CN1089262A - 4-取代的1,2,4-三唑衍生物 - Google Patents
4-取代的1,2,4-三唑衍生物 Download PDFInfo
- Publication number
- CN1089262A CN1089262A CN93109405A CN93109405A CN1089262A CN 1089262 A CN1089262 A CN 1089262A CN 93109405 A CN93109405 A CN 93109405A CN 93109405 A CN93109405 A CN 93109405A CN 1089262 A CN1089262 A CN 1089262A
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- China
- Prior art keywords
- formula
- compound
- triazole
- methyl
- indol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical class N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 title abstract description 4
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims abstract description 34
- 239000000556 agonist Substances 0.000 claims abstract description 11
- 208000024891 symptom Diseases 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 105
- 239000000203 mixture Substances 0.000 claims description 39
- -1 2-(dimethylamino) ethyl group Chemical group 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 30
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 claims description 28
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 20
- 229940002612 prodrug Drugs 0.000 claims description 16
- 239000000651 prodrug Substances 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 14
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 150000003053 piperidines Chemical class 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 5
- 230000004048 modification Effects 0.000 claims description 5
- 238000012986 modification Methods 0.000 claims description 5
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 239000000370 acceptor Substances 0.000 abstract description 10
- 208000019695 Migraine disease Diseases 0.000 abstract description 6
- 206010027599 migraine Diseases 0.000 abstract description 6
- 201000010099 disease Diseases 0.000 abstract 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 66
- 239000000243 solution Substances 0.000 description 52
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 43
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 239000000543 intermediate Substances 0.000 description 15
- 239000002904 solvent Substances 0.000 description 14
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- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 12
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- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 10
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- 238000010898 silica gel chromatography Methods 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical class [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 9
- 150000001299 aldehydes Chemical class 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 7
- 239000006196 drop Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 6
- AZWXAPCAJCYGIA-UHFFFAOYSA-N bis(2-methylpropyl)alumane Chemical compound CC(C)C[AlH]CC(C)C AZWXAPCAJCYGIA-UHFFFAOYSA-N 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
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- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 6
- GPRYKVSEZCQIHD-UHFFFAOYSA-N 1-(4-aminophenyl)ethanone Chemical compound CC(=O)C1=CC=C(N)C=C1 GPRYKVSEZCQIHD-UHFFFAOYSA-N 0.000 description 5
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 description 5
