CN1628107A - 作为脂肪酸氧化抑制剂的杂芳基烷基哌嗪衍生物 - Google Patents
作为脂肪酸氧化抑制剂的杂芳基烷基哌嗪衍生物 Download PDFInfo
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- CN1628107A CN1628107A CNA018177700A CN01817770A CN1628107A CN 1628107 A CN1628107 A CN 1628107A CN A018177700 A CNA018177700 A CN A018177700A CN 01817770 A CN01817770 A CN 01817770A CN 1628107 A CN1628107 A CN 1628107A
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- Prior art keywords
- alkyl
- aryl
- hydrogen
- halogen
- heteroaryl
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- Granted
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- -1 Heteroaryl alkyl piperazine derivatives Chemical class 0.000 title claims description 58
- 230000003647 oxidation Effects 0.000 title description 8
- 238000007254 oxidation reaction Methods 0.000 title description 8
- 235000014113 dietary fatty acids Nutrition 0.000 title description 6
- 239000000194 fatty acid Substances 0.000 title description 6
- 229930195729 fatty acid Natural products 0.000 title description 6
- 150000004665 fatty acids Chemical class 0.000 title description 6
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 title description 5
- 239000003112 inhibitor Substances 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 237
- 201000010099 disease Diseases 0.000 claims abstract description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 23
- 206010002383 Angina Pectoris Diseases 0.000 claims abstract description 16
- 210000002027 skeletal muscle Anatomy 0.000 claims abstract description 13
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 8
- 208000010125 myocardial infarction Diseases 0.000 claims abstract description 8
- 230000006378 damage Effects 0.000 claims abstract description 7
- 210000003205 muscle Anatomy 0.000 claims abstract description 7
- 210000001519 tissue Anatomy 0.000 claims abstract description 7
- 206010007559 Cardiac failure congestive Diseases 0.000 claims abstract description 6
- 210000000056 organ Anatomy 0.000 claims abstract description 6
- 230000035939 shock Effects 0.000 claims abstract description 6
- 230000009885 systemic effect Effects 0.000 claims abstract description 6
- 208000007718 Stable Angina Diseases 0.000 claims abstract description 4
- 125000003118 aryl group Chemical group 0.000 claims description 230
- 229910052760 oxygen Inorganic materials 0.000 claims description 194
- 239000001301 oxygen Substances 0.000 claims description 178
- 125000000217 alkyl group Chemical group 0.000 claims description 174
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 174
- 229910052739 hydrogen Inorganic materials 0.000 claims description 164
- 229910052736 halogen Inorganic materials 0.000 claims description 156
- 150000002367 halogens Chemical class 0.000 claims description 156
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 151
- 125000001072 heteroaryl group Chemical group 0.000 claims description 147
- 239000001257 hydrogen Substances 0.000 claims description 143
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 118
- 150000002431 hydrogen Chemical class 0.000 claims description 71
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 70
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 68
- 125000004193 piperazinyl group Chemical group 0.000 claims description 66
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 54
- 229910052799 carbon Inorganic materials 0.000 claims description 45
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 42
- 239000000203 mixture Substances 0.000 claims description 39
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 32
- 229910004013 NO 2 Inorganic materials 0.000 claims description 31
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 26
- 125000004122 cyclic group Chemical group 0.000 claims description 25
- 125000003545 alkoxy group Chemical group 0.000 claims description 24
- 125000003368 amide group Chemical group 0.000 claims description 23
- 150000001721 carbon Chemical group 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 20
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 20
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 claims description 18
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 17
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 15
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 241000124008 Mammalia Species 0.000 claims description 7
- 230000006793 arrhythmia Effects 0.000 claims description 7
- 206010003119 arrhythmia Diseases 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 150000004885 piperazines Chemical class 0.000 claims description 7
- AWJUIBRHMBBTKR-UHFFFAOYSA-N iso-quinoline Natural products C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 210000002837 heart atrium Anatomy 0.000 claims description 5
- 239000002775 capsule Substances 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 4
- OKQIEBVRUGLWOR-UHFFFAOYSA-N n-naphthalen-1-ylacetamide Chemical compound C1=CC=C2C(NC(=O)C)=CC=CC2=C1 OKQIEBVRUGLWOR-UHFFFAOYSA-N 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 125000004950 trifluoroalkyl group Chemical group 0.000 claims description 4
- 150000002475 indoles Chemical class 0.000 claims description 3
- 125000005025 alkynylaryl group Chemical group 0.000 claims 1
- KYPIASPTMDEDQB-UHFFFAOYSA-N phenylacetic acid anilide Natural products C=1C=CC=CC=1NC(=O)CC1=CC=CC=C1 KYPIASPTMDEDQB-UHFFFAOYSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 abstract description 11
- 150000003839 salts Chemical class 0.000 abstract description 9
- 206010022562 Intermittent claudication Diseases 0.000 abstract description 6
- 208000021156 intermittent vascular claudication Diseases 0.000 abstract description 6
- 206010003130 Arrhythmia supraventricular Diseases 0.000 abstract 1
- 206010047281 Ventricular arrhythmia Diseases 0.000 abstract 1
- 230000001746 atrial effect Effects 0.000 abstract 1
- 208000014674 injury Diseases 0.000 abstract 1
- 238000002560 therapeutic procedure Methods 0.000 abstract 1
- 230000008733 trauma Effects 0.000 abstract 1
- 239000002585 base Substances 0.000 description 190
- 238000006243 chemical reaction Methods 0.000 description 87
- 238000002360 preparation method Methods 0.000 description 80
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 65
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 37
- 239000000243 solution Substances 0.000 description 36
- 230000002194 synthesizing effect Effects 0.000 description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 26
- 239000007787 solid Substances 0.000 description 25
- 238000001819 mass spectrum Methods 0.000 description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 239000012467 final product Substances 0.000 description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 125000004414 alkyl thio group Chemical group 0.000 description 16
- 125000004104 aryloxy group Chemical group 0.000 description 16
- 125000000753 cycloalkyl group Chemical group 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 235000019439 ethyl acetate Nutrition 0.000 description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 13
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 12
- 238000010511 deprotection reaction Methods 0.000 description 12
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 12
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 11
- 125000003396 thiol group Chemical group [H]S* 0.000 description 11
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 238000004821 distillation Methods 0.000 description 10
- 150000002118 epoxides Chemical class 0.000 description 10
- 238000011534 incubation Methods 0.000 description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 9
- 125000005842 heteroatom Chemical group 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 230000000875 corresponding effect Effects 0.000 description 8
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 8
- RRSNDVCODIMOFX-MPKOGUQCSA-N Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O Chemical compound Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O RRSNDVCODIMOFX-MPKOGUQCSA-N 0.000 description 7
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 7
- 229940126214 compound 3 Drugs 0.000 description 7
- 229940125898 compound 5 Drugs 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- 230000009467 reduction Effects 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
- 229940125851 compound 27 Drugs 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 210000004185 liver Anatomy 0.000 description 6
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 5
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 description 5
- ISMDILRWKSYCOD-GNKBHMEESA-N C(C1=CC=CC=C1)[C@@H]1NC(OCCCCCCCCCCCNC([C@@H](NC(C[C@@H]1O)=O)C(C)C)=O)=O Chemical compound C(C1=CC=CC=C1)[C@@H]1NC(OCCCCCCCCCCCNC([C@@H](NC(C[C@@H]1O)=O)C(C)C)=O)=O ISMDILRWKSYCOD-GNKBHMEESA-N 0.000 description 5
- 229940126639 Compound 33 Drugs 0.000 description 5
- 125000002252 acyl group Chemical group 0.000 description 5
- 125000004423 acyloxy group Chemical group 0.000 description 5
- 239000003513 alkali Substances 0.000 description 5
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 description 5
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 5
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 description 5
- 125000000304 alkynyl group Chemical group 0.000 description 5
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 5
- 125000003710 aryl alkyl group Chemical group 0.000 description 5
