CN1145895A - 新的酰胺基乙基取代的芴化合物和其制备方法 - Google Patents
新的酰胺基乙基取代的芴化合物和其制备方法 Download PDFInfo
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- CN1145895A CN1145895A CN96110491A CN96110491A CN1145895A CN 1145895 A CN1145895 A CN 1145895A CN 96110491 A CN96110491 A CN 96110491A CN 96110491 A CN96110491 A CN 96110491A CN 1145895 A CN1145895 A CN 1145895A
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- Prior art keywords
- ethyl
- fluorenes
- compound
- dimethoxy
- methoxyl group
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- -1 fluorene compound Chemical class 0.000 title claims description 25
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N o-biphenylenemethane Natural products C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 title abstract description 4
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 10
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 77
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 63
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 18
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims description 17
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- AIMMVWOEOZMVMS-UHFFFAOYSA-N cyclopropanecarboxamide Chemical compound NC(=O)C1CC1 AIMMVWOEOZMVMS-UHFFFAOYSA-N 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 4
- 241000124008 Mammalia Species 0.000 claims description 4
- 125000002769 thiazolinyl group Chemical group 0.000 claims description 4
- ZETBDNNBXMTTLZ-UHFFFAOYSA-N 2-methylpropanamide Chemical compound CC(C)C(N)=O.CC(C)C(N)=O ZETBDNNBXMTTLZ-UHFFFAOYSA-N 0.000 claims description 3
- WFKAJVHLWXSISD-UHFFFAOYSA-N anhydrous dimethyl-acetamide Natural products CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 claims description 3
- PYRYOLOOOPVOHJ-UHFFFAOYSA-N cyclopentane formamide Chemical compound C(=O)N.C1CCCC1 PYRYOLOOOPVOHJ-UHFFFAOYSA-N 0.000 claims description 3
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 3
- 229920002554 vinyl polymer Chemical group 0.000 claims description 3
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 claims description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 239000012453 solvate Substances 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims 1
- 125000003983 fluorenyl group Chemical class C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 abstract description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 1
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 abstract 1
- 125000005843 halogen group Chemical group 0.000 abstract 1
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 description 33
- YJPIGAIKUZMOQA-UHFFFAOYSA-N Melatonin Natural products COC1=CC=C2N(C(C)=O)C=C(CCN)C2=C1 YJPIGAIKUZMOQA-UHFFFAOYSA-N 0.000 description 32
- 229960003987 melatonin Drugs 0.000 description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 18
- 239000007787 solid Substances 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 13
- 238000001035 drying Methods 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 239000002585 base Substances 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 125000000217 alkyl group Chemical group 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- OHCQJHSOBUTRHG-KGGHGJDLSA-N FORSKOLIN Chemical compound O=C([C@@]12O)C[C@](C)(C=C)O[C@]1(C)[C@@H](OC(=O)C)[C@@H](O)[C@@H]1[C@]2(C)[C@@H](O)CCC1(C)C OHCQJHSOBUTRHG-KGGHGJDLSA-N 0.000 description 8
