CN1120843A - 具有cck拮抗或激动活性的1,5-苯并二氮杂䓬类衍生物 - Google Patents
具有cck拮抗或激动活性的1,5-苯并二氮杂䓬类衍生物 Download PDFInfo
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- CN1120843A CN1120843A CN94191773A CN94191773A CN1120843A CN 1120843 A CN1120843 A CN 1120843A CN 94191773 A CN94191773 A CN 94191773A CN 94191773 A CN94191773 A CN 94191773A CN 1120843 A CN1120843 A CN 1120843A
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- Prior art keywords
- alkyl
- phenyl
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- hydroxyl
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- 230000001270 agonistic effect Effects 0.000 title abstract 2
- ZVAPWJGRRUHKGP-UHFFFAOYSA-N 1h-1,5-benzodiazepine Chemical class N1C=CC=NC2=CC=CC=C12 ZVAPWJGRRUHKGP-UHFFFAOYSA-N 0.000 title description 3
- 230000003042 antagnostic effect Effects 0.000 title description 2
- 241000124008 Mammalia Species 0.000 claims abstract description 15
- 108010052343 Gastrins Proteins 0.000 claims abstract description 11
- AOXOCDRNSPFDPE-UKEONUMOSA-N chembl413654 Chemical compound C([C@H](C(=O)NCC(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](C)NC(=O)[C@@H](CCC(O)=O)NC(=O)[C@@H](CCC(O)=O)NC(=O)[C@@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)CNC(=O)[C@@H](N)CCC(O)=O)C1=CC=C(O)C=C1 AOXOCDRNSPFDPE-UKEONUMOSA-N 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 6
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- 235000020824 obesity Nutrition 0.000 claims abstract description 4
- 102100021022 Gastrin Human genes 0.000 claims abstract 3
- 150000001875 compounds Chemical class 0.000 claims description 163
- -1 amino, dimethylamino Chemical group 0.000 claims description 82
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 59
- 238000000034 method Methods 0.000 claims description 58
- 239000001257 hydrogen Substances 0.000 claims description 37
- 229910052739 hydrogen Inorganic materials 0.000 claims description 37
- 239000000203 mixture Substances 0.000 claims description 37
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 32
- 238000006243 chemical reaction Methods 0.000 claims description 29
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 29
- 150000002431 hydrogen Chemical group 0.000 claims description 27
- 239000000460 chlorine Substances 0.000 claims description 24
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 23
- 229910052731 fluorine Inorganic materials 0.000 claims description 23
- 150000001412 amines Chemical class 0.000 claims description 22
- 239000011737 fluorine Substances 0.000 claims description 22
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 21
- 230000000694 effects Effects 0.000 claims description 21
- 229910052736 halogen Inorganic materials 0.000 claims description 20
- 150000002367 halogens Chemical class 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 20
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 18
- 229910052801 chlorine Inorganic materials 0.000 claims description 16
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 14
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 14
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
- 150000002475 indoles Chemical class 0.000 claims description 12
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 11
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 11
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 10
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 10
- 201000010099 disease Diseases 0.000 claims description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
- 239000012453 solvate Substances 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 125000005605 benzo group Chemical group 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 7
- 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 7
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 7
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 6
- 235000013305 food Nutrition 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 150000003222 pyridines Chemical class 0.000 claims description 6
- 150000003233 pyrroles Chemical class 0.000 claims description 6
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 238000010521 absorption reaction Methods 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 235000019789 appetite Nutrition 0.000 claims description 4
- 230000036528 appetite Effects 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- ODFJOVXVLFUVNQ-UHFFFAOYSA-N acetarsol Chemical compound CC(=O)NC1=CC([As](O)(O)=O)=CC=C1O ODFJOVXVLFUVNQ-UHFFFAOYSA-N 0.000 claims description 3
- 230000000578 anorexic effect Effects 0.000 claims description 3
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- 230000036186 satiety Effects 0.000 claims description 3
- 235000019627 satiety Nutrition 0.000 claims description 3
- 229930192474 thiophene Natural products 0.000 claims description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 230000035479 physiological effects, processes and functions Effects 0.000 claims description 2
- 230000001105 regulatory effect Effects 0.000 claims description 2
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims 1
- 235000021229 appetite regulation Nutrition 0.000 claims 1
- PIIHPBHYDCOPKZ-UHFFFAOYSA-N n-fluoro-n-methylmethanamine Chemical compound CN(C)F PIIHPBHYDCOPKZ-UHFFFAOYSA-N 0.000 claims 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 abstract description 18
- 101800001982 Cholecystokinin Proteins 0.000 abstract description 16
- 102100025841 Cholecystokinin Human genes 0.000 abstract description 15
- 229940107137 cholecystokinin Drugs 0.000 abstract description 15
- 108010089335 Cholecystokinin A Receptor Proteins 0.000 abstract description 4
- 102100034927 Cholecystokinin receptor type A Human genes 0.000 abstract description 4
- 229940088597 hormone Drugs 0.000 abstract description 4
- 239000005556 hormone Substances 0.000 abstract description 4
- 229940125709 anorectic agent Drugs 0.000 abstract 1
- 239000002830 appetite depressant Substances 0.000 abstract 1
