CN101080392B - 作为抗肥胖药剂的哌嗪基吡啶衍生物 - Google Patents
作为抗肥胖药剂的哌嗪基吡啶衍生物 Download PDFInfo
- Publication number
- CN101080392B CN101080392B CN2005800429976A CN200580042997A CN101080392B CN 101080392 B CN101080392 B CN 101080392B CN 2005800429976 A CN2005800429976 A CN 2005800429976A CN 200580042997 A CN200580042997 A CN 200580042997A CN 101080392 B CN101080392 B CN 101080392B
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- CN
- China
- Prior art keywords
- piperazine
- cyclopentyl
- pyridin
- alkyl
- phenyl
- 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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- 239000000883 anti-obesity agent Substances 0.000 title description 2
- 229940125710 antiobesity agent Drugs 0.000 title description 2
- GZRKXKUVVPSREJ-UHFFFAOYSA-N pyridinylpiperazine Chemical class C1CNCCN1C1=CC=CC=N1 GZRKXKUVVPSREJ-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 166
- 150000003839 salts Chemical class 0.000 claims abstract description 27
- 238000000034 method Methods 0.000 claims abstract description 21
- 238000002360 preparation method Methods 0.000 claims abstract description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- -1 1-[2-(4-ethyl-piperazine-1-yl)-pyridin-4-yl]-3-propyl Chemical group 0.000 claims description 110
- 238000006243 chemical reaction Methods 0.000 claims description 78
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 66
- 229910052736 halogen Inorganic materials 0.000 claims description 48
- 150000002367 halogens Chemical class 0.000 claims description 48
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 claims description 44
- JBDSSBMEKXHSJF-UHFFFAOYSA-N cyclopentanecarboxylic acid Chemical compound OC(=O)C1CCCC1 JBDSSBMEKXHSJF-UHFFFAOYSA-N 0.000 claims description 26
- 150000001412 amines Chemical class 0.000 claims description 25
- 239000001257 hydrogen Substances 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 21
- 201000010099 disease Diseases 0.000 claims description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 20
- 239000004202 carbamide Substances 0.000 claims description 19
- 125000000623 heterocyclic group Chemical group 0.000 claims description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 13
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 208000008589 Obesity Diseases 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 235000020824 obesity Nutrition 0.000 claims description 12
- 125000001188 haloalkyl group Chemical group 0.000 claims description 11
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 239000000460 chlorine Substances 0.000 claims description 9
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 claims description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
- 150000003222 pyridines Chemical class 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 239000001301 oxygen Substances 0.000 claims description 7
- 230000002265 prevention Effects 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 7
- 239000005864 Sulphur Substances 0.000 claims description 6
- 229960003966 nicotinamide Drugs 0.000 claims description 6
- 239000011570 nicotinamide Substances 0.000 claims description 6
- 229940124530 sulfonamide Drugs 0.000 claims description 6
- LRGZZEOWQURWFK-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7-octahydroisoquinoline Chemical compound C1NCCC2CCCC=C21 LRGZZEOWQURWFK-UHFFFAOYSA-N 0.000 claims description 5
- QBLXORCRLIVJGT-UHFFFAOYSA-N 1-[2-(4-cyclopentylpiperazin-1-yl)pyridin-4-yl]-3-[(4-fluorophenyl)methyl]urea Chemical compound C1=CC(F)=CC=C1CNC(=O)NC1=CC=NC(N2CCN(CC2)C2CCCC2)=C1 QBLXORCRLIVJGT-UHFFFAOYSA-N 0.000 claims description 5
- NNJSXMHIVAJWLP-UHFFFAOYSA-N 1-cyclohexyl-3-[2-(4-cyclopentylpiperazin-1-yl)pyridin-4-yl]urea Chemical compound C=1C=NC(N2CCN(CC2)C2CCCC2)=CC=1NC(=O)NC1CCCCC1 NNJSXMHIVAJWLP-UHFFFAOYSA-N 0.000 claims description 5
- MPICOCGHQWMGMM-UHFFFAOYSA-N 4-fluoropiperidine-1-carboxylic acid Chemical compound OC(=O)N1CCC(F)CC1 MPICOCGHQWMGMM-UHFFFAOYSA-N 0.000 claims description 5
- 230000004913 activation Effects 0.000 claims description 5
- MEOZFUYXLCDYGA-UHFFFAOYSA-N azepane-1-carboxylic acid Chemical compound OC(=O)N1CCCCCC1 MEOZFUYXLCDYGA-UHFFFAOYSA-N 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 150000002431 hydrogen Chemical group 0.000 claims description 5
- KLPNMKXPEATXCC-UHFFFAOYSA-N n-[2-(4-cyclopentylpiperazin-1-yl)pyridin-4-yl]butanamide Chemical compound CCCC(=O)NC1=CC=NC(N2CCN(CC2)C2CCCC2)=C1 KLPNMKXPEATXCC-UHFFFAOYSA-N 0.000 claims description 5
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 claims description 5
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- BSCCSDNZEIHXOK-UHFFFAOYSA-N phenyl carbamate Chemical compound NC(=O)OC1=CC=CC=C1 BSCCSDNZEIHXOK-UHFFFAOYSA-N 0.000 claims description 4
- ZPPXWZDJDIOJFP-UHFFFAOYSA-N 1,3-dihydroisoindole-2-carboxylic acid Chemical compound C1=CC=C2CN(C(=O)O)CC2=C1 ZPPXWZDJDIOJFP-UHFFFAOYSA-N 0.000 claims description 3
- ZKNJZLXPVBIKIB-UHFFFAOYSA-N 1-[4-(4-cyclopentylpiperazin-1-yl)pyridin-2-yl]-3-(1-phenylethyl)urea Chemical compound C=1C=CC=CC=1C(C)NC(=O)NC(N=CC=1)=CC=1N(CC1)CCN1C1CCCC1 ZKNJZLXPVBIKIB-UHFFFAOYSA-N 0.000 claims description 3
- ZLUUPCCXIKTEBG-UHFFFAOYSA-N 3,4-dihydro-2h-quinoline-1-carboxylic acid Chemical compound C1=CC=C2N(C(=O)O)CCCC2=C1 ZLUUPCCXIKTEBG-UHFFFAOYSA-N 0.000 claims description 3
- ITKJIYTVCFULLG-UHFFFAOYSA-N 3-[2-(4-cyclopentylpiperazin-1-yl)pyridin-4-yl]-1,1-diethylurea Chemical compound CCN(CC)C(=O)NC1=CC=NC(N2CCN(CC2)C2CCCC2)=C1 ITKJIYTVCFULLG-UHFFFAOYSA-N 0.000 claims description 3
- VHFXHGUIAJHCHG-UHFFFAOYSA-N 3-[2-(4-cyclopentylpiperazin-1-yl)pyridin-4-yl]-1-ethyl-1-phenylurea Chemical compound C=1C=CC=CC=1N(CC)C(=O)NC(C=1)=CC=NC=1N(CC1)CCN1C1CCCC1 VHFXHGUIAJHCHG-UHFFFAOYSA-N 0.000 claims description 3
- OCDMMDSCLHTCOE-UHFFFAOYSA-N 3-cyclohexyl-1-[2-(4-cyclopentylpiperazin-1-yl)pyridin-4-yl]-1-methylurea Chemical compound C=1C=NC(N2CCN(CC2)C2CCCC2)=CC=1N(C)C(=O)NC1CCCCC1 OCDMMDSCLHTCOE-UHFFFAOYSA-N 0.000 claims description 3
- BOXROLTUXNBLCI-UHFFFAOYSA-N 3-cyclopentyl-1-[2-(4-cyclopentylpiperazin-1-yl)pyridin-4-yl]-1-methylurea Chemical compound C=1C=NC(N2CCN(CC2)C2CCCC2)=CC=1N(C)C(=O)NC1CCCC1 BOXROLTUXNBLCI-UHFFFAOYSA-N 0.000 claims description 3
- WUUWTJUFSAQTKJ-UHFFFAOYSA-N CC(C)C(C1=CC(=NC=C1)N2CCN(CC2)C3CCCC3)OC(=O)N Chemical group CC(C)C(C1=CC(=NC=C1)N2CCN(CC2)C3CCCC3)OC(=O)N WUUWTJUFSAQTKJ-UHFFFAOYSA-N 0.000 claims description 3
- RDJXAMSHBGWJKS-UHFFFAOYSA-N [4-(4-cyclopentylpiperazin-1-yl)pyridin-2-yl]carbamic acid Chemical compound C1=NC(NC(=O)O)=CC(N2CCN(CC2)C2CCCC2)=C1 RDJXAMSHBGWJKS-UHFFFAOYSA-N 0.000 claims description 3
- TXWOGHSRPAYOML-UHFFFAOYSA-N cyclobutanecarboxylic acid Chemical compound OC(=O)C1CCC1 TXWOGHSRPAYOML-UHFFFAOYSA-N 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- STUHQDIOZQUPGP-UHFFFAOYSA-N morpholin-4-ium-4-carboxylate Chemical compound OC(=O)N1CCOCC1 STUHQDIOZQUPGP-UHFFFAOYSA-N 0.000 claims description 3
- VJPLHQZQWNBNHE-UHFFFAOYSA-N n-[2-(4-cyclopentylpiperazin-1-yl)pyridin-4-yl]-2-(4-fluorophenyl)acetamide Chemical compound C1=CC(F)=CC=C1CC(=O)NC1=CC=NC(N2CCN(CC2)C2CCCC2)=C1 VJPLHQZQWNBNHE-UHFFFAOYSA-N 0.000 claims description 3
- QILWDOXFJAYYTE-UHFFFAOYSA-N n-[2-(4-cyclopentylpiperazin-1-yl)pyridin-4-yl]-2-ethylbutanamide Chemical compound CCC(CC)C(=O)NC1=CC=NC(N2CCN(CC2)C2CCCC2)=C1 QILWDOXFJAYYTE-UHFFFAOYSA-N 0.000 claims description 3
- JVPYBKJTQWAEJF-UHFFFAOYSA-N n-[2-(4-cyclopentylpiperazin-1-yl)pyridin-4-yl]-2-fluorobenzamide Chemical compound FC1=CC=CC=C1C(=O)NC1=CC=NC(N2CCN(CC2)C2CCCC2)=C1 JVPYBKJTQWAEJF-UHFFFAOYSA-N 0.000 claims description 3
- WGNUZTMWIKJMJE-UHFFFAOYSA-N n-[2-(4-cyclopentylpiperazin-1-yl)pyridin-4-yl]-2-phenylacetamide Chemical compound C=1C=NC(N2CCN(CC2)C2CCCC2)=CC=1NC(=O)CC1=CC=CC=C1 WGNUZTMWIKJMJE-UHFFFAOYSA-N 0.000 claims description 3
- PXHSEESNFYAINT-UHFFFAOYSA-N n-[2-(4-cyclopentylpiperazin-1-yl)pyridin-4-yl]-4-fluorobenzamide Chemical compound C1=CC(F)=CC=C1C(=O)NC1=CC=NC(N2CCN(CC2)C2CCCC2)=C1 PXHSEESNFYAINT-UHFFFAOYSA-N 0.000 claims description 3