- 235000019439 ethyl acetate Nutrition 0.000 description 8
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 8
- 238000002390 rotary evaporation Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 150000002825 nitriles Chemical class 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 102000001419 Melatonin receptor Human genes 0.000 description 6
- 108050009605 Melatonin receptor Proteins 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 230000027288 circadian rhythm Effects 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 150000002220 fluorenes Chemical class 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 230000033764 rhythmic process Effects 0.000 description 5
- SUZLHDUTVMZSEV-UHFFFAOYSA-N Deoxycoleonol Natural products C12C(=O)CC(C)(C=C)OC2(C)C(OC(=O)C)C(O)C2C1(C)C(O)CCC2(C)C SUZLHDUTVMZSEV-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- OHCQJHSOBUTRHG-UHFFFAOYSA-N colforsin Natural products OC12C(=O)CC(C)(C=C)OC1(C)C(OC(=O)C)C(O)C1C2(C)C(O)CCC1(C)C OHCQJHSOBUTRHG-UHFFFAOYSA-N 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- XWBDWHCCBGMXKG-UHFFFAOYSA-N ethanamine;hydron;chloride Chemical compound Cl.CCN XWBDWHCCBGMXKG-UHFFFAOYSA-N 0.000 description 4
- 238000007429 general method Methods 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 230000029936 alkylation Effects 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
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- 239000000969 carrier Substances 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
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- 125000004122 cyclic group Chemical group 0.000 description 3
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- 229940079593 drug Drugs 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
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- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 3
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 3
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- VOAAEKKFGLPLLU-UHFFFAOYSA-N (4-methoxyphenyl)boronic acid Chemical compound COC1=CC=C(B(O)O)C=C1 VOAAEKKFGLPLLU-UHFFFAOYSA-N 0.000 description 2
- QJLBHHNUZHKLRU-UHFFFAOYSA-N 2,7-dimethoxyfluoren-1-one Chemical compound COC1=CC=C2C3=CC=C(OC)C(=O)C3=CC2=C1 QJLBHHNUZHKLRU-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
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Abstract
式I的新的取代的芴化合物是活性的裉黑激素兴奋剂。R=C1-6烷基、C3-6环烷基、C2-4烯基、卤素取代的C1-6烷基,或C1-6烷氧基取代的C1-6烷基。
Description
本申请公开了在9位有酰胺基乙基取代基的新的芴化合物。本申请还涉及这些化合物的制备方法,以及使用这些化合物的方法和组合物。这些化合物具有褪黑激素兴奋剂性质,因此被认为可以用于治疗睡眠障碍,例如高速飞行时引起生理节奏的破坏,等等。
褪黑激素(N-乙酰基-5-甲氧基色胺)是合成激素,最初由松果腺分泌。褪黑激素水平表示在生理节奏亮-暗循环的暗期中出现的有最高水平的循环生理节奏模式。褪黑激素与光周期信息的转导作用有关,看来像是调节脊椎动物的各种神精和内分泌功能,包括调节光周期哺乳动物的繁殖、体重和代谢,控制生理节奏节律和调节视网膜生理。
最近的资料表明褪黑激素通过特殊的受体产生其生物作用。使用生物活性的放射性标记的兴奋剂[125I]-2-碘褪黑激素能识别各种中枢神精系统中高亲合力褪黑激素受体。一种由蛙皮肤黑素细胞克隆的这类高亲合力褪黑激素受体的序列已经报道(Ebisawa,etal.,Proc.Natl.Acad.Sci.91:6133-6137,1944)。在哺乳动物脑中放射自显影研究已将褪黑激素受体分布局限在几个具体结构上。虽然在紧密相关的种类之间褪黑激素受体分布有显著差异,但是一般最高结合点密度存在于下丘脑的个别核中。人下丘脑中特殊的[125I]-2-碘褪黑激素结合完全局限在上视束交叉的中心,确信褪黑激素受体定位在人体生物钟中。
