselskab) | AMINOBENZOPHENONES AS INHIBITORS OF IL-1β AND TNF-$g(a) |
WO2001042189A1 (en) * | 1999-12-06 | 2001-06-14 | Leo Pharma A/S | AMINOBENZOPHENONES AS INHIBITORS OF IL-1β AND TNF-$g(a) |
WO2002045752A2 (en) * | 2000-12-08 | 2002-06-13 | Leo Pharma A/S | Dermal anti-inflammatory composition |
Cited By (2)
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CN102574781A (zh) * | 2009-09-30 | 2012-07-11 | 东丽株式会社 | 2,3-二氢-1h-茚-2-基脲衍生物及其药物用途 |
CN102574781B (zh) * | 2009-09-30 | 2014-02-19 | 东丽株式会社 | 2,3-二氢-1h-茚-2-基脲衍生物及其药物用途 |
Also Published As
Publication number | Publication date |
---|---|
US7034015B2 (en) | 2006-04-25 |
HUP0401644A3 (en) | 2008-03-28 |
JP4540984B2 (ja) | 2010-09-08 |
JP2005500400A (ja) | 2005-01-06 |
RU2361855C2 (ru) | 2009-07-20 |
BR0212249A (pt) | 2004-10-05 |
CA2458611A1 (en) | 2003-03-06 |
KR20040029455A (ko) | 2004-04-06 |
IL160442A0 (en) | 2004-07-25 |
HUP0401644A2 (hu) | 2004-11-29 |
PL207487B1 (pl) | 2010-12-31 |
CA2458611C (en) | 2012-05-29 |
RU2004109142A (ru) | 2005-08-20 |
EP1423356A2 (en) | 2004-06-02 |
KR100896667B1 (ko) | 2009-05-14 |
IL160442A (en) | 2011-11-30 |
MXPA04001912A (es) | 2004-07-23 |
AU2002331310B2 (en) | 2008-07-17 |
HK1068606A1 (en) | 2005-04-29 |
WO2003018535A3 (en) | 2004-03-18 |
PL368686A1 (en) | 2005-04-04 |
JP2010189410A (ja) | 2010-09-02 |
US20030119902A1 (en) | 2003-06-26 |
WO2003018535A2 (en) | 2003-03-06 |
CN1561327A (zh) | 2005-01-05 |
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