- GNYNFECTARIGNY-UHFFFAOYSA-N n-[2-(4-cyclopentylpiperazin-1-yl)pyridin-4-yl]propanamide Chemical compound CCC(=O)NC1=CC=NC(N2CCN(CC2)C2CCCC2)=C1 GNYNFECTARIGNY-UHFFFAOYSA-N 0.000 claims description 3
- COLRWWLYMOXRBG-UHFFFAOYSA-N n-[2-(4-ethylpiperazin-1-yl)pyridin-4-yl]butanamide Chemical compound CCCC(=O)NC1=CC=NC(N2CCN(CC)CC2)=C1 COLRWWLYMOXRBG-UHFFFAOYSA-N 0.000 claims description 3
- VSCOZPUUUZHWBS-UHFFFAOYSA-N n-[2-(4-ethylpiperazin-1-yl)pyridin-4-yl]propanamide Chemical compound C1CN(CC)CCN1C1=CC(NC(=O)CC)=CC=N1 VSCOZPUUUZHWBS-UHFFFAOYSA-N 0.000 claims description 3
- GPXVPHOKZFORFN-UHFFFAOYSA-N n-[4-(4-cyclopentylpiperazin-1-yl)pyridin-2-yl]-2-ethylbutanamide Chemical compound C1=NC(NC(=O)C(CC)CC)=CC(N2CCN(CC2)C2CCCC2)=C1 GPXVPHOKZFORFN-UHFFFAOYSA-N 0.000 claims description 3
- MNUAFFFESTVXLJ-UHFFFAOYSA-N n-[4-(4-cyclopentylpiperazin-1-yl)pyridin-2-yl]-2-fluorobenzamide Chemical compound FC1=CC=CC=C1C(=O)NC1=CC(N2CCN(CC2)C2CCCC2)=CC=N1 MNUAFFFESTVXLJ-UHFFFAOYSA-N 0.000 claims description 3
- FXJHIRDVNYZRIJ-UHFFFAOYSA-N n-[4-(4-cyclopentylpiperazin-1-yl)pyridin-2-yl]-3-fluorobenzamide Chemical compound FC1=CC=CC(C(=O)NC=2N=CC=C(C=2)N2CCN(CC2)C2CCCC2)=C1 FXJHIRDVNYZRIJ-UHFFFAOYSA-N 0.000 claims description 3
- DSSJKQADKRKNPN-UHFFFAOYSA-N n-[4-(4-cyclopentylpiperazin-1-yl)pyridin-2-yl]-4-fluorobenzamide Chemical compound C1=CC(F)=CC=C1C(=O)NC1=CC(N2CCN(CC2)C2CCCC2)=CC=N1 DSSJKQADKRKNPN-UHFFFAOYSA-N 0.000 claims description 3
- PEVRGNQYNMPFHQ-UHFFFAOYSA-N n-[4-(4-cyclopentylpiperazin-1-yl)pyridin-2-yl]butanamide Chemical compound C1=NC(NC(=O)CCC)=CC(N2CCN(CC2)C2CCCC2)=C1 PEVRGNQYNMPFHQ-UHFFFAOYSA-N 0.000 claims description 3
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- KCXFHTAICRTXLI-UHFFFAOYSA-N propane-1-sulfonic acid Chemical compound CCCS(O)(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-N 0.000 claims description 3
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- VNSVUIHDPGSUQX-UHFFFAOYSA-N 1-benzyl-3-[[2-(4-cyclopentylpiperazin-1-yl)pyridin-4-yl]methyl]urea Chemical compound C=1C=NC(N2CCN(CC2)C2CCCC2)=CC=1CNC(=O)NCC1=CC=CC=C1 VNSVUIHDPGSUQX-UHFFFAOYSA-N 0.000 claims description 2
- WLEQUQRGLRPQDD-UHFFFAOYSA-N 1-cyclohexyl-3-[[2-(4-cyclopentylpiperazin-1-yl)pyridin-4-yl]methyl]urea Chemical compound C1CCCCC1NC(=O)NCC(C=1)=CC=NC=1N(CC1)CCN1C1CCCC1 WLEQUQRGLRPQDD-UHFFFAOYSA-N 0.000 claims description 2
- LQMZBIPGDWXKBZ-UHFFFAOYSA-N 2-(4-chlorophenyl)-n-[[2-(4-cyclopentylpiperazin-1-yl)pyridin-4-yl]methyl]-3-methylbutanamide Chemical group C=1C=C(Cl)C=CC=1C(C(C)C)C(=O)NCC(C=1)=CC=NC=1N(CC1)CCN1C1CCCC1 LQMZBIPGDWXKBZ-UHFFFAOYSA-N 0.000 claims description 2
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- 239000012948 isocyanate Substances 0.000 claims description 2
- 150000002513 isocyanates Chemical class 0.000 claims description 2
- WRBBCWQJLVUSAM-UHFFFAOYSA-N n-[[2-(4-cyclopentylpiperazin-1-yl)pyridin-4-yl]methyl]-2-phenylacetamide Chemical group C=1C=NC(N2CCN(CC2)C2CCCC2)=CC=1CNC(=O)CC1=CC=CC=C1 WRBBCWQJLVUSAM-UHFFFAOYSA-N 0.000 claims description 2
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- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000000283 vasomotion Effects 0.000 description 1
- 230000001720 vestibular Effects 0.000 description 1
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Abstract
本发明涉及式(I)化合物及其药用盐,其中R1、R2、X、Y、Z和m如说明书和权利要求书中定义,还涉及包含这些化合物的药物组合物和它们的制备方法。所述化合物可用于治疗和/或预防与H3受体的调节有关的疾病。
Description
本发明涉及新型的-吡啶衍生物,它们的制备,含有它们的药物组合物和它们作为药物的应用。本发明的活性化合物可用于治疗肥胖症和其它病症。
具体地,本发明涉及以下通式的化合物,
其中
R为氢或者低级烷基;
R1选自:氢,低级烷基,C3-C7-链烯基,
C3-C7-炔基,低级卤代烷基,低级羟烷基,低级烷氧基烷基,
C3-C7-环烷基和低级C3-C7-环烷基烷基;
X为N和Y为C,或者
Y为N和X为C;
m为0或者1;
Z为C(O)或者SO2;
R2选自:低级烷基,C3-C7-链烯基,C3-C7-炔基,
低级卤代烷基,低级羟烷基,低级烷氧基烷基,
C3-C7-环烷基或者被苯基或者低级烷基取代的C3-C7-环烷基,
低级C3-C7-环烷基烷基,
未取代的苯基或者被低级烷基、低级烷氧基、卤素或者低级卤代烷基单或双取代的苯基,
低级苯基烷基,其中所述的苯环是未取代的或被低级烷基、低级烷氧基、卤素或者低级卤代烷基单或双取代的,
未取代的吡啶基或者被低级烷基、低级烷氧基、卤素或者低级卤代烷基单或双取代的吡啶基,以及
-NR3R4,
或者,在Z为C(O)的情况下,R2也可以为低级烷氧基或者低级烷氧基烷氧基;
R3为氢或者低级烷基;
R4选自:
低级烷基,C3-C7-链烯基,C3-C7-炔基,
低级烷氧基烷基,
C3-C7-环烷基,被苯基取代的C3-C7-环烷基,
低级C3-C7-环烷基烷基,
未取代的苯基或者被低级烷基、低级烷氧基、卤素或者低级卤代烷基单或双取代的苯基,或者
低级苯基烷基,其中苯基是未取代的或被以下基团单或双取代的:低级烷基,低级烷氧基,卤素或者低级卤代烷基;或者
R3和R4与它们连接的氮原子一起形成任选含有另外的选自氮、氧或硫的杂原子的4-、5-、6-或7-元杂环,所述的杂环是未取代的或被一个、两个或三个独立地选自下组的基团取代的:低级烷基,低级烷氧基,氧代基,卤素和卤代烷基,或者是与苯基或环己基环稠合的,所述的苯基或者环己基环是未取代的或被一个、两个或三个独立地选自下组的基团取代的:低级烷基,低级烷氧基,卤素和卤代烷基;
及其药用盐。
已经发现式I的化合物是组胺3受体(H3受体)的拮抗剂和/或反向激动剂。
组胺(2-(4-咪唑基)乙胺)是胺能神经递质中的一种,其广泛分布在整个身体内,例如胃肠道(Burks 1994,Johnson L.R.编辑,Physiology of theGastrointestinal Tract,Raven Press,NY,第211-242页)。组胺调节各种各样的消化病理生理事件,如胃酸分泌,肠运动性(Leurs等,Br J.Pharmacol.1991,102,第179-185页),血管舒缩反应,肠炎症反应和变态反应(Raithel等,Int.Arch.Allergy Immunol.1995,108,127-133)。在哺乳动物的脑中,组胺是在组胺能细胞体中合成的,所述组胺能细胞体是在后底下丘脑的结节乳头状核的中央发现的。从那,细胞体投射到不同脑区域(Panula等,Proc.Natl.Acad.Sci.USA 1984,81,2572-2576;Inagaki等,J.Comp.Neurol1988,273,283-300)。
根据当前知识,组胺通过四种不同的组胺受体(组胺H1、H2、H3和H4受体)介导它在中枢神经系统(CNS)和周围中的所有作用。
H3受体主要定位在CNS中。作为自身受体,H3受体组成型地抑制组胺从组胺能神经元的合成和分泌(Arrang等,Nature 1983,302,832-837;Arrang等,Neuroscience 1987,23,149-157)。作为异源受体(heteroreceptor),H3受体还调节其它神经递质如乙酰胆碱、多巴胺、5-羟色胺和去甲肾上腺素的释放,尤其在中枢神经系统和外周器官如肺、心血管系统和胃肠道中(Clapham & Kilpatrik,Br.J.Pharmacol.1982,107,919-923;Blandina等The Histamine H3 Receptor(Leurs RL和Timmermann H编辑,1998,第27-40页,Elsevier,Amsterdam,The Netherlands)。H3受体是组成型活性的,意思是甚至在没有外源组胺的情况下受体也被增强性(tonically)激活。在抑制性受体如H3受体的情形中,这种内在活性导致神经递质释放的增强抑制。因此,可能重要的是H3R拮抗剂也将具有反向激动剂活性而阻断外源组胺作用和将受体从其固有活性(抑制性)形式转变为中性状态。
H3受体在哺乳动物CNS中的广泛分布指示该受体的生理作用。因此,已经提出作为各种适应证的新药开发目标的治疗潜力。
H3R配体-作为拮抗剂、反向激动剂、激动剂或部分激动剂-的施用可能影响脑和周围中的组胺水平或神经递质的分泌,并因此可以用于治疗数种病症.这些病症包括肥胖症,(Masaki等;Endocrinol.2003,144,2741-2748;Hancock等,European J.of Pharmacol.2004,487,183-197),心血管病症如急性心肌梗死、痴呆和认知障碍如注意缺陷多动障碍(ADHD)和早老性痴呆,神经系统疾病如精神分裂症、抑郁、癫痫、帕金森病和癫痫发作或抽搐、睡眠障碍、发作性睡眠症、疼痛,胃肠病症,前庭功能障碍如美尼尔氏症,药物滥用和晕动症(Timmermann,J.Med.Chem.1990,33,4-11)。
因此,本发明的一个目的是提供选择性的、直接作用的H3受体拮抗剂或者反向激动剂。这些拮抗剂/反向激动剂可用作治疗活性物质,特别是用于治疗和/或预防与H3受体的调节有关的疾病。
在本说明书中,术语″烷基″,单独或者与其它基团组合,表示1-20个碳原子、优选1-16个碳原子、更优选1-10个碳原子的支链或直链一价饱和脂族烃基。
术语″低级烷基″或″C1-C7-烷基″,单独或组合,表示1-7个碳原子的直链或支链烷基,优选1-6个碳原子的直链或支链烷基,特别优选1-4个碳原子的直链或支链烷基。直链和支链C1-C7-烷基的实例有甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、同分异构的戊基、同分异构的己基、同分异构的庚基和同分异构的辛基,优选甲基、乙基和丙基,最优选甲基和乙基。
术语″低级链烯基″或″C3-C7-链烯基″,单独或组合,表示包含烯键和至多7个、优选至多6个、特别优选至多4个碳原子的直链或支链烷基。链烯基的实例有1-丙烯基,2-丙烯基,异丙烯基,1-丁烯基,2-丁烯基,3-丁烯基和异丁烯基。优选的实例有2-丙烯基。
术语″低级炔基″或″C3-C7-炔基″,单独或组合,表示包含三键和至多7个、优选至多6个、特别优选至多4个碳原子的直链或支链烷基。炔基的实例包括2-丙炔基(炔丙基),1-甲基-2-丙炔基,2-丁炔基,3-丁炔基,2-戊炔基和1-戊炔-3-基。
术语″烷氧基″是指基团R′-O-,其中R′是烷基。术语″低级烷氧基″指的是其中R′是低级烷基的基团R′-O-,而术语″低级烷基″具有先前规定的含义(″C1-C7-烷氧基″)。低级烷氧基的实例有例如甲氧基,乙氧基,正丙氧基,异丙氧基,正丁氧基,异丁氧基,仲丁氧基和叔丁氧基,优选甲氧基和乙氧基,最优选甲氧基。
术语″低级烷氧基烷基″或″C1-C7-烷氧基-C1-C7-烷基″是指如上定义的低级烷基,其中所述低级烷基的至少一个氢原子被如上定义的烷氧基替换。其中,优选的低级烷氧基烷基是甲氧基甲基,甲氧基乙基和乙氧基甲基,特别优选甲氧基甲基。
术语″低级烷氧基烷氧基″或″C1-C7-烷氧基-C1-C7-烷氧基″是指如上定义的低级烷氧基,其中所述低级烷氧基的至少一个氢原子被如上定义的烷氧基替换。其中,优选的低级烷氧基烷氧基是甲氧基乙氧基,甲氧基丙氧基和乙氧基乙氧基,特别优选甲氧基乙氧基。
术语″卤素″是指氟、氯、溴和碘,优选氟、氯和溴。
术语″低级卤代烷基″或″卤代-C1-C7-烷基″是指如上定义的低级烷基,其中所述低级烷基的至少一个氢原子被卤素原子替换,所述卤素原子优选氟或氯,最优选氟。其中,优选的卤代低级烷基有三氟甲基,二氟甲基,氟甲基和氯甲基,特别优选三氟甲基。
术语″低级羟烷基″或″羟基-C1-C7-烷基″是指如上定义的低级烷基,其中所述低级烷基的至少一个氢原子被羟基替换。低级羟烷基的实例有羟甲基或羟乙基。
术语″环烷基″或″C3-C7-环烷基″表示含有3-7个碳原子的环烷基环,如环丙基,环丁基,环戊基,环己基或环庚基。如本说明书所定义,所述环烷基环可以被取代。特别优选的是环丙基或环戊基。
术语″低级环烷基烷基″或″C3-C7-环烷基-C1-7-烷基″是指如上定义的低级烷基,其中所述低级烷基的至少一个氢原子被如上定义的环烷基替换。优选的低级环烷基烷基的实例有环丙基甲基或环丙基甲基。
术语″低级苯基烷基″或″苯基-C1-C7-烷基″是指如上定义的低级烷基,其中所述低级烷基的至少一个氢原子被苯基替换。本说明书所定义,苯基环可以被取代。优选的低级苯基烷基的实例有苄基,4-甲基苄基,4-氟苄基,3-甲氧基苄基和3,4-二甲氧基苄基。
术语“形成任选含有另外的选自氮、氧或硫的杂原子的4-、5-、6-或7-元饱和杂环”是指饱和的N-杂环,其可以任选还含有氮、氧或硫原子,如氮杂环丁烷基,吡咯烷基,咪唑烷基,吡唑烷基,噁唑烷基,异噁唑烷基,噻唑烷基,异噻唑烷基,哌啶基,哌嗪基,吗啉基,硫代吗啉基或者氮杂环庚烷基。杂环可以是未取代的或被一个、两个或三个独立地选自下组的基团取代的:低级烷基,低级烷氧基,氧代基,卤素和卤代烷基。杂环还可以与苯基或环己基环稠合,所述的苯基或环己基环是未取代的或被一个、两个或三个独立地选自下组的基团取代的:低级烷基,低级烷氧基,卤素和卤代烷基。这样的稠合杂环的实例有3,4-二氢-1H-异喹啉,八氢喹啉,3,4-二氢-2H-喹啉,1,3-二氢异吲哚和2,3-二氢吲哚。
术语″药用盐″是指保留游离碱或游离酸的生物学效力和性能的那些盐,从生物学或其它观点看来它们不是不合乎需要的。形成这些盐使用的是无机酸如盐酸,氢溴酸,硫酸,硝酸,磷酸等,优选盐酸,和有机酸如乙酸,丙酸,乙醇酸,丙酮酸,草酸(oxylic acid),马来酸,丙二酸,水杨酸,琥珀酸,富马酸,酒石酸,柠檬酸,苯甲酸,肉桂酸,苦杏仁酸,甲磺酸,乙磺酸,对甲苯磺酸,水杨酸,N-乙酰半胱氨酸等。另外,这些盐可以通过将无机碱或有机碱加入游离酸来制备。来源于无机碱的盐包括但不限于钠,钾,锂,铵,钙,镁盐等。来源于有机碱的盐包括但不限于以下各项的盐:伯、仲和叔胺,取代胺,包括天然存在的取代胺,环胺和碱性离子交换树脂,如异丙胺,三甲胺,二乙胺,三乙胺,三丙胺,乙醇胺,赖氨酸,精氨酸,N-乙基哌啶,哌啶,聚胺(polymine)树脂等。式I的化合物也可以以两性离子的形式存在。特别优选的式I化合物的药用盐是盐酸盐。