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- 125000005224 heteroarylcarbonylamino group Chemical group 0.000 description 5
- 125000005553 heteroaryloxy group Chemical group 0.000 description 5
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 5
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 4
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 4
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- TUADYTFWZPZZTP-UHFFFAOYSA-N 2-amino-4-methoxyphenol Chemical compound COC1=CC=C(O)C(N)=C1 TUADYTFWZPZZTP-UHFFFAOYSA-N 0.000 description 4
- BSQLQMLFTHJVKS-UHFFFAOYSA-N 2-chloro-1,3-benzothiazole Chemical compound C1=CC=C2SC(Cl)=NC2=C1 BSQLQMLFTHJVKS-UHFFFAOYSA-N 0.000 description 4
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 4
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 4
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- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 3
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- RFIOZSIHFNEKFF-UHFFFAOYSA-N piperazine-1-carboxylic acid Chemical compound OC(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
-
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
通式(I)的新化合物及其药用酸加成盐:其中化合物用于保护骨骼肌免受由外伤引起的损害或保护在肌肉或全身性疾病如间歇性跛行之后的骨骼肌,治疗休克疾病,保护用于移植的供体组织或器官的治疗中,用于心血管疾病包括心房或心室心律不齐,Prinzmetal(变异性)绞痛,稳定性绞痛,和运动导致的绞痛,充血性心脏病和心肌梗塞的治疗中。
Description
背景技术
1.发明领域
本发明涉及哌嗪衍生物,包含一种或多种该衍生物的治疗剂,以及治疗哺乳动物疾病的方法,特别是,在人类中选自下列疾病的治疗:包括保护骨骼肌免受由创伤导致的损伤,保护肌肉或全身性疾病如间歇性跛行(intermittentclaudication)之后的骨骼肌,治疗休克疾病,保护移植中使用的供体组织和器官,以及治疗心血管疾病包括心房和心室心律不齐,Prinzmetal’s(变异)绞痛,稳定性绞痛,和运动导致的绞痛,充血性心脏病,和心肌梗塞。
2.现有技术
美国专利4,567,264,其说明书插入此引作参考,公开了一类取代的哌嗪化合物,包括已知化合物拉洛来静(ranolazine),即(±)-N-(2,6-二甲基苯基)-4-[2-羟基-3-(2-甲氧基苯氧基)-丙基]-1-哌嗪乙酰胺,及其药用盐,以及它们在治疗心血管疾病,包括心律不齐,变异(variant),运动导致的绞痛,和心肌梗塞中的用途。
美国专利5,506,229,其说明书插入此引作参考,公开了拉洛来静及其药用盐和酯在治疗经历物理或化学损伤的组织,包括心脏麻痹,氧不足或再灌注对心脏或骨骼肌或脑组织损伤,和用于移植物中的用途。特别是,拉洛来静通过部分抑制心脏脂肪酸的氧化具体可用于治疗心律不齐,变异和运动导致的绞痛,和心肌梗塞。该专利还公开了常规的口服和非肠道给药的拉洛来静制剂,包括控释制剂。特别地,美国专利5,506,229的实施例7D描述了胶囊形式的控释制剂,该制剂包含拉洛来静微球和采用控制释放的聚合物包衣的微晶纤维素。
尽管拉洛来静作为非常有用的心血管治疗剂是一重大发现,但仍然需要开发具有比拉洛来静更长的半衰期并且至少具有与拉洛来静类似活性的具有部分脂肪酸氧化抑制剂功能的化合物。
发明简述
本发明包括具有部分脂肪酸氧化抑制剂活性且具有良好治疗半衰期的新的杂芳基烷基哌嗪衍生物。
本发明也包括新的取代哌嗪化合物,该化合物可以给哺乳动物服用以保护骨骼肌免受创伤导致的损伤,保护肌肉或全身性疾病如间歇性跛行之后的骨骼肌,治疗休克疾病,保护移植中使用的供体组织和器官,以及治疗心血管疾病包括心房和心室心律不齐,Prinzmetal(变异)氏绞痛,稳定绞痛,和运动导致的绞痛,充血性心脏病,和心肌梗塞。
本发明包括一类具有下列结构式的取代的哌嗪化合物:
其中m=1或2或3;
q=NH,O,或S;
R1,R2,R3,R4和R5各自独立地选自氢,卤素,NO2,CF3,CN,OR20,SR20,N(R20)2,S(O)R22,SO2R22,SO2N(R20)2,NR20CO2R22,NR20CON(R20)2,COR20,CO2R20,CON(R20)2,NR20SO2R22,C1-15烷基,C2-15链烯基,C2-15炔基,杂环基,芳基,和杂芳基,其中烷基和芳基取代基可任选被一个选自下列的取代基取代:卤素,NO2,CF3,CN,OR20,SR20,N(R20)2,S(O)R22和SO2R22,且其中R1和R2或R2和R3或R3和R4或R4和R5可以与和它们相连的碳原子一起形成6-元芳香环并且该环可以任选被烷基,三氟烷基,烷氧基或卤素取代;
R6,R7和R8各自独立地选自氢或C1-3烷基;
R9,R10,R11,R12,R13,R14,R15和R16各自独立地选自氢,CO2R20,CON(R20)2,C1-4烷基,或芳基,其中烷基和芳基取代基可任选被一个选自下列的取代基取代:卤素,CF3,CN,OR20,N(R20)2,CO2R20,CON(R20)2或芳基,其中R9和R10可以一起形成羰基,或R11和R12可以一起形成羰基,或R13和R14可以一起形成羰基,或R15和R16可以一起形成羰基,或者R11和R13或R9和R15或R9和R11或R11和R15或R9和R13可以连接在一起形成包含1至3个碳原子的环;
R17是任选被1至3个选自下列的取代基取代的杂芳基:氢,卤素,NO2,CF3,CN,OR20,SR20,N(R20)2,S(O)R22,SO2R22,SO2N(R20)2,NR2OCO2R22,NR20CON(R20)2,COR20,CO2R20,CON(R20)2,NR20SO2R22,C1-15烷基,C2-15链烯基,C2-15炔基,杂环基,芳基,和杂芳基,其中烷基和芳基取代基可任选被一个选自下列的取代基取代:卤素,NO2,CF3,CN,OR20,SR20,N(R20)2,S(O)R22或SO2R22;
R20选自H,C1-15烷基,芳基,或杂芳基,其中烷基和芳基取代基可任选被1个选自下列的取代基取代:卤素,烷基,单--或二烷基氨基,烷基,CN,--O--C1-6烷基,或CF3;和
R22选自C1-15烷基,芳基,或杂芳基,其中烷基和芳基取代基可任选被1个选自卤素,烷基,单烷基氨基,二烷基氨基,烷基酰氨基,芳基酰氨基,杂芳基酰氨基,CN,O-C1-6烷基,CF3,或杂芳基的取代基取代。
在另一个方案中本发明是选自下列的取代哌嗪化合物:N-(2,6-二甲基-苯基)-2-(4-{2-羟基-3-[2-(3-三氟甲基苯基)苯并噁唑-5-基氧]-丙基}哌嗪-1-基)乙酰胺,2-{4-[3-(苯并噻唑-2-基氧)-2-羟基-丙基]-哌嗪-1-基}-N-(2,6-二甲基苯基)乙酰胺,N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(2-甲基-苯并噻唑-5-基氧)-丙基]哌嗪-1-基}乙酰胺,4-(3-{4-[(2,6-二甲基苯基氨基甲酰基)-甲基]-哌嗪-1-基}-2-羟基-丙氧基)-1H-吲哚-2-羧酸酰胺,2-{4-[3-(苯并噻唑-6-基氧)-2-羟基-丙基]-哌嗪-1-基}-N-(2,6-二甲基-苯基)乙酰胺,N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(2-甲基-苯并噻唑-6-基氧)-丙基]-哌嗪-1-基}乙酰胺,N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(2-甲基-苯并噻唑-5-基氧)-丙基]-3,5-二甲基-哌嗪-1-基}乙酰胺,2-{4-[2-羟基-3-(2-甲基-苯并噻唑-5-基氧)-丙基]-哌嗪-1-基}-N-(4-羟基-苯基)乙酰胺,N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(2-苯基-苯并噻唑-5-基氧)-丙基]-哌嗪-1-基}乙酰胺,N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(2-苯基-苯并噁唑-5-基氧)-丙基]-哌嗪-1-基}乙酰胺,N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(2-苯基-苯并噻唑-7-基氧)-丙基]-哌嗪-1-基乙酰胺,N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(2-甲基-苯并噻唑-5-基氧)-丙基]-2-氧-哌嗪-1-基}乙酰胺,N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(2-甲基-苯并噁唑-5-基氧)-丙基]-哌嗪-1-基}乙酰胺,N-(2,6-二甲基苯基)-2-(4-{2-羟基-3-[2-(4-三氟甲基-苯基)-苯并噁唑-5-基氧]-丙基}-哌嗪-1-基)乙酰胺,N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(喹噁啉-2-基氧)-丙基]-哌嗪-1-基}乙酰胺,N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(吡啶-3-基氧)-丙基]-哌嗪-1-基}乙酰胺,N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(喹啉-4-基氧)-丙基]-哌嗪-1-基}乙酰胺,N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(异喹啉-5-基氧)-丙基]-哌嗪-1-基}乙酰胺,N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(喹啉-6-基氧)-丙基]-哌嗪-1-基}乙酰胺,N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(2-甲基-喹啉-7-基氧)-丙基]-哌嗪-1-基}乙酰胺,2-{4-[3-(苯并噻唑-2-基氨基)-2-羟基丙基]哌嗪基}-N-(2,6-二甲基苯基)乙酰胺,2-{4-[3-(苯并噁唑-2-基氨基)-2-羟基丙基]哌嗪基}-N-(2,6-二甲基苯基)乙酰胺,2-{4-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]2,5-二甲基哌嗪基}-N-(2,6-二甲基苯基)乙酰胺,2-{4-[(2R)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]2,6-二甲基哌嗪基}-N-(2,6-二甲基苯基)乙酰胺,2-{4-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]-3,3-二甲基哌嗪基}-N-(2,6-二甲基苯基)乙酰胺,2-{(3S)-4-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]-3-甲基哌嗪基}-N-(2,6-二甲基苯基)乙酰胺,2-{(2R)-4-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]-2-甲基哌嗪基}-N-(2,6-二甲基苯基)乙酰胺,2-{4-[(2R)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]-3-甲基哌嗪基}-N-(2,6-二甲基苯基)乙酰胺,2-{4-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]-2,6-二甲基哌嗪基}-N-(2,6-二甲基苯基)乙酰胺,2-{4-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]-2-甲基哌嗪基}-N-(2,6-二甲基苯基)乙酰胺,2-{4-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基](1,4-diazaperhydroepinyl)}-N-(2,6-二甲基苯基)乙酰胺,2-{4-[2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]哌嗪基}-N-(4-羟基苯基)乙酰胺,2-{4-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]-2,6-二甲基哌嗪基}-N-(4-甲酰氨基苯基)乙酰胺,2-{(3S)-4-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]-3-甲基哌嗪基}-N-(2,6-二甲基苯基)乙酰胺,2-{4-[(2R)-2-羟基-3-(2-苯基苯并噻唑-5-基氧)丙基]哌嗪基}-N-(2,6-二甲基苯基)乙酰胺,2-{4-[2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]哌嗪基}-N-(2,6-二甲基-4-羟基苯基)乙酰胺,2-{5-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]-2,5-二氮杂双环[2.2.1]庚-2-基}-N-(2,6-二甲基苯基)乙酰胺,2-{4-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]哌嗪基}-N-(4-磺酰胺基苯基)乙酰胺,2-{(3S)-4-[(2S)-2-羟基-3-(2-苯基苯并噁唑-5-基氧)丙基]-3-甲基哌嗪基}-N-(2,6-二甲基苯基)乙酰胺,2-{4-[2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]哌嗪基}-N-萘基乙酰胺,N-[4-氯-3-(三氟甲基)苯基]-2-{4-[2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]哌嗪基}乙酰胺,2-{4-[2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]哌嗪基}-N-苯基乙酰胺,2-{4-[2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]哌嗪基}-N-(3,4,5-三氯苯基)乙酰胺,2-{4-[2-羟基-3-(4-甲氧基苯基)丙基]哌嗪基}-N-(3,4,5-三氯苯基)乙酰胺,2-{4-[2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]哌嗪基-N-(2-氯-4-甲基苯基)-乙酰胺,2-{4-[2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]哌嗪基}-N-(3,4,5-三氯苯基)乙酰胺,2-{4-[2-羟基-3-(2-苯基苯并噻唑-5-基氧)丙基]哌嗪基}-N-(3,5-二氯苯基)乙酰胺,2-{4-[2-羟基-3-(2-苯基苯并噻唑-5-基氧)丙基]哌嗪基}-N-(3,4-二氯苯基)乙酰胺,2-{4-[2-羟基-3-(2-苯基苯并噻唑-5-基氧)丙基]哌嗪基}-N-[3-甲氧基-5-(三氟甲基)苯基]乙酰胺,2-{4-[2-羟基-3-(2-苯基苯并噻唑-5-基氧)丙基]哌嗪基}-N-[(3,5-二氯)苯基]乙酰胺,和2-{4-[2-羟基-3-(2-((1E)丁-1,3-二链烯基)苯并噻唑-5-基氧)丙基]哌嗪基}-N-[4-氯-2-甲氧基-5-甲基苯基]乙酰胺。
在另外一个方案中,本发明涉及一种给予哺乳动物服用一种或多种本发明组合物的方法,该方法用于治疗选自下述的疾病:保护骨骼肌免受创伤导致的损伤,保护肌肉或全身性疾病如间歇性跛行之后的骨骼肌,治疗休克疾病,保护移植中使用的供体组织和器官,和治疗心血管疾病包括心房和心室心律不齐,Prinzmetal(变异)氏绞痛,稳定绞痛,和运动导致的绞痛,充血性心脏病,和心肌梗塞。
本发明的详细说明
本发明包括一类具有下列结构式的取代哌嗪化合物:
其中m=1,2,或3;
q=NH,O,或S;
R1,R2,R3,R4和R5各自独立地选自氢,卤素,NO2,CF3,CN,OR20,SR20,N(R20)2,S(O)R22,SO2R22,SO2N(R20)2,NR20CO2R22,NR20CON(R20)2,COR20,CO2R20,CON(R20)2,NR20SO2R22,C1-15烷基,C2-15链烯基,C2-15炔基,杂环基,芳基,和杂芳基,其中烷基和芳基取代基可任选被一个选自下列的取代基取代:卤素,NO2,CF3,CN,OR20,SR20,N(R20)2,S(O)R22和SO2R22,且其中R2和R2或R3和R4或R4和R5可以与和它们相连的碳原子一起形成6-元芳香环并且该环可以任选被烷基,三氟烷基,烷氧基或卤素取代;
R6,R7和R8各自独立地选自氢或C1-3烷基;
R9,R10,R11,R12,R13,R14,R15和R16各自独立地选自氢,CO2R20,CON(R20)2,C1-4烷基,或芳基,其中烷基和芳基取代基可任选被一个选自下列的取代基取代:卤素,CF3,CN,OR20,N(R20)2,CO2R20,CON(R20)2或芳基,其中R9和R10可以一起形成羰基,或R11和R12可以一起形成羰基,或R13和R14可以一起形成羰基,或R15和R16可以一起形成羰基,或者R11和R13或R9和R15或R9和R11或R11和R15或R9和R13可以连接在一起形成包含1至3个碳原子的环;
R17是任选被1至3个选自下列的取代基取代的杂芳基:氢,卤素,NO2,CF3,CN,OR20,SR20,N(R20)2,S(O)R22,SO2R22,SO2N(R20)2,NR20CO2R22,NR20CON(R20)2,COR20,CO2R20,CON(R20)2,NR20SO2R22,C1-15烷基,C2-15链烯基,C2-15炔基,杂环基,芳基,和杂芳基,其中烷基和芳基取代基可任选被一个选自下列的取代基取代:卤素,NO2,CF3,CN,OR20,SR20,N(R20)2,S(O)R22或SO2R22;
R20选自H,C1-15烷基,芳基,或杂芳基,其中烷基和芳基取代基可任选被1个选自下列的取代基取代:卤素,烷基,单-或二烷基氨基,烷基,CN,-O-C1-6烷基,或CF3;和
R22选自C1-15烷基,芳基,或杂芳基,其中烷基和芳基取代基可任选被1个选自卤素,烷基,单烷基氨基,二烷基氨基,烷基酰氨基,芳基酰氨基,杂芳基酰氨基,CN,O-C1-6烷基,CF3,或杂芳基的取代基取代。
在优选的方案中,q=NH或O。
在优选的方案中,R1,R2,R3,R4和R5各自独立地选自:氢,卤素,CF3,CN,OR20,SR20,N(R20)2,SO2N(R20)2,CO2R20,CON(R20)2,C1-8烷基,C2-8链烯基,C2-8炔基,杂环基,芳基或者杂芳基,其中烷基和芳基取代基可任选被一个选自下列的取代基取代:卤素,NO2,CF3,CN,OR20,SR20,N(R20)2,S(O)R22,或者SO2R22。在另一个优选的方案中,R1,R2,R3,R4和R5各自独立地选自:氢,卤素,CF3,OR20,C1-5烷基,C2-5链烯基,C2-5炔基,其中烷基取代基可任选被CF3取代。在又一个优选的方案中,R1,R2,R3,R4和R5各自独立地选自:氢,卤素,CF3,OR20,或者C1-3烷基,其中烷基取代基可任选被CF3取代。更优选地,R1,R2,R3,R4和R5各自独立地选自:氢,CF3,OR20,或者C1-2烷基,更优选氢,OR20,或者甲基,且氢或甲基是最优选的。
在另一优选的方案中,任意一对R1和R2或者R2和R3或者R3和R4或者R4和R5可以与和它们相连的碳原子一起形成可任选被烷基,三氟烷基,烷氧基,或者卤素取代的六元芳香环,而其余取代基定义如前文。在此方案中,最优选的是R2和R3与和它们相连的碳原子一起形成六元芳香环。
在优选的方案中,R6,R7和R8各自独立地选自氢或者C1-3烷基,且最优选为氢或者甲基。