- 125000003310 benzodiazepinyl group Chemical class N1N=C(C=CC2=C1C=CC=C2)* 0.000 abstract 1
- 238000012423 maintenance Methods 0.000 abstract 1
- 230000003893 regulation of appetite Effects 0.000 abstract 1
- 230000004580 weight loss Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 96
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 60
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 59
- 239000000243 solution Substances 0.000 description 45
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 42
- 235000019439 ethyl acetate Nutrition 0.000 description 35
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 30
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 29
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- 239000002904 solvent Substances 0.000 description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 25
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- 238000002360 preparation method Methods 0.000 description 21
- 238000004809 thin layer chromatography Methods 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- 238000003756 stirring Methods 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 18
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 18
- 239000007787 solid Substances 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 15
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- 239000000470 constituent Substances 0.000 description 14
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 14
- 210000000232 gallbladder Anatomy 0.000 description 13
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- 150000003254 radicals Chemical class 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
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- 102400000921 Gastrin Human genes 0.000 description 8
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- 238000012360 testing method Methods 0.000 description 7
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 6
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- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 5
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- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
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Abstract
新的苯并二氮杂䓬类化合物(I),该类化合物对CCK-A具有激动剂活性,能调节哺乳动物中的激素胃泌素和缩胆囊素(CCK),因此可以通过调节食欲作为减食欲剂治疗肥胖症和保持体重下降。
Description
本发明涉及新的1,5-苯并二氮杂类衍生物,它们的制备方法、含有它们的药用组合物以及它们在医药方面的应用。更具体地说,本发明涉及具有CCK-A受体激动剂活性的化合物,因此,本发明的化合物能够调节哺乳动物中激素胃泌素和缩胆囊素(CCK)。
缩胆囊素(CCK)和胃泌素是存在于胃肠组织和中枢神经系统的结构上有关的肽。缩胆囊素包括CCK-33,为以其独特分离形式的33个氨基酸的神经肽,其羧基末端8肽CCK-8也是天然产生的神经肽,以及39-和12-氨基酸形式。胃泌素以34-、17-和14-氨基酸形式出现,并且最小活性序列是C-末端4肽,Trp-Met-Asp-Phe-NH2(CCK-4),它是CCK和胃泌素共有的通用结构单元。
CCK和胃泌素是神经和末梢系统中的胃肠激素与神经递质,并且通过与分布全身不同部位的特殊受体结合而发挥它们各自的生物作用。至少有2个称为CCK-A和CCK-B的缩胆囊素受体亚型,它们均在末梢和中枢神经系统中被发现。
通常称为“末梢型”受体的CCK-A受体最初在胰腺、胆囊、回肠、幽门括约肌中以及在迷走神经传入神经纤维上被发现。也在个别的脑区域中发现了CCK-A型受体,并且可提供各种CNS作用。由于CCK-8和CCK-A型具有选择性抑制几种动物的食物吸收的激动剂作用,因此人们对具有A型受体选择性CCK激动剂作用的可用作为减食欲剂的新物质的研究产生了相当大的兴趣。
人们在末梢神经元,胃肠道平滑肌和胃肠粘膜中,尤其是在壁细胞、ECL细胞、D细胞和主要细胞中发现了CCK-B或胃泌素受体。在大脑中CCK-B受体也起主要作用,并且CCK-B受体与调节焦虑、对感觉刺激的反应状态以及精神抑制剂的作用有关。
US 4,988,692(Gasc等)叙述了一组3-酰氨基1-烷基-5-苯基1,5-苯并二氮杂类衍生物,该类衍生物具有缩胆囊素拮抗剂作用,它们可逆转或抑制受体的内源激素功能。
US 4,490,304和PTC申请号WO 90/06973与WO 91/19733叙述了具有CCK-A激动剂活性的肽衍生物。该类化合物被公开可调节动物(尤其是人)的食欲以及治疗和/或预防胃肠道疾病或中枢神经的疾病。
现在我们发现了一组新的3-氨基1,5-苯并二氮杂类化合物,它们具有CCK-A受体激动剂作用,因此它们可调节哺乳动物中的激素胃泌素和缩胆囊素(CCK)。该类化合物中一些化合物还具有CCK-B受体拮抗剂的作用。
因此,本发明提供了通式(I)化合物及其生理适用的盐和溶剂化物。其中X为氢、三氟甲基、烷基、C1-4烷硫基、-O(C1-4烷基)或卤素;
R1为式II或-NR4R5;
R2为(1)在其2位键合的杂环,该杂环可选自吡咯、四氢吡咯、吲哚、苯并呋喃、噻吩、苯并噻吩、二氢吲哚、喹啉或4-氧苯并呋喃,其中所述吡咯、四氢吡咯、吲哚或二氢吲哚在其环的氮原子上可以任意地由下面定义的基团R8取代,所述吲哚、二氢吲哚、喹啉、苯并呋喃、苯并噻吩或4-氧-苯并呋喃在其苯并环上可以任意地由下面定义的R9基团取代,或者
(2)苯基,或由下述基团独立地单或二取代的苯基:卤素、羟基、氰基、羧基、-O(C1-4烷基)、-O(CH2C6H5)、-COO(C1-4烷基)、氨基、二甲氨基、-NHR10、1-吡咯烷基或四唑基;或者
(3)吡啶基,或由下述基团独立地单或二取代的吡啶基:卤素、甲基、羟基、硝基、氰基、羧基、-O(C1-4烷基)、-O(CH2C6H5)、-COO(C1-4烷基)、氨基或二甲氨基:或者
(4)-NHR11,这里R11见下面定义,或者R11为在N-1位置上有基团R10的7-吲哚基;
R3为氢、C1-6烷基、C3-6环烷基、苯基、或由卤素独立地单或二取代的苯基;
R4独立地为C3-6烷基、C3-6环烷基、C3-6链烯基、苯基、-(CH2)pCN或-(CH2)pCOO(C1-4烷基),并且
R5独立地为C3-6烷基、C3-6环烷基、C3-6链烯基、苄基、苯基、或由下述基团独立地单或二取代的苯基:C1-3烷基、氰基、羟基、二甲氨基、-O(C1-4烷基)、-O(CH2C6H5)、-NH(C1-4烷基)、-COO(C1-4烷基)、-N(C1-4烷基)2吡咯烷子基、吗啉代或卤素;或者R4为C1-2烷基,并且R5为在2-或4-位上由氯、甲基、甲氧基或甲氧基羰基取代的苯基;
R6为氢或甲基;
R7为氢、羟基、氟、二甲氨基、-O(C1-4烷基)、或-O(CH2C6H5):
R8为-(CH2)bCOOH:
R9为甲基、氯、硝基、羟基、甲氧基或-NHR10;
R10为氢、乙酰基、C1-4烷基、-SO3H、-SO2CH3、-SO2CF3或-SO2C6H5、C1-4烷氧基羰基;
R11为苯基、或者由下述基团独立地单或二取代的苯基:氟、三氟甲氧基、C1-4烷硫基、-(CH2)cCOOH、-(CH2)cCOO(C1-4烷基)、-(CH2)cSCH3、-(CH2)cSOCH3、-(CH2)cSO2CH3、-(CH2)CONH2、-SCH2COOH、-CONH(SO2CH3)、-CONH(SO2CF3)、-(CH2)cN(C1-4烷基)2、-(CH2)cNH(SO2CF3)、-(CH2)cN(SO2CF3)(C1-4烷基)、-(CH2)cSO2NHCO(C1-4烷基)、-(CH2)cSO2N(C1-4烷基)CO(C1-4烷基)、-(CH2)cCONHSO2(C1-4烷基)、-(CH2)cCON(C1-4烷基)SO2(C1-4烷基)、-(CH2)cOR12-(CH2)cNHR10、或由-(CH2)c(四唑基)、-(CH2)c(甲酰氨基四唑基)或-(CH2)c(吡咯烷基)单取代的苯基,或者R11选自吡啶、或由下述基团独立地单或二取代的吡啶基:卤素、甲基、羟基、硝基、氰基、羧基、-O(C1-4烷基)、氨基、二甲氨基、-NHR10;
R12为氢、C1-6烷基、C3-6环烷基、-CH2C6H5、-CH2COOH、-CH2CONH2、-CH2CONH(C1-4烷基)、-CH2CON(C1-4烷基)2或或
z为1或2;
n为1或2;
p为整数1~4;
b为整数0~3;
c为零或1。
当R1代表式(II)基团时,该基团的实例包括,其中R6为氢,或者尤其为甲基,R7为氢、羟基、甲氧基或氟,n为1。
当R1代表基团NR4R5时,合适基团的实例包括:其中R4代表C3-6烷基如丙基或异丙基、环己基或苯基,R5代表C3-6烷基、苄基,或在对位任意地由羟基、二甲基氨基、甲氧基、氟、吡咯烷子基或吗啉代取代的苯基。在所述基团中,尤其有用的R1基团包括:其中R4为丙基,更好的是异丙基,并且R5代表苯基,或在对位由选自羟基、甲氧基、二甲基氢基、氟或吗啉代取代的苯基。
尤其合适的R1基团的实例包括:R1为式(II)基团,其中R6为甲基、n为1,R7为氢、羟基、氟或甲氧基,或者R1为基团NR4R5,这里R4为丙基或异丙基,R5为在对位任意地由选自羟基、甲氧基、氟、二甲基氨基、吡咯烷子基或吗啉代取代的苯基。
当R2代表选自吲哚、二氢吲哚、苯并呋喃、苯并噻吩、喹啉或4-氧苯并吡喃时,任意的取代基R9通常为选自氢、甲基、甲氧基、羟基、硝基或氨基的基团,如果合适,在氮上任意的取代基(R8)为-CH2CO2H。
当R2为任意取代的苯基时,它通常为苯基,或为由1个或2个相同或不同的基团取代的苯基,这些基团可选自氯、氟、氨基、羟基或羧基。
当R2代表基团NHR11时,R11通常为苯基(任意地由氟、羟基、氨基、二甲基氨基、三氟甲基磺酰氨基、C1-4烷氧基羰基、羧基、1H-四唑-5-基、乙酰氨基或OR12取代,这里R12代表氢、甲基、苄基、CH2CO2H、CH2CONH2、CH2C0NHCH3、CH2CON(CH3)2、或
)或R11为其中N-1取代基(R10)为氢的7-吲唑基。
当R11为单取代的苯基时,该取代基通常在间位。
尤其合适的R2基团的实例包括吲哚、苯并呋喃、噻吩、苯并噻吩、二氢吲哚、喹啉、4-氧苯并吡喃、任意取代的苯基或基团NHR11。R2通常选自吲哚基、二氢吲哚基或苯并呋喃基、任意取代的苯基或基团NHR11。尤其是R2代表吲哚基、任意取代的苯基或NHR11。
当R3代表C1-6烷基时,合适基团的实例包括甲基、乙基、丙基、异丙基、丁基、叔丁基或异戊基。
当R3代表C3-6环烷基时,合适基团的实例包括环丙基、环戊基或环己基。
当R3代表独立地由卤素单或二取代的苯基时,合适基团的实例包括其中卤素取代基为氟,例如2-氟苯基或4-氟苯基。
尤其合适的R3基团的实例包括氢、甲基、环己基、2-氟苯基或苯基,更合适的是苯基。
本发明化合物特别有用的基团包括:R1代表式(II)基团,其中R6为甲基,n为1,R7为氢、氟、羟基或甲氧基,或者尤其是NR4R5,其中R4为丙基或异丙基,R5为在对位任意地由选自羟基、甲氧基、氟、二甲基氨基或吗啉代的基团取代的苯基;R2代表苯基(任意地由1个或2个选自氯、氟、羟基、胺或羧基的基团独立地取代),NHR11,其中R11代表苯基(任意地由下述基团取代:氨基、二甲基氨基、三氟甲基磺酰氨基、羧基、1H-四唑-5-基、乙酰氨基或OR12,这里R12代表氢、甲基、苄基、CH2CO2H、CH2CONH2、CH2CONHCH3、CH2CON(CH3)2、或
