CN1069640C - 噁唑烷酮衍生物,其制备方法及含它们的药物组合物 - Google Patents
噁唑烷酮衍生物,其制备方法及含它们的药物组合物 Download PDFInfo
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- CN1069640C CN1069640C CN95118753A CN95118753A CN1069640C CN 1069640 C CN1069640 C CN 1069640C CN 95118753 A CN95118753 A CN 95118753A CN 95118753 A CN95118753 A CN 95118753A CN 1069640 C CN1069640 C CN 1069640C
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- Prior art keywords
- piperazinyl
- oxazolidine
- ketone
- jia
- piperidyl
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
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- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
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- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
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- 125000005936 piperidyl group Chemical group 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 235000007715 potassium iodide Nutrition 0.000 description 1
- 229960004839 potassium iodide Drugs 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000010970 precious metal Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- 239000012453 solvate Substances 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
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- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
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- 239000005720 sucrose Substances 0.000 description 1
- FRGKKTITADJNOE-UHFFFAOYSA-N sulfanyloxyethane Chemical compound CCOS FRGKKTITADJNOE-UHFFFAOYSA-N 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Chemical compound O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- LZRDHSFPLUWYAX-UHFFFAOYSA-N tert-butyl 4-aminopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(N)CC1 LZRDHSFPLUWYAX-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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- 108010047303 von Willebrand Factor Proteins 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Abstract
通式Ⅰ的化合物及其生理可以接受的盐类，
其中R1与Y的意义已经指明，抑制纤维蛋白原与相应受体的结合，因而可用于治疗血栓、骨质疏松症、肿癌、中风、心肌梗塞、炎症、动脉硬化及溶骨症。
Description
本发明涉及通式Ⅰ的新化合物及其生理可接受盐
其中
X为O,S,NH或NA
Y为氮丙啶基、氮杂环丁基、四氢吡咯基、哌啶子基、六氢氮杂草基或哌嗪基，它们可被R2取代
R1为
R2为-CrH2r-COOR3
R3为H,A或Ar
A为含有1至6个碳原子的烷基
B为H,A，含有3至7个碳原子的环烷基，Ar-CkH2k-或脒基
Ar为苯基或苄基，它们或者为非取代，或着被A,Cl,Br,I,NO2,CN,OA,OH,NH2,NHA和/或NA2单取代或二取代
k为1,2,3或4。
m与r相互独立，为0,1,2,3,或4
n为2,3，或4。
类似的化合物可见于EP-Al-0 381 033
本发明的目的在于找到具有有用的性质的新化合物，特别是那些可用于制备药物的产品。
本发明实现了上述目标，已经发现通式Ⅰ的化合物及其溶剂化物和盐类，它们具有有用的药理性质及良好的耐受性。尤其可抑制纤维蛋白原、纤连蛋白(fibronectin)和(von Willebrand)因子与血小板的纤维蛋白原受体的结合(糖蛋白Ⅱb/Ⅲa)，并且抑制上述三种物质及粘附蛋白，如玻连蛋白，胶原蛋白和层粘连蛋白与各种类型细胞表面上相应的受体结。因此这类化合物可以影响细胞-细胞及细胞-基质的相互作用。它们特别用于预防血小板性栓塞的形成，进而用于治疗血栓、中风、心肌梗塞、局部缺血、炎症、动脉硬化和急性肾衰。这类化合物可以抑制肿瘤细胞的转移，因而作为抗肿瘤药是有效的。
有迹象表明肿瘤细胞能够通过小血栓而穿透到血管内，因而使得免疫***无法发现它们而得到保护。小血栓还有助于肿瘤细胞结合到血管壁上。由于小血栓的形成与纤维蛋白原及其受体(糖蛋白Ⅱb/Ⅲa)的结合有关，纤维蛋白原结合抑制剂似乎同样可以作为肿瘤转移抑制剂。
这类化合物还可作为抗菌剂，可以防止由细菌、真菌或酵母菌引起的各种感染。因而当进行手术，其中使用外源性物质时，这些化合物很适宜作为抗菌剂，这些外源性物质包括生物材料，移植物、导管、心脏起搏器。这类化合物可作为防腐剂使用。抗菌活性已被P.Valentin-Weigand等建立的方法所证实，该方法在Infection andImmunity 2851-2855(1988)上有所描述。
这类化合物的其它性质可由描述在EP-A1-0462 960上的方法来证明，对纤维蛋白原与其受体结合作用的抑制可由EP-A1-0381 033描述的方法来证实。血小板聚集抑制作用可通过Born的体外方法来证实(Nature 4832,927-929,1962)。
本发明还涉及到通式Ⅰ的化合物及其盐类的制备方法，其特征在于：(a)通式Ⅰ的化合物，通过溶剂化或氢解作用，由其功能衍生物中释放出来，或在于(b)通式Ⅱ的化合物：其中Z为Cl,Br,I或反应活性的酯化羟基，及R1和X的意义如上所示，与通式Ⅲ的化合物进行反应，
H-Y Ⅲ其中Y的意义如前所指，或在于(c)一通式Ⅳ的化合物
R1-NH-CH2-CH(XH)-CH2-Y Ⅳ其中R1,X和Y的意义如前所指，与反应活性的碳酸衍生物起反应，或在于(d)通式Ⅴ的化合物
其中X和Y的意义如前所指，与通式Ⅵ的化合物起反应，
其中B的意义如前所指L为
或
其中
Z1为Cl、Br、I、OA、OH或一个具有反应活性的酯化羟基，或
一个易亲核取代离去基或在于
(e)一个或数个R1和/或Y被转变成其它的R1和/或Y，和/或在于
(f)通式Ⅰ的化合物，在用酸式碱处理后转变成其盐类。
通式Ⅰ的化合物中至少有一个手性中心，并且可以几种对映体的形式存在。所有这些类型(如D-和L-型)及其混合物(如DL-型)都包括在通式Ⅰ中。