在优选的方案中,R9,R10,R11,R12,R13,R14,R15和R16各自独立地选自氢,CON(R20)2,C1-4烷基,或R9和R10可以一起形成羰基,或R11和R12可以一起形成羰基,或R13和R14可以一起形成羰基,或R15和R16可以一起形成羰基。在另一方案中,R9,R10,R11,R12,R13,R14,R15和R16各自独立地选自氢或者C1-2烷基,其中R9和R10可以一起形成羰基,或R11和R12可以一起形成羰基,或R13和R14可以一起形成羰基,或R15和R16可以一起形成羰基。在更优选的方案中,R9,R10,R11,R12,R13,R14,R15和R16各自独立地选自氢,或者甲基,其中R9和R10可以一起形成羰基,或R11和R12可以一起形成羰基,或R13和R14可以一起形成羰基,或R15和R16可以一起形成羰基。在另一方案中,R9,R10,R11,R12,R13,R14,R15和R16各自独立地选自氢或者C1-2烷基,其中烷基可任选被一个选自下列的取代基取代:N(R20)2,或者芳基,或者其中R9和R10可以一起形成羰基。在另一优选的方案中,R9,R10,R11,R12,R13,R14,R15和R16各自独立地选自氢或者C1-2烷基,或者其中R9和R10可以一起形成羰基。在更优选的方案中,R11和R15各自独立地选自氢或者甲基,R9,R10,R12,R13,R14和R16各自为氢,且R9和R10可以一起形成羰基。在另一优选的方案中,R9,R10,R11,R12,R13,R14,R15和R16各自为氢。
在一个优选的方案中,R17为可任选被1-2个选自下列的取代基取代的杂芳基:氢,卤素,CF3,OR20,N(R20)2,CON(R20)2,C1-3烷基,芳基或者杂芳基,其中烷基和芳基可任选被一个独立地选自下列的取代基取代:卤素,CF3,OR20,或者N(R20)2。在另一方案中,R17是稠合的含有1至5个杂原子的6,5元环系的杂芳基,所述杂原子选自N,O,或S,并且可以被1至3个选自下列的取代基取代:氢,卤素,NO2,CF3,CN,OR20,SR20,N(R20)2,S(O)R22,SO2R22,SO2N(R20)2,NR20CO2R22,NR20CON(R20)2,COR20,CO2R20,CON(R20)2,NR20SO2R22,C1-15烷基,C2-15链烯基,C2-15炔基,杂环基,芳基或者杂芳基,其中烷基和芳基可任选被一个选自下列的取代基取代:卤素,NO2,CF3,CN,OR20,SR20,N(R20)2,S(O)R22,或者SO2R22。在此方案中,R17优选是稠合的含有1至3个杂原子的6,5元环系的杂芳基,所述杂原子选自N,O,或S,并且可以被1至2个选自下列的取代基取代:氢,卤素,CF3,OR20,N(R20)2,CON(R20)2,C1-8烷基,C2-8链烯基,C2-8炔基,芳基或者杂芳基,其中烷基和芳基可任选被一个选自下列的取代基取代:卤素,CF3,OR20,或者N(R20)2。更优选地R17是稠合的含有1至2个杂原子的6,5元环系的杂芳基,所述杂原子选自N,O,或S,并且可以被1至2个选自下列的取代基取代:氢,卤素,CF3,OR20,N(R20)2,CON(R20)2,C1-3烷基,芳基或者杂芳基,其中烷基和芳基可任选被一个选自卤素,CF3或者OR20取代基取代。甚至在更优选的方案中,R17是选自下列的稠合6,5元环系的杂芳基:吲哚,苯并噻唑和苯并噁唑,并且可任选被1-2个选自下列的取代基取代:氢,卤素,CF3,OR20,N(R20)2,CON(R20)2,C1-3烷基,芳基或者杂芳基,其中烷基和芳基可任选被一个选自下列的取代基所取代:卤素,CF3或者OR20。在此优选的方案中,R17优选是可任选被一个选自下列的取代基取代的苯并噻唑:氢,卤素,CF3,OR20,N(R20)2,CON(R20)2,C1-3烷基,或者芳基,其中烷基和芳基可任选被一个选自卤素或者CF3的取代基取代。在更优选的方案中,R17是2-位可任选被一个选自下列的取代基取代的苯并噻唑:氢,甲基或者苯基。在另一优选的方案中,R17是可任选被选自下列的取代基取代的5-取代苯并噻唑:氢,卤素,CF3,OR20,N(R20)2,CON(R20)2,C1-3烷基,或者芳基,其中烷基和芳基可任选被一个选自卤素或者CF3的取代基取代。5-取代苯并噻唑优选在2-位被一个选自氢、甲基或苯基的取代基取代。
在另一优选的方案中,R17是含有1-4个N原子的6,6元稠合环系的杂芳基,并且可任选被1-3个选自下列的取代基取代:氢,卤素,NO2,CF3,CN,OR20,SR20,N(R20)2,S(O)R22,SO2R22,SO2N(R20)2,NR20CO2R22,NR20CON(R20)2,COR20,CO2R20,CON(R20)2,NR20SO2R22,C1-15烷基,C2-15链烯基,C2-15炔基,杂环基,芳基或者杂芳基,其中烷基和芳基可各自独立地任选被一个选自下列的取代基取代:卤素,NO2,CF3,CN,OR20,SR20,N(R20)2,S(O)R22,或者SO2R22。更优选地,R17是含有1至3个N原子的稠合6,6元环系的杂芳基,并且可任选被1-2个选自下列的取代基取代:氢,卤素,CF3,OR20,N(R20)2,CON(R20)2,C1-8烷基,C2-8链烯基,C2-8炔基,芳基或者杂芳基,其中烷基和芳基可各自独立地任选被一个选自下列的取代基取代:卤素,CF3,OR20,或者N(R20)2。最优选地,R17是含有1-2个N原子的稠合6,6元环系的且可任选被甲基取代的杂芳基。
在又一优选的方案中,R17是含有1-3个杂原子的5或6元环,所述杂原子选自N,S,或O,并且可任选被1-3个选自下列的取代基取代:氢,卤素,NO2,CF3,CN,OR20,SR20,N(R20)2,S(O)R22,SO2R22,SO2N(R20)2,NR20CO2R22,NR20CON(R20)2,COR20,CO2R20,CON(R20)2,NR20SO2R22,C1-15烷基,C2-15链烯基,C2-15炔基,杂环基,芳基或者杂芳基,其中烷基和芳基可各自独立地任选被一个选自下列的取代基取代:卤素,NO2,CF3,CN,OR20,SR20,N(R20)2,S(O)R22,或者SO2R22。更优选地,R17是含有1-3个杂原子的5或6元环,所述杂原子选自N,S,或O,并且可任选被1至2个选自下列的取代基取代:氢,卤素,CF3,OR20,N(R20)2,CON(R20)2,C1-8烷基,C2-8链烯基,C2-8炔基,芳基或者杂芳基,其中烷基和芳基可各自独立地任选被一个选自下列的取代基取代:卤素,CF3,OR20,或者N(R20)2。更优选地,R17是含有1至2个氮原子的6元环,并且可任选被1至2个选自下列的取代基取代:氢,卤素,CF3,OR20,N(R20)2,CON(R20)2,C1-8烷基,C2-8链烯基,C2-8炔基,芳基或者杂芳基,其中烷基和芳基可各自独立地任选被一个选自下列的取代基取代:卤素,CF3,OR20,或者N(R20)2。在本方案中最优选地R17是一个可任选被甲基取代的含有1至2个氮原子的6元环。
在又一个优选的方案中,R17是选自苯并噻唑和苯并噁唑的稠合6,5元环系的杂芳基,并且可任选被一个选自下列的取代基取代:氢,CF3,OR20,C1-3烷基,或者芳基,其中烷基和芳基可任选被一个卤素或者CF3取代,优选可任选被一个甲基取代。
在一个优选的方案中,R20选自H,C1-15烷基,芳基,或杂芳基,其中烷基和芳基取代基可任选被1个选自下列的取代基取代:卤素,烷基,单烷基氨基,二烷基氨基,烷基氰基,-O-C1-6烷基,或CF3;R20选自H,C1-5烷基,芳基,或杂芳基,其中烷基和芳基取代基可任选被1个选自下列的取代基取代:卤素,-OMe,CF3。在更优选的方案中,R20选自H,C1-3烷基,或芳基,其中烷基和芳基可任选被1个分别选自卤素,-OMe,或CF3的取代基取代。最优选地,R20选自H或者C1-3烷基且最优选H或者甲基。
在优选的方案中,R22选自C1-15烷基,芳基,或杂芳基,其中烷基和芳基取代基可任选被1个选自下列的取代基取代:卤素,烷基,单烷基氨基,二烷基氨基,烷基酰氨基,芳基酰氨基,杂芳基酰氨基,CN,O-C1-6烷基,CF3,或杂芳基。
在最优选的方案中,本发明是选自下列的取代哌嗪化合物:N-(2,6-二甲基-苯基)-2-(4-{2-羟基-3-[2-(3-三氟甲基苯基)苯并噁唑-5-基氧]-丙基}哌嗪-1-基)乙酰胺,2-{4-[3-(苯并噻唑-2-基氧)-2-羟基-丙基]-哌嗪-1-基}-N-(2,6-二甲基苯基)乙酰胺,N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(2-甲基-苯并噻唑-5-基氧)-丙基]哌嗪-1-基}乙酰胺,4-(3-{4-[(2,6-二甲基苯基氨基甲酰基)-甲基]-哌嗪-1-基}-2-羟基-丙氧基)-1H-吲哚-2-羧酸酰胺,2-{4-[3-(苯并噻唑-6-基氧)-2-羟基-丙基]-哌嗪-1-基}-N-(2,6-二甲基-苯基)乙酰胺,N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(2-甲基-苯并噻唑-6-基氧)-丙基]哌嗪-1-基}乙酰胺,N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(2-甲基-苯并噻唑-5-基氧)-丙基]-3,5-二甲基-哌嗪-1-基}乙酰胺,2-{4-[2-羟基-3-(2-甲基-苯并噻唑-5-基氧)-丙基]-哌嗪-1-基}-N-(4-羟基-苯基)乙酰胺,N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(2-苯基-苯并噻唑-5-基氧)-丙基]-哌嗪-1-基}乙酰胺,N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(2-苯基-苯并噁唑-5-基氧)-丙基]-哌嗪-1-基}乙酰胺,N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(2-苯基-苯并噻唑-7-基氧)-丙基]-哌嗪-1-基乙酰胺,N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(2-甲基-苯并噻唑-5-基氧)-丙基]-2-氧-哌嗪-1-基}乙酰胺,N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(2-甲基-苯并噁唑-5-基氧)-丙基]-哌嗪-1-基}乙酰胺,N-(2,6-二甲基苯基)-2-(4-{2-羟基-3-[2-(4-三氟甲基-苯基)-苯并噁唑-5-基氧]-丙基}-哌嗪-1-基)乙酰胺,N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(喹噁啉-2-基氧)-丙基]-哌嗪-1-基}乙酰胺,N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(吡啶-3-基氧)-丙基]-哌嗪-1-基}乙酰胺,N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(喹啉-4-基氧)-丙基]-哌嗪-1-基}乙酰胺,N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(异喹啉-5-基氧)-丙基]-哌嗪-1-基}乙酰胺,N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(喹啉-6-基氧)-丙基]-哌嗪-1-基}乙酰胺,N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(2-甲基-喹啉-7-基氧)-丙基]-哌嗪-1-基}乙酰胺,2-{4-[3-(苯并噻唑-2-基氨基)-2-羟基丙基]哌嗪基}N-(2,6-二甲基苯基)乙酰胺,2-{4-[3-(苯并噁唑-2-基氨基)-2-羟基丙基]哌嗪基}-N-(2,6-二甲基苯基)乙酰胺,2-{4-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]-2,5-二甲基哌嗪基}-N-(2,6-二甲基苯基)乙酰胺,2-{4-[(2R)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]-2,6-二甲基哌嗪基}-N-(2,6-二甲基苯基)乙酰胺,2-{4-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]3,3-二甲基哌嗪基}-N-(2,6-二甲基苯基)乙酰胺,2-{(3S)-4-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]-3-甲基哌嗪基}-N-(2,6-二甲基苯基)乙酰胺,2-{(2R)-4-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]-2-甲基哌嗪基}-N-(2,6-二甲基苯基)乙酰胺,2-{4-[(2R)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]-3-甲基哌嗪基}-N-(2,6-二甲基苯基)乙酰胺,2-{4-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]-2,6-二甲基哌嗪基}-N-(2,6-二甲基苯基)乙酰胺,2-{4-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]-2-甲基哌嗪基}-N-(2,6-二甲基苯基)乙酰胺,2-{4-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基](1,4-diazaperhydroepinyl)}-N-(2,6-二甲基苯基)乙酰胺,2-{4-[2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]哌嗪基}-N-(4-羟基苯基)乙酰胺,2-{4-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]-2,6-二甲基哌嗪基}-N-(4-甲酰氨基苯基)乙酰胺,2-{(3S)-4-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]-3-甲基哌嗪基}-N-(2,6-二甲基苯基)乙酰胺,2-{4-[(2R)-2-羟基-3-(2-苯基苯并噻唑-5-基氧)丙基]哌嗪基}-N-(2,6-二甲基苯基)乙酰胺,2-{4-[2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]哌嗪基}-N-(2,6-二甲基-4-羟基苯基)乙酰胺,2-{5-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]-2,5-二氮杂双环[2.2.1]庚-2-基}-N-(2,6-二甲基苯基)乙酰胺,2-{4-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]哌嗪基}-N-(4-磺酰胺基苯基)乙酰胺,2-{(3S)-4-[(2S)-2-羟基-3-(2-苯基苯并噁唑-5-基氧)丙基]-3-甲基哌嗪基}-N-(2,6-二甲基苯基)乙酰胺,2-{4-[2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]哌嗪基}-N-萘基乙酰胺,N-[4-氯-3-(三氟甲基)苯基]-2-{4-[2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]哌嗪基}乙酰胺,2-{4-[2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]哌嗪基}-N-苯基乙酰胺,2-{4-[2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]哌嗪基}-N-(3,4,5-三氯苯基)乙酰胺,2-{4-[2-羟基-3-(4-甲氧基苯基)丙基]哌嗪基}-N-(3,4,5-三氯苯基)乙酰胺,2-{4-[2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]哌嗪基-N-(2-氯-4-甲基苯基)-乙酰胺,2-{4-[2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]哌嗪基}-N-(3,4,5-三氯苯基)乙酰胺,2-{4-[2-羟基-3-(2-苯基苯并噻唑-5-基氧)丙基]哌嗪基}-N-(3,5-二氯苯基)乙酰胺,2-{4-[2-羟基-3-(2-苯基苯并噻唑-5-基氧)丙基]哌嗪基}-N-(3,4-二氯苯基)乙酰胺,2-{4-[2-羟基-3-(2-苯基苯并噻唑-5-基氧)丙基]哌嗪基}-N-[3-甲氧基-5-(三氟甲基)苯基]乙酰胺,2-{4-[2-羟基-3-(2-苯基苯并噻唑-5-基氧)丙基]哌嗪基}-N-[3,5-二氯]苯基}乙酰胺,和2-{4-[2-羟基-3-(2-((1E)丁-1,3-二链烯基)苯并噻唑-5-基氧)丙基]哌嗪基}-N-[4-氯-2-甲氧基-5-甲基苯基]乙酰胺。
此处所用术语具有下列定义。
“卤代”或“卤素”-单独或者结合指所有的卤素原子,即氯(Cl),氟(F),溴(Br),碘(I)。
“羟基”是指基团-OH。
“硫醇基”或“巯基”是指基团-SH。
“烷基”-单独或者结合是指含有1-20个碳原子,优选1-15个碳原子(除非具体定义)的烷烃-衍生的基团。可以是直链烷基、支链烷基或者环烷基。优选地,为含有1-15个,更优选1至8个,甚至更优选1-6,再优选1-4个,最优选1-2个碳原子的直链或者支链的烷基,如甲基、乙基、丙基、异丙基、丁基、叔丁基等等。此处所用术语“低级烷基”正如上述定义的直链烷基。优选地,环烷基是每个环为3-8、优选为3-6元环的单环、双环、或者三环系,如环丙基、环丁基、环戊基、环己基、金刚烷基等等。烷基也包括包含或被环烷基部分间隔的直链或支链烷基。直链或者支链烷基可以连接在任何有效点以生产稳定的化合物。其实例包括但不限于:4-(异丙基)-环己基乙基或2-甲基-环丙基戊基。取代烷基是指分别被1-3个下列基团或取代基取代的前述定义的直链或支链烷基,或环烷基:卤素,羟基,烷氧基,烷硫基,烷基亚磺酰基,烷基磺酰基,酰氧基,芳氧基,杂芳氧基,任选被烷基、芳基、或者杂芳基单取代或者双取代的氨基,脒基,任选被烷基、芳基、杂芳基、或者杂环取代的脲基,任选被烷基、芳基、或者杂芳基N-单取代或者N,N-二取代的氨基磺酰基,烷基磺酰氨基,芳基磺酰氨基,杂芳基磺酰氨基,烷基羰基氨基,芳基羰基氨基、杂芳基羰基氨基等等。
“链烯基”单独或者结合指含有2-20个,优选2-17个,更优选2-10个,甚至更优选2-8个,最优选2至4个碳原子且至少具有一个,优选1-3个,更优选1-2个且最优选1个碳碳双键的直链、支链或者环状烃。对于环烷基,多于1个碳碳双键的共轭并不因此赋予该环芳香性。碳碳双键可以包含在除环丙基之外的环烷基部分,也可以在直链或支链部分。链烯基的实例包括:乙烯基,丙稀基,异丙稀基,丁烯基,环己烯基,环己烯基烷基等等。取代链烯基是指分别被1-3个下列的基团或者取代基取代的上述定义的直链烯基、支链烯基或者环烯基:卤素,羟基,烷氧基,烷硫基,烷基亚磺酰基,烷基磺酰基,酰氧基,芳氧基,杂芳氧基,任选被烷基、芳基、或者杂芳基单取代或者双取代的氨基,脒基,任选被烷基、芳基、杂芳基或者杂环取代的脲基,任选被烷基、芳基、或者杂芳基N-单取代或者N,N-二取代的氨基磺酰基,烷基磺酰氨基,芳基磺酰氨基,杂芳基磺酰氨基,烷基羰基氨基,芳基羰基氨基、杂芳基羰基氨基,羧基,烷氧羰基,芳氧羰基,杂芳氧羰基等,并且可以在任何有效点连接以产生稳定化合物。
“炔基”-单独或结合是指含有2-20,优选2-17,更优选2-10,再优选2-8,最优选2-4个碳原子,且具有至少一个,优选1个碳-碳三键的直链,支链,或环烃基。炔基的实例包括乙炔基,丙炔基,丁炔基等等。取代的炔基是指分别被1至3个下列基团或取代基取代前述定义的直链炔基或支链炔基:卤素,羟基,烷氧基,烷硫基,烷基亚磺酰基,烷基磺酰基,酰氧基,芳氧基,杂芳氧基,任选单或二烷基、芳基或杂芳基取代的氨基,酰氨基,任选被烷基,芳基或杂芳基或杂环基取代的脲,任选被N-单或N,N-二烷基、芳基或杂芳基取代的氨基磺酰基,烷基磺酰基氨基,芳基磺酰基氨基,杂芳基磺酰基氨基,烷基羰基氨基,芳基羰基氨基,杂芳基羰基氨基等等并且连接在任意可以产生稳定化合物的有效点上。
“烷基链烯基”是指基团-R-CR’=CRR””,其中R是低级烷基或取代的低级烷基,R’,R,R””分别为氢,卤素,低级烷基,取代的低级烷基,酰基,芳基,取代的芳基,杂芳基,或取代杂芳基,这些基团如下面定义。
“烷基炔基”是指-RC≡CR’其中R是低级烷基或取代的低级烷基,R’是氢,低级烷基,取代的低级烷基,酰基,芳基,取代的芳基,杂芳基,或取代的杂芳基,这些基团如下面所定义。
“烷氧基”是指基团-OR,其中R是低级烷基,取代的低级烷基,酰基,芳基,取代的芳基,芳烷基,取代的芳烷基,杂烷基,杂芳基烷基,环烷基,取代的环烷基,杂环烷基,或取代的杂环烷基,这些基团如下面所定义。
“烷硫基”是指基团-SR,-S(O)n=1-2-R,其中R是低级烷基,取代的低级烷基,芳基,取代的芳基,芳烷基或取代的芳烷基,这些基团如本文所定义。
“酰基”是指基团-C(O)R,其中R是氢,低级烷基,取代的低级烷基,芳基,取代的芳基等等,这些基团如本文所定义。
“芳氧基”是指基团-OAr,其中Ar是芳基,取代的芳基,杂芳基,或取代的杂芳基,这些基团如本文所定义。
“氨基”是指基团NRR’,其中R和R’各自独立地为氢,或者如本文定义的低级烷基,取代的低级烷基,芳基,取代的芳基,杂芳基,取代的杂芳基,或者酰基。
“酰氨基”是指基团-C(O)NRR’,其中R和R’分别是氢,低级烷基,取代的低级烷基,芳基,取代的芳基,杂芳基,取代的杂芳基,这些基团如本文所定义。
“羧基”是指基团-C(O)OR,其中R是氢,低级烷基,取代的低级烷基,芳基,取代的芳基,杂芳基,或取代的杂芳基,这些基团如本文所定义。
“芳基”单独或结合是指苯基或萘基,任选与优选5-7,更优选5-6元环烷基稠合和/或任选被1至3个选自下列的基团或取代基取代:卤素,羟基,烷氧基,烷硫基,烷基亚磺酰基,烷基磺酰基,酰氧基,芳氧基,杂芳氧基,任选单或二烷基、芳基或杂芳基取代的氨基,脒基,任选被烷基,芳基或杂芳基或杂环基取代的脲,任选被N-单或N,N-二烷基、芳基或杂芳基取代的氨基磺酰基,烷基磺酰基氨基,芳基磺酰基氨基,杂芳基磺酰基氨基,烷基羰基氨基,芳基羰基氨基,杂芳基羰基氨基等等。