- CSDPPAMOQAIHBQ-UHFFFAOYSA-N C(C1=CC=CC=C1)(=O)O.C=N.C=N.C=N.C=N Chemical compound C(C1=CC=CC=C1)(=O)O.C=N.C=N.C=N.C=N CSDPPAMOQAIHBQ-UHFFFAOYSA-N 0.000 description 5
- 229910021529 ammonia Inorganic materials 0.000 description 5
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 238000005984 hydrogenation reaction Methods 0.000 description 5
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 5
- 150000003852 triazoles Chemical class 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 230000003203 everyday effect Effects 0.000 description 4
- 229920000591 gum Polymers 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 239000006187 pill Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- 229930195212 Fischerindole Natural products 0.000 description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 3
- 206010019233 Headaches Diseases 0.000 description 3
- 108010020056 Hydrogenase Proteins 0.000 description 3
- 229920000388 Polyphosphate Polymers 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
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- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical class C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 2
- FNEQHKCQXDKYEO-UHFFFAOYSA-N 1-benzylpyrrole Chemical compound C1=CC=CN1CC1=CC=CC=C1 FNEQHKCQXDKYEO-UHFFFAOYSA-N 0.000 description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- 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
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
个别类的4-取代的1,2,4-三唑衍生物是类
5-HT1受体的选择性激动剂。因此可用于治疗需要
这些受体的选择性激动剂的临床症状,尤其可用于治
疗偏头痛和相关的疾病。
Description
本发明涉及个别类的4-取代的1,2,4-三唑衍生物,该衍生物作用于5-羟色胺(5-HT)受体,是人们所说的“类5-HT1”受体的选择性激动剂。因此它们可用于治疗需要这些受体的选择性激动剂的临床症状。
类5-HT1受体激动剂显示出选择性血管收缩剂的活性,近年来被认为可用于治疗偏头痛(参见,例如:A.Doenicke等人,The Lancet,1988,第1卷,1309-11页)。本发明化合物是类5-HT1受体的选择性激动剂,因此可具体用于治疗偏头痛以及相关的症状,例如:集聚性头痛(cluster headache)、慢性阵发性偏头痛、与血管疾病有关的头痛、紧张性头痛和小儿偏头痛。
EP-A-0313397和WO-A-91/18897描述了个别类被各种不同的5元杂脂肪环取代的色胺衍生物,它们被说成是对具体类型的“类5-HT1”受体特异性的,因此是需要该活性的临床症状的治疗的有效的治疗剂,具体来讲是治疗偏头痛。然而EP-A-0313397和WO-A-91/18897中均没有公开或提示由本发明所提供的具体的4-取代的1,2,4-三唑衍生物。
EP-A-0497512(1992年8月5日公布)描述了一类取代的咪唑、三唑和四唑衍生物,它们被说成是类5-HT1受体的选择性激动剂,因此可特别用于治疗偏头痛及相关症状。
本发明提供式(Ⅰ)化合物或其盐或其药物前体;式(Ⅰ)化合物的结构如下:
式中R代表2-(二甲氨基)乙基基团,或下式(ⅰ)或式(ⅱ)基团:
上式(Ⅰ)化合物具有重要的生物活性,是强效及高选择性的类5-HT1受体的选择性激动剂,并具很好的生物利用度。这些化合物及其盐和其药物前体多数在EP-A-0497512所包括的范围之内,然而EP-A-0497512没有具体公开1,2,4-三唑-4-基衍生物或其盐或其药物前体。
式中R代表式(ⅰ)基团的上式(Ⅰ)化合物在吡咯烷环的3位含不对称碳原子,因此是旋光的。为便于查找,上式(ⅰ)中有关的碳原子用符号“3”来表示。由于分子中有不对称碳原子,因此该化合物可以存在(R)和(S)对映体。因此,本发明范围包括该化合物的各个对映体及其混合物。一个这样的混合物,即人们所说的外消旋混合物或外消旋体含等比例的单一(R)和(S)对映体。此外,本发明提供含至少75%吡咯烷环的3位碳原子是(R)构型或(S)构型的对映体和25%或低于25%的相反的对映体的混合物,也提供含至少85%一种对映体和15%或低于15%的相反的异构体的混合物。最好将该混合物增浓至含至少95%、最好是含至少99%一种对映体和不高于5%、最好是不高于1%的相反的对映体的程度。
为用于药物中,式(Ⅰ)化合物的盐应是药学上可接受的盐。但其它的盐可用于制备本发明化合物或其药学上可接受的盐。适宜的本发明化合物药学上可接受的盐包括酸加成盐;所述酸加成盐可以例如通过将本发明化合物的溶液与药学上可接受的酸溶液混合制得;所述药学上可接受的酸包括例如盐酸、硫酸、富马酸、马来酸、琥珀酸、乙酸、苯甲酸、草酸、柠檬酸、酒石酸、碳酸或磷酸。
本发明包括上式(Ⅰ)化合物的药物前体。一般来讲,这样的药物前体应是式(Ⅰ)化合物的官能衍生物,该衍生物在体内易于转化成所需的式(Ⅰ)化合物。有关适宜的药物前体衍生物的选择及制备的常规方法的描述见例如“Design of Prodrugs”,H.Bundgaard编辑,Elsevier,1985。
本发明范围包括以下具体的化合物及其盐和其药物前体:
(±)-N-甲基-3-[5-(1,2,4-三唑-4-基)-1H-吲哚-3-基]吡咯烷;
式(ⅠA)3(R)-N-甲基-3-[5-(1,2,4-三唑-4-基)-1H-吲哚-3-基]吡咯烷:
式(ⅠB)3(S)-N-甲基-3-[5-(1,2,4-三唑-4-基)-1H-吲哚-3-基]吡咯烷:
式(ⅠC)N-甲基-4-[5-(1,2,4-三唑-4-基)-1H-吲哚-3-基]哌啶:
式(ⅠD)N,N-二甲基-2-[5-(1,2,4-三唑-4-基)-1H-吲哚-3-基]乙胺:
本发明也提供由一种或一种以上上式(Ⅰ)化合物或其药学上可接受的盐或其药物前体连同药学上可接受的载体组成的药用组合物。这些组合物最好为经口、肠道外、鼻内、舌下或直肠给药或经吸入或吹入给药的单位剂量形式如片剂、丸剂、胶囊、粉剂、颗粒剂、灭菌肠道外用溶液和悬浮液、计量气雾剂或液体喷雾剂、滴剂、安瓿、自动注射器装置或栓剂。就制备固体组合物如片剂而言,是将主活性成分与药用载体和其它药用稀释剂如水混合,制成含本发明化合物或其药学上可接受的盐的均匀混合物的固体预制组合物;所述药用载体包括例如常规压片配料如玉米淀粉、乳糖、蔗糖、山梨醇、滑石粉、硬脂酸、硬脂酸镁、磷酸二钙或树胶。当说这些预制组合物是均匀的时,是指活性成分被均匀的分散在该组合物中,这样该组合物就可以被容易地再分成等效的单位剂型如片剂、丸剂和胶囊。然后将该固体预制组合物再分成含0.1-约500mg本发明活性成分的上述类型的单位剂型。可将该新组合物的片剂或丸剂包衣,或者相反,配制成具有长效作用优点的剂型。例如,该片剂或丸剂可以由内配料组分和外配料组分组成,后者以外皮的形式包裹着前者。这两个组分可由肠溶层分开,该肠溶层用来阻止内组分在胃内崩解并使其原封不动地进入十二脂肠或延迟释放。许多材料可用于这样的肠溶层或肠溶包衣,这样的材料包括许多聚合酸和聚合酸与如紫胶、鲸蜡醇和乙酸纤维素这样的物质形成的混合物。
本发明新组合物的经口服或注射给药的液体剂型包括水溶液、适当矫味的糖浆、水性或油性悬浮液和用食用油如棉子油、芝麻油、椰子油或花生油矫味的乳剂以及酏剂和类似的药用溶媒。适宜于水性悬浮剂的分散剂或助悬剂包括合成的和天然的树胶如黄蓍胶、阿拉伯胶、藻酸盐、葡聚糖、羧甲基纤维素钠、甲基纤维素、聚乙烯吡咯烷酮或明胶。
在治疗偏头痛时,适宜的剂量水平约为每日0.01-250mg/Kg,每日约0.05-100mg/Kg为佳,每日约0.05-5mg/Kg为最好。该化合物可按每日1-4次的规范服用。
上式(Ⅰ)化合物可用包括使式(Ⅱ)化合物与式(Ⅲ)化合物或其羰基保护的形式反应的方法来制备;式(Ⅱ)化合物的结构如下:
式(Ⅲ)化合物结构如下:
式中R定义同上。
化合物(Ⅱ)和化合物(Ⅲ)的反应可以一步完成(Fischer吲哚合成);或通过第一步在低温下非环化制得式(Ⅳ)化合物,然后用适当的试剂如多磷酸酯环合,制得式(Ⅰ)化合物;所述式(Ⅳ)化合物的结构如下:
式中R定义同上。
上式(Ⅰ)中R代表式(ⅰ)基团的式(Ⅰ)化合物可用下述另一种方法制成外消旋体;所述方法包括以下步骤:
(A)式(Ⅱ)化合物与式(Ⅴ)化合物或其羰基保护的形式反应制得式(Ⅵ)化合物;所述式(Ⅱ)、式(Ⅴ)和式(Ⅵ)化合物的结构如下:
式中RP代表保护氨基的基团;
(B)将获得的式(Ⅵ)化合物去保护,制得式(Ⅶ)化合物:
以及
(C)将获得的式(Ⅶ)化合物甲基化。
式(Ⅱ)化合物和式(Ⅴ)化合物之间的反应正如式(Ⅱ)化合物和式(Ⅲ)化合物之间反应的情况一样,可以一步完成(Fischer吲哚合成);或通过第一步在低温下非环化制得式(Ⅷ)化合物,然后用适当的试剂如多磷酸酯环合,制得式(Ⅵ)化合物;所述式(Ⅷ)化合物的结构如下:
式中RP定义同上。
保护氨基的基团取代基RP的适当的例子包括酰基如氯乙酰、三氟乙酰、甲酰、苯甲酰、邻苯二甲酰、苯乙酰或吡啶羰基;衍生自碳酸的酰基如乙氧基羰基、苄氧基羰基、叔丁氧基羰基、联苯基异丙氧基羰基、对甲苄氧基羰基、对硝基苄氧基羰基、对溴苄氧基羰基、对苯偶氮基苄氧基羰基,对(对甲氧苯偶氮基)苄氧基羰基或叔戊氧基羰基;衍生自磺酸如对甲苯磺酸的酰基;以及其它基团如苄基、对甲氧基苄基、三苯甲基、邻硝基苯磺酰基或亚苄基。
产物化合物中的保护基团的去除可以根据保护基团的性质采用适当的方法来完成。典型的方法包括在钯催化剂(例如钯碳或钯黑)存在下氢化苄氧基羰基、对硝基苄氧基羰基、对溴苄氧基羰基、对苯偶氮基苄氧基羰基、对(对甲氧苯偶氮基)苄氧基羰基和三苯甲基基团;在冰乙酸或三氟乙酸中用溴化氢处理苄氧基羰基、对溴苄氧基羰基、对苯偶氮基苄氧基羰基和叔丁氧基羰基基团;用乙酸和/或无机酸如盐酸或硫酸处理三苯甲基、叔丁氧基羰基、甲酰基和亚苄基基团;以及用2,3-二氯-5,6-二氰基-1,4-苯醌处理对甲氧基苄基基团。
特殊的保护氨基的基团RP是苄基。当用苄基作保护氨基的基团RP时,除去该基团的优选的方法是氢化。这可以是常规的催化氢化,或者更具体地讲,是公知的转移氢化技术。这后一方法是在氢给体如甲酸铵,次磷酸钠、甲酸三乙铵或甲酸钾且最好是甲酸铵存在下,使用氢化催化剂如钯/碳,10%钯/碳较为理想。当用甲酸铵作氢给体时,反应宜在溶剂如甲醇或含水甲醇中进行,温度在35-45℃范围内有助于反应。
式中R代表式(ⅰ)基团的上式(Ⅰ)化合物的各对映体可以通过拆分按上述制备的外消旋的N-甲基-3-[5-(1,2,4-三唑-4-基)-1H-吲哚-3-基]吡咯烷来制备;或者将其受到保护的衍生物可用本身已知的方法在适当的后续阶段中去保护来制备,已知可使用的拆分方法例如包括非对映异构体的形成和分离。适宜的拆分剂包括能与分子中的氨基基团形成酸加成盐的手性酸。适宜的拆分酸是2-莰酮衍生物如2-莰酮-10-磺酸,α-溴2-莰酮-π-磺酸、羟基亚甲基2-莰酮和樟脑酸;薄荷醇衍生物如孟氧基(menthoxy)乙酸;天然存在的酒石酸和苹果酸的旋光形式以及二乙酰基酒石酸。
此外,手性氨基酸衍生物可用于拆分过程形成酰胺键,例如与吲哚核的1位氮原子形成酰胺键;随后可将形成的酰胺键在温和的条件下裂解。可用的适宜氨基酸是L-苯丙氨酸,其氨基基团可受到保护。
非对映异构体按常规方法如层析法或结晶法分离。层析用适宜的溶剂包括乙酸乙酯和石油醚。结晶法适宜的溶剂包括非极性溶剂如乙醚、二氯甲烷、石油醚和甲醇。
分离后,该适当的非对映异构体被转化成对映体;在该对映体中,吡咯烷环3位的碳原子处于需要的构型,根据需要或者是(R)或者是(S)。必要时,可将得到的吡咯烷环3位碳原子处于相反构型的非对映异构体再外消旋化而进行再拆分。
式中R代表式(ⅰ)基团的上式(Ⅰ)化合物的各对映体也可以通过包括以下步骤的手性操作来制备:
(ⅰ)式(Ⅱ)化合物与式(Ⅸ)化合物或其羰基保护的形式反应,得到式(Ⅹ)化合物;所述式(Ⅱ)、式(Ⅸ)和式(Ⅹ)化合物的结构如下:
式中用*标记的碳原子是(R)构型或(S)构型;
(ⅱ)将获得的式(Ⅹ)化合物去保护,制得式(Ⅺ)化合物:
式中用*标记的碳原子是(R)构型或(S)构型;以及(ⅲ)将得到的式(Ⅺ)化合物甲基化。
上式(Ⅲ)、(Ⅴ)及(Ⅸ)化合物的适宜的羰基保护的形式包括醛缩二甲醇衍生物。
式(Ⅱ)化合物和式(Ⅸ)化合物之间的反应正同式(Ⅱ)与式(Ⅲ)化合物之间以及式(Ⅱ)和式(Ⅴ)化合物之间的反应情况一样,可以一步完成(Fischer吲哚合成);或通过第一步在低温下非环化制得式(Ⅻ)化合物,然后用适当的试剂如多磷酸酯环合,制得式(Ⅹ)化合物;所述式(Ⅻ)化合物的结构如下:
式中用*标记的碳原子是(R)构型或(S)构型。
式(Ⅱ)肼衍生物可由相应的式(ⅩⅢ)苯胺衍生物经重氮化后还原来制备;所述式(ⅩⅢ)苯胺衍生物的结构如下:
重氮化一般用亚硝酸钠/浓HCl来完成,得到的重氮产物用本身已知的方法如用氯化锡(Ⅱ)/浓HCl、亚硫酸钠/浓HCl或亚硫酸钠/浓硫酸来还原。
式(ⅩⅢ)苯胺衍生物适宜通过式(ⅩⅣ)肼衍生物与式(ⅩⅤ)N-乙酰苯胺反应并随后除去N-乙酰保护基团来制备;所述式(ⅩⅣ)肼衍生物和式(ⅩⅤ)N-乙酰苯胺的结构如下:
化合物(ⅩⅣ)和化合物(ⅩⅤ)之间的反应适宜于在回流的甲苯中进行,催化量的对甲苯磺酸有助于该反应。而后除去N-乙酰保护基团的反应一般在热的盐酸水溶液中进行。
式(ⅩⅣ)肼衍生物可以由N,N′-二甲酰肼按下述方法制备:将N,N′-二甲酰肼按J.Chem.Soc.(C),1967,1664页上报道的方法与亚硫酰二氯/N,N-二甲基甲酰胺反应,然后用甲醇钠在甲醇中处理。
式(ⅩⅤ)N-乙酰苯胺可以通过还原相应的式(ⅩⅥ)硝基化合物来制备;所述还原一般通过用氢化催化剂在氢给体如甲酸铵存在下转移氢化,或者通过常规的催化氢化或用氯化锡(Ⅱ)来完成;所述式(ⅩⅥ)硝基化合物的结构如下:
式(ⅩⅥ)硝基化合物可从英国Gillingham,Aldrich Chemical Company Ltd.买到。
式中R代表式(ⅱ)基团的上式(Ⅲ)醛的制备方法用以下反应路线加以说明:
该原料化合物(ⅩⅦ)(1-甲基-4-哌啶酮)可从英国Gillingham,Aldrich Chemical Company Ltd.买到。在该反应路线中的第1步反应包括该化合物在氢化钠存在下与Horner-Emmons试剂MeO2C·CH2·PO(OEt)2反应,用THF作为溶剂。在第2步反应中,得到的哌啶烯酯的双键在HCl乙醇溶液中用钯/炭氢化。随后在第3步中用氢化二异丁基铝(DIBAL-H)在THF中还原甲酯基团侧链,然后经Swern氧化将得到的末端羟甲基基团氧化成(Ⅲ)目标中间体中的醛部分。
式中保护氨基的基团RP为苄基的上式(Ⅴ)典型的中间体的制备方法用以下反应路线加以说明:
该原料化合物(ⅩⅧ)(1-苄基-3-吡咯烷酮)可从英国Gillingham,Aldrich Chemical Company Ltd.买到。在该反应路线中的第1步反应包括该化合物在氢化钠存在下与Horner-Emmons试剂MeO2C·CH2·PO(OEt)2反应,用THF作为溶剂。在第2步反应中,得到的吡咯烷烯酯的双键在HCl乙醇溶液中用钯/炭氢化。随后在第3步中用氢化二异丁基铝(DIBAL-H)在THF中还原甲酯基团侧链,然后经Swern氧化将得到的末端羟甲基基团氧化成(Ⅴ)目标中间体中的醛部分。
上式(Ⅸ)醛衍生物可通过还原相应的式(ⅩⅨ)氰基化合物来制备。进行该转换的适宜的还原剂是氢化二异丁基铝(DIBAL-H),并且该反应适宜在四氢呋喃溶剂中进行。所述式(ⅩⅨ)氰基化合物的结构如下:
式中用*标记的碳原子是(R)构型或(S)构型。
上式(ⅩⅨ)氰基化合物的两个对映体的制备方法均在J.Med.Chem.,1990,33卷,71页中有描述。
上述手性操作的步骤(ⅱ)包括脱去式(Ⅹ)化合物的保护基,除去保护氨基的基团适宜用氢化来完成。这可以是常规的催化氢化,或更具体地讲是公知的上述转移氢化技术。
上述操作的步骤(C)和步骤(ⅲ)包括式(Ⅶ)和式(Ⅺ)化合物分别甲基化。这适宜用常规的N-甲基化技术来完成,例如在还原剂如氰基硼氢钠存在下用甲醛处理式(Ⅶ)化合物或式(Ⅺ)化合物来进行N-甲基化。
以下实施例举例说明本发明化合物的制备。
试验化合物与类5-HT1受体的结合能力按J.Meurosci.,1987,7,894页中所述的方法在由猪尾(pig caudate)制得的膜上进行测定,用2nM硫酸5-羟色胺肌酸酐来测定结合,5-[1,2-3H(N)作放射性配体。氰基吲哚心安(Cyanopindolol)(100nM)和mesulergine(100nM)被用于该测定中以分别隔开5-HT1A和5-HT1C结合部位。在每种情况下,置换50%的特异性结合所需的所附实施例化合物的浓度(IC50)在1μM以下。
用作类5-HT1受体的激动剂的试验化合物的活性用Arch.Pharm.,1990,342,111页中所述的方法依据它们对新西兰白兔的隐静脉的间接收缩的能力来测定。激动剂的效价根据从5-HT(1μM)对该激动剂的浓度的反应的百分数曲线上的-Log10EC50(pEC50)值来计算。结果发现,所附实施例化合物在该测定中的每种情况下其pEC50值均不低于5.0。
实施例1
(±)N-甲基-3-[5-(1,2,4-三唑-4-基)-1H-吲哚-3-基]-吡咯烷2.55草酸盐
中间体1
N-苄基-3-(甲酰甲基)吡咯烷
a)N-苄基-3-(甲氧甲酰甲基)吡咯烷
将二乙基膦酰基乙酸甲酯(26.9g,0.128mol)的THF(50ml)溶液于10℃搅拌下滴加到NaH(5.12g,60%油分散体,0.128mol)的THF(125ml)悬浮液中。将该混合物搅拌0.6小时,滴加N-苄基吡咯烷-3-酮(20.4g,0.117mol)的THF(50ml)溶液,并于50℃加热3小时后真空除去溶剂并将残留物再溶解于二氯甲烷(300ml)和水(100ml)中。分出二氯甲烷相,用水(50ml)和亚硫酸氢钠溶液(2×50ml)洗涤并干燥(硫酸钠)。将粗产物进行硅胶层析,用石油醚/乙酸乙酯(60∶40)洗脱,得不饱和酯的混合物(24.7g,92%)。
将上述不饱和酯(18.8g,81.4mmol)的甲醇(95ml)和2N HCl(40ml)溶液在50磅/平方英寸压力下用Pd-C(1.9g)氢化0.25小时。用硅藻土滤除催化剂并将溶剂真空除去。残留物用饱和碳酸钾溶液(100ml)碱化并用EtOAc(2x)提取。将合并的提取液干燥(硫酸镁)并蒸发。将残留物进行硅胶层析,用二氯甲烷/甲醇(96∶4)洗脱,得标题的甲氧甲酰酯(15.4g,81%);
δ(360MHz,CDCl3)1.40-1.49(1H,m,CH2的CH):2.03-2.12(1H,m,CH2的CH),2.18(1H,dd,J=6.4和9.2Hz,CH2的CH),2.40(2H,d,J=7.5Hz,CH2CO2CH3),2.49-2.63(3H,m,CH和CH2),2.80(1H,dd,J=7.6和9.2Hz,CH of CH2),3.59(2H,ABq,J=13Hz CH2Ph),3.65(3H,s,CH3),7.21-7.31(5H,m,芳-H)。
b)N-苄基-3-(甲酰甲基)吡咯烷
用0.5小时的时间于-35℃将氢化二异丁基铝(105ml 1M甲苯溶液,0.105mol)搅拌下滴加至上述酯(7.0g,30.0mmol)的甲苯(400ml)的溶液中。将该溶液加热至室温并搅拌2小时。然后依次加入甲醇(10ml)、2NNaOH(5ml)和水(5ml)中止反应。将混合物搅拌1小时并将产生的沉淀用硅藻土滤除。真空除去溶剂,得所需的乙醇(5.65g,92%)。
将二甲亚砜(1.66ml,23.4mmol)于-75℃滴加至草酰氯(1.49g,11.7mmol)的二氯甲烷(130ml)溶液中。将该混合物搅拌0.25小时后,加入上述醇(2.0g,9.76mmol)的二氯甲烷(30ml)溶液中并于-75℃搅拌1小时。加入三乙胺(4.94g,48.8mmol)并将反应混合物加热至25℃搅拌1小时。加入水(100ml)和二氯甲烷(400ml)并将该混合物用饱和碳酸钾溶液碱化。分出水相并用二氯甲烷(2x)提取。将合并的提取液干燥(硫酸镁)并蒸发。将残留物进行硅胶层析,用二氯甲烷/乙醇(9∶1)洗脱,得所需的醛(1.63g,82%);
δ(360MHz,CDCl3)1.41-1.50和2.07-2.17(2H,m,CH2),2.20(1H,dd,J=5.9和9.1Hz,CH2的CH),2.54-2.67(5H,m,CH和2个CH2),2.80(1H,dd,J=7.3和9.1Hz,CH2的CH),3.60(2H,ABq,J=13.0Hz,CH2),7.22-7.31(5H,m,芳-H),9.74(1H,t,J=1.6Hz,HCO)。
中间体2
4-(1,2,4-三唑-4-基)苯肼
a)4′-氨基N-乙酰苯胺
将4′-硝基N-乙酰苯胺(5.0g,27.8mmol)的EtOH/EtOAc(160ml,1∶1)、水(15ml)和5N HCl(5.6ml,28.0mmol)溶液在50磅/平方英寸压力下用10%Pd-C(0.50g)氢化0.25小时。用硅藻土滤除催化剂并真空除去溶剂。将产物溶于水中,用2N NaOH碱化,产生游离碱。用EtOAc提取游离碱并将合并的提取液干燥(硫酸镁)并蒸发,得标题的苯胺(3.75g,90%);
δ(250MHz,CDCl3/D4-MeOH)2.10(3H,s,CH3),6.68(2H,d,J=8.8Hz,芳-H),7.27(2H,d,J=8.8Hz,芳-H)。
b)4′-(1,2,4-三唑-4-基)N-乙酰苯胺
