CN1051079C - 苯骈二氮杂䓬衍生物,其制备方法及含它们的药物组合物 - Google Patents
苯骈二氮杂䓬衍生物,其制备方法及含它们的药物组合物 Download PDFInfo
- Publication number
- CN1051079C CN1051079C CN93101848A CN93101848A CN1051079C CN 1051079 C CN1051079 C CN 1051079C CN 93101848 A CN93101848 A CN 93101848A CN 93101848 A CN93101848 A CN 93101848A CN 1051079 C CN1051079 C CN 1051079C
- Authority
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- China
- Prior art keywords
- benzene
- diaza
- pair
- phenyl
- dihydro
- 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.)
- Expired - Lifetime
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- 125000003310 benzodiazepinyl group Chemical class N1N=C(C=CC2=C1C=CC=C2)* 0.000 title abstract 2
- 229940053197 benzodiazepine derivative antiepileptics Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 204
- 150000003839 salts Chemical class 0.000 claims abstract description 47
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 18
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 7
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 656
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 218
- 238000002360 preparation method Methods 0.000 claims description 130
- 238000000034 method Methods 0.000 claims description 126
- -1 pyrrolidyl Chemical group 0.000 claims description 65
- 238000006243 chemical reaction Methods 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 239000001257 hydrogen Substances 0.000 claims description 18
- 150000001412 amines Chemical class 0.000 claims description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
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- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 6
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 6
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- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
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- DXMNJSHCPPFVHG-UHFFFAOYSA-N (hydroxyamino) nitroformate Chemical compound ONOC(=O)[N+]([O-])=O DXMNJSHCPPFVHG-UHFFFAOYSA-N 0.000 claims description 2
- CAVZBWFUMSXZFB-LJWNLINESA-N Amogastrin Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)OC(C)(C)CC)C(N)=O)C1=CC=CC=C1 CAVZBWFUMSXZFB-LJWNLINESA-N 0.000 claims description 2
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- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
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- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 claims description 2
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- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 claims 1
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- 125000000753 cycloalkyl group Chemical group 0.000 abstract description 5
- 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 abstract description 4
- 108010089448 Cholecystokinin B Receptor Proteins 0.000 abstract description 2
- 229940123406 CCK B receptor antagonist Drugs 0.000 abstract 1
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- 125000000468 ketone group Chemical group 0.000 abstract 1
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 40
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- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 31
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- 238000003756 stirring Methods 0.000 description 29
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- 238000004128 high performance liquid chromatography Methods 0.000 description 26
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 25
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 23
- 150000002148 esters Chemical class 0.000 description 22
- 239000012044 organic layer Substances 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 239000000460 chlorine Substances 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- 239000002253 acid Substances 0.000 description 20
- LQQKDSXCDXHLLF-UHFFFAOYSA-N 1,3-dibromopropan-2-one Chemical compound BrCC(=O)CBr LQQKDSXCDXHLLF-UHFFFAOYSA-N 0.000 description 19
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 17
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
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- AHDOQGYAXYGUQV-MRVPVSSYSA-N tert-butyl (2r)-2-(2-bromoacetyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)CBr AHDOQGYAXYGUQV-MRVPVSSYSA-N 0.000 description 1
- RKSOPLXZQNSWAS-UHFFFAOYSA-N tert-butyl bromide Chemical compound CC(C)(C)Br RKSOPLXZQNSWAS-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/24—Oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
通式Ⅰ的苯骈二氮杂䓬衍生物或它们的可以药用的盐:其中:(a)R<sup>1</sup>为-CH<sub>2</sub>CHOH(CH<sub>2</sub>)aR<sup>4</sup>或-CH<sub>2</sub>CO(CH<sub>2</sub>)aR<sup>5</sup>,其中a为0或1,R<sup>4</sup>和R<sup>5</sup>从烷基和环烷基和在杂原子上随意取代的饱和杂环基选择;(b)R<sup>2</sup>和R<sup>3</sup>各自独立地从芳环或杂环残基选择。这些化合物是促胃液素和/或CCK-B受体拮抗剂。
其中:
(a)R1为-CH2CHOH(CH2)aR4或-CH2CO(CH2)aR5,其中a为0或1,R4和R5从烷基和环烷基和在杂原子上随意取代的饱和杂环基选择;
(b)R2和R3各自独立地从芳环或杂环残基选择。
这些化合物是促胃液素和/或CCK-B受体拮抗剂。
Description
本发明涉及可作为对促胃酸激素和/或CCK-B受体具有拮抗作用药物的苯骈二氮杂_衍生物及制备。
在作为中枢神经系统的“苯骈二氮杂_受体”激动剂的精神治疗药物开发的过程中,已经描述了许多苯骈二氮杂_衍生物。近期,已经描述了对CCK-A(胆囊收缩剂-A)和CCK-B受体有拮抗作用的苯骈二氮杂_衍生物。还报道了这些选择性拮抗CCK-B受体的化合物在对服用五肽促胃酸激素的应答中,能够减少胃酸的分泌(V.J.Lotti and R.S.L.Chang,Eur.J.Pharmacol,162,273-280,1989)。例如,在U.S.Patent No.4,820,834中描述了对CCK-B受体有拮抗作用的苯骈二氮杂_衍生物。
本发明的化合物是新化合物。它们不同于U.S.PATENT№.4,820,834中描述的化合物,特别是苯骈二氮杂_核1位取代基的性质不同。本发明包括比U.S.Patent№.4,820834中描述的药理特性好的化合物;本发明中优选的化合物比以前描述的化合物对CCK-B受体有更高的亲和度和/或能更选择性地识别CCK-B和CCK-A受体。
本发明提供了通式I苯骈氮杂_衍生物或它们的可以药用的盐:其中(a)R1为-CH2CHOH(CH2)aR4或-CH2CO(CH2)aR5,式中的a为0或1,R4和R5选择自烷基、环烷基和杂原子上随意取代的饱和杂环基;
(b)R2和R3各自独立地从芳环和杂环残基选择;
(c)W和X独立地选自烷基,烷氧基,卤原子和氢原子。这里的所有“烷基”,“环烷基”,“酰基”和“烷氧基”优选含最高达8个碳原子,“卤原子”可为氟,氯,溴和碘。这里的芳香基(R2,R3)可被取代;它们优选是有5或6个环原子的单环;当为杂环时可含1,2或3个杂原子。优选R2和R3中至少一个是未取代,单取代或二取代苯基或未取代,单取代或二取代2-,3-或4-吡啶基。W和X之一(最好都是)优选为氢原子。
R4最好是(C4-C7直链或支链)烷基;或环烷基或多环烷基(非取代或为一个或多个烷基取代,使得R4含3-8个碳原子);或为通式II或III:其中R6为氢或烷基(例如C1-3烷基)或-CO-烷基(其中烷基例如为C1-3烷基),b为1或2,R5为烷基(如C1-3烷基)或与R4定义相同。
烷基和环烷基例子有:叔丁基,环戊基和环己甲基。
饱和杂环例子有:吡咯烷基,四氢吡喃基。杂原子上取代基包括简单的烷基和酰基(如多达3,4,5或6个碳原子,如甲酰基,乙酰基等)。
芳香残基(R2,R3)上取代基例子有:卤原子(如氟,氯等);羟氨基,硝基,羧酸和氰基;和烷基,烷氧基,烷氨基和二烷氨基,其中每个烷基优选多达6个(例如多达3个)碳原子(甲基;乙基等),对于取代的R2,优选间位取代。
R2最好为非取代苯基;间位取代基从F、Cl、Br、OH、OCH3、NH2、NMe2、NO2、Me、-(CH2)c-CO2H、CN,NHMe,NMeEt,NEt2,CH2NMe2,NHCHO和-(CH2)c-SO3H选择的取代苯基,其中c为0-2;或随意由选自F、Cl、CH3和CO2H的取代基取代的2-,3-或4-吡啶基;R3最好为苯基或2-,3-,或4-吡啶基。
W和X优选都是H,但当为烷基或烷氧基时,优选含1-3个碳原子。
本发明的化合物都至少有一个手性中心,所以可以存在光学异构体。应当理解,这些异构体不论是单体还是混合物,都包括在本发明的范围内。另外,本发明的化合物能与无机酸或有机酸成盐,在一些场合能与碱成盐。这类盐的例子包括盐酸盐,硫酸盐,硝酸盐,或钠盐和钾盐。这些盐也应理解为包括在本发明的范围内。按照本发明的优选化合物,苯骈二氮杂_环上3位的绝对构型为R(见通式IV)。
根据本发明的化合物起拮抗CCK-B和促胃酸激素受体的作用。它们可用作治疗由促胃酸激素控制的生理功能丧失而诱发的疾病的药物,例如胃溃疡和十二指肠溃疡、胃炎、消化性食管炎、胃癌和结肠癌,以及Zollingor-Ellison综合症;可以不出现CCK-A受体相互作用引起的副作用。它们可用于治疗由中枢CCK-B受体控制的生理功能丧失而诱发的疾病(例如用来缓解焦虑或食欲调节)。
根据本发明的优选化合物及其盐列在下面。后面一些化合物作为例证说明本发明涉及的化合物。
1. N-((3RS)-1-叔丁基羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂卓-3-基)-N′-(3-甲苯基)脲(实施例2);
2.N-((3RS)-1-二乙基甲基羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂卓-3-基)-N′-(3-甲基苯基)脲(实施例3);
3.N-((3RS)-1-环丁基羰基甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂卓-3-基)-N′-(3-甲基苯基)脲(实施例1);
4.N-((3RS)-1-环戊基羰基甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂卓-3-基)-N′-(3-甲基苯基)脲(实施例4);
5.N-((3RS)-1-环已基羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲基苯基)脲(实施例7);
6.N-((3RS)-1-环庚基羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲基苯基)脲(实施例5);
7.N-((3RS)-1-环庚基羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-氯苯基)脲(实施例6);
8.N-((3RS)-1-环戊基羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲基苯基)脲(实施例14);
9.N-((3RS)-1-环戊基羰甲基-2,3-二氢-2-氧-5-(3-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲(实施例21);
10.N-((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-(4-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲(实施例15);
11.N-((3RS)-1-环戊基羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-羧苯基)脲(实施例16);
12.N-((3R)-1-环戊基羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲(实施例17);
13.N-((3S)-1-环戊基羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲(实施例18);
14.N-((3RS)-2,3-二氢-2-氧-5-苯基-1-((2R)-2-吡咯烷基羰甲基)-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲基苯基)脲(实施例10);
15.N-((3RS)-2,3-二氢-2-氧-5-苯基-1-((2S)-2-吡咯烷羰甲基)-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲(实施例18);
16.N-((3RS)-1-((2R)-1-乙酰基-2-吡咯烷基羰甲基)-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲基苯基)脲(实施例11);
17.N-((3RS)-1-((2S)-1-乙酰基-2-吡咯烷基羰甲基)-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲基苯基)脲(实施例9);
18.N-((3RS)-1-((2RS)-2-环戊基-2-羟乙基)-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲基苯基)脲(实施例12);
19.N-((3RS)-1-((2SR)-2-环戊基-2-羟乙基)-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲基苯基)脲(实施例13);
20.N-((3R)-1-((2R)-2-环戊基-2-羟乙基)-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲基苯基)脲(实施例19);
21.N-((3R)-1-((2S)-2-环戊基-2-羟乙基)-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲基苯基)脲(实施例20);
22.N-((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-氰苯基)脲(实施例49);
23.N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-氰苯基)脲(实施例50);
24.N-((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-羧甲基苯基)脲(实施例31);
25.N-((3RS)-1-(1-金刚烷基)羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲(实施例51);
26.N-((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-吡啶基)脲(实施例30);
27.N-((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(6-甲基-2-吡啶基)脲(实施例29);
28.N-((3RS)-1-(3-环已基-3-甲基-2-氧丁基)-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲(实施例52);
29.N-((3RS)-1-环已基甲基羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲基苯基)脲(实施例32);
30.N-((3RS)-1-环戊甲基羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲(实施例33);
31.N-((3RS)-1-((1-甲基环已基)羰甲基)-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲基苯基)脲(实施例34);
32.N-((3RS)-1-((1-甲基环戊基)羰甲基)-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲基苯基)脲(实施例46);
33.N-((3R)-1-环戊羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-羧苯基)脲(实施例23);
34.N-((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-羧苯基)脲(实施例22);
35.N-((3R)-1-((2RS)-2-环戊基-2-羟乙基)-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-羧苯基)脲(实施例24);
36.N-((3R)-1-((2R)-2-环戊基-2-羟乙基)-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-羧苯基)脲(实施例25);
37.N-((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-羧基酰胺基苯基)脲(实施例35);
38.N-((3R)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲基苯基)脲(实施例26);
39.N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲(实施例27);
40.N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-羧苯基)脲(实施例28);
41.N-((3RS)-1-叔戊羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲(实施例36);
42.N-((3RS)-1-叔戊羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-羧苯基)脲(实施例37);
43.N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-二甲氨基苯基)脲(实施例38);
44.N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-羧苯基)脲(实施例39);
45.N-((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-苯基-1II-1,4-苯骈二氮杂_-3-基)-N′-(3-二甲氨苯基)脲(实施例40);
46.N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-二甲氨基苯基)脲(实施例41);
47.N-((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲氧苯基)脲(实施例42);
48.N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲氧苯基)脲(实施例43);
49.N-((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-硝基苯基)脲(实施例44);
50.N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-硝基苯基)脲(实施例45);
51.N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲酰胺基苯基)脲(实施例47);
52.N-((3R)-1-((2R)-2-羟基-3,3-二甲基丁基)-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲(实施例48);
53.N-((3R)-1-((2S)-2-羟基-3,3-二甲基丁基)-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲;
54.N-((3RS)-1-(1-甲基环丙基)羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲基苯基)脲(实施例53);
55.N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-(2-氯苯基)-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲基苯基)脲(实施例54);
56.N-((3RS)-1-异丙基羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲(实施例55);
57.N-((3R)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲氨基苯基)脲(实施例56);
58.N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲氨基苯基)脲(实施例57);
59.N-((3R)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-(N-乙基-N-甲氨基)苯基)脲(实施例58);
60.N-((3R)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-二乙氨基苯基)脲(实施例59);
61.N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-二甲氨甲基苯基)脲(实施例60);
62.N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-(N-乙基-N-甲氨基)苯基)脲(实施例61);
63.N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-二甲氨甲基苯基)脲(实施例62);
64.N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-二乙氨基苯基)脲(实施例63);
65.N-((3R)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-二甲氨苯基)脲(实施例64);
66.N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-(4-甲苯基)-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲(实施例65);
67.N-((3R)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-氨基苯基)脲(实施例66);
67.N-((3R)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-氨基苯基)脲(实施例66);
68.N-((3R)-1-叔丁羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲;
69.N-((3R)-1-叔丁羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-氨基苯基)脲;
70.N-((3R)-1-叔丁羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲氨基苯基)脲;
71.N-((3R)-1-叔丁羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-二甲氨基苯基)脲;
72.N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-氨基苯基)脲;
73.N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲氨基苯基)脲;
74.N-((3RS)-1-叔丁羰甲基-7-氯-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲基苯基)脲(实施例67);
75.N-((3RS)-1-叔丁羰甲基-7-氯-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-二甲氨基苯基)脲(实施例68);
76.N-((3RS)-1-叔丁羰甲基-7-氯-2,3-二氢-2-氧-5-(2-氯苯基)-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲基苯基)脲(实施例69);
77.N-((3RS)-1-叔丁羰甲基-2,3-二氢-8-甲基-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲(实施例70);
78.N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-N-乙基-N-甲氨基苯基)脲;
79.N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-二乙氨基苯基)脲。
本发明的化合物可以按照路线1制备。试剂:(a)NaH,DMF;(b)R7COCH2Br;(c)H2,Pd-C或Br;
(d)R2NCO;(e)NaBrH4
R7代表R4(CH2)a或R5(CH2)a当R3=苯基时,原料1为已知化合物〔M.G.Bocketal.,J.Org,Chem,52,3232-3239,1989〕。对于R3的其它例子—例如吡啶基,原料1可以按照Bock等描述的类似途径制备。为了简化,在下面的具体实施例中,化合物1(R3=ph)称为Bock苯骈二氮杂_。
试剂:(f)SOcl2;(g)CH2N2;(h)HBr
然后烷基化的苯骈二氮杂_2(路线1)脱保护。路线1中描述的情况是氨基由Z基团(Z=苄氧羰基)保护,该保护基可通过催化氢化或酸解脱去。当保护基不是Z时,可以适当改变脱保护步骤。脱保护的苯骈二氮杂_然后用异氰酸芳基酯处理(R2NCO)。例如当R2=3-甲苯基时,直接导致上面列出的化合物3(例如化合物1-10等等)。当R2含有保护的功能基时(例如羧酸保护成酯),这种基团必须暴露出来,以便得到列出的化合物。酮3能够用例如硼氢化钠还原,生成对应的醇4(例如化合物18-21等等)。
在一些场合下,用其它路线制备所需的脲更为可取。这种情形列入路线3。试剂:(j)P-O2NC6H4OCOCl;(k)R2NH2保护的苯骈二氮杂_衍生物2按前面说的方法(路线1,步骤(ii))脱保护,但用氯代甲酸对硝基苯酯处理,得到氨基甲酸对硝基苯酯5。在步骤(ii)中,5与氨R2NH2反应,得到脲3。当市场上买不到异氰酸酯R2NCO,而可以买到R2NH2时,该路线特别有用。
这些一般方法现在用具体的但非限制性的实施例进一步阐明。实施例1N-((3RS)-1-环丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲,化合物31A溴甲基环丁基酮〔路线2,步骤(i)-(iii)〕
往冰冷却的环丁羧酸(1.5g,15mmol)的乙醚(10ml)溶液中,加N,N-二异丙基乙胺(2.9ml,16mmol),然后加亚硫酰氯(1.24ml,17mmol)。混合物0℃搅拌45分钟,然后倾入冰冷却的CH2N2(从Diazald_制备,1.41g,66mmol)乙醚溶液中,得到的混合物在2小时以内升至室温。往里滴加HBr的饱和乙醚溶液,直至无氮气放出。得到的溴代甲基酮的醚溶液依次用饱和碳酸氢钾溶液、水和盐水洗,过滤(Whatman_,ps相分离器)并减压浓缩。粗产品通过泡到泡蒸馏(100℃,5mmHg)纯化后,得到标题酮,为无色,易流动的油状物(1.13g,44%)。NMR(CDCl3)δ3.86(2H,s);3.57(1H,quintet,J=8.5Hz);2.5-2.2(6H,m);2.2-1.8(2H,m).1B(3RS)-3-苄氧羰氨基-1-环丁羰甲基-2,3-二氢-5-苯基-1H-1,4-苯骈二氮杂_-2-酮〔路线1,步骤(i)〕
往(3RS)-3-苄氧羰氨基-2,3-二氢-5-苯基-1H-1,4-苯骈二氮杂_-2-酮〔M.G.Bock et al.,J.Org,Chem,52,3232-3239,1987〕(578mg,由605mg-水合物与DMF共沸3次制得,1.5mmol)的DMF(5ml)溶液中,在搅拌,冷至-10℃和氮气保护下,加入氢钠(63mg,80%的油悬浮液,2.1mmol)。该混合物在-10℃搅拌30分钟,在此期间加入实施例1A的溴代甲基酮(389mg,2.25mmol)的DMF(2ML)溶液。得到的混合物搅拌1小时并升至室温,然后倾入稀盐酸水溶液(100ml)中。混合物用乙酸乙酯萃取一次,有机层用水和盐水洗,过滤(Whatman_,1PS相分离器)并减压浓缩。粗产品用闪式硅胶层析纯化(乙酸乙酯∶60-80石油醚,40∶60V/V,洗脱),得到标题苯骈二氮杂_,为玻璃状固体(490mg,68%)。
Rf值:0.54(乙酸乙酯∶60-80石油醚,50∶50)。Rf (EtOAc:60-80 pet ether 50∶50)0.54NMR(CDCl3)δ7.8-7.2(14H,m);6.70(1H,d,J=8Hz);5.47(1H,d,J=8Hz);
5.18(2H,s);4.69(1H,d,J=7.5Hz);4.60(1H,d,J=7.5Hz);3.36(1H,
quintet,J=8Hz);2.5-1.8(6H,m).1C N-((3RS)-1-环丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲〔路线1,步骤(ii)〕
往脱氧的实施例1B的苯骈二氮杂_(490mg,1.02mmol)的冰醋酸(25ml)溶液中,加入5%钯碳催化剂(约200)。往该悬浮液中充氢气4小时,然后用氮气脱气终止反应。混合物过滤,催化剂残渣用甲醇洗。合并的滤液减压浓缩,然后通过与甲苯共挥发除去微量溶剂。残留物溶入二氯甲烷(25ml)中并室温搅拌。往该溶液中加异氰酸间甲苯酯(0.13ml,1.02mmol),并继续搅拌2小时。减压蒸去溶剂,粗产品用闪式硅胶柱层析纯化(乙酸乙酯∶60-80石油醚40∶60V/V洗脱)。最后产品溶入乙酸中,冷冻干燥,得到苯骈二氮杂_,为白色粉末(203mg,41%,HPLC纯度高于95%)。
Rf值:0.12(乙酸乙酯∶60-80石油醚,35∶65)。Rf(EtOAc∶60-80 pet.ether 35∶65)0.12.NMR(CDCl3)δ7.82(2H,d,J=7Hz);7.8-7.2(11H,m);7.09(1H,d,J=8Hz);6.99(1H,d,J=7Hz);5.83(1H,d,J=8Hz);4.78(2H,s);3.44(1H,quintet,J=8.5Hz);2.43(3H,s);2.4-1.9(6H,m).