“取代的芳基”是指任选被1至多个功能基取代的芳基,所述功能基如卤素,低级烷基,低级烷氧基,烷硫基,乙炔基(acetylene),氨基,酰氨基,羧基,羟基,芳基,芳氧基,杂环基,杂芳基,取代的杂芳基,硝基,氰基,硫醇基,磺酰氨基等等。
“杂环基”是指饱和,不饱和或芳香碳环基,具有单环(如吗啉基,吡啶基或呋喃基)或多个稠合环(如萘基吡啶基(naphthpyridyl),喹噁啉基,喹啉基,吲哚啉基(indolizinyl)或苯并[b]噻吩基)并且环中具有至少一个杂原子,如N,O或S,并任选未取代或被下列基团取代:卤素,低级烷基,低级烷氧基,烷硫基,乙炔基,氨基,酰氨基,羧基,羟基,芳基,芳氧基,杂环基,杂芳基,取代的杂芳基,硝基,氰基,硫醇基,磺酰胺基等等。
“杂芳基”-单独或结合是指具有5或6个环原子的单环芳香环结构,或具有8至10个原子的双环芳香基,含有一个或多个,优选1-4个,更优选1-3个,最优选1-2个独立地选自O,S,和N的杂原子,并任选被1至3个选下列基团或取代基取代:卤素,羟基,烷氧基,烷硫基,烷基亚磺酰基,烷基磺酰基,酰氧基,芳氧基,杂芳氧基,任选单或二烷基、芳基或杂芳基取代的氨基,脒基,任选被烷基、芳基、杂芳基或杂环基取代的脲,任选被烷基、芳基或杂芳基N-单或N,N-二取代的氨基磺酰基,烷基磺酰基氨基,芳基磺酰基氨基,杂芳基磺酰基氨基,烷基羰基氨基,芳基羰基氨基,杂芳基羰基氨基等等。杂芳基也包括氧化的S或N,如亚磺酰基,磺酰基和叔环氮原子的N-氧化物。碳或氮原子是杂芳基环结构的连接点以保持稳定的芳香环结构。杂芳基的实例包括吡啶基,哒嗪基,吡嗪基,喹唑啉基,嘌呤基,喹啉基,异喹啉基,嘧啶基,吡咯基,噁唑基,噻唑基,噻吩基,异噁唑基,氧杂噻二唑基,异噻唑基,四唑基,咪唑基,三唑基,呋喃基,苯并呋喃基,吲哚基,苯并噻唑基,苯并噁唑基等等。取代的杂芳基包含连接在有效的可产生稳定化合物的碳或氮上的取代基。
“杂环基”-单独或结合是指具有5-10个原子的非芳香环烷基,其中环上的1至3个碳原子被O,S或N的杂原子置换,并任选苯并稠合或与5-6元杂芳基稠合和/或在环烷基情况下任选被取代。杂环基也可包括氧化的S或N,如亚磺酰基,磺酰基和叔环氮的N-氧化物。连接点在碳原子或氮原子上。杂环基的实例包括四氢呋喃基,二氢吡啶基,哌啶基,吡咯烷基,哌嗪基,二氢苯并呋喃基,二氢吲哚基,等等。取代的杂环基含有连接在可产生稳定化合物的碳或氮原子上的取代的氮。
“取代的杂芳基”是指任选被1个或多个例如下列的功能基单或多取代的杂环基:卤素,低级烷基,低级烷氧基,烷硫基,乙炔基,氨基,酰氨基,羧基,羟基,芳基,芳氧基,杂环基,取代的杂环基,杂芳基,取代的杂芳基,硝基,氰基,硫醇基,磺酰胺基等等。
“芳烷基”是指基团-R-Ar,其中Ar是芳基,R是低级烷基或取代的低级烷基。芳基任选未取代或被如下基团取代:卤素,低级烷基,烷氧基,烷硫基,乙炔基,氨基,酰氨基,羧基,羟基,芳基,芳氧基,杂环基,取代的杂环基,杂芳基,取代的杂芳基,硝基,氰基,硫醇基,磺酰胺基等等。
“杂烷基”是指基团-R-Het,其中Het是杂环基且R是低级烷基。杂烷基可以任选未取代或被如下基团取代:卤素,低级烷基,低级烷氧基,烷硫基,乙炔基,氨基,酰氨基,羧基,芳基,芳氧基,杂环基,取代的杂环基,杂芳基,取代的杂芳基,硝基,氰基,硫醇基,磺酰胺基等等。
“杂芳基烷基”是指基团-R-HetAr其中HetAr是杂芳基且R是低级烷基或取代的低级烷基。杂芳基烷基可以任选未取代或被如下基团取代:卤素,低级烷基,取代的低级烷基,烷氧基,烷硫基,乙炔基,芳基,芳氧基,杂环基,取代的杂环基,杂芳基,取代的杂芳基,硝基,氰基,硫醇基,磺酰胺基等等。
“环烷基”是指含有3-15个碳原子的二价环或多环烷基。
“取代的环烷基”是指含有一个或多个下列取代基的环烷基:卤素,低级烷基,取代的低级烷基,烷氧基,烷硫基,乙炔基,芳基,芳氧基,杂环基,取代的杂环基,杂芳基,取代的杂芳基,硝基,氰基,硫醇基,磺酰胺基等等。
“杂环烷基”指一个或者多个环碳原子被杂原子(如N,O,S或者P)取代的环烷基。
“取代杂环烷基”指含有一个或者多个如下取代基的本文定义的杂环烷基:卤素,低级烷基,低级烷氧基,烷硫基,乙炔基,氨基,酰氨基,羧基,羟基,芳基,芳氧基,杂环基,取代的杂环基,杂芳基,取代的杂芳基,硝基,氰基,硫醇基,磺酰胺基等等。
“烷基环烷基”是指基团-R-环烷基,其中环烷基是环烷基且R是低级烷基或取代的低级烷基。环烷基可任选未取代或被下列基团取代:卤素,低级烷基,低级烷氧基,烷硫基,乙炔基,氨基,酰氨基,羧基,羟基,芳基,芳氧基,杂环基,取代的杂环基,杂芳基,取代的杂芳基,硝基,氰基,硫醇基,磺酰胺基等等。
“烷基杂环烷基”指基团-R-杂环烷基,其中R是低级烷基或者取代低级烷基。杂环烷基可任选未取代或被下列基团取代:卤素,低级烷基,低级烷氧基,烷硫基,氨基,酰氨基,羧基,乙炔基,羟基,芳基,芳氧基,杂环基,取代的杂环基,杂芳基,取代的杂芳基,硝基,氰基,硫醇基,磺酰胺基等等。
“任选的”或“任选地”是指随后描述的事件或情况可以出现或不出现。且说明包括其中事件或情况出现的情况和其中不出现的情况。例如,“任选的药用赋形剂”是指所述制剂可以包括,也可以不包括赋形剂,而不是特指所述情况出现,并且所述制剂包括其中任选的赋形剂存在的情况和它们不存在的情况。
“治疗”和“处理”是对哺乳动物,特别是人的疾病的任何治疗,包括:
(i)预防有患疾病的倾向但还未被诊断出患有疾病的患者出现疾病。
(iii)抑制疾病,如阻止疾病发展;或
(iii)减轻疾病,即导致疾病消退。
所有的上述方案包括其药用酸加成盐,特别是单和二盐酸盐,和其混合物。
具有通式Ia(q=O)或者Ic(q=S)的化合物可以用反应路线1-5所概括的方法制备。本发明化合物的常规合成概括于反应路线1。化合物IV可以通过取代的苯胺II与2-取代的氯代乙酰氯III的N-酰化而制备。化合物II可以商购或通过相应的硝基苯衍生物的还原容易地制备(酸/SnCl2或催化氢化,见Advanced Organic Chemistry,Ed.J.March(1992)A,Wiley Interscience)。某些可商购的相应于通式结构II的取代苯胺包括2,6-二甲基苯胺,2,3-二甲基苯胺,2-甲基苯胺,4-甲基苯胺,4-甲基苯胺,2,4-二氯苯胺,3,4-二氯苯胺,2,5-二氯苯胺,2,4-二氯苯胺,2-氯苯胺,3-氯苯胺,2,6-二氟苯胺,2,5-二氟苯胺,3,4-二氟苯胺,2-氟苯胺,4-氟苯胺,3-氟苯胺,2-氟-6-氯苯胺,4-氟-3-氯苯胺,4-乙酰氧基苯胺。
反应路线1
化合物VI可以通过将化合物IV与N-保护的取代哌嗪V在适宜的溶剂(如DMF,EtOH)中加热反应而得到。化合物V氮原子的保护是仅当其用于控制化合物V与化合物IV加成时的区域化学时才需要。在某些情况下,化合物V可以从商业途径获得。可商购的与通式结构V相应的化合物实例包括2-甲基哌嗪,2,5-二甲基哌嗪,2,6-二甲基哌嗪,2,3,5,6-四甲基哌嗪,哌嗪-2-羧酸,全氢喹噁啉(perhydroquinoxaline),2-氨基甲基-6-甲基哌嗪,2-氨基甲基哌嗪,2-(邻-氯苯基)哌嗪,2-(间-氯苯基)哌嗪。式VI化合物的脱保护可以在标准条件下进行(如Boc用TFA,CBz和苄基用氢化)。化合物Ia或Ic可以通过将式VII化合物与环氧化物VIII在适宜的溶剂(乙醇,DMF,CHCl2,THF)中加热,或者在镧系元素(lanthamide)(III)的路易斯酸存在下室温搅拌(Chini,Met al.,Tetrahedron Lett.,35:433-36(1994))反应而制备。
反应路线2
环氧化物VIII(其中m=1,2或3)可以按反应路线2所述制备。将取代的苯酚或者硫代苯酚IX与氯环氧丙烷,溴环氧丙烷或者4-溴-1,2-环氧丁烷和碳酸钾在丙酮或者氢化钠的DMF溶液中加热可以得到环氧化物VIII。化合物IX可通过商业途径得到。可以商购的式XI化合物包括2-甲基-5-羟基苯并噻唑,2-羟基苯并噻唑,8-羟基喹啉(8-hydroquinolidine),6-羟基喹啉,4-羟基喹啉,5-羟基异喹啉,3-羟基吡啶,2-喹噁啉醇(2-quinoxalinol),和4-(咪唑-1-基)苯酚。在某些情况下,式VIII化合物可以通过商业途径获得。可商购的与通式结构VIII相应的化合物包括4-缩水甘油氧基-2-吲哚甲酰胺(4-glycidyloxy-2-indolecarboxamide)。
化合物IX可以通过用如反应路线3所示将相应的甲基或者苄基醚(X)用路易斯酸脱保护而制备(BBr3,BF3等-见Advanced Organic Chemistry,Ed.J.March(1992)A.Wiley Interscience,p 434)。苄基醚也可以通过在乙醇/环己烯中与氢氧化钯一起回流进行脱保护(见Catalytic hydrogenation over platinummetals,P.N.Rylander,Academic Press,New York,NY,(1976)p 464)。可商购的甲基醚包括6-甲氧基-2-甲基-苯并噻唑。
反应路线3
Y=CH3,苄基
化合物IX也可以如反应路线4所示通过将相应的氨基化合物(XI)重氮化而制备(Boggust,W.A and Cocker,W.J.Chem.Soc.1949,355)。可商购的胺类包括6-氨基苯并噻唑。
反应路线4
化合物X的6,5稠合环系可以通过将可商购的2-氨基苯酚类,2-氨基苯硫酚,或2-氨基苯胺类化合物(XII)的醚与原酸酯类(orthoesters)化合物(XIII)(Musser,J.H.et al.,J.Med.Chem.1985,28,1255-1259)或酰亚胺酸酯(imidates)(XIV)(Gregory,G.I.et al.,J.Chem.Soc.Perkin Trans.1,1973,47-51)进行环化制备,分别如反应路线5和反应路线6所述。可商购的氨基酚类的醚包括4-甲氧基-2-氨基酚,可以商购的原酸酯类包括原甲酸三甲基酯(trimethylorthoformate),原乙酸三甲基酯(trimethyl orthoacetate),酰亚胺酸酯包括乙酰亚胺酸乙酯(ethyl acetimidate)盐酸盐,苯甲酰亚胺酸乙酯(ethyl benzimidate)盐酸盐。
反应路线5
X=O,S,NH Y=Me,苄基 Z=H,C1-4 alk-yl,aryl
反应路线6
X=O,S,NH Y=Me,苄基 Z=C1-4烷基,芳基
化合物XII的苯硫酚类似物可以通过用过硫化钠水合物处理可商购的化合物XV,然后用锡和盐酸还原(Dannley,R.L.and Zazaris,D.A;Can.J.Chem.1965,43,2610-2612)而制备,如反应路线7所示。可商购的硝基化合物包括3-硝基-4-氯苯甲醚。
反应路线7
Hal=Cl,Br,I;Y=Me,苄基
如反应路线8所示,酰亚胺酸酯(imidate)XIV可以通过向可商购的腈XVI的醇溶液中吹入HCl气泡而制备。可商购的腈包括苯基腈,4-三氟甲基苯基腈和3-三氟甲基苯基腈。
反应路线8
W=Me,Et Z=C1-4烷基,芳基
化合物X的含硫6,5稠合环系可以从可商购的苯胺XVII的醚制备(Stevens,M.F.G.et al.,J.Med.Chem.1994,37,1689-1695),如反应路线9所示。硫代酰胺XX可以通过Lawesson’s试剂与酰胺XIX反应而得到,而酰胺则可以通过化合物XVII与化合物XVIII反应制备。在碱性条件下将化合物XX用氰亚铁酸钾环合而得到化合物XXI。可商购的苯胺的醚包括苄氧基苯胺和甲氧基苯胺。
反应路线9
本发明中化合物XXV的一般制备概括在反应路线10中。化合物XXIV可以通过标准条件下将化合物XXIII脱保护而制备。(如BOC基团用TFA,CBZ和苄基用氢化)。化合物XXIII则依次可以通过可商购的被保护的单酮哌嗪类化合物XXII与化合物IV以及氢化钠在合适的溶剂(DMF,THF)中反应制备。可商购的单酮哌嗪包括4-苄氧羰基哌嗪-2-酮。
反应路线10
本发明中化合物Ib(q=NH)的一般合成概括于反应路线11和12中。化合物XXVII可以通过化合物VII与环氧化合物XXVI在合适的溶剂(乙醇,THF)中回流而制备。化合物XXVII的脱保护可以在标准的条件下进行(如DOC基团用TFA;CBZ用氢化或者Pd(OH)2)。化合物Ib可以通过化合物XXVIII与化合物XXIX在合适的溶剂(乙醇,THF)中回流而制备。可商购的化合物XXIX包括2-氯苯并噻唑,2-氯苯并噁唑,2-氯吡啶,2-氯嘧啶,2-氯-4-(三氟甲基)嘧啶,和氯吡嗪。
反应路线11
环氧化物XXVI可按照反应路线12的方案依次制备。可商购的化合物XXX可在标准的条件下进行保护(BOC保护可用BOC酸酐,CBZ保护用CBZ-Cl)。化合物XXV可以通过化合物XXXI与间-氯过苯甲酸在合适的溶剂(如二氯甲烷)中反应而制备。可商购的化合物XXX的实例但不限于烯丙胺。
反应路线12
化合物V可以如反应路线13所述制备。如Pohlman等(J.Org.Chem.(1977),62,1016-1022)所述,用t-BuLi作为碱将化合物XXXII用烷基卤化物烷基化可以得到化合物XXXIII,在用三氟乙酸(TFA)对N-Boc进行脱保护后用二硼烷对XXXIV还原可以得到N-苄基保护形式的化合物V[二硼烷还原见Jacobson等J.Med.Chem,1999,42,1123-1144]。
反应路线13
化合物V也可以通过D或L氨基酸的标准偶合(如EDC或PyBroP)和标准的脱保护而制备,如反应路线14的所述(Cledera,P.等,Tetrahedron,1998,p.12349-12360;Smith,R.A.等,Bioorg.Med.Chem.Lett.1998,p2369-2374)。将二酮哌嗪XXXVII用二硼烷还原可以得到N-苄基保护形式的化合物V。
反应路线14
化合物V也可以如反应路线15所示制备。醛XXXVIII溴化后再与乙二胺(ethylene diamine)反应可得亚胺XLI。催化氢化化合物XLI可得到化合物V(Bogeso,K.P.,et al,J.Med.Chem.1995,38,p 4380-4392)。可商购的醛包括异丁醛。
反应路线15
化合物V也包括哌嗪的双环同系物(1S,4S)(+)-2,5-二氮杂双环[2.2.1]庚烷83,3,8-二氮杂双环[3.2.1]辛烷84,和2,5-二氮杂双环[2.2.2]辛烷85。
可商购的双环同系物包括(1S,4S)(+)-2,5-二氮杂双环[2.2.1]庚烷83;化合物84,85以及83的(1R,4R)异构体可以通过已公开的方法制备(对于84和85见Sturm,P.A.等,J.Med.Chem.1974,17,481-487;对于83见Barish,T.F.和Fox,D.E.J.Org.Chem.,1990,55,1684-1687)。
与上述一般反应路线相应的制备化合物的具体实施例公开于反应路线16-29中,这些反应路线是进一步说明制备本发明化合物可以替换的方法的实例。特别地,将2,6-二甲基苯胺在饱和碳酸氢盐和乙醚(1∶1)作为碱和助溶剂的条件下用2-氯乙酰氯2酰化,相应得到氯代乙酰胺衍生物3。进一步将化合物3与哌嗪通过在乙醇中加热反应得到化合物5。将化合物5与环氧化物6均在乙醇中加热回流反应得到哌嗪衍生物7,如反应路线16所示。化合物6可通过将氯环氧丙烷和苯酚8在丙酮中在K2CO3存在下加热而制备,如反应路线17所示。
反应路线16
反应路线17
如反应路线18所示,苯并噁唑衍生物8通过将化合物13脱保护而制备。化合物10通过将2-氨基-4-甲氧基苯酚12缩合而得到。化合物12可以通过将可商购的4-甲氧基-2-硝基苯酚11催化氢化而得到,如反应路线19所示。化合物13利用3-三氟甲基苯基腈14通过Pinner反应而得到(乙醇/无水HCl)。
反应路线18
反应路线19
反应路线20
用于制备本发明所述化合物的关键中间体的合成如反应路线21-25所示。化合物16通过可商购的6-氨基苯并噻唑的重氮化反应而制备,如反应路线21所示。
反应路线21
化合物19通过化合物12与原乙酸三甲酯(trimethyl orthoacetate)18缩合反应制备,如反应路线22所示。
反应路线22
化合物22可以通过将化合物21用锡和盐酸还原而制备,如反应路线23所示。化合物21通过化合物20与过硫化钠水合物反应而制备。
反应路线23
如反应路线24所示,化合物26通过将化合物25与Lawesson’s试剂反应而制备。化合物25通过苯胺23与苯甲酰氯24反应而制备。硫代酰胺26用氰亚铁酸钾在氢氧化钠水溶液中环化得到化合物27和28的混合物。化合物27和28通过柱层析分离。
反应路线24
化合物27的脱苄基反应通过在乙醇/环己烯中用Pearlmann’s催化剂进行转移氢解而进行,如反应路线25所示。
反应路线25
本发明中化合物34的合成如反应路线26所示。酰胺3可以如反应路线16所述制备。化合物3与通过在DMF中用氢化钠处理而形成的哌嗪单酮30的阴离子manion反应得到化合物31。化合物34通过在乙醇中加热化合物32和环氧化物33而得到。化合物32通过对化合物31催化脱氢进行脱保护而制备。环氧化物33可以用与在反应路线17所述的化合物6相同的方法制备。
反应路线26
本发明中的具体化合物39的合成如反应路线27所示。化合物5的合成如前所述(反应路线16)。将化合物5与环氧化物35在乙醇中加热回流得到化合物36。将化合物36和氢氧化钯在乙醇/环己烯中在回流条件下脱保护得到胺37。最终化合物39通过将化合物37和2-氯苯并噻唑在乙醇和三乙胺(TEA)中反应而制备。
反应路线27
环氧化物35的合成如反应路线28所示。烯丙基胺40和氯甲酸苄基酯在二氯甲烷中反应得到化合物42。间氯过苯甲酸与化合物42反应得到环氧化物35。
反应路线28
可以将本发明化合物的酸加成盐用适宜的碱,如碳酸钾或氢氧化钠,典型地在水溶剂存在下,在约0度至100度的温度下处理而转化成相应的游离碱。游离碱可以通过常规方法分离,如用有机溶剂萃取。
本发明化合物的盐可以利用不同的溶解性和挥发性,或通过用适宜地承载的离子交换树脂而相互转换。这种转换在约0℃至用作反应介质的溶剂沸点之间的温度进行。活性化合物和本文所述盐的服用可以通过用于治疗剂服用的任意可接受的方式进行。该方法包括口服,非肠道,经皮,皮下和其它全身给药模式。除在患者自己不能摄取任何药物的情况外,优选的服药方法是口服。在此情况下需要服用非肠道组合物。
根据所需给药方式,组合物可以是固体形式,半固体形式或液体制剂形式,如片剂,栓剂,丸剂,胶囊,粉末,液体,悬浮液等等,优选地以适宜单剂量服用精确剂量的单位剂量形式。组合物可以包括一种或多种常规的药物赋形剂和至少一种本发明的活性化合物或其药用盐,并且还可以包括其它医药剂,药剂,载体,辅料,稀释剂等等。
服用的活性化合物的量当然根据所治疗的患者,患者的体重,疾病的严重程度,服药方式和处方医生的判断来决定。但是,有效的剂量范围在0.1-30mg/kg/天,优选0.5-20mg/kg/天。对于平均70kg的人来说,服用量为每天7-2100mg,优选35-1400mg/天。由于本发明化合物的许多作用(保护骨骼肌免受创伤导致的损伤,保护肌肉或全身性疾病如间歇性跛行之后的骨骼肌,治疗休克疾病,保护移植中使用的供体组织和器官,和治疗心血管疾病包括心房和心室心律不齐,Prinzmetal(变异)氏绞痛,稳定性绞痛,运动导致的绞痛,充血性心脏病,和心肌梗塞)是通过相似的机理(部分脂肪酸氧化抑制)取得的,剂量(和服用形式)通常都是相同的且优选在所有这些用途范围中。
对于固体组合物,可以使用的常规的无毒固体包括,例如药物级的甘露糖醇,乳糖,淀粉,硬脂酸镁,糖精钠,滑石粉,纤维素,葡萄糖,蔗糖,碳酸镁,等等。上述定义的活性化合物可以用例如聚亚烷基二醇(polyalkyleneglycols),如丙二醇作为载体配制成栓剂。可药用的液体药物组合物可以通过例如将上述定义的活性化合物和任选的药物辅料溶解,分散在赋形剂,例如水,盐水,葡萄糖水溶液,甘油,乙醇等中,以形成溶液或悬浮液。如果需要,服用的药物组合物可以含有少量无毒辅料,如润湿剂或乳化剂,pH缓冲剂等,如乙酸钠,脱水山梨糖醇单月桂酸酯,三乙醇胺乙酸钠,三乙醇胺油酸酯等。制备这类剂量形式的实际方法是已知的,或对本领域技术人员来说是显而易见的;例如,参见Remington’s Pharmaceutical Sciences,Mack Publishing Company,Easton,Pennsylvania,第15版,1975。服用的组合物或制剂无论如何,含有的活性化合物的量是治疗有效量,即可有效减轻所治疗患者的症状的剂量。对于口服,药用无毒组合物通过加入任何常用的赋形剂而制成,如,药物级的甘露糖醇,乳糖,淀粉,硬脂酸镁,糖精钠,滑石粉,纤维素,葡萄糖,蔗糖,碳酸镁,等等。这类组合物可以是溶液,悬浮液,片剂,丸剂,胶囊,粉末,缓释制剂等等。这类组合物可以含有10%-95%,优选1-70%的活性成分。
非肠道给药一般是以注射为特征的,或者皮下,肌肉或者静脉。注射剂可以以常规形式制备,或者为液体溶液或悬浮液,适宜在注射前制成液体溶液或悬浮液的固体形式,或乳液。适宜的赋形剂是,例如水,盐水,葡萄糖,甘油,乙醇等等。此外,如果需要,服用的药物组合物也可以含有少量无毒辅助物质,如润湿剂或乳化剂,pH缓冲剂,如乙酸钠,脱水山梨糖醇单月桂酸酯,三乙醇胺油酸酯等。
最近发明的非肠道给药途径是用缓释或控释系统的植入,以保持剂量的恒定水平。见美国专利3,710,795,插入此引作参考。在另一种最近的方式中,本发明组合物可以用美国专利申请09/321,522,申请日1999年5月27日公开的组合物和/或方法以控释的剂量形式口服给药,该专利的说明书插入此引作参考。
给哺乳动物,优选人通过其它已知的药物剂型服用一种或多种本发明化合物是在本发明范围内的,包括但不限于通过大丸剂(bolus),静脉注射,经皮给药,通过吸入,皮下给药,或其它的本领域技术人员已知的治疗剂给药方法或途径。
下列实施例是本发明的代表,但不能被理解为是对权利要求范围的限定。
实施例1
N-(2,6-二甲基-苯基)-2-(4-{2-羟基-3-[2-(3-三氟甲基苯基)苯并噁唑-5-基氧]-丙基}-哌嗪-1-基)乙酰胺(7):
部分A.