已经发现使用外来的褪黑激素使大鼠的生理节奏的节律同步化(Cassone,etal.,J.Biol.Rhythms,1:219-229,1986)。人人使用褪黑激素治疗认为由生理节奏的节律不同步引起的与高速飞行有关的睡眠障碍(Arendt,et al.,Br.Med.J.292:1170,1986)。另外,使用单剂量褪黑激素诱导人睡眠已经由Wartman在国际专利申请Wo94/07487中请求专利保护。
褪黑激素结合点已经在人体各种组织即视网膜、上视束交叉的中心、脾等中发现。因此,褪黑激素产生多种生理作用,但不是高选择性的,具有产生副作用的很大潜力。褪黑激素兴奋剂比褪黑激素选择性大,具有较小的副作用。
另外,褪黑激素的代谢分布可能是有问题的,化合物在体内很快降解,其口服的生物利用率通常很低,并且是可变的。合适的褪黑激素兴奋剂克服了这些缺点,得到具有较高可预测活性的产物。
因此,褪黑激素兴奋剂特别适用于治疗睡眠障碍和其他生物钟紊乱。褪黑激素兴奋剂也用于进一步研究褪黑激素受体干扰以及对由褪黑激素活性影响的各种症状的治疗,例如抑郁、高速飞行时引起生理节奏的破坏、倒班综合症、睡眠障碍、青光眼、生殖疾病、癌、免疫紊乱和神精内分泌紊乱。
McAfee的美国专利5,206,377公开了具有褪黑激素兴奋剂活性的式1化合物:式中:R1′是C1-6烷氧基;R1″是氢、C1-6烷基或任意取代的苯基;R2是氢或苯基取代的C1-6亚烷基;和R3、R4、R5和R6是C1-6烷基、C1-6烷氧基或任意取代的苯氧基。McAfee的化合物不含有N-酰胺基乙基取代基。
Stamm等人在Chem Ber.,111:PP.2665-6(1978)中说明用N-酰基氮丙啶酰胺基乙基化芴,得到式2化合物:式中:Z是乙氧基、二苯胺基、二乙胺基或苯基。
Severin等人在Chem.Ber.,Vol.110,(1977),P.491-8中说明式5的芴基乙胺的制备方法:
这些公开文献均未公开本发明的化合物。
本发明是关于式I的取代的芴基化合物和使用这些化合物的组合物和方法。
X=H、卤素、OH或OZ;
n=1或2;和
R=C1-6烷基、C3-6环烷基、C2-4烯基、卤素取代的C1-6烷基,或C1-6烷氧基取代的C1-6烷基。
本发明的褪黑激素兴奋剂(melatogergic agents)具有优于类似药剂的一些优点。其很好地用于证明人的上视束交叉中心(SCN)中发现的褪黑激素结合点亲合力的试验中。许多化合物在250nM或更小的浓度下就具有了褪黑激素结合点的亲合力IC50值。
本发明的化合物是兴奋剂,这一点可以由这些化合物具有阻断一些细胞中由forskolin刺激的循环腺苷酸(AMP)积累的类似褪黑激素的能力来确定。另外,许多这类化合物能影响啮齿动物的活性节律,这表明其具有调节哺乳动物生理节奏的节律的能力。
这些和其他优点在研究本发明的说明书和权利要求之后会更清楚。
本说明书中描述的新的褪黑激素兴奋剂(melatonergicagents)是式I化合物:式中:
X=H、卤素、OH或OZ;Z=C1-6烷基、-(CH2)m-CF3(m=0-2)、CD3,或(m′=1-3);
n=1或2;和
R=C1-6烷基C3-6环烷基、C2-4烯基、
卤素取代的C1-6烷基或C1-6烷氧基取
代的C1-6烷基。
“烷氧基”表示直链或支链的烷氧基,-O-烷基,优选的烷氧基包括甲氧基。
“烷基”表示支链或支链的Cn′H(2n+1)基和环状的Cn′H(2n′-1)基。n′是这些基中的C原子数。R或Z中的所有烷基,除了环烷基外,含有1-6个碳原子。优选的烷基包括甲基、乙基、异丙基、正丙基、环丙基和环丁基。
“烯基”表示含有一个不饱和键和至少2个碳原子的一价直链或支链基。这些基是式Cn"H(2n"-1)基,其中n″是存在的碳原子数。优选的烯基包括乙烯基。
本发明的化合物中烷氧基取代的苯基含有7-10个碳原子。这些基可以由1-3个亚甲基(-CH2-)与芴环部分连接。(甲氧基苯基)丙基取代基优选。
本发明化合物中的烷氧基取代的烷基含有总共2-8个碳原子。如上所述,任何烷基可以是直链、支链或环状的。优选的这类基包括甲氧基甲基。
术语“卤素”是Cl、Br、F或I原子。通常在每个卤素取代的烷基中有1-3个卤素取代基。优选的卤素取代基包括Cl和F。卤甲基,例如氯甲基和三氟甲基优选。
D是氘。
m可以是0,1或2,和表示CH2基数。优选m是1。
m′是1,2或3,优选3。
n是1或2,优选1。
一类优选的式I化合物包括Z是甲基和X是氢和甲氧基的化合物。在这些化合物中R是甲基、正丙基、甲氧基甲基、异丙基和乙烯基的化合物优选。这类中的一些化合物是:N-[2-(2-甲氧基芴-9-基)乙基]丁酰胺;N-[2-(2-甲氧基芴-9-基)乙基]乙酰胺;N-[2-(2-甲氧基芴-9-基)乙基]-2-丙烯酰胺;N-[2-(2,7-二甲氧基芴-9-基)乙基]甲氧基乙酰胺;和N-[2-(2,7-二甲氧基芴-9-基)乙基]-2-甲基丙酰胺。
第二类优选的式I化合物是Z是甲基和X是甲氧基的化合物。
这类化合物包括:N-[3-(2,7-二甲氧基芴-9-基)-丙-1-基]丙酰胺;N-[3-(2,7-二甲氧基芴-9-基)-丙-1-基]丁酰胺;N-[3-(2,7-二甲氧基芴-9-基)-丙-1-基]乙酰胺;N-[3-(2,7-二甲氧基芴-9-基)-丙-1-基]环丁烷甲酰胺;N-[3-(2,7-二甲氧基芴-9-基)-丙-1-基]环丙烷甲酰胺;N-[2-(2,7-二甲氧基芴-9-基)乙基]丁-2-烯酰胺;和 N-[2-(2,7-二甲氧基芴-9-基)-乙基]环戊烷甲酰胺;
在第二类化合物中下列化合物更优选:N-[2-(2,7-二甲氧基芴-9-基)-乙基]丁酰胺;N-[2-(2,7-二甲氧基芴-9-基)-乙基]丙酰胺;N-[2-(2,7-二甲氧基芴-9-基)-乙基]环丙烷甲酰胺;N-[2-(2,7-二甲氧基芴-9-基)-乙基]乙酰胺;N-[2-(2,7-二甲氧基芴-9-基)-乙基]环丁烷甲酰胺;和N-[2-(2,7-二甲氧基芴-9-基)-乙基]氯乙酰胺;
第三类优选的化合物是Z是甲基,X是烷氧基或烷氧基苯基烷基和R是烷基的化合物。
另一类优选的化合物是X=OZ=OCH2CH3的化合物。
式I化合物还包括其所有溶剂化物,特别是水合物。
本发明还包括由于结构不对称性的结果而产生的几何异构体和光学异构体。单个异构体的分离通过本技术领域的专业人员已知的各种方法实现。
本发明的化合物用下面一般的图解方法制备:
将合适的芴转化为α,β-不饱和腈,然后催化还原得到乙胺盐酸盐。另一种方法是可以将α,β-不饱和腈环丙烷化,然后还原得到丙胺盐酸盐。两种胺中任何一种用任何一种酰化条件转化为需要的酰胺。该图解的使用在下面更详细地说明。
芴从市场上得到或用下面图解方法制备:
将合适的取代的邻溴酯和苯硼酸用钯催化剂偶合得到联苯中间体,在游离苯酚存在下在有氧时在联苯中间体的一个芳环上烷基化。然后半酯水解成酸,再环化成需要的芴。该图解的使用在下面更详细地说明。
使用方法
本发明的化合物可以用各种途径给药于需要褪黑激素兴奋剂治疗的病人,即患有睡眠障碍等疾病的病人。这样,可以使用口口,经皮的,皮下的,静脉内的,肌内的,直肠的,颊的,鼻内的,和眼的途径。
将本发明的一个或多个化合物与可药用量的一种或多种通用的药物赋形剂混合以制备按需要途径给药的制剂。一般,所述制剂含有一种或几种载体或稀释剂。有用的载体包括固体、半固体或液体,载体具有与活性组分的溶混性或其他相溶性,以便其被传送给病人或宿主。