M.S.(FAB,+ve ion)m/e 481.8(M+H).实施例2N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲,化合物12A叔丁基溴甲基酮〔路线2,步骤(ii)-(iii)〕
往冰冷却的CH2N2(从Diazald_制得,10.4g,49mmol)的乙醚溶液中加特戊酰氯(2ml,16mmol)。搅拌下,3小时内使溶液升至室温,在此期间加入HBr的乙酸乙酯溶液,直至无氮气放出。溶液用盐水洗,过滤(Whatman_1ps相分离器),减压浓缩,得标题酮,为易流动的浅棕色油状物(3.47g,82%,NMR确定的纯度为99%,仍含乙酸乙酯)。
NMR(CDCl3)δ4.15(2H,s);1.20(9H,s).2B(3RS)-3-苄氧羰氨基-1-叔丁羰甲基-2,3-二氢-5-苯基-1H-1,4-苯骈二氮杂_-2-酮〔路线1,步骤(i)〕
按实施例1B的方法制备,使用Bock苯骈二氮杂_(578mg,1.5mmol)、氢钠(63mg,80%的油悬浮液,2.1mmol)和实施例2A的溴甲基酮(491mg,82%纯度,2.25mmol)。粗产品用闪式硅胶柱层析纯化(乙酸乙酯∶60-80石油醚,50∶50V/V洗脱),得标题苯骈二氮杂_,为玻璃状固体(700mg,97%)。
Rf值:0.56(乙酸乙酯∶60-80石油醚,50∶50)NMR(CDCl3)δ7.8-7.2(14H,m);6.74(1H. d,J=8Hz);5.53(1H,d,J=8Hz);
5.23(2H,s);5.05(1H,d,J=18Hz);4.77(1H,d,J=18Hz);1.33(9H,s).2C N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲〔路线1,步骤(ii)〕
按照实施例1C制备,用实施例2B的苯骈二氮杂_(700mg,1.45mmol),50%钯碳(约300mg)及异氰酸间甲苯酯(0.19ml,1.5mmol)。粗产品用闪式硅胶柱层析纯化(乙酸乙酯∶60-80石油醚40∶60V/V洗脱),溶入醋酸中,冷冻干燥,得标题苯骈二氮杂_,为白色粉末(233mg,33%,HPLC纯度在97%以上)。
Rf值:0.31(乙酸乙酯∶60-80石油醚,40∶60)NMR(CDCl3)δ7.72(2H,d,J=8Hz);7.7-7.0(12H,m);6.87(1H,d,J=7Hz);
5.73(1H,d,J=8Hz);4.92(1H,d,J=18Hz);4.82(1H,d,J=18Hz);2.32
(3H,s);1.26(9H,s).M.S.(FAB,+ve ion)m/e 483.2(M+H).实施例3N-((3RS)-1-二乙基甲基羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲,化合物23A 溴甲基二乙基甲基酮〔路线2,步骤(i)-(iii)〕
0℃下往2-乙基丁酸(2.09g,18mmol)中加亚硫酰氯(5.2ml,715mmol),生成的混合物升至室温并搅拌25分钟。混合物用无水THF稀释,然后在环境温度下减压浓缩,再用无水THF共沸除去最后的微量亚硫酰氯。残留油状物溶入无水THF(10ml)中,倾到冰冷的CH2N2(从Diazald_制备,9g,42mmol)的乙醚溶液中,生成的混合物升至室温并搅拌90分钟。用乙酸(5次)处理反应液,碱化(5%KHCO3)并用乙酸乙酯萃取(3次)。合并的有机层先用水洗,然后用饱和盐水洗,过滤(whatman_,1ps相分离器),并减压浓缩。粗油用闪式硅胶柱层析纯化(乙酸乙酯∶40-60石油醚,5∶95V/V洗脱),得重氮甲基二乙基甲基酮,为浅黄色液体(261mg,1.86mmol)。往该重氮酮的乙酸乙酯(10ml)溶液中,室温下分次加HBr的饱和乙酸乙酯溶液,直至不再有氮气释放为止。反应液碱化(50%KHCO3)并用乙酸乙酯萃取(2次)。合并的有机层用水洗,饱和盐水洗,过滤(Whatman_,1ps相分离器)并减压浓缩。粗品用闪式硅胶柱层析纯化(乙酸乙酯∶40-60石油醚从4∶96至10∶90V/V梯度洗脱),得标题酮,为浅棕色易流动油状物(268mg,77%)。NMR(CDCl3)(for the major rotamer 88.8%).δ3.95(2H,s);1.56-1.46(4H,m);
2.75-2.65(1H,m);0.91-0.85(6H,m).3B(3RS)-3-苄氧羰氨基-1-二乙基甲基羰甲基-2,3-二氢-5-苯基-1H-1,4-苯骈二氮杂_-2-酮〔路线1,步骤(i)〕
按实施例1B的方法制备,使用Bock苯骈二氮杂卓(3.56mg,0.925mmol)、氢钠(39mg,80%的油悬浮液,1.3mmol)、实施例3A的溴甲基酮(2.68mg,1.4mmol)。粗产品用闪式硅胶层析纯化(乙酸乙酯∶40-60石油醚,25∶85V/V洗脱),得标题苯骈二氮杂_,为无色油(351mg)。
Rf值:0.35(乙酸乙酯∶40-60石油醚,40∶60)NMR(CDCl3)δ7.64-7.13(14H,m);6.67(1H,d,J=8.25Hz);5.43(1H,d,J=
8.25Hz);5.27(2H,s);5.15(1H,d,J=18Hz);4.78(1H,d,J=18Hz);2.45
-2.35(1H,m);1.76-1.42(4H,m);0.90-0.85(6H,m).3C N-((3RS)-1-二乙基甲基羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲基苯基)脲〔路线1,步骤(ii)〕
按照实施例1C的方法制备,使用实施例3B的苯骈二氮杂_(351mg,0.68mmol)、50%的钯碳(350mg)和异氰酸间甲苯酯(87ml,0.71mmol)。粗产品用闪式硅胶柱层析纯化(乙酸乙酯∶40-60石油醚35∶65V/V洗脱),得标题化合物,为白色固体(229mg,68%,HPLC纯度高于99%)。
Rf值:0.24(乙酸乙酯∶40-60石油醚,40∶60)NMR(CDCl3)δ7.66-6.80(15H,m);5.66(1H,d,J=8Hz);4.73(1H,d,J=18
Hz);4.64(1H,d,J=18Hz);2.49-2.31(1H,m);2.26(3H,s);1.71-1.39
(4H,m);0.86-0.81(6H,m).M.S.(FAB,+ve ion)m/e 497.3(M+H).实施例4N-((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲,化合物44A 溴甲基环戊基酮〔路线2,步骤(i)-(iii)〕
按照实施例3A的方法制备。中间体重氮酮由环戊羧酸(2.05g,18mmol)、亚硫酰氯(5.2ml,72mmol)和CH2N2(由Diazald_制备,9g,42mmol)制备,并用闪式硅胶层析纯化(乙酸乙酯∶40-60石油醚15∶85V/V洗脱)。重氮酮然后用HBr的饱和乙酸乙酯溶液处理。闪式硅胶层析纯化后(乙酸乙酯∶40-60石油醚,从4∶96至10∶90V/V梯度洗脱)得标题酮,为浅棕色易流动油(1.29g,37%)。NMR(CDCl3)δ3.99(2H,s),3.18(1H,q,J=8Hz),1.93-1.56(8H,m).4B (3RS)-3-苄氧羰氨基-1-环戊羰甲基-2,3-二氢-5-苯基-1H-1,4-苯骈二氮杂_-2-酮〔路线1,步骤(i)〕
按照实施例1B的方法制备,使用Bock苯骈二氮杂_(578mg,1.5mmol)、氢钠(63mg,80%的油悬浮液,2.1mmol)及实施例4A的溴代甲基酮(431mg,2.25mmol)。粗产品用闪式硅胶层析纯化(乙酸乙酯∶40-60石油醚30∶70V/V,洗脱)得标题化合物,为无色结晶性固体(682mg,88.5%)。
Rf值:0.25(乙酸乙酯∶40-60石油醚,40∶60)NMR(CDCl3)δ7.64-7.17(14H,m);6.60(1H,d,J=8.25Hz);5.42(1H,d,J=
8.25Hz);5.14(2H,s);4.78(1H,d,J=17.8Hz);4.63(1H,d,J=17.8Hz);
2.92(1H,q,J=8Hz);1.85-1.55(8H,m).4C N-((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲〔路线2,步骤(ii)
按照实施例1C的方法制备,使用实施例4B的苯骈二氮杂_(680mg,1.32mmol)、5%的钯碳(600mg)和异氰酸间甲苯酯(169ul,1.39mmol)。粗产品用闪式硅胶层析纯化(乙酸乙酯∶40-60石油醚,35∶65V/V,洗脱),得标题化合物(463mg,71%)。标题化合物用热甲醇重结晶,得161.8mg结晶性固体(HPLC纯度高于99%)。
Rf值:0.16(乙酸乙酯∶40-60石油醚,40∶60)NMR(CDCl3)δ7.66-6.80(15H,m);5.65(1H,d,J=8Hz);4.74(1H,d,J=18
Hz);4.67(1H,d,J=18Hz);2.95-2.83(1H,m)2.28(3H,s);1.90-1.53
(6H,m).M.S.(FAB,+ve ion)m/e 495.2(M+H).
实施例5N-((3RS)-1-环庚羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲,化合物65A 溴甲基环庚基酮〔路线2,步骤(i)-(iii)〕
按照实施例3A的方法制备,中间体重氮酮由环庚羧酸(3g,21mmol)、亚硫酰氯(6.24ml,84mmol)及CH2N2(从Diazald_制备,12g,56mmol)制备,并用闪式硅胶层析纯化(乙酸乙酯∶40-60石油醚,10∶90V/V,洗脱)。重氮酮然后用HBr的饱和乙酸乙酯溶液处理。闪式硅胶层析纯化(乙酸乙酯“40-60石油醚,5∶95至10∶90V/V,梯度洗脱),得到标题酮,为棕色油状物(1.8g,8.22mmol,39%)。
NMR(CDCl3)δ3.98(2H,s);2.95-2.85(1H,m);1.93-1.50(12H,m).5B (3RS)-3-苄氧羰氨基-1-环庚羰甲基-2,3-二氢-5-苯基-1H-1,4-苯骈二氮杂卓-2-酮〔路线1,步骤(i)〕
按照实施例1B的方法制备,使用Bock苯骈二氮杂卓(578mg,1.5mmol)、氢钠(63mg,80%的油悬浮液,2.1mmol)及实施例5A的溴代甲基酮(493mg,2.25mmol)。30分钟后反应完全。
粗产品用闪式硅胶层析纯化(乙酸乙酯∶40-80石油醚,40∶60V/V,洗脱),得标题化合物,为无色结晶性固体(764mg,93%)。
Rf值:0.3(乙酸乙酯∶40-60石油醚,40∶60)NMR(CDCl3)δ7.64-7.13(14H,m);6.64(1H,d,J=8.25Hz);5.42(1H,d,J=
8.25 Hz);5.14(2H,s),4.79(1H,d,J=17.5Hz);4.63(1H,d,J=17.5Hz);
2.65-2.56(1H,m);1.93-1.28(12H,m).5C N-((3RS)-1-环庚羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲,〔路线1,步骤(ii)〕
按照实施例1C的方法制备,使用实施例5B的苯骈二氮杂_(787mg,1.5mmol)、5%钯碳(600g)及异氰酸间甲苯酯(0.20ml,1.58mmol)。粗产品用闪式硅胶层析纯制(乙酸乙酯∶40-60石油醚,30∶70V/V,洗脱),得标题化合物,为白色固体(53.6mg,10%,HPLC纯度高于98%)。
Rf值:0.27(乙酸乙酯∶40-60石油醚,40∶60)
M.S.(FAB,+ve ion)m/e 523.3(M+H).
实施例6N((3RS)-1-环庚羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-氯苯基)脲,化合物7〔路线1,步骤(ii)〕
按照实施例1C的方法制备,使用实施例5B的苯骈二氮杂_(764mg,1.41mmol)、5%钯碳(600mg)及异氰酸间氯苯酯(180ul,1.48mmol)。粗产品用热乙酸乙酯重结晶,得标题化合物,为白色结晶性固体(379mg,69.8%)(HPLC纯度高于99%)。NMR(CDCl3)δ7.68-6.89(15H,m);5.64(1H,d,J=8Hz);4.74(1H,d,J=18
Hz);4.66(1H,d,J=18Hz);2.60-2.52(1H,m);1.92-1.22(12H,m).M.S.(FAB +ve ion)m/e 543.1(M+H).实施例7N-((3RS)-1-环已基羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲,化合物57A 溴甲基环已基酮〔路线2,步骤(i)-(iii)〕
按照实施例3A的方法制备。重氮酮从环已羧酸(1.92g,15mmol)、亚硫酰氯(4.46ml,60mmol)和重氮甲烷(从Diazald_制备,7.16g,33.4mmol)制备。未纯化的重氮酮用HBr的饱和乙酸乙酯溶液处理,直至无氮气放出。硅胶色谱纯化(乙酸乙酯∶石油醚,5∶95洗脱)得标题化合物,为黄色油状物(0.91g,30%)。
NMR(CDCl3)δ4.00(2H,s);2.75(1H,m);1.95-1.20(10H,m).7B(3RS)-3-苄氧羰氨基-1-环已羰甲基-2,3-二氢-5-苯基-1H-1,4-苯骈二氮杂_-2-酮〔路线1,步骤(i)〕
按照实施例1B的方法制备,使用Bock苯骈二氮杂_(385mg,1.0mmol)、氢钠(42mg,80%的油悬浮液,1.4mmol)和实施例7A的溴代甲基酮(308mg,1.5mmol)。产品用闪式硅胶层析纯化(乙酸乙酯∶40-60石油醚,35∶65V/V,洗脱)得标题化合物,为无色固体(490mg,96%)。
Rf值:0.3(乙酸乙酯∶40-60石油醚,40∶60)NMR(CDCl3)δ:7.8-7.2(14H,m);6.65(1H,d,J=8.2Hz);5.42(1H,d,J=8.2
Hz);5.18(2H,s)4.72(2H,d,J=7.5Hz);4.61(2H,d,J=7.5Hz);2.40(1H,
m);1.9-1.0(10H,m).