N-(2,6-二甲基苯基)-2-氯乙酰胺(3)的合成:
将2,6-二甲基苯胺(9.8g,81.2mmol)溶解在乙醚(100mL)和饱和NaHCO3(100mL)水溶液中并将反应混合物在冰/水浴中冷却。用2小时向该冷却溶液中滴加氯乙酰氯2(9.17g,81.2mmol)。将混合物加热至室温保持14小时。将混合物用乙酸乙酯(3×50)萃取。将合并的有机层用硫酸镁干燥,过滤并浓缩。将残余物用乙醚研制并过滤得到白色固体化合物3。
部分B
N-(2,6-二甲基苯基)-哌嗪-1-基-乙酰胺(5)的合成:
在化合物3(5g,25.2mmol)的乙醇(100mL)溶液中加入哌嗪4(2.1g,25.0mmol)和N,N-二异丙基胺(3.2g,25.2mmol)。将反应混合物加热回流24小时。将混合物真空浓缩并将残余物通过柱色谱纯化(10∶1,DCM∶MeOH)得到化合物5。
部分C
5-(环氧乙烷-2-基-甲氧基)-2-[(3-三氟甲基)苯基]苯并噁唑(6)的合成:
1. 2-氨基-4-甲氧基苯酚(12)的合成:
将4-甲氧基-2-硝基苯酚11(10g,59.1mmol)的溶液和钯/碳(1.0g)的甲醇(100mL)溶液放到帕尔振荡器(Parr shaker),通H2(50psi)60分钟。将反应混合物用Celite521过滤,滤饼用甲醇洗涤。滤出液在真空蒸馏得到褐色固体化合物12。
2. 3-三氟甲基-苯甲亚胺酸(benzimidic acid)乙酯盐酸盐的合成(13):
向α,α,α-三氟甲基间甲苯基氰14(1g,5.84mmol)的乙醇(10mL,无水)溶液中通入HCI(气体,无水)气泡10分钟,溶液搅拌过夜。蒸馏溶剂得到白色固体化合物13。得到的固体不需纯化可用于下一步反应。
3. 5-甲氧基-2-(3-三氟甲基苯基)-苯并噁唑(10)的合成:
化合物13和化合物12(850mg,6.13mmol)的THF(10mL)溶液加热回流并搅拌过夜。反应混合物冷却,THF在真空蒸馏。将残余物溶解于乙酸乙酯并用水洗涤。有机层用硫酸镁干燥并用活性炭NoritA处理。混合物用Celite521过滤,真空蒸馏。将残余物用柱色谱纯化(20%乙酸乙酯/己烷)得到浅黄色固体化合物10。
4. 2-[(3-三氟甲基)苯基]苯并噁唑-5-酚(8)的合成:
化合物10(200mg,0.68mmol)溶于5ml二氯甲烷,滴加BBr3(1M二氯甲烷溶液,1mL,1mmol)。反应液搅拌48小时。蒸馏(真空)除溶剂,并将残余物溶解在乙酸乙酯中,用饱和的NaHCO3洗涤,有机层用硫酸镁干燥,真空蒸馏,将残余物用柱色谱纯化(30%乙酸乙酯/己烷)得到白色固体化合物8。
5. 5-(环氧乙烷-2-基-甲氧基)-2-[(3-三氟甲基)苯基]苯并噁唑(6)的合成:
向溶于DMF(2mL无水)的NaH(7mg,60%分散在油中,0.18mmol)中滴加化合物8(54mg,0.19mmol)的DMF(2ml,无水)溶液,反应液搅拌15分钟。向上述反应液中滴加环氧氯丙烷(50μL,0.63mmol),搅拌过夜。蒸馏(真空)除溶剂,残余物溶于水中,用乙酸乙酯萃取。合并有机层,硫酸镁干燥,蒸馏得到透明油状化合物6。
部分D
N-(2,6-二甲基苯基)-2-(4-{2-羟基-3-[2-(3-三氟甲基苯基)苯并噁唑-5-基氧]-丙基}-哌嗪-1-基)乙酰胺(7)的合成:
化合物5(183mg,0.73mmol)和化合物6溶于乙醇(2mL)和三乙基胺(0.2mL),加热到90℃,搅拌过夜。将反应混合物冷却,蒸馏(真空)除溶剂得到油状物。将油状物用制备TLC纯化(5/0.5/94.5甲醇/氢氧化胺/二氯甲烷)得白色固体化合物7:质谱(MH+)=583.4。
实施例2
2-{4-[3-(苯并噻唑-2-基氧)-2-羟基-丙基]-哌嗪-1-基}-N-(2,6二甲基苯基)乙酰胺(43):
2-(环氧乙烷-2-基甲氧基)苯并噻唑(44)的合成:
化合物44的制备方法与化合物6同,用2-羟基苯并噻唑代替实施例1中部分C-5的化合物8。
化合物43的制备方法与化合物7同,用化合物44代替化合物7的制备中部分D的化合物6即可:质谱(MH+)=455.3
实施例3
N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-[2-甲基-苯并噻唑-5-基氧]-丙基]-哌嗪-1-基}乙酰胺(45):
2-甲基-5-(环氧乙烷-2-基甲氧基)苯并噻唑(33)的合成:
化合物33的制备方法与化合物6同,用2-甲基苯并噻唑-5-酚代替实施例1中部分C-5的化合物8。
化合物45的制备方法与化合物7同,用化合物33代替化合物7的制备中部分D的化合物6即可:质谱(MH+)=469.3
实施例4
4-(3-[4-[(2,6-二甲基苯基氨基甲酰基)-甲基]-哌嗪-1-基]-2-羟基-丙氧基)-1H-吲哚-2-羧酸酰胺(46):
化合物19制备方法与化合物7同,用商购的4-缩水甘油氧基-2-吲哚甲酰胺(4-glycidyloxy-2-indolecarboxamide)代替化合物7的部分D的化合物6:质谱(MH+)=480.4
实施例5
2-{4-[3-(苯并噻唑-6-基氧)-2-羟基-丙基]-哌嗪-1-基}-N-(2,6二甲基苯基)乙酰胺(47):
苯并噻唑-6-酚(16)的合成:
6-氨基苯并噻唑(1.0g,6.66mmol)溶于水(22mL)和硫酸(16mL),在5℃加入亚硝酸钠(460mg,6.72mmol)水溶液(水的量为13mL),保持温度低于5℃。反应液搅拌15分钟。反应混合物加热到160℃,缓慢加入硫酸(50mL)和水(38mL)配成的溶液。反应混合物搅拌1小时。混合物冷却后,加入50%的氢氧化钠水溶液,使得PH=7。混合物用乙酸乙酯萃取,并用盐水洗涤。合并有机层并用硫酸镁干燥,蒸馏得半固体。将半固体用柱色谱纯化(40%乙酸乙酯/己烷)得灰白色固体化合物苯并噻唑-6-酚16。
6-(环氧乙烷-2-基甲氧基)苯并噻唑(48)的合成:
化合物48的制备方法与化合物6同,用化合物16代替实施例1中部分C-5的化合物8。
化合物47的制备方法与化合物7同,用化合物48代替化合物7的制备中部分D的化合物6即可:质谱(MH+)=455.3
实施例6
N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-[2-甲基-苯并噻唑-6-基氧]-丙基]-哌嗪-1-基}乙酰胺(49):
2-甲基苯并噻唑-6-酚(50)的合成:
如实施例1部分C-4所述,化合物50由可商购的6-甲氧基-2甲基苯并噻唑制备。
2-甲基-6-(环氧乙烷-2-基甲氧基)苯并噻唑(51)的合成:
化合物51的制备方法与化合物6同,用化合物50代替实施例1中部分C-5的化合物8。
化合物49的制备方法与化合物7同,用化合物51代替化合物7的制备中部分D的化合物6即可:质谱(MH+)=469.3。
实施例7
N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-[2-甲基-苯并噻唑-5-基氧]-丙基]-3,5-二甲基哌嗪-1-基}乙酰胺(52):
N-(2,6-二甲基苯基)-2-(3,5-二甲基哌嗪-1-基)乙酰胺(53)的合成:
化合物53的制备方法与化合物3相同,用2,6-二甲基哌嗪代替实施例1中部分A的哌嗪。
化合物52的制备方法与化合物7同,在化合物7制备的部分D,用化合物33代替化合物6,用化合物53代替化合物5即可:质谱(MH+)=497.4。
实施例8
2-{4-[2-羟基-3-(2-甲基-苯并噻唑-5-基氧)-丙基]-哌嗪-1-基}-N-(4-羟基-苯基)乙酰胺(54):
乙酸4-氨基苯基酯(55)的合成:
化合物55的制备方法与化合物12同,用乙酸4-硝基苯基酯代替实施例1中部分C-1的化合物11。
乙酸4-(2-氯乙酰胺基)苯基酯(56)的合成:
化合物56的制备方法与化合物3同,用化合物55代替实施例1中部分A的化合物1。
乙酸4-(2-哌嗪基乙酰胺基)苯基酯(57)的合成:
化合物57的制备方法如实施例1中B部分所示,用化合物56代替化合物3。
化合物54的制备方法与化合物7同,在化合物7制备的部分D,用化合物33代替化合物6,用化合物57代替化合物5即可:质谱(MH+)=457.5。
实施例9
N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(2-苯基-苯并噻唑-5-基氧)-丙基]-哌嗪-1-基}乙酰胺(58):
苯基-N-[3-(苯基甲氧基)苯基]甲酰胺(25)的合成:
向3-苯甲氧基苯胺23(1.0g,5.0mmol)和TEA(0.74mL,5.3mmol)的二氯甲烷溶液中滴加苯甲酰氯(0.61mL,5.26mmol),混合物搅拌过夜。反应混合物用水稀释,真空过滤收集所得固体。固体空气中干燥,得到白色固体化合物25。
苯基-{[3-(苯基甲氧基)苯基]氨基}甲烷-1-硫酮(26)的合成:
化合物25(455mg,1.5mmol)和Lawesson’s试剂(0.6mol,等量)溶于氯苯(15mL),加热到120℃,搅拌1.5小时。反应物冷却后蒸馏(真空)除溶剂。将残余物用柱色谱纯化(乙酸乙酯/己烷1∶9)得到黄色固体化合物26。
2-苯基-5(苯基甲氧基)苯并噻唑(27)的合成:
化合物26(960mg,3mmol)溶于乙醇(5mL),加入氢氧化钠水溶液(30%,8mol等量)。混合物用水(6mL)稀释,最终溶液为10%的氢氧化钠水溶液。在90℃将反应液加入搅拌过的铁氰化钾(4mol等量)和等量水(1mL)配制的溶液,所得反应混合物加热30min。反应混合物冷却,产物用乙酸乙酯萃取。有机层干燥蒸馏。残留物为化合物27和28的混合物,用柱色谱纯化(乙酸乙酯/己烷,1∶99)得白色固体化合物27。
2-苯基苯并噻唑-5-酚(29)的合成:
氢氧化钯(100mg)加入化合物27(260mg,0.8mmol)的乙醇/环己烷(5mL/2mL)溶液中,然后加热回流16小时。反应混合物冷却,Celite过滤除去催化剂。蒸馏除溶剂得白色固体化合物29。
5-(环氧乙烷-2-基甲氧基)-2-苯基苯并噻唑(59)的合成:
化合物59的制备方法与化合物6同,用化合物29代替实施例1中部分C-5的化合物8。
化合物58的制备方法与化合物7同,用化合物59代替化合物7的制备中部分D的化合物6即可:质谱(MH+)=531.6。
实施例10
N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(2-苯基-苯并噁唑-5-基氧)-丙基]-哌嗪-1-基}乙酰胺(60):
5-(环氧乙烷-2-基甲氧基)-2-苯基苯并噁唑(61)的合成:
化合物61的制备方法与化合物6同,用苯甲酰亚胺酸乙酯(ethylbenzimidate)盐酸盐代替实施例1中部分C1-5的化合物13。
化合物60的制备方法与化合物7同,用化合物61代替化合物7的制备中部分D的化合物6即可:质谱(MH+)=515.3。
实施例11
N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(2-苯基-苯并噻唑-7-基氧)-丙基]-哌嗪-1-基乙酰胺(62):
7-(环氧乙烷-2-基甲氧基)-2-苯基苯并噻唑(63)的合成:
化合物63的制备方法与化合物59同,用脱保护的化合物28代替实施例9中化合物29。
化合物62的制备方法与化合物7同,用化合物63代替化合物7的制备中部分D的化合物6即可:质谱(MH+)=531.3。
实施例12
N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(2-甲基-苯并噻唑-5-基氧)-丙基]-2-氧-哌嗪-1-基}乙酰胺(64):
4-{[N-(2,6-二甲基苯基)氨基甲酰基]甲基}-3-氧哌嗪基羧酸苯基甲基酯(31)的合成:
化合物30(252mg,1.3mmol)的THF(13mL)溶液和NaH(62mg,1.6mmol)加入化合物13(300mg,1.3mmol)中。溶液充氮条件下搅拌过夜。用水(0.1mL)终止反应并用硫酸钠干燥。溶液浓缩,用柱色谱纯化,得固体化合物31。N-(2,6-二甲基苯基)-2-(2-氧哌嗪基)乙酰胺(32)的合成:
化合物31的甲醇(10mL)溶液加入10%钯碳。反应容器通入氢气(40p.s.i)搅拌4小时。过滤除去催化剂,滤液浓缩,用柱色谱纯化(1∶15 MeOH∶DCM),得半固体化合物32。
化合物64的制备方法与化合物7同,在化合物7制备的部分D,用化合物33代替化合物6,用化合物32代替化合物5即可:质谱(MH+)=483.3。
实施例13
N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(2-甲基-苯并噁唑-5-基氧基)-丙基]-哌嗪-1-基}乙酰胺(65):
5-甲氧基-2-甲基-苯并噁唑(19)的合成:
2-氨基-4-甲氧基苯酚17(8g,57.4mmol)加入50mL三甲基原醋酸酯(trimethyl orthoacetate)18中加热回流,搅拌24小时。反应冷却后,蒸馏(真空)除过量的化合物18,残留物溶于乙酸乙酯并用水洗涤。有机层用硫酸镁干燥,然后用活性炭NoritA处理。所得反应液用Celite521过滤,蒸馏得油状物。油状物经硅胶色谱(20%乙酸乙酯/环己烷)得淡黄色固体化合物19。
2-甲基-5-环氧乙烷-2-基甲氧基苯并噁唑(67)的合成:
化合物67的制备方法与化合物6同,用6-羟基-2-甲基苯并噁唑66代替实施例1中部分C-5的化合物8。
化合物66如实施例1的部分C-4所示可通过化合物19的脱保护制备。
化合物65的制备方法与化合物7同,用化合物67代替化合物7的制备中部分D的化合物6即可:质谱(MH+)=543.4。
实施例14
N-(2,6-二甲基苯基)-2-(4-{2-羟基-3-[2-(4-三氟甲基-苯基)-苯并噁唑-5-基氧]-丙基}-哌嗪-1-基)乙酰胺(68):
5-(环氧乙烷-2-基甲氧基)-2-(4-三氟甲基-苯基)苯并噁唑(69)的合成:
化合物69的制备方法与化合物6同,用4-三氟甲基benzimidic酸乙酯盐酸盐代替实施例1中部分C1-5的化合物13。
化合物68的制备方法与化合物7同,用化合物69代替化合物7的制备中部分D的化合物6即可:质谱(MH+)=583.4。
实施例15
N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(喹噁啉-2-基氧)-丙基]-哌嗪-1-基}乙酰胺(70):
2-(环氧乙烷-2-基甲氧基)喹噁啉(71)的合成:
化合物71的制备方法与化合物6同,用喹噁啉2-酚代替实施例1中部分C-5的化合物8。
化合物70的制备方法与化合物7同,用化合物71代替化合物7的制备中部分D的化合物6即可:质谱(MH+)=450.9。
实施例16
N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(吡啶-3-基氧基)-丙基]-哌嗪-1-基}乙酰胺(72):
3-(环氧乙烷-2-基甲氧基)吡啶(73)的合成:
化合物73的制备方法与化合物6同,用3-羟基-吡啶代替实施例1中部分C-5的化合物8即可。
化合物72的制备方法与化合物7同,用化合物73代替化合物7的制备中D部分的化合物6即可:质谱(MH+)=399.4。
实施例17
N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(喹啉-4-基氧基)-丙基]-哌嗪-1-基}乙酰胺(74):
4-(环氧乙烷-2-基甲氧基)喹啉(75)的合成:
化合物75的制备方法与化合物6同,用4-羟基-喹啉代替实施例1中部分C-5的化合物8。
化合物74的制备方法与化合物7同,用化合物75代替化合物7的制备中部分D的化合物6即可:质谱(MH+)=449.4。
实施例18
N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(异喹啉-5-基氧基)-丙基]-哌嗪-1-基}乙酰胺(76):
5-(环氧乙烷-2-基甲氧基)异喹啉(77)的合成:
化合物77的制备方法与化合物6同,用5-羟基异喹啉代替实施例1中部分C-5的化合物8。
化合物76的制备方法与化合物7同,用化合物77代替化合物7的制备中部分D的化合物6即可:质谱(MH+)=449.4。
实施例19
N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(喹啉-6-基氧基)-丙基]-哌嗪-1-基}乙酰胺(78):
6-(环氧乙烷-2-基甲氧基)喹啉(79)的合成:
化合物79的制备方法与化合物6同,用6-羟基-喹啉代替实施例1中部分C-5的化合物8。
化合物78的制备方法与化合物7同,用化合物79代替化合物7的制备中部分D的化合物6即可:质谱(MH+)=449.4。
实施例20
N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(2-甲基-喹啉-7-基氧基)-丙基]-哌嗪-1-基}乙酰胺(80):