式I的化合物也可以是溶剂化的,例如水合的。可以在制备过程中进行溶剂化,或例如可以因最初无水的式I化合物的吸湿特性而进行(水合)。术语药用盐还包括生理上可接受的溶剂化物。
″异构体″是具有相同分子式但是它们原子的键合的性质或顺序不同或它们原子的空间排列不同的化合物。其原子空间排列不同的异构体被称为″立体异构体″。彼此非镜像的立体异构体被称为″非对映异构体″,而非可重叠的镜像立体异构体被称为″对映体″,或者有时称为光学异构体。与四个不全同的取代基结合的碳原子被称为″手性中心″。
详细地,本发明涉及以下通式的化合物,
其中
R为氢或者低级烷基;
R1选自:氢,低级烷基,C3-C7-链烯基,
C3-C7-炔基,低级卤代烷基,低级羟烷基,低级烷氧基烷基,
C3-C7-环烷基和低级C3-C7-环烷基烷基;
X为N和Y为C,或者
Y为N和X为C;
m为0或者1;
Z为C(O)或者SO2;
R2选自:低级烷基,C3-C7-链烯基,C3-C7-炔基,
低级卤代烷基,低级羟烷基,低级烷氧基烷基,
C3-C7-环烷基或者被苯基或者低级烷基取代的C3-C7-环烷基,
低级C3-C7-环烷基烷基,
未取代的苯基或者被低级烷基、低级烷氧基、卤素或者低级卤代烷基单或双取代的苯基,
低级苯基烷基,其中所述的苯环是未取代的或被低级烷基、低级烷氧基、卤素或者低级卤代烷基单或双取代的,
未取代的吡啶基或者被低级烷基、低级烷氧基、卤素或者低级卤代烷基单或双取代的吡啶基,以及
-NR3R4,
或者,在Z为C(O)的情况下,R2也可以为低级烷氧基或者低级烷氧基烷氧基;
R3为氢或者低级烷基;
R4选自:
低级烷基,C3-C7-链烯基,C3-C7-炔基,
低级烷氧基烷基,
C3-C7-环烷基,被苯基取代的C3-C7-环烷基,
低级C3-C7-环烷基烷基,
未取代的苯基或者被低级烷基,低级烷氧基,卤素或者低级卤代烷基单或双取代的苯基,或者
低级苯基烷基,其中苯基是未取代的或被以下基团单或双取代的:低级烷基,低级烷氧基,卤素或者低级卤代烷基;或者
R3和R4与它们连接的氮原子一起形成任选含有另外的选自氮、氧或硫的杂原子的4-、5-、6-或7-元杂环,所述的杂环是未取代的或被一个、两个或三个独立地选自下组的基团取代的:低级烷基,低级烷氧基,氧代基,卤素和卤代烷基,或者是与苯基或环己基环稠合的,所述的苯基或者环己基环是未取代的或被一个、两个或三个独立地选自下组的基团取代的:低级烷基,低级烷氧基,卤素和卤代烷基;
及其药用盐。
因此,取代基R1选自:氢,低级烷基,C3-C7-链烯基,C3-C7-炔基,低级卤代烷基,低级羟烷基,低级烷氧基烷基,C3-C7-环烷基和低级C3-C7-环烷基烷基。根据本发明的优选式I化合物是其中R1为低级烷基或者C3-C7-环烷基的那些化合物,更优选其中R1为C3-C7-环烷基的那些化合物,并且最优选其中R1为环戊基的那些化合物。还非常优选其中R1为乙基或者异丙基的式I化合物。
m为0或者1的整数。特别优选其中m为0的那些式I化合物。但是,其中m为1的式I化合物也是本发明的一个优选实施方案。
本发明优选的式I化合物是以下的那些化合物,其中R为氢和R2选自:低级烷基,C3-C7-链烯基,
C3-C7-炔基,低级卤代烷基,低级羟烷基,低级烷氧基烷基,
C3-C7-环烷基或者被苯基取代的C3-C7-环烷基,
低级C3-C7-环烷基烷基,
未取代的苯基或者被低级烷基、低级烷氧基、卤素或者低级卤代烷基单或双取代的苯基,
低级苯基烷基,其中所述的苯环是未取代的或被低级烷基、低级烷氧基、卤素或者低级卤代烷基单或双取代的,
未取代的吡啶基或者被低级烷基、低级烷氧基、卤素或者低级卤代烷基单或双取代的吡啶基,和-NR3R4,
或者,在Z为C(O)的情况下,R2也可以为低级烷氧基或者低级烷氧基烷氧基。
根据本发明的一组优选式I化合物是以下的那些化合物,其中R2选自:低级烷基,C3-C7-链烯基,C3-C7-炔基,低级卤代烷基,低级羟烷基,低级烷氧基烷基,
C3-C7-环烷基或者被苯基或者低级烷基取代的C3-C7-环烷基,
低级C3-C7-环烷基烷基,
低级苯基烷基,其中所述的苯环是未取代的或被低级烷基、低级烷氧基、卤素或者低级卤代烷基单或双取代的,
未取代的吡啶基或者被低级烷基,低级烷氧基,卤素或者低级卤代烷基单或双取代的吡啶基,和-NR3R4,或者,在Z为C(O)的情况下,R2也可以为低级烷氧基或者低级烷氧基烷氧基。
在此组内,更优选其中R2选自:低级烷基,C3-C7-环烷基和低级烷氧基烷基的式I化合物。
此外,优选式I的化合物,其中R2为低级苯基烷基,其中苯基是未取代的或被以下基团单或双取代的:低级烷基,低级烷氧基,卤素或者低级卤代烷基。
还优选本发明式I的化合物,其中R2为基团-NR3R4,并且R3和R4如上所定义,特别优选其中R3和R4为低级烷基的那些化合物。
另一组优选的式I化合物是以下的那些化合物,其中R2为基团-NR3R4,R3为氢或者低级烷基和R4选自:低级烷基,C3-C7-链烯基,C3-C7-炔基,低级烷氧基烷基,C3-C7-环烷基,
被苯基取代的C3-C7-环烷基,低级C3-C7-环烷基烷基,
未取代的苯基或者被低级烷基,低级烷氧基,卤素或者低级卤代烷基单或双取代的苯基,以及
低级苯基烷基,其中苯基是未取代的或被以下基团单或双取代的:低级烷基,低级烷氧基,卤素或者低级卤代烷基。
此外,优选式I的化合物,其中R2为-NR3R4并且R3和R4与它们连接的氮原子一起形成任选含有另外的选自氮、氧或硫的杂原子的4-、5-、6-或7-元杂环,所述的杂环是未取代的或被一个、两个或三个独立地选自下组的基团取代的:低级烷基,低级烷氧基,氧代基,卤素和低级卤代烷基,或者是与苯基或环己基环稠合的,所述的苯基或者环己基环是未取代的或被一个、两个或三个独立地选自下组的基团取代的:低级烷基,低级烷氧基,卤素和卤代烷基。
在此组内特别优选的是以下的那些化合物,其中R3和R4与它们连接的氮原子一起形成5-,6-或者7-元杂环。优选地,所述的杂环为未取代的或被独立地选自低级烷基,卤素或者低级卤代烷基中的一个或者两个基团取代的,或者它与苯基或环己环稠合。最优选地,R3和R4与所述的氮原子一起形成基团哌啶,吗啉,吡咯烷,2-甲基-吡咯烷,2-三氟甲基吡咯烷,2-异丙基吡咯烷,2-甲基哌啶,3-甲基-哌啶,4-甲基哌啶,2,6-二甲基哌啶,4-氟哌啶,4,4-二氟-哌啶,3,3-二氟哌啶,4-三氟甲基-哌啶,八氢喹啉,3,4-二氢-2H-喹啉,3,4-二氢-1H-异喹啉,1,3-二氢异吲哚,2,3-二氢吲哚和氮杂环庚烷。
本发明进一步优选的化合物是以下的那些化合物,其中R2为基团-NR3R4,R3为氢和R4为低级苯基烷基,其中苯基是未取代的或被以下基团单或双取代的:低级烷基,低级烷氧基,卤素或者低级卤代烷基。
此外,优选本发明的式I化合物,其中R2为未取代的苯基或者被以下基团单或双取代的苯基:低级烷基,低级烷氧基,卤素或者低级卤代烷基。
一优选组的式I化合物是其中Z为SO2的那些化合物。这些化合物为具有下式I-A的化合物:
其中X,Y,R,R1,R2和m如上面所定义。
此外,优选式I的化合物,其中Z为C(O)。这些化合物为具有下式I-B的化合物:
其中X,Y,R,R1,R2和m如上面所定义。
在此组内,特别优选其中Z为C(O)并且R2为-NR3R4的那些化合物,因此表示下式I-C的化合物:
其中X,Y,R,R1,R3,R4和m如上面所定义。
本发明的式I化合物为其中X为N并且Y为C的那些化合物,因此表示下式I-D的化合物:
其中R,R1,R2,Z和m如上面所定义。
本发明还包括式I化合物,其中X为C并且Y为N,因此表示下式I-E的化合物:
其中R,R1,R2,Z和m如上面所定义。
特别优选的是根据本发明的式I化合物,其中R为氢。
还优选的是式I化合物,其中R为低级烷基,特别优选其中R为甲基的那些化合物。
优选的式I化合物的实例有以下:
1-[2-(4-乙基-哌嗪-1-基)-吡啶-4-基]-3-丙基-脲,
3-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-1,1-二乙基-脲,
N-[2-(4-乙基-哌嗪-1-基)-吡啶-4-基]-丙酰胺,
N-[2-(4-乙基-哌嗪-1-基)-吡啶-4-基]-丁酰胺,
N-[2-(4-乙基-哌嗪-1-基)-吡啶-4-基]-C-苯基-甲磺酰胺,
C-(4-氯-苯基)-N-[2-(4-乙基-哌嗪-1-基)-吡啶-4-基]-甲磺酰胺,
N-[2-(4-乙基-哌嗪-1-基)-吡啶-4-基]-3-氟-苯磺酰胺,
4-氯-N-[2-(4-乙基-哌嗪-1-基)-吡啶-4-基]-苯磺酰胺,
1-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-3-(4-氟-苄基)-脲,
N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-丙酰胺,
N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-丁酰胺,
环己烷羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-3-甲氧基-苯甲酰胺,
C-(4-氯-苯基)-N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲磺酰胺,
环丙烷羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
环丁烷羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
环戊烷羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-2-乙基-丁酰胺,
N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-2-氟-苯甲酰胺,
N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-4-氟-苯甲酰胺,
N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-2-甲氧基-苯甲酰胺,
2-氯-N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-烟酰胺,
N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-2-苯基-乙酰胺,
N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-2-(4-氟-苯基)-乙酰胺,
N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-2-(3-甲氧基-苯基)-乙酰胺,
[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-氨基甲酸异丁酯,
1-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-3-丙基-脲,
1-环己基-3-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-脲,
哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
吗啉-4-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
吡咯烷-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
4,4-二氟-哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
2-甲基-哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
3-甲基-哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
4-甲基-哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
2,6-二甲基-哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
4-氟-哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
3,3-二氟-哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
4-三氟甲基-哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
八氢-喹啉-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
八氢-异喹啉-2-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
3,4-二氢-2H-喹啉-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
3,4-二氢-1H-异喹啉-2-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
2-甲基-吡咯烷-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
2-三氟甲基-吡咯烷-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
2-异丙基-吡咯烷-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
1,3-二氢-异吲哚-2-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
2,3-二氢-吲哚-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
3-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-1-异丙基-1-(2-甲氧基-乙基)-脲,
氮杂环庚烷-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
3-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-1-乙基-1-苯基-脲,
3-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-1-(4-甲氧基-苯基)-1-甲基-脲,
N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基甲基]-丁酰胺,
环己烷羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基甲基]-酰胺,
N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基甲基]-2-苯基-乙酰胺,
N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基甲基]-4-氟-苯甲酰胺,
2-(4-氯-苯基)-N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基甲基]-3-甲基-丁酰胺,
1-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基甲基]-3-丙基-脲,
1-环己基-3-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基甲基]-脲,
1-苄基-3-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基甲基]-脲,
丙烷-1-磺酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基甲基]-酰胺,
二甲胺-1-磺酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基甲基]-酰胺,
C-(4-氯-苯基)-N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基甲基]-甲磺酰胺,
N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基甲基]-苯磺酰胺,
N-[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-丙酰胺,
环丙烷羧酸[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-酰胺,
N-[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-丁酰胺,
N-[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-2-甲氧基-乙酰胺,
环戊烷羧酸[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-酰胺,
N-[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-2-乙基-丁酰胺,
环己烷羧酸[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-酰胺,
N-[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-2-氟-苯甲酰胺,
N-[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-3-氟-苯甲酰胺,
N-[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-4-氟-苯甲酰胺,
N-[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-2-甲氧基-苯甲酰胺,