合适的载体包括乳糖、右旋糖、蔗糖、山梨糖醇、甘露醇、淀粉、阿拉伯胶、磷酸钙、藻朊酸盐、黄蓍胶、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆、甲基纤维素、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁、矿物油,等等。这些载体的混合物也是可用的。
其他有用的赋形剂包括润滑剂、湿润剂、胶凝剂、乳化剂、防腐剂、着色剂、香料、调味剂、干燥剂,等等。混合物也可以使用。
通常,包括本发明化合物的组合物含有约0.1-10%活性化合物和99.9-90%或其他合适量的赋形剂。
剂量水平由病人需要和治疗医生的医疗诊断决定。但是,一般剂量每天约0.1-100mg用于治疗睡眠障碍或生理节奏节律紊乱。
本发明的化合物最优选用于人患者,也可以用于其他受治疗者,即动物,优选哺乳动物。
具体实施方案
构成本发明的化合物,其制备方法和生物作用从研究下列实施例会完全清楚。下列实施例仅为了说明本发明但不认为是用来限定本发明的范围。在用于说明上述合成方法的下列实施例中,温度用摄氏度表示,熔点未校正。核磁共振(NMR)是波谱特性,指的是与参比标准四甲基硅烷(TMS)比较的化学位移(δ),以每百万中份数(ppm)表示。1H NMR波谱数据中不同的化学位移的相对面积相应于分子中特殊功能型氢原子的数。对于峰裂数化学位移的性质以宽单峰(bs),单峰(s),多重峰(m),双重峰(d)或三重峰(t)报道。使用的缩写有DMSO-d6(氘化二甲基亚砜),CPCl3(氘化氯仿)和其他通用的缩写。红外(IR)光谱说明仅包括具有官能基鉴定值的吸收波数。IR定使用纯化合物膜和使用溴化钾作稀释剂。元素分析数据以重量百分数报道。
除非另有说明,本说明书中使用的所有百分数是重量百分数,以组合物总重量为基础。
下列实施例详细说明式I化合物的制备方法。本技术领域技术熟练的人员会明白原料和方法的改变可以制备本说明书中说明的其他化合物。从上面的说明如下面的实施例可以相信本技术领域技术熟练的人员可以最完全地实施本发明。
合适的原料如2-羟基-9-芴从市场上得到;2,7-二羟基-9-芴根据Andrews等人(Journal of Medicinal Chemistry,1974,17,882)和Agarwal(Journal of Medicinal Chemistry,1967,10,99)描述的方法制备或从市场上得到。
实施例
这些实施例详述制备式I的各种化合物的方法和这些化合物的生物活性。
实施例1:2-[9-(2-甲氧基芴基)]乙胺盐酸盐
将2-羟基-9-芴酮(0.042mol),碳酸钾(0.20mol)和甲基碘(0.042mol)在乙腈中的溶液加热至回流并保持一夜。反应混合物冷却,用真空除去溶剂,得到固体。该固体溶于二氯甲烷中,用饱和碳酸钠溶液洗涤,用MgSO4干燥,除去溶剂,得到固体,鉴定为2-甲氧基-9-芴酮。在室温下用注射器将氰甲基膦酸二乙酯(7.43g,0.042mol)加入NaH(1.61g,0.067mol)在THF(200ml)中的悬浮液中;反应混合物搅拌15分钟后观察到浅黄色溶液。向该溶液中滴加2-甲氧基-9-芴酮(8.89g,0.042mol)的THF(100ml)溶液。反应混合物在室温下搅拌一夜。用真空除去溶剂,剩余物溶于二氯甲烷中,用水洗涤,用MgSO4干燥,浓缩,得到橙色固体。该固体溶于乙腈中,用己烷洗涤,浓缩乙腈溶液,得到橙色固体,通过1H NMR表明是α,β-不饱和腈(79%)。向α,β-不饱和腈化合物(7.72g,0.033mol),PtO2(0.77g),CHCl3(23ml)在EtOH(150ml)中的溶液/悬浮液中加入H2(50Psi),在Parr加的氢设备上振动18小时。反应混合物过滤,真空浓缩,得到白色固体。该固体用Et2O洗涤,真空干燥,得到白色固体(69%)。
实施例2:2-[9-(2,7-二甲氧基芴基)]乙胺盐酸盐
按照与实施例1中制备2-[9-(2-甲氧基芴基)]乙胺类似的方法从2,7-二羟基-9-芴酮开始制备。1H NMR(300MHz,CDCl3)δ7.60(d,J=8.0Hz,2H),7.00(d,J=2.0Hz,2H),7.85(dd,J=8.0,2.0Hz,2H),3.90-4.10(m,1H),3.85(s,6H),2.50-2.60(m,2H),2.10-2.30(m,2H).用另一种方法,必须的中间体2,7-二甲氧基芴酮制备如下:将2-溴-5-甲氧基苯甲酸甲酯(1.60g,6.53mmol),4-甲氧基苯硼酸(1.30q,8.55mmol)和三(二亚苄基丙酮)合二钯(O)(0.20g,0.22mmol)加入到二甲氧基乙烷(25ml)和2M碳酸钠(25ml)中。反应混合物在回流下搅拌16小时后倾析,剩余物用乙酸乙酯萃取。使合并的有机层干燥(MgSO4),用旋转蒸发除去溶剂,得到1.50g偶合产物(5.51mmol,产率84%)。酯(10.80g,39.70mmol)在回流的乙醇(500ml)中用1N氢氧化钠(80ml)水解。冷却的反应混合物用二氯甲烷萃取,然后用1N盐酸酸化。酸性溶液用二氯甲烷萃取。合并有机层,除去溶剂,用旋转蒸发浓缩,得到9.00g酸(34.88mmol,产率88%)。将9.00g(34.88mmol)酸溶于亚硫酰氯(250ml)中,在回流下搅拌6小时,反应混合物冷却至室温,用旋转蒸发除去溶剂,得到8.20g 2,7-二甲氧基芴酮(34.17mmol,产率98%),红色固体。
实施例3:2-甲氧基-7-戊氧基芴酮
将2-溴-5-羟基苯甲酸甲酯(9.30g,40.26mmol),4-甲氧基苯硼酸(6.54g,43.00mmol)和三(二亚苄基丙酮)合二钯(O)(0.30g,0.33mmol)加入二甲氧基乙烷(75ml)和2M碳酸钠(75ml)中。反应混合物在回流下搅拌6小时,然后冷却、倾析,剩余物用乙酸乙酯洗涤。混合的有机层干燥(MgSO4),用旋转蒸发除去溶剂,得到9.45g偶合产物(36.64mmol,产率91%)。
偶合产物(1.06物4.10mmol)通过在DMF中于75℃用戊基碘(1.16g,5.85mmol)和碳酸钾(1.38钾10.00mmol)处理16小时进行烷基化。冷却的反应混合物在乙酸乙酯和水之间分配。用旋转蒸发从合并的有机层中除去溶剂,得到烷基化产物。烷基化产物在回流的乙醇(50ml)中用1N氢氧化钠(10ml)水解,直到TLC显示皂化完成为止。冷却的反应混合物用1N盐酸酸化,用二氯甲烷萃取。有机层干燥(MgSO4),用旋转蒸发浓缩,得到酸。该酸溶于亚硫酰氯(50ml)中,在65℃加热30分钟。溶液冷却至室温,用旋转蒸发除去亚硫酰氯。剩余物溶于二氯甲烷(50ml)中,加入氯化铝(0.67g,5.00mmol)。反应混合物在室温下搅拌2小时后加入含有100ml 1N盐酸和冰的烧杯中抑制反应。分离出二氯甲烷层,酸性层用二氯甲烷洗涤。将混合的有机层干燥(MgSO4),用旋转蒸发除去溶剂,得到1.05g 2-甲氧基-7-戊氧基芴酮(3.55mmol,产率87%),红色固体。1H NMR(300Mhz,CDCl3)δ7.28(d,J=8.3Hz,2H),7.14(s,2H),6.93(d,J=8.3Hz,2H),3.96(q,J=7.5Hz,2H),3.82(s,3H),1.80(p,J=7.6Hz,2H),1.42(m,4H),0.93(t,J=7.5Hz,3H).