在此前述及后述，取代基及参数A,B,L,X,Y,Z,R1至R3,Ar,k,m,n及r，如除另有说明外，则都具有通式Ⅰ至Ⅵ所规定的意义。如果几个基团同时存在于同一分子中且具有相同的定义范围时，它们可以视为相互独立的不同定义。
在上述各种通式中，基团A具有1-6个碳原子，优选1,2,3或4个碳原子。特别是，A优选为甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基或叔丁基，反戊基，1-,2-，或3-甲基丁基，1,1-,1,2-或2,2-二甲基丙基、1-乙基丙基、己基，或1-,2-，3-或4-甲基戊基。
R1优选为4-哌啶基、1-苄基-4-哌啶基、4-哌啶基甲基、4-哌啶基乙基、1-脒基-4-哌啶基、1-脒基-4-哌啶基甲基、4-哌嗪基乙基、4-哌嗪基丙基、4-哌嗪基丁基、1-脒基4-哌嗪基乙基或1-脒基4-哌嗪基丙基。
R2优选为-(CH2)2-COOR3,-(CH2)3-COOR3，或-CH2COOR3，
R3优选为：H，甲基、乙基或苄基。
Ar优选为未取代的苄基。
X优选为o、y为哌嗪或哌啶基。
参数k和m优选为零或1,n优选为2或3,r优选为1,2或3。
在通式Ⅰ化合物中，优选其中至少一个原子团、基团和/或参数为上述优选定义中的一种的那些化合物。一些优选的化合物由相应于式Ⅰ的通式Ⅰa至Ⅰh表示，但其中
Ⅰa中X为氧，R1为4-哌啶基；
Ⅰb中X为氧，R1为1-脒基-4-哌啶基；
Ⅰc中X为氧，R1为1-苄基-4-哌啶基；
Ⅰd中X为氧，R1为4-哌啶基甲基，4-哌啶基乙基或4-哌啶
基丙基；
Ⅰe中X为氧，R1为1-脒基-4-哌啶基甲基，1-脒基4-哌啶
基乙基或1-脒基-4-哌啶基-丙基；
Ⅰf中X为氧，R1为1-苄基-4-哌啶基甲基、1-苄基-4-哌
啶基-乙基或1-苄基-4-哌啶基-丙基；
Ⅰg中X为氧，R1为1-哌嗪基乙基，1-脒基-4-哌嗪基乙基
或1-苄基-4-哌嗪基乙基；
Ⅰh中X为氧，R1为1-哌嗪基丙基，1-脒基-4-哌嗪基丙基
或1-苄基-4-哌嗪基丙基。
通式Ⅰi及Ⅰai至Ⅰhi的化合物更好，它们对应于通式Ⅰ和通式Ⅰa至通式Ⅰh，但另外Y为3-R2-氮杂环丁基，2-R2-吡咯烷基，2-R2-哌啶子基，3-R2-哌啶子基，4-R2-哌啶子基，4-R2-哌嗪基或3-R2-哌嗪基。及R2为-COOR3,-CH2COOR3,-(CH2)2COOR3 或-(CH2)3COOR3
通式Ⅰ的化合物反及用来制备它们的原料可按照已知的方法制备，这些方法在文献上已有描述(如：Houben-Weyl的经典者作-Methoden der Organische Chemie(有机化学方法)，Georg-Thieme-Verlag,Stuttgart；以及EP-A1-0 381 033,EP-A1-0 462 960)。也即在已知的反应条件下进行，这些反应条件适用于所提及的反应，这些方法还可用于母体已知的各种变体，但此处并不详细论及。
如果需要，起始原料还可就地制备，以至于它们可不从反应混合物中分离，而立即进行下一步的反应，而得到通式Ⅰ的化合物。
通式Ⅰ的化合物能够通过对其功能衍生物的溶剂解作用，特别是水解或氢解而释出得到。
用于水解或氢解的优选的原料是那些其它方面与通式Ⅰ一致，但其中一个或多个游离氨基或羟基被相应的保护氨基和/或保护羟基代替，优选用氨基保护基代替与N相连的H原子，特别是用R’-N基团来代替HN，其中R’为氨基保护基，和/或同羟基保护基团代替羟基中的H，例如，在那些与通式Ⅰ对应的化合物中，将-COOH变成-COOR”，其中R”为羟基保护基团。
几种相同或不同的保护氨基和/或羟基的基团也可存在于原料的分子中，如果存在的保护基彼此不同，在很多情况下它们可以选择性地除去。
“氨基保护基”通常为人所知，并涉及到这样一类基团，适合用来保护(封闭)一个氨基使不发生化学反应，组分子中其它部位所期望的化学反应完成后，该保护基应易于除去。这种类型的典型基团有：特别是未取代或取代的酰基、芳基(例如，2,4-二硝基苯基(DNP)，芳烷氧甲基(如苄氧甲基(BOM))或芳烷基团(如：苄基，4-硝苄基，三苯甲基)由于在期待的反应(或反应序列)完成后，氨基保护基即被除去，所以它们的性质与体积并不重要；但含有1-20，特别是1-8个碳原子的保护基更佳。“酰基”这种表达可以在非常广的意义上加以说明，这种意义与所存在的方法有关。它包括衍生自脂肪的、芳脂的、芳香的或杂环羧酸或者磺酸的酰基，尤其是烷氧羰基、芳氧羰基以及特别是芳烷氧羰基。这类酰基的例子为脂肪酰基，例如乙酰基、丙酰基、丁酰基、芳脂酰基如苯乙酰基；芳酰基如苯甲酰基或甲苯甲酰基；芳氧链烷酰基如苯氧乙酰基；烷氧羰基如甲氧羰基、乙氧羰基，2,2,2-三氯乙氧羰基，异丙氧羰基，叔丁氧羰基(BOC)，2-碘乙氧羰基，芳烷氧羰基如苄氧羰基(CBZ)，4-甲氧苄氧羰基和9-芴甲氧酰基(FMOC)。更好的氨基保护基团为BOC、DNP和BOM，以及CBZ，苄基和乙酰基。
“羟基保护基”同样也为人所知，涉及到适于保护羟基不发生化学反应的一类基团，但在分子中其它部位所希望的反应完成后，羟基保护基应易被除去。这种类型的典型基团为上述提到的未取代或取代的芳基、芳烷基或酰基，以及烷基。羟基保护基的性质与大小并不重要，因为它们在所预期的反应或反应序列完成后，即可除去。含有1-20，特别是1-10个碳原子的保护基为更好，羟基保护基的例子除别的以外还有叔丁基、苄基、对硝基苯甲酰基，对甲苯磺酰基和乙酰基，特别是苄基及乙酰基更佳。
用作原料的通式Ⅰ的化合物的官能衍生物，能够用已有的方法来制备，例如在所描述的标准著作及提到的专利申请中就可以查到，例如通过与通式Ⅱ和Ⅲ的化合物反应就可制得，但至少这些化合物中的一种应含有保护基，而不是H原子。
从其官能衍生物释放出的通式Ⅰ化合物，取决于所用的保护基团。使用的强酸，例如使用三氟醋酸或高氯酸，但也可用其他无机强酸如盐酸或硫酸，强有机羧酸如三氯乙酸或磺酸如苯磺酸或对甲苯磺酸，可能加入惰性溶剂，量并非总是需要。
理想的惰性溶剂是有机酸，如：羧酸中的醋酸，醚类中的四氢呋喃或二氧六环，酰胺类中的二甲基甲酰氨胺(DMF)，卤代烃类如二氯甲烷，亚砜类如二甲基亚砜(DMSO)，以及醇类如甲醇、乙醇或异丙醇以及水。上述溶剂的混合物也适用。未加其它溶剂的过量三氟醋酸更为可取；高氯酸以70％高氯酸与乙酸的混合物形式使用，其中二者混合比例为9∶1。脱保护的反应温度可以控制在0～50℃之间，最佳反应温度为15～30℃(室温)。
除去BOC，例如可以选用40％三氟乙酸的二氯甲烷溶液或使用3～5N氯化氢的二氧六环溶液，反应温度为15～60，除去FMOC可用5～20％的二甲胺、二乙胺或哌啶的DMF溶液，反应温度为15～50℃。用约3～10％的二巯基乙醇的DMF/水溶液，可除去DNP，反应温度为15-30℃。
通过氢解除去的保护基团(如MOM,CBZ和苄基)可在催化剂存在下通氢而除去(催化剂如钯一类的贵金属，可方便地吸附于碳上)。反应所用合适的溶剂如上所指，尤其是醇类，例如甲醇或乙醇或酰胺中的DMF。通常氢解在约0～100℃的温度及1～200巴的压力下进行，在20～30℃和1～10巴的条件下更好，这是一条规律。例如CBZ在5～10％Pd-C的甲醇溶液，20～30℃下可容易地发生氢解。
通式Ⅰ的化合物也可由通式Ⅱ的化合物与通式Ⅲ的碱反应而制得。这种情况下，可以方便地使用已知的N-烷基化方法。
离去基团Z为下列更好：Cl,Br,I,C1～C6的烷基磺酰氧基如甲磺酰氧基或乙磺酰氧基或C6～C10的芳磺酰氧基如苯磺酰氧基、对-甲苯磺酰氧基或1-或2-萘磺酰氧基。
该反应优选在下列条件下进行：其它碱的存在下，这些碱包括碱金属或碱土金属的氢氧化物或碳酸盐如氢氧化钠、氢氧化钾、或氢氧化钙，碳酸钠、碳酸钾、或碳酸钙，在惰性溶剂中，例如在卤代烷如二氯甲烷中醚如THF、或二氯六环中，酰胺如DMF或二甲基乙酰胺中，腈类如乙腈中，反应温度在约-10～200℃之间，在0～120℃之间更好。如果离去基团Z不是碘时，建议加入一些碘化物，如碘化钾。
通常通式Ⅱ的原料都是新化合物。它们可由制备而得。例如通过通式R1-NH2的取代哌啶或哌嗪与通式R5CH2-CHR6-CH2OH(其中R5为Z,R6为XR7,R7是一种保护基，R5和R6一起为O)的化合物反应，制得通式R1-NH-CH2-CHR8-CH2OH(其中R8为XR7或OH)的化合物。如果适当地除去保护基R7即可得到式R1-NH-CH2-CH(XH)-CH2OH的化合物，该化合物再与碳酸衍生物反应，例如与碳酸二乙酯反应可得到3-R1-5-羟甲基-2-噁唑烷二酮，并把羟甲基变成CH2Z，例如用SOCl2、SOBr2甲磺酰氨或对甲苯磺酰氨来完成。通过通式H-Y(Ⅲ)所示的化合物是已知的，或可用已知化合物的类似方法来制备。