并且其中取代基最好是在间位)或吲哚,其中氮原子任意地由基团-CH2CO2H取代,而苯并环任意地由氯、甲基、甲氧基、硝基、羟基或氨基取代:R3代表氢、甲基、环己基、2-氟苯基或苯基,尤其是2-氟苯基或苯基:X代表氟并且Z为1或,尤其是X为氢。
对CCK-A受体具有很高的选择性亲合性并且具有特殊效果的一类尤其令人感兴趣的本发明化合物是其中R2为吲哚基。在该类化合物中优选的基团是:其中在吲哚基的氮原子上由基团-CH2CO2H取代,或者更优选的是该氮原子未被取代,并且该吲哚基的苯并环上任意地由选自氯、甲基、甲氧基、硝基、羟基或氨基取代。
特别优选的本发明化合物是:
1H-吲哚-2-羧酸{1-[异丙基-(4-甲氧基苯基)氨基甲酰基甲基]-2,4-二氧-5-苯基-2,3,4,5-四氢-1H-苯并[b][1,4]二氮杂-3-基}-酰氨及其对映体。
本文所述的术语烷基通常意指直链和支链的脂肪族相应的烷基。例如C1-6烷基意指包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基等。
本文所述的术语环烷基意指相应烷基的所有脂环族异构体。例如本文所述术语C3-6烷基意指包括下述基团例如环丙基、环戊基和环己基。
术语卤素意指F、Cl、Br或I。
作为基团或基团一部分的术语四唑是指(1H)-四唑-5-基基团及其互变异构体。
熟悉本技术领域的专业人员明白,式(I)化合物中存在立构中心。因此,本发明包括式(I)的所有可能的立体异构体和几何异构体,并且不仅包括外消旋化合物,而且还包括旋光异构体。当要求式(I)化合物的单一对映体时,它可以通过将最终产物的拆开或者通过从异构体上纯的起始原料或任何方便的中间体经立体有择合成得到。最终产品的拆开、异构体上纯的中间体或起始原料的立体有择合成可以按本技术领域已知的合适方法进行。参见E.L.Eliel:Stereochemistry of Carbon Compounds(Mcgraw Hill,1962)和S.H.Wilen:Tables of Resolving Agents。此外,如果式(I)化合物可能互变异构,那么本发明的意指包括该化合物所有的互变异构形式。
熟悉本技术领域的专业人员明白,本发明化合物还可以用于形成其药学上可接受的盐或溶剂化物。式(I)化合物的生理上可接受的盐包括由药学上可接受的无机或有机酸形成的常用的盐以及季铵的酸加成盐。合适的盐的较具体的实例包括盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、硝酸盐、高氯酸盐、富马酸盐、乙酸盐、丙酸盐、琥珀酸盐、羟基乙酸盐、甲酸盐、乳酸盐、马来酸盐、酒石酸盐、柠檬酸盐、双羟萘酸盐、丙二酸盐、羟基马来酸盐、苯基乙酸盐、谷氨酸盐、苯甲酸盐、水杨酸盐、富马酸盐、甲苯磺酸盐、甲磺酸盐、萘-2-磺酸盐、苯磺酸盐等。其他的酸例如草酸,虽然其本身不是药学上可接受的,但在制备本发明化合物及它们的药学上可接受的盐中可以用于制备盐作为中间体。下面提到的本发明化合物包括式(I)化合物以及它们的药上可接受的盐和溶剂化物。
本发明化合物具有CCK-A激动剂活性,由于可以与CCK-A受体结合,或者充分地或部分地刺激胆囊收缩和/或减少动物摄食,因此本发明化合物是充分的或部分的缩胆囊素激动剂。
作为CCK-A受体的激动剂,本发明化合物是有用的减食欲剂,用于治疗肥胖症和有关的疾病例如糖尿病或高血压。此外,本申请公开的化合物提供了诱导哺乳动物(尤其是人)的饱满感、食欲调节和改变食物吸收从而可以调节食欲、治疗肥胖症和使体重减轻的新方法。
此外,应用M.Pate1和C.F.Spraggs[Br.J.Pharmac.,(1992),106,275~282]以及J.J.Reeves和R.Stables[Br.J.Pharmac.,(1985),86,677~684]所述方法表明,本发明的一些化合物对CCK-4刺激的分离的豚鼠回肠纵向肌肉-肠肌层丛的收缩和五肽胃泌素刺激的分离的大鼠胃粘膜中酸的分泌均有抑制作用,因此本发明的一些化合物对特定位置的CCK-B和胃泌素受体也具有相当的拮抗剂活性。
本发明化合物对CCK-A和CCK-B受体有关的亲合性可以用常用的已知方法,例如Fornos等(J.Pharmacol Exp.Ther.,1992261,1056~1063)所述的方法进行测定。
本发明化合物抑制胃酸分泌的能力,例如抑制五肽胃泌素刺激的酸分泌作用,可以应用Hedges和Parsons(Journal of Physiology1977,267,191~194)所描述的方法用有意识的胃瘘管大鼠进行测定。
本发明尤其提供了用于治疗,特别是作为人用药物的式(I)化合物或其药学上可接受的盐或溶剂化物。
另一方面,本发明提供了应用式(I)化合物或其药学上可接受的盐或溶剂化物制备治疗上述疾病的药物,其中减轻CCK和/或胃泌素的作用具有治疗上有益的效果。
再一方面,本发明提供了治疗哺乳动物(包括人)疾病的方法,尤其是治疗其中减轻CCK和/或胃泌素的作用具有治疗的效果,该方法包括给患者服用治疗上有效剂量的式(I)化合物或其药学上可接受的盐或溶剂化物。
熟悉本技术领域的专业人员明白,这里提到的治疗应延伸至预防以及已确诊疾病或综合症的治疗。此外,还应明白,用于治疗所需的本发明化合物的剂量随需治疗的疾病性质、患者的年龄和情况而改变,并且最终由主治医师或兽医自行决定。然后,一般来讲成人治疗应用的剂量通常在0.02~5000mg/天范围,例如1~1500mg/天。所需剂量通常为单次剂量或作为在合适间隔(例如每天分2、3、4或更多次)服用的均分剂量。
虽然用于治疗的本发明化合物可以作为原料药在治疗上服用,但是最好使其有效成分以药用配方给药。因此,本发明还提供了含有式(I)化合物或其药学上可接受的盐和一种或多种药学上可接受的载体以及任意的其他治疗和/或预防成分的药用配方。所述载体必须是“可接受的”:与配方中的其他成分可配伍并且对服用者没有危害。
本发明的组合物包括下述剂型,尤其可以配制成口服、口腔含化剂、非经胃肠道给药、植入剂或直肠给药的剂型,但是优选口服给药剂型。作为口腔含化剂给药,该组合物可以为按通常方式配制的片剂或锭剂形式。口服给药的片剂和胶囊剂可以含有常用的赋形剂如粘合剂例如糖浆、阿拉伯胶、明胶、山梨糖醇、西黄蓍胶、淀粉胶浆或聚乙烯吡咯烷酮;填充剂例如乳糖、白糖、微晶纤维素、玉米淀粉、磷酸钙或山梨糖醇;润滑剂例如硬脂酸镁、硬脂酸、滑石、聚乙二醇或二氧化硅;崩解剂例如土豆淀粉或淀粉羟基乙酸钠或湿润剂例如十二烷基硫酸钠。片剂可以按照本技术领域熟知的方法进行包衣。
另外,本发明化合物可以配制成口服液体制剂例如水混悬液剂或油混悬液剂、溶液剂、乳剂、糖浆剂或酏剂。此外,含有本发明化合物的配方可以为干燥的产品,在应用之前将其与水或其他合适的媒液进行配制。所述液体制剂可以含有常用的添加剂如混悬剂例如山梨糖醇、糖浆、甲基纤维素、葡萄糖/白糖糖浆、明胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶或氢化的食用脂肪;乳化剂例如卵磷脂、山梨糖醇酐单油酸酯或阿拉伯胶;非水媒液(包括可食用的油)例如杏仁油、精馏椰子油、油质酯、丙二醇或乙醇;防腐剂例如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯或抗坏血酸。所述组合物还可以配制栓剂,该栓剂含有例如常用的栓剂基质如可可脂或其他的甘油酯。
此外,本发明组合物可以配制成注射或连续输注的非经胃肠给药的形式。注射剂型可以为在油质或水媒液中的混悬液剂、溶液剂或乳剂,并且还可以含有辅助剂例如混悬剂、稳定剂和/或分散剂。另外,有效成分可以为粉剂,在应用之前将其与合适的媒液(例如无菌、无热源的水)进行配制。
本发明的组合物还可以配制或缓释型制剂。该长效制剂可以通过植入(例如植于皮下或肌内)或通过肌内注射给药。因此,本发明的化合物可以与合适的多聚材料或疏水材料或离子交换树脂进行配制,例如在合适的油中配制成乳剂,或作为微溶的衍生物例如作为微溶的盐。
本发明组合物可以含有0.1~99%有效成分,作为片剂和胶囊剂通常含有30~95%有效成分,作为液体制剂通常含有3~50%有效成分。
通式(I)化合物可以按下面所述通法进行制备。在下面的叙述中,除非另有说明,否则基团X和R1-12同式(I)化合物中的定义。
通式(I)化合物及其盐可以按下述的通法进行制备。在下面的叙述中,除非另有说明,否则基团R1~R12和X同式(I)化合物中的定义。
首先,按照通法A,式(I)化合物可以通过胺式(III)与化合物R11Y(IV)反应制备,其中R1、R2、R3、X和Z同式(I)化合物中的定义,R11Y(IV)中Y为基团-NCO、HNCOCl或NHCORa,这里Ra为硝基取代的苯氧基或1-咪唑基。
上述反应通常在合适的溶剂如卤代烃(例如二氯甲烷)、醚(例如四氢呋喃)或腈(例如乙腈)或它们的混合溶剂存在下,于0°~80℃进行。
式(IV)化合物(其中Y为-NCO)可以买到,或者通过胺H2N-R11与光气或三光气于合适溶剂如二氯甲烷中反应制得。式(IV)化合物(其中Y为NHCOCl)也可以通过胺H2N-R11与光气或三光气于合适溶剂如二氯甲烷中反应制得。式(IV)化合物(其中Y为NHCORa,并且Ra为1-咪唑基)可以通过胺H2N-R11与羰基二咪唑于合适溶剂(如二氯甲烷、乙醚、四氢呋喃)中,在0°~80℃(通常在室温)反应制得。式(Ⅳ)化合物(其中Y为NHCORa,并且Ra为硝基取代的苯氧基)可以通过胺H2N-R11与合适的氯代甲酸酯RaCOCl在碱(如吡啶、三乙胺)存在下,于合适的溶剂(如二氯甲烷)中,在0°~50℃反应制得。
此外,按照通法B,式(I)化合物可以通过中间体式(V)与胺式(IV)任意地在碱如叔胺(例如三乙胺)存在下反应制备,其中Y为基团-NCO、NHCOCl或NHCORa,这里Ra为硝基取代的苯氧基或1-咪唑基,
H2N-R11 (VI)
上述反应通常在合适的溶剂如卤代烃(例如二氯甲烷)或醚(例如四氢呋喃)或酰胺(例如N,N-二甲基甲酰胺)中任意地于室温~溶剂的回流温度进行。
式(V)化合物通常可以在原处由式(III)胺制得。
方法(B)的特殊情况是,如果Y为基团NHCORa,并且Ra为1-咪唑基,那么上述1-酰基咪唑式(V)可以在原处由胺式(VI)与式(III)化合物于羰基二咪唑存在下,在上面所述条件下进行混合生成,
对于方法(B),如果Y为基团NHCORa,并且Ra为硝基取代的苯氧基,那么与伯胺式(VI)的反应最好在碱如叔胺(例如三乙胺)存在下进行。
对于方法B,如果Y为异氰酸酯基团-N=C=O,那么与伯胺(VI)的反应最好在非质子传递溶剂如卤代烃(例如二氯甲烷)中进行。在加入伯胺式(VI)之前所述异氰酸酯通常先在原处制备。
其中Ra为任意取代的苯氧基的式(V)化合物,可以通过伯胺式(III)与相应的硝基取代的苯基氯代甲酸酯在碱如吡啶存在下制备。该反应可以在溶剂如卤代烃(例如二氯甲烷)中于0°~50℃进行。
其中Ra为1-咪唑基团的式(V)化合物可以通过式(III)化合物与羰基二咪唑在合适的溶剂如卤代烃(例如二氯甲烷)或醚(例如四氢呋喃)存在下,于0°~80℃(通常在室温)进行反应制得。
其中Y为异氰酸酯基-N=C=O或氨基甲酰氯-NHCOCl的式(V)化合物可以通过伯胺(III)与光气(COCl2)或三光气在合适的溶剂(如二氯甲烷)中反应制得。
R1COCH2hal (VIII)
其中hal=Cl或Br。
上述反应通常按下法进行:使式(VII)化合物与强碱如氢化钠在极性非质子传递溶剂(如N,N-二甲基甲酰胺)中反应,接着与乙酰基卤化物(VIII)反应。
乙酰基卤化物(VIII)可以由胺R1-H与相应的卤代乙酰溴在二氯甲烷中于0℃和合适的碱如三乙胺存在下反应制得。
其中R1为基团-NR4R5的胺R1-H可以由胺H2N-R5与合适的醛或酮的还原性烷基化作用制得。
按照通法D,通式(I)化合物还可以由中间体式(III)与酸式(IX)按下述方法进行制备,
HOOC-R2 (IX)
因此,中间体式(III)与酸式(IX)的反应在合适的脱水剂如二环己基碳二亚胺(DCC)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)或双(2-氧-3-噁唑烷基)膦酰氯(BOP)存在下进行。
另外,通式(I)化合物可以通过中间体式(III)与式(IX)酸的活性衍生物如该酸的酰氯或酸酐(包括混合酐)反应制备。
通法D优选的溶剂包括N,N-二甲基甲酰胺或二氯甲烷。优选的温度为0°~60℃。该反应优选的碱包括三乙胺或N,N-二甲氨基吡啶(DAMP)。
此外,按照通法(E),可将本发明化合物转变成另一本发明化合物。因此,例如其中R8为基团(CH2)bCO2H的式(I)化合物可以通过其中R8为氢的式(I)化合物与化合物Br(CH2)bCOOR*(这里R*为C1-4烷基)在强碱如氢化钠存在下进行反应,接着按通常方法例如酸或碱性水解脱去羧基保护基来制备。
其中W为CH-N3的式(X)化合物通过在合适的催化剂(如5-10%钯-碳或钯-碳酸钙,或氧化铂(IV))存在下进行氢化,可以还原为式(III)化合物。该反应通常在溶剂如链烷醇(例如乙醇)、酯(例如乙酸乙酯)或乙酸存在下进行。
其中W为C=N-NHPh的式(X)化合物可以通过与锌或乙酸反应还原为式(III)化合物。该反应可以在0°~50℃进行。
其中W为CHN3的式(X)化合物可以从其中W为CH2的式(X)化合物按下法制备:用强碱如氢化钠或叔丁醇钾进行处理,接着用三-异丙基苯磺酰基叠氮化物或二叔丁氧基叠氮基二羧酸酯进行处理。该反应通常在溶剂如醚(例如四氢呋喃)中于-78°~20℃进行。
其中W为C=NNHPh或CH2的式(X)化合物可以通过邻-苯二胺(XI)与二酰氯(XII,其中Q为CH2或C=NNHPh)在合适的溶剂如醚(例如四氢呋喃)中反应制得,
其中Q为C=NNHPh的式(XII)化合物可以通过丙酮二酸与苯腙反应,接着与五氯化磷反应制得。