N-[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-3-甲氧基-苯甲酰胺,
N-[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-4-甲氧基-苯甲酰胺,
2-氯-N-[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-烟酰胺,
[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-氨基甲酸2-甲氧基-乙酯,
1-[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-3-(2-甲氧基-苯基)-脲,
1-[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-3-(1-苯基-乙基)-脲,
环己烷羧酸[2-(4-异丙基-哌嗪-1-基)-吡啶-4-基]-酰胺,
3-甲基-环己烷羧酸[2-(4-异丙基-哌嗪-1-基)-吡啶-4-基]-酰胺,
环戊烷羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基-酰胺,
3-甲基-环己烷羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基-酰胺,
环己烷羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基-酰胺,
3-甲基-环己烷羧酸[2-(4-异丙基-哌嗪-1-基)-吡啶-4-基]-甲基-酰胺,
环己烷羧酸[2-(4-异丙基-哌嗪-1-基)-吡啶-4-基]-甲基-酰胺,
哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基-酰胺,
吡咯烷-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基-酰胺,
4,4-二氟-哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基-酰胺,
3-环己基-1-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-1-甲基-脲,
3-环戊基-1-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-1-甲基-脲,
及其药用盐。
本发明特别优选的式I化合物有以下:
1-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-3-(4-氟-苄基)-脲,
N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-丁酰胺,
环己烷羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
环戊烷羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
1-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-3-丙基-脲,
1-环己基-3-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-脲,
哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
4,4-二氟-哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
3-甲基-哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
4-甲基-哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
2,6-二甲基-哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
4-氟-哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
八氢-喹啉-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
八氢-异喹啉-2-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
氮杂环庚烷-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
环丙烷羧酸[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-酰胺,
环戊烷羧酸[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-酰胺,
环己烷羧酸[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-酰胺,
3-甲基-环己烷羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基-酰胺,
4,4-二氟-哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基-酰胺,
及其药用盐。
另外,式I化合物的药用盐和式I化合物的药用酯单独地构成本发明的优选实施方案。
式I化合物可以与酸如常规药用酸形成酸加成盐,例如盐酸盐,氢溴酸盐,磷酸盐,乙酸盐,富马酸盐,马来酸盐,水杨酸盐,硫酸盐,丙酮酸盐,柠檬酸盐,乳酸盐,扁桃酸盐,酒石酸盐,和甲磺酸盐。优选盐酸盐。式I化合物的溶剂化物以及水合物和它们的盐也形成本发明的一部分。
此外,吡啶环的N-原子可以作为N-氧化物基团存在。式I化合物的这种N-氧化物也形成本发明的一部分。
式I化合物可以含有一个或多个不对称碳原子并且可以以旋光纯对映异构体、对映异构体的混合物如例如外消旋物、旋光纯非对映异构体、非对映异构体混合物、非对映异构体的外消旋物或非对映异构体的外消旋物的混合物的形式存在。例如通过不对称合成或不对称色谱法(使用手性吸附剂或洗脱剂的色谱法)拆分外消旋物可以获得旋光形式。本发明包括所有这些形式。
应当理解本发明通式I的化合物可以在官能团上衍生以提供能够在体内转变回为母体化合物的衍生物。能够在体内产生通式I的母体化合物的生理学上可接受和代谢不稳定的衍生物也在本发明的范围内。
本发明的另一方面是制备如上定义的式I化合物的方法,该方法包括
a)将式II的化合物,
其中X,Y,R,R1和m如上所定义,
与式III的磺酰氯或氨磺酰氯反应:
R2-SO2-Cl III
其中R2如上所定义,
得到式I-B的化合物:
其中X,Y,R,R1,R2和m如上面所定义,或者
b)使式II的化合物:
其中X,Y,R,R1和m如上所定义,
与式IV的氯化物反应:
R2-C(O)Cl IV
其中R2如上所定义,
得到式I-B的化合物:
其中X,Y,R,R1,R2和m如上面所定义,或者
c)使式II的化合物:
其中X,Y,R,R1和m如上所定义,
与式V的异氰酸酯反应:
R4-N=C=O V
其中R4如上所定义,
得到式I-C的化合物:
其中R3为氢和X,Y,R,R1,R4和m如上面所定义,或者
d)用氯甲酸苯酯活化式II的化合物:
其中X,Y,R,R1和m如上所定义,
得到下式的氨基甲酸苯酯:
其然后与下式的胺反应:
H-NR3R4 VII,
其中R3和R4如上面所定义,
得到式I-C的化合物:
其中X,Y,R,R1,R3,R4和m如上面所定义,
并且如果需要,将式I-A,I-B或者I-C的化合物转化为药用盐。
更具体地,式I化合物可以通过以下提供的方法、通过实施例提供的方法或通过类似方法制备。对于单个反应步骤的适当的反应条件对于本领域技术人员是已知的。原材料或者可商购,或者可以通过类似于以下提供的方法的方法、通过本文引用的参考文献中或实施例中描述的方法、或通过本领域已知的方法制备。
可以在顺序或会聚的合成路线中进行本发明式I化合物的制备。在下面的方案中示出了本发明的合成。进行反应和得到产物的纯化所需要的技能对于本领域的技术人员是已知的。在方法的下列描述中使用的取代基和符号具有上面给出的含义,除非有另外相反指示。
方案1
可以根据方案1如下制备通式I的化合物:
a)氯取代的吡啶衍生物与哌嗪类化合物的偶合广泛地描述于文献中,并且程序对于本领域的技术人员是已知的(对于进行这样的反应而在文献中描述的反应条件,参见例如:Comprehensive Organic Transformations:A Guide to Functional Group Preparations,2nd Edition,Richard C.Larock.John Wiley & Sons,New York,NY.1999).通过与哌嗪衍生物IX(适宜时,可商购的,或可以由文献中描述的方法或本领域中已知的方法得到的)的反应,可以合宜地将2-氯-4-氰基吡啶(VIII)或2-氯-4-硝基吡啶(XI)分别转变成为相应的吡啶衍生物XII或X和XIII.该反应可以在溶剂存在或不存在下并且在碱存在或不存在下进行.我们发现合宜的是,在溶剂如水和/或二甲基甲酰胺(DMF)的存在下并且在碱如二异丙基-乙胺(DIPEA)存在下进行该反应.对所采用的溶剂的性质没有特别限制,条件是它对反应或参加反应的试剂没有不利的影响,并且它可以溶解试剂至少到一定程度.适宜溶剂的实例包括DMF,二氯甲烷(DCM),二噁烷,四氢呋喃(THF)等.对在此阶段使用的碱的性质没有特别限制,并且这里可以平等地使用在这种类型的反应中通常采用的任何碱.这样的碱的实例包括三乙胺和二异丙基乙胺等.反应可以在宽温度范围内进行,并且精确的反应温度对于本发明不是关键的.我们发现合宜的是,在从环境温度加热至回流的情况下,进行该反应.反应所需要的时间也可以广泛地变化,这取决于许多因素,值得注意的是反应温度和试剂的性质.0.5h至几天的时间通常将足以得到吡啶衍生物XII或X和XIII.
b)可以在各种还原条件下分别实现X或XII中的氰基或硝基官能团的还原,得到氨基甲基吡啶衍生物II-A(式II的化合物,其中m为1)或氨基吡啶衍生物II-B(式II的化合物,其中m为0)。对于任一反应的反应条件广泛地描述于文献中,并且程序对于本领域的技术人员是已知的(对于进行这样的反应而在文献中描述的反应条件,参见例如:Comprehensive Organic Transformations:A Guide to Functional GroupPreparations,2nd Edition,Richard C.Larock.John Wiley & Sons,NewYork,NY.1999)。我们发现合宜的是,在溶剂中,并且在酸存在或不存在下,用阮内镍或钯/木炭(Pd/C)氢化X或XII。我们发现合宜的是,在溶剂如甲醇或乙酸乙酯中进行该反应。对采用的溶剂的性质没有特别限制,条件是它对反应或参加反应的试剂没有不利的影响,并且它可以溶解试剂至少到一定程度。适宜溶剂的实例包括甲醇,乙醇,乙酸乙酯等。对在此阶段使用的酸的性质没有特别限制,并且这里可以平等地使用在这种类型的反应中通常采用的任何碱。这样的酸的实例包括乙酸或HCl,等。还原可以通过氢来实现,但是这里可以平等地使用在这种反应中采用的任何其它还原剂。精确的氢压力或精确的反应温度对于本发明不是关键的。反应可以在宽温度范围和宽氢气压力范围内进行。我们发现合宜的是,在从环境温度加热至回流的情况下,进行该反应。反应所需要的时间也可以广泛地变化,这取决于许多因素,值得注意的是反应温度和试剂的性质。但是,0.5h至几天的时间通常将足以得到吡啶衍生物II-A(m为1)。
由中间体XIII开始,可以将氯官能团通过与氨在宽范围的条件下反应而转变为相应的胺。但是,我们发现合宜的是,使XIII与氨在溶剂中或在没有溶剂的情况下,在铜或铜盐的存在或不存在下反应。对所采用的溶剂的性质没有特别限制,条件是它对反应或参加反应的试剂没有不利的影响,并且它可以溶解试剂至少到一定程度。适宜溶剂的实例包括甲醇,乙醇等。我们发现合宜的是,在从环境温度加热至250℃的情况下,进行该反应。反应所需要的时间也可以广泛地变化,这取决于许多因素,值得注意的是反应温度和试剂的性质。但是,0.5h至几天的时间通常将足以得到氨基吡啶衍生物II-C。对于进行这样的反应而在文献中描述的反应条件,参见例如:Comprehensive Organic Transformations:A Guide to Functional Group Preparations,2nd Edition,Richard C.Larock.John Wiley & Sons,New York,NY.1999
c)可以由适宜的原料,根据本领域中已知的方法,制备磺酰胺、酰胺、氨基甲酸酯和脲.II-A、II-B或II-C中的氨基部分到磺酰胺、酰胺、氨基甲酸酯和脲的转化可以由文献中描述的方法来进行.例如,胺衍生物II得到通式I的化合物的转化是通过在溶剂如二氯甲烷中并且在碱存在或不存在下,II分别与适宜的磺酰氯或氨磺酰氯(式III的化合物)或与酰氯、氯甲酸酯或者碳酸酯(式IV化合物),或与异氰酸酯(如上所定义的式V化合物)反应而进行的.式III、IV或V的化合物是可商购的或可以由已知的方法制备的.对所采用的溶剂的性质没有特别限制,条件是它对反应或参加反应的试剂没有不利的影响,并且它可以溶解试剂至少到一定程度.适宜溶剂的实例包括氯仿或二噁烷,THF等.对在此阶段使用的碱的性质没有特别限制,并且这里可以平等地使用在这种类型的反应中通常采用的任何碱.这样的碱的实例包括三乙胺和二异丙基乙胺等.反应可以在宽温度范围内进行,并且精确的反应温度对于本发明不是关键的.我们发现合宜的是,在从环境温度加热至回流的情况下,进行该反应.反应所需要的时间也可以广泛地变化,这取决于许多因素,值得注意的是反应温度和试剂的性质.但是,0.5h至几天的时间通常将足以得到式I的吡啶衍生物.对于进行这样的反应而在文献中描述的反应条件,参见例如:Comprehensive Organic Transformations:A Guideto Functional Group Preparations,2nd Edition,Richard C.Larock.JohnWiley & Sons,NewYork,NY.1999。
为了得到如上面所定义的其中R2为-NR3R4的式I化合物,可以在本领域技术人员已知的各种条件下活化II。但是,我们发现合宜的是,用氯甲酸苯酯活化式II中的胺官能团,以得到相应的式V的氨基甲酸苯酯。该反应可以在溶剂和/或碱的存在或不存在下进行。对采用的溶剂的性质没有特别限制,条件是它对反应或参加反应的试剂没有不利的影响,并且它可以溶解试剂至少到一定程度。适宜溶剂的实例包括二氯甲烷(DCM),氯仿,THF等。对在此阶段使用的碱的性质没有特别限制,并且这里可以平等地使用在这种类型的反应中通常采用的任何碱。这样的碱的实例包括三乙胺和二异丙基乙胺等。反应可以在宽温度范围内进行,并且精确的反应温度对于本发明不是关键的。我们发现合宜的是,在从环境温度加热至回流的情况下,进行该反应。反应所需要的时间也可以广泛地变化,这取决于许多因素,值得注意的是反应温度和试剂的性质。但是,0.5h至几天的时间通常将足以得到中间体氨基甲酸苯酯。随后,将反应混合物用式VI的胺(HNR3R4,如上面所定义)处理。反应可以在宽温度范围内进行,并且精确的反应温度对于本发明不是关键的。我们发现合宜的是,在从环境温度加热至回流的情况下,进行该反应。反应所需要的时间也可以广泛地变化,这取决于许多因素,值得注意的是反应温度和试剂的性质。但是,0.5h至几天的时间通常将足以得到式I的化合物。
d)其中R为低级烷基的式II-D化合物可以由N-(2-氯吡啶-4-基)乙酰胺(可商购)或者N-(4-氯吡啶-2-基)乙酰胺通过本领域中已知的烷基化方法来制备,例如通过在强碱如氢氧化钾存在下用烷基碘烷基化来制备。然后,得到的式XIV的N-烷基-乙酰胺衍生物与适宜的式XV的哌嗪类化合物反应,最后在强酸性条件(4N盐酸)下裂开乙酰基,得到式IIa的化合物,其中R为低级烷基(参见方案2)。
方案2
如上所述,本发明的式I化合物可作为药物用于治疗和/或预防与H3受体的调节相关的疾病。这类疾病的实例有肥胖症,代谢综合征(X综合征),神经疾病包括早老性痴呆,痴呆,与年龄相关的记忆功能障碍、轻度认知损伤,认知缺陷,注意缺陷多动障碍,癫痫,神经性疼痛,炎性疼痛,偏头痛,帕金森病,多发性硬化,中风,头晕,精神分裂症,抑郁,成瘾,晕动症和睡眠障碍,包括嗜眠病,和其它疾病,包括哮喘,变态反应,变态反应诱导的气道反应,充血,慢性阻塞性肺病和胃肠病症。优选作为治疗和/或预防肥胖症的药物的应用。
本发明因此还涉及药物组合物,其包含如上定义的化合物和药用载体和/或辅药。
此外,本发明涉及如上定义的化合物,其用作治疗活性物质,特别是作为用于治疗和/或预防与H3受体的调节有关的疾病的治疗活性物质。这些疾病的实例有肥胖症,代谢综合征(X综合征),神经系统疾病,包括早老性痴呆,痴呆,年龄相关的记忆功能障碍,轻度认知损伤,认知缺陷,注意缺陷多动障碍,癫痫,神经性疼痛,炎性疼痛,偏头痛,帕金森病,多发性硬化,中风,头晕,精神分裂症,抑郁,成瘾,晕动症和睡眠障碍,包括嗜眠病,和其它疾病,包括哮喘,变态反应,变态反应诱导的气道反应,充血,慢性阻塞性肺病和胃肠病症。
在另一个实施方案中,本发明涉及一种治疗和/或预防与H3受体的调节有关的疾病的方法。这些疾病的实例有肥胖症,代谢综合征(X综合征),神经系统疾病,包括早老性痴呆,痴呆,年龄相关的记忆功能障碍,轻度认知损伤,认知缺陷,注意缺陷多动障碍,癫痫,神经性疼痛,炎性疼痛,偏头痛,帕金森病,多发性硬化,中风,头晕,精神分裂症,抑郁,成瘾,晕动症和睡眠障碍,包括嗜眠病,和其它疾病,包括哮喘,变态反应,变态反应诱导的气道反应,充血,慢性阻塞性肺病和胃肠病症。治疗和/或预防肥胖症的方法是优选的。
本发明另外涉及如上定义的式I化合物在治疗和/或预防与H3受体的调节有关的疾病中的应用.这些疾病的实例有肥胖症,代谢综合征(X综合征),神经系统疾病,包括早老性痴呆,痴呆,年龄相关的记忆功能障碍,轻度认知损伤,认知缺陷,注意缺陷多动障碍,癫痫,神经性疼痛,炎性疼痛,偏头痛,帕金森病,多发性硬化,中风,头晕,精神分裂症,抑郁,成瘾,晕动症和睡眠障碍,包括嗜眠病,和其它疾病,包括哮喘,变态反应,变态反应诱导的气道反应,充血,慢性阻塞性肺病和胃肠病症.如上定义的式I化合物在治疗和/或预防肥胖症中的应用是优选的.