通式Ⅰ的化合物还可通过通式Ⅳ的化合物(或其活性衍生物)与碳酸的活性衍生物反应而制得。
合适的碳酸衍生物主要是碳酸二烷基酯如碳酸二乙酯，还有氯甲酸烷基酯如氯甲烷乙酯。碳酸衍生物可以方便地过量使用，以作为反应溶剂或反应悬浮剂更好。然而如果对于这个反应是惰性的，上述溶剂也可以单独加入。我们更主张加入碱，特别是碱金属的烷氧化物，如叔丁醇钾。在0～150℃的温度下，反应可以方便地进行，70～120℃更好。
通常，通式Ⅳ的原料是新化合物。将上述提到的式R1-NH-CH2-CH(XH)-CH2OH的化合物官能团化制得式R1-NH-CH2-CH(XH)-CH2-E的化合物，然后与通式H-Y(Ⅲ)的化合物反应，即可制得式Ⅳ起始物。
为了制备通式Ⅰ的化合物，其中R1为1-脒基啶或1-脒基哌嗪基，可用相应的哌啶或哌嗪化合物与脒化剂反应来制备。优选的脒化剂是1-脒基-3,5-二甲基吡唑，特别是其硝酸盐。在惰性的单一溶剂或混合溶剂中，如水/二氧六环，于0～120℃(60～120℃更佳)的温度下，在其它碱的存在下如三乙胺或乙基二异丙基胺，该反应可以更好地进行。
通式Ⅰ的化合物还可通过通式Ⅴ化合物与通式Ⅵ的派啶或哌嗪衍生物反应而制备。
通式Ⅴ的化合物可以通过H2N-CH2-CH(XH)-CH2-Y的化合物，(其中X和Y的意义已经指明)与活性碳酸衍生物反应制备。反应条件及适合的碳酸衍生物可参阅如前的详细说明。
通常，通式Ⅵ的化合物是已知的，或可通过本身上已知的方法制取，例如那些B不为H的式Ⅵ化合物，可通过通式Ⅵ(B=H)的对应的哌啶或哌嗪衍生物的官能化反应而制得。
按照胺的N-烷基化方法，尤其是本质上为已知物的环胺的氮烷基化方法，以及前面描述的通式Ⅱ的化合物和通式Ⅲ的化合物的反应方法，这些反应可以很容易进行。
还存在进一步的可能，即将通式Ⅰ的化合物中的R1和Y其中之一或两个都转变成通式Ⅰ的化合物的另外的R1和Y。
特别是羧基可以酯化，酯基可以解离，苄基可以氢化除去，或是氨基可以脒化。氨基或羟基保护基也可引入或除去。
对于酯化反应，通式Ⅰ的酸(R3=H)可在盐酸或硫酸这样的强酸存在下，反应温度在0～100℃之间，优选20-50℃，用过量的R3-OH的醇(R3=A或苄基)来处理。
相反，通式Ⅰ(R3=A或苄基)的酯可通过上述溶剂解，如在0-40℃，优选10-30℃下，用于水/二氧六环中的NaOH或KOH，被转变为式Ⅰ相应的酸(R3=H)。
通式Ⅰ的碱可与酸反应而转变成相应的酸加成盐。这种反应中，合适的酸尤其应为能生成生理上可以接受的盐的酸。可以使用无机酸，如硫酸、硝酸，氢卤酸，氯化氢式溴化氢，磷酸如正磷酸，氨基磺酸；也可使用有机酸，特别是脂肪酸、脂环酸、芳脂酸、芳香或杂环一元或多元羧酸，磺酸或硫酸，如甲酸、乙酸，三氟乙酸，丙酸，新戊酸，二乙基乙酸，丙二酸，丁二酸，庚二酸，富马酸，马来酸、乳酸，酒石酸，苹果酸，柠檬酸，葡糖酸，抗坏血酸，尼古丁酸，异尼古丁酸，甲磺酸或乙磺酸，乙二磺酸，2-羟乙磺酸，苯磺酸，对甲苯磺酸，萘磺酸或萘二磺酸以及月桂磺酸。与生理上不可接受的酸生成的盐，如苦味酸盐，可用来分离和/或提纯通式Ⅰ的化合物。
如果希望制成游离碱，可以用强碱如氢氧化钠或氢氧化钾或碳酸钠或碳酸钾来处理相应的盐，使游离碱从母体盐中释出。
还能够将通式Ⅰ(R3=H)的羧酸转变成其金属盐或铵盐，例如通过与适当的碱反应可制得钠盐、钾盐或钙盐。
通式Ⅰ的化合物含有一个或多个手性中心，因而可以外消旋的形式或光学活性形式存在。所得到的外消旋体可通过本质上已知的物理或化学方法拆分成对映体。最好通过与光学活性拆分试剂的反应，使外消旋体生成非对映体。合适的拆分试剂有光学活性的酸，如D-型和L-型的酒石酸，二乙酰基酒石酸，二苯甲酰基酒石酸，扁桃酸，苹果酸，乳酸或各种光学活性的樟脑磺酸如β-樟脑磺酸。借助于填充有光学活性拆分试剂(如二硝苯甲酰苯基甘氨酸)的栓层析来拆分对映体也是有利的；一种合适的洗脱剂为如己烷/异丙醇/乙腈的混合溶剂，其体积比为82∶15∶3。
当然，还可按照上述方法，利用光学活性的原料(如通式Ⅱ的化合物)来获得通式Ⅰ的光学活性化合物。
通式Ⅰ的新化合物及其生理上可以接受的盐类可以用来制造药物组合物，制造时将它与至少一种赋形剂或助剂相混合必要时还可加入一种或多种其它活性物质，制成合适的剂型。所得到的组合物制剂可用来作为人药或兽药。合适的赋型剂为有机或无机物，它们适于肠道(如口服或直肠的)或非肠道给药，或适于以吸入喷雾剂形式给药，这些赋型剂不与这类新化合物反应，例如水、植物油、苄醇、聚乙二醇，甘油三羧酸酯或其它脂肪酸甘油酯，明胶，大豆卵磷脂，碳水化合物如乳糖或淀粉，硬脂酸镁，滑石粉或纤维素都是适用的赋型剂。对于口服给药，片剂，包衣片剂，胶囊，糖浆，糖汁或滴剂特别合适。肠溶包衣片剂和胶囊更引人有吸收力。对于直肠给药，应使用栓剂，对于非肠道给药用溶液，油剂或水剂更好，以及悬浮剂、乳剂或植入剂。
对于吸入喷雾给药，气雾剂中的活性物质既可溶解于也可悬浮在喷射混合物中。这种情况下活性化合物可容易地制成微粒型，可以允许一种或多种外加的生理上可以耐受的溶剂存在，如乙醇。吸入的液体可借于普通的吸入器给药。这些新化合物也可以冷冻干燥，所得的冻干产品可用于生产注射剂。这些制剂可以呈无菌的，和/或者含有辅助剂如防腐剂，稳定剂和/或保湿剂，乳化剂，调节渗透压的盐类，缓冲物，着色剂和/或芳香化合物。如果需要，还可加入一种或多种活性化合物，如一种或几种维生素。
通常本发明的化学物质，其给药剂量与其它商业上所售的药物类似，尤其与EP-A-459 256中所描述的化合物类似，在约5mg-1g/每剂量单位之间，尤其为每个剂量单位50和500mg。日服剂量约每公斤体重0.1～20mg，尤其为每公斤体重1～10mg。每一病人的具体剂量，由各种因素决定，如所服具体化合物的活性，年龄，体重，总的健康状况，性别，饮食，给药时间与途径，***速率，合用的药物及所治疗病情的严重性。口服给药优先考虑。
本文所指的所有温度均指℃，以下实施例中“常规后处理”指：加水，如果需要，按照终产物的结构，调节PH为2～8，通过离子交换柱过滤，有机相用无水硫酸钠干燥后，蒸发，如需要，冷冻干燥，产品用硅胶柱层析和/或重结晶纯化。
实施例1
3.0g的3-(-BOC-4-哌啶基)-5-甲磺酰氯甲基噁唑烷-2-酮[1-BOC-4-氨基哌啶与2,3-环氧-1-丙醇反应而得到4-(2,3-二羟基丙基氨基)哌啶，在叔丁醇钾的存在下与硫酸二乙酯反应得到3-(1-BOC-4-哌啶基-5-羟基甲基噁唑烷-2-酮，接着用甲磺酰氯进行酯化]溶于10ml的DMF中，加入到1.6g3-哌嗪丙酸甲酯(“A”)[由3-氯丙酸甲酯与哌嗪反应制得]与20mlDMF的溶液中，混合物在室温下搅拌60分钟，除去溶剂，按常法后处理，得到3-(1-BOC-4-哌啶基)-5-[4-(2-甲氧羰乙基)-哌嗪基]-甲基噁唑烷-2-酮；
下列化合物可以用类似方法，通过“A”与下列物质反应制得，“A”与3-(1-苄基-4-哌啶基)-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-(1-苄基-4-哌啶基)-5-[4-(2-甲氧羰乙基)哌
嗪基]甲基噁唑烷-2-酮，m.p.86～87℃“A”与3-(1-N-BOC-咪基-4-哌啶基)-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-(1-N-BOC-咪基-4-哌啶基)-5-[4-(2-甲氧
羰基乙基)哌嗪基]甲基噁唑烷-2-酮；“A”与3-(1-苄基-4-哌啶基甲基)-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-(1-苄基-4-哌啶基甲基)-5-[4-(2-甲氧羰乙基)哌嗪基]甲基噁唑烷-2-酮；“A”与3-(1-N-BOC-甲基-4-哌啶基甲基)-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-(1-N-BOC-咪基-4-哌啶基甲基)-5-[4-(2-
甲氧羰乙基)哌嗪基]甲基噁唑烷-2-酮；“A”与3-[2-(1-苄基-4-哌啶基)乙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[2-(1-苄基-4-哌啶基)乙基]-5-[4-(2-甲