因此,使胺式(XIII)与化合物R1COCH2hal(其中hal为氯或溴)任意地在碘化钠存在下,于溶剂如N,N-二甲氨基甲酰胺中进行反应。
下面陈述中间体式(III)的另一制备方法,该方法包括用氢化钠处理中间体式(XIV),接着在合适溶剂如二甲基甲酰胺中于0℃加入乙酰卤(VIII),得到受保护的中间体式(XV), 用合适的催化剂如5-10%Pd/C,在合适的溶剂如甲醇、乙醇、乙酸乙酯、氯仿或乙酸中,于室温进行催化氢化(40~60psi),将中间体(XV)转变为所需的胺(III)。另外,在二氯甲烷中用HBr进行处理,可以将中间体(XVI)转变为胺(III)。
中间体(XVI)可以从苯二胺(XIII)通过下述方法制备。
使二胺(XIII)与对甲氧基苯甲酰氯反应,接着用氢化锂铝还原生成的酰胺,得到N-受保护的二胺(XVII),
通过与Ce(NO2)6NH4(硝酸铈铵)反应,可以将式(XVIII)化合物转变成所需的化合物(XVI)。
式(I)化合物含有至少1个不对称碳原子,即与取代的脲基连接的二氮杂环的碳原子。应用一般的方法例如手性高效液相色谱法,通过拆开外消旋化合物可以得到式(I)化合物特定的对映体。另外,应用上述从胺(III)制备式(I)化合物的任一方法,从相应胺(式III)的对映体可以制备所需的对映体。胺(式III)的对映体可以从外消旋胺(式II),应用一般的方法例如与具有适当旋光性的酸形成盐,或者用制备性手性高效液相色谱法制备。
实施例
下面的实施例详细叙述本发明一些化合物的具体合成方法并进一步举例通法A-E的具体应用。因此,下面的实施例决不是企图限制所述本发明的范围。
一般方法
除非另有说明,否则所有的起始原料是从市场上买来的并未经进一步纯化。以缩写表示下面的溶剂和试剂:四氢呋喃(THF)、二甲基亚砜(DMSO)、二氯甲烷(DCM)、三氟乙酸(TFA)、二甲基甲酰胺(DMF)、1,1-羰基二咪唑(CDI)、异丁基氯甲酸酯(iBuCF)、N-羟基琥珀酰亚胺(HOSu)、N-羟基苯并三唑(HOBT)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)、双(2-氧-3-噁唑烷基)膦酰氯(BOP)、叔丁氧基羰基(BOC)、苄氧基羰基(CbZ)。
1H-NMR是在Varian VXR-300或Varian Unity-300仪器上记录的。化学位移以百万分之一(ppm,d单位)表示。偶合常数以赫兹(Hz)为单位。裂解方式以s(单峰)、d(二重峰)、t(三重峰)、q(四重峰)、m(多重峰)、b(宽峰)表示。低分辨率质谱(MS)在JOEL JMS-AX505HA、JOEL SX-102或SCIEX-APliii质谱仪上记录。电子喷射电离(electrosprayionization(ESI))、化学电离(CI)、电子撞击(EI)或快速原子轰击(FAB)方法中,所有的质谱均记录阳离子状态。红外(IR)光谱在Nicolet 510 FT-IR红外分光光度仪上用1-mmNaCl槽得到。旋光在Perkin-Elmer 241旋光计上测得。所有的反应均用0.25mm E.Merck硅胶板(60F-254)的薄层层析进行检查,用紫外光观察,或以7%磷钼酸或茴香醛的乙醇溶液显色。快速柱层析在硅胶(230~400目,Merck)上进行。
用装有Delta-pak径向压缩筒(C18柱,300A,15m,47mm×300mm)的Waters Model 3000 Delta Prep型制备性反向高压液相色谱法(RP-HPLC)将产品进行纯化。在所有的情况下均采用线性梯度,并且流速为100ml/分钟(to=5.0分钟)。所有的溶剂均含有0.1%三氟乙酸(TFA)。分析纯度用装有Waters 990二极管排列光谱仪(t范围200~400nM)的Waters 600E系统通过RP-HPLC法测定。固定相为Vydac C18柱(5m,4.6mm×250mm)。流速为1.0×1.5ml/分钟(to=2.8或3.0分钟),溶剂系统见上面所述。数据以tr(保留时间,分钟)表示(%乙腈-时间)。
应用以上所述的通法A-E制备下面的本发明化合物。
实施例1
2-[2,4-二氧-5-苯基-3-(3-苯基-脲基)-2,3,4,5-四氢-苯并[b][1,4]二氮杂-1-基]-N-异丙基-N-苯基-乙酰胺
在搅拌下,向冷却至3℃的1-(2,4-二氧-1-苯基-2,3,4,5-四氢-1H-苯并[b][1,4]-二氟杂-3-基)-3-苯基脲(0.100g)的N,N-二甲基甲酰胺(2ml)溶液中加入氢化钠(0.0104g;60%在矿物油中的混悬液)。将混合物搅拌20分钟,然后一次性加入2-溴-N-异丙基-N-苯基乙酰胺(0.0656g)。所得的混合物于室温搅拌过夜。粗品反应混合物经制备性RP-HPLC纯化,以100ml/分的速率在30分钟内用含有0.1%三氟乙酸缓冲液的60~72%乙腈的水溶液进行梯度洗脱。将含有所需物质的部分合并,冷冻并冷冻干燥,得到标题化合物(0.0653g),为白色粉末。1HNMR(300MHz,DMSO-d6):d0.95(d,J=7.3Hz,3H),0.98(d,J=7.3Hz,3H),4.19(d,J=16.6Hz,1H),4.48(d,J=16.9Hz,1H),4.79(m,1H),5.04(d,J=7.8Hz,1H),6.87-6.92(m,1H),6.95(d,J=7.6Hz,1H),7.18-7.57(m,17H),9.14(s,1H);MS(FAB):m/z=562(MH+);TLC(CH2Cl2/CH3OH,19∶1):R1=0.19;RP-HPLC(Vydac C-18,25cm×4.6mm;60-72%CH3CN在H2O与0.1%TFA缓冲液;30分钟;1ml/min):tr=17.5min(to=2.5min);m.p.:230-235℃
在PirkLe covalent(L)-苯基甘氨酸柱(25cm×10.0mm)上分离标题化合物的对映体(0.014g),用甲醇/水(80∶20)以5ml/分的速率进行恒溶剂成分洗脱,将从第4次(相当于第1次洗脱的对映体)注入而得到的洗脱液合并,并在减压下蒸发,得到对映体1,为白色粉末。同样,将相当于第2次洗脱的对映体部分合并,并在减压下蒸发,得到对映体2,为白色粉末。对映体1:手性HPLC(Pirkle covalent(L)-苯基甘氨酸,25cm×4.6mm;CH3OH/H2O(78∶22)恒溶剂成分;1.5ml/min):tr=14.5min(to=2min);MS(FAB):m/z=562.1(MH+)对映体2:手性HPLC(Pirkle covalent(L)-苯基甘氨酸,25cm×4.6mm;CH3OH/H2O(78∶22)恒溶剂成分;1.5ml/min):tr=18min(to=2min);MS(FAB):m/z=562.0(MH+)
实施例2
1H-吲哚-2-羧酸[1-(异丙基-苯基-氨基甲酰基甲基)-2,4-二氧-5-苯基-2,3,4,5-四氢-1H-苯并[b][1,4]二氮杂-3-基]-酰胺
于环境温度在剧烈搅拌下,向2-(3-氨基-2,4-二氧-5-苯基-2,3,4,5-四氢-苯并[b][1,4]二氮杂-1-基)-N-异丙基-N-苯基乙酰胺(0.116g)的N,N-二甲基甲酰胺(5ml)溶液中依次加入吲哚-2-羧酸(0.0423g,0.262mmol)、N-羟基苯并三唑(0.0354g)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.0503g)。滴加三乙胺(8滴)以继续达到溶液的碱度(pH=9)。所得的混合物在环境温度下搅拌5小时。在真空下蒸除溶剂,得到黄色油状物,该油状物经硅胶(9g)快速层析纯化,用乙酸乙酯和己烷(2∶3,200ml)混合液洗脱。将含有所需产品的部分合并,在真空下蒸发,得到标题化合物(0.141g),为白色泡沫状物。1H NMR(300MHz,CDCl3):d1.06(d,J=7.3Hz,3H),1.09(d,J=7.3Hz,3H),4.22(d,J=16.6Hz,1H),4.40(d,J=16.4Hz,1H),5.02(m,1H),5.50(d,J=7.1Hz,1H),7.02(d,J=8.1Hz,1H),7.10-7.47(m,16H),7.57(d,J=6.8Hz,1H),7.67(d,J=7.8Hz,1H),9.29(brs,1H);MS(FAB):m/z=586.0(MH+);TLC(EtOAc/己烷(2∶3)):Rf=0.16;RP-HPLC(Vydac C-18,25cm×4.6mm;51-60%CH3CN在H2O与0.1%TFA缓冲液;30分钟;1ml/min):tr=19.5min(to=3min)
实施例3
1H-吲哚-2-羧酸{1-[异丙基-(4-甲氧基苯基)-氨基甲酰基-甲基]-2,4-二氧-5-苯基-2,3,4,5-四氢-1H-苯并[b][1,4]二氮杂-3-基}-酰胺
于室温在搅拌下,向2-(3-氨基-2,4-二氧-5-苯基-2,3,4,5-四氢-苯并[b][1,4]二氮杂-1-基)-N-异丙基-N-(4-甲氧基-苯基)-乙酰胺(500mg)的N,N-二甲基甲酰胺(15ml)溶液中依次加入吲哚-2-羧酸(174mg)、N-羟基苯并三唑(143mg)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.203g)。所得混合物在室温下搅拌18小时。在减压下蒸除溶剂,得到黄色油状物,将该油状物溶于乙酸乙酯(75ml)中,用水(2×30ml)洗涤,经硫酸钠干燥,过滤并在减压下浓缩,得到褐色泡沫状物。粗品在Delta-Pak C-18柱上经制备性HPLC纯化,以100ml/分的速率在30分钟内用含0.1%三氟乙酸缓冲液的50%~60%乙腈的水溶液进行线性梯度洗脱。将合适的部分合并,冷冻并冷冻干燥,得到标题化合物的TFA盐(0.550g),为白色粉末。1HNMR(300MHz,CDCl3):d1.06(m,6H),3.85(s,3H),4.27(d,J=16.6Hz,1H),4.34(d,J=16.6Hz,1H),4.99(m,1H),5.51(d,J=7.4Hz,1H),6.96-7.42(m,17H),7.66(m,2H),9.54(brs,1H)TLC(二氯甲烷/甲醇(9∶1)):Rf=0.64MS(FAB):m/z=616.2(MH+)(计算值.for C36H33N5O5=615.2484)
实施例4
2-[1-(异丙基-苯基-氨基甲酰基甲基)-2,4-二氧-5-苯基-2,3,4,5-四氢-1H-苯并[b][1,4]二氮杂-3-基氨基甲酰基]-吲哚-1-基-乙酸
在剧烈搅拌下,向冷却至3℃的1H-吲哚-2-羧酸[1-(异丙基-苯基-氨基甲酰基甲基)-2,4-二氧-5-苯基-2,3,4,5-四氢-1H-苯并[b][1,4]二氮杂-3-基]-酰胺(0.101g)的N,N-二甲基甲酰胺(3ml)溶液中加入氢化钠(0.0083g)(60%在矿物油中的混悬液)。20分钟后加入叔丁基溴乙酸酯(0.0336g)。所得混合物在冰浴冷却下搅拌90分钟,随后慢慢地温热至室温并搅拌过夜。在减压下蒸发溶剂,得到棕色油状物,将该油状物溶于二氯甲烷(30ml)中,并依次用饱和碳酸氢钠水溶液(20ml)和盐水(20ml)洗涤。所得的溶液经硫酸钠干燥,过滤并在减压下蒸发,得到黄色油状物(0.142g),该油状物经硅胶(9g)快速层析纯化,用乙酸乙酯和己烷(1∶2,200ml)混合液洗脱。将含所需产品的部分合并,并蒸发,得到{2-[1-(异丙基-苯基-氨基甲酰基甲基)-2,4-二氧-5-苯基-2,3,4,5-四氢-1H-苯并[b][1,4]二氮杂-3-基氨基甲酰基]-吲哚-1-基}-乙酸叔丁基酯(0.092g),为白色泡沫状物。1H NMR(300MHz,CDCl3):d 1.07(d,J=4.9Hz,3H),1.09(d,J=4.6Hz,3H),1.37(s,9H),4.17(d,J=16.6Hz,1H),4.44(d,J=16.9Hz,1H),5.01(m,1H),5.18(d,J=17.1Hz,1H),5.24(d,J=18Hz,1H),5.47(d,J=7.6Hz,1H),7.01(dd,J=1.2,8.3Hz,1H),7.13-7.51(m,17H),7.57(d,J=7.3Hz,1H),7.67(d,J=7.8Hz,1H);MS(FAB):m/z=700.2(MH+);TLC(EtOAc/己烷,23):Rf=0.35;RP-HPLC(Vydac C-18,25cm×4.6mm;60-70%CH3CNinH2Owith0.1%TFA缓冲液,30分钟;1ml/min):tr=17.5min(to=3min)
于室温在搅拌下,向{2-[1-(异丙基-苯基-氨基甲酰基甲基)-2,4-二氧-5-苯基-2,3,4,5-四氢-1H-苯并[b][1,4]二氮杂-3-基氨基甲酰基]-吲哚-1-基}-乙酸权丁基酯(0.072g)的二氯甲烷(4ml)溶液中逐步地加入三氟乙酸(1.5ml)。反应物搅拌30分钟后,在减压下蒸发二氯甲烷和三氟乙酸,得到透明的玻璃状物。该玻璃状物在C-18柱上经制备性RP-HPLC纯化,以100ml/分的速率在30分钟内用含0.1%三氟乙酸缓冲液的45%-55%乙腈的水溶液进行梯度洗脱。将含所需物质的部分合并,冷冻并冷冻干燥,得到标题化合物(0.050g),为白色粉末。1H NMR(300MHz,CDCl3):d1.07(d,J=4.4Hz,3H),1.10(d,J=4.4Hz,3H),4.23(d,J=16.6Hz,1H),4.40(d,J=16.6HZ,1H),5.01(m,1H),5.06(s,2H),5.44(d,J=7.1Hz,1H),7.03(dd,J=1.2,8.1Hz,1H),7.17-7.52(m,17H),7.67(d,J=8.1Hz,1H),7.74(d,J=7.1Hz,1H);MS(ES):m/z=644.2(MH+);TLC(CH2Cl2/CH3OH(19∶1)):Rf=0.15;RP-HPLC(Vydac C-18,25cm×4.6mm;45-55%CH3CN在H2O与0.1%TFA缓冲液,30分钟;1ml/min):tr=22min(to=3min).