7C N-(3RS)-1-环已羰甲基-2,3-二氢-2-氧-5-苯基
-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲,〔路线1,步骤(ii)〕
按照实施例1C的方法制备,使用实施例7B的苯骈二氮杂_(480mg,0.945mmol)、5%钯碳(约400mg)和异氰酸间甲苯酯(0.130ml,1mmol)。粗产品用闪式硅胶层析纯化(乙酸乙酯∶40-60石油醚,35∶65,V/V洗脱)并用乙酸乙酯/石油醚结晶,得标题苯骈二氮杂_,为无色固体(245mg,52%,HPLC纯度高于98%)。
Rf值:0.32(乙酸乙酯∶40-60石油醚)NMR(CDCl3)δ7.7(2H,d,J=8Hz);7.65-7.00(12H,m);6.88(1H,d,J=7Hz);
5.62(1H,d,J=8Hz);4.67(2H,s);2.39(1H,m);2.21(3H,s);1.9-0.8
(10H,m).M.S.(FAB +ve ion)m/e 509(M+H).实施例8N-((3RS)-2,3-二氢-2-氧-5-苯基-1-((2S)-2-吡咯烷羰甲基)-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲盐酸盐,化合物158A(2S)-1-叔丁氧羰基-2-吡咯烷基重氮甲基酮〔路线2,步骤(i)-(ii)〕
在-20℃下往叔丁氧羰-2-脯氨酸(5.5g,25.6mmol)、N-甲基吗啉(3.1ml,28.2mmol)及无水四氢呋喃(80ml)的溶液中加氯代甲酸异丁酯(3.5ml,27.1mmol)。混合物在-10℃下搅拌1小时,然后倾入冰冷却的CH2N2(从Diazald_制备,18g,84mmol)的乙醚溶液,生成的混合物在2小时内升至室温。用乙酸消耗掉过量的CH2N2,得到的溶液用5%KHCO3水溶液碱化,再用乙酸乙酯萃取。分离有机相,有机相用水洗,盐水洗,过滤(Whatman_)1ps相分离器),减压浓缩。粗产品用闪式硅胶柱层析纯化(乙酸乙酯∶40-60石油醚,35∶65,V/V,洗脱)。得到的标题化合物立即用于下步反应。
Rf:0.12(乙酸乙酯∶40-60石油醚,30∶70)。8B(2S)-1-叔丁氧羰基-2-吡咯烷基溴甲基酮〔路线2,步骤(iii)〕
往搅拌的实施例8A的重氮酮的乙酸乙酯溶液中滴加饱和HBr的乙酸乙酯溶液,直至不释放氮气为止。得到的溴代甲基酮溶液依次用饱和KHCO3溶液、水和盐水洗,过滤(Whatman_ 1ps相分离器)并减压浓缩。粗产品用闪式硅胶柱层析纯化(乙酸乙酯∶40-60石油醚,15∶85,V/V洗脱)得标题化合物,为棕色油状物(1.25g,17%,两步产率)。
Rf:0.2(乙酸乙酯∶40-60石油醚)NMR(CDCl3)δ4.66-4.49(1H,broad m),4.1-4.0(2H,broad m),3.73-3.50
(2H,broad m),2.40-1.67(4H,m),1.46 and 1.44(9H,2 singlets).8C(3RS)-3-苄氧羰氨基-1-((2S)-1-叔丁氧羰基-2-吡咯烷羰甲基)-2,3-二氢-5-苯基-1H-1,4-苯骈二氮杂_-2-酮,路线1,步骤(i)〕
按照实施例1B的方法制备,使用Bock苯骈二氮杂_(1.2g,2.97mmol)、氢钠(125mg,80%油悬浮液,4.2mmol)和实施例8B的溴甲基酮(1.25g,4.46mmol)。
产品用闪式硅胶柱层析纯化(乙酸乙酯∶40-60石油醚,35∶65V/V洗脱),得标题化合物(798mg,45%)。NMR(CDCl3)δ7.62-7.18(14H,m),6.65(1H,d,J=8Hz),5.42(1H,d,J=8
Hz),5.14(2H,s),4.95-4.72(1H,m),4.64-4.40(1H,m),4.38-4.28(1H,
m),3.60-3.44(2H,m),2.23-1.82(4H,m),1.44(9H,s).8D N-((3RS)-1-((2S)-1-叔丁氧羰基-2-吡咯烷羰甲基)-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲〔路线1,步骤(iii)〕
按照实施例1C的方法制备,使用实施例8C的苯骈二氮杂_(798mg,1.33mmol)、5%钯碳(约600mg)及异氰酸间甲苯酯(180ul,1.4mmol)。粗产品用闪式硅胶柱层析纯化(乙酸乙酯∶40-60石油醚,35∶65V/V洗脱),得标题化合物,为无色油(559mg,71.1%)。NMR(CDCl3)δ7.65-6.81(15H,m),5.66(1H,d,J=9Hz),4.97-4.56(2H,m),4.40-4.25(1H,m),3.56-3.38(2H,m),2.27(3H,s),2.21-1.86(4H,m),1.44 and 1.42(9H,2 singlets).8E N-((3RS)-2,3-二氢-2-氧-5-苯基-1-(2S)-2-吡咯烷羰甲基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲盐酸盐
实施例8D的叔丁氧羰保护的化合物(559mg,0.95mmol)溶入氯化氢-二氧六环(4M,xs),室温搅拌30分钟。溶液减压浓缩,用无水甲苯共沸两次,除去微量的二氧六环。残留物用氯仿/乙醚结晶,得标题盐,为白色固体(245mg,48。5%,HPLC纯度在98%以上)。
Rf:0.32(氯仿∶甲醇∶乙酸,12∶2∶1)
M.S.(FAB,+ve ion)m/e 495.2(M+H).实施例9N-((3RS)-1-(2S)-1-乙酰基-2-吡咯烷羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲,化合物17
0℃氮气保护下往实施例8E的苯骈二氮杂_盐(166mg,0.32mmol)的二氯甲烷溶液中加DIEA(0.11ml,0.63mmol),然后加乙酰氯(22ul,0.32mmol)。10分钟后反应完全。混合物减压浓缩,残留物在二氯甲烷和0.3M的KHSO4之间分配。分离有机层,无水硫酸钠干燥,过滤(Whatman_1ps相分离器),并减压浓缩。粗产中用闪式硅胶柱层析纯化(乙酸乙酯∶乙酸,100∶2V/V,洗脱),得到的白色固体溶入乙腈/水中,并冷冻干燥,得标题化合物,为白色粉末(148mg,89%,HPLC纯度在99%以上)。NMR(CDCl3)δ7.91-6.95(14H,m),6.76(1H,m),5.68-5.62(1H,m),4.94-
4.43(3H,m),3.48-3.35(2H,m),2.35(1H,s),2.23(3H,s),2.1-1.79
(6H,m).MS (FAB,+ve ion)m/e=538.3(M+H).实施例10N-((3RS)-2,3-二氢-2-氧-5-苯基-1-((2R)-2-吡咯烷羰甲基)-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲盐酸盐,化合物1410A (2R)-1-叔丁氧羰基-2-吡咯烷基重氮甲基酮〔路线2,步骤(i)-(ii)〕
按照实施例8A的方法制备,用叔丁氧羰-D-脯氨酸(4g,19.4mmol)、NMM(2.1ml,19.4mmol)和氯甲酸异丁酯(2.7ml,20.5mmol)。闪式硅胶柱层析纯化(乙酸乙酯∶40-60石油醚,35∶65,V/V,洗脱)得标题化合物,为油状物(1.68g,38%)。NMR(CDCl3)δ5.45(1H,d,J=23Hz),4.24(1H,d,J=23Hz),3.51-3.43(2H,
m),2.19-1.83(4H,m),1.47 and 1.43(9H,2 singlets).10B(2R)-1-叔丁氧羰基-2-吡咯烷基溴代甲基酮〔路线2,步骤(iii)〕
按实施例8B的方法制备,使用实施例10A的重氮酮(1.68g,7.4mmol)。粗产品用闪式硅胶柱层析纯化(乙酸乙酯∶40-60石油醚,20∶80V/V,洗脱)得到标题酮,为棕色油(986mg,47.5%)。
Rf:0.19(乙酸乙酯∶40-60石油醚,20∶80)10C(3RS)-3-苄氧羰氨基-1-((2R)-1-叔丁氧羰基-2-吡咯烷基羰甲基-2,3-二氢-5-苯基-1H-1,4-苯骈二氮杂_-2-酮〔路线1,步骤(i)〕
按照实施例1B的方法制备,使用Bock苯骈二氮杂_(950mg,2.35mmol)、氢化钠(99mg,80%油悬浮液,3.29mmol)及实施例10B中的溴代甲基酮(986mg,3.75mmol)。产品用闪式硅胶柱层析纯化(乙酸乙酯∶40-60石油醚,40∶60V/V,洗脱),得标题化合物(1.3g,92%)。NMR(CDCl3)δ7.62-7.18(14H,m),6.68(1H,d,J=8Hz),5.43(1H,d,J=8
Hz),5.14(2H,s),5.09-4.8(1H,m),4.65-4.4(1H,m),4.37-4.27(1H,m),
3.49-3.44(2H,m),2.22-1.85(4H,m),1.43(9H,s).10D N-((3RS)-1-((2R)-1-叔丁氧羰-2-吡咯烷基羰甲基)-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲〔路线1,步骤(ii)〕
按照实施例1C的方法制备,使用实施例10C的苯骈二氮杂_(394mg,0.65mmol)、5%钯碳(约200mg)及异氰酸间甲苯酯(88ul,0.68mmol)。粗产品用闪式硅胶柱层析纯化(乙酸乙酯∶40-60石油醚,40∶60V/V,洗脱),得标题化合物,为结晶性固体(175mg,65%)。NMR(CDCl3)δ7.63-7.0(13H,m),6.97-6.78(1H,m),5.64(1H,d,J=10Hz),
4.8-4.7(2H,m),4.37-4.08(1H,m),3.48-3.37(2H,m),2.24(3H,s),2.05
(3H,s),2.2-1.76(4H,m),1.49-1.34(9H,2 singlets).10E N-((3RS)-2,3-二氢-2-氧-5-苯基-1-((2R)-2-吡咯烷基羰甲基)-1H-1,4-苯骈二氮杂卓-3-基)-N′-(3-甲苯基)脲盐酸盐
按照实施例8E的方法制备,使用实施例10D的苯骈二氮杂卓(175mg,0.3mmol)。粗产品溶入乙酸并冷冻干燥,得标题化合物,不经纯化,为白色粉末(125mg,78%,HPLC纯度在99%以上)。
M.S.(FAB,+ve ion)m/e=496.2(M+H).实施例11(N-((3RS)-1-((2R)-1-乙酰基-2-吡咯烷基羰甲基)-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲,化合物16
按照实施例9的方法制备,使用实施例10E的苯骈二氮杂_盐(244mg,0.46mmol)、DIEA(0.16ml,0.92mmol)及乙酰氯(32.7ul,0.46mmol)。粗产品用闪式硅胶柱层析纯化(乙酸乙酯∶乙酸,100∶2,V/V洗脱),得到的纯品溶入冰乙酸并冷冻干燥,得标题化合物,为白色粉末(173mg,70%,HPLC纯度在99%以上)。
M.S.(FAB,+ve ion)m/e=538.3(M+H).实施例12N-((3RS)-1-((2RS)-2-环戊基-2-羟乙基)-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲基苯基)脲,化合物18和实施例13N-((3RS)-1-((2SR)-2-环戊基-2-羟乙基)-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲,化合物19
0℃下往实施例4C的苯骈二氮杂_(240mg,0.49mmol)的乙醇溶液中加氢化钠(29mg,0.76mmol)。得到的混合物于0℃搅拌30分钟,然后室温搅拌90分钟。混合物减压浓缩,残留物用闪式硅胶柱层析纯化(乙酸乙酯∶40-60石油醚,35∶65,V/V,洗脱),得两种化合物。每种都溶入乙腈/水中,冷冻干燥,得标题化合物。极性低的产物:66mg、26%,HPLC纯度在98%以上。
Rf:0.14(乙酸乙酯∶40-60石油醚,35∶65)NMR(CDCl3)δ7.74-6.90(14H,m),6.78(1H,d,J=8Hz),5.62(1H,d,J=8
Hz),4.41-4.34(1H,m),3.65-3.55(2H,m),2.22(3H,s),1.67-1.11(9H,
m).M.S.(FAB,+ve ion)497.2(M+H)极性高的产物:95mg,38%,HPLC纯度在96%以上。
Rf:0.10(乙酸乙酯∶40-60石油醚,35∶65)NMR(CDCl2)δ7.73-7.0(14H,m),6.87-6.78(1H,m),5.59-5.56(1H,d,J=8
Hz),4.05-3.70(3H,m),2.24(3H,s),1.76-1.14(9H,m).M.S.(FAB,+ve ion)497.0(M+H)实施例14N-((3RS)-1-环戊基羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲,化合物814A(3RS)-3-苄氧羰氨基-1-环戊羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-2-酮〔路线1,步骤(i)〕
将(3RS)-3-苄氧羰氨基-2,3-二氢-5-(2-吡啶基-1H-1,4-苯骈二氮杂_-2-酮(R.M.Freidinger et al.Eur.Pat.№.0434364A2)(388mg,1mmol)的DMF(5ml)溶液冷至-10℃,在氮气气下加氢钠(42mg,80%的油悬浮液,1.4mmol)。混合物在-10℃搅拌30分钟,同时加实施例4A的溴代甲基酮(250mg,1.4mmol)。搅拌下在1小时内使混合物升至室温,然后倾到稀盐酸水溶液(100ml)中。混合物用乙酸乙酯萃取2次,然后有机层用盐水洗,过滤(Whatman_1ps相分离器)并减压浓缩。粗产品用闪式硅胶柱层析纯化(乙酸乙酯/40-60石油醚,90∶10V/V洗脱),得标题化合物,为无色固体(426mg,86%)。
Rf:0.35(乙酸乙酯)NMR(CDCl3)δ8.62(1H,d,J=8Hz),8.17(1H,d,J=8Hz),7.78(1H,t,J=8
Hz),7.50(1H,t,J=8Hz),7.4-7.15(9H,m),6.76(1H,c,J=8.5Hz),5.51
(1H,d,J=8.5Hz),5.16(2H,m),4 80(1H,d,J=17.5Hz),4.42(1H,d,J=
17.5Hz),2.92(1H,m),1.9-1.5(8H,m).14B N-((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲,〔路线1,步骤(ii)〕
实施例14A的苯骈二氮杂_(426mg,0.86mmol)用40%HBr的乙酸(6ml)溶液处理,混合物室温搅拌2小时。混合物用甲苯共沸2次后,残留物在乙酸乙酯和1MNaOH之间分配。有机层过滤(Whatman_1ps相分离器),蒸发,溶入CH2Cl2(5ml)并用异氰酸间甲苯酯(130ul,0.95mmol)处理,同时室温下搅拌2小时。混合物蒸发并色谱纯化(乙酸乙酯/40-60石油醚,70∶30V/V洗脱),得到的黄色固体用乙腈重结晶,得无色产物(73mg,17%)。
Rf:0.38(乙酸乙酯/已烷,60∶40V/V)NMR(CDCl3)δ8.6(1H,d,J=6Hz),7.95(1H,d,J=6Hz),7.6-7.0(10H,m),
6.80(1H,d,J=8.5Hz),5.78(1H,d,J=8.5Hz),5.10(1H,d,J=14Hz),
5.00(1H,d,J=14Hz),2.82(1H,m),2.14(3H,s),1.90-1.50(8H,m).M.S.(FAB,+ve ion)m/e 496.3(M+H)实施例15N-((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-(4-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲,化合物1015A(3RS)-3-苄氧羰氨基-1-环戊羰甲基-2,3-二氢-2-氧-5-(4-吡啶基)-1H-1,4-苯骈二氮杂_-2-酮〔路线1,步骤(i)〕
(3RS)-3-苄氧羰氨基-2,3-二氢-5-(4-吡啶基)-1H-1,4-苯骈二氮杂_-2-酮(Freidonger et al.Eur.Pat.№.0434364A2)(388mg,1mmol)的溶液如象实施例14A描述的那样烷基化,得到的产物色谱纯化(乙酸乙酯洗脱)后为无色固体(460mg,93%)。
Rf:0.22(乙酸乙酯)NMR(CDCl3)δ8.62(2H,d,J=7.5Hz),7.55(3H,m),7.4-7.1(8H,m),6.80(1H,
d,J=8.5Hz),5.42(1H,d,J=8.5Hz),5.12(2H,s),4.72(2H,m),2.85(1H,
m),1.9-1.4(8H,m).15B N((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-(4-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲,〔路线1,步骤(ii)〕
实施例15A的苯骈二氮杂_(375mg,0.724mmol)如同实施例14B描述的那样转化为脲。产品用色谱纯化(氯仿/甲醇/乙酸,200∶2∶1,V/V/V洗脱),得白色固体(59mg,16%)。
Rf:0.30(乙酸乙酯)NMR(CDCl3)δ8.62(2H,d,J=7.5Hz),7.7-7.0(11H,m),6.8(1H,m),5.62(1H,
d,J=8.5Hz),4.85(1H,d,J=16Hz),4.60(1H,d,J=16Hz),2.80(1H,m),
2.15(3H,s),1.8-1.4(8H,m).M.S.(FAB,+ve ion)m/e 496.2(M+H)实施例16N-((3RS)-1-环戊羰甲基-2,3-二氮-2-氧-5-苯基-1H-1,4-苯骈二氮杂卓-3-基)-N′-(3-羧苯基)脲,化合物1116A(3RS)-3-对硝基苄氧羰氨基-1-环戊羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂卓-2-酮〔路线3,步骤(i)〕
实施例4B的苯骈二氮杂卓(2.04g,4.13mmol)在5%钯碳(1.2g)催化下按照实施例1C描述的方法氢化。得到的胺溶入无水四氢呋喃(15ml)及三乙胺(0.626ml,4.5mmol)中,溶液冷至0℃。混合物在搅拌下用氯代甲酸对硝基苯酯(0.91g,4.5mmol)处理,并在室温下搅拌1小时,然后蒸发并用闪式硅胶柱层析纯化(乙酸乙酯/已烷,40∶60V/V,洗脱),生成黄色固体(675mg,32%)。
Rf:0.52(乙酸乙酯/已烷)NMR(CDCl3)δ8.2(2H,d,J=8Hz),7.6-7.0(12H,m),5.42(1H,d,8.5Hz),
4.82(1H,d,J=16.5Hz),4.62(1H,d,J=16.5Hz),2.97(1H,m),1.9-1.4
(8H,m).16B N((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-羧苯基)脲〔路线3,步骤(ii)〕
实施例16A的苯骈二氮杂_(175mg,0.333mmol)的DMF(5ml)溶液在搅拌下加间氨基苯甲酸(72mg,0.52mmol)及三乙胺(125ul)。混合物在45℃搅拌18小时,冷却并用乙酸乙酯稀释。混合物用0.3MHCl和盐水洗,然后过滤(Whatman_1ps相分离器)并蒸发。残留物用闪式硅胶柱层析纯化(乙酸乙酯/已烷/乙酸60∶40∶2V/V/V稀释),得到标题化合物,为无色固体(132mg,76%)。
Rf:0.25(乙酸乙酯/已烷/乙酸,60∶40∶2V/V/V)NMR(CDCl3)δ8.41(1H,s),8.37(1H,d,J=7.5Hz),8.16(1H,d,J=7.5Hz),
7.82(1H,s),7.7-7.2(12H,m),5.65(1H,d,J=8.5Hz),5.81(1H,d,J=15
Hz),4.66(1H,d,J=15Hz),2.95(1H,m),1.95-1.5(8H,m).M.S.(FAB,+ve ion)m/e 419(M+Na-H2NC6H4CO2H)实施例17N-((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲,化合物12
实施例4B的苯骈二氮杂_(1.13g,2.3mmol)按实施例4C描述的方法氮化,生成的胺经色谱纯化(氯仿/甲醇/乙酸,25∶2∶1洗脱),得黄色油。该油状物溶入乙腈并在搅拌下加(S)扁桃酸(335mg,2.20mmol),30分钟后加3,5-二氯水杨醛(10mg),搅拌过夜,抽滤收集生成的沉淀并用冷乙腈洗,得到白色固体(680mg,59%)。
该固体(460mg,0.897mmol)在氯仿和0.5M的NaOH之间分配。有机层用盐水洗,过滤(Whatman_1ps相分离器)并蒸发。残留物溶入二氯甲烷中(5ml),并用异氰酸间甲苯酯(110ul,0.852mmol)室温处理1小时。混合物蒸发并用色谱纯化(乙酸乙酯/已烷,40∶60V/V洗脱),得无色;固体(320mg,76%)。
Rf:0.16(乙酸乙酯/已烷40∶60V/V)
〔α〕D=+100.4°(CHCl3,C=0.96)
NMR和MS与实施例4C同。实施例18(N-((3S)-1-环戊羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲,化合物13
实施例4B的苯骈二氮杂_(1.98g,4mmol)按实施例4C描述的方法氢化,生成的胺色谱纯化(氯仿/甲醇/乙酸,25∶2∶1洗脱),得黄色油(1.15g,79%)。该油状物溶入乙腈中并加(S)扁桃酸(290mg,1.91mmol),混合物室温搅拌过夜。过滤收集生成的沉淀(300mg,19%),滤液蒸发,并在氯仿和0.25MNaOH之间分配。有机层用盐水洗,过滤(Whatman 1ps相分离器)并蒸发。残留物溶入乙腈中并加(R)-扁桃酸(420mg,2.77mmol),混合物在0℃搅拌20分钟,然后加3,5-二氯水杨醛(5mg)并继续室温搅拌过夜。收集生成的白色沉淀并用冷乙腈洗(800mg,56%)。
该固体(780mg,1.52mmol)在氯仿和0.25MNaOH之间分配,有机层用盐水洗,过滤(Whatman_1ps相分离器)并蒸发。残留物溶入CH2Cl2(10ml)并用异氰酸间甲苯酯(220ul,1.70mmol)室温处理1小时。混合物蒸发并色谱纯化(乙酸乙酯/已烷40∶60V/V洗脱),得无色固体(650mg,87%)。
Rf:0.16(乙酸乙酯/已烷40∶60V/V)
〔α〕D=-96.0°(CHCl3,C=1.58)
NMR和MS与实施例4C同。实施例19N-((3R)-1-((2R)-2-环戊基-2-羟乙基)-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲基苯基)脲,化合物20和实施例20N((3R)-1-((2S)-2-环戊基-2-羟乙基)-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲,化合物21
实施例17的苯骈二氮杂卓(355mg,0.677mmol)按实施例12和13描述的方法,在乙醇中用硼氢化钠处理。残留物用色谱纯化(乙酸乙酯/已烷,35∶65V/V洗脱)得两种标题化合物。
极性低的化合物105mg 31%
极性高的化合物145mg 43%
TLC、NMR和MS与实施例12及13同。实施例21N-((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-(3-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲,化合物921A 2-硝基-α-(3-吡啶基)苄醇
3-溴吡啶(7.90g,50mmol)溶入无水THF(50ml)中,在-100℃(内温)下滴加正丁基锂(1.6M溶液,32ml,51.2mmol),混合物在-100℃搅拌15分钟。滴加2-硝基苯甲醛(8.25g,54.6mmol)的THF(20ml)溶液,混合物在40分钟内升至0℃。混合物用水(5ml)终止反应,然后蒸发,并在乙酸乙酯和5%KHCO3溶液之间分配。有机层用盐水洗,过滤(Whatman_1ps相分离器)并蒸发。残留物色谱法纯化(乙酸乙酯/已烷,95∶5V/V洗脱)得黄色固体(5.72g,50%)。
Rf:0.30(乙酸乙酯)
NMR(CDCl3)δ8.38(1H,d,J=1.5Hz);8.26(1H,m);7.96(2H,m);7.70(2H,
m);7.45(1H,m);7.22(1H,m);6.45(1H,s).13C NMR(CDCl3)δ148.0,147.9,147.6,138.5,138.3,135.2,133.6,128.9,128.5,
124.5,123.5,68.6.21B 3-(2-硝基苯甲酰基)吡啶
卓酰氯(2.3ml,25.8mmol)溶入CH2Cl2(40ml)中,并在-60℃下10分钟内滴加硫酸二甲酯(3.67ml,5m1.75mmol)。加入实施例21A的醇(5.22g,22.7mmol)的CH2Cl2(5ml)溶液,接着加三乙胺(15.8ml,113.3mmol)。混合物在-60℃下搅拌5分钟,然后室温搅拌12小时。混合物用乙酸乙酯稀释,用5%KHCO3和盐水洗,过滤(Whatman_1PS相分离器)并蒸发。残留物色谱分离(乙酸乙酯/已烷,90∶10V/V洗脱)得黄色固体(3.25g,63%)。
Rf:0.38(乙酸乙酯)
NMR(CDCl3)δ8.90(1H,d,J=1.5Hz);8.82(1H,m);8.31(1H,d,J=8Hz);8.18
(1H,dd,J1=8Hz,J2=1.5Hz);7.80(2H,m);7.50(2H,m).13C NMR(CDCl3)δ192.0,153.9,150.3,146.3,136.0,134.9,134.4,131.4,131.0,
128.5,124.6,123.6.21C 3-(2-氨基苯甲酰基)吡啶
实施例21B的酮(1.83g,8.06mmol)溶入乙醇/水(1∶1。V/V,10ml)并用铁粉(2.78g,48mmol)处理。混合物加热回流然后加浓盐酸(0.17ml)的乙醇/水(1∶1,V/V,2)溶液。再加热1小时,混合物冷却、过滤和蒸发。残留物在0.5MNaOH和CHCl3之间分配,有机层用盐水洗,过滤(Whatman_1ps相分离器)、色谱纯化(乙酸乙酯/已烷,65∶35V/V,洗脱),得黄色固体(700mg,44%)。