2-甲基-7-(环氧乙烷-2-基甲氧基)喹啉(81)的合成:
化合物81的制备方法与化合物6同,用7-羟基-2-甲基-喹啉代替实施例1中部分C-5的化合物8。
化合物80的制备方法与化合物7同,用化合物81代替化合物7的制备中部分D的化合物6即可:质谱(MH+)=463.5。
实施例21
2-{4-[3-(苯并噻唑-2-基氨基)-2-羟基丙基]-哌嗪基}-N-(2,6-二甲基苯基)乙酰胺(39):
(苯甲氧基)-N-丙-2-乙基甲酰胺(42)的合成:
在0℃向烯丙胺(3.34g,5.85mmol)的二氯甲烷(100mL)和三乙胺(16mL)溶液中加入苯甲基氯甲酸酯(8.25ml,5.78mmol)。反应混合物在0℃搅拌2小时,再在室温搅拌90分钟。蒸馏除去溶剂,将残留物用闪式柱色谱(30%EtOAc/己烷)纯化得透明油状化合物42。
N-(环氧乙烷-2-基甲氧基)(苯基甲氧基)甲酰胺(35)的合成:
化合物42(5.0g,2.61mmol)与间-氯过苯甲酸(11.71g,9.1mmol)在二氯甲烷(110mL)中室温反应18小时。蒸馏除去二氯甲烷得粘稠油状物,用闪式柱色谱(30%EtOAc/己烷)纯化得透明油状化合物35。
N-(2,6-二甲基苯基)-2-(4-{2-羟基-3-[苯基甲氧基]甲酰胺]丙基}哌嗪)乙酰胺(36)的合成:
化合物42(2.5g,1.2mmol)和化合物5(5.94g,2.4mmol)在乙醇(100ml)和三乙胺(3.34ml)中的溶液回流18小时。除去溶剂,将残留物用闪式柱色谱(乙酸乙酯)纯化得白色固体化合物36。
2-[4-(3-氨基-2-羟基丙基)哌嗪]-N-(2,6-二甲基苯基)乙酰胺(37)的合成:
化合物36(3.0g,0.66mmol)的甲醇(70mL)溶液在10%钯碳(0.337g)存在下,搅拌通氢气16小时。过滤除去催化剂,然后浓缩得粘稠固体化合物37。
化合物37(75mg)的乙醇(2mL)溶液中加入三乙胺(0.13mL)和2-氯苯并噻唑(87mg),加热回流16小时。反应混合物浓缩后用制备TLC(5%MeOH/二氯甲烷)纯化得白色固体化合物39。质谱(MH+)=454.4。
实施例22
2-{4-[3-(苯并噁唑-2-基氨基)-2-羟基丙基]哌嗪基}-N-(2,6-二甲基苯基)乙酰胺(82);
化合物82的制备方法与化合物39的制备方法同,用2-氯-苯并噁唑代替实施例21中的2-氯-苯并噻唑。质谱(MH+)=438.4。
下列化合物的制备方法与实施例1-21所述的制备方法相同,所有下列化合物都具有满意的质谱数据(MH+)。
2-{4-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]-2,5-二甲基哌嗪基}-N-(2,6-二甲基苯基)乙酰胺
2-{4-[(2R)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]-2,6-二甲基哌嗪基}-N-(2,6-二甲基苯基)乙酰胺
2-{4-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]-3,3-二甲基哌嗪基}-N-(2,6-二甲基苯基)乙酰胺
2-{(3S)-4-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]-3-甲基哌嗪基}-N-(2,6-二甲基苯基)乙酰胺
2-{(2R)-4-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]-2-甲基哌嗪基}-N-(2,6-二甲基苯基)乙酰胺
2-{4-[(2R)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]-3-甲基哌嗪基}-N-(2,6-二甲基苯基)乙酰胺
2-{4-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]-2,6-二甲基哌嗪基}-N-(2,6-二甲基苯基)乙酰胺
2-{4-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]-2-甲基哌嗪基}-N-(2,6-二甲基苯基)乙酰胺
2-{4-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基](1,4-diazaperhydroepinyl)}-N-(2,6-二甲基苯基)乙酰胺
2-{4-[2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]哌嗪基}-N-(4-羟基苯基)乙酰胺
2-{4-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]-2,6-二甲基哌嗪基}-N-(4-甲酰氨基苯基)乙酰胺
2-{(3S)-4-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]-3-甲基哌嗪基}-N-(2,6-二甲基苯基)乙酰胺
2-{4-[(2R)-2-羟基-3-(2-苯基苯并噻唑-5-基氧)丙基]哌嗪基}-N-(2,6-二甲基苯基)乙酰胺
2-{4-[2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]哌嗪基}-N-(2,6-二甲基-4-羟基苯基)乙酰胺
2-{5-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]-2,5-二氮杂双环[2.2.1]庚-2-基}-N-(2,6-二甲基苯基)乙酰胺
2-{4-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]哌嗪基}-N-(4-磺酰胺基苯基)乙酰胺
2-{(3S)-4-[(2S)-2-羟基-3-(2-苯基苯并噁唑-5-基氧)丙基]-3-甲基哌嗪基}-N-(2,6-二甲基苯基)乙酰胺
2-{4-[2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]哌嗪基}-N-萘基乙酰胺
N-[4-氯-3-(三氟甲基)苯基]-2-{4-[2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]哌嗪基}乙酰胺
2-{4-[2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]哌嗪基}-N-苯基乙酰胺
2-{4-[2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]哌嗪基}-N-(3,4,5-三氯苯基)乙酰胺
2-{4-[2-羟基-3-(4-甲氧基苯基)丙基]哌嗪基-N-(3,4,5-三氯苯基)-乙酰胺
2-{4-[2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]哌嗪基-N-(2-氯-4-甲基苯基)-乙酰胺
2-{4-[2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]哌嗪基}-N-(3,4,5-三氯苯基)乙酰胺
2-{4-[2-羟基-3-(2-苯基苯并噻唑-5-基氧)丙基]哌嗪基}-N-(3,5-二氯苯基)乙酰胺
2-{4-[2-羟基-3-(2-苯基苯并噻唑-5-基氧)丙基]哌嗪基}-N-(3,4-二氯苯基)乙酰胺
2-{4-[2-羟基-3-(2-苯基苯并噻唑-5-基氧)丙基]哌嗪基}-N-[3-甲氧基-5-(三氟甲基)苯基]乙酰胺
2-{4-[2-羟基-3-(2-苯基苯并噻唑-5-基氧)丙基]哌嗪基}-N-[3,5-二氯]苯基}乙酰胺
2-{4-[2-羟基-3-(2-((1E)丁-1,3-二链烯基)苯并噻唑-5-基氧)丙基]哌嗪基}-N-[4-氯-2-甲氧基-5-甲基苯基]乙酰胺。
实施例23
线粒体试验
用Nedergard和Cannon(Methods in Enzymol.,55,3,1979)等方法分离大鼠心脏线粒体。
棕榈酰基辅酶A氧化反应--棕榈酰基辅酶A氧化反应在总体积100毫升含有下列的试剂中进行:110mMKCl,33mM pH为8的Tris缓冲液,2mM KPi,2mMMgCl2,0.1mM EDTA,14.7mM脱脂BSA,0.5mM苹果酸,13mM肉毒碱,1mMADP,52毫克线粒体蛋白,和16mM 1-C14棕榈酰基辅酶A(Sp.活性60mCi/mmole;20microCi/ml,每一试验用5毫升)。将溶于DMSO中的本发明化合物以下列浓度加入:100microM,和50microM。在每次试验中,使用DMSO作对照。在30℃保持15分钟后,将酶反应物离心(20,000g,1分钟),取70毫升上清液加入活化的反相硅酸柱(约0.5ml硅酸)。将该柱用2ml水洗脱,并用0.5ml洗脱液作闪烁计数以测定以C14的捕获量作为C14标记的碳酸氢盐离子的量。
表1
用棕榈酰基CoA作为底物的线粒体脂肪酸氧化的抑制-两种浓度的化合物与对照对比的%和IC50
化合物# | 100μm(%) | 50μm(%) | IC50(μm) |
7 | -- | 77 | -- |
39 | 27 | -- | -- |
43 | 21 | -- | -- |
45 | 87 | -- | ~20 |
46 | 61 | -- | ~125 |
47 | 70 | -- | ~125 |
49 | 3 | -- | -- |
52 | 95 | -- | ~1 |
54 | 81 | -- | ~8 |
60 | -- | 61 | -- |
62 | -- | 62 | -- |
64 | 41 | -- | -- |
68 | -- | 68 | -- |
70 | 12 | -- | -- |
72 | 8 | -- | -- |
74 | 12 | -- | -- |
76 | 26 | -- | -- |
78 | 42 | -- | -- |
80 | 22 | -- | -- |
82 | 22 | -- | -- |
实施例25
代谢稳定性:将本发明的化合物与人肝S-9微粒体碎片一起温孵,以测定代谢稳定性。在37℃保温30分钟后,用LC质谱测定残余的母体药物的量。每个化合物的响应因子(response factors)通过建立标准曲线并在样品分析期间使用内标而测定。5个试验中在30分钟的时间点残余的拉洛来静(ranolazine)百分数的平均值是57%。本发明化合物在如下方案中测定并且用残余的母体百分数除以残余的拉洛来静的平均值(57%)得到代谢稳定因子(metabolic stabilityfactor)。稳定因子大于1.2的化合物在肝S-9测定中比拉洛来静稳定,稳定因子在1.2和0.8之间的化合物在肝S-9测定的稳定性与拉洛来静相当。稳定因子小于0.8的化合物在肝S-9测定中比拉洛来静的稳定性差。
该试验的目的是为了比较在人肝S9部分保温30分钟后本发明化合物的残余百分数与拉洛来静的残余百分数。
试剂:
使用下列试剂:磷酸钾,0.5M pH7.4(温育缓冲液),保持在室温;保存在4℃的0.05M MgCl2;β-烟酰胺腺嘌呤二核苷酸磷酸酯,四钠盐,还原形式(NADPH),在使用当天用Sigma Lot# 79H7044配制的0.02M水溶液(~16.6mg/mL)。1mM拉洛来静或化合物43,45,47,52,70,74,76,78,和80置于ACN中并进一步稀释得到100μM 10%的ACN溶液;从Gentest得到的人S9原料:20mg/mL。
方法:
温育的混合物制备如下:
表2
成分 | 每0.25mL温育混合物中的体积 | 最终浓度 |
10μM CVT化合物 | 25μL | 10μM |
MgCl2 | 25μL | 0.005M |
NADPH | 25μL | 0.002M |
S9 | 25μL | 2mg/mL |
温育缓冲液 | 25μL | 0.05M |
水 | 125μL | ---- |
*1%有机溶剂(乙腈)用于温育混合物中。通常,每次通过预先混合0.75mLMgCl2,0.75mL温育缓冲液,0.75mLNADPH,3.75mL水制备30份温育用液。然后用吸取200μL/温育用液,加入25μL试验化合物,混合,通过加入S-9开始反应。
将所有成分与温育缓冲液混合并再吸取200μL/管+25μL试验化合物以及25μL S-9。
37℃预保温5分钟后,在0和30分钟启动反应,移去50μl等份的温育混合物并加入100μL含有内标的9∶1乙腈∶甲醇。
将混合物离心并将100μL等份上清液稀释在1mL溶剂C中(0.1%甲酸水溶液)。通过LC/MS(注射10μL)分析0和30分钟时样品中的化合物与内标比例的变化。
分析和数据计算:
用内标和ODS-C18柱通过LC/MS以0.25ml/分钟的流速对起始化合物和有效代谢物进行样品分析。根据上述方法获得本发明化合物与拉洛来静比较的相对稳定性因子,见表3。
表3
化合物# | 肝S9稳定性因子 |
拉洛来静 | 1.0 |
43 | 0.6 |
45 | 0.8 |
46 | 1.1 |
47 | 1.5 |
52 | 0.5 |
70 | 0.1 |
74 | 1.0 |
76 | 0.8 |
78 | 0.6 |
80 | 0.5 |
Claims (43)
1.具有下列结构式的取代哌嗪化合物:
其中m=1,2,或3;
q=NH,O,或S;
R1,R2,R3,R4和R5各自独立地选自氢,卤素,NO2,CF3,CN,OR20,SR20,N(R20)2,S(O)R22,SO2R22,SO2N(R20)2,NR20CO2R22,NR20CON(R20)2,COR20,CO2R20,CON(R20)2,NR20SO2R22,C1-15烷基,C2-15链烯基,C2-15炔基,杂环基,芳基,和杂芳基,其中烷基和芳基取代基可任选被一个选自下列的取代基取代:卤素,NO2,CF3,CN,OR20,SR20,N(R20)2,S(O)R22和SO2R22,且其中R1和R2或R2和R3或R3和R4或R4和R5可以与和它们相连的碳原子一起形成6-元芳香环并且该环可以任选被烷基,三氟烷基,烷氧基或卤素取代;
R6,R7和R8各自独立地选自氢或C1-3烷基;
R9,R10,R11,R12,R13,R14,R15和R16各自独立地选自氢,CO2R20,CON(R20)2,C1-4烷基,或芳基,其中烷基和芳基取代基可任选被一个选自下列的取代基取代:卤素,CF3,CN,OR20,N(R20)2,CO2R20,CON(R20)2或芳基,其中R9和R10可以一起形成羰基,或R11和R12可以一起形成羰基,或R13和R14可以一起形成羰基,或R15和R16可以一起形成羰基,条件是R11和R13或R9和R15或R9和R11或R11和R15或R9和R13可以连接在一起形成包含1至3个碳原子的环;
R17是任选被1至3个选自下列的取代基取代的杂芳基:氢,卤素,NO2,CF3,CN,OR20,SR20,N(R20)2,S(O)R22,SO2R22,SO2N(R20)2,NR20CO2R22,NR20CON(R20)2,COR20,CO2R20,CON(R20)2,NR20SO2R22,C1-15烷基,C2-15链烯基,C2-15炔基,杂环基,芳基,和杂芳基,其中烷基和芳基取代基可任选被一个选自下列的取代基取代:卤素,NO2,CF3,CN,OR20,SR20,N(R20)2,S(O)R22或SO2R22;
R20选自H,C1-15烷基,芳基,或杂芳基,其中烷基和芳基取代基可任选被1个选自下列的取代基取代:卤素,烷基,单-或二烷基氨基,烷基,CN,-O-C1-6烷基,或CF3;和
R22选自C1-15烷基,芳基,或杂芳基,其中烷基和芳基取代基可任选被1个选自卤素,烷基,单烷基氨基,二烷基氨基,烷基酰氨基,芳基酰氨基,杂芳基酰氨基,CN,O-C1-6烷基,CF3,或杂芳基的取代基取代。
2.权利要求1的化合物,其中q=NH或O;
R1,R2,R3,R4和R5各自独立地选自:氢,卤素,CF3,CN,OR20,SR20,N(R20)2,SO2N(R20)2,CO2R20,CON(R20)2,C1-8烷基,C2-8链烯基,C2-8炔基,杂环基,芳基或者杂芳基,其中烷基和芳基可任选被一个选自下列基团的取代基取代:卤素,NO2,CF3,CN,OR20,SR20,N(R20)2,S(O)R22,或者SO2R22;
R6,R7和R8各自独立地选自氢或者C1-3烷基;
R9,R10,R11,R12,R13,R14,R15和R16各自独立地选自氢,CON(R20)2,或C1-4烷基,或者其中R9和R10可以一起形成羰基,或R11和R12可以一起形成羰基,或R13和R14可以一起形成羰基,或R15和R16可以一起形成羰基;
R17是任选被1至3个选自下列的取代基取代的杂芳基:氢,卤素,NO2,CF3,CN,OR20,SR20,N(R20)2,S(O)R22,SO2R22,SO2N(R20)2,NR20CO2R22,NR20CON(R20)2,CO2R20,CON(R20)2,NR20SO2R22,C1-15烷基,C2-15链烯基,C2-15炔基,杂环基,芳基,和杂芳基,其中烷基和芳基取代基可任选被一个选自下列的取代基取代:卤素,NO2,CF3,CN,OR20,SR20,N(R20)2,S(O)R22和SO2R22;和
