CN87100928A - 哌啶衍生物及其药物组合物 - Google Patents
哌啶衍生物及其药物组合物 Download PDFInfo
- Publication number
- CN87100928A CN87100928A CN87100928.5A CN87100928A CN87100928A CN 87100928 A CN87100928 A CN 87100928A CN 87100928 A CN87100928 A CN 87100928A CN 87100928 A CN87100928 A CN 87100928A
- Authority
- CN
- China
- Prior art keywords
- piperidines
- compound
- pharmacology
- derivative
- methylsulfonyl amido
- 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.)
- Granted
Links
- 150000003053 piperidines Chemical class 0.000 title claims abstract description 167
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 34
- 239000001257 hydrogen Substances 0.000 claims abstract description 32
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 32
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 10
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 9
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 7
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims abstract description 5
- 125000003944 tolyl group Chemical group 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 118
- 238000000034 method Methods 0.000 claims description 79
- 150000003839 salts Chemical class 0.000 claims description 38
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 37
- 239000000203 mixture Substances 0.000 claims description 29
- 238000006243 chemical reaction Methods 0.000 claims description 22
- 238000002360 preparation method Methods 0.000 claims description 16
- 150000002431 hydrogen Chemical class 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 230000009467 reduction Effects 0.000 claims description 9
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 6
- 239000012188 paraffin wax Substances 0.000 claims description 6
- 230000007062 hydrolysis Effects 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000004450 alkenylene group Chemical group 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical group C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 claims 1
- 229930195733 hydrocarbon Natural products 0.000 claims 1
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- 206010003119 arrhythmia Diseases 0.000 abstract description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 78
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- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 48
- 238000005481 NMR spectroscopy Methods 0.000 description 36
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- -1 isobutyl- Chemical group 0.000 description 28
- 239000000243 solution Substances 0.000 description 27
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- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 18
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- 235000002639 sodium chloride Nutrition 0.000 description 13
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- 230000006793 arrhythmia Effects 0.000 description 9
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- KGIGUEBEKRSTEW-UHFFFAOYSA-N 2-vinylpyridine Chemical compound C=CC1=CC=CC=N1 KGIGUEBEKRSTEW-UHFFFAOYSA-N 0.000 description 8
- 230000003531 anti-dysrhythmic effect Effects 0.000 description 8
- 150000001721 carbon Chemical group 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 8
- 230000008025 crystallization Effects 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- 238000006722 reduction reaction Methods 0.000 description 8
- 235000011121 sodium hydroxide Nutrition 0.000 description 8
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 7
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- 239000002585 base Substances 0.000 description 7
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 7
- 235000015320 potassium carbonate Nutrition 0.000 description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 7
- 239000002253 acid Substances 0.000 description 6
- 239000003513 alkali Substances 0.000 description 6
- 239000012141 concentrate Substances 0.000 description 6
- 238000000354 decomposition reaction Methods 0.000 description 6
- 235000007715 potassium iodide Nutrition 0.000 description 6
- 229960004839 potassium iodide Drugs 0.000 description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- CUYAYRDAKAKHLZ-UHFFFAOYSA-N 3-(2-piperidin-1-ylethyl)pyridine Chemical class C1CCCCN1CCC1=CC=CN=C1 CUYAYRDAKAKHLZ-UHFFFAOYSA-N 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 5