实施例4:3-[9-(2,7-二甲氧基芴基)]
丙胺盐酸盐
在氮气氛下氢化钠(0.6g,22mmol)用己烷洗涤并悬浮于20ml无水THF中。在15分钟内分批缓慢地加入氰甲基膦酸二乙酯(2.8g,16mmol),加完后不均匀的反应混合物成为透明的溶液。反应混合物在室温下搅拌30分钟。分批加入溶于30ml THF中的酮(4.2酮16mmol),反应混合物回流一夜。粗反应混合物冷却至室温,倒入150ml水中,用几份40ml CH2Cl2萃取。合并的有机层用MgSO4干燥,真空浓缩,得到酒红色固体。该α,β-不饱和腈(3.9g)用于后面反应中。
在氮气氛下将氢化钠(1.1g,44mmol)用己烷洗涤并悬浮于100ml无水DMSO中。将不均匀的反应混合物充分搅拌,同时加入部分碘化三甲基氧化锍(9.9g,45mmol)。搅拌溶液直到停止发泡。反应混合物冷却至-60℃。在20分钟内分批加入α,β-不饱和腈在40ml无水DMSO中的溶液。反应混合物加热至室温并搅拌一夜。粗反应混合物缓慢地倒入饱和的NH4Cl溶液中,接着加入EtOAc。水层用EtOAc洗涤几次,合并的有机层用MgSO4干燥,真空浓缩。得到的浅褐色油,用快速色谱(EtOAc/己烷梯度)提纯2级后得到需要的腈(43%)(2.1g;mp=131-133℃;浅黄色固体):
1H-NMR(300MHz,CDCl3)δ7.58(m,2H),6.91(m,3H),6 42(m,1H),3.85(s,3H),3.80(s,3H),2.33(m,1H),2.11(m,2H);13C-NMR(75MHz,CDCl3)δ158.8,158.7,144.9,142.2,120.2,117.8,114.1,112.9,106.8,104.9,55.5,34.8,21.7,14.8;FTIR(KBr)2833,2237,1623,1582,1470cm-1;元素分析,计算值18H15NO2:C,77.96;H,5.45;N,5.05.实验值:C,77.80;H,5.49;N,5.00.
将腈(4.3g)溶于200ml 1∶1的EtOH/EtOAc和20ml NH4OH中。混合物在阮内-Ni存在下加氢4小时(TLC,1∶1 EtOAc/Hex)。将粗混合物过滤、真空浓缩,溶于CH2Cl2和乙腈中,用MgSO4干燥,过滤,真空浓缩至干燥。得到的固体溶于MeOH和乙腈中,加入浓HCl(0.52ml,17mmol)。浓缩至干燥后,白色固体用己烷研制,过滤和干燥。得到产物(46%)(2.3g;mp=218-221℃):1H-NMR(300MHz,CDCl3)δ7.64(d,2H,J=8.3Hz),7.14(d,2H,J=2Hz),6.90(dd,2H,J=8.3,2.0Hz),3.95(t,1H,J=52Hz),3.81(s,6H),2.66(t,2H,J=8.8Hz),2.12-2.05(9m,2H),1.30-1.20(m,2H);13C-NMR(75MHz,CDCl3)δ158.3,147.9,133.5,119.8,112.8,110.3,55.3,463,28.9,22.9;FTIR(KBr)3425,2946,1243cm-1;元素分析,计算值C18H21NO2·HCl·0.15H2O:C,67.03;H,6.97;N,4.34;实验值:C,66.85;H,7.03;N,4.21
实施例5:一般方法,N-[2-(2,7-二甲
氧基芴-9-基)乙基]丙酰胺
将2-[9-(2,7-二甲氧基芴基)乙胺盐酸盐(0.0083mol)悬浮于CH3CN(150ml)中,加入过量的Et3N(0.024mol)。搅拌混合物直到原料完全溶解。加入丙酰氯(0.0083mol),反应混合物搅拌一夜。用真空除去乙腈。剩余物用过量水洗涤,用CH2Cl2萃取。分离有机层,干燥(MgSO4),过滤,真空浓缩,得到固体,用从EtOAc/己烷中重结晶提纯,m.p.134-140℃;有关化合物用硅胶柱色谱或反相HPLC提纯。1H NMR(300MHz,CDCl3)δ7.52(d,J=8.3Hz,2H),7.06(d,J=2.4Hz,2H),6.87(dd,J=8.3,2.3Hz,2H),4.87(bs,1H),3.98(t,J=5.1Hz,1H),3.83(s,6H),3.04(m,2H),2.29(q,J=6.6Hz,2H),1.96-1.82(m,2H),0.92(t,J=7.6Hz,3H);13C NMR(75MHz,CDCl3)δ173.4,158.8,147.7,133.9,119.9,113.0,110.1,55.6,45.7,36.1,31.9,29.5,9.49;IR(KBr)3260,1640,1240cm-1;MS(DCI)m/e MH+=326;元素分析,计算值C20H23NO3:C,73.82;H,7.12;N,4.30;实验值:C,73.63;H,7.17;N,4.22.