氧羰乙基)哌嗪基]甲基噁唑烷-2-酮；“A”与3-[2-(1-N-BOC-咪基-4-哌啶基)乙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[2-(1-N-BOC-咪基-4-哌啶基)乙基]-5-[4-
(2-甲氧羰乙基)哌嗪基]甲基噁唑烷-2-酮；“A”与3-[3-(1-苄基-4-哌啶基)丙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[3-(1-苄基-4-哌啶基)丙基]-5-[4-(2-甲
氧羰乙基)哌嗪基]甲基噁唑烷-2-酮；“A”与3-[3(1-N-BOC-咪基-4-哌啶基)丙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[3(1-N-BOC-咪基-4-哌啶基)丙基]-5-[4-
(2-甲氧羰基)哌嗪基]甲基噁唑烷-2-酮；“A”与3-[4-(1-苄基-4-哌啶基)丁基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[4-(1-苄基-4-哌啶基)丁基]-5-[4-(2-甲
氧羰乙基)哌嗪基]甲基噁唑烷-2-酮；“A”与3-[4-(1-N-BOC-咪基-4-哌啶基)丁基-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[4-(1-N-BOC-咪基-4-哌啶基)丁基]-5-[4-
(2-甲氧羰乙基)哌嗪基]甲基噁唑烷-2-酮；“A”与3-[2-(1-苄基-4-哌嗪基)乙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[2-(1-苄基-4-哌嗪基)乙基]-5-[4-(2-甲
氧羰乙基)哌嗪基]甲基噁唑烷-2-酮；“A”与3-[2-(1-N-BOC-咪基-4-哌嗪基)乙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[2-(1-N-BOC-咪基-4-哌嗪基)乙基]-5-[4-
(2-甲氧羰乙基)哌嗪基]甲基噁唑烷-2-酮；“A”与3-[3-(1-苄基-4-哌嗪基)丙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[3-(1-苄基-4-哌嗪基)丙基]-5-[4-(2-甲
氧羰乙基)哌嗪基]甲基噁唑烷-2-酮；“A”与3-[3-(1-N-BOC-咪基-4-哌嗪基)丙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[3-(1-N-BOC-咪基-4-哌嗪基)丙基]-5-[4-
(2-甲氧羰乙基)哌嗪基]甲基噁唑烷-2-酮；“A”与3-[4-(1-苄基-4-哌嗪基)丁基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[4-(1-苄基-4-哌嗪基)丁基]-5-[4-(2-甲
氧羰乙基)哌嗪基]甲基噁唑烷-2-酮；“A”与3-[4-(1-N-BOC-咪基-4-哌嗪基)丁基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[4-(1-N-BOC-咪基-4-哌嗪基)丁基]-5-[4-
(2-甲氧羰乙基)哌嗪基]甲基噁唑烷-2-酮；“A”与3-(1-甲基-4-哌啶基)-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-(1-甲基-4-哌啶基)-5-[4-(2-甲氧羰乙基)哌
嗪基]甲基噁唑烷-2-酮；“A”与3-(1-异丙基-4-哌啶基)-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-(1-异丙基-4-哌啶基)-5-[4-(2-甲氧羰乙
基)哌嗪基]甲基噁唑烷-2-酮；“A”与3-(1-叔丁基-4-哌啶基甲基)-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-(1-叔丁基-4-哌啶甲基)-5-[4-(2-甲氧羰乙
基)哌嗪基]甲基噁唑烷-2-酮；“A”与3-(1-乙基-4-哌啶甲基)-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-(1-乙基-4-哌啶甲基)-5-[4-(2-甲氧羰乙
基)哌嗪基]甲基噁唑烷-2-酮；“A”与3-[2-(1-异丙基-4-哌啶基)乙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[2-(1-异丙基-4-哌啶基)乙基]-5-[4-(2-
甲氧羰乙基)哌嗪基]甲基噁唑烷-2-酮；“A”与3-[2-(1-环己基-4-哌啶基)乙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[2-(1-环己基-4-哌啶基)乙基]-5-[4-(2-
甲氧羰乙基)哌嗪基]甲基噁唑烷-2-酮；“A”与3-[3-(1-甲基-4-哌啶基)丙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[3-(1-甲基-4-哌啶基)丙基]-5-[4-(2-甲
氧羰乙基)哌嗪基]甲基噁唑烷-2-酮；“A”与3-[3-(1-环戊基-4-哌啶基)丙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[3-(1-环戊基-4-哌啶基)丙基]-5-[4-(2-
甲氧羰乙基)哌嗪基]甲基噁唑烷-2-酮；“A”与3-[4-(1-叔丁基-4-哌啶基)丁基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[4-(1-叔丁基-4-哌啶基)丁基]-5-[4-(2-
甲氧羰乙基)哌嗪基]甲基噁唑烷-2-酮；“A”与3-[4-(1-环丙基-4-哌啶基)丁基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[4-(1-环丙基-4-哌啶基)丁基]-5-[4-(2-
甲氧羰乙基)哌嗪基]甲基噁唑烷-2-酮；“A”与3-[2-(1-甲基-4-哌嗪基)乙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[2-(1-甲基-4-哌嗪基)乙基]-5-[4-(2-甲
氧羰乙基)哌嗪基]甲基噁唑烷-2-酮；“A”与3-[2-(1-环丙基-4-哌嗪基)乙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[2-(1-环丙基-4-哌嗪基)乙基]-5-[4-(2-
甲氧羰乙基)哌嗪基]甲基噁唑烷-2-酮；“A”与3-[3-(1-乙基-4-哌嗪基)丙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[3-(1-乙基-4-哌嗪基)丙基]-5-[4-(2-甲
氧羰乙基)哌嗪基]甲基噁唑烷-2-酮；“A”与3-[3-(1-异丙基-4-哌嗪基)丙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[3-(1-异丙基-4-哌嗪基)丙基]-5-[4-(2-
甲氧羰乙基)哌嗪基]甲基噁唑烷-2-酮；“A”与3-[4-(1-丙基-4-哌嗪基)丁基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[4-(1-丙基-4-哌嗪基)丁基]-5-[4-(2-甲
氧羰乙基)哌嗪基]甲基噁唑烷-2-酮；“A”与3-[4-(1-环己基-4-哌嗪基)丁基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[4-(1-环己基-4-哌嗪基)丁基]-5-[4-(2-
甲氧羰乙基)哌嗪基]甲基噁唑烷-2-酮；
实施例2
类似于实施例1，2.2g的3-哌嗪基丙酸苄酯(“B”)与2.6g的3-(1-苄基-4-哌啶基)-5-甲磺酰氧基甲基噁唑-2-酮反应，可得到3-(1-苄基-4-哌啶基)-5-[4-(2-苄氧羰乙基)哌嗪基]甲基噁唑烷-2-酮，m.p91-92℃
用类似的方法通过“B”的反应可得下列化合物，“B”与3-(1-苄基-4-哌啶基甲基)-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-(1-苄基-4-哌啶甲基)-5-[4-(2-苄氧羰乙