- 230000002378 acidificating effect Effects 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 125000004076 pyridyl group Chemical group 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- FYLODQMFORFXJR-UHFFFAOYSA-N 4-(2-methylpiperidin-1-yl)pyridine Chemical compound CC1CCCCN1C1=CC=NC=C1 FYLODQMFORFXJR-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical group [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 230000002107 myocardial effect Effects 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 208000003663 ventricular fibrillation Diseases 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 230000029936 alkylation Effects 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- OMFXVFTZEKFJBZ-HJTSIMOOSA-N corticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OMFXVFTZEKFJBZ-HJTSIMOOSA-N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
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- 150000003335 secondary amines Chemical class 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
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- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- BOEZQHJKAJAUIA-UHFFFAOYSA-N 1-(2-pyrrolidin-1-ylethyl)piperidine Chemical class C1CCCN1CCN1CCCCC1 BOEZQHJKAJAUIA-UHFFFAOYSA-N 0.000 description 2
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- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
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- ACLHMTUUTCLYMP-UHFFFAOYSA-N 2-(2-methylpiperidin-1-yl)pyridine Chemical compound CC1CCCCN1C1=CC=CC=N1 ACLHMTUUTCLYMP-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
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Abstract
一类新的治疗心律不齐有效的哌啶衍生物,其化学式如下;式中R1为低级烷基或甲苯基;R2为氢、羟基、低级烷氧基或低级烷基;R3为氢、低级烷基、低级链烯基、环烷基或环烷基烷基;X为-CO-、-CH2-或-CHOH-;g为1~3的整数;n为1~3的整数;Y为氢、低级烷基、低级链烯基、氰基、—CH2COOR;R的含义如说明书中所指。
Description
本发明涉及哌啶衍生物及其具有优良医疗效果的药理学允许的盐类,它们的生产方法及含有它们的药剂。
心律不齐是一种心脏疾病如心肌炎和心力衰竭的并发症。严重时,它促成心室颤动而导致突然死亡。
虽然目前市场上有各种各样的抗心律不齐剂,但既有满意效果又高度安全的药剂尚未得到。例如,按照沃-威廉斯(Vaugha-Williams)分类的对上行动作电位最大速率(Vmax)产生选择性抑制的第Ⅰ类抗心律不齐剂,对防止心室纤维性颤动疗效不佳。此外,这类药存在安全问题,它们引起心肌收缩减弱,并由于抑制了搏动而导致心律不齐。分别属于第Ⅱ和第Ⅳ类的β-肾上腺素阻断剂和钙离子拮抗剂虽然比第Ⅰ类抗心律不齐剂的安全性高,但其缺点是它们的作用仅局限于某一类型的心律不齐或作用不明显。
第三类抗心律不齐剂是一种对动作电位持续时间产生选择性延长而不明显降低其最大速率(Vmax)的药物。虽然还没有纯的且强效的第Ⅲ类抗心律不齐剂问世,但这类药物预期可有效地防止心室颤动,而且从定义看,它们不会引起心肌收缩减弱或由于抑制动作电位的产生而诱发心律不齐,上述现象可见于第Ⅰ类抗心律不齐药物。
鉴于上述情况,开发纯的强效的第Ⅲ类抗心律不齐药剂已是人们期待的事。
本发明提供了新的哌啶衍生物及其药理学允许的盐类,哌啶衍生物的制备方法,含有上述哌啶衍生物或其药理学允许的盐类作为活性成分的药剂。
本发明提供了新的哌啶衍生物类似物,该类似物具有一个不同于哌啶环的杂环,以及其药理学可接受的盐。
这些化合物具有下示通式:
其中R1为低级烷基或甲苯基;R2为氢、羟基、低级烷氧基或低级烷基;R3为氢、低级烷基、低级链烯基、环烷基或环烷基烷基;X为-CO-、-CH2-或-CHOH-;g为1~3的整数;h为1~3的整数;Y为氢、低级烷基、低级链烯基、氰基、-CH2COOR;其中R为氢或低级烷基、环烷基、环烷基烷基、
(L为1或2)、-A-B、A为-(CH2)n-、(n为1~5的整数)、具有1至5个碳原子的由直链烷烃衍生的二价基团,该烷烃上的一个或多个碳原子直链连接着低级烷基、苯基或羟基、移去该链两端碳原子上连接的各1个氢原子构成上述亚烷基、
具有1至5个碳原子的由直链烯烃衍生的二价基团,该直链烯烃上相邻两个碳原子间形成双键,移去该链两端碳原子上连接的各1个氢原子构成上述亚烯基、
-(CH2)k-S-(k为2至5的整数)、-(CH2)p-CO-(p为1至4的整数),B为氰基、-NR4R5或以下基团
R4和R5各自为氢或低级烷基,R6为氢、低级烷基、低级烷氧基、氰基、咪唑基、羟基或囟原子,R7和R8各自为氢、囟原子、低级烷基、低级烷氧基或甲磺酰胺基,R9、R10和R11各自为氢或低级烷基。
优先建议的具体化合物是:其中g和h各自为3;g为3,h为1;g为2,h为3;g为1,h为2;以及g为1或2,h为2或3的化合物。
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11以及A中的低级烷基最好是1至6个碳原子的直链或支链烷基,例如甲基、乙基、正-丙基、正-丁基、异丙基、异丁基、1-甲基丙基、叔-丁基、正-戊基、1-乙基丙基、异戊基和正-己基。R2、R6、R7以及R8中的烷氧基最好是从上述定义的烷基衍生的烷氧基。R6、R7以及R8中的囟原子最好是氯、溴、碘或氟。
在定义A时的术语“具有1至5个碳原子的由直链烷烃衍生的二价基团,该烷烃上的一个或多个碳原子直链连接着烷基、苯基或羟基,移去该链两端碳原子上连接的一个氢原子构成上述亚烷基”是指直链烷烃,该烷烃末端碳原子或其它碳原子上连接有低级烷基(如甲基)、苯基或羟基,从两个末端碳原子上各移去一个氢原子衍生的二价基团,这类基团的较佳实例包括下面的基团,它们是:
,
术语“具有1至5个碳原子的由直链烯烃衍生的二价基团,该直链烯烃上相邻两个碳原子间形成双键,移去该链两端碳原子上连接的各1个氢原子构成上述亚烷基团”是指例如下式基团;-CH2-CH=CH-以及-CH2-CH2-CH=CH-。
药理学允许的盐类包括无机酸盐如:盐酸盐、硫酸盐、氢溴酸盐、高氯酸盐、氢碘酸盐以及有机酸盐如,草酸盐、马来酸盐、富马酸盐、琥珀酸盐以及甲磺酸盐。
本发明预期的具有优良的抗心律不齐活性并高度安全的通式(Ⅰ)化合物及其药理学允许的盐类可用作抗心律不齐剂。此外,预期这些化合物将对顽固性心律不齐及其它药物不起作用的心律不齐产生疗效。
制备过程
可用各种不同方法制备本发明通式(Ⅰ)化合物,下面是该方法的典型实施例:
制备过程A
制备过程B
预期的具有上述通式的化合物,其中R3为低级烷基、低级链烯基或环烷基,可按下法制备。
制备过程C
过程D
X为-CH2-的通式(Ⅰ)化合物的制法如下:
过程E
方法A提供了步骤3中的本发明化合物。当Y是下述的一个基团时本发明化合物还可通过下示方法制备:
方法E-1
的化合物按下法制备,此-A-B基称作Y3
上述各步骤按下面详细描述的方法进行。
步骤1
按照弗里德尔-克拉夫茨(Friedel-Crafts)反应将磺基苯胺衍生物(Ⅱ)在路易斯(Lewis)酸诸如三氯化铝、氯化锡和氯化锌存在下在惰性溶剂诸如二硫化碳、二氯甲烷、氯仿和硝基苯中与一个有反应性的酸衍生物诸如具有下式结构的羧酸酐或酰囟反应
其中R′为一低级烷基或苯基,g和h的定义同上,制得相应的苯胺衍生物(Ⅲ)
步骤2
从步骤1中制得的化合物(Ⅲ)的酰基在本步骤中水解。水解是在例如稀的碱性水溶液或稀的无机酸水溶液中进行。在优选的具体例中水解是在回流下在2至6N盐酸或0.5至3N氢氧化钠水溶液中进行。
步骤3
(1)当Y不是氢而是Y′时
步骤2的化合物(Ⅳ)通常与具有下式:
Z-Y′(Ⅴ),例如Z-A-B和
的化合物相缩合,其中Z为一消去基团,可以是囟原子诸如氯、溴或碘、甲烷磺酰氧基及对甲苯磺酰氧基。
本过程的优选具体例中,制备化合物(Ⅶ)的反应是在去酸剂如碳酸钾或碳酸钠和碘化钾(当Z不是碘时)存在下,在溶剂诸如N,N-二甲基甲酰胺、二甲基亚砜、乙腈、丙酮、丁醇、丙醇、乙醇或甲醇中,在温度约为50至120℃的条件下进行。
更具体地是将一个非取代或取代的乙烯基吡啶(Ⅵ)与步骤2的化合物(游离碱)(Ⅳ)或其药理学允许的酸加成盐在低级醇诸如甲醇、乙醇、或丙醇或它们与水的混合液中在室温至约100℃的温度范围内反应,得到预期的化合物(ⅩⅩⅥ)。在本过程中当用游离碱为起始原料时,采用酸催化剂诸如乙酸或盐酸或用碱金属催化剂诸如金属钠,可得较好的结果。
在步骤4至6中,将步骤3中所得的化合物(Ⅶ)还原,制得化合物(Ⅷ)或(Ⅸ)。
步骤4
步骤3中制得的化合物(Ⅶ)在本步骤中还原。还原反应按常规方法进行,例如将化合物(Ⅶ)与硼氢化钠或硼氢化锂在溶剂,诸如甲醇、乙醇、2-丙醇、二甲基甲酰胺或二甲基亚砜中在约-10℃至室温的温度范围内反应可得本发明预期的醇(Ⅷ)
步骤5