实施例6-31:
下列化合物根据实施例5中概述的一般方法用合适的胺盐酸盐和酰氯制备。
实施例32:N-2-(2-甲氧基-7-(1-戊氧基))
实施例 | 化合物 | 熔点(℃) |
6 | N-[2-(2-甲氧基芴-9-基)乙基]丁酰胺 | 97-99 |
7 | N-[2-(2,7-二甲氧基芴-9-基)乙基]环丙烷甲酰胺 | 152-153 |
8 | N-[2-(2,7-二甲氧基芴-9-基)乙基]乙酰胺 | 147 |
9 | N-[2-(2,7-二甲氧基芴-9-基)乙基]甲氧基乙酰胺 | 94-95 |
10 | N-[2-(2,7-二甲氧基芴-9-基)乙基]丁酰胺 | 126 |
上上 | N-[2-(2-甲氧基芴-9-基)乙基]-2-丙烯酰胺 | 143-145 |
12 | N-[2-(2-甲氧基芴-2-基)乙基]乙酰胺 | 133-135 |
实施例 | 化合物 | 熔点(℃) |
13 | N-[2-(2,7-二甲氧基芴-9-基)乙基]环丁烷甲酰胺 | 145-146 |
14 | N-[2-(2,7-二甲氧基芴-9-基)乙基]-2,2-二甲基丙酰胺 | 88-89 |
15 | N-[2-(2,7-二甲氧基芴-9-基)乙基]-2-甲基丙酰胺 | 145-146 |
16 | N-[2-(2,7-二甲基芴-9-基)乙基]氯乙酰胺 | 122-123 |
17 | N-[2-(2,7-二甲氧基芴-9-基)乙基]环戊烷甲酰胺 | 155-156 |
18 | N-[2-(2,7-二甲氧基芴-9-基)乙基]丁-2-烯酰胺 | 130-132 |
19 | N-[3-(2,7-二甲氧基芴-9-基)丙-1-基]环丁烷甲酰胺 | 110-113 |
实施例 | 化合物 | 熔点(℃) |
20 | N-[3-(2,7-二甲氧基芴-9-基)丙-1-基]乙酰胺 | 139-141 |
21 | N-[3-(2,7-二甲氧基芴-9-基)丙-1-基]丁酰胺 | 88-90 |
22 | N-[3-(2,7-二甲氧基芴-9-基)丙-1-基]丙酰胺 | 120-122 |
23 | N-[3-(2,7-二甲酰基芴-9-基)丙-1-基]环丙烷甲酰胺 | 141-142 |
24 | N-[2-(2-氟-7-甲氧基芴-9-基)乙基]丙酰胺 | 72-73 |
25 | N-[2-(2,7-二(甲氧基-d3)芴-9-基)乙基]乙酰胺 | 141-143 |
26 | N-[2-(2,7-二(甲氧基-d3)芴-9-基)乙基]丙酰胺 | 138-140 |
实施例 | 化合物 | 熔点(℃) |
27 | N-[2-(2,7-二(甲氧基-d3)芴-9-基)乙基]环丙烷甲酰胺 | 133-136 |
28 | N-[2-(2,7-二甲氧基-d3)芴-9-基)乙基]丁酰胺 | 117-120 |
29 | N-[2-(2-乙氧基-7-甲氧基芴-9-基)乙基]丙酰胺 | 95-98 |
30 | N-[2-(2-羟基-7-甲氧基芴-9-基)乙基]丙酰胺 | 50-60 |
31 | N-[2-(2,7-二甲氧基芴-9-基)乙基]丙酰胺 | 225-228 |
芴-9-基)乙基丙酰胺根据实施例5中概述的一般方法用丙酰氯制备。
1H NMR(300MH[300MHz,CDCl3)δ7.53(d,J=8.3Hz,2H),7.02(s,2H),6.88(d,J=8.3Hz,2H),4.90(bs,1H),3.95(m,3H),3.84(s,3H),3.04(m,2H),2.30(q,J=5.3Hz,2H),1.87(q,J=7.6Hz,2H),1.77(m,2H)1.43(m,4H),0.93(t,J=7.5Hz,6H); 13C NMR(75MHz,CDCl3)δ173.8,158.6,158.2,147.6,134.1,133.8,119.8,113.5,113.0,110.7,110.1,68.2,55.5,45.6,36.0,31.7,29.3,29.0,28.1,22.4,13.9,9.4.元素分析,计算值C24H31NO3·0.25H2O:C,74.68;H,8.23;N,3.63.实验值:C,7457;H,8.20,N,3.68.实施例33:N-2-(2-甲氧基-7-(3-(3-甲
氧基苯基)丙氧-1-基))芴-9-基)
乙基丙酰胺根据实施例5中概述的一般方法用丙酰氯制备。
1H NMR(300MHz,CDCl3)δ7.54(d,J=8.3Hz,2H),7.21(t,J=7.8Hz,2H),7.03(s,2H),6.91-6.73(m,4H),4.92(bs,1H),4.01(m,3H),3.90(s,3H),3.85(s,3H),3.06(q,J=6.2Hz,2H).2.82 (t,J=7.9Hz,2H),2.28(q,J=6.6Hz,2H),2.12(P,J=7.8Hz,2H)1.89(q,J=7.6Hz,2H),0.95(t,J=7.6Hz,3H);13C NMR(75MHz,CDCl3)δ173.4158.8,158.1,147.7,143.2,133.9,130.4,128.4,120.9,118.8,114.7,114.2,112.5,112.0,111.2,110.2,109.9,109.2,67.3,56.5,54.2,46.5,36.1,32.2,31.9,30.8,29.4,10.4,8.7.元素分析,计算值C29H33NO4·0.67H2O:C,73.85;H,7.34;N,2.97.实验值:C,73.81;H,7.02,N,2.84.