基)哌嗪基]甲基噁唑烷-2-酮；“B”与3-[2-(1-苄基-4-哌啶基)乙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[2-(1-苄基-4-哌啶基)乙基]-5-[4-(2-苄
氧羰乙基)哌嗪基]甲基噁唑烷-2-酮；“B”与3-[3-(1-苄基-4-哌啶基)丙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[3-(1-苄基-4-哌啶基)丙基]-5-[4-(2-苄
氧羰乙基)哌嗪基]甲基噁唑烷-2-酮；“B”与3-[4-(1-苄基-4-哌啶基)丁基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[4-(1-苄基-4-哌啶基)丁基]-5-[4-(2-苄
氧羰乙基)哌嗪基]甲基噁唑烷-2-酮；
实施例3
与实施例1类似，以2-哌嗪基乙酸甲酯为原料[由α-氯代乙酸甲酯与哌嗪反应而制得]，与3-(1-BOC-哌啶基)-5-甲磺酰氧甲基噁唑-2-酮反应，常法后处理，得到3-(1-BOC-4-哌啶基)-5-[4-甲氧羰甲基)哌嗪基]甲基噁唑烷-2-酮。
下列化合物可用类似的方法得到，由2-哌嗪基乙酸甲酯，与3-(1-苄基-4-哌啶基)-5-甲磺酰氧甲基噁唑烷-2-酮反应，制得
3-(1-苄基-4-哌啶基)-5-[4-甲氧羰甲基)哌嗪
基]甲基噁唑烷-2-酮；与3-(1-N-BOC-咪基-4-哌啶基)-5-甲磺酰氧甲基噁唑烷-2-酮反应，制得
3-(1-N-BOC-咪基-4-哌啶基)-5-[4-甲氧羰甲
基)哌嗪基]甲基噁唑烷-2-酮；与3-(1-苄基-4-哌啶基甲基)-5-甲磺酰氧甲基噁唑烷-2-酮反应，制得
3-(1-苄基-4-哌啶基甲基)-5-[4-甲氧羰甲基)哌
嗪基]甲基噁唑烷-2-酮；与3-(1-N-BOC-咪基-4-哌啶基甲基)-5-甲磺酰氧甲基噁唑烷-2-酮反应，制得
3-(1-N-BOC-咪基-4-哌啶甲基)-5-[4-甲氧羰甲
基)哌嗪基]甲基噁唑烷-2-酮；；与3-[2-(1-苄基-4-哌啶基)乙基]-5-甲磺酰氧甲基噁唑烷-2-酮反应，制得
3-[2-(1-苄基-4-哌啶基)乙基]-5-[4-甲氧羰
甲基)哌嗪基]甲基噁唑烷-2-酮；与3-[2-(1-N-BOC-咪基-4-哌啶基)乙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[2-(1-N-BOC-咪基-4-哌啶基)乙基]-5-[4-
甲氧羰甲基)哌嗪基]甲基噁唑烷-2-酮；与3-[3-(1-苄基-4-哌啶基)丙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[3-(1-苄基-4-哌啶基)丙基]-5-[4-甲氧羰
甲基)哌嗪基]-甲基噁唑烷-2-酮；与3-[3-(1-N-BOC-咪基-4-哌啶基)丙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[3-(1-N-BOC-咪基-4-哌啶基)丙基]-5-[4-
甲氧羰甲基)哌嗪基]甲基噁唑烷-2-酮；与3-[4-(1-苄基-4-哌啶基)丁基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[4-(1-苄基-4-哌啶基)丁基]-5-[4-(甲氧
羰甲基)哌嗪基]甲基噁唑烷-2-酮；与3-[4-(1-N-BOC-咪基-4-哌啶基)丁基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[4-(1-N-BOC-咪基-4-哌啶基)丁基]-5-[4-
(甲氧羰甲基)哌嗪基]甲基噁唑烷-2-酮；与3-[2-(1-苄基-4-哌嗪基)乙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[2-(1-苄基-4-哌嗪基)乙基]-5-[4-(甲氧
羰甲基)哌嗪基]甲基噁唑烷-2-酮；与3-[2-(1-N-BOC-咪基-4-哌嗪基)乙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[2-(1-N-BOC-咪基-4-哌嗪基)乙基]-5-[4-
(甲氧羰甲基)哌嗪基]甲基噁唑烷-2-酮；与3-[3-(1-苄基-4-哌嗪基)丙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[3-(1-苄基-4-哌嗪基)丙基]-5-[4-(甲氧
羰甲基)哌嗪基]甲基噁唑烷-2-酮；与3-[3-(1-N-BOC-咪基-4-哌嗪基)丙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[3-(1-N-BOC-咪基-4-哌嗪基)丙基]-5-[4-
(甲氧羰甲基)哌嗪基]甲基噁唑烷-2-酮；与3-[4-(1-苄基-4-哌嗪基)丁基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[4-(1-苄基-4-哌嗪基)丁基]-5-[4-(甲氧
羰甲基)哌嗪基]甲基噁唑烷-2-酮；与3-[4-(1-N-BOC-咪基-4-哌嗪基)丁基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[4-(1-N-BOC-咪基-4-哌嗪基)丁基]-5-[4-
(甲氧羰甲基)哌嗪基]甲基噁唑烷-2-酮；与3-(1-甲基-4-哌啶基)-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-(1-甲基-4-哌啶基)-5-[4-(甲氧羰甲基)哌嗪
基]甲基噁唑烷-2-酮；与3-(1-异丙基-4-哌啶基)-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-(1-异丙基-4-哌啶基)-5-[4-(甲氧羰甲基)哌
嗪基]甲基噁唑烷-2-酮；与3-(1-叔丁基-4-哌啶基甲基)-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-(1-叔丁基-4-哌啶基甲基)-5-[4-(甲氧羰甲
基)哌嗪基]甲基噁唑烷-2-酮；与3-(1-乙基-4-哌啶甲基)-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-(1-乙基-4-哌啶基甲基)-5-[4-(甲氧羰甲基)
哌嗪基]甲基噁唑烷-2-酮；与3-[2-(1-异丙基-4-哌啶基)乙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[2-(1-异丙基-4-哌啶基)乙基]-5-[4-(甲
氧羰甲基)哌嗪]甲基噁唑烷-2-酮；与3-[2-(1-环己基-4-哌啶基)乙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[2-(1-环己基-4-哌啶基)乙基]-5-[4-(甲
氧羰甲基)哌嗪基]甲基噁唑烷-2-酮；与3-[3-(1-甲基-4-哌啶基)丙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[3-(1-甲基-4-哌啶基)丙基]-5-[4-(甲氧
羰甲基)哌嗪基]甲基噁唑烷-2-酮；与3-[3-(1-环戊基-4-哌啶基)丙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[3-(1-环戊基-4-哌啶基)丙基]-5-[4-(甲
氧羰甲基)哌嗪基]甲基噁唑烷-2-酮；与3-[4-(1-叔丁基-4-哌啶基)丁基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[4-(1-叔丁基-4-哌啶基)丁基]-5-[4-(甲
氧羰甲基)哌嗪基]甲基噁唑烷-2-酮；与3-[4-(1-环丙基-4-哌啶基)丁基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[4-(1-环丙基-4-哌啶基)丁基]-5-[4-(甲
氧羰甲基)哌嗪基]甲基噁唑烷-2-酮；与3-[2-(1-甲基-4-哌嗪基)乙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[2-(1-甲基-4-哌嗪基)乙基]-5-[4-(甲氧