将芳香酮化合物(Ⅶ)与2或多克分子数的三烷基硅烷,最好是三乙基硅烷,在过量三氟乙酸中于室温至100℃下反应数天制备化合物(Ⅸ),并可用二氯乙烷、四氯化碳、氯仿、二氯甲烷或乙腈为溶剂。
步骤6
将与步骤4相同的方法制得的醇化合物(Ⅷ)与酸,最好与20%硫酸-乙酸反应片刻得一脱水化合物,该脱水物经催化氢化制得化合物(Ⅸ)
步骤7
具有通式Ⅰ的化合物(Ⅶ)′,其中R3为氢,在本步骤中进行N-烷基化反应。将化合物(Ⅶ)′与通式(Ⅹ)的囟代烷在碱存在下于溶剂诸如,二甲基甲酰胺、二甲基亚砜、低级烷基醇,例如甲醇、乙醇或丙醇或丙酮中,在反应温度约为50至120℃的条件下反应可制得预期的化合物(Ⅺ)。本步骤所用的碱包括如,碳酸钾、碳酸钠、碳酸氢钠、乙醇钠、甲醇钠或氢化钠。
当用2克摩尔或更多的囟代烷(R3·Hal)(Ⅹ)时,只要Y是氢,就可以进行双烷基化、双-低级链烯基的链烯基化以及双环烷基的烷基化反应。与此类似,用方法B步骤8可以进行N-烷基化反应。
用与步骤4至6中所示的相同方法将所得化合物(Ⅺ)还原,进一步得(Ⅷ)′或(Ⅸ)′。
步骤9至11
用与步骤5(还原)、步骤2(水解)和步骤7和8(烷基化)所示的相同的方法进行9至11中的每一步骤。
步骤12
用曼尼希(Mannich)反应将仲胺(ⅩⅦ)转换成叔胺(ⅩⅪ)。将含活泼氢的化合物诸如呋喃化合物,吡咯化合物与带甲基的含氮杂环用胺和甲醛或多聚甲醛,最好在溶剂如水和醇中在用乙酸或盐酸的酸性条件及室温至100℃的温度下进行缩合。
步骤13
用曼尼希(Mannich)反应将仲胺烷基化。此反应可按与步骤12相同的方法进行。也可用仲胺的盐酸盐而不是其游离碱来制备化合物(ⅩⅩⅤ)。
上述制得的哌啶衍生物可以用常规方法转换成它们的药理学可接受的盐类。
为利于对本发明的理解,下面列举本发明化合物的典型例子,但决不意味着对本发明的限制。下面是这些化合物的游离碱。
1.4-(4-甲磺酰胺基苯甲酰基)-1-〔2-(3-吡啶基)乙基〕哌啶,
2.4-(4-甲磺酰胺基苯甲酰基)-1-(4-吡啶基)-甲基哌啶,
3.4-(4-甲磺酰胺基苯甲酰基)-1-〔3-(4-吡啶基)丙基〕哌啶,
4.1-(6-甲基-3-吡啶)甲基-4-(4-甲磺酰胺基苯甲酰基)哌啶,
5.4-(4-甲磺酰胺基苯甲酰基)-1-〔2-(4-吡啶基)乙基〕哌啶,
6.1-〔2-(3,4-二甲氧基苯基)乙基〕-4-(4-甲磺酰胺基苯甲酰基)哌啶,
7.4-(4-甲磺酰胺基苯甲酰基)-1-〔4-(3-吡啶基)丁基〕哌啶,
8.4-(4-甲磺酰胺基苯甲酰基)-1-〔2-(4-吡啶硫基)乙基〕哌啶,
9.4-(4-甲磺酰胺基苯甲酰基)哌啶,
10.4-(4-甲磺酰胺基苯甲酰基)-1-〔3-(3-吡啶基)丙基〕哌啶,
11.4-(4-甲磺酰胺基苯甲酰基)-1-〔5-(3-吡啶基)戊基〕哌啶,
12.1-(6-氯-3-吡啶基)甲基-4-(4-甲磺酰胺基苯甲酰基)哌啶,
13.4-(4-甲磺酰胺基苯甲酰基)-1-〔2-(2-吡啶基)乙基〕哌啶,
14.4-(4-甲磺酰胺基苯甲酰基)-1-(2-苯基乙基)-哌啶,
15.4-(2-羟基-4-甲磺酰胺基苯甲酰基)-1-(4-吡啶基)甲基哌啶,
16.4-〔2-羟基-4-甲磺酰胺基苯甲酰基)-1-(2-苯乙基)哌啶,
17.4-(4-甲磺酰胺基苯甲酰基)-1-(3-吡啶基)甲基哌啶,
18.4-(4-甲磺酰胺基苯甲酰基)-1-(2-吡啶基)甲基哌啶,
19.4-(4-甲磺酰胺基苯甲酰基)-1-菸酰基-甲基哌啶,
20.4-(4-甲磺酰胺基苯甲酰基)-1-〔2-(2-噻吩基)乙基〕哌啶,
21.4-(4-甲磺酰胺基苯甲酰基)-羟甲基-1-〔2-(2-吡啶基)乙基〕哌啶,
22.4-(2-甲氧基-4-甲磺酰胺基苯甲酰基)-1-(4-吡啶基)甲基哌啶,
23.1-〔2-(4-氯苯基)乙基〕-4-(4-甲磺酰胺基苯甲酰基)哌啶,
24.1-〔2-(4-甲氧基苯基)乙基〕-4-(4-甲磺酰胺基苯甲酰基)哌啶,
25.4-(4-甲磺酰胺基苯甲酰基)-1-〔3-(3-吡啶基)-2-丙烯基〕哌啶,
26.4-(4-乙磺酰胺基苯甲酰基)-1-(4-吡啶基)-甲基哌啶,
27.4-(4-乙磺酰胺基苯甲酰基)-1-(2-苯乙基)哌啶,
28.1-苄基-4-(4-甲磺酰胺基苯甲酰基)哌啶,
29.1-〔2-(4-氟苯基)乙基〕-4-(4-甲磺酰胺基苯甲酰基)哌啶,
30.4-(4-甲磺酰胺基苯甲酰基)-1-(3-苯丙基)哌啶,
31.4-(4-甲磺酰胺基苯甲酰基)-1-(2-噻吩基甲基)甲基哌啶,
32.1-〔2-(4-羟苯基)乙基〕-4-(4-甲磺酰胺基苯甲酰基)哌啶,
33.1,4-双(4-甲磺酰胺基苯甲酰基)哌啶,
34.1-〔6,7-二氢-5H-7-环戊烷并〔b〕吡啶基〕-甲基-4-(4-甲磺酰胺基苯甲酰基)-哌啶,
35.N-甲基-4-(4-甲磺酰胺基苯甲酰基)-1-〔2-(3-吡啶基)乙基〕哌啶,
36.N-丁基-4-(4-甲磺酰胺基苯甲酰基)-1-〔2-(3-吡啶基)乙基〕哌啶,
37.4-(4-甲磺酰胺基苯甲酰基)-1-〔1-(4-吡啶基)乙基〕哌啶,
38.4-(4-甲磺酰胺基苯甲酰基)-1-〔1-苯基-1-(4-吡啶基)甲基〕哌啶,
39.1-〔2-(4-甲苯基)乙基〕-4-(4-甲磺酰胺基苯甲酰基)哌啶,
40.4-(4-甲磺酰胺基苯甲酰基)-1-(1-萘基)-甲基哌啶,
41.1-〔2-羟基-2-(4-甲磺酰胺基苯甲酰基)-乙基〕-4-(4-甲磺酰胺基苯甲酰基)-哌啶,
42.1-〔2-羟基-2-(3-吡啶基)乙基〕-4-(4-甲磺酰胺基苯甲酰基)哌啶,
43.1-(2-羟基-2-苯乙基)-4-(4-甲磺酰胺基苯甲酰基)哌啶,
44.1-(2-氯苯基)甲基-4-(4-甲磺酰胺基苯甲酰基)哌啶,
45.1-〔2-(5-乙基-2-吡啶基)乙基〕-4-(4-甲磺酰胺基苯甲酰基)哌啶,
46.1-〔2-(6-甲基-2-吡啶基)乙基〕-4-(4-甲磺酰胺基苯甲酰基)哌啶,
47.1-〔2-(6-甲基-3-吡啶基)乙基〕-4-(4-甲磺酰胺基苯甲酰基)哌啶,
48.1-〔3-(6-甲基-3-吡啶基)丙基〕-4-(4-甲磺酰胺基苯甲酰基)哌啶,
49.1-〔1-(3-甲氧基-2-吡啶基)甲基〕-4-(4-甲磺酰胺基苯甲酰基)哌啶,
50.1-〔2-(5-甲基-4-吡啶硫基)乙基〕-4-(4-甲磺酰胺基苯甲酰基)哌啶,
51.1-〔1-(2-甲氧基-5-吡啶基)甲基〕-4-(4-甲磺酰胺基苯甲酰基)哌啶,
52.1-〔1-(3-羟基-2-吡啶基)甲基〕-4-(4-甲磺酰胺基苯甲酰基)哌啶,
53.1-〔2-(6-乙基-2-吡啶基)乙基〕-4-(4-甲磺酰胺基苯甲酰基)哌啶,
54.1-〔3-(5-乙基-2-吡啶基)丙基〕-4-(4-甲磺酰胺基苯甲酰基)哌啶,
55.1-〔4-(5-乙基-2-吡啶基)丁基〕-4-(4-甲磺酰胺基苯甲酰基)哌啶,
56.1-〔2-(5-丁基-2-吡啶基)乙基〕-4-(4-甲磺酰胺基苯甲酰基)哌啶,
57.1-〔2-(2-甲基-4-吡啶基)乙基〕-4-(4-甲磺酰胺基苯甲酰基)哌啶,
58.1-〔2-(2-乙基-4-吡啶基)乙基〕-4-(4-甲磺酰胺基苯甲酰基)哌啶,
59.1-〔2-(2-氯-5-吡啶基)乙基〕-4-(4-甲磺酰胺基苯甲酰基)哌啶,
60.1-〔3-(2-氯-5-吡啶基)丙基〕-4-(4-甲磺酰胺基苯甲酰基)哌啶,以及
61.4-(4-甲磺酰胺基苯甲酰基)-1-〔2-(4-甲基-5-噻唑基)乙基〕哌啶,
62.1-〔4-(1-咪唑基)苯甲酰基甲基〕-4-(4-甲磺酰胺基苯甲酰基)哌啶,
63.1-〔2-(3-(2-氰基)吡啶基〕乙基〕-4-(4-甲磺酰胺基苯甲酰基)哌啶,
64.1-〔3-〔3-(2-氰基)吡啶基〕丙基〕-4-(4-甲磺酰胺基苯甲酰基)哌啶,
65.1-〔3-〔4-(2-氰基)吡啶基〕丙基〕-4-(4-甲磺酰胺基苯甲酰基)哌啶,
66.1-〔2-(1-咪唑基)-3-吡啶甲基〕-4-(4-甲磺酰胺基苯甲酰基)哌啶,
67.1-(5-甲基-2-呋喃基)甲基-4-(4-甲磺酰胺基苯甲酰基)哌啶,
68.1-(1-甲基-2-吡咯基)甲基-4-(4-甲磺酰胺基苯甲酰基)哌啶,
69.1-(1-咪唑基-3-丙基)-4-(4-甲磺酰胺基苯甲酰基)哌啶,
70.4-(4-甲磺酰胺基)-1-〔2-(3-哒嗪基)-乙基〕哌啶,
71.4-(4-甲磺酰胺基苯甲酰基)-1-〔2-(4-嘧啶基)-2-丙烯基〕哌啶,
72.4-(4-甲磺酰胺基苯甲酰基)-1-(2-吡嗪基甲基)哌啶,
73.4-(4-甲磺酰胺基苯甲酰基)-1-〔2-(2-吡嗪基)乙基〕哌啶,
74.1-〔2-(1,2-二氢-6-甲基-2-氧-3-吡啶腈-5-基)-2-氧乙基〕-4-(4-甲磺酰胺基苯甲酰基)哌啶,
75.4-(4-甲磺酰胺基苯甲酰基)-1-(6-尿嘧啶甲基)哌啶,
76.1-〔2-(3-吲哚基)乙基〕-4-(4-甲磺酰胺基苯甲酰基)哌啶,
77.4-(4-甲磺酰胺基苯甲酰基)-1-(2-邻苯二甲酰亚氨乙基)哌啶,
78.4-(4-甲磺酰胺基苯甲酰基)-1-(2-喹啉基甲基)哌啶,
79.4-(4-甲磺酰胺基苯甲酰基)-1-(3-喹啉基甲基)哌啶,
80.1-(1-咪唑并〔1,2-a〕吡啶甲基)-4-(4-甲磺酰胺基苯甲酰基)哌啶,
81.1-〔2-(1-咪唑并〔1,2-a〕吡啶基)乙基〕-4-(4-甲磺酰胺基苯甲酰基)哌啶,
82.1-(6-咪唑并〔1,2-a〕吡啶基甲基)-4-(4-甲磺酰胺基苯甲酰基)哌啶,
83.1-〔2-(3-咪唑并〔1,2-a〕吡啶基)-2-氧乙基〕-4-(4-甲磺酰胺基苯甲酰基)哌啶,
84.1-(2-苯并咪唑基甲基)-4-(4-甲磺酰胺基苯甲酰基)哌啶,
85.4-(4-甲磺酰胺基苯甲酰基)-1-〔2-(2-喹喔啉基)乙基〕哌啶,
86.4-(4-甲磺酰胺基苯甲酰基)-1-〔2-(7-茶碱基)-乙基〕哌啶,
87.1-(9-基)-4-(4-甲磺酰胺基苯甲酰基)哌啶,
88.1-乙基-4-(4-甲磺酰胺基苯甲酰基)哌啶,
89.1-正-丁基-4-(4-甲磺酰胺基苯甲酰基)哌啶,
90.1-环己基甲基-4-(4-甲磺酰胺基苯甲酰基)哌啶,
91.1-(2-甲基-2-丙烯基)-4-(4-甲磺酰胺基苯甲酰基)哌啶,
92.1-(乙氧羰基甲基)-4-(4-甲磺酰胺基苯甲酰基)哌啶,
93.1-氰基-4-(4-甲磺酰胺基苯甲酰基)哌啶,
94.1-氰甲基-4-(4-甲磺酰胺基苯甲酰基)哌啶,
95.1-(3-氰丙基)-4-(4-甲磺酰胺基苯甲酰基)哌啶,
96.1-〔2-(N,N′-二乙氨基)乙基〕-4-(4-甲磺酰胺基苯甲酰基)哌啶,
97.4-(4-甲磺酰胺基苯甲酰基)-1-〔2-(1-吡咯烷基)乙基〕哌啶,
98.4-(4-甲磺酰胺基苯甲酰基)-1-〔2-(1-哌啶基)乙基〕哌啶,
99.4-(4-甲磺酰胺基苯甲酰基)-1-〔2-(4-吗啉基)乙基〕哌啶,