实施例34:褪黑激素兴奋剂结合的测定
1.试剂
(a)50m含有12.5mM MgCl2和2mM EDTA的Tris缓冲液(在37℃pH7.4)。
(b)洗涤缓冲液:20mM含有2mM MgCl2的Tris碱(在室温下pH7.4)
(c)褪黑激素(最终浓度10-5M)
(d)2-[125I]碘代褪黑激素(最终浓度100pM)
来源:NEN
2.膜制备
将受体CDNA(人ML1A)亚克隆成PCDNA3,用Lipofectamine引入NIH3T3细胞中。分离转移的抗遗传的NIH3T3细胞,分离和表征单菌落表达的高水平的2-[125I]-碘代褪黑激素结合。细胞片状沉淀物在-80℃冷冻备用。为了制备膜匀浆,片状物在冰上熔化,再悬浮于TME缓冲液,Tris碱,MgCl2,EDTA(在37℃ pH7.4)中,补充抑肽酶、壳肽素和苯甲基磺酰氟。细胞用dunce均浆器均化,并离心。得到的片状沉淀物用dounce均浆器再悬浮于TME中,冷冻。试验那天,小等分试样在冰上熔化,并再悬浮于TME缓冲液中。
3.培养
在37℃培养1小时。反应用过滤终止。
该方法以在Reppert,S.M.,Weaver,D.R.,and Ebisawa,R.Neuron,13,1177-1185(1994)中公开的方法为基础。
下面表列出选择的式I化合物和证明其有效的结合数据。
选择的式I化合物的结合数据
*+++=IC50<10nM;++=IC50<100nM;+=IC50<500nM
化合物 | 实施例 | 结合亲合力 |
N-[2-(2,7-二甲氧基芴-9-基)乙基]丙酰胺 | 5 | +++ |
N-[2-(2-甲氧基芴-9-基)乙基]丁酰胺 | 6 | ++ |
N-[2-(2,7-二甲氧基芴-9-基)乙基]甲氧基乙酰胺 | 9 | ++ |
N-[2-(2-甲氧基芴-9-基)乙基]-2-丙烯酰胺 | 11 | ++ |
N-[2-(2,7-二甲氧基芴-9-基)乙基]环丁烷甲酰胺 | 13 | +++ |
N-[2-(2,7-二甲氧基芴-9-基)乙基]-2,2-二甲基丙酰胺 | 14 | + |
N-[3-(2,7-二甲氧基芴-9-基)丙-1-基]乙酰胺 | 20 | ++ |
N-[2-(2-乙氧基-7-甲氧基芴-9-基)乙基]丙酰胺 | 29 | ++ |
实施例35:官能活性的测定
在完整的细胞中循环AMP累积:褪黑激素
细胞:
从细胞培养烧瓶中取出培养基,在合适时用Hank盐溶液或PBS洗涤。细胞从烧瓶中移出。在用血细胞计数器计数时加入足够的培养基以使细胞浓度达到4×105/ml。在培养平皿上培养细胞时将渗析的或热去活的胎牛血清(FBS)加入培养基中。将1ml细胞悬浮液加入每个孔中,然后加入2ml培养基。细胞培养一夜。
溶液:
1.储备溶液:普通培养基(无血清或添加剂)+20mM HEPES
2.IBM×溶液:培养基/HEPES+1mM IBMS
3.试验溶液:90%储备溶液+10%IBM×溶液
每个孔加入3ml预培养用的试验溶液和3ml试验用的溶液。每个试验条件做3次试验。
4.药物溶液
a)基底试验溶液+DMSO
b)Forskolin兴奋溶液:最终浓度10μM
c)Forskolin+竞争剂(褪黑激素)溶液:最终浓度10μM,forskolin+需要浓度的竞争剂(褪黑激素)。
反应:
所有试验在37℃做3次。在整个反应中有细胞的培养平皿保持在37℃的浅水溶中。从孔中取出培养基,加入3ml预培养的培养基。10分钟后,除去溶液,加入3ml药物溶液。10分钟后除去培养基,用HCl停止反应,试样在室温下最少放置1h。以每个平皿中取出1ml试样放入microfuge管中,离心除去悬浮的细胞。稀释至1:100后进行放射免疫测定(RIA)。
下面的表列出选择的式I化合物和证明其有效的固有的活性数据。
选择的式I化合物的官能数据
*I.A.(固有的活性)=Emax(试验化合物)/Emax(褪黑激素)Emax=最大作用
化合物名称 | EX. | I.A.* |
N-[2-(2,7-二甲氧基芴-9-基)乙基]丙酰胺 | 5 | 1.14 |
N-[2-(2,7-二甲氧基芴-9-基)乙基]丁酰胺 | 10 | 1.15 |
N-[2-(2,7-二甲氧基芴-9-基)乙基]环丙烷甲酰胺 | 7 | 1.02 |
可以对本发明做适当改进,例如本技术领域一般技术熟练的人员可以想到的那些改进,都不脱离本发明的范围。
Claims (20)
2.权利要求1的化合物,其中X和ZO中至少一个是甲氧基。
3.权利要求2的化合物,其中R是甲基、乙基、正丙基、环丙基、环戊基、环丁基或氯甲基。
4.权利要求3的化合物,选自:
N-[2-(2,7-二甲氧基芴-9-基)乙基]环戊烷甲酰胺;
N-[2-(2-甲氧基芴-9-基)乙基]丁酰胺;
N-[2-(2-甲氧基芴-9-基)乙基]乙酰胺;
N-[2-(2,7-二甲氧基芴-9-基)乙基]丁酰胺;
N-[2-(2,7-二甲氧基芴-9-基)乙基]丙酰胺;
N-[2-(2,7-二甲氧基芴-9-基)乙基]环丙烷甲酰胺;
N-[2-(2,7-二甲氧基芴-9-基)乙基]乙酰胺;
N-[2-(2-乙氧基-7-甲氧基芴-9-基)乙基]丙酰胺;
N-[2-(2-羟基-7-甲氧基芴-9-基)乙基]丙酰胺;
N-[2-(2,7-二甲氧基芴-9-基)乙基]环丁烷甲酰胺;和
N-[2-(2,7-二甲氧基芴-9-基)乙基]氯乙酰胺。
5.权利要求2的化合物,其中R是甲氧基甲基、甲基乙烯基、乙烯基、异丙基或叔丁基。
6.权利要求5的化合物,选自:
N-[2-(2,7-二甲氧基芴-9-基)乙基]丁-2-烯酰胺;
N-[2-(2-甲氧基芴-9-基)乙基]-2-丙烯酰胺;
N-[2-(2,7-二甲氧基芴-9-基)乙基]甲氧基乙酰胺;
N-[2-(2,7-二甲氧基芴-9-基)乙基]-2-甲基丙酰胺;和
N-[2-(2,7-二甲氧基芴-9-基)乙基]2,2-二甲基丙酰胺;
7.权利要求2的化合物,其中n=2。
8.权利要求7的化合物,选自:
N-[3-(2,7-二甲氧基芴-9-基)-丙-1-基]丙酰胺;
N-[3-(2,7-二甲氧基芴-9-基)-丙-1-基]丁酰胺;
N-[3-(2,7-二甲氧基芴-9-基)-丙-1-基]乙酰胺;
N-[3-(2,7-二甲氧基芴-9-基)-丙-1-基]环丁烷甲酰胺;
N-[3-(2,7-二甲氧基芴-9-基)-丙-1-基]环丙烷甲酰胺;
10.权利要求1的化合物,是N-[2-(2-甲氧基芴-9-基)乙基]丁酰胺;
11.权利要求1的化合物,是N-[2-(2,7-二甲氧基芴-9-基)乙基]丙酰胺;
12.权利要求1的化合物,是N-[2-(2,7-二甲氧基芴-9-基)乙基]环丁烷甲酰胺。
13.权利要求1的化合物,是N-[2-(2,7-二甲氧基芴-9-基)乙基]氯乙酰胺。
14.权利要求1的化合物,是N-[2-(2,7-二甲氧基芴-9-基)乙基]丁酰胺
15.权利要求1的化合物,是N-[2-(2,7-二甲氧基芴-9-基)乙基]乙酰胺。
16.权利要求1的化合物,是N-[2-(2,7-二甲氧基芴-9-基)乙基]环丙烷甲酰胺。
17.权利要求1的化合物,其中X是OZ而Z是CH2CH3。
18.权利要求1的化合物,其中X是OZ而Z是CD3。
19.治疗需要治疗的哺乳动物睡眠障碍的方法,包括将有效量的式I化合物给药于所述哺乳动物。
20.治疗睡眠障碍的药物组合物,包括有效量的式I化合物和适量的可药用的载体。
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WO1998038991A1 (en) * | 1997-03-05 | 1998-09-11 | Bristol-Myers Squibb Company | Polycyclic ethyl alkylamide melatonergic agents |