将上述苯胺(3.52g,23.4mmol)、N,N-二甲基甲酰胺吖嗪(N,N-dimethylformamide azine)(3.33g,23.4mmol;J.Chem,Soc.C.1967,1664页)和对甲苯磺酸-水合物(0.223g,1.17mmol)在无水甲苯(100ml)中的混合物加热回流17小时。滤出米黄色的沉淀,用甲苯和二氯甲烷洗涤并真空干燥,得所需的三唑(4.29g,91%);
δ(250MHz,D4-MeOH,d6-DMSO)2.14(3H,s,CH3),7.60(2H,d,J=8.8Hz,芳-H),7.78(2H,d,J=8.8Hz,芳-H),8.96(2H,s,芳-H)。
C)4′-(1,2,4-三唑-1-基)苯胺
将上述的N-乙酰苯胺(4.91g,24.3mmol)的HCl(5N,100ml)溶液于125℃加热1.5小时。将混合物冷却至0℃,用浓NaOH水溶液碱化并用二氯甲烷(x5)提取。将合并的提取液干燥(硫酸镁)并蒸发。将残留物进行硅胶层析,用二氯甲烷/甲醇/氨(80∶8∶1)洗脱,得标题的苯胺(2.94g,76%);
δ(250MHz,CDCl3)3.80(2H,s,NH2),6.71(2H,d,J=8.8Hz,芳-H),7.08(2H,d,J=8.8Hz,芳-H),8.36(2H,s,芳-H)。
d)4′-(1,2,4-三唑-4-基)苯肼
将NaNO2(0.69g,9.99mmol)的水(8ml)溶液于-21℃滴加至上述的苯胺(1.60g,9.99mmol)的浓HCl/水(分别为23ml和3ml)溶液中,滴加速度为能将温度维持在-10℃以下。将混合物搅拌0.3小时后在真空条件下迅速通过多孔状淀土过滤。将滤液加至冷的(-20℃)SnCl2·2H2O(9.02g,40.0mmol)的浓HCl(17ml)溶液中,将混合物于-20℃搅拌0.25小时,然后于室温搅拌1.25小时。滤出生成的固体,用乙醚洗涤并真空干燥。将粗产物溶于水中,用浓NaOH水溶液碱化并用EtOAc(x5)提取。将合并的提取液干燥(硫酸镁)并蒸发,得标题产物(0.95g,54%);
δ(CDCl3/D4-MeOH)3.98(3H,宽s,NH和NH2),6.97(2H,d,J=12.0Hz,芳-H),7.25(2H,d,J=12.0Hz,芳-H),8.48(2H,s,芳-H)。
(±)N-苄基-3-[5-(1,2,4-三唑-4-基)1H-吲哚-3-基]吡咯烷
将中间体(0.416g,2.37mmol)和中间体1(0.4g,1.96mmol)的硫酸(4%,45ml)溶液加热回流40小时。将混合物冷却至室温,加入二氯甲烷(100ml)并用饱和碳酸钾溶液碱化水层(PH12/13)。分出水层并进一步用二氯甲烷(x5)提取。将合并的提取液干燥(硫酸镁)并蒸发。将残留物进行硅胶层析,用二氯甲烷/甲醇(9∶1)洗脱,得标题的苄基吡咯烷(0.183g,22.5%);
δ(250MHz,CDCl3)1.87-2.06(1H,m,CH2的CH),2.30-2.43(1H,m,CH2的CH),2.69-3.02(4H,m,2个CH2)3.57-3.68(1H,m,CH),3.71(2H,ABq,J=13Hz,CH2Ph),7.05-7.36(7H,m,芳-H),7.46(1H,d,J=8.5Hz,芳-H),7.78(1H,d,J=2.0Hz,芳-H),8.46(2H,s,芳-H),8.71(1H,宽s,NH)。
(±)-N-H-3-[5-(1,2,4-三唑-4-基)-1H-吲哚-3-基]吡咯烷
将上述的苄基吡咯烷(0.183g,0.53mmol)、甲酸铵(0.176g,2.79mmol)和10%Pd-C(0.183g)的甲醇(17ml)混合物于室温搅拌0.25小时,然后于70℃搅拌0.9小时。用硅藻土滤除催化剂,真空除去溶剂。将粗产物进行硅胶层析,用二氯甲烷/甲醇/氨(20∶8∶1)洗脱,得所需的NH-吡咯烷(99mg,73%)。
δ(360MHz,D4-MeOH)
1.82-1.95和2.16-2.30(各为1H,各为m,CH2),2.76-3.10(3H,m,CH2的CH和CH2),3.24-3.50(2H,m,CH2的CH和CH),7.16(1H,s,芳-H),7.17(1H,dd,J=1.5和8.4Hz,芳-H),7.42(1H,d,J=8.4Hz,芳-H),7.69(1H,d,J=1.5Hz,芳-H),8.80(2H,s,芳-H)。
(±)N-甲基-3-[5-(1,2,4-三唑-4-基)-1H-吲哚-3-基]吡咯烷2.55草酸盐
将HCHO(35mg 38%(重量/体积)溶液;0.44mmol)的甲醇(8ml)溶液于0℃搅拌下加至上述的胺(90mg,0.36mmol)、NaCNBH3(28mg,0.45mmol)和冰乙酸(0.05ml,0.89mmol)的甲醇(8ml)溶液中,并于0℃搅拌2小时,然后于室温搅拌0.7小时。加入饱和碳酸钾溶液(6ml),真空除去溶剂。将得到的残留物溶于EtOAc(125ml)中并用盐水(x2)洗涤。将合并的水液再用EtOAc(x2)提取,并将合并的提取液干燥(硫酸镁)并蒸发。将残留物进行闪层析,用二氯甲烷/甲醇/氨(40∶8∶1)洗脱,得所需的产物(78mg,82%)并制得了2.55草酸盐;mp40℃(吸湿)。
元素分析 实测值:C,48.84;
H,5.02;N,13.60.C15H17N5.2.5(C2H2O4).0.2H2O.0.03(EtOH).0.03(Et2O)理论值:C,48.51;H,4.62;N,14.02%,δ(360MHz,D2O)2.26-2.44和2.58-2.76(各为1H,各为m,CH2),3.01和3.02(总计3H,各为s,CH3),3.22-4.16(总计5H,2个CH2和CH),7.39(1H,dd,J=1.5和8.6Hz,芳-H),7.46和7.49(总计1H,各为s,芳-H),7.67(1H,d,J=8.6Hz,芳-H),7.84(1H,d,J=1.5Hz,芳-H),9.28(2H,s,芳-H)。
实施例2
3(S)-N-甲基-3[5-(1,2,4-三唑-4-基)-1H-吲哚-3-基]吡咯烷苯甲酸盐
中间体3
3(S)-N-[(R)-1-苯基乙基]-3-(甲酰甲基)吡咯烷
a)3(S)-N[(R)-1-苯基乙基]-3-(氰基甲基)吡咯烷
按文献方法(J.Med.Chem.1990,33卷(第1期),第71页)由3(R)-N-[(R)-1-苯基乙基]-3-(羟甲基)吡咯烷制得。
b)3(S)-N-[(R)-1-苯基乙基]-3-(甲酰甲基)吡咯烷
将氢化二异丁基铝(37.4ml 1M甲苯溶液,37.4mmol)加到上述的腈(4.0g,18.7mmol)的THF(100ml)溶液中并于室温搅拌3小时,加入乙酸乙酯(40ml)和饱和氯化铵溶液(30ml)。将混合物搅拌0.25小时后加4%硫酸(10ml)并搅拌0.5小时。用碳酸钾溶液碱化并用EtOAc(3x)提取。将合并的提取液干燥(硫酸钠)并蒸发,将粗产物进行硅胶层析,用二氯甲烷/甲醇(9∶1)洗脱,得标题的醛(2.3g,57%);
δ(360MHz,CDCl3)1.37(3H,d,J=6.6Hz,CH3CH),1.37-1.48(1H,m,CH2的CH),2.02-2.12(2H,m,CH和CH2的CH),2.39-2.46,2.51-2.65和2.81-2.85(分别为1H,4H和1H,各为m,3个CH2),3.21(1H,q,J=6.6Hz,CHCH3),7.20-7.32(5H,m,芳-H)。
3(S)-N-甲基-3-[5-(1,2,4-三唑-4-基)1H-吲哚-3-基]吡咯烷苯甲酸盐
用实施例1所述的方法,由肼、中间体2和醛、中间体3制得标题化合物。制得的苯甲酸盐mp187-190℃。
元素分析实测值:C,68.11;H,6.13;N,18.11.C15H17N5.C7H6O2理论值:C,67.85;H,5.95;N,17.98%.