100.4-(4-甲磺酰胺基苯甲酰基)-1-〔3-(1-哌啶基)丙基〕哌啶,
101.1-〔3-(4-吡啶基)丙基〕-4-〔4-(对-甲苯磺酰胺基)苯甲酰基〕哌啶,
102 1-〔2-(6-甲基-2-吡啶基)乙基〕-4-〔4-对-甲苯磺酰胺基)苯甲酰基〕哌啶,
103.4-(4-甲磺酰胺基苄基)-1-〔2-(3-吡啶基)乙基〕哌啶,
104.1-〔2-(3,4-二甲氧基苯基)乙基〕-4-(4-甲磺酰胺基苄基)哌啶,
105.3-(4-甲基磺酰胺基苯甲酰基)-1-〔2-(3-吡啶基)乙基〕哌啶,
106.1-〔2-(6-甲基-2-吡啶基)乙基〕-3-(4-甲磺酰胺基苯甲酰基)哌啶,
107.3-(4-甲磺酰胺基苯甲酰基)-1-〔2-(3-吡啶基)乙基〕吡咯烷,
108.1-〔2-(6-甲基-2-吡啶)乙基〕-3-(4-甲磺酰胺基苯甲酰基)吡咯烷,
109.1-〔2-(3,4-二甲氧基苯基)乙基〕-3-(4-甲磺酰胺基苯甲酰基)哌啶,
110.1-乙基-4-(N-乙基-4-甲磺酰胺基苯甲酰基)哌啶,
111.1-正丁基-4-(N-正丁基-4-甲磺酰胺基苯甲酰基)哌啶,
112.1-环己基甲基-4-(N-环己基甲基-4-甲磺酰胺基苯甲酰基)哌啶,
113.1-(2-甲基-2-丙烯基)-4-〔N-(2-甲基-2-丙烯基)-4-甲磺酰胺基苯甲酰基〕哌啶,
114 4-(4-甲磺酰胺基苯甲酰基)-1-(2-(4-甲磺酰胺基苯基)-2-氧代乙基)哌啶。
通过延长动作电位持续期实验证明,本发明的哌啶衍生物可延长不应期,防止心律不齐而对心肌传导速率不产生任何影响。这些哌啶衍生物是按上述沃-威廉斯氏(Vaughan-Williams)分类的第Ⅲ类抗心律不齐剂。
以下实验实例将进一步阐明本发明的化合物的效果。
试验实施例1
对离体的豚鼠心肌的动作电位持续期的效应
从哈脱莱(Hartley)劳损的雄性豚鼠剥离出300~400g右心室乳头肌并用针固定于丙烯酸溶底部。乳头肌用95% O2和5% CO2组成的混合气体饱和的蒂罗特(Tyrode)氏溶液喷洒,保持37℃。此乳头肌以1Hz每1毫秒周期的矩形脉冲和超高压刺激。用注用3M KCl的常规玻璃显微电极记录动作电位。测定动作电位持续期和动作电位的上行最大速率(Vmax)。每种受试化合物以10-6M或10-5M包含在蒂罗特氏溶液中并将其喷洒。前10分钟观察10-6M溶液的效应,另10分钟观察10-5M溶液的效应。
结果示于表1中。实验1中所用的受试化合物如下。心得怡,一种β-肾上腺受体拮抗剂用作对照药,此化合物已知可延长心肌动作电位持续期。
试验化合物
化合物A:1-苄基-4-(4-甲磺酰胺基苯甲酰基)哌啶盐酸盐
化合物B:4-(4-甲磺酰胺基苯甲酰基)-1-(2-苯乙基)哌啶盐酸盐
化合物C:1-〔2-(4-氯苯基)乙基〕4-(4-甲磺酰胺基苯甲酰基)哌啶盐酸盐
化合物D:1,4-二(4-甲磺酰胺基苯甲酰基)哌啶盐酸盐
化合物E:1-〔2-(3,4-二甲氧苯基)乙基〕-4-(4-甲磺酰胺基苯甲酰基)哌啶盐酸盐
化合物F:4-(4-甲磺酰胺基苯甲酰基)-1-〔2-(2-噻吩基)乙基〕哌啶甲磺酸盐
化合物G:4-(4-甲磺酰胺基苯甲酰基)-1-(4-吡啶基)甲基哌啶二盐酸盐
化合物H:4-(4-甲磺酰胺基苯甲酰基)-1-〔2-(2-吡啶基)乙基〕哌啶二盐酸盐
化合物I:4-(4-甲磺酰胺基苯甲酰基)-1-〔2-(3-吡啶基)乙基〕哌啶二盐酸
化合物J:4-(4-甲磺酰胺基苯甲酰基)-1-〔2-(4-吡啶基)乙基〕哌啶二盐酸盐,和
化合物K:4-(4-甲磺酰胺基苯甲酰基)-1-烟酰哌啶。
化合物L:4-(4-甲磺酰胺基苯甲酰基)-1-(2-喹啉基甲基)哌啶二
(28) 盐酸盐
化合物M:4-(4-甲磺酰胺基苯甲酰基)-1-(3-喹啉基甲基)哌啶二
(29) 盐酸盐
化合物N:1-〔2-(3-咪唑并〔1,2-a〕吡啶基)-2-氧代乙基〕-4-
(7) (4-甲磺酰胺基苯甲酰基)哌啶二盐酸盐
化合物O:1-(1-咪唑并〔1,2-a〕吡啶基甲基)-4-(4-甲磺酰胺基
(30) 苯甲酰基)哌啶二盐酸盐
化合物P:1-乙基-4-(4-甲磺酰胺基苯甲酰基)哌啶酸盐
(12)
化合物Q:1-(6-咪唑并〔1,2-a〕吡啶基甲基)-4-(4-甲磺酰胺基
(31) 苯甲酰基)哌啶二盐酸盐
化合物R:4-(4甲磺酰胺基苯甲酰基)-1-(3-(4-吡啶基)丙基)哌啶
二盐酸盐
化合物S:1-(2-(6-甲基-2-吡啶基)乙基)-4-(4-甲磺酰胺基苯甲
酰基)哌啶二盐酸盐
实验实施例2
对麻醉后狗ECG的QTC-间期的效应
杂种狗用氨氟醚麻醉。于第五肋间打开胸腔并切开心包露出左心室。固定于丙烯酸板上的单极电极接于冠状动脉左前下行支集聚的心室表面。通过电极从左心室表面记录心电图。受试化合物通过插入前臂静脉的导管注入。
化合物B在剂量为0.1mg/Kg时引起QTc-间期延长51%(即435~665毫秒)。化合物G在0.1,0.3和1mg/Kg剂量时,分别引起QTc-间期延长17%,27%和35%,当注入0.1和0.3mg/Kg受试化合物J时,分别延长21%和42%。
当受试化合物为L时,0.1mg/Kg的QTc-延长为31%,0.3mg/Kg的QTc延长为56%。当受试化合物为M时,0.1mg/Kg的QTc延长为7%,0.3mg/Kg时为14%。化合物R的给药剂量为0.03mg/Kg和0.1mg/Kg时,QTc-间期延长分别为13%和21%。化合物S的给药剂量为0.01mg/Kg和0.03mg/Kg时的QTc-间期分别延长30%和42%。以1.0mg/Kg心得怡作对照,延长率为12%。
试验实例3
对小鼠的急性毒性
用20~30g雄性ddy小鼠作急性毒性试验。用上下法(up-and-down)计算LD50值。将化合物G,J,M,N,O,R和心得怡溶于盐水中得到16mg/ml贮备液。10g体重的动物用0.1ml溶液,给药剂量相当于160mg/Kg样品。化合物B,F,L和S(游离体)分别溶于20%聚乙二醇中得到浓度为8mg/ml的贮备液。给药剂量由贮备液体积决定。溶液用1-ml结核菌素注射器注入尾静脉。注射后30分钟判断存活和死亡。结果示
于表2。
从上面试验实例1和2可以看出,本发明的化合物有第Ⅲ类抗心律不齐剂所要求的药理性质,即在试管内延长心肌动作电位而不明显降低动作电位的上行最大速率(Vmax),并且延长麻醉狗QTc间期。此外,它们的效应比对照药-心得怡强得多。
预期本发明化合物可有效地用于治疗和预防所有类型的心律不齐包括心室和心房(上心室)心律不齐。特别是可予期本发明化合物可控制再复性心律不齐和预防由于心室纤维性颤动造成的突然死亡。
本发明化合物可以口服或肠胃外给药(肌肉注射、皮下注射或静脉注射)。使用剂量无特殊限定,取决于心律不齐类型,症状,年岁,患者状况和体重而予以调整。当与其它药剂或治疗方法配合时,还取决于所用药剂或治疗方法的种类、使用的频繁程度和预期效果。估计成人常用口服剂量是1~100毫克/日,5~50毫克/日较好,最好是5~15毫克/日。每日给药一次或多次。注射时,估计剂量是0.01~1mg/Kg,最好是0.03~0.1mg/Kg。
本发明的化合物可以制成例如粉末、细小颗粒、颗粒、片剂、胶囊、栓剂和注射液。这些制剂以常规方法用普通载体生产。
更具体地说,例如通过加赋形剂生产口服固体制剂,必要时加粘合剂、分解剂、润滑剂、着色剂,矫味剂等到活性成分中,混合物加工成片剂,糖衣片剂,粒剂,粉剂,胶囊剂等。
赋形剂的例子包括乳糖,谷物淀粉,白糖,葡萄糖,山梨糖醇,结晶纤维素和二氧化硅。粘合剂的例子包括聚乙烯醇,聚乙烯醚,乙基纤维素,甲基纤维素,阿拉伯胶,西黄蓍胶,明胶,虫胶,羟丙基纤维素,羟丙基淀粉和聚乙烯吡啶烷酮。分散剂的例子包括淀粉,琼脂,明胶粉,结晶纤维素,碳酸钙,碳酸氢钠,柠檬酸钙,糊精和果胶。润滑剂的例子包括硬脂酸镁,滑石粉,聚乙二醇,二氧化硅和凝固的植物油。着色剂是指可接受的药物添加剂。矫味剂的例子包括可可粉,薄荷醇,芳香酸,欧薄荷油,冰片和桂皮粉。当然,这些片剂和粒剂可以用糖,明胶等包糖衣。
在生产注射液时,如果需要可以在活性成分中加入pH调节剂,缓冲剂,稳定剂,加溶剂等,静脉注射液以常规方法生产。
以下实施例进一步说明本发明,但并不限制本发明。
生产本发明的化合物的最后步骤将由以下实施例说明,在这些实施例中所用原料的生产在以下参考实施例中说明。
<步骤Ⅰ>
参考实施例1
(±)-N-苯甲酰基3-哌啶甲酸的制备
将20.0g(155m mol)(±)-3-哌啶甲酸溶解于33ml20%氢氧化钠水溶液中。滴加23.84g苯甲酰氯,其滴加速度以反应温度不超过20℃为宜。滴加60ml 20%氢氧化钠水溶液,所得混合物于0℃下搅拌1小时,然后,用二氯甲烷提取。用水和饱和氯化钠水溶液洗涤有机层,硫酸镁干燥并浓缩。固体残余物用乙醇重结晶得到18.0g(产率:40%)预期化合物,为白色结晶。
熔点:187~188℃
NMR(90℃,DMSO-d6)δ1.3~2.2(4H,m)
2.2~4.4(5H,m)7.42(5H,s)12.0~12.6(1H,br)
重复上述过程,用(±)-β-脯氨酸代替(±)-3-哌啶甲酸,得到下面的化合物:
(±)-N-苯甲酰基-β-脯氨酸
熔点:111-113℃
NMR(90MHz,CDCl3)δ2.18(2H,类四重峰,J=7Hz)2.8-3.3(1H,m)3.35-4.00(4H,m)7.36(5H,m)
(步骤Ⅱ)
参考实施例2
(±)-N-苯甲酰基-3-哌啶甲酰氯的制备
将10.0g(42.9m mol)(±)-N-苯甲酰基-3-哌啶甲酸溶解于15ml亚硫酰氯中。溶液中加入数滴二甲基甲酰胺,室温下搅拌2小时。减压蒸出过量的亚硫酰氯,几乎定量地得到所要的化合物,为无色油状物。
重复以上同样过程,用(±)-N-苯甲酰基-β-脯氨酸代替(±)-N-苯甲酰基-3-哌啶甲酸,得到下面的化合物:
(±)-N-苯甲酰基-β-脯氨酰氯
参考实例2所得到的此酸的酰氯不必提纯即可用于下面反应(参考实例3)。
(步骤Ⅲ)
参考实施例3
1-乙酰基-4-(4-甲磺酰胺基苯甲酰基)哌啶
将14.40g(0.108mol)氯化铝悬浮于25ml二氧甲烷中。在搅拌下加5.50g(0.029mol)1-乙酰基异哌啶甲酰氯和5.00g(0.029ml)甲磺酰苯胺于此悬浮液中,所得混合物回流2小时。冷却后,将此液体反应混合物倾于100ml冰/水中并激烈搅拌此混合物。过滤回收如此形成的结晶并干燥,得到7.22g所要化合物。
熔点:210-211.5℃
NMR(90MHz,DMSO-d6)δ1.20-2.00(4H,m),2.00(3H,s),2.60-4.00(4H,m),3.10(3H,s),4.36(1H,宽峰),7.28(2H,d,J=8Hz),10.34(1H,s,D2O交换)。