实施例5
2-(2,4-二氧-5-苯基-3-{3-[3-(1H-四唑-5-基)-苯基]-脲基}-2,3,4,5-四氢-苯并[b][1,4]二氮杂-1-基)N-异丙基-N-苯基乙酰胺
于室温在剧烈搅拌下,向2-(3-氨基-2,4-二氧-5-苯基-2,3,4,5-四氢-苯并[b][1,4]二氮杂-1-基)-N-异丙基-N-苯基-乙酰胺(0.070g)的四氢呋喃(3ml)溶液中一次性加入1,1-羰基二咪唑(0.025g)。得到的混合物于室温搅拌90分钟。一次性加入3-(2H-四唑-5-基)苯胺盐酸盐(31.3mg),反应混合物加热回流过夜。将反应混合物过滤并浓缩滤液,得到黄色油状物。该油状物在C-18柱上经制备性RP-HPLC纯化,以100ml/分的速率在30分钟内用含0.1%三氟乙酸缓冲液的43~53%乙腈的水溶液进行梯度洗脱。将含有所需物质的部分合并,冷冻并冷冻干燥,得到标题化合物,为白色粉末(50mg)。1H NMR(300MHz,DMSO-d6):d 0.96(d,J=7.3Hz,3H),0.98(d,J=7.3Hz,3H),4.20(d,J=16.8Hz,1H),4.49(d,J=17.1Hz,1H),4.79(m,1H),5.06(d,J=7.3Hz,1H),6.98(m,2H),7.24-7.55(m,17H),8.17(s,1H),9.44(s,1H)MS(FAB):m/z=630.2(MH+)(计算值forC34H31N9O4=629.2502)TLC(CH2Cl2/CH3OH(9∶1)):Rf=0.24RP-HPLC(Vydac C-18,25cm×4.6mm;43-53%CH3CN在H2O与0.1%TFA缓冲液;30分钟;1ml/min):tr=15min(to=3min)
实施例6
3-{3-[1-异丙基-苯基-氨基甲酰基甲基)-2,4-二氧-5-苯基-2,3,4,5-四氢-1H-苯并[b][1,4]二氮杂-3-基]脲基}苯甲酸乙酯
向2-(3-氨基-2,4-二氧-5-苯基-2,3,4,5-四氢苯并[b][1,4]二氮杂-1-基-N-异丙基-N-苯基乙酰胺(288mg)的二氯甲烷(3ml)溶液中加入3-乙氧基羰基苯基异氰酸酯(124mg)的二氯甲烷(3ml)溶液。使反应于室温下搅拌30分钟。在真空下蒸除二氯甲烷,残余物混悬于乙腈中并在搅拌下加热回流1小时。在冷至0℃化合物40析出。滤液用冷的乙腈洗涤,得到标题化合物,为白色固体(312mg,76%)。1H-NMR(300MHz,d6-DMSO):d 9.4(s,1H),8.05(s,1H),7.6-6.9(m,18H),5.05(d,9Hz,1H),4.8(m,1H),4.48(d,16 Hz,1H),4.3(dd,6.8 Hz,2H),4.18(d,15.8 Hz,1H),1.27(t,7.2 Hz,3H),0.96(m,6H);MS(FAB)=634(MH+).
实施例7
3-{3-[1-(异丙基-苯基-氨基甲酰基甲基)-2,4-二氧-5-苯基-2,3,4,5-四氢-1H-苯并[b][1,4]二氮杂-3-基]-脲基}苯甲酸
将3-{3-[1-(异丙基-苯基-氨基甲酰基甲基)-2,4-二氧-5-苯基-2,3,4,5-四氢-1H-苯并[b][1,4]二氮杂-3-基]-脲基}苯甲酸乙酯(312mg,0.493mol)的甲醇(23ml)和四氢呋喃(10ml)溶液加热回流。加入5%碳酸钾水溶液(6.5ml),并保持回流2.5小时。反应混合物在真空下浓缩,残余物用1NHCl和水中和并研磨,得到粗产品。将粗产品溶于乙酸乙酯(20ml)中,加热回流3小时,然后冷却。过滤分离生成的沉淀,在真空下干燥,得到标题化合物,为白色固体(225mg,75%)。1H-NMR(300MHz,d6-DMSO):d 9.4(s,1H),8.05(s,1H),7.6-6.9(m,18H),5.05(d,9Hz,1H),4.8(m,1H),4.48(d,16Hz,1H),4.18(d,15.8Hz,1H),0.96(m,6H);MS(FAB)=606(MH+)。
陈述上述实施例以便更好的叙述制备本发明化合物的合成方法。此外,用于本发明通法的具体的中间体可以按下述方法制备。
中间体1
2-(苯基亚肼基)丙二酸
于室温在剧烈搅拌下,向丙酮二酸-水合物(29.33 g)的乙醇(140ml)和水(300ml)溶液中在40分钟内滴加苯肼(23.3g)。得到的泥浆状物于室温搅拌过夜。过滤分离固体,依次用冷水(100ml)和乙醇(25ml)洗涤并空气干燥。然后在干燥仪内于75℃真空干燥过夜,得到标题化合物,为黄色固体(42.38g)1H(300MHz,DMSO-d6):d 7.12(t,1H),7.35-7.48(m,4H):m.p.:155-157℃(分解)。
中间体2
2-(苯基亚肼基)-丙二酰二氯
于5℃向搅拌的中间体1(14.73g)的氯仿(90m1)泥浆状物中在20分钟内分批加入五氯化磷(36.84g)。加毕,溶液温至室温并搅拌1小时,接着加热回流3小时。溶液在冰浴上冷却,过滤分离生成的沉淀,用冷的己烷(50ml)洗涤,并在真空下干燥过夜,得标题化合物(13.4g),为亮黄色固体。1H(300MHz,DMSO-d6):d 7.12(t,1H),7.20-7.56(m,4H);m.p.:135-138℃(分解)。
中间体3
4-甲氧基-N-(2-苯基氨基苯基)苯甲酰胺
在氮气氛和剧烈搅拌下,将N-苯基-1,2-苯二胺(20.15g)的二氯甲烷(325ml)溶液和三乙胺(11.07g)在冰/丙酮浴上冷却。于20分钟内滴加溶于二氯甲烷(100ml)中的茴香酰氯(18.66g),同时保持温度<5℃。使反应混合物温至室温并搅拌2小时。有机溶液依次用水(200ml)、2 N稀HCl(80ml)和饱和盐水溶液(160ml)洗涤,然后经硫酸钠干燥并经二氧化硅垫(150g)过滤。二氧化硅用乙酸乙酯(1L)洗脱,洗脱液在真空下蒸发,得到粉红色固体。该固体与乙醚(350m])一起研磨过夜,于冰浴上冷却、过滤、并在真空下干燥,得到标题化合物,为淡粉红色固体(21.67g)。1H(300MHz,CDCl3):d 3.82(s,3H),5.75(brs,1H),6.80-6.91(m,5H),7.12-7.29(m,5H),7.62(d,J=8.8Hz,2H),8.15(dd,J=1.7,7.8Hz,1H),8.36(s,1H);TLC(EtOAc/Hex,1∶4):Rf=0.24;m.p.:148-150℃
中间体4
N-(4-甲氧基苄基)-N′-苯基-苯-1,2-二胺
向冷至5℃的搅拌的氢化铝锂(1.0g)的THF(40ml)溶液中于45分钟内加入4-甲氧基-N-(2-苯基氨基-苯基)苯甲酰胺(5.0g)的THF(30ml)溶液。加毕,反应混合物加垫回流1.5小时。将溶液冷至室温,过量的氢化铝锂用乙醇处理,直至氢气逸出停止。加入饱和碳酸氢钠水溶液(100ml),得到的溶液用乙酸乙酯(3×100ml)萃取。合并有机萃取液经硫酸钠干燥并经二氧化硅垫过滤。二氧化硅垫用乙酸乙酯(500ml)洗涤,并将有机部分合并。在真空下浓缩滤液,得到的棕色油状物在放置中固化,得到标题化合物(4.78g)。1H(300MHz,CDCl3):d 3.79(s,3H),4.27(s,2H),4.52(brs,1H),5.08(s,1H),6.67-6.74(m,4H),6.79-6.86(m,3H),7.04-7.24(m,6H);TLC(EtOAc/Hex(1∶4)):Rf=0.57
中间体5
1-(4-甲氧基苄基)-5-苯基-3-(苯基亚肼基)-1,5-二氢-苯并[b][1,4]二氮杂-2,4-二酮
在搅拌下于冰/甲醇浴上,在30分钟内将中间体4(4.86g)的THF(40ml)溶液和2-(苯基亚肼基)丙二酰基二氯(5.58g)的THF(40ml)溶液同时地滴加。将该溶液温至室温并搅拌过夜。过滤分出黄色沉淀,用冷的THF(40ml)洗涤,空气干燥并在真空下干爆过夜,得到标题化合物(6.23g),为黄色固体。
1H(300MHz,CDCl3):d 3.78(s,3H),4.69(d,J=14.7Hz,1H),5.76(d,J=14.9Hz,1H),6.80-6.87(m.3H),7.02-7.12(m,4H),7.19-7.40(m,11H),11.19(s,1H);MS(FAB):m/z=477.0(MH+);TLC(EtOAc/Hex,1∶4):Rf=0.18
中间体6
3-氨基-1-(4-甲氧基苄基)-5-苯基-1,5-二氢苯并[b][1,4]二氮杂-2,4-二酮
向剧烈搅拌和冷至10℃的锌粉(6.49g)的乙酸(50ml)泥浆状物中在15分钟内加入1-(4-甲氧基苄基)-5-苯基-3-(苯基亚肼基)-1,5-二氢苯并[b][1,4]二氮杂-2,4-二酮(5.75 g,12.1mmol)的乙酸(30ml)泥浆状物。加毕,将溶液温至室温并搅拌3小时。过滤分出锌粉,用乙酸乙酯(75ml)洗涤。滤液在真空下浓缩,并在水(60ml)和乙酸乙酯(100ml)之间分配。用饱和碳酸钠水溶液调节pH至9,并分离各相。水相用乙酸乙酯(2×75ml)萃取,将有机层合并,经硫酸镁干燥,过滤并在真空下浓缩,得到的黄色油状物在真空下干燥,得到标题化合物(4.79g)。
NMR(300 MHz,CDCl3):d 3.05(s,2H),3.75(s,3H),4.35(s,1H),4.64(d,J=14.7HZ,1H),5.82(d,J=14.7Hz,1H),6.59-6.85(m,6H),7.06-7.29(m,6H),7.51(d,J=7.4Hz,1H);MS(FAB):m/z=388.2(MH+);TLC(CH2Cl2/CH38H(9∶1)):Rf=0.50
中间体7
3-氨基-1-苯基-1,5-二氢苯并[b][1,4]二氮杂-2,4-二酮
于室温下向搅拌的3-氨基-1-(4-甲氧基苄基)-5-苯基-1,5-二氢苯并[b][1,4]二氮杂-2,4-二酮(0.50g)的乙腈/水(9∶1,12ml)溶液中在10分钟内分次加入硝酸铈铵(1.84g)。溶液于室温搅拌过夜。该溶液在真空下浓缩,得到的固体在饱和碳酸钾水溶液(40ml)和乙醇(60ml)之间分配。分离各相,水相用乙醇(4×50ml)萃取。将乙醇部分合并,经硫酸钠干燥,并在真空下浓缩,得到褐色固体。该固体用煮沸的CH2Cl2(10×60ml)充分地萃取,将有机相合并,经硫酸钠干燥,过滤并浓缩,得到标题化合物(0.30g),为褐色固体。1H(300MHz,DMSO-d6):d 1.98(brs,2H),4.08(s,1H),6.86(d,J=8.4Hz,1H),7.11-7.46(m,8H),10.78(br s,1H);13C(75.429MHz,DMSO-d6):d 56.98,123.41,126.22,126.51,127.34,128.30,128.89,130.15,132.29,134.42,142.36,168.13,169.39.MS(FAB):m/z=268.10(MH+);TLC(CH2Cl2/CH3OH,15∶1):Rf=0.21
中间体3
1-(2,4-二氧-1-苯基-2,3,4,5-四氢-1H-苯并[b][1,4]二氮杂-3-基)-3-苯基脲
于室温在搅拌下,向3-氨基-1-苯基-1,5-二氢-苯并[b][1,4]-二氮杂-2,4-二酮(0.398g)的二氯甲烷(5ml)泥装状物中逐渐加入苯基异氰酸酯(0.177g)。反应混合物于室温搅拌2小时,在该期间之后过滤分出淡黄色沉淀,得到标题化合物(0.413g)。1H NMR(300MHz,DMSO-d6):d 4.97(d,J=7.5Hz,1H),6.88-6.97(m,3H),7.13-7.47(m,12H),9.16(s,1H),10.78(brs,1H);TLC(CH2Cl2/CH3OH,19∶1):Rf=0.21
中间体9
N-异丙基-N-苯基-2-(2-苯基氨基苯基氨基)乙酰胺
将碳酸钾(6.9g)加到N-苯基苯二胺(9.2g)的DMF和2-溴-N-异丙基-N-苯基乙酰胺(12.7g)的DMF(200ml)溶液中,并将混合物搅拌过夜。在真空下蒸除DMF,残余物溶于乙酸乙酯(400ml)中,用1N稀HCl(4×250ml)充分地洗涤。有机层用水(2×200ml)洗涤,干燥(Na2SO4)并蒸发,得到17.8g粗的烷基化产物。该油状物经硅胶(600g)层析纯化,首先用CHCl3(8000ml)然后用己烷∶乙酸乙酯(2∶1,8000ml)作为洗脱剂,得到标题化合物(10g),为油状物。
1H-NMR(300MHz,CDCl3):d7.42-6.8(m,14H),6.36(d,1H),4.95(m,1H),3.22(s,2H),1.05(d,6H);MS(FAB)=360(MH+);TLC,Rf=0.18(CHCl3).