δ(360MHz,D2O)2.26-2.44和2.58-2.76(各为1H,各为m,CH2),3.03(3H,s,CH3),3.22-4.16(总计.5H,2个CH2和CH),7.34(1H,dd,J=1.5和8.6Hz,芳-H),7.46-7.57(总计4H,m,芳-H),7.65(1H,d,J=8.6Hz,芳-H),7.76(1H,d,J=1.5Hz,芳-H),7.86-7.88(2H,m,芳-H),8.82(2H,s,芳-H).
实施例3
3(R)-N-甲基-3-[5-(1,2,4-三唑-4-基)-1H-吲哚-3-基]吡咯烷苯甲酸盐
用实施例1所述的方法,由3(R)-N-[(R)-1-苯基乙基]-3-(氰基甲基)吡咯烷和中间体2制得标题化合物。制得的苯甲酸盐mp 188-189℃。
元素分析实测值:C,68.12;H,6.06;N,18.10.C15H17N5.C7H6O2理论值:C,67.85;H,5.95;N,17.98%.δ(360MHz,d6-DMSO)1.91-2.00和2.29-2.42(各为1H,各为m,CH2),2.42(3H,s,CH3),2.60-2.88(总计,3H,m,CH2和CH2的CH),3.14-3.17和3.58-3.68(各为1H,各为m,CH2的CH和CH),7.31(1H,dd,J=1.5和8.6Hz,芳-H),7.34(1H,d,J=1.5Hz,芳-H),7.44-7.50和7.54-7.59(总计.4H,各为m,芳-H),7.85(1H,d,J=1.5Hz,芳-H),7.93-7.95(2H,m,芳-H),9.02(2H,s,芳-H).
实施例4
N-甲基-4-[5-(1,2,4-三唑-4-基)-1H-吲哚-3-基]哌啶苯甲酸盐
中间体4
N-甲基-4-(甲酰甲基)哌啶
a)N-甲基-4-(甲氧甲酰次甲基)哌啶
将二乙基膦酰基乙酸甲酯(88.69g,0.422mol)在搅拌和氮气条件下滴加至氢化钠(18.56g,60%油分散体,0.464mol)的THF(300ml)悬浮液中,滴加速度为可将温度维持在30℃以下。将混合物搅拌1小时,并滴加N-甲基-4-哌啶酮(47.71g,0.422mol)的THF(150ml)溶液。将混合物于60℃加热4.5小时,然后真空除去溶剂并将残留物再溶于二氯甲烷(300ml)和水(200ml)中,分出二氯甲烷层,依次用水(200ml)和饱和亚硫酸氢钠溶液(2×70ml)洗涤并干燥(硫酸镁)。将粗产物进行硅胶层析,用甲醇/乙醚(5∶95)洗脱,得标题产物(19.75g,28%)。
1H NMR(250MHz,CDCl3)δ2.30(3H,s,N-CH3),2.35(2H,t,J=6Hz,CH2),2.40-2.50(4H,m,2个CH2),3.00(2H,t,J=6Hz,CH2),3.70(3H,s,CO2CH3),5.65(1H,s,乙烯基CH).
b)N-甲基-4-(甲氧甲酰甲基)哌啶
将上述的不饱和酯(19.5g,0.115mol)的MeOH(140ml)、水(28ml)和5NHCl(23.1ml,0.115mol)溶液在40磅/平方英寸压力下用10%Pd-C(1.95g)氢化0.5小时。用硅藻土滤除催化剂并将溶剂真空去除。将残留物溶于水(70ml)中,用饱和碳酸钾溶液碱化,生成游离碱。用EtOAc提取游离碱并将合并的提取液干燥(硫酸镁)并蒸发,得标题的酯(8.41g,43%).
1HNMR(250MHz,CDCl3)δ1.24-1.37(2H,m,CH2),1.69-1.81(3H,m,CH2和CH),1.94(2H,td,J=11.9和2.2Hz,CH2),2.23-2.26(5H,m包括在δ2.26的S,NCH3和CH2),2.82(2H,宽d,J=11.6Hz,CH2),3.67(3H,s,CO2Me).
c)N-甲基-4-(2-羟基乙基)哌啶
在搅拌及氮气条件下,将氢化二异丁基铝(120ml 1M甲苯溶液,0.120mol)于-35℃滴加至上述的酯(8.19g,0.047mol)的甲苯(350ml)溶液中。用1小时的时间将该溶液加热至室温后再冷却至-30℃,并通过依次加入甲醇(5ml),水(5ml)和2NNaOH(5ml)终止反应。将混合物加热至室温并将得到的沉淀用硅藻土滤除。真空除去溶剂并使残留物通过氧化铝填塞垫,用甲醇/二氯甲烷(4∶96)洗脱,得标题产物(5.51g,82%)。
1HNMR(360MHz,CDCl3)δ1.23-1.47(3H,m,CH2和CH),1.52(2H,q,J=6.6Hz,CH2),1.69(2H,宽d,J=13.0Hz,CH2),1.91(2H,td,J=11.5和2.1Hz,CH2),2.18(3H,s,CH3),2.83(2H,宽d,J=11.8Hz,CH2),3.69(2H,t,J=6.6Hz,CH2).
d)N-甲基-4-(甲酰甲基)哌啶
在搅拌及通氮气条件下,将二甲亚砜(6.56ml,92.4mmol)于-70℃滴加至草酰氯(4.03ml,46.2mmol)的二氯甲烷(300ml)溶液中。将混合物搅拌0.2小时后加入上述的醇(5.51g,38.5mmol)的二氯甲烷(80ml)溶液并于-70℃搅拌1小时。加入三乙胺(26.8ml,192mmol)并将反应混合物加热至室温。加入水和二氯甲烷并将混合物用饱和碳酸钾溶液碱化。分出水相并用二氯甲烷(x4)提取。将合并的提取液干燥(硫酸镁)并蒸发。将粗产物进行氧化铝层析,用甲醇/二氯甲烷(1∶99)洗脱,得标题的醛(3.68g,69%);
1HNMR(360MHz,CDCl3)δ1.35(2H,qd,J=11.9和3.8Hz,CH2),1.69-1.73(2H,m,CH2),1.81-2.00(3H,m,CH2和CH),2.23(3H,s,CH3),2.35-2.38(2H,m,CH2),2.83(2H,宽d,J=11.9Hz,CH2),9.78(1H,t,J=2.0Hz,CHO).