重复以上同样过程,用对-甲苯磺酰苯胺代替甲磺酰苯胺或用参考实例2制得的(±)-N-苯甲酰基-3-哌啶甲酰氯或(±)-N-苯甲酰基-β-脯氨酰氯代替1-乙酰基异哌啶甲酰氯,得到下面的化合物:
1-乙酰基-4-(4-乙磺酰胺基苯甲酰基)哌啶
NMR(90MHz,CDCl3)δ:1.35(3H,t,J=7Hz),1.5~2.10(4H,m),2.11(3H,s),2.65~3.70(3H,m),3.16(2H,q,J=7Hz),3.88(1H,brd,J=12Hz),4.51(1H,br,J=12Hz),7.28(2H,d,J=8Hz),7.83(2H,d,J=8Hz),8.60(1H,brs,D2O 交换)
1-乙酰基-4-(2-羟基-4-甲磺酰胺基苯甲酰基)哌啶
NMR(90MHz,CDCl3)δ:1.2~2.0(4H,m),1.99(3H,s),3.10(3H,s),4.16(1H,brd,J=13Hz),6.62~6.80(2H,m),7.90(1H,d,J=8Hz),10.34(1H,s,D2O 交换),13.22(1H,s,D2O 交换)
1-乙酰基-4-(2-甲氧基-4-甲磺酰胺基苯甲酰基)哌啶
NMR(90MHz,DMSO-d6)δ:1.2~2.0(4H,m),2.00(3H,s),3.12(3H,s),3.88(3H,s),6.86(1H,dd,J=8.2Hz),6.96(1H,d,J=2Hz),7.57(1H,d,J=8Hz),10.34(1H,s,D2O 交换)
1-乙酰基-4-(4-对-甲苯磺酰胺基苯甲酰基)哌啶
NMR(90MHz,CDCl3)δ 1.4-2.0(4H,m),2.14(3H,s)2.37(3H,s)2.5-3.6(3H,m)3.92(1H,brd,J=14Hz)4.57(1H,brd,J=14Hz)7.23(4H,d,J=8Hz)7.75(2H,d,J=8Hz)7.83(2H,d,J=8Hz)8.80(1H,br)
(±)-1-苯甲酰基-3-(4-甲磺酰胺基苯甲酰基)哌啶
NMR(90MHz,DMSO-d6)δ 1.5-2.2(4H,m)3.00(3H,s)7.24(2H,m)7.42(5H,s)7.88(2H,m)等。
(±)-1-苯甲酰基-3-(4-甲磺酰胺基苯甲酰基)吡咯烷
NMR(90MHz,CDCl3)δ 1.9-3.0(3H,m)3.01(3H,s)3.4-4.2(4H,m)7.34(7H,m)7.84(2H,m)
参考实施例4
1-乙酰基-N-甲基-4-(4-甲磺酰胺基苯甲酰基)哌啶
在氮气下将3.24g(10.0m mol)1-乙酰基-4-(4-甲磺酰胺基苯甲酰基)哌啶加到0.29g(12.0m mol)氢化钠与30ml二甲基甲酰胺的悬浮液中并于60℃下搅拌20分钟。加1.7g(12.0m mol)碘甲烷于液体混合物中并于60℃下搅拌此混合物1小时。然后,加100ml氯仿,用水和饱和氯化钠水溶液洗涤此混合物。浓缩氯仿层,残余的油状物经色谱柱(氯仿∶甲醇=99∶1)提纯得到2g所要化合物。
熔点:162-163℃
o NMR(90MHz,CDCl3)δ:1.5~2.1(4H,m)2.11(3H,s),2.95(3H,s),3.37(3H,s),3.92(1H,br,J=13Hz),4.56(1H,d,J=13Hz),7.50(2H,d,J=8Hz),7.96(2H,d,J=8Hz)
(步骤Ⅳ)参考实施例5
1-乙酰基-4-(4-甲磺酰胺基苄基)哌啶的制备
7.50g(23.1m mol)参考实例3所得的1-乙酰基-4-(4-甲磺酰胺基苯甲酰基)哌啶溶解于110ml二氯乙烷中。将11.0ml三乙基甲硅烷和17.8ml三氟乙酸加到此溶液中并回流此混合物50小时。冷却后,加入20%氢氧化钠水溶液使中和。以二氯甲烷提取后,用水和饱和氯化钠水溶液洗涤有机层,硫酸镁干燥并浓缩。以硅酸柱色谱法(氯仿∶甲醇=98∶2)提纯所得油状残余物,得到3.30g(产率:46%)白色结晶状所要产物。
熔点:145-146℃
NMR(90MHz,CDCl3)δ1.4-2.0(3H,m),2.08(3H,s),2.2-3.1(4H,m),3.00(3H,s),3.78(1H,宽峰,J=13Hz),4.56(1H,宽峰,J=13Hz),7.12(4H,m)。
元素分析(C15H22N2O3S):
C M N
理论值(%) 58.04 7.14 9.02
实验值(%) 57.64 6.93 9.00
(步骤Ⅴ,第1部分)
实施例1
盐酸
4-(4-甲磺酰胺基苯甲酰基)哌啶盐酸盐
将43.4g(0.142mol)1-乙酰基-4-(4-甲磺酰胺基苯甲酰基)哌啶悬浮于1升3N盐酸中,在回流下搅拌此悬浮液3小时。反应完成后,冷却液体反应混合物,过滤所得白色结晶,用水洗涤,干燥,得到37.8g(产率:84%)所要化合物。
熔点:>265℃(分解)
NMR(90MHz,DMSO-d6)δ1.6-2.1(4H,m),3.12(3H,s),7.33(2H,D,J=8Hz,8.01(2H,d,j=8Hz),8.8-9.5(2H,宽,DO交换),10.46(1H,s,D2O交换)。
元素分析(C13H18N2O3S·HCl):
C H N
理论值(%) 48.98 6.01 8.79
实验值(%) 48.64 5.77 8.65
重复上面同样的过程,用上面参考实例中同样的原料,得到以下化合物:
实施例2
4-(4-乙磺酰胺基苯甲酰基)哌啶盐酸盐
熔点:>220℃(分解)
o NMR(90MHz,DMSO-d6)δ:1.22(3H,t,7Hz),1.62~2.1(4H,m),2.8~3.9(4H,m),3.21(3H,q,J=7Hz),7.34(2H,d,J=8Hz),8.01(2H,d,J=8Hz),8.8~9.5(2H,br),10.38(1H,s,D2O 交换)
元素分析 C14H20N2O3S·HCl:
C H N
理论值(%) 50.52 6.06 8.42
实验值(%) 50.31 6.30 8.29
实施例3
4-(2-羟基-4-甲磺酰胺基苯甲酰基)哌啶盐酸盐
熔点:>250℃
o NMR(90MHz,DMSO-d6)δ:1.6~2.1(4H,m),3.10(3H,s),6.65~6.87(2H,m),7.89(1H,d,J=8Hz),8.6~9.4(2H,br,D2O 交换),10.40(1H,s,D2O 交换),12.05(1H,s,D2O)
元素分析 C13H18N2O4S·HCl:
C H N
理论值(%) 46.64 5.72 8.37
实验值(%) 46.71 5.97 8.30
实施例4
4-(2-甲氧基-4-甲磺酰胺基苯甲酰基)哌啶盐酸盐
熔点:>220℃(分解)
o NMR(90MHz,DMSO-d6)δ:1.5~2.1(4H,m),3.12(3H,s),3.88(3H,s),6.86(1H,dd,J=8,2Hz),6.96(1H,d,J=2Hz),7.58(1H,d,J=8Hz),9.0(2H,br,D2O 交换),10.32(1H,s,D2O 交换)
元素分析(C14H2N2O5S·HCl):
C H N
理论值(%) 48.20 5.78 8.03
实验值(%) 48.32 5.93 7.81
重复上面同样的过程,用1-乙酰基-4-(4-对-甲苯磺酰胺基苯甲酰基)哌啶或1-乙酰基-4-(4-甲磺酰胺基苄基)哌啶代替1-乙酰基-4-(4-甲磺酰胺基苯甲酰基)哌啶,得到以下化合物:
实施例5
4-(4-对-甲苯磺酰胺基苯甲酰基)哌啶盐酸盐
熔点:240-242℃
· NMR(90MHz,DMSO-d6)δ 1.6-2.1(4H,m)2.5-3.8(5H,m)2.36(3H,s)7.24(2H,d,J=8Hz)7.36(2H,d,J=8Hz)7.76(2H,d,J=8Hz)7.90(2H,d,J=8Hz)9.0(2H,br)10.97(1H,s)
元素分析(C19H22N2O3S·HCl·H2O):
C H N
理论值(%) 55.27 5.61 6.78
实验值(%) 55.25 5.68 6.85
实施例6
4-(4-甲磺酰胺基苄基)哌啶盐酸盐
熔点:255-257℃
NMR(90MHz,DMSO-d6)δ1.2-2.0(5H,m),2.94(3H,s),7.14(4H,s),9.0(2H,宽),9.67(1H,s)。
元素分析(C13H20N2O2S·HCl):
C H N
理论值(%) 51.22 6.94 9.19
实验值(%) 51.26 6.86 9.16
(步骤Ⅴ,第2部分)
实施例7
(±)-3-(4-甲磺酰胺基苯甲酰基)哌啶盐酸盐
将参考实例3所得5.70g(14.8m mol)(±)-1-苯甲酰基-3-(4-甲磺酰胺基苯甲酰基)哌啶溶解于120ml 5N盐酸和80ml甲醇的混合物中,回流所得溶液8小时。浓缩反应液,所得固体残余物从乙醇中重结晶,得到2.61g(产率:55%)所要化合物,为白色结晶。
熔点:235-237℃
NMR(90MHz,DMSO-d6)δ1.4-2.2(4H,m),2.6-4.1(5H,m),3.11(3H,s),7.35(2H,d,J=8Hz),7.98(2H,d,J=8Hz),8.0-8.5(2H,宽),10.48(1H,宽)。
元素分析(C13H18N2O3S·HCl):
C H N
理论值(%) 48.98 6.01 8.79
实验值(%) 48.86 5.87 8.77
实施例8
重复实例7的过程,用(±)-1-苯甲酰基-3-(4-甲磺酰胺基苯甲酰基)吡咯烷代替(±)-1-苯甲酰基-3-(4-甲磺酰胺基苯甲酰基)哌啶,得到以下化合物:
(±)-3-(4-甲磺酰胺基苯甲酰基)吡咯烷盐酸盐
熔点:198-200℃
NMR(90MHz,DMSO-d6)δ1.7-2.5(2H,m),3.0-3.8(4H,m),3.14(3H,s),4.20(1H,类四重峰,J=7Hz),7.36(2H,d,J=8Hz),8.01(2H,d,J=8Hz),9.5(2H,宽),10.26(1H,s)。
元素分析(C12H16N2O3S·HCl):
C H N
理论值(%) 47.29 5.62 9.19
实验值(%) 47.17 5.49 9.11
实施例9
N-甲基-4-(4-甲磺酰胺基苯甲酰基)哌啶盐酸盐
从参考实例4制得的1.90g 1-乙酰基-N-甲基-4-(4-甲磺酰胺基苯甲酰基)哌啶得到1.43g(产率:90%)所要化合物。
熔点:254-255℃
NMR(90MHz,DMSO-d6)δ1.5-2.1(4H,m),3.04(3H,s),3.32(3H,s),7.57(2H,d,J=8Hz),8.06(2H,d,J=8Hz),8.8-9.6(2H,宽,D2O交换)。