中间体10
2-[2,4-二氧-5-苯基-3-(苯基亚肼基)-2,3,4,5-四氢苯并[b][1,4]二氮杂-1-基]-N-异丙基-N-苯基乙酰胺
于0℃在氮气氛下,将N-异丙基-N-苯基-2-(2-苯基氨基苯基氨基)-乙酰胺(10g)和2-(苯基亚肼基)-丙二酰二氯(6.83g)分别溶于THF(100ml)中,并于搅拌下同时加到含有THF(100ml)的烧瓶中。反应混合物温至室温并搅拌4小时。在真空下蒸除THF,残余物溶于乙酸乙酯(200ml)中。乙酸乙酯溶液用10%碳酸钠水溶液(2×200ml)和水(2×200ml)洗涤,干燥(Na2SO4)并在真空下浓缩。残余的泡沫状物用乙醚(50ml)处理,析出标题化合物,为亮黄色固体(7.5g)。将母液浓缩,得到褐色泡沫状物(2.5g)。1H-NMR(300MHz,CDCl3):d 11.4 and 10.85(s,1H),7.6-6.8(m,19H),5.05(m,1H),4.4(m,2H),1.05(m,6H);MS(FAB)=532(MH+);TLC,Rf=0.19(hexane∶ethyl acetate,2∶1).
中间体11
2-(3-氨基-2,4-二氧-5-苯基-2,3,4,5-四氢苯并[b][1,4]二氯杂-1-基)-N-异丙基-N-苯基乙酰胺
将锌粉(9.1g)分次加到冷至0℃的2-[2,4-二氧-5-苯基-3-(苯基亚肼基)-2,3,4,5-四氢苯并[b][1,4]二氮杂-1-基]-N-异丙基-N-苯基乙酰胺(7.5g)的冰乙酸泥浆状物中。将反应温至室温并另外搅拌1小时。通过硅藻土垫过滤出锌粉,在真空下蒸出冰乙酸。残余物溶于乙酸乙酯(200ml)中并用10%碳酸钠水溶液(2×100ml)和水(2×100ml)洗涤,干燥(Na2SO4)并蒸发,得到褐色油状物。与己烷和乙酸乙酯一起研磨,得到标题化合物,为淡褐色粉末(6.3g)。1H-NMR(300 MHz,CDCl3):d 7.6-6.8(m,14H),5.05(m,1H),4.3-4.0(m,3H)1.05(d,6H);MS(FAB)=448(MH+);TLC,Rf=0.25(chloroform∶methanol,9∶1).
中间体12
2-(3-氨基-2,4-二氧-5-苯基-2,3,4,5-四氢-苯并[b][1,4]二氮杂-1-基)-N-异丙基-N-(4-甲氧基苯基)乙酰胺
在室温下向搅拌的2-[2,4-二氧-5-苯基-3-(苯基-3-(苯基-亚肼基)-2,3,4,5-四氢苯并[b][1,4]二氮杂-1-基)-N-异丙基-N-(4-甲氧基-苯基)乙酰胺(4.28g)的乙酸(50ml)溶液中加入锌粉(4.11g)并搅拌3小时。滤出锌粉,滤液在真空下浓缩,得到的油状物在水(60ml)和乙酸乙酯(100ml)之间分配。用6N氢氧化钠调节pH至8,并分离各相。水相用乙酸乙酯(2×75ml)萃取,将有机相合并,经硫酸镁干燥、过滤、并在真空下浓缩,得到黄色泡沫状物。粗产品经硅胶(80g)快速层析纯化,依次用乙酸乙酯(260ml)洗脱(为了除去杂质)和二氯甲烷/甲醇(19∶1,200ml)洗脱(为了洗脱产物)。将合适的部分合并并浓缩、得到标题化合物(2.58g),为黄色泡沫状物。1H(300MHz,CDCl3):d 1.08(d,J=6.6Hz,6h),2.22(br s,2H),3.85(s,3H),4.12-4.35(m,3H),5.01(m,1H),6.91-7.00(m,3H),7.12(m,2H),7.22-7.43(m,8H)TLC(CH2Cl2/CH3OH(19∶1)):Rf=0.25
中间体13
2-[2,4-二氧-5-苯基-3-(苯基-亚肼基)-2,3,4,5-四氢苯并[b][1,4]二氮杂-1-基]-N-异丙基-N-(4-甲氧基-苯基)乙酰胺
在搅拌下,于冰/甲醇浴上并在30分钟内将N-异丙基-N-(4-甲氧基-苯基)-2-(2-苯基氨基苯基氨基)-乙酰胺(3.00g)的THF(30ml)溶液和2-(苯基-亚肼基)丙二酰二氯(1.89g)的THF(30ml)溶液同时滴加。加毕,使溶液温至室温并搅拌过夜。溶剂在减压下蒸发,得到的油状物溶于乙酸乙酯(250ml)中,用饱和碳酸氢钠溶液洗涤并经硫酸钠干燥、过滤、并在减压下浓缩,得到标题化合物(4.28g),为黄色泡沫状物。1H(300MHz,CDCl3):d 1.13(m,6H),3.87(s,3H),4.17-4.55(m,2H),5.05(m,1H),6.88-7.60(m,18H),10.68(s,0.5H),11.44(s,0.5H)TLC(EtOAc/Hex(2∶3)):Rf=0.38
中间体14
N-异丙基-N-(4-甲氧基-苯基)-2-(2-苯基氨基-苯基氨基)乙酰胺
向N-苯基-苯-1,2-二胺(3.08g)的DMF(35ml)溶液中加入碳酸钾(2.31g)和2-溴-N-异丙基-N-(4-甲氧基-苯基)-乙酰胺(4.79g)并于室温搅拌18小时。在真空下蒸除溶剂,得到的油状物溶于乙酸乙酯(250ml)中,用1N稀HCl(4×100ml)洗涤,经硫酸钠干燥、过滤和浓缩,得到棕色油状物。该油状物在硅胶(70g)上进行快速层析,用乙酸乙酯/己烷(1∶4,1L)洗脱。将含有所需产品部分合并,在减压下浓缩,得到标题化合物,为褐色泡沫状物(3.95g)。1H NMR(300MHz,CDCl3):d 1.05(d,J=6.9Hz,6H),3.44(s,2H),3.87(s,3H),4.97(m,1H),5.37(brs,1H)6.36(d,J=7.4Hz,1H),6.69(t,1H),6.71-7.21(m,11H)TLC(EtOAc/己烷(1∶4)):Rf=0.18
中间体15
2-溴-N-异丙基-N-(4-甲氧基苯基)乙酰胺
在搅拌和室温下,向异丙基-(4-甲氧基-苯基)胺(25.11g)的二氯甲烷(250ml)溶液中加入三乙胺(15.38g)。将溶液在冰浴(<3℃)上冷却,并在搅拌和冰浴冷却下于45分钟内滴加溶于二氯甲烷(100ml)的溴乙酰溴(30.68g)。反应混合物于室温搅拌过夜,用0.3N HCl(300ml)和盐水(300ml)洗涤,经硫酸钠干燥、过滤、在减压下蒸发,得到暗棕色油状物。该油状物经硅胶垫(150g)过滤,硅胶垫用乙酸乙酯/己烷(1∶1,900ml)洗脱,滤液在减压下蒸发,得到标题化合物(41.05g),为棕色油状物,在静置中析出结晶。1H NMR(300MHz,CDCl3):d 1.04(d,J=6.8Hz,6H),3.53(s,2H),3.84(s,3H),4.93(m,1H),6.93(d,J=9.1Hz,2H),7.10(d,J=9.1Hz,3H)TLC(EtOAc/己烷(3∶17)):Rf=0.18
中间体16
异丙基-(4-甲氧基-苯基)-胺
在室温下向搅拌的4-甲氧基-苯基胺(1.24g)的甲醇(15ml)溶液中依次加入冰乙酸(415mg)、丙酮(669mg)以及1M氰基硼氢化钠的THF(12.7ml)溶液。反应混合物于室温下搅拌过夜。用6N HCl调节pH至2并搅拌30分钟,在此期间后将过量的氰基硼氢化钠完全处理掉。用1N NaOH调节pH至8.5,得到的溶液用乙醚(2×50ml)和乙酸乙酯(50ml)萃取。将有机萃取液合并,经硫酸钠干燥、过滤并在减压下浓缩,得到标题化合物(1.42g),为黄色油状物。1H NMR(300MHz,CDCl3):d 1.18(d,J=6.1Hz,6H),2.92(brs,1H),3.55(m,1H),3.75(s,3H),6.57(d,J=9.1Hz,2H),6.78(d,J=8.8Hz,2H)TLC(EtOAc/Hex(2∶3)):Rf=0.72
中间体17
3-氨基苯乙腈
将3-硝基苯乙腈(8.0g)的EtOH(100ml)溶液用5%钯-碳(0.8g)在1个大气压下氢化4小时。通过Hyflo过滤除去催化剂并蒸发滤液。将残余物进行层析,用EA∶己烷(1∶2)洗脱,得到标题化合物(5.25g),为橙色油状物。T.l.c.hexane∶EA(2∶1)Rf0.45;NMR(300MHz,CDCl3)d 3.792H,s);3.9(2H,br);6.7(3H,m);7.2(H,M).