羰甲基)哌嗪基]甲基噁唑烷-2-酮；与3-[2-(1-环丙基-4-哌嗪基)乙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[2-(1-环丙基-4-哌嗪基)乙基]-5-[4-(甲
氧羰甲基)哌嗪基]甲基噁唑烷-2-酮；与3-[3(1-乙基-4-哌嗪基)丙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[3-(1-乙基-4-哌嗪基)丙基]-5-[4-(甲氧
羰甲基)哌嗪基]甲基噁唑烷-2-酮；与3-[3-(1-异丙基-4-哌嗪基)丙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[3-(1-异丙基-4-哌嗪基)丙基]-5-[4-(甲
氧羰甲基)哌嗪基]甲基噁唑烷-2-酮；与3-[4-(1-丙基-4-哌嗪基)丁基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[4-(1-丙基-4-哌嗪基)丁基]-5-[4-(甲氧
羰甲基)哌嗪基]甲基噁唑烷-2-酮；与3-[4-(1-环己基-4-哌嗪基)丁基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[4-(1-环己基-4-哌嗪基)丁基]-5-[4-(甲
氧羰甲基)哌嗪基]甲基噁唑烷-2-酮；
下列化合物可以用类似方法，通过4-哌嗪基丁酸甲酯的反应制得，与3-(1-苄基-4-哌啶基)-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-(1-苄基-4-哌啶基)-5-[4-(3-甲氧羰丙基)哌
嗪基]甲基噁唑烷-2-酮；与3-(1-N-BOC-咪基-4-哌啶基)-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-(1-N-BOC-咪基-4-哌啶基)-5-[4-(3-甲氧
羰丙基)哌嗪基]甲基噁唑烷-2-酮；与3-(1-苄基-4-哌啶基甲基)-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-(1-苄基-4-哌啶基甲基)-5-[4-(3-甲氧羰丙
基)哌嗪基]甲基噁唑烷-2-酮；与3-(1-N-BOC-咪基-4-哌啶基甲基)-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-(1-N-BOC-咪基-4-哌啶基甲基)-5-[4-(3-
甲氧羰丙基)哌嗪基]甲基噁唑烷-2-酮；与3-[2-(1-苄基-4-哌啶基)乙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[2-(1-苄基-4-哌啶基)乙基]-5-[4-(3-甲
氧羰丙基)哌嗪基]甲基噁唑烷-2-酮；与3-[2-(1-N-BOC-咪基-4-哌啶基)乙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[2-(1-N-BOC-咪基-4-哌啶基)乙基]-5-[4-
(3-甲氧羰丙基)哌嗪基]甲基噁唑烷-2-酮；与3-[3-(1-苄基-4-哌啶基)丙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[3-(1-苄基-4-哌啶基)丙基]-5-[4-(3-甲
氧羰丙基)哌嗪基]甲基噁唑烷-2-酮；与3-[3-(1N-BOC-咪基-4-哌啶基)丙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[3-(1N-BOC-咪基-4-哌啶基)丙基]-5-[4-
(3-甲氧羰丙基)哌嗪基]甲基噁唑烷-2-酮；与3-[4-(1-苄基-4-哌啶基)丁基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[4-(1-苄基-4-哌啶基)丁基]-5-[4-(3-甲
氧羰丙基)哌嗪基]甲基噁唑烷-2-酮；与3-[4-(1-N-BOC-咪基-4-哌啶基)丁基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[4-(1-N-BOC-咪基-4-哌啶基)丁基]-5-[4-
(3-甲氧羰丙基)哌嗪基]甲基噁唑烷-2-酮；与3-[2-(1-苄基-4-哌嗪基)乙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[2-(1-苄基-4-哌嗪基)乙基]-5-[4-(3-甲
氧羰丙基)哌嗪基]甲基噁唑烷-2-酮；与3-[2-(1-N-BOC-咪基-4-哌嗪基)乙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[2-(1-N-BOC-咪基-4-哌嗪基)乙基]-5-[4-
(3-甲氧羰丙基)哌嗪基]甲基噁唑烷-2-酮；与3-[3-(1-苄基-4-哌嗪基)丙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[3-(1-苄基-4-哌嗪基)丙基]-5-[4-(3-甲
氧羰丙基)哌嗪基]甲基噁唑烷-2-酮；与3-[3-(1-N-BOC-咪基-4-哌嗪基)丙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[3-(1-N-BOC-咪基-4-哌嗪基)丙基]-5-[4-
(3-甲氧羰丙基)哌嗪基]甲基噁唑烷-2-酮；与3-[4-(1-苄基-4-哌嗪基)丁基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[4-(1-苄基t-4-哌嗪基)丁基]-5-[4-(3-甲
氧羰丙基)哌嗪基]甲基噁唑烷-2-酮；与3-[4-(1-N-BOC-咪基-4-哌嗪基)丁基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[4-(1-N-BOC-咪基-4-哌嗪基)丁基]-5-[4-
(3-甲氧羰丙基)哌嗪基]甲基噁唑烷-2-酮；与3-(1-甲基-4-哌啶基)-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-(1-甲基-4-哌啶基)-5-[4-(3-甲氧羰丙基)哌
嗪基]甲基噁唑烷-2-酮；与3-(1-异丙基-4-哌啶基)-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-(1-异丙基-4-哌啶基)-5-[4-(3-甲氧羰丙
基)哌嗪基]甲基噁唑烷-2-酮；与3-(1-叔丁基-4-哌啶基甲基)-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-(1-叔丁基-4-哌啶基甲基)-5-[4-(3-甲氧羰
丙基)哌嗪基]甲基噁唑烷-2-酮；与3-(1-乙基-4-哌啶基甲基)-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-(1-乙基-4-哌啶基甲基)-5-[4-(3-甲氧羰丙
基)哌嗪基]甲基噁唑烷-2-酮；与3-[2-(1-异丙基-4-哌啶基)乙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[2-(1-异丙基-4-哌啶基)乙基]-5-[4-(3-
甲氧羰丙基)哌嗪基]甲基噁唑烷-2-酮；与3-[2-(1-环己基-4-哌啶基)乙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[2-(1-环己基-4-哌啶基)乙基]-5-[4-(3-
甲氧羰丙基)哌嗪基]甲基噁唑烷-2-酮；与3-[3-(1-甲基-4-哌啶基)丙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[3-(1-甲基-4-哌啶基)丙基]-5-[4-(3-甲
氧羰丙基)哌嗪基]甲基噁唑烷-2-酮；与3-[3-(1-环戊基-4-哌啶基)丙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[3-(1-环戊基-4-哌啶基)丙基]-5-[4-(3-
甲氧羰丙基)哌嗪基]甲基噁唑烷-2-酮；与3-[4-(1-叔丁基-4-哌啶基)丁基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[4-(1-叔丁基-4-哌啶基)乙基]-5-[4-(3-