CO4980885A1 (es) * | 1997-12-29 | 2000-11-27 | Ortho Mcneil Pharm Inc | Compuestos de trifenilpropanamida utiles en el tratamiento de inflamaciones y metodos para preparar dicho compuesto |
CA2412208C (en) * | 2000-06-29 | 2009-08-18 | Neurosearch A/S | Use of 3-substituted oxindole derivatives as kcnq potassium channel modulators |
US7066774B2 (en) * | 2004-06-30 | 2006-06-27 | Emerson Electric Co. | Electrical connector and sleeve apparatus and method of assembly |
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US4282170A (en) * | 1980-04-17 | 1981-08-04 | Eli Lilly And Company | 9-Carbamoyl-9-(2-cyanoethyl)fluorenes |
US4508735A (en) * | 1983-09-21 | 1985-04-02 | Eli Lilly And Company | Anti-arrhythmic N-alkanoylaminoalkyl fluorenes |
AU614716B2 (en) * | 1985-08-14 | 1991-09-12 | G.D. Searle & Co. | Phenyl substituted dipeptide amides |
WO1993001159A1 (en) * | 1991-07-10 | 1993-01-21 | Merck Sharp & Dohme Limited | Fused tricyclic compounds, pharmaceutical compositions containing them and their use in therapy |
US5206377A (en) * | 1991-12-05 | 1993-04-27 | Whitby Research, Inc. | Compounds useful as antiproliferative agents |
RU2051151C1 (ru) * | 1992-01-16 | 1995-12-27 | Дзе Дюпон Мерк Фармасьютикал Компани | Азотсодержащие гетероциклические производные флуорена |
US5449683A (en) * | 1992-10-01 | 1995-09-12 | Massachussetts Institute Of Technology | Methods of inducing sleep using melatonin |
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- 1996-05-21 NZ NZ286630A patent/NZ286630A/en unknown
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- 1996-05-23 TW TW085106135A patent/TW323272B/zh active
- 1996-05-27 IL IL11842896A patent/IL118428A0/xx unknown
- 1996-05-31 EP EP96108723A patent/EP0747345A3/en not_active Ceased
- 1996-05-31 NO NO962233A patent/NO962233L/no unknown
- 1996-06-05 CN CN96110491A patent/CN1145895A/zh active Pending
- 1996-06-05 PL PL96314638A patent/PL314638A1/xx unknown
- 1996-06-05 JP JP8142548A patent/JPH08333315A/ja active Pending
- 1996-06-05 HU HU9601537A patent/HUP9601537A3/hu unknown
- 1996-06-05 KR KR1019960020502A patent/KR970001311A/ko not_active Application Discontinuation
- 1996-06-05 CZ CZ961629A patent/CZ162996A3/cs unknown
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104844400A (zh) * | 2015-04-13 | 2015-08-19 | 南京邮电大学 | 一种9-芴酮类及其t型寡聚苯撑骨架类化合物的制备方法 |
CN104844400B (zh) * | 2015-04-13 | 2017-03-22 | 南京邮电大学 | 一种9‑芴酮类及其t型寡聚苯撑骨架类化合物的制备方法 |
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AR004666A1 (es) | 1999-03-10 |
KR970001311A (ko) | 1997-01-24 |
SG48454A1 (en) | 1998-04-17 |
PL314638A1 (en) | 1996-12-09 |
NO962233L (no) | 1996-12-09 |
TW323272B (zh) | 1997-12-21 |
CZ162996A3 (en) | 1997-01-15 |
NZ286630A (en) | 1997-11-24 |
HUP9601537A2 (en) | 1997-01-28 |
HUP9601537A3 (en) | 1997-11-28 |
EP0747345A3 (en) | 1997-07-30 |
ZA964128B (en) | 1997-01-09 |
HU9601537D0 (en) | 1996-07-29 |
US5736578A (en) | 1998-04-07 |
AU697037B2 (en) | 1998-09-24 |
JPH08333315A (ja) | 1996-12-17 |
NO962233D0 (no) | 1996-05-31 |
AU5471696A (en) | 1996-12-19 |
EP0747345A2 (en) | 1996-12-11 |
IL118428A0 (en) | 1996-09-12 |
MX9602065A (es) | 1997-09-30 |
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