中间体18
3-(2H-四唑-5-基)苯基胺盐酸盐
在氮气氛下将3-氨基苯基腈(10.0g)和三丁基锡叠氮化物(42g)一起于160℃加热120分钟。经冷却的混合物用乙醚(300ml)稀释,用2N稀HCl(2×200ml)萃取,合并的水萃取液在冰-甲醇浴中冷却30分钟。过滤分离生成的沉淀并用乙醚(100ml)洗涤、干燥,得到淡粉红色固体。用甲醇(600ml)重结晶,得到标题化合物,为米色固体(12.1g)。1H NMR(300MHz,DMSO-d6):d 7.32(d,J=7.8Hz,1H),7.57(t,1H),7.82(m,2H)m.p.:256-262℃(分解)
应用上述通法A-E还可以制得下述本发明化合物,为了方便起见将化合物列于下面表1~9中并列出制备下述化合物的合成方法。为了叙述的方便和容易核对,提供了结构式(A)-(H)以便与表1-9发生联系。表1~9中提供的基团R13-21仅仅为了叙述的方便和容易核对化合物。表1(A)化合物 R4 R5 通法1 CH3 2-Cl-C6H4- C2 CH3 2-CH3-C6H4- C3 CH3 2-COOCH3C6H4- C4 CH3 4-OCH3C6H4- C5 CH3 4-COOCH3C6H4- C6 (CH3)2CH- C6H5- C7 CH3CH2CH2- C6H5- C8 CH3CH2CH2CH2- C6H5- C9 环己基 C6H5- C10 C6H5- C6H5- C11 (CH3)2CH- C6H5CH2- C12 (CH3)2CH- (CH3)2CH- C表2(R)化合物 R13 R14 R15 通法13 H H H D14 2-NH2 4-Cl H D15 2-NH2 H H D16 2-NH2 4-F H D17 2-COOH H H D18 3-COOH H H D19 2-OH 4-Cl OCH3 D20 2-F 4-Cl OCH3 D21 2-NH2 4-Cl OCH3 D表3(C)化合物 R3 R8 R9 R16 通法22 C6H5- H H H D23 C6H5- -CH2COOH H H E24 C6H5 -CH2CH2CH2COOH H H E25 C6H5- H 5-OCH3 H D26 C6H5- -CH2COOH 5-OCH3 H E27 C6H5- -CH2COOH 5-Cl H E28 C6H5- H 5-CH3 H D29 C6H5- -CH2COOH 5-CH3 H E30 C6H5- H 5-OH H D31 C6H5- H 7-NO2 H D32 C6H5- H 7-NH2 H D33 C6H5- H H OCH3 D34 C6H5- H H N(CH3)2D35 C6H5- H H 吗啉代 D36 CH3 H H H D37 CH3 -CH2COOH H H E38 H H H H D39 H H H OCH3 D表4(D)化合物R17 R18 通法40 H 3-OH A41 H 3-NH2 A42 H 3-四唑基 A/B43 H 3-COOCH2CH3 A44 H 3-COOH A45 H 3-NHSO2CF3 A46 H 3-OCH3 A47 H 3-SCH3 A48 H 3-N(CH3)2 A49 H 3-SOCH3 A50 H 3-SOOCH3 A51 H 3-F A52 H 3-CH2COOH A53 H 3-OCH2COOH A54 4-OH H C55 4-OCH3 H C56 4-OCH3 3-COOCH2CH3 A57 4-OCH3 3-COOH A58 4-N(CH3)2 H C59 4-N(CH3)2 3-OH A60 4-N(CH3)2 3-NH2 A61 4-吗啉代 H C62 4-吗啉代 COOH C63 4-N(CH3)2 3-COOCH2CH3 A64 4-N(CH3)2 3-COOH A表5(E)化合物 R6 R7 R19 通法65 H H H C66* -CH3 H H C67* -CH3 H H C68*** -CH3 H 3-OH A69*** -CH3 H 3-OH A70** -CH3 H 3-COOH A71** -CH3 H 3-COOH A72*** -CH3 6-F H C73*** -CH3 6-F H C74**** -CH3 6-OCH3 H C75**** -CH3 6-OCH3 H C***************表示非对映体表6(F)化合物 R7 R8 R9 通法76 H H H D77- F H 7-NH2 D78- F H 7-NH2 D∵*表示非对映体表7(G)
表8(H)化合物 R22 R23 R3 合成方法88 H H CH3 C89 H 3-COOH CH3 A90 H 3-COOH H A91 H 2-OH CH3 A
化合物 | R20 | R21 | 合成方法 |
豚鼠胆囊测定法组织制备:
用颈部脱臼法活杀豚鼠,取出胆囊。将分离出的胆囊清除粘附的结缔组织,每只动物的胆囊被切成二个环状(长2~4mm)。接着将此胆囊环悬挂在器官室内,室内充满了生理盐水溶液,其成分如下:(mM):NaCl(118.4);KCl(4.7);MgSO4×H2O(1.2);CaCl2×2H2O(2.5):KH2PO3(1.2):NaHCO3(25)和葡萄糖(11.1)。使此温浴液保持在37℃,并以95%O2/5%CO2通气。用金链和不锈钢悬挂线将胆囊组织与等张力位移换能器(Grass,Model FTO3D)相连接。然后其反应记录在多道生理记录仪上(Grass,Model 7E)。以每只动物的一片胆囊组织作为时间/溶剂对照,不给予待测化合物。测定方法:
逐渐伸展胆囊环组织(历时120分钟以上),使之达到1克的基础休止张力,以后在整个实验过程中保持这个张力状态。在对基础张力调整的过程中,使环组织暴露于乙酰胆碱(ACH,10-6M)4次,以确证环组织的收缩性。然后使环组织暴露于次最大剂量的硫酸的CCK-8(Sigma,3×10-9M)。在得到稳定的收缩反应后,迅速冲洗环组织3次,并且每5到10分钟休息1小时,使之重新达到一个稳定的基线状态。
化合物先溶解于二甲基亚砜(DMSO)中,然后用水稀释,并通过制作递增浓度-反应曲线的方法对待测化合物进行测定(待测化合物的浓度为10-11M到3×10-6M),接着,在最大剂量待测化合物存在的情况下,以制作浓度-反应曲线的方法对硫酸化CCK-8(10-10M到10-6M)进行测定。测定结束前,加入ACH(10mM),使之引起最大的收缩。对于每一个待测化合物,最少应作3次活性测定。
下面表10列出了通过(I)的代表性化合物的实验数据。浓度为30μM的待测化合物,其对豚鼠胆囊(GPGB)的激动剂活性,是以乙酰胆碱(Ach)诱发的最大收缩的百分数来表示的。
熟悉本专业的技术人员明白,本发明化合物在用于治疗时,可以在前述无毒性作用的剂量范围内给药,如数据所示,对于大白鼠甚至剂量高达12mg/kg也未显示出任何毒性作用。
18小时禁食引起的摄食范例
用雄性,Long-Evans大白鼠(Charles River Co.,Raleigh,NC),体重300~375克,先单个关在悬挂的不锈钢笼内(17.8×25.4×17.8cm高)饲养至少一星期,可随意饮水(笼子后部有自动饮水喷孔),也可随意取食(Lab Blox,Purina Rodent LaboratoryChow#5001),环境为每12小时循环明/暗交替一次(6:00到18:00为照明时间),室温约22.8℃。实验前,在16:00撤除全部食物,保留饮水。次日早晨9:00给大白鼠称体重。在9:45大白鼠被给予待测化合物或安慰剂(2mg/kg),给药途径可以为腹膜内注射(i.p.),经口给药(peros,或p.o.)或者通过预置的十二指肠内插管给药,给药后将大白鼠放入它们原来的笼中。10:00喂食物,10:30对剩余的和洒落的食物进行称重。
豚鼠胆囊测定法,
豚鼠胆囊收缩百分数
(相对于Ach)
化合物号 30μM
3 42%
6 66%
7 34%
9 43%
10 43%
13 46%
14 64%
15 55%
16 90%
17 49%
22 59%
23 73%
24 44%
25 26%
28 53%
30 44%
32 71%
33 55%
40 95%
41 81%
42 79%
44 83%
54 87%
55 70%
58 66%
59 92%
60 96%
64 90%
66 54%
67 78%
68 52%
69 83%
70 93%
71 98%
72 42%
73 62%
79 32%
82 88%
89 66%药剂学实施例
片剂
a.有效成分 50mg
干燥的乳糖(USP) 163mg
微晶纤维素(NF) 69mg
预胶凝化的淀粉(Ph.Eur.) 15mg
硬脂酸镁(USP) 3mg
片重 300mg
将有效成分、微晶纤维素、乳糖和预胶凝化的淀粉通过500微米筛,并在合适的混合容器中混合。硬脂酸镁通过250微米筛,并与上述有效成分混合物混合。混合物用合适的冲头压片。
b.有效成分 50mg
乳糖-水合物(USP) 120mg
预胶凝化的淀粉(Ph.Eur.) 20mg
交联聚乙烯吡咯烷酮(NF) 8mg
硬脂酸镁(USP) 2mg
片重 200mg
将有效成分、乳糖和预胶凝化的淀粉混合,并用水制颗粒。将湿颗粒干燥并磨细。硬脂酸镁和交联聚乙烯吡咯烷酮通过250微米筛,并与上述颗粒混合。用合适的压片冲头将得到的混合物压片。
胶囊剂
a.有效成分 50mg
预胶凝化的淀粉(Ph.Eur.) 148mg
硬脂酸镁(USP) 2mg
装填物重 200mg
将有效成分和预胶凝化的淀粉通过500微米筛,混合,并与润滑剂硬脂酸镁(通过250微米筛)混合。将混合物装入合适大小的硬明胶胶囊中。
b.有效成分 50mg
乳糖-水合物(USP) 223mg
聚乙烯吡咯烷酮(USP) 12mg
交联聚乙烯吡咯烷酮(NF) 12mg
硬脂酸镁 3mg
装填物重 300mg
将有效成分和乳糖混合,并用聚乙烯吡咯烷酮溶液制颗粒。湿颗粒经干燥并磨细。硬脂酸镁和交联聚乙烯吡咯烷酮通过250微米筛,并与上述颗粒混合。将得到的混合物装入合适大小的硬明胶胶囊中。
Claims (19)
1.式(I)化合物及其生理上可接受的盐和溶剂化物:其中X为氢、三氟甲基、烷基、C1-4烷硫基、-O(C1-4烷基)或卤素;
R2为(1)在其2位键合的杂环,该杂环可选自吡咯、四氢吡咯、吲哚、苯并呋喃、噻吩、苯并噻吩、二氢吲哚、喹啉或4-氧苯并呋喃,其中所述吡咯、四氢吡咯、吲哚或二氢吲哚在其环的氮原子上可以任意地由下面定义的基团R8取代,所述吲哚、二氢吲哚、喹啉、苯并呋喃、苯并噻吩或4-氧-苯并呋喃在其苯并环上可以任意地由下面定义的R9基团取代,或者
(2)苯基,或由下述基团独立地单或二取代的苯基:卤素、羟基、氰基、羧基、-O(C1-4烷基)、-O(CH2C5H5)、-COO(C1-4烷基)、氨基、二甲氨基、-NHR10、1-吡咯烷基或四唑基;或者