甲氧羰丙基)哌嗪基]甲基噁唑烷-2-酮；与3-[4-(1-环丙基-4-哌啶基)丁基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[4-(1-环丙基-4-哌啶基)丁基]-5-[4-(3-
甲氧羰丙基)哌嗪基]甲基噁唑烷-2-酮；与3-[2-(1-甲基-4-哌嗪基)乙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[2-(1-甲基-4-哌嗪基)乙基]-5-[4-(3-甲
氧羰丙基)哌嗪基]甲基噁唑烷-2-酮；与3-[2-(1-环丙基-4-哌嗪基)乙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[2-(1-环丙基-4-哌嗪基)乙基]-5-[4-(3-
甲氧羰丙基)哌嗪基]甲基噁唑烷-2-酮；与3-[3-(1-乙基-4-哌嗪基)丙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[3-(1-乙基-4-哌嗪基)丙基]-5-[4-(3-甲
氧羰丙基)哌嗪基]甲基噁唑烷-2-酮；与3-[3-(1-异丙基-4-哌嗪基)丙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[3-(1-异丙基-4-哌嗪基)丙基]-5-[4-(3-
甲氧羰丙基)哌嗪基]甲基噁唑烷-2-酮；与3-[4-(1-丙基-4-哌嗪基)丁基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[4-(1-丙基-4-哌嗪基)丁基]-5-[4-(3-甲
氧羰丙基)哌嗪基]甲基噁唑烷-2-酮；与3-[4-(1-环己基-4-哌嗪基)丁基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，制得
3-[4-(1-环己基-4-哌嗪基)丁基]-5-[4-(3-
甲氧羰丙基)哌嗪基]甲基噁唑烷-2-酮；
实施例4
0.6g的3-(1-BOC-4-哌啶基)-5-[4-(2-甲氧羰乙基)哌嗪基]甲基噁唑烷-2-酮[按实施例1制得]悬浮在40ml 2NHCl的二氧六环溶液中，此混合物室温下搅拌3小时，除去溶剂，常法后处理，得到3-(4-哌啶基)-5-[4-(2-甲氧羰乙基)哌嗪基]甲基噁唑烷-2-酮的盐酸盐。
下列化合物可用类似的方法，通过除去实施例1中制得化合物的BOC保护基而制得。3-(1-咪基-4-哌啶基)-5-[4-(2-甲氧羰乙基)哌嗪基]甲基噁唑烷-2-酮；3-(1-咪基-4-哌啶基甲基)-5-[4-(2-甲氧羰乙基)哌嗪基]甲基噁唑烷-2-酮；3-[2-(1-咪基-4-哌啶基)乙基]-5-[4-(2-甲氧羰乙基)哌嗪基]甲基噁唑烷-2-酮；3-[3-(1-咪基-4-哌啶基)丙基]-5-[4-(2-甲氧羰乙基)哌嗪基]甲基噁唑烷-2-酮；3-[4-(1-咪基-4-哌啶基)丁基]-5-[4-(2-甲氧羰乙基)哌嗪基]甲基噁唑烷-2-酮；3-[2-(1-咪基-4-哌嗪基)乙基]-5-[4-(2-甲氧羰乙基)哌嗪基]甲基噁唑烷-2-酮；3-[3-(1-咪基-4-哌嗪基)丙基]-5-[4-(2-甲氧羰乙基)哌嗪基]甲基噁唑烷-2-酮；3-[4-(1-咪基-4-哌嗪基)丁基]-5-[4-(2-甲氧羰乙基)哌嗪基]甲基噁唑烷-2-酮；
实施例5
类似于实施例4，以实施例3中的化合物为原料，下列化合物的盐酸盐可通过除去BOC保护基而得到：3-(4-哌啶基)-5-[4-(甲氧羰甲基)哌嗪基]甲基噁唑-2-酮3-(1-咪基-4-哌啶基)-5-[4-(甲氧羰甲基)哌嗪基]甲基噁唑烷-2-酮；3-(1-咪基-4-哌啶基甲基)-5-[4-(甲氧羰甲基)哌嗪基]甲基噁唑烷-2-酮；3-[2-(1-咪基-4-哌啶基)乙基]-5-[4-(甲氧羰甲基)哌嗪基]甲基噁唑烷-2-酮；3-[3-(1-咪基-4-哌啶基)丙基]-5-[4-(甲氧羰甲基)哌嗪基]甲基噁唑烷-2-酮；3-[4-(1-咪基-4-哌啶基)丁基]-5-[4-(甲氧羰甲基)哌嗪基]甲基噁唑烷-2-酮；3-[2-(1-咪基-4-哌嗪基)乙基]-5-[4-(甲氧羰甲基)哌嗪基]甲基噁唑烷-2-酮；3-[3-(1-咪基-4-哌嗪基)丙基]-5-[4-(甲氧羰甲基)哌嗪基]甲基噁唑烷-2-酮；3-[4-(1-咪基-4-哌嗪基)丁基]-5-[4-(甲氧羰甲基)哌嗪基]甲基噁唑烷-2-酮；3-(1-咪基-4-哌啶基)-5-[4-(3-甲氧羰丙基)哌嗪基]甲基噁唑烷-2-酮3-(1-咪基-4-哌啶基甲基)-5-[4-(3-甲氧羰丙基)哌嗪基]甲基噁唑烷-2-酮；3-[2-(1-咪基-4-哌啶基)乙基)-5-[4-(3-甲氧羰丙基)哌嗪基]甲基噁唑烷-2-酮；3-[3-(1-咪基-4-哌啶基)丙基)-5-[4-(3-甲氧羰丙基)哌嗪基]甲基噁唑烷-2-酮；3-[4-(1-咪基-4-哌啶基)丁基)-5-[4-(3-甲氧羰丙基)哌嗪基]甲基噁唑烷-2-酮；3-[2-(1-咪基-4-哌嗪基)乙基)-5-[4-(3-甲氧羰丙基)哌嗪基]甲基噁唑烷-2-酮；3-[3-(1-咪基-4-哌嗪基)丙基)-5-[4-(3-甲氧羰丙基)哌嗪基]甲基噁唑烷-2-酮；3-[4-(1-咪基-4-哌嗪基)丁基)-5-[4-(3-甲氧羰丙基)哌嗪基]甲基噁唑烷-2-酮。
实施例6
0.8g的3-(1-BOC-4-哌啶基)-5-[4-(2-甲氧羰乙基)哌嗪基]甲基噁唑烷-2-酮[按实施例1的方法制得]悬浮于60ml甲醇中，混合物用2N NaOH水溶液处理，并室温搅拌4小时。除去溶剂，残余物用水溶解，加入稀盐酸调pH至3，反应混合物通过离子交换柱过滤。滤液用MgSO4干燥，除去溶剂，冷冻干燥，得到3-(1-BOC-4-哌啶基)-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮。
下列化合物可以按类似的方法，通过水解实施例1～5中的产物而制得：3-(1-苄基-4-哌啶基)-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-(1-N-BOC-咪基-4-哌啶基)-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-(1-苄基-4-哌啶基甲基)-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-(1-N-BOC-咪基-4-哌啶基甲基)-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-[2-(1-苄基-4-哌啶基)乙基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-[2-(1-N-BOC-咪基-4-哌啶基)乙基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-[3-(1-苄基-4-哌啶基)丙基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-[3-(1-N-BOC-咪基-4-哌啶基)丙基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-[4-(1-苄基-4-哌啶基)丁基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-[4-(1-N-BOC-咪基-4-哌啶基)丁基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-[2-(1-苄基-4-哌嗪基)乙基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-[2-(1-N-BOC-咪基-4-哌嗪基)乙基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-[3-(1-苄基-4-哌嗪基)丙基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-[3-(1-N-BOC-咪基-4-哌嗪基)丙基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-[4-(1-苄基-4-哌嗪基)丁基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