Rf:0.45(乙酸乙酯)NMR(CDCl3)δ8.72(1H,d,J=1.5Hz);8.60(1H,d,J=7Hz);7.80(1H,m);7.20
(3H,m);6.60(1H,d,J=8Hz);6.48(1H,t,J=8Hz);6.12(2H,br.s).13C NMR(CDCl3)δ196.3,151.3,149.6,149.5,136.4,135.7,134.5,133.5,123.0,
117.2,115.6,115.4.21D (3RS)-3-苄氧羰氨基-2,3-二氢-5-(3-吡啶基)-1H-1,4-苯骈二氮杂_-2-酮
标题化合物采用Freidinger等的方法(Eur.Pat.№.0434364A2)从实施例21C的胺(700mg,3.57mmol)制备,得白固体(142mg,10%)。
Rf:0.2(乙酸乙酯)NMR(CDCl3)δ10.12(1H,s);8.6(2H,m);7.83(1H,d,J=7Hz);7.4-7.0(5H,m);6.76(1H,d,J=8Hz);5.25(1H,d,J=8Hz);5.08(2H,s).21E(3RS)-3-苄氧羰氨基-1-环戊羰甲基-2,3-二氢-5-(3-吡啶基)-1H-1,4-苯骈二氮杂_-2-酮〔路线1,步骤(i)〕
实施例21D的苯骈二氮杂_(142mg,0.35mmol)按实施例1B描述的方法,用实施例4A的溴代甲基酮(90mg,0.49mmol)烷基化。经色谱纯化(乙酸乙酯/已烷,95∶5,V/V洗脱)后,得到的标题化合物为白色固体(164mg,96%)。
Rf:0.28(乙酸乙酯)NMR(CDCl3)δ8.68(1H,s);8.58(1H,d,J=1.5Hz);7.98(1H,d,J=8Hz);7.88
(1H,s);7.45(1H,m);7.3-7.1(3H,m);6.62(1H,d,J=8Hz);5.37(1H,d,J
=8Hz);5.06(2H,s);4.63(2H,s);2.80(1H,m);1.8-1.4(8H,m).21F N-((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-(3-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲,〔路线1,步骤(ii)〕
实施例21E的苯骈二氮杂_(160mg,0.32mmol)在-70℃下溶入CH2Cl2(2ml)中,搅拌下滴加三溴化硼(1.0M的CH2Cl2溶液,2.0ml)。混合物在1小时内升至室温并继续搅拌3小时。溶液用水处理并在乙酸乙酯和1MNaOH之间分配。有机层用盐水洗,过滤(Whatman_1ps相分离器)并蒸发。残留物溶入CH2Cl3(3ml)中并在室温下与异氰酸间甲苯酯(45ul,0.35mmol)反应1小时。混合物蒸发后色谱纯化(乙酸乙酯/已烷,90∶10,V/V洗脱)得标题化合物,为白色固体(70mg,44%)
Rf:0.28(乙酸乙酯)NMR(CDCl3)δ8.88(1H,s);8.80(1H,d,J=1.5Hz);8.30(1H,d,J=8Hz);7.70
-7.20(10H,m);6.96(1H,m);5.80(1H,d,J=8Hz);5.01(1H,d,J=14
Hz);4.80(1H,d,J=14Hz);3.02(1H,m);2.41(3H,s);2.0-1.65(8H,m).M.S.(FAB)[M+H]+=496.3实施例22N-((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-羧苯基)脲,化合物3422A N-((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲氧羰苯基)脲〔路线1,步骤(ii)〕
实施例14A的苯骈二氮杂_(180mg,0.363mmol)溶入二氯甲烷(3ml),并在氮气下冷至-70℃。滴加三溴化硼(2.2ml,1M的CH2Cl2溶液),混合物搅拌1小时以上,该过程中撤去冷浴,然后在室温下再搅拌2小时。混合物用冰水处理,用乙酸乙酯稀释,用1MNaOH洗。有机层用盐水洗,过滤(Whatman_1ps相分离器),蒸发后得棕色油。
3-氨基苯甲酸甲酯(151mg,1mmol)在二氯甲烷(2ml)中于-20℃,氮气下用三光气(110mg,0.77mmol)和吡啶(81ul,1mmol)处理,混合物在-20℃搅拌30分钟后再加吡啶(81ul,1mmol),然后加上面制得的胺。混合物室温搅拌1小时,然后蒸发,并在乙酸乙酯和5%KHCO3之间分配。有机层用10%柠檬酸洗,盐水洗,过滤(Whatman_1ps相分离器)并蒸发,残留物色谱纯化(乙酸乙酯洗脱),得灰白色固体(95mg,49%)。
Rf:0.28(乙酸乙酯)NMR (CDCl3)δ8.60(d,1H,J=2Hz);7.10-8.10(M,13H);5.65(d,1H,J=8
Hz);4.62(m,2H);3.8(s,3H);2.95(m,1H);1.4-1.95(m,8H).22B N-((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-羧苯基)脲
实施例22A的苯骈二氮杂_(95mg,0.176mmol)溶入二氧六环/水(1∶1,V/V,2ml)并在室温下与LiOH-H2O(12mg,1.5eq)反应16小时。混合物蒸发并在CHCl3和10%柠檬酸之间分配。有机层用盐水洗,过滤(WHATMAN_1PS相分离器)并蒸发。残留物色谱纯化(氯仿/甲醇/乙酸,100∶2∶1.V/V/V洗脱)得到的白色固体从二氧六环/水冷冻干燥,得标题化合物34mg,37%)。NMR(CDCl3)δ8.62(d,1H,J=2Hz);7.1-8.2(m,13H);5.70(d,1H,J=8Hz);
4.58(m,2H);3.0(m,1H);1.4-2.0(m,8H).M.S.(+ve FAB)(M+H)+=526.2.实施例23N-((3R)-1-环戊羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-羧苯基)脲,化合物33
实施例4B的苯骈二氮杂_按实施例17描述的方法氢化和拆分。生成的(S)-扁桃酸盐(430mg,0.838mmol)在氯仿和0.25MNaOH之间分配,有机层用盐水洗,过滤(Whatman_1ps相分离器)并蒸发,得到游离胺,为无色油。
间氨基苯甲酸甲酯(315mg,2.1mmol)溶入二氯甲烷(3ml)和吡啶(170ul,2.1mmol)中,并在氮气下冷至-60℃。加入三光气(207mg,0.7mmol),混合物搅拌15分钟,温度升至-20℃。再加吡啶(170ul,2.1mmol),并在-20℃下再搅拌10分钟,然后加入上面得到的胺的CH2Cl2(1ml)溶液,继续在室温下搅拌2小时。混合物用乙酸乙酯稀释,用1MHCl和盐水洗,过滤(Whatman_1ps相分离器),色谱纯化(乙酸乙酯/已烷,40∶60V/V洗脱),得到中间体酯,为无色固体(375mg,83%)。
酯溶入二氧六环/水(1∶1,V/V,5ml)并与LiOH-H2O(41mg,1.4eq)室温反应16小时。混合物蒸发,并在乙酸乙酯和1MHCl之间分配。有机层用盐水洗,过滤(Whatman_1ps纸)并蒸发。残留物色谱纯化(乙酸乙酯/已烷/乙酸,60/40/2,V/V/V洗脱)得标题化合物,为无色固体(300mg,75%)。
Rf:0.24(乙酸乙酯/已烷/乙酸,60∶40∶2,V/V/V)
〔α〕D=+68.4(乙酸乙酯,C=0.92)
1HNMR和MS与实施例16同。实施例24和25N-((3R)-1-((2RS)-2-环戊基-2-羟乙基)-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-羧苯基)脲,化合物35和N-((3R)-1-(2R)-2-环戊基-2-羟乙基)-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-羧苯基)脲,化合物36
实施例23的苯骈二氮杂_(120mg,0.229mmol)在0℃下溶入乙醇并与硼氢化钠(16mg,0.4mmol)反应15分钟,然后混合物室温搅拌2小时,蒸发,残留物色谱纯化(乙酸乙酯/已烷/乙酸,60/40/2,V/V/V洗脱)得两种产物;
实施例24为1∶1极性大和极性小异构体的混合物(33mg)
实施例25为纯极性大的异构体(46mg)
TLC(乙酸乙酯/已烷/乙酸60/40/2,V/V/V)
Rf:极性小异构体=0.24
Rf:极性大异构体=0.20
MS:(M+H)+=527,两异构体相等。实施例26N-((3R)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲,化合物38
实施例2B的苯骈二氮杂_进行氢化,生成的胺按照实施例17的方法拆分为(R)-异构体(S)扁桃酸盐。其中一部分盐(150mg,0.299mmol)在氯仿和0.25MNaOH之间分配。有机层用盐水洗,过滤(Whatman_1ps纸)并蒸发。残留物溶入二氯甲烷,并加异氰酸间甲苯酯(42ul,0.33mmol)。混合物室温搅拌1小时,蒸发后色谱纯化(乙酸乙酯/已烷40/60,V/V洗脱)得到的白色固体从乙腈/水冷冻干燥(125mg,87%)。
数据同实施例2C。实施例27N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲,化合物3927A(3RS)-3-苄氧羰氨基-1-叔丁羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-2-酮〔路线1,步骤(i)〕
3(RS)-3-苄氧羰氨基-2,3-二氢-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-2-酮(R.M.Freinger et al.Eur.Pat.№.0434364A2)(2.02g,5mmol)按照实施例14A的方法用1-溴频哪酮(1.08g,6mmol)烷基化,色谱纯化后(乙酸乙酯/已烷,80∶20V/V洗脱)得白色固体(2.16g,86%)。27B N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲〔路线1,步骤(ii)〕
实施例27A的-部分苯骈二氮杂_(502mg,1mmol)于-70℃溶入CH2Cl2(2ml)并滴加BBr3(6.5ml,1.0M的CH2Cl2溶液),混合物搅拌3小时,在该期间撤去冷浴。混合物用水处理,然后在乙酸乙酯和1MNaOH之间分配。有机层用盐水洗,过滤(Whatman_1ps纸)并蒸发。残留物溶入CH2Cl2(3ml)并与异氰酸间甲苯酯(135ul,1.05mmol)在室温下反应1小时。混合物蒸发并色谱纯化(乙酸乙酯/已烷75∶25V/V洗脱),得到的白色固体用乙腈重结晶(180mg,38%)。
Rf:0.28(乙酸乙酯/已烷,60∶40V/V)1HNMR(CDCl3)δ8.78(d,1H,J=2Hz);8.27(d,1H,J=7Hz);7.95(m,1H);7.65-
6.9(m,11H);5.83(d,1H,J=8Hz);5.10(d,1H,J=16Hz);4.70(d,1H,J=
16Hz);2.42(s,3H);1.40(s,9H).M.S.(FAB)(M+H)+484.4实施例28N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-羧苯基)脲,化合物40
实施例2B的苯骈二氮杂_按实施例1C描述的方法氢化,生成的胺(600mg,1.72mmol)溶入无水THF(8ml)和三乙胺(260ul,1.9mmol)。氯代甲酸对硝基苯酯(0.38g,1.9mmol)的THF(3ml)溶液滴加到反应物内,得到的混合物室温搅拌1小时,蒸发并色谱纯制(乙酸乙酯/已烷,40∶60,V/V洗脱),得白色固体(670mg)。该固体溶入DMF(10ml)并与间氨基苯甲酸(245mg,1.75mmol)于45℃反应18小时。混合物蒸发并用色谱纯化(乙酸乙酯/已烷/乙酸,60∶40∶2,V/V/V洗脱),产品用乙腈重结晶,得标题化合物(328mg,38%)。1HNMR(CDCl3)δ7.8-7.0(14H,m);6.80(1H,d,J=7Hz);5.6(1H,d,J=8Hz);
4.9(1H,d,J=18Hz);4.8(1H,d,J=18Hz);1.40(9H,s).M.S.(FAB)(M+H)+=513.4实施例29N-((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(6-甲基-2-吡啶基)脲,化合物27
按实施例1C的方法制备,使用实施例4B的苯骈二氮杂_(165mg,0.33mmol)、5%钯碳(80mg)以及按下述方法制备的异氰酸酯:
2-氨基-6-皮考林(108mg,1mmol)的二氯甲烷(10ml)溶液搅拌下,-20℃加三光气(110mg,0.37mmol)及吡啶(79mg,1mmol)。混合物搅拌30分钟并使升至室温。加入吡啶(79mg,1mmol)。反应物加热沸腾30分钟。生成的异氰酸酯溶液冷至0℃,并直接使用。
粗产品用闪式硅胶柱层析纯化(乙酸乙酯∶40-60石油醚,80∶20V/V洗脱),得标题化合物,为白色固体(45mg,28%,HPLC纯度超过96%)。
Rf:0.20(乙酸乙酯/40-60石油醚,20∶80)NMR(CDCl3)δ10.8(1H,broad S);7.70-6.80(13H,m);5.70(1H,d,J=8Hz);
4.82(1H,d,J=17Hz);4.75(1H,d,J=17Hz);2.95(1H,Quintet,J=7Hz);
2.60(3H,s);1.95-1.75(4H,m);1.70-145(4H,m).M.S.(FAB,+ve ion)m/e 496.0(M+H).
实施例30
N-((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-苯基-1H
-1,4-苯骈二氮杂_-3-基)-N′-(3-吡啶基)脲,化合物26
按实施例1C的方法制备,使用实施例4B的苯骈二氮杂_(270mg,0.55mmol)、5%钯碳(100mg)及按下法制备的异氰酸酯:
往烟酸(172mg,1.4mmol)和二异丙基乙胺(250ul,1.4mmol)的THF(15ml)溶液中,搅拌下,0℃加氯代甲酸异丁酯(182ul,1.4mmol)。混合物0℃搅拌30分钟,然后加叠氮化钠(97mg,1.5mmol)的水(1ml)溶液,混合物搅拌2小时,同时升温至室温。混合物减压浓缩,残留物溶入乙酸乙酯,用冷的饱和KHCO3和冷盐水洗,过滤(Whatman_1ps相分离器),并减压浓缩。残留物在THF(5ml)中60℃加热5分钟,生成的异氰酸酯直接使用。
粗产品用闪式硅胶柱层析纯化(氯仿/甲醇/乙酸,100∶2∶1V/V/V洗脱),得标题化合物,为结晶性固体(34mg,13%,HPLC纯度在99%以上)。
Rf:0.10(氯仿/甲醇/乙酸,100∶2∶1)NMR(CDCl3)8.70-7.20(16H,m);5.50(1H,d,J=8Hz);4.75(1H,d,J=18
Hz);4.67(1H,d,J=18Hz);3.70(1H,m),1.90-1.20(8H,m).M.S.(FAB,+ve ion)m/e 482.0(M+H).实施例31N-((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-羧甲基苯基)脲,化合物2431A 3-氨基苯乙酸甲酯
往3-氨基苯乙酸(3.02g,20mmol)和甲醇(60啊l)的溶液中加乙酰氯(2ml,28mmol)。反应物在沸腾下加热6小时。反应物冷至室温后减压蒸去溶剂。生成的产物溶入氯仿中,并用饱和KHCO3和盐水洗,过滤(Whatman 1ps相分减压浓缩,得标题酯,为棕色流动性油(3.0g,91%)。NMR(CDCl3)δ7.35-6.90(4H,m);4.75(2H,s);3.80(3H,s);3.65(2H,s).31B N-((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂卓-3-基)-N′-(3-甲氧羰甲基苯基)脲〔路线1,步骤(ii)〕
按实施例1C的方法制备,使用实施例4B的苯骈二氮杂卓(165mg,0.33mmol0、5%钯碳(80mg)和按实施例29的方法从实施例31A的胺制备的异氰酸酯。
粗产品用闪式硅胶柱层析纯化(乙酸乙酯/已烷,60∶40,V/V)得到甲酯,为白色固体(180mg,97%)。
Rf:0.23(乙酸乙酯/已烷,60∶40)。31C N-((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂卓-3-基)-N′-(3-羧甲苯基)脲
往实施例31B的苯骈二氮杂卓(180mg,0.32mmol)的二氧六环(10ml)溶液中加LiOH-H2O(27ml,0.64mmol)的水溶液。混合物搅拌18小时,然后加入稀盐酸(10ml)。混合物用乙酸乙酯萃取2次,合并的有机层用水和盐水洗,过滤(Whatman 1ps相分离器)并减压浓缩。粗产品用闪式硅胶柱层析纯化(乙酸乙酯/已烷/乙酸,70∶30∶2,V/V/V,洗脱),得到标题化合物,为白色固体(105mg,61%,HPLC纯度在98%以上)。
Rf:0.20(乙酸乙酯/已烷/乙酸,70∶30∶2)NMR(CDCl3)δ8.00(1H.s);7.65-6.90(15H,m);5.65(1H,d,J=8Hz);4.71
(2H,s);3.50(2H,s);1.95-1.50(9H,m).M.S.(FAB,+ve ion)m/e 539.1(M+H).实施例32N-((3RS)-1-环已甲基羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂卓-3-基)-N′-(3-甲苯基)脲,化合物2932A 溴代甲基环已基甲基酮〔路线2,步骤(i)-(iii)
按实施例3A的方法制备。中间体重氮酮从环已基乙酸(4.27g,30mmol)、亚硫酰氯(8.7ml,120mmol)和CH2N2(从Diazald
制备,14.3g,66mmol)制备,用闪式硅胶柱层析纯化(乙酸乙酯/已烷,15∶85,V/V洗脱)。然后重氮酮用HBr的乙酸乙酯溶液处理。闪式硅胶柱层析纯化(乙酸乙酯/已烷,5∶95,V/V洗脱)得标题化合物,为浅棕色流动性的油(2.8g,43%)。NMR(CDCl3)δ3.99(2H,s);2.70(2H,d,J=8Hz);2.00(1H,m);1.85-1.10(10H,m).32B(3RS)-3-苄氧羰氨基-1-环已基甲基羰甲基-2,3-二氢-5-苯基-1H-1,4-苯骈二氮杂卓-2-酮〔路线1,步骤(i)〕
按实施例1B的方法制备,使用Bock苯骈二氮杂卓(250mg,0.62mmol)、氢化钠(26mg,80%的油悬浮液,0.87mmol)和实施例32A的溴代甲基酮(219mg,1mmol)。粗产品用闪式硅胶柱层析纯化(乙酸乙酯/已烷,35∶65V/V洗脱),得标题化合物,为无色结晶性固体(315mg,97%)。
Rf:0.25(乙酸乙酯/已烷,40∶60)NMR(CDCl3)δ7.50-7.00(14H,m);6.60(1H,d,J=8Hz);5.40(1H,d,J=8
Hz);5.10(2H,s);4.78(1H,d,J=17Hz);4.67(1H,d,J=17Hz);2.35(2H,
m);1.85(1H,m),1.65-0.90(10H,m).32C N-((3RS)-1-环已基甲基羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂卓-3-基)-N′-(3-甲苯基)脲〔路线1,步骤(ii)〕
按照实施例1C的方法制备,使用实施例32B的苯骈二氮杂卓(315mg,0.60mmol)、5%钯碳(250mg)和异氰酸间甲苯酯(91ul,0.71mmol)。粗产品用闪式硅胶柱层析纯化(乙酸乙酯/已烷,40∶60,V/V洗脱),得标题化合物,用乙腈重结晶后为白色固体(51mg,16%,HPLC纯度超过98%)。
Rf:0.20(乙酸乙酯/已烷,40∶60)NMR(CDCl3)δ7.80-6.90(15H,m);5.70(1H,d,J=8Hz);4.74(1H,d,J=
Hz);4.67(1H,d,J=18Hz);2.45-2.20(5H,m);1.95-0.90(11H,m).M.S.(FAB +ve ion)m/e 523.1(M+H)实施例33N-((3RS)-2-环戊甲羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂卓-3-基)-N′-(3-甲苯基)脲,化合物3033A 溴代甲基环戊甲基酮〔路线2,步骤(i)-(iii)〕
按照实施例3A的方法制备。中间体重氮酮从环戊基乙酸(2.85g,30mmol)、亚硫酰氯(8.7ml,120mmol)和CH2N2(从Diazald制备,14.3g,66mmol)制备,闪式硅胶柱层析纯化(乙酸乙酯/40-60石油醚,15∶85,V/V洗脱)。然后重氮酮用饱和HBr的乙酸乙酯溶液处理。闪式硅胶柱层析(乙酸乙酯/40-60石油醚,5∶95,V/V洗脱)得标题酮,为易流动的油(2.1g,34%)。NMR(CDCl3)δ3.99(2H,s);2.80(2H,d,J=8Hz);2.35(1H,m);1.95-1.30(8H,m).33B(3RS)-3-苄氧羰氨基-1-环戊基甲基羰甲基-2,3-二氢-5-苯基-1H-1,4-苯骈二氮杂卓-2-酮〔路线1,步骤(i)〕
按实施例1B的方法制备,使用Bock苯骈二氮杂卓(250mg,0.62mmol)、氢化钠(26mg,80%的油悬浮液,0.87mmol)及实施例33A的溴代甲基酮(205mg,1mmol)。粗产品用闪式硅胶柱层析纯化(乙酸乙酯/已烷,35∶65V/V洗脱),得标题化合物,为无色结晶性固体(300mg,95%)。
Rf:0.25(乙酸乙酯/已烷,40∶60)NMR(CDCl3)δ7.70-6.75(15H,m);5.50(1H,d,J=8Hz);5.20(2H,s);4.74(1H,d,J=18Hz);4.67(1H,d,J=18Hz);2.50(2H,m);2.25(1H,m);1.85-1.15(8H,m).33C N-((3RS)-1-环戊基甲基羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂卓-3-基)-N′-(3-甲苯基)脲〔路线1,步骤(ii)〕
按照实施例1C的方法制备,使用实施例33B的苯骈二氮杂卓(300mg,0.59mmol)、5%钯碳(250mg)和异氰酸间甲苯酡(91ul,0.71mmol)。粗产品用闪式硅胶柱层析纯化(乙酸乙酯/已烷,40∶60,V/V洗脱),得标题化合物,乙腈结晶,得白色固体(171mg,57%,HPLC纯度超过99%)。
Rf:0.20(乙酸乙酯/已烷,40∶60)NMR(CDCl3)δ7.85-6.98(15H,m);5.85(1H,broad s);4.80(2H,s);2.55(2H,
m);2.45(3H,s);2.43-2.30(1H,m);1.90-1.20(8H,m).M.S.(FAB,+ve ion)m/e 509.1(M+H).实施例34N-((3RS)-1-(1-甲基环已基)羰甲基)-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂卓-3-基)-N′-(3-甲苯基)脲,化合物3134A溴甲基(1-甲基环已基)酮〔路线2.步骤(i)-(iii)〕
使用实施例3A的方法制备。中间体重氮酮从1-甲基-1-环已基羧酸(4.27g,30mmol)、亚硫酸氯(8.7ml,120mmOl)和CH2N2(从DiagaldR_制备,14.3g,66mmol)。重氯酮不经纯化就与饱和HBr的乙酸乙酯溶液反应。闪式硅胶层析纯化(乙酸乙酯/已烷5∶95V/V洗脱),得到的酮为流动性油(1.90g,29%)。
NMR(CDCl3)δ4.25(2H,s);2.05(2H,m);1.70-1.40(8H,m);1.25(3H,s).34B(3RS)-3-苄氧羧氨基-1-(1-甲基环已基)羰甲基)-2.3-二氢-5-苯基-1.4-苯骈二氮杂_-2-酮〔路线1,步骤(i)〕
按实施例1B的方法制备,使用Bock苯骈二氮杂_(250mg,0.62mmol)、氢钠(26mg,80%的油悬溶液,0.87mmol)及实施例34A的溴代甲基酮(219mg,1mmol)。粗产品用闪式硅胶柱层析纯化(乙酸乙脂/已烷,35∶65 V/V洗脱)。得到标题化合物,为无色结晶性固体(270mg,86%)。
Rf:0.24(乙酸乙酯∶已烷40∶60)。NMR(CDCl3)δ7.70-7.10(14H,m);6.80(1H,d,J=8Hz);5.55(1H,d,J=8Hz);5.30(2H,s);5.10(1H,d,J=17Hz);4.75(1H,d,J=17Hz);2.10(2H,m);1.70-1.40(10H,m);1.30(3H,s).34C N-((3RS)-1-((1-甲基环已基)羰甲基)-2.3-二氢-2-氧-5-苯基-1H-1.4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲〔路线1,步骤(ii)〕
按照实施例1C的方法制备,使用实施例34B的苯骈二氮杂_(270g,0.52mmol)、5%钯碳(150mg)和异氰酸间甲苯酯(84ul,0.66mmol)。粗产品用闪式硅胶柱层析纯化(乙酸乙酯/已烷,40∶60V/V,洗脱),得标题化合物,用乙腈结晶,得结晶性固体(98mg,36%,HPLC纯度超过99%)。
Rf:0.20(乙酸乙酯/已烷,40∶60)。NMR(CDCl3)δ7.70-6.90(15H,m);5.80(1H,d,J=8Hz);4.90(1H,d,J=17
Hz);4.75(1H,d,J=17Hz);2.30(3H,s);2.00(2H,m);1.60-1.35(10H,
m);1.20(3H,s).M.S.(FAB +ve ion)m/e 523.3(M+H).实施例35N-(C3RS)-1-环戊基羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-羧基酰胺苯基)脲,化合物37。
按照实施例16B的方法制备,使用实施例16A的苯骈二氮杂_(225mg,0.43mmol)和3-氨基苯甲酸胺(87mg,0.64mmol)。粗产品用闪式硅胶柱层析纯化(乙酸乙酯洗脱)得标题化合物,为结晶性固体(30mg,13%,HPLC纯度在99%以上)。Rf:0.20(乙酸乙酯)。
NMR(CDCl3)δ8.95(1H,s);8.27(1H,d,J=8Hz);8.21(1H,d,J=8Hz);7.65-
7.20(15H,m);5.55(1H,d,J=8Hz);4.65(2H,s);2.90(1H,quintet,J=8
Hz);1.85-1.50(8H,m).