R20选自H,C1-15烷基,芳基,或杂芳基,其中烷基和芳基取代基可任选被1个选自下列基团的取代基取代:卤素,烷基,单烷基氨基,二烷基氨基,烷基氰基,-O-C1-6烷基,或CF3。
3.权利要求1的化合物,其中R1,R2,R3,R4和R5各自独立地选自:氢,卤素,CF3,OR20,C1-5烷基,C2-5链烯基,或C2-5炔基,其中烷基可任选被CF3所取代;
R6,R7和R8各自独立地选自氢或者C1-3烷基;
R9,R10,R11,R12,R13,R14,R15和R16各自独立地选自氢,CON(R20)2,或者C1-4烷基,其中R9和R10可以一起形成羰基,或R11和R12可以一起形成羰基,或R13和R14可以一起形成羰基,或R15和R16可以一起形成羰基;
R17是任选被1至2个选自下列的取代基取代的杂芳基:氢,卤素,CF3,OR20,N(R20)2,CON(R20)2,C1-8烷基,C2-8链烯基,C2-8炔基,芳基或者杂芳基,其中烷基和芳基可任选被一个选自下列基团的取代基取代:卤素,CF3,OR20,或者N(R20)2;和
R20选自H,C1-8烷基,芳基,或杂芳基,其中烷基和芳基取代基可任选被1个选自下列基团的取代基取代:卤素,-O-C1-3烷基,或CF3。
4.权利要求1的组合物,其中R1,R2,R3,R4和R5各自独立地选自:氢,卤素,CF3,OR20,C1-3烷基,C2-3链烯基,或C2-3炔基,其中烷基可任选被CF3所取代;
R6,R7和R8各自独立地选自氢或甲基;
R9,R10,R11,R12,R13,R14,R15和R16各自独立地选自氢或者C1-2烷基,其中R9和R10可以一起形成羰基,或R11和R12可以一起形成羰基,或R13和R14可以一起形成羰基,或R15和R16可以一起形成羰基;
R17是任选被1至2个选自下列的取代基取代的杂芳基:氢,卤素,CF3,OR20,N(R20)2,CON(R20)2,C1-5烷基,C2-3链烯基,C2-3炔基,芳基或者杂芳基,其中烷基和芳基可任选被一个独立选自下列基团的取代基取代:卤素,CF3,OR20,或者N(R20)2;和
R20选自H,C1-5烷基,芳基,或杂芳基,其中烷基和芳基取代基可任选被1个选自下列基团的取代基取代:卤素,-OMe,或CF3。
5.权利要求1的组合物,其中m=1;
R1,R2,R3,R4和R5各自独立地选自:氢,卤素,CF3,OR20,或C1-3烷基,其中烷基可任选被CF3所取代;
R6,R7和R8各自独立地选自氢或甲基;
R9,R10,R11,R12,R13,R14,R15和R16各自独立地选自氢或者甲基,其中R9和R10可以一起形成羰基,或R11和R12可以一起形成羰基,或R13和R14可以一起形成羰基,或R15和R16可以一起形成羰基;
R17是任选被1至2个选自下列的取代基取代的杂芳基:氢,卤素,CF3,OR20,N(R20)2,CON(R20)2,C1-3烷基,芳基或者杂芳基,其中烷基和芳基可任选被一个独立选自下列基团的取代基取代:卤素,CF3,OR20,或者N(R20)2;
和
R20选自H,C1-3烷基,或芳基,其中烷基和芳基取代基可任选被1个选自下列基团的取代基取代:卤素,-OMe,或CF3。
6.权利要求1的化合物,其中R17是稠合的含有1至5个选自N,O,或S的杂原子的6,5元环系的杂芳基,并且可以被1至3个选自下列的取代基取代:氢,卤素,NO2,CF3,CN,OR20,SR20,N(R20)2,S(O)R22,SO2R22,SO2N(R20)2,NR20CO2R22,NR20CON(R20)2,COR20,CO2R20,CON(R20)2,NR20SO2R22,C1-15烷基,C2-15链烯基,C2-15炔基,杂环基,芳基或者杂芳基,其中烷基和芳基可任选被一个独立选自下列的取代基取代:卤素,NO2,CF3,CN,OR20,SR20,N(R20)2,S(O)R22,或者SO2R22。
7.权利要求6的组合物,其中q=NH,O;
R1,R2,R3,R4和R5各自独立地选自:氢,卤素,CF3,CN,OR20,SR20,N(R20)2,SO2N(R20)2,CO2R20,CON(R20)2,C1-8烷基,C2-8链烯基,C2-8炔基,杂环基,芳基或者杂芳基,其中烷基和芳基可任选被一个选自下列基团的取代基取代:卤素,NO2,CF3,CN,OR20,SR20,N(R20)2,S(O)R22,或者SO2R22;
R6,R7和R8各自独立地选自氢或C1-3烷基;
R9,R10,R11,R12,R13,R14,R15和R16各自独立地选自氢,CON(R20)2,C1-4烷基,或芳基,其中烷基和芳基取代基可任选被一个选自下列的取代基取代:卤素,CF3,OR20,N(R20)2,CON(R20)2,或芳基,其中R9和R10可以一起形成羰基,或R11和R12可以一起形成羰基,或R13和R14可以一起形成羰基,或R15和R16可以一起形成羰基,条件是R11和R13或R9和R15或R9和R11或R11和R15或R9和R13可以连接在一起形成环;
R17是稠合的含有1至4个选自N,O,或S的杂原子的6,5元环系的杂芳基,并且可以被1-3个选自下列的取代基取代:氢,卤素,NO2,CF3,CN,OR20,SR20,N(R20)2,S(O)R22,SO2R22,SO2N(R20)2,NR20CO2R22,NR20CON(R20)2,CO2R20,CON(R20)2,NR20SO2R22,C1-15烷基,C2-15链烯基,C2-15炔基,杂环基,芳基或者杂芳基,其中烷基和芳基可任选被一个选自下列的取代基取代:卤素,NO2,CF3,CN,OR20,SR20,N(R20)2,S(O)R22,或者SO2R22;和
R20选自H,C1-15烷基,芳基,或杂芳基,其中烷基和芳基取代基可任选被1个选自下列的取代基取代:卤素,烷基,单烷基氨基,二烷基氨基,烷基-CN,-O-C1-6烷基,或CF3。
8.权利要求6的化合物,其中q=NH或O;
R1,R2,R3,R4和R5各自独立地选自:氢,卤素,CF3,OR20,C1-5烷基,C2-5链烯基,或C2-5炔基,其中烷基可任选被CF3所取代或者其中R1和R2或R2和R3或R3和R4或R4和R5可以与和它们相连的碳原子一起形成6-元芳香环,并且该环可以任选被烷基,三氟烷基,烷氧基或卤素取代;
R6,R7和R8各自独立地选自氢或C1-3烷基;
R9,R10,R11,R12,R13,R14,R15和R16各自独立地选自氢,CON(R20)2,C1-3烷基,或芳基,其中烷基和芳基取代基可任选被一个选自下列的取代基取代:卤素,N(R20)2,和芳基,或者其中R9和R10可以一起形成羰基,或R11和R12可以一起形成羰基,条件是R11和R13或R9和R15或R9和R11或R11和R15或R9和R13可以连接在一起形成环;
R17是稠合的含有1至3个选自N,O,或S的杂原子的6,5元环系的杂芳基,并且可任选被1至2个选自下列的取代基取代:氢,卤素,CF3,OR20,N(R20)2,CON(R20)2,C1-8烷基,C2-8链烯基,C2-8炔基,芳基或者杂芳基,其中烷基和芳基可任选被一个选自下列的取代基取代:卤素,CF3,OR20,或者N(R20)2;
和
R20选自H,C1-8烷基,芳基,或杂芳基,其中烷基和芳基取代基可任选被1个选自下列基团的取代基取代:卤素,-O-C1-3烷基,或CF3。
9.权利要求6的化合物,其中q=NH或者O;
R1,R2,R3,R4和R5各自独立地选自:氢,卤素,CF3,OR20,C1-3烷基,C2-3链烯基,C2-3炔基,其中烷基可任选被CF3所取代;
R6,R7和R8各自独立地选自氢或甲基;
R9,R10,R11,R12,R13,R14,R15和R16各自独立地选自氢,CON(R20)2,C1-3烷基,或芳基,其中烷基和芳基取代基可任选被一个选自下列的取代基取代:卤素,N(R20)2,或者芳基,其中R9和R10可以一起形成羰基,条件是R11和R13或R9和R15或R9和R11或R11和R15或R9和R13可以连接在一起形成环;
R17是稠合的含有1至2个选自N,O,或S的杂原子的6,5元环系的杂芳基,并且可以被1至2个选自下列的取代基取代:氢,卤素,CF3,OR20,N(R20)2,CON(R20)2,C1-4烷基,芳基或者杂芳基,其中烷基和芳基可任选被一个选自下列的取代基取代:卤素,CF3,或OR20;和
R20选自H,C1-5烷基,芳基,或杂芳基,其中烷基和芳基取代基可任选被1个选自下列基团的取代基取代:卤素,-OMe,或CF3。
10.权利要求6的化合物,其中q=NH或者O;
R1,R2,R3,R4和R5各自独立地选自:氢,卤素,CF3,OR20,或C1-3烷基,其中烷基可任选被CF3所取代,并且其中R2和R3可以与和它们相连的碳原子一起形成6-元芳香环,并且该环可以任选被烷基,三氟烷基,烷氧基或卤素取代;
R6,R7和R8各自独立地选自氢或甲基;
R9,R10,R11,R12,R13,R14,R15和R16各自独立地选自氢,或C1-2烷基,其中烷基取代基可任选被一个选自下列的取代基取代:N(R20)2,或者芳基,或者其中R9和R10可以一起形成羰基;
R17是稠合的含有1至2个选自N,O,或S的杂原子的6,5元环系的杂芳基,并且可以被1至2个选自下列的取代基取代:氢,卤素,CF3,OR20,N(R20)2,CON(R20)2,C1-3烷基,芳基或者杂芳基,其中烷基和芳基可任选被一个选自下列基团的取代基取代:卤素,CF3,或OR20;和
R20选自H,C1-3烷基,或芳基,其中烷基和芳基取代基可任选被1个选自下列基团的取代基取代:卤素,-OMe,或CF3。
11.权利要求10的组合物,其中q=O;和
R17是选自吲哚,苯并噻唑,苯并噁唑的稠合6,5元环系的杂芳基,并且可以被1至2个选自下列的取代基取代:氢,卤素,CF3,OR20,N(R20)2,CON(R20)2,C1-3烷基,芳基或者杂芳基,其中烷基和芳基可任选被一个选自下列基团的取代基所取代:卤素,CF3或者OR20。
12.权利要求10的组合物,其中q=O;
R1,R2,R3,R4和R5各自独立地选自:氢,CF3,OR20,或C1-2烷基,且其中R2和R3可以与和它们相连的碳原子一起形成6-元芳香环,并且该环可以任选被烷基,三氟烷基,烷氧基或卤素取代;
R6,R7和R8各自独立地为自氢;
R9,R10,R11,R12,R13,R14,R15和R16各自独立地选自氢,C1-2烷基,或者其中R9和R10可以一起形成羰基;
R17是选自吲哚,苯并噻唑,苯并噁唑的稠合6,5元环系的杂芳基,并且可以被1个选自下列的取代基取代:氢,卤素,CF3,OR20,N(R20)2,CON(R20)2,C1-3烷基,或者芳基,其中烷基和芳基可任选被一个选自下列基团的取代基所取代:卤素,或CF3;和
R20选自H,或C1-3烷基;
13.权利要求12的化合物,其中R17是可任选被一个选自下列的取代基取代的苯并噻唑:氢,卤素,CF3,OR20,N(R20)2,CON(R20)2,C1-3烷基,或者芳基,其中烷基和芳基可任选被一个选自下列基团的取代基所取代:卤素或者CF3。
14.权利要求12的化合物,其中R17是2-位可任选被一个选自下列的取代基取代的苯并噻唑:氢,甲基、或苯基。
15.权利要求12的化合物,其中R17是可任选被一个选自下列的取代基取代的5-取代苯并噻唑:氢,卤素,CF3,OR20,N(R20)2,CON(R20)2,C1-3烷基,或者芳基,其中烷基和芳基可任选被一个选自下列基团的取代基所取代:卤素或者CF3;
R20选自H或甲基;
16.权利要求12的化合物,其中R17是2-位可任选被一个选自下列的取代基取代的5-取代苯并噻唑:氢,甲基、苯基;和
R20选自H或甲基;
17.权利要求12的化合物,其中q=O;
R1,R2,R3,R2和R5各自独立地选自:氢,OR20,或甲基;
R6,R7和R8各自为氢;
R11和R15各自独立地选自氢或者甲基,R9,R10,R12,R13,R14和R16各自为氢,且R9和R10可以一起形成羰基。
R17是2-位被甲基取代的5-取代苯并噻唑;和
R20为H。
18.权利要求12的化合物,其中q=O;
R1,R2,R3,R4和R5各自独立地选自:氢,OR20,或甲基;
R6,R7和R8各自为氢;
R11和R15各自独立地选自氢或者甲基,R9,R10,R12,R13,R14和R16各自为氢,且R9和R10可以一起形成羰基;
R17是2-位被苯基取代的5-取代苯并噻唑;和
R20为H。
19.权利要求12的化合物,其中q=O;
R1,R4和R5各自独立地选自:氢,OR20,或甲基,且其中R2和R3可以与和它们相连的碳原子一起形成6-元芳香环,并且该环可以任选被烷基,三氟烷基,烷氧基或卤素取代;
R6,R7和R8各自为氢;
R11和R15各自独立地选自氢或者甲基,R9,R10,R12,R13,R14和R16各自为氢,且R9和R10可以一起形成羰基;
R17是2-位被甲基取代的5-取代苯并噻唑;和
R20为H。
20.权利要求6或7或8或9或10或11或者权利要求12或13或14或15或16的化合物,其中R17是2-位被甲基取代的5-取代苯并噻唑;
21.权利要求6或7或8或9或10或11或12或13或14或15,或权利要求16的化合物,其中R17是2-位被苯基取代的5-取代苯并噻唑;
22.权利要求1的化合物,其中R17是含有1-4个N原子的6,6-元稠合环系的杂芳基,并且可任选被1-3个选自下列的取代基取代:氢,卤素,NO2,CF3,CN,OR20,SR20,N(R20)2,S(O)R22,SO2R22,SO2N(R20)2,NR20CO2R22,NR20CON(R20)2,COR20,CO2R20,CON(R20)2,NR20SO2R22,C1-15烷基,C2-15链烯基,C2-15炔基,杂环基,芳基或者杂芳基,其中烷基和芳基可任选被一个独立选自下列基团的取代基取代:卤素,NO2,CF3,CN,OR20,SR20,N(R20)2,S(O)R22,或者SO2R22。
23.权利要求22的化合物,其中q=O;
R1,R2,R3,R4和R5各自独立地选自:氢,卤素,CF3,CN,OR20,SR20,N(R20)2,SO2N(R20)2,CO2R20,CON(R20)2,C1-8烷基,C2-8链烯基,C2-8炔基,杂环基,芳基或者杂芳基,其中烷基和芳基可任选被一个选自下列基团的取代基取代:卤素,NO2,CF3,CN,OR20,SR20,N(R20)2,S(O)R22,或者SO2R22;
R6,R7和R8各自独立地选自氢或C1-3烷基;
R9,R10,R11,R12,R13,R14,R15和R16各自独立地选自氢,CON(R20)2,C1-4烷基,或芳基,其中烷基和芳基取代基可任选被一个选自下列的取代基取代:卤素,CF3,OR20,N(R20)2,CON(R20)2或芳基,其中R9和R10可以一起形成羰基,或R11和R12可以一起形成羰基,或R13和R14可以一起形成羰基,或R15和R16可以一起形成羰基,条件是R11和R13或R9和R15或R9和R11或R11和R15或R9和R13可以连接在一起形成环;
R20选自H,C1-15烷基,芳基,或杂芳基,其中烷基和芳基取代基可任选被1个选自下列的取代基取代:卤素,烷基,单烷基氨基,二烷基氨基,烷基-CN,-O-C1-6烷基,或CF3;
24.权利要求22的化合物,其中q=O;
R1,R2,R3,R4和R5各自独立地选自:氢,卤素,CF3,OR20,C1-5烷基,C2-5链烯基,或C2-5炔基,其中烷基可任选被CF3取代;
R6,R7和R8各自独立地选自氢或C1-3烷基;
R9,R10,R11,R12,R13,R14,R15和R16各自独立地选自氢,CON(R20)2,C1-3烷基,或芳基,其中烷基和芳基取代基可任选被一个选自下列的取代基取代:卤素,N(R20)2,和芳基,或者其中R9和R10可以一起形成羰基,或R11和R12可以一起形成羰基,条件是R11和R13或R9和R15或R9和R11或R11和R15或R9和R13可以连接在一起形成环;
R17是含有1至3个N原子的6,6-元稠合环系的杂芳基,并且可任选被1-2个选自下列的取代基取代:氢,卤素,CF3,OR20,N(R20)2,CON(R20)2,C1-8烷基,C2-8链烯基,C2-8炔基,芳基或者杂芳基,其中烷基和芳基可任选被一个独立选自下列基团的取代基取代:卤素,CF3,OR20,或者N(R20)2;和
R20选自H,C1-8烷基,芳基,或杂芳基,其中烷基和芳基取代基可任选被1个选自下列基团的取代基取代:卤素,-O-C1-3烷基,或CF3。
25.权利要求22的化合物,其中q=O;
R1,R2,R3,R4和R5各自独立地选自:氢,OR20,或者甲基;
R6,R7和R8各自为氢;
R9,R10,R11,R12,R13,R14,R15和R16各自独立地选自氢,C1-2烷基,或者R9和R10可以一起形成羰基;