另外,本发明涉及如上定义的式I化合物在制备药物中的应用,所述药物用于治疗和/或预防与H3受体的调节有关的疾病。这些疾病的实例有肥胖症,代谢综合征(X综合征),神经系统疾病,包括早老性痴呆,痴呆,年龄相关的记忆功能障碍,轻度认知损伤,认知缺陷,注意缺陷多动障碍,癫痫,神经性疼痛,炎性疼痛,偏头痛,帕金森病,多发性硬化,中风,头晕,精神分裂症,抑郁,成瘾,晕动症和睡眠障碍,包括嗜眠病,和其它疾病,包括哮喘,变态反应,变态反应诱导的气道反应,充血,慢性阻塞性肺病和胃肠病症。如上定义的式I化合物在制备用于治疗和/或预防肥胖症的药物中的应用是优选的。
式I化合物和它们的药用盐具有有价值的药理学性质。特别地,已经发现本发明的化合物是良好的组胺3受体(H3R)拮抗剂和/或反向激动剂。
进行下列试验以测定式(I)化合物的活性。
与
3
H-(R)α-甲基组胺的结合测定
使用HR3-CHO膜进行饱和结合实验,如Takahashi,K,Tokita,S.,Kotani,H.(2003)J.Pharmacol.Exp.Therapeutics 307,213-218所述制备所述HR3-CHO膜。
将适当量的膜(60至80μg蛋白/孔)与递增浓度的3H(R)α-甲基组胺二盐酸盐(0.10至10nM)温育。使用200倍过量的冷(R)α-甲基组胺二氢溴酸盐(500nM终浓度)来测定非特异性结合。在室温下进行温育(在深-孔平板中振荡3小时)。每孔中的终体积为250μl。温育后接着在GF/B滤器(用100μl的在Tris 50mM中的0.5%PEI预先浸透,在200rpm振荡2小时)上快速过滤。使用细胞收获器进行过滤,然后将滤板用冰冷的含有0.5M NaCl的洗涤缓冲液洗涤5次。在收获后,将该板在55℃干燥60分钟,然后我们加入闪烁液(Microscint 40,每孔40μl),在室温下在200rpm振荡平板2小时后,在Packard top-counter中测定滤器上的放射量。
结合缓冲液:50mM Tris-HCl pH 7.4和5mM MgCl2x 6H2O pH 7.4。洗涤缓冲液:50mM Tris-HCl pH 7.4和5mM MgCl2x6H2O和0.5M NaClpH 7.4。
H3R反向激动剂的亲和力的间接测量:12个递增浓度(范围从10μM至0.3nM)的所选化合物始终在使用人HR3-CHO细胞系的膜的竞争结合实验中测试。适量的蛋白,例如约500cpm在Kd结合的RAMH,以250μl的终体积在96-孔板中在3H(R)α-甲基组胺(1nM终浓度=Kd)的存在下室温温育1小时。使用200倍过量的冷(R)α-甲基组胺二氢溴酸盐来测定非特异性结合。
所有化合物在单一浓度下一式两份进行测试。显示[3H]-RAMH的抑制超过50%的化合物再次进行试验以在系列稀释实验中测定IC50。Ki′s由IC50基于Cheng-Prusoff方程式的IC50计算(Cheng,Y,Prusoff,WH(1973)Biochem Pharmacol 22,3099-3108)。
本发明的化合物显示的Ki值的范围为约1nM至约1000nM,优选约1nM至约100nM,更优选约1nM至约30nM。下表显示本发明的一些选择的化合物的测量值。
下表显示本发明的一些选择的化合物的测量值。
K<sub>i</sub>(nM) | |
实施例11 | 8.5 |
实施例48 | 76.7 |
实施例66 | 48.6 |
式(I)的化合物和它们的药用盐和酯可用作药物,例如以药物制剂形式用于经肠的、肠胃外或局部给药。它们可以这样给药,例如经口给药,其形式如片剂、包衣片剂、糖锭剂、硬和软明胶胶囊、溶液剂、乳剂或混悬剂;直肠给药,如以栓剂形式;肠胃外给药,如以注射液或输液形式;或者局部给药,如以软膏剂、乳膏剂或油剂形式。
药物制剂的制备可以是以本领域技术人员熟悉的方式进行的,将所述的式(I)化合物及其可药用的及合适的、非毒性的、惰性的、治疗相容的固体或液体载体物质以及如果需要,与普通的药物辅药一起制成盖仑给药形式。
合适的载体材料不仅有无机载体材料,而且有有机载体材料。因此,可以使用例如乳糖、玉米淀粉或其衍生物、滑石、硬脂酸或其盐作为用于片剂、包衣片剂、糖锭剂和硬明胶胶囊的载体材料。软明胶胶囊的合适载体材料为,例如植物油、蜡、脂肪以及半固体和液体多元醇(但是,根据活性成分的性质,软明胶胶囊可能不需要载体)。制备溶液或糖浆的合适载体材料为,例如水、多元醇、蔗糖,转化糖等。注射液的合适载体材料为,例如水,醇类,多元醇,甘油和植物油。栓剂的合适载体材料为,例如天然或硬化油、蜡、脂肪和半液体或液体多元醇。局部制剂的合适载体材料为甘油酯类、半合成和合成甘油酯类、氢化油、液态蜡、液体石蜡、液态脂肪醇、甾醇类、聚乙二醇和纤维素衍生物。
可考虑使用常用的稳定剂、防腐剂、湿润和乳化剂、稠度改善剂、增香剂、用于改变渗透压的盐、缓冲物质、增溶剂、着色剂以及掩蔽剂和抗氧化剂作为药物辅药。
根据所要控制的疾病、患者的年龄和个体状况以及给药方式,式(I)化合物的剂量可以在宽的限度内变化,当然,在每个具体病例中将和个体需求相适合。对于成年患者,可考虑的日剂量为约1mg到约1000mg,特别是约1mg到约100mg。根据剂量,将日剂量以数个剂量单位施用是方便的。
药物制剂方便地包含约0.1-500mg、优选0.5-100mg的式(I)化合物。
如下实施例用于更详细地说明本发明。然而,它们不意在以任何方式限制本发明的范围。
实施例
中间体1
1-乙基-4-(4-硝基-吡啶-2-基)-哌嗪
将2g(13mmol)2-氯-4-硝基吡啶,1.73g(15mmol)1-乙基-哌嗪和0.81g(6mmol)N,N-二异丙基乙基胺(DIPEA)在19ml DMF和20ml水中的混合物加热至100℃24h.将沉淀滤出,用4ml的水洗涤3次,并且真空下干燥24h,得到2.03g(68%)的标题化合物,为黄色油(m/e):236.7(MH+;100%)。
中间体2
2-(4-乙基-哌嗪-1-基)-吡啶-4-基胺
将2.03g(9mmol)1-乙基-4-(4-硝基-吡啶-2-基)-哌嗪在30ml甲醇中的溶液用0.052g Pd/C,1巴的氢气于室温氢化3h。将混合物过滤并且蒸发至干燥,得到标题化合物,为黄色固体,其在没有进一步纯化下使用(m/e):207.1(MH+;100%)。
中间体3
1-环戊基-4-(4-硝基-吡啶-2-基)-哌嗪
和中间体4
1-(2-氯-吡啶-4-基)-4-环戊基-哌嗪
将5.6g(35mmol)2-氯-4-硝基吡啶,5.75g(37mmol)1-环-戊基哌嗪和4,59g(35mmol)N,N-二异丙基乙基胺在35ml DMF和12ml水中的混合物加热至95℃3h。在蒸发至干燥之后,将剩余物放入150ml NaHCO3水溶液和150ml乙酸乙酯中。将水相每次用150ml乙酸乙酯萃取2次,并且将合并的有机相每次用100ml NaHCO3水溶液洗涤2次,并且用100ml NaCl饱和水溶液洗涤,用MgSO4干燥,并且蒸发至干燥。将剩余物通过柱色谱纯化,得到2.85g(29%)1-环戊基-4-(4-硝基-吡啶-2-基)-哌嗪(m/e):277.3(MH+;100%)和4.47g(47%)1-(2-氯-吡啶-4-基)-4-环戊基-哌嗪(m/e):266.3(MH+;100%)。
中间体5
2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺
2.85g(10mmol)1-环戊基-4-(4-硝基-吡啶-2-基)-哌嗪和0.285g Pd/C(10%)在25ml甲醇中的混合物用1巴的氢气于室温处理3h。过滤后将混合物蒸发至干燥,得到2.34g(92%)的标题化合物,为微褐色固体。(m/e):247.4(MH+;100%)。
中间体6
4-(4-环戊基-哌嗪-1-基)-吡啶-2-基胺
将5.84g(22mmol)1-(2-氯-吡啶-4-基)-4-环戊基-哌嗪,0.8g铜粉在41ml在甲醇中的7M氨中的的混合物加热至150℃18h。在蒸发至干燥后,将剩余物由用二氯甲烷/甲醇和NEt3形成的梯度洗脱的二氧化硅纯化。混合产物级分的蒸发得到1.29g(24%)的标题化合物,为微褐色固体。(m/e):247.3(MH+;100%)。
中间体7
2-(4-环戊基-哌嗪-1-基)-异烟腈
将2g(14mmol)2-氯-4-氰基吡啶和2.34g(15mmol)1-环戊基哌嗪在5ml DMF中的混合物加热至80℃16h。将混合物在减压下蒸发,并且将剩余物用100ml1M NaHCO3水溶液处理,并且用100ml乙酸乙酯萃取2次。将合并的有机相用MgSO4干燥,并且在减压下蒸发,得到3.4g(92%)的标题化合物,为灰色固体。(m/e):257.3(MH+;100%)。
中间体8
C-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基胺
将在10ml甲醇中的2.8g(11mmol)2-(4-环戊基-哌嗪-1-基)-异烟腈、15ml乙酸乙酯和5ml氨的溶液用阮内镍,用1巴的氢气于30℃氢化4h.将混合物过滤,并且将剩余物用20ml乙酸乙酯洗涤3次.在有机相蒸发之后,将剩余物由反相制备HPLC纯化,合并的产物级分蒸发后得到1.21g(42%)的标题化合物,为黄色固体.(m/e):261.3(MH+;100%)。
实施例1
1-[2-(4-乙基-哌嗪-1-基)-吡啶-4-基]-3-丙基-脲
将20.6mg(0.1mmol)2-(4-乙基-哌嗪-1-基)-吡啶-4-基胺、15mg(0.15mmol)三乙胺和9.4mg(0.11mmol)1-异氰酸根合-丙烷在1ml二氯甲烷中的混合物于室温搅拌16h。蒸发之后,将剩余物放入1ml甲醇/乙腈1/1中,并且经过用乙腈/水(0.05%三乙胺)梯度洗脱的反相制备HPLC。将合并的产物级分蒸发至干燥,得到7.2mg(25%)的标题化合物.(m/e):292.3(MH+;100%)。
根据用于合成实施例1所述的程序,分别由中间体2、5、6和8和表1中列出的可商购试剂合成出了另外的吡啶衍生物。实施例汇编于表1中,并且包括实施例2至实施例56。
表1
No | MW | 名称 | 原料 | MH<sup>+</sup>实测 |
2 | 262.36 | N-[2-(4-乙基-哌嗪-1-基)-吡啶-4-基]-丙酰胺 | 2-(4-乙基-哌嗪-1-基)-吡啶-4-基胺(中间体2)和丙酰氯 | 263.1 |
3 | 276.38 | N-[2-(4-乙基-哌嗪-1-基)-吡啶-4-基]-丁酰胺 | 2-(4-乙基-哌嗪-1-基)-吡啶-4-基胺(中间体2)和丁酰氯 | 277.3 |
4 | 360.48 | N-[2-(4-乙基-哌嗪-1-基)-吡啶-4-基]-C-苯基-甲磺酰胺 | 2-(4-乙基-哌嗪-1-基)-吡啶-4-基胺(中间体2)和苯基-甲磺酰氯 | 361.3 |
5 | 394.92 | C-(4-氯-苯基)-N-[2-(4-乙基-哌嗪-1-基)-吡啶-4-基]-甲磺酰胺 | 2-(4-乙基-哌嗪-1-基)-吡啶-4-基胺(中间体2)和(4-氯-苯基)-甲磺酰氯 | 395.2 |
6 | 364.44 | N-[2-(4-乙基-哌嗪-1-基)-吡啶-4-基]-3-氟-苯磺酰胺 | 2-(4-乙基-哌嗪-1-基)-吡啶-4-基胺(中间体2)和3-氟-苯磺酰氯 | 365.1 |
No | MW | 名称 | 原料 | MH<sup>+</sup>实测 |
7 | 380.9 | 4-氯-N-[2-(4-乙基-哌嗪-1-基)-吡啶-4-基]-苯磺酰胺 | 2-(4-乙基-哌嗪-1-基)-吡啶-4-基胺(中间体2)和4-氯-苯磺酰氯 | 381.3 |
8 | 397.5 | 1-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-3-(4-氟-苄基)-脲 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和1-氟-4-异氰酸甲酯基-苯 | 398.4 |
9 | 302.42 | N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-丙酰胺 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和丙酰氯 | 303.2 |
No | MW | 名称 | 原料 | MH<sup>+</sup>实测 |
10 | 316.45 | N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-丁酰胺 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和丁酰氯 | 317.2 |
11 | 356.51 | 环己烷羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和环己烷碳酰氯 | 357.3 |
12 | 380.49 | N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-3-甲氧基-苯甲酰胺 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和3-甲氧基-苯甲酰氯 | 381.3 |
13 | 434.99 | C-(4-氯-苯基)-N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲磺酰胺 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和(4-氯-苯基)-甲磺酰氯 | 435.4 |
No | MW | 名称 | 原料 | MH<sup>+</sup>实测 |
14 | 314.43 | 环丙烷羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和环丙烷碳酰氯 | 315.2 |
15 | 328.46 | 环丁烷羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和环丁烷碳酰氯 | 329.4 |
16 | 342.49 | 环戊烷羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和环戊烷碳酰氯 | 343.3 |
17 | 344.5 | N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-2-乙基-丁酰胺 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和2-乙基-丁酰氯 | 345.3 |
18 | 368.46 | N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-2-氟-苯甲酰胺 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和2-氟-苯甲酰氯 | 369.2 |
No | MW | 名称 | 原料 | MH<sup>+</sup>实测 |
19 | 368.46 | N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-4-氟-苯甲酰胺 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和4-氟-苯甲酰氯 | 369.2 |
20 | 380.49 | N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-2-甲氧基-苯甲酰胺 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和2-甲氧基-苯甲酰氯 | 381.4 |
21 | 385.9 | 2-氯-N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-烟酰胺 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和2-氯-烟酰氯 | 386.3 |