M.S.(FAB +ve ion)m/e 524(M+H).实施例36N-((3RS)-1-叔戊基羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲,化合物4136A 1-溴-3,3-二甲基-戊酮-2〔路线2,步骤(i)-(ii)〕
按照实施例3A的方法制备。中间体重氮酮从2,2-二甲基丁酸(5.8g,50mmol)、亚硫酰氯(14.6ml,200mmol)和CH2N2(从Di-ayaldR(R)制备,21.5g,100mmol)制备,闪式硅胶柱层析纯化(乙酸乙酯/已烷,20∶80,V/V洗脱)。重氮酮然后与饱和HBr的乙酸乙酯溶液反应。闪式硅胶柱层析纯化(乙酸乙酯/已烷,15∶85,V/V洗脱)得标题酮,为浅棕色油(1.50g,16%)。NMR(CDCl3)δ4.25(2H,s);1.70(1H,q,J=8Hz);1.30(6H,s);0.97(3H,t,
J=8Hz).36B N-((3RS)-1-叔戊基羰甲基-3-苄氧羰氨基-2-,3-二氢-5-苯基-1H-1,4-苯骈二氮杂_-2-酮〔路线1,步骤(i)〕
按实施例1B的方法制备,使用Bock苯骈二氮杂_(500mg,1.25mmol)、氢化钠(54mg,80%油悬浮液,1.75mmol)和实施例36A的溴代甲基酮(300mg,1.5mmol)。粗产品用闪式硅胶柱层析纯化(乙酸乙酯/已烷,35∶65,V/V洗脱)得标题化合物,为无色结晶性固体(565mg,91%)。
Rf:0.20(乙酸乙酯/已烷,40∶60)NMR(CDCl3)δ7.90-7.30(14H,m);6.90(1H,d,J=8Hz);5.80(1H,d,J=8
Hz);5.40(2H,s);5.10(1H,d,J=18Hz);4.75(1H,d,J=18Hz);1.90(2H,
m);1.40(6H,s);1.00(3H,t,J=8Hz).36C N-((3RS)-1-叔戊羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N,-(3-甲苯基)脲〔路线1,步骤(ii)〕
按照实施例1C的方法方法制备,使用实施例36B的苯骈二氮杂_(240mg,0.46mmol)、5%钯碳(250mg)和异氰酸间甲苯酯(76ul,0.6mmol)。粗产品用闪式硅胶柱析纯化(乙酸乙酯/已烷,40∶60,V/V洗脱)。得标题化合物,乙腈结晶后为白色固体(98mg,43%,HPLC纯度超过99%)
Rf:0.20(乙酸乙酯/已烷,40∶60)。NMR(CDCl3)δ7.50-6.80(15H,m);5.65(1H,d,J=8Hz);4.70(1H,d,J=18
Hz);4.65(1H,d,J=18Hz);2.20(3H,s);1.50(2H,q,J=8Hz);1.00(6H,
s);0.70(3H,t,J=8Hz).M.S.(FAB +ve ion)m/e 497.2(M+H).实施例37
N-((3RS)-1-叔戊基羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-羰苯基)脲,化合物42,37A(3RS)-3-对硝基苄氧羰氨基-1-叔戊基羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-2-酮〔路线3,步骤(i)〕
按照实施例16A的方法制备,使用实施例36B的苯骈二氮杂_(325mg,0.68mmol)、5%钯碳(250mg)和氯代甲酸对硝基苯酯(150mg,0.75mmol)。粗产品用闪式硅胶柱层析纯化(乙酸乙酯/已烷,35∶65,V/V洗脱)。得黄色固体样产物(135mg,38%)。
Rf:0.28(乙酸乙酯/已烷,40∶60)。NMR(CDCl3)δ8.10(2H,d,J=8Hz);7.50-7.00(12H,m);5.40(1H,d,J=8
Hz);4.85(1H,d,J=17Hz);4.60(1H,d,J=17Hz);1.55(2H,q,J=8Hz);
1.10(6H,s);0.75(3H,t,J=8Hz).37BN-((3RS)-1-叔戊羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-羧苯基)脲〔路线3,步骤(ii)〕
按照实施例16B的方法制备,使用实施例37A的苯骈二氮杂_(135mg,0.26mmol)和间氨基苯甲酸(54mg,0.39mmol)。粗产品用闪式硅胶柱层析纯化(乙酸乙酯/已烷/乙酸,60∶40∶2,V/V/V洗脱)得标题化合物,乙腈结晶后为无色固体(30mg,22%,HPLC纯度超过97%)。
Rf:0.20(乙酸乙酯/已烷/乙酸,60∶40∶2)。NMR (CDCl3)δ8.10-6.80(16H,m);5.50(1H,d,J=8Hz);4.80(1H,d,J=18
Hz);4.65(1H,d,J=18Hz);1.40(2H,q,J=8Hz);1.00(6H,s);0.70(3H,t,
J=8Hz).M.S.(FAB +ve ion)m/e 527.1(M+H).实施例38N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-二甲氨苯基)脲,化合物43
按照实施例27B的方法制备,使用实施例27A的苯骈二氮杂_(185mg,0.38mmol)、BBr3(2.5ml,1.0M CH2Cl2溶液)和按下法制备的异氰酸酯
往3-二甲氨基苯甲酸(165mg,1mmol)的甲苯(5ml)溶液中加二苯基磷酰叠氮(275mg,1mmol)和三乙胺(101mg,1mmol)。混合物室温搅拌2小时,然后加热回流3小时。上述游离胺的甲苯(5ml)溶液加到冷混合物中并室温搅拌过夜,蒸发后溶入乙酸乙酯。用5%KHCO3、水和盐水洗,过滤(WhatmanR_1PS相分离器)并蒸发,色谱纯化(乙酸乙酯洗脱),得无色固体(38mg,20%,HPLC纯度为91%)。
Rf:0.15(乙酸乙酯)NMR(CDCl3)δ8.78(d,1H,J=2Hz);8.27(d,1H,J=8Hz);7.95(m,1H);7.65-
6.6(m,11H);5.83(d,1H,J=8Hz);5.05(d,1H,J=16Hz);4.60(d,1H,J=
16H2);3.00(s,6H);1.40(s,9H).M.S.(FAB)(M+H)+实施例39N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-羧苯基)脲,化合物4439A异苯二酸单甲酯
异苯二甲酸二甲酯(2.28g,11.7mmol)溶入二氧六环(25ml)并与LIOH·H2O(510mg,12.1mmol)的(15ml)水溶液按实施例31B中描述的反应。产物用色谱纯化(乙酸乙酯/已烷/乙酸,50∶50∶2,V/V/V,洗脱),得标题化合物(1.1g,48%)。
NMR(CDCl3)δ8.45(s,1H);8.10(2H,m);7.45(1H,m);3.80(3H,s).39BN-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲氧羰苯基)脲〔路线1,步骤(ii)〕
按实施例27B的方法制备,使用实施例27A的苯骈二氮杂_(185mg,0.38mmol)、BBr3(2.5ml,1.0M的CH2Cl2溶液)以及用实施例39A的酸(250mg,1.4mmol)按实施例38的方法制备的异氰酸酯。产物用色谱纯化(乙酸乙酯洗脱),得标题化合物(110mg,56%)NMR(CDCl3)δ8.30(1H,d,J=2Hz);7.95-7.00(13H,m);5.60(1H,d,J=8
Hz);4.80(1H,d,J=16Hz);4.50(1H,d,J=16Hz);3.70(3H,s);1.20(9H,
s).39C((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-羰苯基)脲
按实施例31B的方法制备,使用实施例39B的苯骈二氮杂_(110mg,0.21mmol)和LiOH·H2O(17mg,0.42mmol)。粗产品用闪式硅胶色谱纯化(氯仿/甲醇/乙酸,75∶2∶1,V/V/V洗脱),得标题化合物,从乙腈/水冷冻干燥后得到白色固体产物(20mg,19%,HPLC纯度超过98%)。
Rf:0.12(乙酸乙酯/乙酸,100∶2)。
NMR(CDCl3)δ8.50(1H,d,J=2Hz);8.10-7.35(13H,m);5.65(1H,s);5.15
(1H,d,J=18Hz);4.90(1H,d,J=18Hz);1.35(9H,s).
M.S.(FAB)(M+H)+实施例40
N-((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-二甲氨苯基)脲,化合物45
按实施例1C的方法制备,使用实施例4B的苯骈二氮杂_(400mg,0.8mmol)、5%钯碳(400mg)以及按实施例38制备的异氰酸酯(3mmol)。粗产品用闪式硅胶柱层析纯化(乙酸乙酯/已烷,60∶40,V/V洗脱)得标题化合物,因乙腈结晶后为白色固体(84mg,25%,HpLC纯度在99%以上)。
Rf:0.20(乙酸乙酯/已烷,60∶40,V/V)。NMR(CDCl3)δ7.60-6.50(15H,m);5.65(1H,d,J=8Hz),4.65(s,2H),2.8(s,
6H);1.90-1.40(9H,m).M.S.(FAB,+ve ion)m/e 524.5(M+H)实施例41N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-二甲氨苯基)脲,化合物46。
按实施例1C的方法制备,使用实施例2B的苯骈二氮杂_(380mg,0.8mmol)、5%钯碳(300mg)和按实施例38制备的异氰酸酯(3mmol)。
粗产品用闪式胶硅柱层析纯化(乙酸乙酯/已烷,55∶45,V/V洗脱),乙腈结晶,得标题化合物,为白色粉末(127mg,31%,HpLC纯度在99%以上)。
Rf:0.23(乙酸乙酯/已烷,60∶40)NMR(CDCl3)δ7.60-6.9(15H,m);5.60(1H,d,J=8Hz);4.78(1H,d,J-18Hz);4.68(1H,d,J=18Hz);2.80(6H,s);1.20(9H,s).M.S.(FAB,+ve ion)m/e 512.5(M+H).实施例42N-((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲氧苯基)脲。化合物47
按实施例1C的方法制备,使用实施例4B的苯骈二氮杂_(400mg,0.8mmol)、5%钯碳(300mg),及异氰酸3-甲氧苯酯(136μl,1.04mmol)。粗产品用闪式硅胶柱层析纯化(乙酸乙酯/已烷,50∶50,V/V洗脱),得标题化合物,乙腈结晶后为白色粉末(265mg,65%,HPLC纯度超过99%)。
Rf:0.20(乙酸乙酯/已烷,50∶50)NMR(CDCl3)δ7.66-6.80(15H,m);5.75(1H,d,J=8Hz);4.85(2H,d,J=8
Hz);3.90(3H,s);3.00(1H,m);1.95-1.40(8H,m).M.S.(FAB,+ve ion)m/e实施例43N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲氧苯基)脲,化合物48
按实施例及1C的方法制备,使用实施例2B的苯骈二氮杂_(385mg,0.8mmol)5%钯碳(300mg)和异氰酸3-甲氧苯酯(136μl,1.04mmol)。粗产品用闪式硅胶柱层析纯化(乙酸乙酯/已烷,45∶55,V/V洗脱),乙腈结晶,得白色粉状标题化合物(249mg,63%,HpLC纯度在99%以上)。
Rf:0.23(乙酸乙酯/已烷,50∶50)NMR(CDCl3)δ7.60-6.50(15H,m);5.85(1H,d,J=8Hz);4.92(1H,d,J=18
Hz);4.82(1H,d,J=18Hz);3.90(3H,s);1.30(9H,s).M.S.(FAB,+ve ion)m/e实施例44N-((3RS)-1-环戊羰甲基)-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-硝基苯基)脲,化合物49
按实施例1C的方法制备,使用实施例4B的苯骈二氮杂_(400mg,0.8mmol)、5%钯碳(300ml)和异氰酸3-硝基苯酯(171mg,1.04mmol)。粗产品用闪式硅胶柱层析纯化(乙酸乙酯/已烷,45∶55,V/V洗脱)’得到的标题化合物为浅黄色固体(291mg,69%,HpLC纯度在99%以上)。
Rf:0.22(乙酸乙酯/已烷,50∶50)NMR(CDCl3)δ8.00-7.10(15H,m);5.65(1H,d,J=8Hz);4.74(1H,d,J=17
Hz);4.67(1H,d,J=17Hz);2.95(1H,m);1.90-1.30(8H,m).实施例45N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1,4-苯骈二氮杂_-3-基)-N’-(3-硝基苯基)脲,化合物50
按实施例1C的方法方制备,使用实施例2B的苯骈二氮杂_(385mg,0.8mmol)、5%钯碳(300mg)和异氰酸3-硝基苯酯(171mg,1.04mmol)。粗产品用闪式硅胶柱层析纯化(乙酸乙酯/已烷,45∶55,V/V洗脱),乙腈结晶,得到标题化合物,为浅黄色固体(283mg,69%,HpLC纯度在99%以上)。
Rf:0.24(乙酸乙酯/已烷,50∶50)NMR(CDCl3)δ8.10-6.90(15H,m);5.65(1H,d,J=8Hz);4.85(2H,s);1.25
(9H,s).M.S.实施例46N-((3RS)-1-(1-甲基环戊基)羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲,化合物3246A 1-甲基环戊基羰酸
环已烯(25ml,0.246mol)5℃与浓硫酸(100ml)和甲酸(18.9ml,0.5mol)反应2小时。混合物倾到冰上并用乙酸乙酯萃取2次。有机萃取物用盐水洗,然后用2M KOH萃取。碱性萃取物用2M盐酸酸化,用氯仿苯取,过滤(whatmanR(R),1PS相分离器)并蒸发。生成的棕色油通过泡连泡的蒸馏(125℃/油泵),得标题化合物,为无色油(860mg,2%)。46B溴甲基1-甲基环戊基酮[路线2,步骤(i)-(iii)]
按实施例3A的方法制备。中间体重氮酮从实施例46A的酸(860mg,6.7mmol)、亚硫酰氯(2ml,30mmol)及CH2N2(从Diagal-d_4.3g,20mmol)制备。然后重氮酮用饱和HBr的乙酸乙酯处理。闪式硅胶柱层析纯化(乙酸乙酯/已烷,7∶93,V/V),得标题化合物(270mg,2%)。NMR(CDCl3)δ4.20(2H,s);2.15-1.45(8H,m);1.35(3H,s)46C(3RS)-3-苄氧羰氨基-1-(1-甲基环戊基)羰甲基-2,3-二氮-5-苯基-1H-1,4-苯骈二氮杂_-2-酮[路线1,步骤(i)]
按照实施例1B的方法制备,使用Bock苯骈二氮杂_(202mg,0.5mmol)、氢钠(21mg,85%的悬浮液,0.70mmol)和实施例46B的溴代甲基酮(133mg,0.65mmol)。粗产品用闪式硅胶纯化(乙酸乙酯/已烷,40/60,V/V洗脱)得标题化合物,为无色结晶性固体(190mg,74%)
Rf:0.24(乙酸乙酯/已烷,40∶60)NMR(CDCl3)δ7.55-7.05(14H,m);6.55(1H,d,J=8Hz);5.35(1H,d,J=8Hz);
5.05(2H,s);4.77(1H,d,J=17Hz);4.66(1H,d,J=17Hz);2.10-1.40(8H,
m);1.20(3H,s).46D N-((3RS)-1-((1-甲基环戊基)羰甲基-2.3-二氢-2-氧-5-苯基-1H-1.4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲,[路线1,步骤(ii)]。
按实施例1C的方法制备,使用实施例46C的苯骈二氮杂_(190mg,0.37mmol)、5%钯碳(150mg)和异氰酸间甲苯酯(65μl,0.50mmol)。粗产品用闪式硅胶柱层析纯化(乙酸乙酯/已烷,40∶60,V/V洗脱),得到的标题化合物从乙腈/水冷冻干燥为白色固体(102mg,54%,HpLC纯度超过97%)。
Rf:0.20(乙酸乙酯/已烷,40∶60)NMR(CDCl3)δ7.70-6.90(15H,m);5.70(1H,d,J=8Hz);4.88(1H,d,J=17Hz);4.82(1H,d,J=17Hz);2.30(3H,s);2.10-1.40(8H,m);1.25(3Hs).M.S.(FAB +ve ion)m/e509.3[M+H]实施例47N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3基)-N’-(3-甲酰胺苯基)脲,化合物5147A3-甲酰胺基苯甲酸
乙酸酐(50ml)加到98%甲酸(85ml)中。混合物室温搅拌30分钟,然后加3-氨基苯甲酸(10g,73mmol),混合物室温搅拌1小时。加水(850ml),混合物室温搅拌过夜。收集生成的白色沉淀(10.66g,88%)。NMR(CDCl3)δ8.90-7.50(7H,m).47BN-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲酰氨苯基)脲[路线1,步骤(ii)]
实施例2B的苯骈二氮杂_按实施例1C描述的方法氢化,生成的胺(250mg,0.71mmol)在甲苯(2ml)中与使用实施例47A的酸(40mg,2.5mmol)按照实施例38制备的异氰酸酯反应。产品用闪式硅胶柱层析纯化(用乙酸乙酯和氯仿/甲醇/乙醇,80∶20∶1,V/V/洗脱),用乙腈结晶,得无色固体(75mg,21%,HpLC纯度超过97%)。1H NMR(CDCl3)δ8.90-8.10(3H,m);7.75-7.10(
H,m);6.70(
H,d,J=
18Hz);5.75(1H,m);4.90(1H,m);1.30(9H,3s).M.S.[M+H]+=512.2.实施例48N-((3R)-1-((2R)-2-羟基-3,3-二甲基丁基)-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲,化合物52
实施例26的苯骈二氮杂卓脲(180mg,0.373mmol)溶入甲醇和二氯甲烷的混合物(5ml,1/1,V/V)中,加入CeCl3·7H2O(155mg,0.416mmol)’混合物搅拌使所有的固体溶解,然后冷至-78℃。加入硼氢化钠(20mg,0.529mmol),混合物在-78℃搅拌10分钟,然后在-10℃搅拌1小时,2小时内升至室温。混合物在氯仿和盐水之间分配,有机层干燥,蒸发。残留物用闪式硅胶层析纯化(乙酸乙酯/已烷,40∶60,V/V洗脱),得无色固体(105mg,58%,HpLC纯度在98%以上)。
Rf:0.31(乙酸乙酯/40-60石油醚,40∶60)1H NMR(CDCl3)δ7.8-6.9(15H,m),5.6(1H,d,J=8Hz);4.35(1H,m);3.6(2H,
m);2.2(3H,s);0.85(9H,s).