N-甲基-4-[5-(1,2,4-三唑-4-基)-1H-吲哚-3-基]哌啶苯甲酸盐
将中间体2的二盐酸盐(2.11g,8.51mmol)和中间体4(1.0g,7.09mmol)的硫酸(4%,100ml)溶液加热回流22小时。将混合物冷却至0℃,用饱和碳酸钾溶液碱化并用EtOAc(5×200ml)提取。将合并的提取液干燥(硫酸钠)并蒸发。将残留物进行硅胶层析,用二氯甲烷/甲醇/氨(60∶8∶1)洗脱,得标题的三唑(1.08g,54%)。制得的→苯甲酸盐mp 218-220℃。
元素分析实测值:C,68.54;H,6.12;N,17.32.C23H25N5O2理论值:C,68.47;H,6.25;N,17.36%.1HNMR(360MHz,D2O)δ1.90-2.05(2H,m,CH2),2.20-2.38(2H,m,CH2),2.95(3H,s,CH3),3.07-3.30(3H,m,CH和CH2),3.58-3.72(2H,m,CH2),7.26(1H,dd,J=1.8和8.6Hz,芳-H),7.35(1H,s,芳-H),7.44-7.61(4H,m,芳-H),7.71(1H,d,J=1.8Hz,芳-H),7.86-7.89(2H,m,芳-H),8.94(2H,s,芳-H).
实施例5
N,N-二甲基-2-[5-(1,2,4-三唑-4-基)-1H吲哚-3-基]乙胺苯甲酸盐
将中间体2的二盐酸盐(1.50g,6.04mmol)和4-N,N-二甲氨基丁醛缩二甲醇(0.976g,6.05mmol)的硫酸水溶液(4%,120ml)于室温搅拌2小时,然后加热回流40小时。冷却至室温后,加入二氯甲烷,并用饱和碳酸钾水溶液碱化水层。分出水层,再用二氯甲烷(x3)提取。将合并的有机相干燥(硫酸镁)并蒸发。将残留物进行硅胶层析,用二氯甲烷/甲醇/氨(60∶8∶1)洗脱,得标题的三唑(0.70g,45%)。通过将苯甲酸的乙醚溶液加到该三唑的甲醇-乙醚溶液中制得苯甲酸盐;mp172-174℃。
元素分析实测值:C,66.59;H,6.28;N,18.42.C21H23N5O2理论值:C,66.83;H,6.14;N,18.55%).1H NMR(360MHz,D2O)δ2.95(6H,s,NMe2),3.26(2H,t,J=7.4Hz,CH2),3.50(2H,t,J=7.4Hz,CH2),7.32(1H,d,J=6.8Hz,芳-H),7.46-7.55(4H,m,芳-H),7.63(1H,d,J=8.6Hz,芳-H),7.73(1H,s,芳-H),7.88(2H,d,J=6.8Hz,芳-H),8.81(2H,s,芳-H).
实施例6
片剂制备
按以下所述制备分别含1.0、2.0、25.0、26.0、50.0和100mg下列化合物的片剂。
(±)-N-甲基-3-[5-(1,2,4-三唑-4-基)-1H-吲哚-3-基]吡咯烷2.55草酸盐
3(S)-N-甲基-3-[5-(1,2,4-三唑-4-基)-1H-吲哚-3-基]吡咯烷苯甲酸盐
3(R)-N-甲基-3-[5-(1,2,4-三唑-4-基)-1H-吲哚-3-基]吡咯烷苯甲酸盐
N-甲基-4-[5-(1,2,4-三唑-4-基)-1H-吲哚-3-基]哌啶苯甲酸盐
N,N-二甲基-2-[5-(1,2,4-三唑-4-基)-1H-吲哚-3-基]乙胺苯甲酸盐
含1-25mg活性化合物剂量的片剂
含量(mg)
活性化合物 1.0 2.0 25.0
微晶纤维素 49.25 48.75 37.25
改性食用玉米淀粉 49.25 48.75 37.25
硬脂酸镁 0.50 0.50 0.50
含26-100mg活性化合物剂量的片剂
含量(mg)
活性化合物 26.0 50.0 100.0
微晶纤维素 52.0 100.0 200.0
改性食用玉米淀粉 2.21 4.25 8.5
硬脂酸镁 0.39 0.75 1.5
将所有的活性化合物、纤维素以及部分玉米淀粉混合并用10%玉米淀粉糊制粒。将得到的颗粒过筛、干燥并与剩余的玉米淀粉和硬脂酸镁混合。然后将得到的颗粒压制成每片含活性成分为1.0mg、2.0mg、25.0mg、26.0mg、50.0mg和100mg的片剂。
Claims (10)
2、选自以下所列的化合物及其盐和其药物前体:
(±)-N-甲基-3-[5-(1,2,4-三唑-4-基)-1H-吲哚-3-基]吡咯烷;
3(S)-N-甲基-3-[5-(1,2,4-三唑-4-基)-1H-吲哚-3-基]吡咯烷;
3(R)-N-甲基-3-[5-(1,2,4-三唑-4-基)-1H-吲哚-3-基]吡咯烷。
3、N-甲基-4-[5-(1,2,4-三唑-4-基)-1H-吲哚-3-基]哌啶,及其盐和其药物前体。
4、N-甲基-4-[5-(1,2,4-三唑-4-基)-1H-吲哚-3-基]哌啶的苯甲酸盐。
5、N,N-二甲基-2-[5-(1,2,4-三唑-4-基)-1H-吲哚-3-基]乙胺,及其盐和其药物前体。
6、由按权利要求1定义的式(Ⅰ)化合物或其药学上可接受的盐或其药物前体同药学上可接受的载体组成的药用组合物。
7、有治疗用途的按照权利要求1定义的式(Ⅰ)化合物或其药学上可接受的盐或其药物前体。
8、按照权利要求1定义的式(Ⅰ)化合物或其药学上可接受的盐或其药物前体在生产治疗和/或预防需要类5-HT1受体的选择性激动剂的临床症状的药物方面的用途。
9、按照权利要求1定义的式(Ⅰ)化合物的制备方法,它包括:(Ⅰ)式(Ⅱ)化合物与式(Ⅲ)化合物或其羰基保护的形式反应;
式(Ⅱ)化合物结构如下:
式(Ⅲ)化合物结构如下:
式中R定义同上;或者
(Ⅱ)式中R代表式(ⅰ)基团的式(Ⅰ)化合物的外消旋体的制备:
(A)式(Ⅱ)化合物与式(Ⅴ)化合物或其羰基保护的形式反应,制得式(Ⅵ)化合物;所述式(Ⅱ)、式(Ⅴ)和式(Ⅵ)化合物的结构如下:
式中RP代表保护氨基的基团;
(B)将获得的式(Ⅵ)化合物去保护,制得式(Ⅶ)化合物:
(C)将获得的式(Ⅶ)化合物甲基化;或者(Ⅲ)式中R代表式(ⅰ)基团的式(Ⅰ)化合物的各对映体的制备:
拆分外消旋的N-甲基-3-[5-(1,2,4-三唑-4-基)-1H-吲哚-3-基]吡咯烷或其受到保护的衍生物,必要时将如此得到的化合物去保护;或者
(Ⅳ)式中R代表式(ⅰ)基团的式(Ⅰ)化合物的各对映体的制备:
(ⅰ)式(Ⅱ)化合物与式(Ⅸ)化合物或其羰基保护的形式反应,得到式(Ⅹ)化合物;所述式(Ⅱ)、式(Ⅸ)和式(Ⅹ)化合物的结构如下:
式中用*标记的碳原子是(R)构型或(S)构型;
(ⅱ)将获得的式(Ⅹ)化合物去保护,制得式(Ⅺ)化合物:
式中用*标记的碳原子是(R)构型或(S)构型;以及
(ⅲ)将得到的式(Ⅺ)化合物甲基化。
10、治疗和/或预防需要类5-HT1受体的选择性激动剂的临床症状的方法,它包括:给需要这样的治疗的病人服用有效量的按权利要求1定义的式(Ⅰ)化合物或其药学上可接受的盐或其药物前体。
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
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GB929216264A GB9216264D0 (en) | 1992-07-30 | 1992-07-30 | Therapeutic agents |
GB929216192A GB9216192D0 (en) | 1992-07-30 | 1992-07-30 | Therapeutic agents |
GB9216192.6 | 1992-10-23 | ||
GB9216264.3 | 1992-10-23 | ||
GB929222261A GB9222261D0 (en) | 1992-10-23 | 1992-10-23 | Therapeutic agents |
GB9222261.1 | 1992-10-23 |
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CN1089262A true CN1089262A (zh) | 1994-07-13 |
CN1037101C CN1037101C (zh) | 1998-01-21 |
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CN93109405A Expired - Fee Related CN1037101C (zh) | 1992-07-30 | 1993-07-30 | 4-取代的1,2,4-三唑衍生物、其制备方法及其用途 |
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US (1) | US5554629A (zh) |
EP (1) | EP0581538B1 (zh) |