No | MW | 名称 | 原料 | MH<sup>+</sup>实测 |
22 | 364.49 | N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-2-苯基-乙酰胺 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和苯基乙酰氯 | 365.4 |
23 | 382.48 | N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-2-(4-氟-苯基)-乙酰胺 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和(4-氟-苯基)-乙酰氯 | 383.4 |
24 | 394.52 | N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-2-(3-甲氧基-苯基)-乙酰胺 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和(3-甲氧基-苯基)-乙酰氯 | 395.3 |
25 | 346.47 | [2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-氨基甲酸异丁酯 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和氯甲酸异丁酯 | 347.2 |
26 | 331.46 | 1-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-3-丙基-脲 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和1-异氰酸根合-丙烷 | 332.3 |
No | MW | 名称 | 原料 | MH<sup>+</sup>实测 |
27 | 371.53 | 1-环己基-3-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-脲 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和1-异氰酸根合-环己烷 | 372.3 |
28 | 330.48 | N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基甲基]-丁酰胺 | C-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基胺(中间体8)和丙酰氯 | 331.5 |
No | MW | 名称 | 原料 | MH<sup>+</sup>实测 |
29 | 370.54 | 环己烷羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基甲基]-酰胺 | C-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基胺(中间体8)和环己烷碳酰氯 | 357.4 |
30 | 378.52 | N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基甲基]-2-苯基-乙酰胺 | C-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基胺(中间体8)和苯基乙酰氯 | 379.3 |
31 | 382.48 | N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基甲基]-4-氟-苯甲酰胺 | C-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基胺(中间体8)和4-氟-苯甲酰氯 | 383.3 |
32 | 455.05 | 2-(4-氯-苯基)-N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基甲基]-3-甲基-丁酰胺 | C-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基胺(中间体8)和2-(4-氯-苯基)-3-甲基-丁酰氯 | 455.6 |
33 | 345.49 | 1-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基甲基]-3-丙基-脲 | C-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基胺(中间体8)和1-异氰酸根合-丙烷 | 346.3 |
No | MW | 名称 | 原料 | MH<sup>+</sup>实测 |
34 | 385.56 | 1-环己基-3-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基甲基]-脲 | C-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基胺(中间体8)和1-异氰酸根合-环己烷 | 386.4 |
No | MW | 名称 | 原料 | MH<sup>+</sup>实测 |
35 | 393.53 | 1-苄基-3-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基甲基]-脲 | C-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基胺(中间体8)和异氰酸甲酯基-苯 | 394.1 |
36 | 366.53 | 丙烷-1-磺酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基甲基]-酰胺 | C-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基胺(中间体8)和丙烷-1-磺酰氯 | 368.1 |
37 | 367.52 | 二甲胺-1-磺酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基甲基]-酰胺 | C-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基胺(中间体8)和二甲氨基-1-磺酰氯 | 367.3 |
38 | 449.02 | C-(4-氯-苯基)-N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基甲基]-甲磺酰胺 | C-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基胺(中间体8)和(4-氯-苯基)-甲磺酰氯 | 449 |
39 | 400.54 | N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基甲基]-苯磺酰胺 | C-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基胺(中间体8)和苯磺酰氯 | 401.1 |
40 | 302.42 | N-[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-丙酰胺 | 4-(4-环戊基-哌嗪-1-基)-吡啶-2-基胺(中间体6)和丙酰氯 | 303.4 |
No | MW | 名称 | 原料 | MH<sup>+</sup>实测 |
No | MW | 名称 | 原料 | MH<sup>+</sup>实测 |
41 | 314.43 | 环丙烷羧酸[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-酰胺 | 4-(4-环戊基-哌嗪-1-基)-吡啶-2-基胺(中间体6)和环丙烷碳酰氯 | 315.2 |
42 | 316.45 | N-[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-丁酰胺 | 4-(4-环戊基-哌嗪-1-基)-吡啶-2-基胺(中间体6)和丁酰氯 | 317.3 |
43 | 318.42 | N-[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-2-甲氧基-乙酰胺 | 4-(4-环戊基-哌嗪-1-基)-吡啶-2-基胺(中间体6)和甲氧基-乙酰氯 | 319.3 |
44 | 342.49 | 环戊烷羧酸[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-酰胺 | 4-(4-环戊基-哌嗪-1-基)-吡啶-2-基胺(中间体6)和环戊烷碳酰氯 | 343.3 |
45 | 344.5 | N-[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-2-乙基-丁酰胺 | 4-(4-环戊基-哌嗪-1-基)-吡啶-2-基胺(中间体6)和2-乙基-丁酰氯 | 345.3 |
46 | 356.51 | 环己烷羧酸[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-酰胺 | 4-(4-环戊基-哌嗪-1-基)-吡啶-2-基胺(中间体6)和环己烷碳酰氯 | 357.3 |
47 | 368.46 | N-[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-2-氟-苯甲酰胺 | 4-(4-环戊基-哌嗪-1-基)-吡啶-2-基胺(中间体6)和2-氟-苯甲酰氯 | 369.2 |
48 | 368.46 | N-[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-3-氟-苯甲酰胺 | 4-(4-环戊基-哌嗪-1-基)-吡啶-2-基胺(中间体6)和3-氟-苯甲酰氯 | 369.2 |
49 | 368.46 | N-[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-4-氟-苯甲酰胺 | 4-(4-环戊基-哌嗪-1-基)-吡啶-2-基胺(中间体6)和4-氟-苯甲酰氯 | 369.2 |
No | MW | 名称 | 原料 | MH<sup>+</sup>实测 |
No | MW | 名称 | 原料 | MH<sup>+</sup>实测 |
50 | 380.49 | N-[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-2-甲氧基-苯甲酰胺 | 4-(4-环戊基-哌嗪-1-基)-吡啶-2-基胺(中间体6)和2-甲氧基-苯甲酰氯 | 381.4 |
51 | 380.49 | N-[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-3-甲氧基-苯甲酰胺 | 4-(4-环戊基-哌嗪-1-基)-吡啶-2-基胺(中间体6)和3-甲氧基-苯甲酰氯 | 381.4 |
52 | 380.49 | N-[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-4-甲氧基-苯甲酰胺 | 4-(4-环戊基-哌嗪-1-基)-吡啶-2-基胺(中间体6)和4-甲氧基-苯甲酰氯 | 381.4 |
53 | 385.9 | 2-氯-N-[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-烟酰胺 | 4-(4-环戊基-哌嗪-1-基)-吡啶-2-基胺(中间体6)和2-氯-烟酰氯 | 386.3 |
54 | 348.45 | [4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-氨基甲酸2-甲氧基-乙酯 | 4-(4-环戊基-哌嗪-1-基)-吡啶-2-基胺(中间体6)和氯甲酸-2-甲氧基乙酯 | 349.4 |
55 | 395.51 | 1-[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-3-(2-甲氧基-苯基)-脲 | 4-(4-环戊基-哌嗪-1-基)-吡啶-2-基胺(中间体6)和1-异氰酸根合-2-甲氧基-苯 | 295.33 |
No | MW | 名称 | 原料 | MH<sup>+</sup>实测 |
56 | 393.53 | 1-[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-3-(1-苯基-乙基)-脲 | 4-(4-环戊基-哌嗪-1-基)-吡啶-2-基胺(中间体6)和(1-异氰酸根合-乙基)-苯 | 394.2 |
实施例57
3-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-1,1-二乙基-脲
将0.18g(0.73mmol)2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺0.12g(0.74mmol)氯甲酸苯酯和0.11g(1.4mmol)吡啶在6ml二氯甲烷中的混合物于室温反应1.5h,并且将立即生成的[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-氨基甲酸苯酯((m/e):367.4(MH+;100%))在没有进一步纯化下使用。将1ml的该溶液与26.7mg(0.36mmol)二乙胺混合物,并且于室温反应16h。在所有挥发物蒸发之后,将剩余物放入乙腈/DMF中,并且经过用乙腈/水/NEt3梯度反相洗脱的反相制备HPLC纯化,产物级分蒸发之后,得到10.8mg(53%)的标题化合物(m/e):346.5(MH+;100%)。
根据用于合成实施例57所述的程序(用氯甲酸苯酯的活化),分别由中间体2、5、6和8和表2中列出的可商购试剂合成出了另外的吡啶衍生物。实施例汇编于表2中,并且包括实施例58至实施例81。
表2
No | MW | 名称 | 原料 | MH<sup>+</sup>实测 |
58 | 357.5 | 哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和哌啶 | 358.1 |
59 | 359.47 | 吗啉-4-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和吗啉 | 360.5 |
60 | 343.47 | 吡咯烷-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和吡咯烷 | 344.1 |
No | MW | 名称 | 原料 | MH<sup>+</sup>实测 |
61 | 393.48 | 4,4-二氟-哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和4,4-二氟-哌啶 | 394.1 |
No | MW | 名称 | 原料 | MH<sup>+</sup>实测 |
62 | 371.53 | 2-甲基-哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和2-甲基哌啶 | 372.3 |
63 | 371.53 | 3-甲基-哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和3-甲基哌啶 | 372.3 |
64 | 371.53 | 4-甲基-哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和4-甲基哌啶 | 372.3 |