M.S.(FAB,+ve ion)m/e=485.3[M+H]实施例49N-((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-氰基苯基)脲,化合物22
按照实施例1C的方法制备,使用实施例4B的苯骈二氮杂_(300mg,0.6mmol)、5%钯碳(150mg)和按照实施例30的方法从3-氰基苯甲酸(295mg,2mmol)制备的异氰酸酯。粗产品用闪式硅胶柱层析纯化(氯仿/乙酸,100∶2,V/V洗脱),得到的标题化合物从乙氰/水冷冻干燥,为白色结晶性固体(30mg,10%,HpLC纯度在97%以上)。NMR(CDCl3)δ8.20-8.05(4H,m);7.70-7.10(11H,m);5.50(1H,d,J=8Hz);
4.75(1H,d,J=17Hz);4.66(1H,d,J=17Hz);1.75-1.35(9H,m).M.S.(FAB):[M+H]+=506.1实施例50N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-氰基苯基)脲,化合物23
按照实施例1C的方法制备,使用实施例2B的苯骈二氮杂_(290mg,0.6mmol)、5%钯碳(150mg)和按照实施例30从3-氰基苯甲酸(295mg,2mmol)制备的异氰酸酯。粗产品用闪式硅胶柱层析纯化(氯仿/已酸,100∶2,V/V洗脱),从乙腈/水冷冻干燥,得标题化合物(36mg,12%,HpLC纯度超过96%)。NMR(CDCl3)δ8.20-8.05(4H,m);7.70-7.10(11H,m);5.50(1H,d,J=8Hz);
4.90(1H,d,J=17Hz);4.70(1H,d,J=17Hz);1.15(9H,s).M.S.(FAB):[M+H]+=494.2实施例51N-((3RS)-1-(1-金刚烷基)羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲,化合物2551A 1-金刚烷基溴代甲基酮[路线2,步骤(ii)-(iii)]
按实施例3A的方法制备。中间体重氮酮从1-金刚烷酰氯(2.98mg,15mmol)和CH2N2(从DiagaldR(R)制备,8.7g,40mmol)制备,按着用饱和HBr的乙酸乙酯溶液处理。闪式硅胶柱层析纯化(乙酸乙酯/已烷,8∶92,洗脱),得标题化合物,为浅棕色流动状油(2.30g,60%)。NMR(CDCl3)δ4.20(2H,s);2.15-1.75(15H,m).51B(3RS)-1-(1-金刚烷基)羰甲基-3-苄氧羰氨基-2,3-二氢-5-苯基-1H-1,4-苯骈二氮杂_-2-酮[路线1,步骤(i)]
按实施例1B的方法制备,使用Bock苯骈二氮杂_(202mg,0.5mmol)、氢化钠(21mg,80%油悬溶液,0.70mmol)和实施例51A的溴代甲基酮(167mg,0.65mmol)。粗产品用闪式硅胶柱层析纯化(乙酸乙酯/已烷,40∶60,V/V洗脱)得标题化合物,为无色的结晶性固体(130mg,46%)。NMR(CDCl3)δ7.75-7.15(14H,m);6.80(1H,d,J=8Hz);5.55(1H,d,J=8Hz);
5.25(2H,s);5.07(1H,d,J=17Hz);4.76(1H,d,J=17Hz);2.15-1.80
(15H,m).51C N-((3RS)-1-(1-金刚烷基)羰甲基-2,-3-二氢-2-氧-5-苯基-1H-1.4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲[路线1,步骤(ii)]。
按照实施例1C的方法制备,使用实施例51B的苯骈二氮杂_(130mg,0.23mmol)、5%钯碳(100mg)和异氰酸间甲苯酯(45μl,0.35mmol)。粗产品用闪式硅胶柱层析纯化(乙酸乙酯/已烷,35∶65,V/V洗脱),从乙腈/水冷冻干燥,得白色固体(57mg,44%,HpLC纯度在96%以上)。NMR(CDCl3)δ7.75-7.10(14H,m);6.82(1H,d,J=8Hz);5.75(1H,d,J=8Hz);
4.90(1H,d,J=17Hz);4.80(1H,d,J=17Hz);2.30(3H,s);2.10-1.60
(15H,m).M.S.(FAB +ve ion)m/e 561.3[M+H]实施例52N-((3RS)-1-(3-环已基-3-甲基-2-氧丁基)-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲,化合物2852A 2-甲基-2-苯基丙酸甲酯
往苯乙酸甲酯(10.5g,70mmol)的THF(125ml)溶液中,0℃下加氢钠(2.25g,80%的油悬溶液,75mmol)。混合物0℃搅拌30分钟,然后加碘甲烷(4.4ml,70mmol)’混合物0℃再搅拌30分钟。再加氢钠(2.25g,80%油悬溶液,75mmol)’混合物0℃搅拌30分钟,然后加碘甲烷(8.8ml,140mmol),混合物室温放置48小时。反应混合物用水处理,混合物浓缩,除去THF。残留物溶入乙酸乙酯,并依次用5%KHCO3,0.3M KHSO4及盐水洗,过滤(WhatmanR(R),IPS,相分离器),蒸发得油状标题化合物(3.20g,26%)。
NMR(CDCl3)δ7.50-7.25(5H,m);3.60(3H,s);1.55(6H,s).52B2-甲基-2-苯基丙酸
实施例52A的甲酯(3.20g,18mmol)的二氧六环(25ml)溶液与LiOH·H2O(1.5g,36mmol)的水(15ml)溶液按实施例31B描述的方法反应,得无色油状标题化合物(1.85g,63%)。
NMR(CDCl3)δ7.50-7.25(6H,m);1.55(6H,s).52C 2-环已基-2-甲基丙酸
实施例52B的酸(1.85g,11.3mmol)的甲醇(100ml)溶液用氮气脱气10分钟。加5%铑碳(2g),混合物再脱气10分钟,然后室温/60p,s,i(巴)氢化4天。混合物通过硅藻土过滤,滤液蒸发得标题化合物,为无色油(1.70g,88%)。
NMR(CDCl3)δ1.90-1.00(11H,m);1.20(6H,s).52D 1-溴-3-环已基-3-甲基丁酮-2[路线2,步骤(i)-(iii)]
按照实施例3A的方法制备。中间体重氮酮使用实施例52C的酸(1170g,10mmol)、亚硫酰氯(2ml,30mmol)和CH2N2(从DiagaldR(R)制备,8.7g,40mmol)制备,然后用饱和HBr的乙酸溶液处理。闪式硅胶柱层析纯化(乙酸乙酯/已烷,5∶95,V/V洗脱)得标题化合物,为浅棕色流动状油(280mg,11%)。
NMR(CDCl3)δ4.30(2H,s);2.90-1.10(11H,m);1.20(6H,s).52E(3RS)-3-苄氧羰氨基-1-(3-环已基-3-甲基-2-氧丁基)-2,3-二氢-5-苯基-1H-1,4苯基-1H-1,4-苯骈二氮杂_-2-酮[路线1,步骤(i)]
按照实施例1B的方法制备,使用Bock苯骈二氮杂_(202mg,0.5mmol)、氢钠(21mg,80%油悬溶液,0.70mmol)及实施例52D的溴代甲基酮(160mg,0.65mmol)。粗产品用闪式硅胶柱层析纯化(乙酸乙酯/已烷,35∶65,V/V洗脱),得标题化合物,为无色结晶性固体(70mg,25%)。NMR(CDCl3)δ7.55-7.05(14H,m);6.55(1H,d,J=8Hz);5.30(1H,d,J=8Hz);
5.02(2H,s);4.78(1H,d,J=17Hz);4.58(1H,d,J=17Hz);1.70-0.90
(11H,m);1.00(6H,s)52F N-((3RS)-1-(3-环已基-3-甲基-2-氧丁基)-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲·[路线1,步骤(iii)]
按实施例1C的方法制备,使用实施例52E的苯骈二氮杂_(70mg,0.13mmol)、5%钯碳(50mg)和异氰酸间甲苯酯(20μl,0.16mmol)。粗产品用闪式硅胶柱层析纯化(乙酸乙酯/已烷,40∶60,V/V纯化)。从乙腈/水冷冻干燥,得标题化合物为白色固体(35mg,50%,HpLC纯度在95%以上)。NMR(CDCl3)δ7.70-6.95(14H,m);6.60(1H,m);5.75(1H,d,J=8Hz);4.90
(1H,d,J=17Hz);4.83(1H,d,J=17Hz);2.35(3H,s);1.90-0.95(11H,m);
1.10(6H,s).M.S.[M+H]+=551.3.实施例53N-((3RS)-1-(1-甲基环已基)羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲,化合物5453A溴甲基1-甲基环丙基酮
0℃下往甲基-甲基环丙基酮(5g,50.9mmol)甲醇(30ml)溶液中,滴加溴(2.6ml,51mmol)。混合物0℃搅拌2小时。加水(15ml),混合物室温搅拌过夜。再加水(45ml),产品用乙醚萃取。有机层依次用10%K2CO3,水和盐水洗,CaCl2干燥30分钟,过滤(WhatmanR(R)IPS相分离器)减压浓缩,得标题化合物,为清亮的流动性油(8.2g,91%)。NMR(CDCl3)δ3.95(2H,s);1.40(3H,s);1.30(2H,t,J=7Hz);0.80(2H,t,J=7Hz).53B(3RS)-3-苄氧羰氨基-1-(1-甲基环丙基)羰甲基-2,3-二氢-1H-1,4-苯骈二氮杂_-2-酮[路线1,步骤(i)]
按实施例1B的方法制备,使用Bock苯骈二氮杂_(202mg,0.5mmol)、氢化钠(21mg,80%油悬浮液,0.70mmol)及实施例53A的溴代甲基酮(133g,0.75mmol)。粗产品用闪式硅胶柱层析纯化(乙酸乙酯/已烷,40∶60,V/V纯化),得标题化合物,为无色结晶性固体(190mg,79%)。NMR(CDCl3)δ7.55-7.10(14H,m);6.65(1H,d,J=8Hz);5.40(1H,d,J=8Hz);
5.10(2H,s);4.77(1H,d,J=17Hz);4.55(1H,d,J=17Hz);1.40(3H,s,);
1.25(2H,t,J=7Hz);0.75(2H,t,J=7Hz).53C N-((3RS)-1-(1-甲基环丙基)羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_)-N’-(3-甲基苯基)脲[路线1,步骤(ii)]按照实施例1C的方法制备,使用实施例53B的苯骈二氮杂_(190mg,0.4mmol)、5%钯碳(200mg),和异氰酸间甲苯酯(65μl,0.5mmol)。粗产品用闪式硅胶柱层析纯化(乙酸乙酯/已烷,45∶55,V/V洗脱),得标题化合物,从乙腈/水冷冻干燥,为白色固体(150mg,78%,HpLC纯度在98%以上)。
Rf:0.16(乙酸乙酯/乙烷,40∶60)NMR(CDCl3)δ7.70-7.10(14H,m);6.85(1H,d,J=8Hz);5.75(1H,d,J=8Hz);
4.82(1H,d,J=17Hz);4.75(1H,d,J=17Hz);2.35(3H,s);1.45(3H,s);
1.30(2H,t,J=7Hz);0.90(2H,t,J=7Hz).M.S.(FAB,+ve ion)m/e 481.2[M+H].实施例54N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-(2-氯苯基)-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲,化合物5554A(3RS)-3-苄氧羰氨基-1-叔丁羰甲基-7-氯-5-(2-氯苯基)-1H-1.4-苯骈二氮杂_-2-酮〔路线1,步骤(i)〕
按实施例1B的方法制备,使用(3RS)-3-苄氧羰氨基-7-氯-5-(2-氯苯基)-1H-1,4-苯骈二氮杂_-2-酮(241mg,0.51mmol),制备方法与Bock苯骈二氮杂_类似)、氢钠(22mg,80%油悬浮液,0.72mmol)及1-溴频哪酮(179mg,1mmol)。粗产品用闪式硅胶柱层析纯化(乙酸乙酯/已烷,30∶70,V/V洗脱),得标题化合物(145mg,52%)。NMR (CDCl3)δ7.80-7.30(12H,m);6.80(1H,d,J=8Hz);5.60(1H,d,J=8Hz);
5.30(2H,s);5.25(1H,d,J=17Hz);4.60(1H,d,J=17Hz);1.35(9H,s).54BN-((3RS)-1-叔丁基羰甲基-2,3-二氢-2-氧-5-(2-氯苯基)-1H-1,4-苯骈二氮杂_-3-基)-N,-(3-甲苯基)脲,〔路线1,步骤(ii)〕
按实施例1C的方法制备,使用实施例54A的苯骈二氮杂_(145mg,0.26mmol)、5%钯碳(120mg)和异氰酸间甲苯酯(40μl,0.32mmol)。粗产品用闪式硅胶柱层析纯化(乙酸乙酯/已烷,40/60,V/V洗脱),从乙腈/水中冷冻干燥,得标题化合物,为白色固体(45mg,31%)。NMR(CDCl3)δ7.70-6.95(14H,m);5.80(1H,d,J=8Hz);5.30(1H,d,J=
17Hz);4.60(1H,d,J=17Hz);2.40(3H,s),1.30(9H,s).M.S(FAB,+ve ion)m/e 517.2[M+H]注:7-氯取代基在氢解过程中失去。实施例55N-((3RS)-1-异丙羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲,化合物5655A1-溴-3-甲基丁酮-2〔路线2,步骤(i)-(iii)〕
按照实施例3A的方法制备。中间体重氮酮从异丁酸(8.82g,100mmol)、亚硫酰氯(30ml,400mmol)和CH2N2(从Diagald_,制备,43g,200mmol)制备,然后用饱和HBr的乙酸乙酯/已烷,6∶94,V/V洗脱),得标题化合物,为流动的油(300mg,1.8%)。NMR(CDCl3)δ4.25(2H,s);3.00(1H,heptet,J=8Hz);1.25(6H,d,J=8Hz).55B(3RS)-3-苄氧羰氨基-1-异丙羰甲基-2,3-二氢-5-苯基-1H-1,4-苯骈二杂_-2-酮〔路线1,步骤(ii)〕
按照实施例1B的方法制备,使用Bock苯骈二氮杂_(606mg,1.5mmol)、氢钠(63mg,80%油悬浮液,2.1mmol)及实施例55A的溴代甲基酮(300mg,1.8mmol)。粗产品用闪式硅胶柱层析纯化(乙酸乙酯/已烷,40∶60,V/V洗脱),得标题化合物,为结晶性固体(250mg,36%)。NMR(CDCl3)δ7.70-7.20(14H,m);6.75(1H,d,J=8Hz);5.50(1H,d,J=8Hz);
5.20(2H,s);4.85(1H,d,J=17Hz);4.75(1H,d,J=17Hz);2.80(1H,
heptet,J=8Hz);1.25(6H,d,J=8Hz).55C N-((3RS)-1-异丙羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲〔路线1,步骤(ii)〕
按实施例27B的方法制备,使用实施例55B的苯骈二氮杂_(250mg,0.53mmol)、BBr3(3.2ml,1.0M CH2Cl2溶液)及异氰酸间甲苯酯(40μl,0.31mmol)。粗产品用闪式硅胶柱层析纯化(乙酸乙酯/已烷,55∶45,V/V洗脱),从乙腈/水冷冻干燥,得产物,为白色固体(51mg,21%,HpLC纯度有98%以上)。
Rf:0.16(乙酸乙酯/已烷,50∶50)NMR(CDCl3)δ7.70-7.15(14H,m);6.85(1H,d,J=8Hz);5.70(1H,d,J=8Hz);
4.75(2H,s);2.70(1H,heptet,J=8Hz);2.30(3H,s);1.18(6H,d,J=8Hz).M.S.(FAB,+ve ion)m/e 469.3[M+H]实施例56N-((3R)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲氨基苯基)脲,化合物5756A N-甲基-3-甲氧羰基甲酰苯胺
按实施例1B的方法制备,使用3-羧甲酰苯胺(2.28g,13.8m-mol)、氢化钠(1.05g,80%油的悬浮液,34.5mmol)及碘甲烷(2.85ml,45mmol)。粗产品用闪式硅胶柱层析纯化(乙酸乙酯/乙烷,60∶40,V/V,洗脱)得标题化合物,为无色结晶性固体(2.30g,86%)NMR(CDCl3)δ8.50(1H,s);7.90-7.40(4H,m);3.95(3H,s);3.40(3H,s)56BN-甲基-3-羧甲酰苯胺
按照实施例31B的方法制备,使用实施例56A的酯(1.90g,9.8m mol)和LiOH·H2O(840mg,20mmol)。后处理得标题化合物,为无色结晶性固体(985mg,56%)56C N-((3R)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N,-(3-(N-甲酰基-N-甲氨基)苯基)脲〔路线1,步骤(ii)〕
拆分的实施例26的苯骈二氮杂_(980mg,2.8mmol)溶入甲苯(10ml),然后与按照实施例38的方法从实施例56B的酸(985mg,5.5mmol)制备的异氰酸酯反应。产物用闪式硅胶柱层析纯化(乙酸乙酯/已烷,75∶25,V/V洗脱),得标题化合物(960mg,65%)。NMR(CDCl3)δ 8.45(1H,s);7.65-7.05(14H,m);6.70(1H,d,J=8Hz);5.70
(1H,d,J=8Hz);4.98(1H,d,J=17Hz);4.75(1H,d,J=17Hz);3.20(3H,
s);1.30(9H,s).56D N-((3R)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲氨苯基)脲
实施例56C的苯骈二氮杂_(960mg,1.8mmol)溶入丙酮(15ml)并用4N盐酸(9ml)处理。混合物室温搅拌3天,然后蒸发,溶入CH2Cl2,用5%KHCO3洗,过滤(Whatman_,IPS相分离器)并蒸发。残留物用闪式硅胶柱层析纯化(氯仿/甲醇/乙酸120∶2∶1V/V/V,洗脱),用乙腈/水结晶,得标题化合物,为白色固体(400mg,45%,HpLC纯度超过99%)NMR(CDCl3)δ7.70-7.20(13H,m);6.75(1H,s);6.65(1H,d,J=8Hz);6.30
(1H,d,J=8Hz);5.75(1H,d,J=8Hz);4.85(2H,s);2.80(3H,s);1.20(9H,
s).M.S.(FAB +ve ion)m/e498.3[M+H]实施例57N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲氨苯基)脲,化合物5857A N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-(N-甲酰基-N-甲氨基)苯基)脲,〔路线1,步骤(ii)〕
按照实施例27B的方法制备,使用实施例27A的苯骈二氮杂_(340mg,0.7mmol)、BBr3(4.4ml,1.0M CH2Cl2溶液)和按照实施例38的方法从实施例56B的酸(420mg,2.3mmol)制备的异氰酸酯。产品用闪式硅胶柱层析纯化(乙酸乙酯洗脱)得标题化合物(185mg,50%)。NMR(CDCl3)δ8.25(1H,d,J=8Hz);8.00(1H,s);7.60-6.80(12H,m);6.40
(1H,d,J=8Hz);5.35(1H,d,J=8Hz);4.62(1H,d,J=17Hz);4.30(1H,d,J
=17Hz);2.90(3H,s);0.90(9H,s).57BN-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲氨苯基)脲
按照实施例56B的方法制备,使用实施例57A的苯骈二氮杂_(185mg,0.35mmol),丙酮(5ml)及4N盐酸(3ml)。粗产品用闪式硅胶柱层析纯化(氯仿/甲醇/乙酸,120∶2∶1,V/V/V,洗脱)从乙腈/水冷冻干燥,得标题化合物,为白色固体(67mg,38%,HpLC纯度在95%以上)。NMR(CDCl3)δ8.30(1H,d,J=8Hz);7.95(1H,d,J=8Hz);7.60(1H,t,J=
7Hz);7.35(1H,t,J=7Hz);7.20-6.85(8H,m);6.50(1H,d,J=8Hz);6.30
(1H,d,J=8Hz);6.10(1H,d,J=8Hz);5.40(1H,d,J=8Hz);4.75(1H,d,J
=17Hz);4.40(1H,d,J=17Hz);2.60(3H,s);0.95(9H,s).M.S.(FAB +ve ion)m/e 499.3[M+H]实施例58N-((3R)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-(N-乙基-N-甲氨基)苯基)脲,化合物5958A 3-(N-乙基-N-甲氨基)苯甲酸甲酯
按实施例56D的方法制备,使用实施例56A的酯(2.35g,12.2mmol),丙酮(100ml)和4N盐酸(60ml)。0℃下将生成的胺溶入甲醇/乙酸(99∶1,70ml)。加入乙醛(1,0ml,18mmol)和NaB-H3CN(1.13g,18mmol)。混合物0℃,搅拌2小时,蒸发,溶入乙酸乙酯,用5%KHCO3和盐水洗,过滤(Whatman_,IPS相分离器)并蒸发。残留物用闪式硅胶柱层析纯化(乙酸乙酯/已烷,15∶85,V/V洗脱)得标题化合物(2.15g,91%)。NMR(CDCl3)δ7.40-7.25(3H,m);6.90(1H,m);3.90(3H,s);3.45(2H,quartet,
J=7Hz);2.95(3H,s);1.15(3H,t,J=7Hz).58B3-(N-乙基-N-甲氮基)苯甲酸
按照实施例31B的方法制备,使用实施例58A的酯(2.15g,1.11mmol)及LiOH·H2O(920mg,22mmol)。粗产品用闪式硅胶柱层析纯化(乙酸乙酯/已烷/乙酸,35∶65∶2,V/V/V,洗脱)得标题化合物(1.9g,95%)。58C N-((3R)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-(N-乙基-N-甲氨基苯基)脲。〔路线1,步骤(ii)〕
拆分的实施例26的苯骈二氮杂_(245mg,0.7mmol)的甲苯(5ml)溶液与按照实施例38的方法从实施例58B的酸制备的异氰酸酯(250mg,1.4mmol)制备的异氰酸酯反应。产品用闪式硅胶柱层析纯化(乙酸乙酯,45∶55,V/V洗脱),用乙腈结晶得标题化合物,为白色固体(237mg,64%,HpLC纯度在99%以上)。NMR(CDCl3)δ7.70-7.05(13H,m);6.58(1H,d,J=8Hz);6.50(1H,d,J=8Hz);
5.80(1H,d,J=8Hz);4.90(1H,d,J=17Hz);4.83(1H,d,J=17Hz);3.40
(2H,quartet,J=7Hz);2.95(3H,s);1.25(9H,s);1.15(3H,t,J=7Hz).M.S.(FAB,+ve ion)m/e526.3[M+H]实施例59N-((3R)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-二甲氨苯基)脲,化合物6059A 3-乙氧羰基-N-乙基甲酰苯胺
按照实施例1B的方法制备,使用3-羧基甲酰苯胺(5.0g,30-mmol),氢钠(2.26g,80%油悬浮液)及碘甲烷(5.2ml,64mmol)。产品用闪式硅胶柱层析纯化(乙酸乙酯/已烷,50∶50,V/V),得标题化合物(6.00g,27.1mmol)。NMR(CDCl3)δ8.50(1H,s);8.00-7.50(4H,m);4.50(2H,q,J=7Hz);4.00(2H,
q,J=7Hz);1.50(3H,t,J=7Hz);1.30(3H,t,J=7Hz).59B3-二乙基氨基苯甲酸乙酯
按实施例56D的方法制备,使用实施例59A的乙酯(3.5g,15.8mmol)、丙酮(130ml)和4N盐酸(80ml)。得到的胺按照实施例58A的方法,使用乙醛(1.3ml,23.3mmol)和NaBH3CN(1.46g,23.3mmol)制备。粗产品用闪式硅胶柱层析纯化(乙酸乙酯/已烷,10∶90,V/V洗脱)得标题化合物(1.90g,54%)。NMR(CDCl3)δ7.95-7.80(3H,m);7.40(1H,m);4.90(2H,q,J=7Hz);3.90(4H,q,J=7Hz);1.95(3H,t,J=7Hz);1.75(6H,t,J=7Hz).59C 3-二乙基氨基苯甲酸
按照实施例31B的方法制备,使用实施例59B的酯(1.90g,8.6mmol)及LiOH·H2O(720mg,17.2mmol)。粗产品用闪式硅胶柱层析纯化(乙酸乙酯/已烷/乙酸,30∶70∶2,V/V/V,洗脱)得标题化合物(1.0g,60%)。59D N-((3R)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-二氨基苯基)脲〔路线1,步骤(ii)〕