R17是任选被甲基取代的含有1至2个N原子的6,6-元稠合环系的杂芳基;和
R20为H。
26.权利要求22的化合物,其中q=O;
R1,R2,R3,R4和R5各自独立地选自:氢或者甲基;
R6,R7和R8各自为氢;
R9,R10,R11,R12,R13,R14,R15和R16各自为氢;
R17是任选被甲基取代的含有1至2个N原子的6,6-元稠合环系的杂芳基。
27.权利要求1的化合物,其中R17是含有1-3个选自N,S,或O的杂原子的5或6元环,并且可任选被1-3个选自下列的取代基取代:氢,卤素,NO2,CF3,CN,OR20,SR20,N(R20)2,S(O)R22,SO2R22,SO2N(R20)2,NR20CO2R22,NR20CON(R20)2,COR20,CO2R20,CON(R20)2,NR20SO2R22,C1-15烷基,C2-15链烯基,C2-15炔基,杂环基,芳基或者杂芳基,其中烷基和芳基可任选被一个独立选自下列基团的取代基取代:卤素,NO2,CF3,CN,OR20,SR20,N(R20)2,S(O)R22,或者SO2R22。
28.权利要求27的化合物,其中q=O;
R1,R2,R3,R4和R5各自独立地选自:氢,卤素,CF3,CN,OR20,SR20,N(R20)2,SO2N(R20)2,CO2R20,CON(R20)2,C1-8烷基,C2-8链烯基,C2-8炔基,杂环基,芳基或者杂芳基,其中烷基和芳基可任选被一个选自下列基团的取代基取代:卤素,NO2,CF3,CN,OR20,SR20,N(R20)2,S(O)R22,或者SO2R22;
R6,R7和R8各自独立地选自氢或C1-3烷基;
R9,R10,R11,R12,R13,R14,R15和R16各自独立地选自氢,CON(R20)2,C1-4烷基,或芳基,其中烷基和芳基取代基可任选被一个选自下列的取代基取代:卤素,CF3,OR20,N(R20)2,CON(R20)2或芳基,其中R9和R10可以一起形成羰基,或R11和R12可以一起形成羰基,或R13和R14可以一起形成羰基,或R15和R16可以一起形成羰基,条件是R11和R13或R9和R15或R9和R11或R11和R15或R9和R13可以连接在一起形成环;
R17是含有1-3个选自N,S,或O的杂原子的5或6元环,并且可任选被1-3个选自下列的取代基取代:氢,卤素,NO2,CF3,CN,OR20,SR20,N(R20)2,S(O)R22,SO2R22,SO2N(R20)2,NR20CO2R22,NR20CON(R20)2,COR20,CO2R20,CON(R20)2,NR20SO2R22,C1-15烷基,C2-15链烯基,C2-15炔基,杂环基,芳基或者杂芳基,其中烷基和芳基可任选被一个独立选自下列基团的取代基取代:卤素,NO2,CF3,CN,OR20,SR20,N(R20)2,S(O)R22,或者SO2R22;
R20选自H,C1-15烷基,芳基,或杂芳基,其中烷基和芳基取代基可任选被1个选自下列的取代基取代:卤素,烷基,单烷基氨基,二烷基氨基,烷基-CN,-O-C1-6烷基,或CF3;和
R22选自C1-15烷基,芳基,或杂芳基,其中烷基和芳基取代基可任选被1个选自下列基团的取代基取代:卤素,烷基,单烷基氨基,二烷基氨基,烷基酰氨基,芳基酰氨基,杂芳基酰氨基,CN,O-C1-6烷基,CF3,或杂芳基。
29.权利要求27的化合物,其中q=O;
R1,R2,R3,R4和R5各自独立地选自:氢,卤素,CF3,OR20,C1-5烷基,C2-5链烯基,或C2-5炔基,其中烷基可任选被CF3取代;
R6,R7和R8各自独立地选自氢或C1-3烷基;
R9,R10,R11,R12,R13,R14,R15和R16各自独立地选自氢,CON(R20)2,C1-3烷基,或芳基,其中烷基和芳基取代基可任选被一个选自下列的取代基取代:卤素,N(R20)2,和芳基,或者其中R9和R10可以一起形成羰基,或R11和R12可以一起形成羰基,条件是R11和R13或R9和R15或R9和R11或R11和R15或R9和R13可以连接在一起形成环;
R17是含有1-3个选自N,S,或O的杂原子的5或6元环,并且可任选被1-2个选自下列的取代基取代:氢,卤素,CF3,OR20,N(R20)2,CON(R20)2,C1-8烷基,C2-8链烯基,C2-8炔基,芳基或者杂芳基,其中烷基和芳基可任选被一个独立选自下列基团的取代基取代:卤素,CF3,OR20,或者N(R20)2;和
R20选自H,C1-8烷基,芳基,或杂芳基,其中烷基和芳基取代基可任选被1个选自下列基团的取代基取代:卤素,-O-C1-3烷基,或CF3。
30.权利要求29的化合物,其中R17是含有1-2氮原子的6元环,并且可任选被1-2个选自下列的取代基取代:氢,卤素,CF3,OR20,N(R20)2,CON(R20)2,C1-8烷基,C2-8链烯基,C2-8炔基,芳基或者杂芳基,其中烷基和芳基可任选被一个独立选自下列基团的取代基取代:卤素,CF3,OR20,或者N(R20)2。
31.权利要求30的化合物,其中q=O;
R1,R2,R3,R4和R5各自独立地选自:氢,OR20,或者甲基;
R6,R7和R8各自为氢;
R9,R10,R11,R12,R13,R14,R15和R16各自独立地选自氢,C1-2烷基,或者R9和R10可以一起形成羰基;
R17是可任选被甲基取代的含有1-2个氮原子的6元环;和
R20为H。
32.权利要求30的化合物,其中q=O;
R1,R2,R3,R4和R5各自独立地选自:氢或者甲基;
R6,R7和R8各自为氢;
R9,R10,R11,R12,R13,R14,R15和R16各自为氢;和
R17为可任选被甲基取代的含1个N原子的6元环。
33.权利要求10的组合物,其中q=NH;和
R17是含有1-2个选自N,O,或S的杂原子的6,5-元稠合环系的杂芳基,并且可任选被1-2个选自下列的取代基取代:氢,卤素,CF3,OR20,N(R20)2,CON(R20)2,C1-3烷基,芳基或者杂芳基,其中烷基和芳基可任选被一个选自下列基团的取代基取代:卤素,CF3,OR20,或者N(R20)2;
34.权利要求10的组合物,其中q=NH;
R1,R2,R3,R4和R5各自独立地选自:氢,CF3,OR20,或者C1-2烷基;
R6,R7和R8各自为氢;
R9,R10,R11,R12,R13,R14,R15和R16各自独立地选自氢或者C1-2烷基,或者R9和R10可以一起形成羰基;
R17为选自苯并噻唑和苯并噁唑的6,5-元稠合环系的杂芳基,并可任选被1个选自下列的取代基取代:氢,CF3,OR20,C1-3烷基,或者芳基,其中烷基和芳基可任选被一个选自下列基团的取代基所取代:卤素或者CF3;和
R20选自H或者C1-3烷基。
35.权利要求10的组合物,其中q=NH;
R1,R2,R3,R4和R5各自独立地选自氢或者甲基;
R6,R7和R8各自为氢;
R9,R10,R11,R12,R13,R14,R15和R16各自为氢;和
R17是选自苯并噻唑和苯并噁唑的6,5-元稠合环系的杂芳基,且可任选被甲基取代。
36.选自下列的化合物:N-(2,6-二甲基-苯基)-2-(4-{2-羟基-3-[2-(3-三氟甲基苯基)苯并噁唑-5-基氧]-丙基}哌嗪-1-基)乙酰胺,2-{4-[3-(苯并噻唑-2-基氧)-2-羟基-丙基]-哌嗪-1-基}-N-(2,6-二甲基苯基)乙酰胺,N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(2-甲基-苯并噻唑-5-基氧)-丙基]哌嗪-1-基}乙酰胺,4-(3-{4-[(2,6-二甲基苯基氨基甲酰基)-甲基]-哌嗪-1-基}-2-羟基-丙氧基)-1H-吲哚-2-羧酸酰胺,2-{4-[3-(苯并噻唑-6-基氧)-2-羟基-丙基]-哌嗪-1-基}-N-(2,6-二甲基-苯基)乙酰胺,N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(2-甲基-苯并噻唑-6-基氧)-丙基]哌嗪-1-基}乙酰胺,N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(2-甲基-苯并噻唑-5-基氧)-丙基]-3,5-二甲基-哌嗪-1-基}乙酰胺,2-{4-[2-羟基-3-(2-甲基-苯并噻唑-5-基氧)-丙基]-哌嗪-1-基}-N-(4-羟基-苯基)乙酰胺,N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(2-苯基-苯并噻唑-5-基氧)-丙基]-哌嗪-1-基}乙酰胺,N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(2-苯基-苯并噁唑-5-基氧)-丙基]-哌嗪-1-基}乙酰胺,N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(2-苯基-苯并噻唑-7-基氧)-丙基]-哌嗪-1-基乙酰胺,N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(2-甲基-苯并噻唑-5-基氧)-丙基]-2-氧-哌嗪-1-基}乙酰胺,N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(2-甲基-苯并噁唑-5-基氧)-丙基]-哌嗪-1-基}乙酰胺,N-(2,6-二甲基苯基)-2-(4-{2-羟基-3-[2-(4-三氟甲基-苯基)-苯并噁唑-5-基氧]-丙基}-哌嗪-1-基)乙酰胺,N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(喹噁啉-2-基氧)-丙基]-哌嗪-1-基}乙酰胺,N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(吡啶-3-基氧)-丙基]-哌嗪-1-基}乙酰胺,N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(喹啉-4-基氧)-丙基]-哌嗪-1-基}乙酰胺,N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(异喹啉-5-基氧)-丙基]-哌嗪-1-基}乙酰胺,N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(喹啉-6-基氧)-丙基]-哌嗪-1-基}乙酰胺,N-(2,6-二甲基苯基)-2-{4-[2-羟基-3-(2-甲基-喹啉-7-基氧)-丙基]-哌嗪-1-基}乙酰胺,2-{4-[3-(苯并噻唑-2-基氨基)-2-羟基丙基]哌嗪基}-N-(2,6-二甲基苯基)乙酰胺,2-{4-[3-(苯并噁唑-2-基氨基)-2-羟基丙基]哌嗪基}-N-(2,6-二甲基苯基)乙酰胺,2-{4-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]2,5-二甲基哌嗪基}-N-(2,6-二甲基苯基)乙酰胺,2-{4-[(2R)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]-2,6-二甲基哌嗪基}-N-(2,6-二甲基苯基)乙酰胺,2-{4-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]-3,3-二甲基哌嗪基}-N-(2,6-二甲基苯基)乙酰胺,2-{(3S)-4-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]-3-甲基哌嗪基}-N-(2,6-二甲基苯基)乙酰胺,2-{(2R)-4-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]-2-甲基哌嗪基}-N-(2,6-二甲基苯基)乙酰胺,2-{4-[(2R)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]-3-甲基哌嗪基}-N-(2,6-二甲基苯基)乙酰胺,2-{4-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]-2,6-二甲基哌嗪基}-N-(2,6-二甲基苯基)乙酰胺,2-{4-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]-2-甲基哌嗪基}-N-(2,6-二甲基苯基)乙酰胺,2-{4-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基](1,4-diazaperhydroepinyl)}-N-(2,6-二甲基苯基)乙酰胺,2-{4-[2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]哌嗪基}-N-(4-羟基苯基)乙酰胺,2-{4-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]-2,6-二甲基哌嗪基}-N-(4-甲酰氨基苯基)乙酰胺,2-{(3S)-4-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]-3-甲基哌嗪基}-N-(2,6-二甲基苯基)乙酰胺,2-{4-[(2R)-2-羟基-3-(2-苯基苯并噻唑-5-基氧)丙基]哌嗪基}-N-(2,6-二甲基苯基)乙酰胺,2-{4-[2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]哌嗪基}-N-(2,6-二甲基-4-羟基苯基)乙酰胺,2-{5-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]-2,5-二氮杂双环[2.2.1]庚-2-基}-N-(2,6-二甲基苯基)乙酰胺,2-{4-[(2S)-2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]哌嗪基}-N-(4-胺磺酰基苯基)乙酰胺,2-{(3S)-4-[(2S)-2-羟基-3-(2-苯基苯并噁唑-5-基氧)丙基]-3-甲基哌嗪基}N-(2,6-二甲基苯基)乙酰胺,2-{4-[2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]哌嗪基}-N-萘基乙酰胺,N-[4-氯-3-(三氟甲基)苯基]-2-{4-[2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]哌嗪基}乙酰胺,2-{4-[2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]哌嗪基}N-苯基乙酰胺,2-{4-[2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]哌嗪基}-N-(3,4,5-三氯苯基)乙酰胺,2-{4-[2-羟基-3-(4-甲氧基苯基)丙基]哌嗪基-N-(3,4,5-三氯苯基)-乙酰胺,2-{4-[2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]哌嗪基N-(2-氯-4-甲基苯基)-乙酰胺,2-{4-[2-羟基-3-(2-甲基苯并噻唑-5-基氧)丙基]哌嗪基}-N-(3,4,5-三氯苯基)乙酰胺,2-{4-[2-羟基-3-(2-苯基苯并噻唑-5-基氧)丙基]哌嗪基}-N-(3,5-二氯苯基)乙酰胺,2-{4-[2-羟基-3-(2-苯基苯并噻唑-5-基氧)丙基]哌嗪基}-N-(3,4-二氯苯基)乙酰胺,2-{4-[2-羟基-3-(2-苯基苯并噻唑-5-基氧)丙基]哌嗪基}-N-[3-甲氧基-5-(三氟甲基)苯基]乙酰胺,2-{4-[2-羟基-3-(2-苯基苯并噻唑-5-基氧)丙基]哌嗪基}-N-[3,5-二氯]苯基}乙酰胺,和2-{4-[2-羟基-3-(2-((1E)丁-1,3-二链烯基)苯并噻唑-5-基氧)丙基]哌嗪基}-N-[4-氯-2-甲氧基-5-甲基苯基]乙酰胺。
37.一种治疗方法,包括给需要下列治疗的哺乳动物服用治疗有效量的权利要求1的化合物:保护骨骼肌抵抗由创伤导致的损伤,保护肌肉或全身性疾病之后的骨骼肌,治疗休克疾病,保护移植中使用的供体组织和器官,或治疗心血管疾病。
38.权利要求37的方法,其中心血管疾病选自心房和心室心律不齐,Prinzmetal(变异)氏绞痛,稳定性绞痛,运动导致的绞痛,充血性心脏病,或者心肌梗塞。
39.权利要求37或者38的方法,其中治疗有效量的范围在约0.01至约100mg/kg哺乳动物体重。
40.权利要求37或者38的方法,其中哺乳动物是人。
41.一种药物组合物,含有权利要求1的组合物和一种或多种药物赋形剂。
42.权利要求41的药物组合物,其中药物组合物是溶液形式。
43.权利要求41的药物组合物,其中药物组合物为片剂或胶囊形式。
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