65 | 385.56 | 2,6-二甲基-哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和2,6-二甲基哌啶 | 386.3 |
66 | 375.49 | 4-氟-哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和4-氟-哌啶 | 376.4 |
67 | 393.48 | 3,3-二氟-哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和3,3-二氟-哌啶 | 394.4 |
68 | 425.5 | 4-三氟甲基-哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和4-三氟甲基-哌啶 | 426.3 |
No | MW | 名称 | 原料 | MH<sup>+</sup>实测 |
69 | 411.59 | 八氢-喹啉-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和十氢-喹啉 | 412.5 |
70 | 411.59 | 八氢-异喹啉-2-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和十氢-异喹啉 | 412.5 |
No | MW | 名称 | 原料 | MH<sup>+</sup>实测 |
71 | 405.55 | 3,4-二氢-2H-喹啉-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和1,2,3,4-四氢-喹啉 | 406.4 |
72 | 405.55 | 3,4-二氢-1H-异喹啉-2-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和1,2,3,4-四氢-异喹啉 | 406.4 |
73 | 357.5 | 2-甲基-吡咯烷-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和2-甲基-吡咯烷 | 358.5 |
74 | 411.47 | 2-三氟甲基-吡咯烷-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和2-三氟甲基-吡咯烷 | 412.4 |
No | MW | 名称 | 原料 | MH<sup>+</sup>实测 |
75 | 385.56 | 2-异丙基-吡咯烷-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和2-异丙基-吡咯烷 | 386.4 |
76 | 391.52 | 1,3-二氢-异吲哚-2-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和2,3-二氢-1H-异吲哚 | 392.3 |
77 | 391.52 | 2,3-二氢-吲哚-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和2,3-二氢-1H-吲哚 | 392.2 |
No | MW | 名称 | 原料 | MH<sup>+</sup>实测 |
78 | 389.54 | 3-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-1-异丙基-1-(2-甲氧基-乙基)-脲 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和异丙基-(2-甲氧基-乙基)-胺 | 390.4 |
79 | 371.53 | 氮杂环庚烷-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和氮杂环庚烷 | 372.3 |
80 | 393.53 | 3-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-1-乙基-1-苯基-脲 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和乙基-苯基-胺 | 394.4 |
81 | 409.53 | 3-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-1-(4-甲氧基-苯基)-1-甲基-脲 | 2-(4-环戊基-哌嗪-1-基)-吡啶-4-基胺(中间体5)和(4-甲氧基-苯基)-甲基-胺 | 410.4 |
中间体9
2-(4-异丙基-哌嗪-1-基)-吡啶-4-基胺
a)步骤1:N-[2-(4-异丙基-哌嗪-1-基)-吡啶-4-基]-乙酰胺
将4.6g(27mmol)N-(2-氯吡啶-4-基)乙酰胺(可商购)和5.2g(41mmol)1-(2-丙基-)-哌嗪在2ml DMF中的混合物加热至150℃4h。粗产物通过用DCM(1%NEt3)和甲醇形成的梯度洗脱的二氧化硅快速柱色谱法纯化,产物级分蒸发后,得到3.38g(47%)的标题化合物,为白色固体。MS:(m/e):263.4(MH+)。
b)步骤2:2-(4-异丙基-哌嗪-1-基)-吡啶-4-基胺
将2.1g(8mmol)N-[2-(4-异丙基-哌嗪-1-基)-吡啶-4-基]-乙酰胺和10.5ml 4N HCl在25ml二噁烷中的混合物加热至100℃2h。在所有挥发物蒸发之后,将剩余物用水和NaHCO3饱和水溶液处理,并且用DCM萃取。将合并的有机层用NaCl饱和水溶液洗涤,用MgSO4干燥,并且蒸发。将剩余物与DCM一起研磨,并且干燥,得到1g(57%)的标题化合物,为白色固体。MS:(m/e):221.3(MH+)。
实施例82
环己烷羧酸[2-(4-异丙基-哌嗪-1-基)-吡啶-4-基]-酰胺
根据用于合成实施例1所述的程序,由2-(4-异丙基-哌嗪-1-基)-吡啶-4-基胺(中间体9)和环己烷碳酰氯(可商购)合成标题化合物。MS:(m/e):331.1(MH+)。
实施例82
3-甲基-环己烷羧酸[2-(4-异丙基-哌嗪-1-基)-吡啶-4-基]-酰胺
根据用于合成实施例1所述的程序,由2-(4-异丙基-哌嗪-1-基)-吡啶-4-基胺(中间体9)和3-甲基-环己烷碳酰氯(可商购)合成标题化合物。MS:(m/e):345.2(MH+)。
中间体10
[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基-胺盐酸盐
a)步骤1:N-(2-氯-吡啶-4-基)-N-甲基-乙酰胺
将10g(59mmol)N-(2-氯吡啶-4-基)乙酰胺(可商购),9.8g(17.6mmol)粉碎的KOH和4.1ml(6.4mmol)甲基碘在60ml丙酮中的混合物于室温搅拌2h。在所有挥发物蒸发之后,将剩余物放入水中,并且用乙酸乙酯萃取。将合并的有机层用MgSO4干燥,并且蒸发,得到7.1g(66%)的标题化合物,为灰白色固体。MS:(m/e):345.2(MH+)。
b)步骤2:N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-N-甲基-乙酰胺
将4g(22mmol)N-(2-氯-吡啶-4-基)-N-甲基-乙酰胺和3.5g(23mmol)1-(环戊基)-哌嗪的混合物加热至120℃24h。粗产物通过用庚烷和乙酸乙酯(0.1%NEt3)形成的梯度洗脱的二氧化硅快速柱色谱法纯化,产物级分蒸发后得到3.3g(50%)的标题化合物,为淡褐色油。MS:(m/e):303.3(MH+)。
c)步骤3:[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基-胺盐酸盐
将3.3g(11mmol)N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-N-甲基-乙酰胺和12ml 4N HCl在5ml水和25ml二噁烷中的混合物于室温搅拌。在挥发物蒸发之后,将剩余物与由丙酮和二噁烷形成的混合物一起研磨,并且在真空下干燥,得到2.3g(72%)的标题化合物(中间体10),为灰白色固体。MS:(m/e):261.2(MH+)。
实施例84
环戊烷羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基-酰胺
根据用于合成实施例1所述的程序,由[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基-胺;盐酸盐(中间体10)和环戊烷碳酰氯(可商购)合成标题化合物。MS:(m/e):357.1(MH+)。
实施例85
3-甲基-环己烷羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基-酰胺
根据用于合成实施例1所述的程序,由[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基-胺;盐酸盐(中间体10)和3-甲基-环己烷碳酰氯(可商购)合成标题化合物。MS:(m/e):385.2(MH+)。
实施例86
环己烷羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基-酰胺
根据用于合成实施例1所述的程序,由[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基-胺盐酸盐(中间体10)和环己烷碳酰氯(可商购)合成标题化合物。MS:(m/e):371.2(MH+)。
中间体11
[2-(4-异丙基-哌嗪-1-基)-吡啶-4-基]-甲基-胺盐酸盐
a)步骤1:N-[2-(4-异丙基-哌嗪-1-基)-吡啶-4-基]-N-甲基-乙酰胺
将4g(22mmol)N-(2-氯-吡啶-4-基)-N-甲基-乙酰胺和2.8g(22mmol)1-(2-丙基)-哌嗪的混合物加热至120℃24h。粗产物由庚烷和乙酸乙酯(0.1%NEt3)形成的梯度洗脱的二氧化硅快速柱色谱纯化,产物级分蒸发之后,得到2.5g(41%)的标题化合物,为淡褐色油。MS:(m/e):277.2(MH+)。
b)步骤2:[2-(4-异丙基-哌嗪-1-基)-吡啶-4-基]-甲基-胺盐酸盐
将2.5g(9mmol)N-[2-(4-异丙基-哌嗪-1-基)-吡啶-4-基]-N-甲基-乙酰胺和10ml 4N HCl在5ml水和25ml二噁烷中的混合物于室温搅拌。在挥发物蒸发之后,将剩余物与由丙酮和二噁烷形成的混合物一起研磨,并且在真空下干燥,得到1.8g(76%)的标题化合物(中间体11),为淡红色固体。MS:(m/e):235.2(MH+)。
实施例87
3-甲基-环己烷羧酸[2-(4-异丙基-哌嗪-1-基)-吡啶-4-基]-甲基-酰胺
根据用于合成实施例1所述的程序,由[2-(4-异丙基-哌嗪-1-基)-吡啶-4-基]-甲基-胺盐酸盐(中间体11)和3-甲基-环己烷碳酰氯(可商购)合成标题化合物。MS:(m/e):359.2(MH+)。
实施例88
环己烷羧酸[2-(4-异丙基-哌嗪-1-基)-吡啶-4-基]-甲基-酰胺
根据用于合成实施例1所述的程序,由[2-(4-异丙基-哌嗪-1-基)-吡啶-4-基]-甲基-胺盐酸盐(中间体11)和环己烷碳酰氯(可商购)合成标题化合物。MS:(m/e):345.1(MH+)。
实施例89
哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基-酰胺
将20mg(0.08mmol)[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基-胺盐酸盐(中间体10),46mg(0.08mmol)双光气和31mg(0.3mmol)NEt3在1mlTHF中的混合物用43mg(0.5mmol)哌啶(可商购)处理,并且于室温搅拌30min。在所有挥发物蒸发之后,将剩余物放入甲醇/DMF中,并且经过由用乙腈/水(0.05%三乙胺)梯度洗脱的反相制备HPLC纯化。将合并的产物级分蒸发至干燥,得到15mg(52%)的标题化合物,为白色固体。MS(m/e):372.1(MH+;100%)。
实施例90
吡咯烷-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基-酰胺
根据用于合成实施例89所述的程序,由[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基-胺盐酸盐(中间体10),双光气和吡咯烷(可商购)合成标题化合物。MS(m/e):358.0(MH+;100%)。
实施例91
4,4-二氟-哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基-酰胺
根据用于合成实施例89所述的程序,由[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基-胺盐酸盐(中间体10),双光气和4,4-二氟-哌啶(可商购)合成标题化合物。MS(m/e):408.3(MH+;100%)。
实施例92
3-环己基-1-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-1-甲基-脲
根据用于合成实施例1所述的程序,由[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基-胺盐酸盐(中间体10)和异氰酸根合-环己烷(可商购)合成标题化合物。MS:(m/e):386.4(MH+)。
实施例93
3-环戊基-1-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-1-甲基-脲
根据用于合成实施例1所述的程序,由[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基-胺盐酸盐(中间体10)和异氰酸根合-环戊烷(可商购)合成标题化合物。MS:(m/e):372.3(MH+)。
实施例A
可以以常规方式制备含有下列成分的薄膜包衣片剂:
成分 每片
核:
式(I)化合物 10.0mg 200.0mg
微晶纤维素 23.5mg 43.5mg
无水乳糖 60.0mg 70.0mg
聚乙烯吡咯烷酮K30 12.5mg 15.0mg
淀粉羟乙酸钠 12.5mg 17.0mg
硬脂酸镁 1.5mg 4.5mg
(核重) 120.0mg 350.0mg
薄膜包衣
羟丙基甲基纤维素 3.5mg 7.0mg
聚乙二醇6000 0.8mg 1.6mg
滑石 1.3mg 2.6mg
氧化铁(Iron oxyde)(黄色) 0.8mg 1.6mg
二氧化钛 0.8mg 1.6mg
筛分活性成分,与微晶纤维素混和,将混合物与聚乙烯吡咯烷酮的水溶液制粒。将颗粒与淀粉羟乙酸钠和硬脂酸镁混和并且压制,分别获得120或350mg的核。将所述核用上述薄膜包衣的水溶液/悬浮液包衣。
实施例B
可以以常规方式制备含有下列成分的胶囊:
成分 每胶囊
式(I)化合物 25.0mg
乳糖 150.0mg
玉米淀粉 20.0mg
滑石 5.0mg
筛分各组分并混合和填充到2#胶囊中。
实施例C
注射液可以具有下列组成:
式(I)化合物 3.0mg
明胶 150.0mg
苯酚 4.7mg
碳酸钠 至获得最终pH为7
注射液用水 加至1.0ml
实施例D
可以以常规方式制备含有下列成分的软明胶胶囊:
胶囊内容物
式(I)化合物 5.0mg
黄蜡 8.0mg
氢化大豆油 8.0mg
部分氢化植物油 34.0mg
大豆油 110.0mg
胶囊内容物重量 165.0mg
明胶胶囊
明胶 75.0mg
甘油85% 32.0mg
Karion 83 8.0mg(干物质)
二氧化钛 0.4mg
氧化铁黄 1.1mg
将活性成分溶解在其它成分的温热熔融体中,将混合物填充到适当尺寸的软明胶胶囊中.按照本领域常用方法处理填充的软明胶胶囊.