元素分析(C14H20N2SO3·HCl):
C H N
理论值(%) 50.50 6.37 8.42
实验值(%) 50.43 6.42 8.39
实施例10
4-(4-甲磺酰胺基苯甲酰基)-1-(4-吡啶甲基)哌啶二盐酸盐
将1.13g(18.8m mol)甲醇钠加到3.0g(9.4m mol)4-(4-甲磺酰胺基苯甲酰基)哌啶盐酸盐和1.55g(9.4m mol)4-氯甲基吡啶盐酸盐与90ml乙腈的悬浮液中。于室温下搅拌此混合物10分钟。加2.88g碳酸钾于此混合物中,然后回流此混合物3小时。冷却后,过滤液体反应混合物,浓缩滤液,通过硅胶色谱法(氯仿∶甲醇=95∶5)提纯此残余物。用盐酸乙醇将产品转化成其盐酸盐,并用甲醇/异丙醇重结晶,得到1.4g所要化合物。
熔点:~207℃(分解)
NMR(400MHz,DMSO-d6)δ1.85-2.30(4H,m),3.11(3H,s),4.53(2H,s),7.31(2H,d,J=8.8Hz),7.98(2H,d,J=8.8Hz),8.17(2H,d,J=4.9Hz),8.92(2H,d,J=5.9Hz),10.41(1H,s,D2O交换),11.6-12.0(1H,宽,D2O交换)。
元素分析(C19H23N3O3S·2HCl):
C H N
理论值(%) 51.12 5.64 9.41
实验值(%) 51.04 5.41 9.28
实施例11
4-(4-甲磺酰胺基苯甲酰基)-1-[2-(3-吡啶基)乙基]哌啶二盐酸盐
将35g(0.101mol)4-(4-甲磺酰胺基苯甲酰基)哌啶盐酸盐和55g碳酸钾浮液于700ml二甲基甲酰胺中并于40℃下搅拌此悬浮液20分钟。加19.6g(0.101ml)3-(2-氯乙基)吡啶盐酸盐和6.0g(0.036mol)碘化钾于此悬浮液中并于90℃下搅拌此混合物3.5小时。过滤液体反应混合物,浓缩滤液,残余物经硅胶色谱法(氯仿∶甲醇=93∶7)提纯。用盐酸乙醇将提纯后的产物转化为其盐酸盐,从甲醇/异丙醇中重结晶得到13.4g所要化合物。
熔点:200-207℃
NMR(100MHz,DMSO-d6)δ1.8-2.3(4H,m),3.11(3H,s),7.32(2H,d,J=8Hz),7.90-8.10(3H,m),8.50(1H,d,J=6.2Hz),8.8(1H,d,J=6Hz),8.93(1H,d,J=2Hz),10.43(1H,s,D2O交换),10.90-11.40(1H,宽,D2O交换)。
元素分析(C20H25N3O3S·2HCl):
C H N
理论值(%) 52.17 5.91 9.13
实验值(%) 52.00 5.86 8.83
实施例12
4-(4-甲磺酰胺基苯甲酰基)-1-[3-(4-吡啶基)丙基]哌啶二盐酸盐
将0.295g(0.926m mol)4-(4-甲磺酰胺基苯甲酰基)哌啶盐酸盐和0.380g(4.52m mol)碳酸氢钠悬浮于4ml二甲基甲酰胺中并于85℃下搅拌此悬浮液40分钟。加入0.20g(1.04m mol)4-(3-氯丙基)吡啶盐酸盐和0.31g(1.87m mol)碘化钾并于85℃下搅拌此混合物1.5小时。过滤液体反应混合物并浓缩滤液,所得残余物经硅胶色谱法(氯仿∶甲醇∶氨水=96∶4∶0.4)提纯。用盐酸乙醇将提纯后的产物转化为其盐酸盐,用己醇重结晶得到0.288g(66%)所要化合物。
熔点:230℃(分解)
NMR(100MHz,DMSO-d6)δ1.8-2.4(6H,m),3.10(3H,s),7.30(2H,d,J=8Hz),7.95(2H,d,J=8Hz),7.97(2H,d,J=6Hz),8.83(2H,d,J=6Hz),10.44(1H,宽,D2O交换),10.90-11.40(1H,宽,D2O交换)。
元素分析(C21H27N3O3S·2HCl):
C H N
理论值(%) 53.16 6.16 8.86
实验值(%) 52.95 6.10 8.73
实施例13
1-[2-(6-甲基-2-吡啶基)乙基]4-(4-甲磺酰胺基苯甲酰基)哌啶二盐酸盐
将0.254g(0.797m mol)4-(4-甲磺酰胺基苯甲酰基)哌啶盐酸盐和0.22g(1.88m mol)6-甲基-2-乙烯基吡啶和0.15g乙酸钠悬浮于3ml甲醇和水(1∶1)的混合物中,回流此悬浮液2小时过滤液体反应混合物,浓缩滤液。残余物经硅胶色谱法(氯仿∶甲醇∶氨水=96∶4∶0.4)提纯。用盐酸乙醇将提纯后的产物转化为其盐酸盐,用乙醇重结晶,得到0.285g(产率:81%)所要化合物。
熔点:219℃(分解)
NMR(90MHz,DMSO-d6)δ1.6-2.4(4H,m),2.74(3H,s),3.12(3H,s),7.33(2H,d,J=8Hz),7.70(1H,d,J=7Hz),7.78(1H,d,J=7Hz),8.02(2H,d,J=8Hz),8.33(1H,t,J=8Hz),10.47(1H,s,D2O交换),11.2(1H,宽,D2O交换)。
元素分析(C21H27N3O3S·2HCl):
C H N
理论值(%) 53.16 6.16 8.86
实验值(%) 52.94 6.16 8.73
实施例14
4-(4-甲磺酰胺基苯甲酰基)-1-[2-(4-吡啶基)乙基]哌啶二盐酸盐
(合成实例29化合物的另一方法)
将10.0g(31.4m mol)4-(4-甲磺酰胺基苯甲酰基)哌啶盐酸盐悬浮于20ml 1.32g氢氧化钠的水溶液中并于室温下搅拌此悬浮液1小时。过滤形成的固体,用水洗涤并干燥,得到8.28g结晶。将此机械悬浮于由15ml水、15ml甲醇和0.2ml乙酸组成的溶液中。加3.39g 4-乙烯基吡啶于此悬浮液中,回流10小时。冷却后,过滤形成的结晶,并用盐酸乙醇液将其转化成盐酸盐,得到7.54g所要化合物。
此化合物的熔点和NMR与实例29中从4-(4-甲磺酰胺基苯甲酰基)吡啶盐酸盐和4-(2-氯乙基)吡啶所得化合物的相同,而实例29的方法与实例13的方法相同。
(步骤Ⅵ,第1部分)
实施例15
1-{2-(2-咪唑并[1,2-a]吡啶基)乙基}-4-(4-甲磺酰胺基苯甲酰基)哌啶
1.02g(3.2m mol)4-(4-甲磺酰胺基苯甲酰基)哌啶盐酸盐,1.34g碳酸氢钠和10ml二甲基甲酰胺于80℃下搅拌1小时。加入0.48g 2-(2-氯乙基)咪唑并[1,2-a]吡啶盐酸盐和0.53g碘化钾并于80℃下搅拌此混合物2小时。过滤此混合物,浓缩滤液,残余物经硅胶色谱法(氯仿∶甲醇∶氨水=90∶9∶1)提纯。浓缩预期化合物的馏分,固体残余物从乙酸乙酯中重结晶,得到0.25g(产率:18%)所要化合物。
熔点:190-191℃
NMR(90MHz,DMSO-d6)δ1.4-1.9(4H,m),2.18(2H,m),2.4-3.6(7H,m),3.10(3H,s),6.80(1H,dt,J=5.2Hz),7.04-7.34(4H,m),7.72(1H,s),7.95(2H,d,J=8Hz),8.45(1H,d,J=7Hz)
元素分析(C22H26N4O3S):
C H N
理论值(%) 61.95 6.14 13.14
实验值(%) 61.92 6.10 12.92
实施例16
1-[2-(3-咪唑并[1,2-a]吡啶基)-1-氧代乙基]-4-(4-甲磺酰胺基苯甲酰基)哌啶二盐酸盐
ⅰ)将22.1g 3-乙酰基咪唑并[1,2-a]吡啶溶解于220ml乙酸中。于0℃下滴加35.1ml30%氢溴酸乙酸溶液。然后,于0℃下滴加28.6g溴。于40℃下搅拌此混合物2小时,滤出所得结晶。将所得结晶溶解于100ml水中。用过量的碳酸氢钠水溶液调节此溶液至碱性,然后用乙酸乙酯提取。浓缩有机层,所得棕色固体经硅胶柱色谱法(用乙酸乙酯洗脱)提纯,得到13.5g(产率:40%)3-溴乙酰基咪唑并[1,2-a]吡啶,为黄色结晶。
ⅱ)由1.91g(6.0m mol)4-(4-甲磺酰胺基苯甲酰基)哌啶盐酸盐,3.0g碳酸钾和40ml二甲基甲酰胺组成的悬浮液于80℃下搅拌1小时。冷至室温后,加入上面步骤ⅰ)所得的1.99g 3-溴乙酰基咪唑并[1,2-a]吡啶并于室温下搅拌6小时。过滤反应混合物,浓缩滤液,所得固体残余物经硅胶色谱法(氯仿∶甲醇=96∶4)提纯。用盐酸乙醇液将提纯后的产物转化为其二盐酸盐,从甲醇/丙酮中重结晶得到1.75g(产率:58%)所要化合物。
熔点:176-178℃
NMR(400MHz,DMSO-d6)δ1.95-2.10(4H,m),3.12(3H,s),3.33(2H,m),3.48-3.90(3H,m),4.96(2H,s),7.34(2H,d,J=8.8Hz),7.51(1H,t,J=7.1Hz),7.89(1H,dd,J=7.8,7.3Hz),8.02(2H,d,J=8.8Hz),9.01(1H,s),9.54(1H,d,J=6.8Hz),10.50(1H,s,D2O交换),10.72(1H,宽,D2O交换),
元素分析(C22H24N4O4S·2HCl·2H2O):
C H N
理论值(%) 49.39 5.35 10.47
实验值(%) 49.46 5.09 10.41
(步骤Ⅵ,第3部分)
实施例17
4-(4-甲磺酰胺基苯甲酰基)-1-[2-(1-吡咯烷基)乙基]哌啶二草酸盐
将10.0g(31.4m mol)4-(4-甲磺酰胺基苯甲酰基)哌啶盐酸盐悬浮于20ml11.32g氢氧化钠的水溶液中并于室温下搅拌此悬浮液1小时。滤出形成的结晶,水洗,干燥,得8.28g 4-(4-甲磺酰胺基苯甲酰基)哌啶。2.0g(7.09m mol)所得结晶,1.57g氯乙基吡咯烷基盐酸盐,2.35g碘化钾和40ml二甲基甲酰胺的混合物在80℃下搅拌3小时。过滤反应混合物,浓缩滤液,残余物固体经硅胶色谱法(氯仿∶甲醇∶氨水=90∶9∶1)提纯。用0.32g草酸乙醇溶液转化此纯产物为其二草酸盐。从甲醇/乙醇中重结晶后,得到0.40g(产率:10%)所要化合物。
熔点:214-216℃
NMR(90MHz,DMSO-d6)δ1.4-2.3(8H,m),2.4-3.6(13H,m),3.08(3H,s),7.21(2H,d,J=8Hz),7.88(1H,d,J=8Hz)。
元素分析(C19H29N2O3S·2(COOH)2):
C H N
理论值(%) 49.37 5.94 7.51
实验值(%) 49.40 5.85 7.37
(步骤Ⅵ,第4部分)
实施例18
1-(5-甲基-2-呋喃基)甲基}-4-(4-甲磺酰胺基苯甲酰基)哌啶
将1.88毫升福尔马林和1.07克甲基呋喃加入4.43克(15.7毫摩尔)实例17的游离4-(4-甲磺酰胺基苯甲酰基)哌啶、1.57g冰醋酸和10毫升水的混合物中,所得混合物在90℃下搅拌2小时。冷却后,用20%的氢氧化钠水溶液中和并用二氯甲烷提取。用水和饱和食盐水溶液洗涤有机层,以硫酸镁干燥,浓缩。固体残渣在乙醇/甲醇中重结晶,得到所需的化合物4.16g(得率:70%)。