JP (1) | JP2599557B2 (zh) |
CN (1) | CN1037101C (zh) |
AT (1) | ATE177096T1 (zh) |
AU (1) | AU664102B2 (zh) |
CA (1) | CA2101219A1 (zh) |
DE (1) | DE69323667T2 (zh) |
ES (1) | ES2127789T3 (zh) |
IL (1) | IL106445A (zh) |
MX (1) | MX9304595A (zh) |
WO (1) | WO1994003446A1 (zh) |
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GB9402016D0 (en) * | 1994-02-02 | 1994-03-30 | Merck Sharp & Dohme | Therapeutic agents |
GB9402011D0 (en) * | 1994-02-02 | 1994-03-30 | Merck Sharp & Dohme | Therapeutic agents |
GB9410031D0 (en) * | 1994-05-19 | 1994-07-06 | Merck Sharp & Dohme | Therapeutic agents |
US5552402A (en) * | 1994-05-19 | 1996-09-03 | Merck, Sharp & Dohme Ltd. | Five-membered heteroaromatic compounds as 5-HT receptor agonists |
US5854268A (en) * | 1994-08-02 | 1998-12-29 | Merck Sharp & Dohme, Ltd. | Azetidine, pyrrolidine and piperidine derivatives |
US5521196A (en) * | 1994-10-05 | 1996-05-28 | Eli Lilly And Company | 5-HT1F agonists for the treatment of migraine |
GB9423460D0 (en) * | 1994-11-21 | 1995-01-11 | Merck Sharp & Dohme | Therapeutic agents |
US5521197A (en) * | 1994-12-01 | 1996-05-28 | Eli Lilly And Company | 3-<1-alkylenearyl>-4-<1,2,3,6-tetrahydropyridinyl>-and 3-<1-alkylenearyl>-4-piperidinyl-1h-indoles: new 5-HT1F agonists |
PL322843A1 (en) * | 1995-03-20 | 1998-02-16 | Lilly Co Eli | 5-substituted 3-91,2,3,6-tetrahydropyridin-4-yl)- and 3-9piperydin-4-4-yl0-1h-indoles nevel 5-htif natagonists |
US5942536A (en) * | 1995-10-10 | 1999-08-24 | Eli Lilly And Company | N- 2-substituted-3-(2-aminoethyl)-1H-indol-5-YL!-Amides: new 5-HT1F agonists |
US5998438A (en) * | 1996-11-26 | 1999-12-07 | Allelix Biopharmaceuticals, Inc. | 5-cyclo indole compounds |
CA2299286A1 (en) | 1997-08-09 | 1999-02-18 | Laramie Mary Gaster | Bicyclic compounds as ligands for 5-ht1 receptors |
FR2767827A1 (fr) * | 1997-09-03 | 1999-02-26 | Adir | Nouveaux derives de l'indole et de l'indazole, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
US7189753B1 (en) | 1997-11-06 | 2007-03-13 | Cady Roger K | Preemptive prophylaxis of migraine |
AU2713399A (en) * | 1998-03-09 | 1999-09-27 | H. Lundbeck A/S | 5-heteroaryl substituted indoles |
BRPI0607517A2 (pt) | 2005-04-13 | 2009-09-08 | Neuraxon Inc | compostos de indol substituìdo, composição farmacêutica compreendendo o mesmo, método para tratar e uso do mesmo |
WO2007118314A1 (en) | 2006-04-13 | 2007-10-25 | Neuraxon, Inc. | 1,5 and 3,6- substituted indole compounds having nos inhibitory activity |
AU2008323526A1 (en) | 2007-11-16 | 2009-05-22 | Neuraxon, Inc. | Indole compounds and methods for treating visceral pain |
WO2010084507A2 (en) * | 2008-07-15 | 2010-07-29 | Sun Pharmaceutical Industries Ltd. | Process for the preparation of n-methyl-2-[3-(1-methyl-4-piperidyl)-1h-indol-5-yl]-ethanesulfonamide and its acid addition salts |
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DE2520816C3 (de) * | 1975-05-09 | 1979-02-15 | Bayer Ag, 5090 Leverkusen | Methinfarbstoffe |
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ZW19381A1 (en) * | 1980-08-12 | 1983-03-09 | Glaxo Group Ltd | Heterocyclic compounds |
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EP0581538A1 (en) | 1994-02-02 |
IL106445A0 (en) | 1993-11-15 |
US5554629A (en) | 1996-09-10 |
AU4215593A (en) | 1994-02-03 |
CN1037101C (zh) | 1998-01-21 |
MX9304595A (es) | 1994-02-28 |
DE69323667T2 (de) | 1999-09-30 |
ATE177096T1 (de) | 1999-03-15 |
DE69323667D1 (de) | 1999-04-08 |
JPH06184139A (ja) | 1994-07-05 |
ES2127789T3 (es) | 1999-05-01 |
IL106445A (en) | 1998-01-04 |
WO1994003446A1 (en) | 1994-02-17 |
CA2101219A1 (en) | 1994-01-31 |
JP2599557B2 (ja) | 1997-04-09 |
AU664102B2 (en) | 1995-11-02 |
EP0581538B1 (en) | 1999-03-03 |
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