拆分的实施例26的氨基苯骈二氮杂_(175mg,0.5mmol)的甲苯(5ml)溶液,与按照实施例38的方法使用实施例59C的酸(240mg,1.2mmol)制备的异氰酸酯反应。粗产品用闪式硅胶柱层析纯化(乙酸乙酯/已烷,45∶55,V/V洗脱)乙腈结晶,得标题化合物,为白色固体(147mg,55%,HpLC纯度超过99%)。NMR(CDCl3)δ7.70-7.05(13H,m);6.60(1H,d,J=8Hz);6.50(1H,d,J=8Hz);
5.80(1H,d,J=8Hz);4.90(1H,d,J=17Hz);4.76(1H.d,J=17Hz);3.45
(4H,q,J=7Hz);1.30(9H,s);1.20(6H,t,J=7Hz).M.S.(FAB,+ve ion)m/e540.3[M+H]
实施例60N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-二甲氨基甲基苯基)脲,化合物6160A 3-二甲氨基甲基苄腈
3-氰基苯甲醛(2.50g,19mmol)的甲醇/乙酸(25ml,99∶1)溶液在0℃下加二甲胺(2.5ml,50mmol)然后加NaBH3CN(1.80g,29mmol)。混合物0℃搅拌18小时,蒸发,溶入乙酸乙酯,用5%KHCO3和盐水洗,过滤(Whatman_,IPS相分离器)并蒸发。粗产品用闪式硅胶柱层析纯化(乙酸乙酯/甲醇,98∶2,V/V,洗脱)得标题化合物(1.15g,38%)。
NMR(CDCl3)δ7.75-7.60(4H,m);3.50(2H,s);2.35(6H,s).60B 3-二甲氨基甲基苯甲酸甲酯
实施例60A的腈(1.5g,7.2mmol)的4M Hcl/甲醇(200ml)溶液0℃搅拌2小时,室温搅拌18小时,加水(25ml),混合物室温搅拌1小时,蒸发后与甲苯共沸,溶入氯仿,5%KHCO3洗,过滤(Whatman_,IPS相分离器)蒸发,得标题化合物(1.20g,86%)。NMR(CDCl3)δ8.00-7.50(4H,m);4.00(3H,s);3.60(2H,s);2.30(6H,s).60C 3-二甲氨甲基苯甲酸
按照实施例31B的方法方法制备,使用实施例60B的酯(1.20g,6.2mmol)和LiOH·H2O(540mg,13mmol)。粗产品用闪式硅胶柱层析纯化(氯仿/甲醇/乙酸,25∶10∶1,V/V/V)得标题化合物(750mg,68%)。60D N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-二甲氨甲基苯基)脲,〔路线1,步骤(ii)〕
实施例2B的苯骈二氮杂_按实施例1C描述的方法氢化,生成的胺(192mg,0.55mmol)在甲苯中与按实施例38的方法从实施例60C的酸(250mg,1.4mmol)制备的异氰酸酯反应。产品用闪式硅胶柱层析纯化(氯仿/甲醇/乙酸,20∶2∶1,V/V/V,洗脱),乙腈结晶,得标题化合物,为白色固体(50mg,17%,HpLC纯度超过99%)。NMR(CDCl3)δ7.55-6.90(15H,m);5.57(1H,d,J=8Hz);4.80(1H,d,J=
17Hz);4.70(1H,d,J=17Hz);3.40(2H,s);2.25(6H,s);1.15(9H,s).M.S.(FAB,+ve ion)m/e 526.3[M+H]实施例61N-((3RS)-2-叔丁羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-(N-乙基-基甲氨基)苯基)脲,化合物62
实施例27A的苯骈二氮杂_按实施例27B的方法脱保护,生成的胺(200mg,0.57mmol)在甲苯(5ml)中与按实施例38的方法从实施例58B的酸(250mg,1.4mmol)制备的异氰酸酯反应。产品用闪式硅胶柱层析纯化(乙酸乙酯/已烷,90∶10,V/V,洗脱),从乙腈/水冷冻干燥,得标题化合物,为白色固体(125mg,42%,HpLC纯度在95%以上)。M.S.(FAB,+ve ion)m/e 527.3[M+H]
Rf:0.23(乙酸乙酯/已烷,90∶10)实施例62N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-二甲氨甲基苯基)脲,化合物63
实施例27A的苯骈二氮杂_按实施例27B的方法脱保护,生成的胺(200mg,0.57mmol)在甲苯(5ml)中与按实施例38的方法从实施例60C的酸(250mg,1.4mmol)制备的异氰酸酯反应。产品用闪式硅胶柱层析纯化(氯仿/甲醇/乙酸,18∶4∶1,V/V/V,洗脱),用乙酸乙酯/乙烷结晶,得标题化合物,为白色固体(76mg,25%,HPLC纯度超过99%)。NMR(CDCl3)δ8.50(1H,d,J=8Hz);8.00-7.20(12H,m);6.80(1H,d,J=8Hz);
5.60(1H,d,J=8Hz);4.80(1H,d,J=17Hz);4.50(1H,d,J=17Hz);3.40
(2H,s);2.20(6H,s);1.20(9H,s).M.S.(FAB,+ve ion)m/e527.3[M+H]实施例63N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-二乙氨基苯基)脲,化合物64
实施例27A的苯骈二氮杂_按实施例27B的方法脱保护,生成的胺(200mg,0.57mmol)在甲苯(5ml)中与按实施例38的方法,使用实施例59C的酸(212mg,1.1mmol)制备的异氰酸酯反应。产品用闪式硅胶柱层析纯化(乙酸乙酯/已烷,75∶25,V/V,洗脱),乙腈结晶,得标题化合物,为白色固体(200mg,65%,HpLC纯度在99%以上)。NMR(CDCl3)δ8.60(1H,d,J=8Hz);8.17(1H,d,J=8Hz);7.70-6.90(10H,m);
6.40(2H,m);5.75(1H,d,J=8Hz);4.90(1H,d,J=17Hz);4.40(1H,d,J=
17Hz);3.30(4H,q,J=7Hz);1.20(9H,s);1.15(6H,t,J=8Hz).M.S.(FAB,+ve ion)m/e541.4 [M+H]实施例64N-((3R)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-二甲氨苯基)脲,化合物65
从实施例26的拆分的氨基苯骈二氮杂_(1.88g,5.4mmol)按照实施例38的方法制备。产品用闪式硅胶柱层析纯化(乙酸乙酯/已烷,55∶45,V/V,洗脱),从二氧六环/水冷冻干燥,得标题化合物,为白色固体(1.70g,62%,HpLC纯度超过98%)。
Rf:0.21(乙酸乙酯/已烷,60∶40,V/V)
M.S.(FAB,+ve ion)m/e 512.3[M+H]
[α]D=+97.3°(c=0.776,CHCl3)实施例65N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-(4-甲苯基)-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲,化合物6665A(3RS)-3-苄氧羰氨基-1-叔丁羰甲基-2,3-二氢-5-(4-甲苯基)-1H-1,4-苯骈二氮杂_-2-酮〔路线1,步骤(i)〕
按照实施例2B的方法,从(3RS)-3-苄氧羰氨基-2,3-二氢-5-(4-甲苯基)-1H-1,4-苯骈二氮杂_-2-酮(200mg,0.53mmol,类似于Bock苯骈二氮杂_制备)制备。产品用闪式硅胶柱层析纯化(乙酸乙酯/已烷,35∶65,V/V,洗脱),得标题化合物,为无色油(252mg,96%)。NMR(CDCl3)δ7.53(3H,m);7.41-7.13(9H,m);6.68(1H,d,J=8Hz);5.44
(1H,d,J=8Hz);5.18(2H,s);5.00(1H,d,J=17Hz);4.67(1H,d,J=
17Hz);2.42(3H,s);1.28(9H,s).65BN-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-(4-甲苯基)-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲〔路线1,步骤(ii)〕
按照实施例14B的方法从实施例65A的苯骈二氮杂_制备。产品用闪式硅胶柱层析纯化(乙酸乙酯/已烷,37;63,V/V,洗脱),从二氧六环/水冷冻干燥,得标题化合物,为白色固体(118mg,47%,HpLC纯度在98%以上)。
Rf:0.18(乙酸乙酯/已烷,40∶60,V/V)NMR(CDCl3)δ9.02-8.92(3H,m);8.82-8.20(11H,m);7.10(1H,d,J=5Hz);
6.32(1H,d,J=8Hz);6.17(1H,d,J=8Hz);3.82(3H,s);3.72(3H,s);2.66
(9H,s).M.S.(FAB,+ve ion)m/e=497.3[M+H]实施例66
N-((3R)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-氨基苯基)脲,化合物6766A N-((3R)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-硝基苯基)脲〔路线1,步骤(ii)〕
拆分的实施例26的氨基苯骈二氮杂_与实施例45中描述的异氰酸间硝基苯酯反应,得无色油状物(490mg,94%)。
数据与实施例45同。
66B N-((3R)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_(245mg,0.468mmol)溶入1M氯化铵溶液(8ml)中并与锌粉(620mg)反应,当往混合物中缓慢加乙醇时,激烈搅拌。30分钟后,混合物过滤并蒸发。残留物用闪式硅胶柱层析纯化(乙酸乙酯/已烷,80∶20,V/V,洗脱),从乙腈/水中冷冻干燥,得标题化合物,为白色固体(115mg,67%,HpLC纯度超过98%)。
Rf:0.64(乙酸乙酯)1H NMR(CDCl3)δ7.8-7.0(11H,m);6.9(1H,t,J=8.5Hz);6.75(m,2H);6.35(1H,
d,J=8.5Hz);5.7(1H,d,J=8.5Hz);4.95(2H,s);3.75(2H,br.s.);1.21(9H,
s).[α]D=+25°(c=0.993,MeOH)M.S.(FAB,+ve ion)m/e=484.3[M+H]实施例67N-((3RS)-1-叔丁羰甲基-7-氯-2,3-二氢-2-氧-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲化合物7467A(3RS)-3-苄氧羰氨基-1-叔丁羰甲基-7-氯-2,3-二氢-5-苯基-1H-1,4-苯骈二氮杂_-2-酮〔路线1,步骤(i)〕
按照实施例1B的方法,从(3RS)-3-苄氧羰氨基-7-氯-2,3-二氢-5-苯基-1H-1,4-苯骈二氮杂_-2-酮(440mg,1.46mmol,类似于Bock苯骈二氮杂_的制备)、氢钠(62mg,80%油悬浮液,2.04mmol)及1-溴频哪酮(537mg,3mmol)制备。粗产品用闪式硅胶柱层析纯化(乙酸乙酯/已烷,30∶70,V/V洗脱),得标题化合物(700mg,93%)。NMR(CDCl3)δ7.70-7.30(13H,m);6.8(1H,d,J=8Hz);5.60(1H,d,J=8Hz);
5.30(2H,s);5.05(1H,d,J=17Hz);4.80(1H,d,J=17Hz);1.35(9H,s).67BN-((3RS)-1-叔丁羰甲基-7-氯-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲〔路线1,步骤(ii)〕
按照实施例27B的方法制备,使用实施例67A的苯骈二氮杂_(270mg,0.52mmol)、BBr3(3.4ml,1.0M的CH2CL2溶液)及异氰酸间甲苯酯(90μl,0.66mmol)。产品用色谱纯化(乙酸乙酯/已烷,40∶60,V/V洗脱),从乙腈/水冷冻干燥,得标题化合物,为白色固体(83mg,31%,HpLC纯度在99%以上)。NMR(CDCl3)δ7.70-6.95(14H,m);5.80(1H,d,J=8Hz);4.90(2H,s);2.40
(3H,s);1.25(9H,s).M.S.(FAB,+ve ion)m/e 517.2[M+H]实施例68N-((3R.S)-1-叔丁羰甲基-7-氯-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-二甲氨苯基)脲,化合物75
按实施例27B的方法制备,使用实施例67A的苯骈二氮杂_(430mg,0.83mmol)、BBr3(5.0ml,1.0M的CH2CL2溶液)及按照实施例38的方法从3-二甲氨基苯甲酸(400mg,2.4mmol)制备的异氰酸酯。产品用闪式硅胶柱层析纯化(乙酸乙酯/已烷,45∶55,V/V洗脱),从乙腈/水冷冻干燥,得标题化合物,为白色固体(100mg,22%,HpLC纯度在98%以上)。NMR(CDCl3)δ7.60-6.90(12H,m);6.50(1H,d,J=8Hz);6.40(1H,d,J=8Hz);5.60(1H,d,J=8Hz);4.75(2H,s);2.90(6H,s);2.10(3H,s);1.15(9H,s).M.S.(FAB,+ve ion)m/e 546.3[M+H]实施例69N-((3RS)-1-叔丁羰甲基)-7-氯-2,3-二氢-2-氧-5-(2-氯苯基)-1H-1,4苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲,化合物76
按照实施例27B的方法制备,使用实施例54A的苯骈二氮杂_(170mg,0.31mmol)、BBr3(2ml,1.0M的CH2CL2溶液)和异氰酸间甲苯酯(60μl,0.4mmol)。产品用闪式硅胶柱层析纯化(乙酸乙酯/已烷,35∶65,V/V洗脱),从乙腈/水冷冻干燥,得标题化合物,为白色固体(39mg,51%,HpLC纯度在99%以上)。
Rf:0.25(乙酸乙酯/已烷,40∶60)实施列70 M.S.(FAB,+ve ion)m/e 551.2[M+H]N-((3RS)-1-叔丁羰甲基-2,3-二氢-8-甲基-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲,化合物7770A(3RS)-3-苄氧羰氨基-1-叔丁羰氨基-2,3-二氢-8-甲基-5-苯基-1H-1,4-苯骈二氮杂_-2-酮〔路线1,步骤(i)〕
按照实施例2B的方法,从(3RS)-3-苄氧羰氨基-2,3-二氢-8-甲基-5-苯基-1H-1,4-苯骈二氮杂_-2-酮(240mg,类似于Bock苯骈二氮杂_制备)制备。产品用闪式硅胶柱层析纯化(乙酸乙酯/已烷,30∶70,V/V,洗脱),得标题化合物,为无色油状物(289mg,91%)。
Rf:0.17(乙酸乙酯/已烷,30∶70,V/V)NMR(CDCl3)δ7.67(2H,m);7.4(9H,m);7.25(1H,d,J=8Hz);6.96(1H,s);
6.70(1H,d,J=9Hz);5.47(1H,d,J=9Hz);5.19(2H,s);4.98(1H,d,J=
18Hz);4.70(1H,d,J=18Hz);2.46(3H,s);1.30(9H,s).化合物53,68-73和79按上述实施例描述的类似方法制备。70BN-((3RS)-1-叔丁羰甲基-2,3-二氢-8-甲基-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲〔路线1,步骤(ii)〕
按照实施例14B的方法,从实施例70A的苯骈二氮杂_(289mg,0.58mmol)制备。产品用闪式硅胶柱层析纯化(乙酸乙酯/已烷,37∶63,V/V洗脱),从二氧六环/水冷冻干燥,得标题化合物,为白色固体(106mg,37%,HpLC纯度在98%以上)。
Rf:0.18(乙酸乙酯/已烷,40∶60,V/V)NMR(CDCl3)δ7.67(2H,m);7.46(2H,m);7.26-6.79(9H,m);5.68(1H,d,J=
7Hz);4.93(1H,d,J=11Hz);4.75(1H,d,J=11Hz);2.45(3H,s);2.33(3H,
s);1.27(9H,s).M.S.(FAB,+ve ion)m/e=497.2[M+H]本发明的化合物是CCK-B受体强有力的选择性拮抗剂,其抑制五肽促胃酸激素刺激的胃酸分泌。这些活性的测定方法描述如下:CCK-B受体结合度测定
切下的100只非麻醉SD鼠的头,从每只鼠头中切出全部脑,以10倍量体积的0.32M蔗糖水溶液,使用Taflon匀浆器制备匀浆,这样获得的匀浆用冷离心在900转离心10分钟,上清液在11500转,再离心15分钟。这样获得的沉淀分散到50μM含0.08%Triton X-100的Tris-HCl缓冲液(PH7.4)中,悬浮液放置30分钟,再在11500转离心15分钟,得到的沉淀用5mM Tris-HCl缓冲液洗两次,用50mM Tris-HCl缓冲液洗两次,并按此次序离心分离,洗过的沉淀悬浮在50mM的TRIS-HCl缓冲液中,这样制备的悬浮液在-80℃放置,得到所需膜制品。
膜制品被加热到室温,用10mM HEPES缓冲液(含130mMNaCl,5mM MgCl2,1mM EGTA,和0.25mg/ml杆菌肽;PH6.5)稀释,25℃在〔125I〕BH-CCK-8和待测化合物存在下培育120分钟,减压过滤分离。在1μM CCK-8存在下测定非特异性结合。使用r—计数器测定标记的配基结合到受体上的量,记录IC50值,这就是待测化合物抑制特异性结全50%所需要的浓度。CCK-A受体结晶度测定
一只SD鼠的膜腺用Polytrome型匀浆器在20倍本积的50mM Tris-HCl缓冲液(PH7.7)中制匀浆,使用超速离心机在50000转下将匀浆离心2次,得到的沉淀悬浮在40倍体积的50mMTris-HCl缓冲液中(含0.2%BSA,5mM MgCl2,0.1mg/ml杆菌肽和5mM DTT;ph7.7),悬浮液在-80℃放置,得到所需的膜制品。
膜制品被加热至室温,用缓冲液稀释到1∶10,在〔3H〕L-364,718和待测化合物存在下,37℃培育30分钟,减压过滤分离。在1μML-364 718和待测化合物存在下,37℃培育30分钟,减压过滤分离。在1μML-364,718存在下测定非特异性结合。使用液闪记数器测定标记的配基结合到受体上的量,记录IC50值,这就是抑制特异性结合50%所需要的浓度。
对CCK-A受体结合率高的CCK-B促胃液素拮抗剂,由于治疗中可以导致象胆固醇和胆结石形成的副作用,而认为是不期望的。因此对CCK-B受体的选择性治疗剂是最好的治疗。用IC50(CCK-A)/IC50(CCK-B)之比表示选择性;比值越大,选择性越好。
下面的表综合了优选化合物例子的CCK-B和CCK-A结合数据以及A/B比值。与美国专利No.4.820.834的实施例281的化合物做比较(也写作L-365,260),本发明的大多数化合物对CCK-B受体的选择性与对CCK-A受体的选择性的差异比美国专利No.4.820,834中实施例281的化合物报道的也高很多。
受体结合的亲合率IC50(nM)化合物 CCK-B CCK-A A/B比美国专利4,820,834中实施例281的化合物 29 12,000 410实施例4 0.23 440 1,900″ 9 7.3 >10,000 >1,400″ 12 1.4 >10,000 >7,100″ 13 0.11 >10,000 >91,000″ 14 0.12 2,600 22,090″ 17 0.07 2,500 36,000″ 19 0.92 1,100 1,200″ 22 3.5 >10,000 >2,900″ 23 0.08 870 11,000″ 24 0.97 >10,000 >10,000″ 25 0.65 >10,000 >15,000″ 31 0.53 3,400 6,400″ 32 0.28 480 1,700″ 34 0.38 >10,000 >26,000″ 35 1.1 1,900 1,700″ 36 0.57 720 1,300″ 37 1.1 5,600 5,100″ 39 0.10 240 2,400
受体结合的亲合率IC50(nM)化合物 CCK-B CCK-A A/B比实施例41 6.2 6,700 1,100″ 42 0.07 360 5,100″ 44 0.17 1,600 9,400″ 45 0.16 590 3,700″ 56 0.11 120 1,100″ 66 0.5 950 1,900抑制五肽促胃酸激素一刺激大鼠胃酸分泌的测定:
导管插入用乌拉坦麻醉的大鼠(腹膜给药,1.25g/Kg)气管中,切开腹膜暴露胃和十二指肠部分,结扎喷门以后,聚乙烯管插入胃前面。十二指肠的细长部分做试验,聚乙烯管从暴露部分插入胃,结扎幽门,固定导管。在3ml/分的速度下从胃前面向幽门灌流生理盐水(PH调至7.0),用PH-稳定器(Art-201,Toa Electronics,Ltd产品)连续滴定灌流液以测定胃酸分泌。连续滴定时使用25mM NaoH溶液使PH达到7.0,结果用每10分钟分泌的胃酸量(μEg/10分)表示。五肽促胃酸激素腹膜给药,15μg/Kg/小时。给予五肽促胃酸激素引起胃酸分泌增加,60分钟后达到峰位,此后稳定地保持该水平。然后静脉给予待测药物,测定胃酸分泌;记录ED50值,这就是使胃酸分泌降至50%水平所需要的用药量。代表性的ED50值表述如下:美国专利4,820,834 ED50(μmol/kg)中实施例281的化合物 4.2实施例4化合物 0.016实施例5化合物 0.018实施例7化合物 0.047
抑制五肽促胃酸激素刺激狗的胃液分泌的试验
分析在雄性猎狗(7-12Kg)上进行,所用狗是在对其Heiden-hain窝进行了外科手术及随后常规步骤后二个月使用的。每只狗每星期仅用一次。
该动物在实验前18小时禁食但给水。胃液通过重力引流从胃插管每15分钟收集一次,用0.05N NaOH自动滴定(Comtite-7,Hiranuma,Tokyo,Japan)到PH7.0来测定酸产出量。五肽促胃酸激素(8/mg/kg/小时)灌流后3小时口服药物.每一药物的作用用抑制刺激的酸产量的百分比表示。下表表明代表性实施例显出最大抑制。每一结果是3-5只动物的平均。
抑制率(剂量)
美国专利4,820,834
中实施例281的化合物 0%(100μmol/kg)
实施例26化合物 53%(3μmol/kg)
实施例27化合物 66%(3μmol/kg)
实施例38化合物 100%(3μmol/kg)
实施例64化合物 100%(3μmol/kg)前面描述的实验说明本发明的化合物是强有力的CCK-B选择性拮抗剂,并抑制五肽促胃酸释放激素刺激的胃酸分泌。所以它们在治疗CCK-B受体作为介导因子的疾病状态中有用。这些疾病状态包括胃—肠系统失调,例如胃和十二指肠溃疡、胃炎、消化性食道炎、Eollinger-Ellison综合症、胃—过敏的胰腺炎、以及胃过敏的肿瘤。中枢神经系统疾患,例如焦虑和精神病亦可用本发明的化合物进行治疗。这些化合物也能用来控制食欲和疼痛。
本发明的化合物及其盐可以口服给药(包括舌下给药)或非肠道给药,剂型有片剂、粉剂、胶束、丸剂、液体、注射剂、悬浮剂、软膏、以及橡皮膏。
制药中用的载体和赋形剂可以是固体、液体、无毒的药物,例如乳糖、硬脂酸镁、淀粉、滑石粉、明胶、琼脂、果胶、阿拉伯大胶草、橄榄油、芝麻油、可可奶油、乙二醇、及其它商品。
使用本发明的化合物的处方例描述如下:
片剂例
20mg片剂的制备
组成 | 20mg片剂 | 40mg片剂 |
实施例4的化合物 | 20mg | 40mg |
乳糖 | 73.4mg | 80mg |
玉米淀粉 | 18mg | 20mg |
羟丙基纤维素 | 4mg | 5mg |
羧甲基纤维素钙 | 4mg | 4.2mg |
硬脂酸镁 | 0.6mg | 0.8mg |
总重 | 120mg, | 150mg |
实施例4的化合物(100g)乳糖(367g)和玉米淀粉(90g)使用流动颗粒包衣机(Ohawara Sei-Sakusho产品)均匀地混合在一起,然后将10%羟丙基纤维素(200g)水溶液加热分散到混合物中,完成制粒。干燥后,颗粒过20目筛,加入20g羰甲基纤维素Ca和3g硬脂酸镁,混合物用装有7mm×8.4R冲头旋转压片机(HataTekkosho产品)压片,这样压成的片重120mg。40mg片剂的制备
实施例4的化合物(140g),乳糖(280g)和玉米淀粉(70g)使用流动颗粒包衣机(Ohgnara Seisa-Kusho产品)均匀混合,将10%羟丙基纤维素水溶液(175g)喷到混合物上,制成羰颗粒。干燥后,颗粒过20目筛,然后加入14.7g羧甲基纤维素Ca和2.8g硬脂酸镁,混合物用装有7.5mm×9R冲头的旋转压片机(Hata Tekkosho产品)压片,压成的片重为150mg。临床使用的本发明的化合物的剂量由医生根据被治疗患者的实际病情、体重、年龄、性别、病史和其它因素确定。一般的口服剂量在1至1000mg/天,一次服用或多次服用。
Claims (16)
1.通式I的苯胼二氮杂_衍生物或它们的药用盐类:其中:
(a)R1为-CH2CHOH(CH2)aR4或-CH2CO(CH2)aR5,其中a为0或1,R4和R5选自直链或支链C1-8烷基、未取代或被一或多个直链或支链C1-8烷基取代的C3-8环烷基、选自吡咯烷基和四氢吡喃基的饱和杂环,且在杂原子上有任选取代,取代基选自低级C1-6烷基或低级C1-6酰基,或R5为金刚烷基;