熔点:181-182℃
NMR(90MHz,DMSO-d6)δ1.3-1.9(4H,m),1.9-2.3(2H,m),2.23(3H,d,J=1Hz),2.6-3.4(3H,m),3.10(3H,s),3.43(2H,s),5.97(1H,m6.13(1H,d,J=3Hz),7.28(2H,d,J=8Hz),7.94(2H,d,J=8Hz)
元素分析:C19H24N2O4S
C H N
理论值(%) 60.62 6.43 7.44
实验值(%) 60.43 6.46 7.44
(步骤Ⅵ,第5部分)
实施例19
4-(4-甲磺酰胺基苯甲酰基)-1-[2-(2-喹喔啉基)-乙基]哌啶
将5.0克(15.7毫摩尔)4-(4-甲磺酰胺基苯甲酰基)哌啶盐酸盐悬浮于5毫升乙醇中,再向其中加入2.49克2-甲基喹喔啉和7.0毫升福尔马林,在90℃下将此混合物搅拌1小时。冷却后,用20%氢氧化钠水溶液中和,所形成的结晶从乙酸乙酯中重结晶,得到所需之化合物0.32克(得率:5%)。
熔点:156-157℃
NMR(90MHz,DMSO-d6)δ1.4-2.0(4H,m),2.0-2.4(7H,m),2.6-3.5(7H,m),3.13(3H,s),7.31(2H,d,J=8Hz),7.73-8.15(6H,m),8.91(1H,s)
元素分析:C23H26N4O3S
C H N
理论值(%) 62.99 5.98 12.78
实验值(%) 62.83 5.95 12.61
(步骤Ⅵ,第6部分)
实施例20和21
1-乙基-4-(4-甲磺酰胺基苯甲酰基)哌啶和1-乙基-4-(N-乙基-4-甲磺酰胺基苯甲酰基)哌啶
在80℃下将含2.54克(7.97毫摩尔)4-(4-甲磺酰胺基苯甲酰基)哌啶盐酸盐、5克碳酸钾和40毫升二甲基甲酰胺的悬浮液搅拌1小时。加入1.3g(8.3毫摩尔)碘乙烷并于80℃下搅拌此混合物12小时。将混合物过滤,滤液浓缩至得到固体残渣。用硅胶柱色谱法(氯仿∶甲醇∶氨水=(90∶9∶1)将残渣纯化。所要馏分浓缩至干燥,再将残渣用盐酸乙醇溶液转化成其盐酸盐,在甲醇/乙酸乙酯中重结晶后,得到所需之化合物。
实施例20
1-乙基-4-(N-乙基-4-甲磺酰胺基苯甲酰基)哌啶盐酸盐:0.23克
熔点:188-191℃
NMR(90MHz,DMSO-d6)δ1.04(3H,t,J=7Hz),1.28(3H,t,J=7Hz),1.65-2.30(4H,m),2.60-3.95(7H,m),3.05(3H,s),3.78(2H,q,J=7Hz),7.57(2H,d,J=8Hz),8.06(2H,d,J=8Hz)
元素分析:C17H26N2O3S·HCl
C H N
理论值(%) 54.45 7.27 7.47
实验值(%) 54.20 7.09 7.24
实施例21
1-乙基-4-(4-甲磺酰胺基苯甲酰基)哌啶盐酸盐:1.70克
熔点:204-207℃
NMR(90MHz,DMSO-d6)δ1.27(3H,t,J=7Hz1.64-2.23(4H,m),2.62-3.90(7H,m),3.13(3H,s),7.34(2H,d,J=8Hz),8.01(2H,d,J=8Hz),10.42(1H,宽峰)
元素分析:C15H22N2O3S·HCl
C H N
理论值(%) 51.93 6.70 8.08
实验值(%) 51.76 6.57 7.86
实施例22
N-甲基4-(4-甲磺酰胺基苯甲酰基)-1-[2-(3-吡啶基)乙基]哌啶二盐酸盐
将1.5克(3.26毫摩尔)4-(4-甲磺酰胺基苯甲酰基)-1-[2-(3-吡啶基)乙基]哌啶二盐酸盐加入0.242克(10.08毫摩尔)氢化钠于30毫升二甲基甲酰胺的悬浮液中,于60℃下将此混合物搅拌5小时。随后在室温下加入0.56克(3.94毫摩尔)碘甲烷并将所得到的混合物在该温度下搅拌2小时。将液体反应混合物过滤,滤液浓缩至得到残渣,以硅胶柱色谱法(氯仿∶甲醇=97∶3)纯化。以盐酸乙醇溶液将所得的产物转化成盐酸盐,得到所需的化合物0.5克。
熔点:~182℃
NMR(90MHz,DMSO-d6)δ1.8-2.4(4H,m),3.02(3H,s),3.31(3H,s),7.48(2H,d,J=8Hz),7.98(3H,m),8.45(1H,宽峰,J=7Hz),8.80(2H,m),
元素分析:C21H27N3O3S·2HCl
C H N
理论值(%) 53.16 6.16 8.86
实验值(%) 53.37 6.12 8.65
实施例23
N-丁基4-(4-甲磺酰胺基苯甲酰基)-1-[2-(3-吡啶基)乙基]哌啶二盐酸盐
除以碘代正丁烷代替碘甲烷外,按实例22的方法进行反应,所得产物以硅胶色谱法纯化,得到所需之化合物。物理性质如下:
熔点:110-111℃
NMR(90MHz,CDCl3)δ:0.88(3H,t),1.2-3.3(19H,m),2.88(3H,s),3.73(2H,t,J=8Hz),7.2(1H,q,J=6.6Hz),7.46(2H,d,J=8Hz),7.5-7.64(1H,m),7.98(2H,d,J=8Hz),8.46(1H,dd,J=2,6Hz),8.5(1H,d,J=2Hz)
元素分析:C24H23N3O3S
C H N
计算值(%) 64.97 7.51 9.47
实验值(%) 64.90 7.41 9.43
实施例24
4-(4-甲磺酰胺基苯甲酰基)羟甲基-1-[2-(2-吡啶基)乙基]哌啶二盐酸盐
将2.0克(5.16毫摩尔)4-(4-甲磺酰胺基苯甲酰基)-1-[2-(2-吡啶基)乙基]哌啶溶于150毫升甲醇,在冰冷却下向此溶液加入0.39克硼氢化钠,将此混合物在0℃下搅拌1小时。在0℃下滴入盐酸乙醇溶液以酸化此液体反应混合物并滤出所形成的无机物。浓缩滤液,将所得的油状残渣溶于乙醇。加氨水使溶液成碱性并进一步将形成的无机物滤出。浓缩滤液,将所得的油状残渣经硅胶柱色谱法(氯仿∶甲醇∶氨水=90∶9∶1)进行纯化。以常用方法将所得的油转化成盐酸盐,得到所需之化合物0.76克。
熔点:~182℃
NMR(90MHz,DMSO-d6)δ1.3-2.4(4H,m),2.92(3H,s),4.22(1H,宽峰),7.23(4H,m),7.6-7.9(2H,m),8.28(1H,dt,J=1,7Hz),8.65(1H,d,J=5Hz),9.64(1H,s,重水交换)10.8(1H,宽峰,重水交换)
元素分析:C21H29N3O3S·2HCl
C H N
计算值(%) 52.94 6.56 8.82
实验值(%) 53.16 6.83 8.61
实施例25
N-甲基4-(4-甲磺酰胺基苯甲酰基)-1-[2-(3-吡啶基)乙基]哌啶二盐酸盐
(合成实例22化合物的另一方法)
将0.8克(2.7毫摩尔)N-甲基-4-(4-甲磺酰胺基苯甲酰基)哌啶二盐酸盐、0.52克(2.7毫摩尔)3-(2-氯乙基)吡啶盐酸盐、3.0克碳酸钾和0.2克碘化钾溶于15毫升二甲基甲酰胺,在90℃下将此溶液搅拌3.5小时。冷却后滤出无机物,滤液浓缩至得到残渣,按硅胶色谱法(氯仿∶甲醇=97∶3)将残渣纯化。用常用方法使纯产物转化为其盐酸盐,得到所需之化合物0.6克。此产物的熔点和核磁共振数据与实例22的数据符合。
实施例26-115
列于表3-12的每一化合物是按实例1-25中相同的方法由示于参考实例3-5中的哌啶化合物、吡咯烷化合物和它们的囟化物制得的。
现已制得本发明的各种化合物,包括杂环或稠合芳环化合物。
Claims (9)
1、通式(I)的哌啶衍生物及其在药理上可接受的盐的制备方法,
式中R1是低级烷基或甲苯基;R2是氢、羟基、低级烷氧基或低级烷基;R3是氢、低级烷基、低级链烯基、环烷基或环烷基烷基;X是-CO-、-CH2-或-CHOH-;g是1~3的整数;h是1~3的整数;Y是氢、低级烷基、低级链烯基、氰基、-CH2COOR,其中R是氢或低级烷基、环烷基、环烷基烷基
其中L是1或2、
Y或是-A-B,其中A为-(CH2)n-,(n为1~5的整数)、含1~5个碳原子的直链亚烷基,它是从直链烷烃衍生的二价基团,此直链烷烃有低级烷烃、苯基或羟基直接连于一个或多个构成此烷烃的碳原子上,将两端碳原子上的各一个氢除去而形成、
含1~5个碳原子的直链亚烯基,它是从直链烯烃衍生的二价基团,此直链烯烃在相邻的两个碳原子间有双键,将两端碳原子上的各1个氢除去而形成、
-(CH2)k-S-(K为2~5的整数)、-(CH2)pCO-(P为1~4的整数),B为氰基、-NR4R5、或以下基团
其中R4和R5各为氢或低级烷基、R6为氢、低级烷基、低级烷氧基、氰基、咪唑基、羟基或囟素;
R7和R8各为氢、囟素、低级烷基、低级烷氧基或甲磺酰胺基;R9、R10和R11各为氢或低级烷基,
该方法选自于下列方法1-9:
1.该方法包括水解X为-CO-和Y为-COR′(其中R′为低级烷基)的通式(I)化合物,得到X为-CO-和Y为H的通式(I)化合物;
4.该方法包括还原X为-CO-的通式(Ⅰ)化合物,得到X为-CHOH-的通式(Ⅰ)化合物;
5.该方法包括R3为氢和X为-CO-的通式(Ⅰ)化合物与化合物R′Hal反应,得到R3为R′和X为-CO-,R′为低级烷基,Hal为囟素的通式(Ⅰ)化合物;
6.该方法包括还原R3为R′和X为-CO-的通式(Ⅰ)化合物,得到R3为R′和X为-CHOH-的通式(Ⅰ)化合物;
7.该方法包括还原X为-CO-或-CHOH-的通式(Ⅰ)化合物,得到X为-CH2-的通式(Ⅰ)化合物;
9.该方法包括使Y为氢和/或R3为氢的通式(Ⅰ)化合物反应,以便得到R3和/或Y为低级烷基、低级链烯基或环烷基的通式(Ⅰ)化合物。
(2)按权利要求1所述的方法制备哌啶衍生物或其在药理上可接受的盐,其中X为式-CO-的基团。
(3)按权利要求1所述的方法制备哌啶衍生物或其在药理上可接受的盐,其中
X为式
的基团。
(4)按权利要求1所述的方法制备哌啶衍生物或其在药理上可接受的盐,其中A为式-(CH2)n-的基团,n为1~5的整数。
(5)按权利要求1所述的方法制备哌啶衍生物或其在药理上可接受的盐,其中B为
(6)按权利要求1所述的方法制备哌啶衍生物或其在药理上可接受的盐,其中B为式
(7)按权利要求1所述的方法制备哌啶衍生物或其在药理上可接受的盐,其中X为式-CO-的基团;A为式-(CH2)n-的基团,其中n为1~5的整数;B为式
(8)按权利要求1所述的方法制备哌啶衍生物或其在药理上可接受的盐,其中X为式-CO-的基团;A为式-(CH2)n-的基团,其中n为1~5的整数;B为式