(3)吡啶基,或由下述基团独立地单或二取代的吡啶基:卤素、甲基、羟基、硝基、氰基、羧基、-O(C1-4烷基)、-O(CH2C6H5)、-COO(C1-4烷基)、氨基或二甲氨基;或者
(4)-NHR11,这里R11见下面定义,或者R11为在N-1位置上有基团R10的7-吲哚基;
R3为氢、C1-6烷基、C3-6环烷基、苯基、或由卤素独立地单或二取代的苯基;
R4独立地为C3-6烷基、C3-6环烷基、C3-6链烯基、苯基、-(CH2)pCN或-(CH2)pCOO(C1-4烷基),并且
R5独立地为C3-6烷基、C3-6环烷基、C3-6链烯基、苄基、苯基、或由下述基团独立地单或二取代的苯基:C1-3烷基、氰基、羟基、二甲氨基、-O(C1-4烷基)、-O(CH2C6H5)、-NH(C1-4烷基)、-C0O(C1-4烷基)、-N(C1-4烷基)2吡咯烷子基、吗啉代或卤素;或者R4为C1-2烷基,并且R5为在2-或4-位上由氯、甲基、甲氧基或甲氧基羰基取代的苯基;
R6为氢或甲基;
R7为氢、羟基、氟、二甲氨基、-O(C1-4烷基)、或-O(CH2C6H5);
R8为-(CH2)bCOOH;
R9为甲基、氯、硝基、羟基、甲氧基或-NHR10;
R10为氢、乙酰基、C1-4烷基、-SO3H、-SO2CH3、-SO2CF3或-SO2C6H5、C1-4烷氧基羰基;
R11为苯基、或者由下述基团独立地单或二取代的苯基:氟、三氟甲氧基、C1-4烷硫基、-(CH2)cCOOH、-(CH2)cCOO(C1-4烷基)、-(CH2)cSCH3、-(CH2)cSOCH3、-(CH2)cSO2CH3、-(CH2)CONH2、-SCH2COOH、-CONH(SO2CH3)、-CONH(SO2CF3)、-(CH2)cN(C1-4烷基)2、-(CH2)cNH(SO2CF3)、-(CH2)cN(SO2CF3)(C1-4烷基)、-(CH2)cSO2NHCO(C1-4烷基)、-(CH2)cSO2N(C1-4烷基)CO(C1-4烷基)、-(CH2)cCONHSO2(C1-4烷基)、-(CH2)cCON(C1-4烷基)SO2(C1-4烷基)、-(CH2)cOR12-(CH2)cNHR10、或由-(CH2)c(四唑基)、-(CH2)c(甲酰氨基四唑基)或-(CH2)c(吡咯烷基)单取代的苯基,或者R11选自吡啶、或由下述基团独立地单或二取代的吡啶基:卤素、甲基、羟基、硝基、氰基、羧基、-O(C1-4烷基)、氨基、二甲氨基、-NHR10;
R12为氢、C1-6烷基、C3-6环烷基、-CH2C6H5、-CH2COOH、-CH2CONH2、-CH2CONH(C1-4烷基)、-CH2CON(C1-4烷基)2或或
z为1或2:
n为1或2
p为整数1~4;
b为整数0~3;
c为零或1。
2.根据权利要求1所述的化合物,这里R1代表式(II)基团,其中R6为甲基,R7为氢、羟基、甲氧基或氟,n为1,或者R1代表基团NR4R5,这里R4代表C3-6烷基、环己基或苯基,R5代表C3-6烷基、或在对位任意地由羟基、二甲基氨基、甲氧基、氟、吡咯烷子基或吗啉代取代的苯基。
3.根据权利要求1或2所述的化合物,其中R1代表基团NR4R5,R4代表丙基或异丙基,R5代表苯基、或在对位由选自羟基、甲氧基、二甲基氨基、氟或吗啉代的基团取代的苯基。
5.根据权利要求1~4中任何一项所述的化合物,其中R2代表在氮原子上未被取代,并且其中苯并环任意地由选自氯、甲基、甲氧基、硝基、羟基或氨基取代的吲哚基团。
6.根据权利要求1~5中任何一项所述的化合物,其中R3代表氢、甲基、环己基、2-氟苯基或苯基。
7.根据权利要求1~6中任何一项所述的化合物,其中R3代表苯基。
8.根据权利要求1~7中任何一项所述的化合物,其中X代表氢。
9.式(I)化合物及其对映体,其中R1代表NR4R5;R4代表异丙基;R5代表对甲氧基苯基R2代表未被取代的2-吲哚基;R3代表苯基,X代表氢。
10.根据权利要求1~9中任何一项所述的用于治疗的化合物。
11.应用权利要求1~9中任何一顼所述的化合物制备的治疗疾病的药物,在这里减轻胃泌素或CCK的作用具有治疗的效果。
12.治疗哺乳动物(包括人)疾病的方法,在这里减轻胃泌素和/或CCK的作用具有治疗的效果,该方法包括服用有效剂量的权利要求1~9中任何一项所述的化合物。
13.含有权利要求1~9中任何一项所述化合物以及一种或多种生理上适用的载体或赋形剂的药用组合物。
14.制备权利要求1所述化合物的方法,该方法包括:
(a)使式(III)化合物与化合物R11Y(IV)反应,其中R1、R3、X和Z同式(I)中的定义。在化合物R11Y(IV)中,Y为基团-NCO、HNCOCl或NHCORa,这里Ra为硝基取代的苯氧基或1-咪唑基,R11同式(I)中的定义,或者为其可转化的基团。
Y为基团-NCO、-NHCOCl或NHCORa,这里Ra为硝基取代的苯氧基或1-咪唑基,
H2N-R11 (VI)其中R11同式(I)中的定义,并且是其可转化的基团。
HOOC-R2 (IX)其中R2同式(I)中的定义,或为其可转化的基团,并且如果需要或要求,可以转化上述化合物为另一本发明的化合物。
15.治疗哺乳动物肥胖及其有关疾病的方法,该方法包括给该哺乳动物服用治疗上有效剂量的权利要求1的化合物,结果在该哺乳动物中取得了减食欲的效果。
16.调节哺乳动物食物吸收的方法,该方法包括给该哺乳动物服用治疗上有效剂量的权利要求1的化合物,结果调节了食物吸收。
17.诱发哺乳动物饱满感的方法,该方法包括给该哺乳动物服用治疗上有效剂量的权利要求1的化合物,结果导致了饱满感。
18.调节哺乳动物食欲的方法,该方法包括给该哺乳动物服用治疗上有效剂量的权利要求1的化合物,结果取得了食欲的调节。
19.式(I)化合物及其生理上可接受的盐和溶剂化物,其中X为氢、三氟甲基、烷基、C1-4烷硫基、-O(C1-4烷基)或卤素;
R2为(1)在其2位键合的杂环,该杂环可选自吡咯、四氢吡咯、吲哚、苯并呋喃、或者二氢吲哚,
其中所述吡咯、四氢吡咯、吲哚或二氢吲哚在其环的氮原子上可以任意地由下面定义的基团R8取代,所述吲哚、二氢吲哚、或苯并呋喃、在其苯并环上可以任意地由下面定义的R9基团取代,或者
(2)苯基,或由下述基团独立地单或二取代的苯基:卤素、羟基、氰基、羧基、-O(C1-4烷基)、-O(CH2C6H5)、-COO(C1-4烷基)、氨基、二甲氨基、-NHR10、1-吡咯烷基或四唑基;或者
(3)吡啶基,或由下述基团独立地单或二取代的吡啶基:卤素、甲基、羟基、硝基、氰基、羧基、-O(C1-4烷基)、-O(CH2C6H5)、-COO(C1-4烷基)、氨基或二甲氨基;或者
(4)-NHR11,这里R11见下面定义,或者R11为在N-1位置上有基团R10的7-吲哚基;
R3为氢、C1-6烷基、C3-5环烷基、苯基、或由卤素独立地单或二取代的苯基;
R4独立地为C3-6烷基、C3-6环烷基、C3-6链烯基、苯基、-(CH2)pCN或-(CH2)PCOO(C1-4烷基),并且
R5独立地为C3-6烷基、C3-6环烷基、C3-6链烯基、苄基、苯基、或由下述基团独立地单或二取代的苯基:C1-3烷基、氰基、羟基、二甲氨基、-O(C1-4烷基)、-O(CH2C6H5)、-NH(C1-4烷基)、-COO(C1-4烷基)、吡咯烷子基、或卤素或者R4为C1-2烷基,并且R5为在2-或4-位上由氯、甲基、甲氧基或甲氧基羰基取代的苯基;
R6为氢或甲基;
R7为氢、羟基、氟、二甲氨基、-O(C1-4烷基)、或-O(CH2C6H5);
R8为-(CH2)bCOOH;
R9为甲基、氯、硝基、羟基、甲氧基或-NHR10;
R10为氢、C1-4烷基、-SO3H、-SO2CH3、-SO2CF3或-SO2C6H5;
R11为苯基、或者由下述基团独立地单或二取代的苯基:氟、三氟甲氧基、C1-4烷硫基、-(CH2)cCOOH、-(CH2)cCOO(C1-4烷基)、-(CH2)cSCH3、-(CH2)cSOCH3、-(CH2)cSO2CH3、-(CH2)CONH2、-SCH2COOH、-CONH(SO2CH3)、-CONH(SO2CF3)、-(CH2)cN(C1-4烷基)2、-(CH2)cNH(SO2CF3)、-(CH2)cN(SO2CF3)(C1-4烷基)、-(CH2)cSO2NHCO(C1-4烷基)、-(CH2)cSO2N(C1-4烷基)CO(C1-4烷基)、-(CH2)cCONHSO2(C1-4烷基)、-(CH2)cCON(C1-4烷基)SO2(C1-4烷基)、-(CH2)cOR12-(CH2)cNHR10、或由-(CH2)c(四唑基)、-(CH2)c(甲酰氨基四唑基)或-(CH2)c(吡咯烷基)单取代的苯基,或者R11选自吡啶、或由下述基团独立地单或二取代的吡啶基:卤素、甲基、羟基、硝基、氰基、羧基、-O(C1-4烷基)、氨基、二甲氨基、-NHR10;
z为1或2;
n为1或2;
p为整数1~4;
b为整数0~3;
c为零或1。
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GB939307833A GB9307833D0 (en) | 1993-04-15 | 1993-04-15 | Modulators of cholecystokinin and gastrin |
GB9307833.5 | 1994-03-29 |
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CN1333077C (zh) * | 2005-04-15 | 2007-08-22 | 华南农业大学 | 缩胆囊素活性片段的串联表达及其应用 |
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-
1993
- 1993-04-15 GB GB939307833A patent/GB9307833D0/en active Pending
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1994
- 1994-01-04 US US08/525,659 patent/US5646140A/en not_active Expired - Lifetime
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1130351C (zh) * | 1996-12-10 | 2003-12-10 | 泽里新药工业株式会社 | 1,5-苯并二氮杂䓬衍生物 |
CN1333077C (zh) * | 2005-04-15 | 2007-08-22 | 华南农业大学 | 缩胆囊素活性片段的串联表达及其应用 |
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