实施例E
可以以常规方式制备含有下列成分的小药囊:
式(I)化合物 50.0mg
乳糖,细粉 1015.0mg
微晶纤维素(AVICEL PH 102) 1400.0mg
羧甲基纤维素钠 14.0mg
聚乙烯吡咯烷酮K30 10.0mg
硬脂酸镁 10.0mg
调味添加剂 1.0mg
将活性成分与乳糖、微晶纤维素和羧甲基纤维素钠混和,与聚乙烯吡咯烷酮在水中的混合物一起制粒。将颗粒与硬脂酸镁和调味添加剂混和并装入小药囊。
Claims (28)
1.通式I的化合物:
其中
R为氢或者C1-C7-烷基;
R1为C1-C7-烷基或C3-C7-环烷基;
X为N并且Y为C,或者
Y为N并且X为C;
m为0或者1;
Z为C(O)或者SO2;
R2选自:C1-C7-烷基,C3-C7-链烯基,C3-C7-炔基,卤代-C1-C7-烷基,羟基-C1-C7-烷基,C1-C7-烷氧基C1-C7-烷基,C3-C7-环烷基或者被苯基或者C1-C7-烷基取代的C3-C7-环烷基,C3-C7-环烷基-C1-C7-烷基,
未取代的苯基或者被C1-C7-烷基、C1-C7-烷氧基、卤素或者卤代-C1-C7-烷基单或双取代的苯基,苯基-C1-C7-烷基,其中所述的苯环是未取代的或被C1-C7-烷基、C1-C7-烷氧基、卤素或者卤代-C1-C7-烷基单或双取代的,
未取代的吡啶基或者被C1-C7-烷基、C1-C7-烷氧基、卤素或者卤代-C1-C7-烷基单或双取代的吡啶基,以及
-NR3R4,
或者,在Z为C(O)的情况下,R2也可以为C1-C7-烷氧基或者C1-C7-烷氧基-C1-C7-烷氧基;
R3为氢或者C1-C7-烷基;
R4选自:C1-C7-烷基,C3-C7-链烯基,C3-C7-炔基,C1-C7-烷氧基-C1-C7-烷基,
C3-C7-环烷基,被苯基取代的C3-C7-环烷基,
C3-C7-环烷基-C1-C7-烷基,
未取代的苯基或者被C1-C7-烷基、C1-C7-烷氧基、卤素或者卤代-C1-C7-烷基单或双取代的苯基,或者苯基-C1-C7-烷基,其中苯基是未取代的或被以下基团单或双取代的:C1-C7-烷基,C1-C7-烷氧基,卤素或者卤代-C1-C7-烷基;或者
R3和R4与它们连接的氮原子一起形成任选含有另外的选自氮、氧或硫的杂原子的4-、5-、6-或7-元杂环,所述的杂环是未取代的或被一个、两个或三个独立地选自下组的基团取代的:C1-C7-烷基,C1-C7-烷氧基,氧代基,卤素和卤代烷基,或者是与苯基或环己基环稠合的,所述的苯基或者环己基环是未取代的或被一个、两个或三个独立地选自下组的基团取代的:C1-C7-烷基,C1-C7-烷氧基,卤素和卤代烷基;
及其药用盐。
2.根据权利要求1的式I化合物,其中R1为C3-C7-环烷基。
3.根据权利要求1或2的式I化合物,其中R1为乙基或者异丙基。
4.根据权利要求1或2的式I化合物,其中m为0。
5.根据权利要求1或2的式I化合物,其中m为1。
6.根据权利要求1或2的式I化合物,其中R为氢,并且R2选自:C1-C7-烷基,C3-C7-链烯基,
C3-C7-炔基,卤代-C1-C7-烷基,羟基-C1-C7-烷基,C1-C7-烷氧基C1-C7-烷基,
C3-C7-环烷基或者被苯基取代的C3-C7-环烷基,
C3-C7-环烷基-C1-C7-烷基,
未取代的苯基或者被C1-C7-烷基、C1-C7-烷氧基、卤素或者卤代-C1-C7-烷基单或双取代的苯基,苯基-C1-C7-烷基,其中所述的苯环是未取代的或被C1-C7-烷基、C1-C7-烷氧基、卤素或者卤代-C1-C7-烷基单或双取代的,未取代的吡啶基或者被C1-C7-烷基、C1-C7-烷氧基、卤素或者卤代-C1-C7-烷基单或双取代的吡啶基,以及
-NR3R4,
或者,在Z为C(O)的情况下,R2也可以为C1-C7-烷氧基或者C1-C7-烷氧基C1-C7-烷氧基。
7.根据权利要求1或2的式I化合物,其中R2选自:C1-C7-烷基,C3-C7-链烯基,C3-C7-炔基,卤代-C1-C7-烷基,羟基-C1-C7-烷基,C1-C7-烷氧基-C1-C7-烷基,
C3-C7-环烷基或者被苯基或者C1-C7-烷基取代的C3-C7-环烷基,
C3-C7-环烷基-C1-C7-烷基,苯基-C1-C7-烷基,其中所述的苯环是未取代的或被C1-C7-烷基,C1-C7-烷氧基,卤素或者卤代-C1-C7-烷基单或双取代的,未取代的吡啶基或者被C1-C7-烷基,C1-C7-烷氧基,卤素或者卤代-C1-C7-烷基单或双取代的吡啶基,和-NR3R4,或者,在Z为C(O)的情况下,R2也可以为C1-C7-烷氧基或者C1-C7-烷氧基-C1-C7-烷氧基。
8.根据权利要求1或2的式I化合物,其中R2选自:C1-C7-烷基,C3-C7-环烷基和C1-C7-烷氧基-C1-C7-烷基。
9.根据权利要求1或2的式I化合物,其中R2为苯基C1-C7-烷基,其中苯基是未取代的或被以下基团单或双取代的:C1-C7-烷基,C1-C7-烷氧基,卤素或者卤代-C1-C7-烷基。
10.根据权利要求1或2的式I化合物,其中R2为
-NR3R4和R3和R4如权利要求1中所定义。
11.根据权利要求10的式I化合物,其中R3和R4为C1-C7-烷基。
12.根据权利要求10的式I化合物,其中R3为氢或者C1-C7-烷基,并且R4选自:C1-C7-烷基,C3-C7-链烯基,
C3-C7-炔基,C1-C7-烷氧基-C1-C7-烷基,C3-C7-环烷基,被苯基取代的C3-C7-环烷基,C3-C7-环烷基-C1-C7-烷基,
未取代的苯基或者被C1-C7-烷基,C1-C7-烷氧基,卤素或者卤代-C1-C7-烷基单或双取代的苯基,以及苯基-C1-C7-烷基,其中苯基是未取代的或被以下基团单或双取代的:C1-C7-烷基,C1-C7-烷氧基,卤素或者卤代-C1-C7-烷基。
13.根据权利要求10的式I化合物,其中R3和R4与它们连接的氮原子一起形成任选含有另外的选自氮、氧或硫的杂原子的4-、5-、6-或7-元杂环,所述的杂环是未取代的或被一个、两个或三个独立地选自下组的基团取代的:C1-C7-烷基,C1-C7-烷氧基,氧代基,卤素和卤代烷基,或者是与苯基或环己基环稠合的,所述的苯基或者环己基环是未取代的或被一个、两个或三个独立地选自下组的基团取代的:C1-C7-烷基,C1-C7-烷氧基,卤素和卤代烷基。
14.根据权利要求1或2的式I化合物,其中R2为未取代的苯基或者被以下基团单或双取代的苯基:C1-C7-烷基,C1-C7-烷氧基,卤素或者卤代C1-C7-烷基。
15.根据权利要求1或2的式I化合物,其中Z为SO2。
16.根据权利要求1或2的式I化合物,其中Z为C(O)。
17.根据权利要求1或2的式I化合物,其中Z为C(O)和R2为-NR3R4。
18.根据权利要求1或2的式I化合物,其中X为N并且Y为C。
19.根据权利要求1或2的式I化合物,其中X为C,并且Y为N。
20.根据权利要求1或2的式I化合物,其中R为氢。
21.根据权利要求1或2的式I化合物,其中R为甲基。
22.根据权利要求1的式I化合物,其选自:
1-[2-(4-乙基-哌嗪-1-基)-吡啶-4-基]-3-丙基-脲,
3-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-1,1-二乙基-脲,
N-[2-(4-乙基-哌嗪-1-基)-吡啶-4-基]-丙酰胺,
N-[2-(4-乙基-哌嗪-1-基)-吡啶-4-基]-丁酰胺,
N-[2-(4-乙基-哌嗪-1-基)-吡啶-4-基]-C-苯基-甲磺酰胺,
C-(4-氯-苯基)-N-[2-(4-乙基-哌嗪-1-基)-吡啶-4-基]-甲磺酰胺,
N-[2-(4-乙基-哌嗪-1-基)-吡啶-4-基]-3-氟-苯磺酰胺,
4-氯-N-[2-(4-乙基-哌嗪-1-基)-吡啶-4-基]-苯磺酰胺,
1-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-3-(4-氟-苄基)-脲,
N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-丙酰胺,
N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-丁酰胺,
环己烷羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-3-甲氧基-苯甲酰胺,
C-(4-氯-苯基)-N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲磺酰胺,
环丙烷羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
环丁烷羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
环戊烷羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-2-乙基-丁酰胺,
N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-2-氟-苯甲酰胺,
N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-4-氟-苯甲酰胺,
N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-2-甲氧基-苯甲酰胺,
2-氯-N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-烟酰胺,
N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-2-苯基-乙酰胺,
N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-2-(4-氟-苯基)-乙酰胺,
N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-2-(3-甲氧基-苯基)-乙酰胺,
[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-氨基甲酸异丁酯,
1-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-3-丙基-脲,
1-环己基-3-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-脲,
哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
吗啉-4-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
吡咯烷-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
4,4-二氟-哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
2-甲基-哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
3-甲基-哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
4-甲基-哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
2,6-二甲基-哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
4-氟-哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
3,3-二氟-哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
4-三氟甲基-哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
八氢-喹啉-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
八氢-异喹啉-2-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
3,4-二氢-2H-喹啉-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
3,4-二氢-1H-异喹啉-2-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
2-甲基-吡咯烷-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
2-三氟甲基-吡咯烷-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
2-异丙基-吡咯烷-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
1,3-二氢-异吲哚-2-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
2,3-二氢-吲哚-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
3-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-1-异丙基-1-(2-甲氧基-乙基)-脲,
氮杂环庚烷-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
3-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-1-乙基-1-苯基-脲,
3-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-1-(4-甲氧基-苯基)-1-甲基-脲,
N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基甲基]-丁酰胺,
环己烷羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基甲基]-酰胺,
N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基甲基]-2-苯基-乙酰胺,
N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基甲基]-4-氟-苯甲酰胺,
2-(4-氯-苯基)-N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基甲基]-3-甲基-丁酰胺,
1-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基甲基]-3-丙基-脲,
1-环己基-3-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基甲基]-脲,
1-苄基-3-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基甲基]-脲,
丙烷-1-磺酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基甲基]-酰胺,
二甲胺-1-磺酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基甲基]-酰胺,
C-(4-氯-苯基)-N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基甲基]-甲磺酰胺,
N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基甲基]-苯磺酰胺,
N-[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-丙酰胺,
环丙烷羧酸[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-酰胺,
N-[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-丁酰胺,
N-[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-2-甲氧基-乙酰胺,
环戊烷羧酸[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-酰胺,
N-[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-2-乙基-丁酰胺,
环己烷羧酸[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-酰胺,
N-[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-2-氟-苯甲酰胺,
N-[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-3-氟-苯甲酰胺,
N-[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-4-氟-苯甲酰胺,
N-[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-2-甲氧基-苯甲酰胺,
N-[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-3-甲氧基-苯甲酰胺,
N-[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-4-甲氧基-苯甲酰胺,
2-氯-N-[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-烟酰胺,
[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-氨基甲酸2-甲氧基-乙酯,
1-[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-3-(2-甲氧基-苯基)-脲,
1-[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-3-(1-苯基-乙基)-脲,
环己烷羧酸[2-(4-异丙基-哌嗪-1-基)-吡啶-4-基]-酰胺,
3-甲基-环己烷羧酸[2-(4-异丙基-哌嗪-1-基)-吡啶-4-基]-酰胺,
环戊烷羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基-酰胺,
3-甲基-环己烷羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基-酰胺,
环己烷羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基-酰胺,
3-甲基-环己烷羧酸[2-(4-异丙基-哌嗪-1-基)-吡啶-4-基]-甲基-酰胺,
环己烷羧酸[2-(4-异丙基-哌嗪-1-基)-吡啶-4-基]-甲基-酰胺,
哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基-酰胺,
吡咯烷-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基-酰胺,
4,4-二氟-哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基-酰胺,
3-环己基-1-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-1-甲基-脲,
3-环戊基-1-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-1-甲基-脲,
及其药用盐。
23.根据权利要求1的式I化合物,其选自:
1-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-3-(4-氟-苄基)-脲,
N-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-丁酰胺,
环己烷羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
环戊烷羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
1-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-3-丙基-脲,
1-环己基-3-[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-脲,
哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
4,4-二氟-哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
3-甲基-哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
4-甲基-哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
2,6-二甲基-哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
4-氟-哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
八氢-喹啉-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
八氢-异喹啉-2-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
氮杂环庚烷-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-酰胺,
环丙烷羧酸[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-酰胺,
环戊烷羧酸[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-酰胺,
环己烷羧酸[4-(4-环戊基-哌嗪-1-基)-吡啶-2-基]-酰胺,
3-甲基-环己烷羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基-酰胺,
4,4-二氟-哌啶-1-羧酸[2-(4-环戊基-哌嗪-1-基)-吡啶-4-基]-甲基-酰胺,
及其药用盐。
24.一种用于制备根据权利要求1的化合物的方法,该方法包括:
a)将式II化合物
其中X,Y,R,R1和m如权利要求1中所定义,
与式III的磺酰氯或氨磺酰氯反应:
R2-SO2-Cl III
其中R2如权利要求1中所定义,
得到式I-A的化合物:
其中X,Y,R,R1,R2和m如权利要求1中所定义,或者
b)使式II的化合物:
其中X,Y,R,R1和m如权利要求1中所定义,
与式IV的氯化物反应:
R2-C(O)Cl IV
其中R2如权利要求1中所定义,
得到式I-B的化合物:
其中X,Y,R,R1,R2和m如权利要求1中所定义,或者
c)使式II的化合物:
其中X,Y,R,R1和m如权利要求1中所定义,
与式V的异氰酸酯反应:
R4-N=C=O V
其中R4如权利要求1中所定义,
得到式I-C的化合物:
其中X,Y,R,R1,R4和m如权利要求1中所定义,或者
d)用氯甲酸苯酯活化式II的化合物:
其中X,Y,R,R1和m如权利要求1中所定义,
得到下式的氨基甲酸苯酯:
其然后与下式的胺反应:
H-NR3R4 VII,
其中R3和R4如权利要求1中所定义,
得到式I-C的化合物:
其中X,Y,R,R1,R3,R4和m如权利要求1中所定义,并且如果需要,将式I-A,I-B或者I-C的化合物转化为药用盐。
25.药物组合物,其包含根据权利要求1至23中任何一项的化合物以及药用载体和/或辅药.
26.根据权利要求25的药物组合物,其用于治疗和/或预防与H3受体的调节有关的疾病。
27.根据权利要求1至23中任何一项的化合物在制备药物中的应用,所述药物用于治疗和/或预防与H3受体的调节有关的疾病。
28.根据权利要求27的应用,用于治疗和/或预防肥胖症。
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ATE466842T1 (de) * | 2004-12-03 | 2010-05-15 | Hoffmann La Roche | 3-substituierte pyridinderivate als h3- antagonisten |
JP2009534355A (ja) * | 2006-04-19 | 2009-09-24 | アボット ゲーエムベーハー ウント カンパニー カーゲー | セロトニン5ht6受容体の調節に応答する障害を治療するために好適な複素環化合物 |
CN101421234A (zh) | 2006-04-19 | 2009-04-29 | 艾博特股份有限两合公司 | 适于治疗对5-羟色胺5ht6受体调节有反应的病症的杂环芳基砜 |
ES2546815T3 (es) | 2006-12-15 | 2015-09-28 | Bristol-Myers Squibb Company | Análogos de arilpropilamida, arilacrilamida, arilpropinamida o arilmetilurea como inhibidores del factor XIa |
KR101600278B1 (ko) | 2008-06-12 | 2016-03-08 | 얀센 파마슈티카 엔.브이. | 히스타민 h4 수용체의 다이아미노-피리딘, 피리미딘, 및 피리다진 조절제 |
US8614201B2 (en) | 2009-06-05 | 2013-12-24 | Janssen Pharmaceutica Nv | Heterocyclic amides as modulators of TRPA1 |
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BR112013012078A2 (pt) * | 2010-11-15 | 2019-09-24 | Abbvie Inc | inibidores de nampt e rock |
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WO2003004480A2 (en) * | 2001-07-02 | 2003-01-16 | Novo Nordisk A/S | Substituted piperazine and diazepanes as histamine h3 receptor agonists |
US20030236259A1 (en) * | 2002-02-05 | 2003-12-25 | Rolf Hohlweg | Novel aryl- and heteroarylpiperazines |
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US7456175B2 (en) | 2008-11-25 |
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CA2590339A1 (en) | 2006-06-22 |
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US20060135528A1 (en) | 2006-06-22 |
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