(9)按权利要求1所述的方法制备哌啶衍生物或其在药理上可接受的盐,其中R1为低级烷基;X为式-CO-的基团;A为式-(CH2)n-的基团,其中n为1~5的整数;B为式
(10)按权利要求1所述的方法制备哌啶衍生物或其在药理上可接受的盐,此衍生物是4-(4-甲磺酰胺基苯甲酰基)-1-〔2-(3-哌啶基)乙基〕哌啶。
(11)按权利要求1所述的方法制备哌啶衍生物或其在药理上可接受的盐,此衍生物是4-(4-甲磺酰胺基苯甲酰基)-1-(4-哌啶基甲基)哌啶。
(12)按权利要求1所述的方法制备哌啶衍生物或其在药理上可接受的盐,此衍生物是4-(4-甲磺酰胺基苯甲酰基)-1-〔3-(4-哌啶基)丙基〕哌啶。
(13)按权利要求1所述的方法制备哌啶衍生物或其在药理上可接受的盐,此衍生物是1-(6-甲基-3-吡啶基)甲基-4-(4-甲磺酰胺基苯甲酰基)哌啶。
(14)按权利要求1所述的方法制备哌啶衍生物或其在药理上可接受的盐,此衍生物是4-(4-甲磺酰胺基苯甲酰基)-1-〔2-(4-吡啶基)乙基〕哌啶。
(15)按权利要求1所述的方法制备哌啶衍生物或其在药理上可接受的盐,此衍生物是1-〔2-(3,4-二甲氧基苯基)乙基〕-4-(4-甲磺酰胺基苯甲酰基)哌啶。
(16)按权利要求1所述的方法制备哌啶衍生物或其在药理上可接受的盐,此衍生物是4-(4-甲磺酰胺基苯甲酰基)-1-〔4-(3-吡啶基)丁基〕哌啶。
(17)按权利要求1所述的方法制备哌啶衍生物或其在药理上可接受的盐,此衍生物是4-(4-甲磺酰胺基苯甲酰基)-1-〔2-(4-吡啶基硫)乙基〕哌啶。
(18)按权利要求1所述的方法制备哌啶衍生物或其在药理上可接受的盐,此衍生物是4-(4-甲磺酰胺基苯甲酰基)哌啶。
(19)按权利要求1所述的方法制备哌啶衍生物或其在药理上可接受的盐,此衍生物是4-(4-甲磺酰胺基苯甲酰基)-1-〔3-(3-吡啶基)丙基〕哌啶。
(20)按权利要求1所述的方法制备哌啶衍生物或其在药理上可接受的盐,此衍生物是1-(5-氯-3-吡啶基)乙基-4-(4-甲磺酰胺基苯甲酰基)哌啶。
(21)按权利要求1所述的方法制备哌啶衍生物或其在药理上可接受的盐,此衍生物是4-(4-甲磺酰胺基苯甲酰基)-1-〔2-(2-吡啶基)乙基〕哌啶。
(22)按权利要求1所述的方法制备哌啶衍生物或其在药理上可接受的盐,此衍生物是4-(4-甲磺酰胺基苯甲酰基)-1-(2-苯乙基)哌啶。
(23)按权利要求1所述的方法制备哌啶衍生物或其在药理上可接受的盐,此衍生物是1-〔2-(6-甲基-3-吡啶基)乙基-4-(4-甲磺酰胺基苯甲酰基)哌啶。
(24)按权利要求1所述的方法制备哌啶衍生物或其在药理上可接受的盐,此衍生物是1-〔2-(5-乙基-2-吡啶基)乙基〕-4-(4-甲磺酰胺基苯甲酰基)哌啶。
(25)按权利要求1所述的方法制备哌啶衍生物或其在药理上可接受的盐,此衍生物是1-〔2-(6-甲基-2-吡啶基)乙基〕-4-(4-甲磺酰胺基苯甲酰基)哌啶。
(26)按权利要求1所述的方法制备哌啶衍生物或其在药理上可接受的盐,此衍生物是1-(6-氯-3-吡啶基)甲基-4-(4-甲磺酰胺基苯甲酰基)哌啶。
(27)按权利要求1所述的方法制备哌啶衍生物,其中g和h各为2。
(28)按权利要求1所述的方法制备哌啶衍生物,其中g为3,h为1。
(29)按权利要求1所述的方法制备哌啶衍生物,其中g为2,h为3。
(30)按权利要求1所述的方法制备哌啶衍生物,其中g为1,h为2。
(31)按权利要求1所述的方法制备哌啶衍生物,其中g为1或2,h为2或3。
(32)一种药物组合物,此组合物包括权利要求1中所规定的药理上有效量的哌啶衍生物或其药理上可接受的盐和药理上可接受的载体。
(33)一种应用权利要求1所规定的哌啶衍生物或其药理上可接受的盐治疗或预防心律不齐的方法。
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JP3927086 | 1986-02-26 | ||
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CN1019973C CN1019973C (zh) | 1993-03-03 |
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US (3) | US4876262A (zh) |
EP (1) | EP0235752B1 (zh) |
JP (1) | JPH0780841B2 (zh) |
KR (1) | KR910002563B1 (zh) |
CN (1) | CN1019973C (zh) |
AT (1) | ATE97405T1 (zh) |
AU (1) | AU599632B2 (zh) |
CA (1) | CA1317941C (zh) |
DE (1) | DE3788145T2 (zh) |
DK (2) | DK93287A (zh) |
ES (1) | ES2059315T3 (zh) |
HU (1) | HU199794B (zh) |
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- 1987-02-18 US US07/016,035 patent/US4876262A/en not_active Expired - Lifetime
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- 1987-02-24 DK DK093287A patent/DK93287A/da not_active Application Discontinuation
- 1987-02-25 NZ NZ219401A patent/NZ219401A/xx unknown
- 1987-02-25 CA CA000530571A patent/CA1317941C/en not_active Expired - Fee Related
- 1987-02-25 CN CN87100928A patent/CN1019973C/zh not_active Expired - Fee Related
- 1987-02-25 JP JP62042368A patent/JPH0780841B2/ja not_active Expired - Lifetime
- 1987-02-25 HU HU87730A patent/HU199794B/hu not_active IP Right Cessation
- 1987-02-26 AT AT87102743T patent/ATE97405T1/de not_active IP Right Cessation
- 1987-02-26 EP EP87102743A patent/EP0235752B1/en not_active Expired - Lifetime
- 1987-02-26 AU AU69513/87A patent/AU599632B2/en not_active Ceased
- 1987-02-26 DE DE87102743T patent/DE3788145T2/de not_active Expired - Fee Related
- 1987-02-26 KR KR1019870001676A patent/KR910002563B1/ko not_active IP Right Cessation
- 1987-02-26 ES ES87102743T patent/ES2059315T3/es not_active Expired - Lifetime
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1989
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CN105778896A (zh) * | 2016-04-08 | 2016-07-20 | 山东大学 | 苯基(4-哌啶基)甲酮类hERG钾离子通道的小分子荧光探针 |
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Publication number | Publication date |
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JPS62281858A (ja) | 1987-12-07 |
JPH0780841B2 (ja) | 1995-08-30 |
CN1019973C (zh) | 1993-03-03 |
HU199794B (en) | 1990-03-28 |
EP0235752A2 (en) | 1987-09-09 |
AU6951387A (en) | 1987-08-27 |
PH23283A (en) | 1989-06-30 |
NZ219401A (en) | 1990-07-26 |
ES2059315T3 (es) | 1994-11-16 |
KR870007888A (ko) | 1987-09-22 |
DE3788145T2 (de) | 1994-04-28 |
HUT46675A (en) | 1988-11-28 |
NO870747D0 (no) | 1987-02-24 |
DE3788145D1 (de) | 1993-12-23 |
DK110395A (da) | 1995-10-02 |
CA1317941C (en) | 1993-05-18 |
US4996215A (en) | 1991-02-26 |
AU599632B2 (en) | 1990-07-26 |
NO170484C (no) | 1992-10-21 |
ATE97405T1 (de) | 1993-12-15 |
US5118689A (en) | 1992-06-02 |
NO170484B (no) | 1992-07-13 |
EP0235752B1 (en) | 1993-11-18 |
US4876262A (en) | 1989-10-24 |
EP0235752A3 (en) | 1990-07-25 |
KR910002563B1 (ko) | 1991-04-26 |
DK93287D0 (da) | 1987-02-24 |
NO870747L (no) | 1987-08-27 |
DK93287A (da) | 1987-08-27 |
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