(b)R2和R3各自独立地选自未取代或取代的5-或6-员芳香单环或5-或6-员含1-3个杂原子的杂环,其中取代基选自:卤原子,羟氨基,硝基,羧酸,氰基,C1-6烷基,C1-6烷氧基,C1-6烷基氨基或二C1-6烷基氨基;
(c)W和X独自选自氢,卤素,C1-6烷基和C1-8烷氧基。
2.权利要求1要求的化合物,其中R4为C4-C7直链或支链烷基;或未取代或被一或多个直链或支链C1-8烷基取代的C3-8环烷基;R5为C1-3烷基或金刚烷基或同R4定义。
3.权利要求1或2要求的化合物,其中R2和R3中至少有一个为未取代或取代的苯基或吡啶基。
4.权利要求3要求的化合物,其中R2和R3至少有一个为未取代,单取代或二取代苯基或未取代、单取代或二取代2-,3-或4-吡啶基。
5.权利要求1或2要求的化合物,其中
R1为-CH2CO(CH2)aR5,其中a和R5如权利要求1中所述,
R2为未取代苯基;取代基从F、Cl、Br、OH、OCH3、NH2、NMe2,NO2、Me、(CH2)c-CO2H、CN、NHMe、NMeEt、NEt2、CH2NMe2、NHCHO和(CH2)c-SO3H中选择的间位取代苯基,其中C为0至2,或任选取代的2-,3-,或4-吡啶基、取代基从F、Cl、CH3和COOH选择;
R3为苯基或2-,3-,或4-吡啶基。
6.权利要求1或2的化合物,其中R1为-CH2CHOH(CH2)aR4,其中,a和R4如权利要求1中所述,R2及R3如权利要求5中定义。
7.权利要求1或2要求的化合物,其中苯骈二氮杂_环3位的绝对构型为如式IV所示的R构型,其中R1,R2和R3如权利要求1中所述,
8.权利要求1或2要求的化合物,其中W和X为氢。
9.权利要求1要求的化合物,其中至少一个化合物选自下面化合物或它们的可以药用的盐:
1).N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N′-(3-甲苯基)脲;
2).N-((3RS)-1-二乙基甲基羰甲基-2,3-二氢-2-氧-5
-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)
脲;
3).N-((3RS)-1-环丁羰甲基-2,3-二氢-2-氧-5-苯基
-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲;
4).N-((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-苯基
-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲基苯基)脲;
5).N-((3RS)-1-环已羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲基苯基)脲;
6).N-((3RS)-1-环庚羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲基苯基)脲;
7).N-((3RS)-1-环庚羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-氯苯基)脲;
8).N-((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲;
9).N-((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-(3-吡啶基)-1H-1 1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲;
10).N-((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-(4-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲;
11).N-((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-羧苯基)脲;
12).N-((3R)-1-环戊羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲;
13).N-((3S)-1-环戊羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲;
14.N-((3RS)-2,3-二氢-2-氧-5-苯基-1-((2R)-2-吡咯烷基羰甲基)-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲;
15).N-((3RS)-2,3-二氢-2-氧-5-苯基-1-((2S)-2-吡咯烷基羰甲基)-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲;
16).N-((3RS)-1-((2R)-1-乙酸基-2-吡咯烷基羰甲基)-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲;
17).N-((3RS)-1-((2S)-1-乙酸基-2-吡咯烷基羰甲基)-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲;
18).N-((3RS)-1-((2RS)-2-环戊基-2-羟乙基)-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲;
19).N-((3RS)-1-(2SR)-2-环戊基-2-羟乙基)-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲;
20).N-((3R)-1-((2R)-2-环戊基-2-羟乙基)-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲;
21).N-((3R)-1-((2S)-2-环戊基-2-羟乙基)-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲;
22).N-((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-氰基苯基)脲;
23).N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-氰基苯基)脲;
24).N-((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-羧甲苯基)脲;
25).N-((3RS)-1-(1-金刚烷基)羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲;
26).N-((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-吡啶基)脲;
27).N-((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(6-甲基-2-吡啶基)脲;
28).N-((3RS)-1-(3-环已基-3-甲基-2-氧丁基)-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲;
29).N-((3RS)-1-环已甲基羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲;
30).N-((3RS)-1-环戊甲基羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲;
31).N-((3RS)-1-((1-甲基环已基)羰甲基)-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲;
32).N-((3RS)-1-((1-甲环戊基)羰甲基)-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲;
33).N-((3R)-1-环戊羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-羧苯基)脲;
34).N-((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-羧苯基)脲;
35).N-((3R)-1-((2RS)-2-环戊基-2-羟乙基)-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-羧苯基)脲;
36).N-((3R)-1-环戊基-2-羟乙基)-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-羧苯基)脲;
37).N-((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-羧基酰胺基苯基)脲;
38).N-((3R)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲;
39).N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲;
40).N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-羧基苯基)脲;
41).N-((3RS)-1-叔戊羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲;
42).N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-羧基苯基)脲;
43).N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲胺苯基)脲;
44).N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-羧基苯基)脲;
45).N-((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-二甲氨苯基)脲;
46).N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-二甲氨苯基)脲;
47).N-((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲氯苯基)脲;
48).N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲氧苯基)脲;
49).N-((3RS)-1-环戊羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-硝基苯基)脲;
50).N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-硝基苯基)脲;
51).N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲酰胺基苯基)脲;
52).N-((3R)-1-((2R)-2-羟基-3,3-二甲丁基)-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲;
53).N-((3R)-1-((2S)-2-羟基-3,3-二甲丁基)-2,3-二氢-2-氧-5-苯基-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲;
54).N-((3RS)-1-((1-甲基环丙基)羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲;
55).N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-(2-氯苯基)-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲;
56).N-((3RS)-1-异丙羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲;
57).N-((3R)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲氨苯基)脲;
58).N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲氨苯基)脲;
59).N-((3R)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-(N-乙基-N-甲氨基)苯基)脲;
60).N-((3R)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-二乙氨苯基)脲;
61).N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-二甲氨甲基苯基)脲;
62).N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-(N-乙基-N-甲氨基)苯基)脲;
63).N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-二甲氨基甲基苯基)脲;
64).N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-二乙氨苯基)脲;
65).N-((3R)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-二甲氨苯基)脲;
66).N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-(4-甲基苯基)-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲;
67).N-((3R)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-氨基苯基)脲;
68).N-((3R)-1-叔丁羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲;
69).N-((3R)-1-叔丁羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-氨苯基)脲;
70).N-((3R)-1-叔丁羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲氨苯基)脲;
71).N-((3R)-1-叔丁羰甲基-2,3-二氢-2-氧-5-(2-吡啶基)-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-二甲氨苯基)脲;
72).N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基)-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-氨苯基)脲;
73).N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲氨苯基)脲;
74).N-((3RS)-1-叔丁羰甲基-7-氯-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲;
75).N-((3RS)-1-叔丁羰甲基-7-氯-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-二甲氨苯基)脲;
76).N-((3RS)-1-叔丁羰甲基-7-氯-2,3-二氢-2-氧-5-(2-氯苯基)-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲;77).N-((3RS)-1-叔丁羰甲基-2,3-二氢-8-甲基-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-甲苯基)脲;
78).N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(N-乙基-N-甲氨苯基)脲;
79).N-((3RS)-1-叔丁羰甲基-2,3-二氢-2-氧-5-苯基-1H-1,4-苯骈二氮杂_-3-基)-N’-(3-二乙氨苯基)脲。
10.含有权利要求1-9任一要求的化合物作为活性成份的药物组合物。
11.权利要求10的药物组合物,其为作为CCK-B或促胃液素受体拮抗剂的药物组合物。
12.权利要求10的药物组合物,其为用于治疗因促胃液素功能失调引起的胃和十二指肠溃疡、胃炎、消化性食管炎、胃和结肠癌,以及Zollinger Ellisom综合症的药物组合物。
13.权利要求10的药物组合物,其为用于治疗由中枢CCK-B受体控制的生理功能失调引起的疾病的药物组合物。
16.制备通式I的苯骈二氮杂_或它们的药用活性盐的方法,其中R1为-CH2CHOH(CH2)aR4,a、R2、R3和R4如权利要求1定义,其包括I与碱金属硼氢化物反应,其中R1为-CH2CO(CH2)aR4,a、R2、R3和R4如权利要求1定义。
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GB9204221A GB2264492B (en) | 1992-02-27 | 1992-02-27 | Benzodiazepine derivatives |
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GB929212740A GB9212740D0 (en) | 1992-02-27 | 1992-06-16 | Benzodiazephine derivatives |
GB9212740.6 | 1992-06-16 |
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JPH07500589A (ja) * | 1991-10-24 | 1995-01-19 | メルク シヤープ エンド ドーム リミテツド | ベンゾジアゼピン誘導体、並びにコレシストキニン及び/又はガストリンレセプターのアンタゴニストとしての該誘導体の使用 |
GB2282595A (en) * | 1993-08-25 | 1995-04-12 | Yamanouchi Pharma Co Ltd | Benzodiazepine derivatives |
GB2282594A (en) * | 1993-08-25 | 1995-04-12 | Yamanouchi Pharma Co Ltd | Benzodiazepine derivatives |
US5556969A (en) * | 1994-12-07 | 1996-09-17 | Merck Sharp & Dohme Ltd. | Benzodiazepine derivatives |
AUPO284396A0 (en) * | 1996-10-08 | 1996-10-31 | Fujisawa Pharmaceutical Co., Ltd. | Benzodiazepine derivatives |
US6100254A (en) * | 1997-10-10 | 2000-08-08 | Board Of Regents, The University Of Texas System | Inhibitors of protein tyrosine kinases |
EP1391203A4 (en) * | 2001-05-11 | 2005-09-14 | Astellas Pharma Inc | ANTITUMORAL AGENTS |
US7524837B2 (en) | 2003-05-12 | 2009-04-28 | Janssen Pharmaceutica N.V. | Benzotriazapinone salts and methods for using same |
US8053413B2 (en) * | 2005-06-06 | 2011-11-08 | The Board Of Trustees Of The University Of Illinois | Methods for treating sleep disorders by cholecystokinin (CCK) receptor B antagonists |
CN101669557B (zh) * | 2009-08-20 | 2012-07-25 | 杭州六易科技有限公司 | 一种清热解毒凉茶的制作方法 |
WO2011037128A1 (ja) | 2009-09-28 | 2011-03-31 | 日本曹達株式会社 | 含窒素ヘテロ環化合物およびその塩ならびに農園芸用殺菌剤 |
BR112016011727A2 (pt) | 2013-11-22 | 2017-08-08 | CL BioSciences LLC | Antagonistas de gastrina para o tratamento e prevenção de osteoporose |
GB201414116D0 (en) * | 2014-08-08 | 2014-09-24 | Trio Medicines Ltd | Benzodiazepine derivatives |
GB201513979D0 (en) * | 2015-08-07 | 2015-09-23 | Trio Medicines Ltd | Synthesis of benzodiazepine derivatives |
EP3509617A4 (en) * | 2016-09-09 | 2020-05-13 | On Target Laboratories, LLC | NIR IMAGING AND USE OF THE CHOLECYSTOKININ-2 RECEPTOR |
US10881667B2 (en) * | 2018-10-30 | 2021-01-05 | City University Of Hong Kong | Method and composition for treating epilepsy |
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CA2026856A1 (en) * | 1989-10-05 | 1991-04-06 | Mark G. Bock | 3-substituted-1,4-benzodiazepines useful as oxytocin |
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JPH07505121A (ja) | 1995-06-08 |
AU672390B2 (en) | 1996-10-03 |
NO943133D0 (no) | 1994-08-24 |
RU94038255A (ru) | 1996-07-10 |
CN1075717A (zh) | 1993-09-01 |
PT628033E (pt) | 2003-12-31 |
DE69333108D1 (de) | 2003-08-28 |
CA2129990C (en) | 2006-01-10 |
TW438783B (en) | 2001-06-07 |
HUT67963A (en) | 1995-05-29 |
US5962451A (en) | 1999-10-05 |
WO1993016999A1 (en) | 1993-09-02 |
FI943941A (fi) | 1994-10-26 |
NO943133L (no) | 1994-08-24 |
IL104853A (en) | 1997-11-20 |
ES2203616T3 (es) | 2004-04-16 |
ATE245632T1 (de) | 2003-08-15 |
HU9402212D0 (en) | 1994-09-28 |
US5688943A (en) | 1997-11-18 |
FI943941A0 (fi) | 1994-08-26 |
HU224012B1 (hu) | 2005-04-28 |
EP0628033A1 (en) | 1994-12-14 |
JP2571344B2 (ja) | 1997-01-16 |
RU2139282C1 (ru) | 1999-10-10 |
AU3639193A (en) | 1993-09-13 |
FI121234B (fi) | 2010-08-31 |
NO311215B1 (no) | 2001-10-29 |
DE69333108T2 (de) | 2004-04-15 |
CA2129990A1 (en) | 1993-09-02 |
EP0628033B1 (en) | 2003-07-23 |
DK0628033T3 (da) | 2003-11-10 |
IL104853A0 (en) | 1993-06-10 |
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