-[4-(1-N-BOC-咪基-4-哌嗪基)丁基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-(1-甲基-4-哌啶基)-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-(1-异丙基-4-哌啶基)-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-(1-叔丁基-4-哌啶基甲基)-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-(1-乙基-4-哌啶基甲基)-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-[2-(1-异丙基-4-哌啶基)乙基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-[2-(1-环己基-4-哌啶基)乙基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-[3-(1-甲基-4-哌啶基)丙基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-[3-(1-环戊基-4-哌啶基)丙基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-[4-(1-叔丁基-4-哌啶基)丁基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-[4-(1-环丙基-4-哌啶基)丁基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-[2-(1-甲基-4-哌嗪基)乙基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-[2-(1-环丙基-4-哌嗪基)乙基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-[3-(1-乙基-4-哌嗪基)丙基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-[3-(1-异丙基-4-哌嗪基)丙基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-[4-(1-丙基-4-哌嗪基)丁基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-[4-(1-环己基-4-哌嗪基)丁基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-(1-苄基-4-哌啶基)-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-(1-苄基-4-哌啶基甲基)-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-[2-(1-苄基-4-哌啶基)乙基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-[3-(1-苄基-4-哌啶基)丙基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-[4-(1-苄基-4-哌啶基)丁基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-(1-BOC-4-哌啶基)-5-[4-羧甲基哌嗪基]甲基噁唑烷-2-酮；3-(1-苄基-4-哌啶基)-5-[4-羧甲基哌嗪基]甲基噁唑烷-2-酮；3-(1-N-BOC-咪基-4-哌啶基)-5-[4-羧甲基哌嗪基]甲基噁唑烷-2-酮；3-(1-苄基-4-哌啶基甲基)-5-[4-(羧甲基哌嗪基]甲基噁唑烷-2-酮；3-(1-N-BOC-咪基-4-哌啶基甲基)-5-[4-羧甲基哌嗪基]甲基噁唑烷-2-酮；3-[2-(1-苄基-4-哌啶基)乙基]-5-[4-(羧甲基哌嗪基]甲基噁唑烷-2-酮；3-[2-(1-N-BOC-咪基-4-哌啶基)乙基]-5-[4-(羧甲基哌嗪基]甲基噁唑烷-2-酮；3-[3-(1-苄基-4-哌啶基)丙基]-5-[4-(羧甲基哌嗪基]甲基噁唑烷-2-酮；3-[3-(1-N-BOC-咪基-4-哌啶基)丙基]-5-[4-(羧甲基哌嗪基]甲基噁唑烷-2-酮；3-[4-(1-苄基-4-哌啶基)丁基]-5-[4-(羧甲基哌嗪基]甲基噁唑烷-2-酮；3-[4-(1-N-BOC-咪基-4-哌啶基)丁基]-5-[4-(羧甲基哌嗪基]甲基噁唑烷-2-酮；3-[2-(1-苄基-4-哌嗪基)乙基]-5-[4-(羧甲基哌嗪基]甲基噁唑烷-2-酮；3-[2-(1-N-BOC-咪基-4-哌嗪基)乙基]-5-[4-(羧甲基哌嗪基]甲基噁唑烷-2-酮；3-[3-(1-苄基-4-哌嗪基)丙基]-5-[4-(羧甲基哌嗪基]甲基噁唑烷-2-酮；3-[3-(1-N-BOC-咪基-4-哌啶基)丙基]-5-[4-(羧甲基哌嗪基]甲基噁唑烷-2-酮；3-[4-(1-苄基-4-哌嗪基)丁基]-5-[4-(羧甲基哌嗪基]甲基噁唑烷-2-酮；3-[4-(1-N-BOC-咪基-4-哌嗪基)丁基]-5-[4-(羧甲基哌嗪基]甲基噁唑烷-2-酮；3-(1-甲基-4-哌啶基)-5-[4-羧甲基哌嗪基]甲基噁唑烷-2-酮；3-(1-异丙基-4-哌啶基)-5-[4-羧甲基哌嗪基]甲基噁唑烷-2-酮；3-(1-叔丁基-4-哌啶基甲基)-5-[4-羧甲基哌嗪基]甲基噁唑烷-2-酮；3-(1-乙基-4-哌啶基甲基)-5-[4-羧甲基哌嗪基]甲基噁唑烷-2-酮；3-[2-(1-异丙基-4-哌啶基)乙基]-5-[4-羧甲基哌嗪基]甲基噁唑烷-2-酮；3-[2-(1-环己基-4-哌啶基)乙基]-5-[4-羧甲基哌嗪基]甲基噁唑烷-2-酮；3-[3-(1-甲基-4-哌啶基)丙基]-5-[4-羧甲基哌嗪基]甲基噁唑烷-2-酮；3-[3-(1-环戊基-4-哌啶基)丙基]-5-[4-羧甲基哌嗪基]甲基噁唑烷-2-酮；3-[4-(1-叔丁基-4-哌啶基)丁基]-5-[4-羧甲基哌嗪基]甲基噁唑烷-2-酮；3-[4-(1-环丙基-4-哌啶基)丁基]-5-[4-羧甲基哌嗪基]甲基噁唑烷-2-酮；3-[2-(1-甲基-4-哌嗪基)乙基]-5-[4-羧甲基哌嗪基]甲基噁唑烷-2-酮；3-[2-(1-环丙基-4-哌嗪基)乙基]-5-[4-羧甲基哌嗪基]甲基噁唑烷-2-酮；3-[3-(1-乙基-4-哌嗪基)丙基]-5-[4-羧甲基哌嗪基]甲基噁唑烷-2-酮；3-[3-(1-异丙基-4-哌嗪基)丙基]-5-[4-羧甲基哌嗪基]甲基噁唑烷-2-酮；3-[4-(1-丙基-4-哌嗪基)丁基]-5-[4-羧甲基哌嗪基]甲基噁唑烷-2-酮；
3-[4-(1-环己基-4-哌嗪基)丁基]-5-[4-羧甲基哌嗪基]甲基噁唑烷-2-酮；
3-(1-苄基-4-哌啶基)-5-[4-(3-羧丙基)哌嗪基]甲基噁唑烷-2-酮；3-(1-N-BOC-咪基-4-哌啶基)-5-[4-(3-羧丙基)哌嗪基]甲基噁唑烷-2-酮；3-(1-苄基-4-哌啶基甲基)-5-[4-(3-羧丙基)哌嗪基]甲基噁唑烷-2-酮；3-(1-N-BOC-咪基-4-哌啶基甲基)-5-[4-(3-羧丙基)哌嗪基]甲基噁唑烷-2-酮；3-[2-(1-苄基-4-哌啶基)乙基]-5-[4-(3-羧丙基)哌嗪基]甲基噁唑烷-2-酮；3-[2-(1-N-BOC-咪基-4-哌啶基)乙基]-5-[4-(3-羧丙基)哌嗪基]甲基噁唑烷-2-酮；3-[3-(1-苄基-4-哌啶基)丙基]-5-[4-(3-羧丙基)哌嗪基]甲基噁唑烷-2-酮；3-[3-(1-N-BOC-咪基-4-哌啶基)丙基]-5-[4-(3-羧丙基)哌嗪基]甲基噁唑烷-2-酮；3-[4-(1-苄基-4-哌啶基)丁基]-5-[4-(3-羧丙基)哌嗪基]甲基噁唑烷-2-酮；3-[4-(1-N-BOC-咪基-4-哌啶基)丁基]-5-[4-(3-羧丙基)哌嗪基]甲基噁唑烷-2-酮；3-[2-(1-苄基-4-哌嗪基)乙基]-5-[4-(3-羧丙基)哌嗪基]甲基噁唑烷-2-酮；3-[2-(1-N-BOC-咪基-4-哌嗪基)乙基]-5-[4-(3-羧丙基)哌嗪基]甲基噁唑烷-2-酮；3-[3-(1-苄基-4-哌嗪基)丙基]-5-[4-(3-羧丙基)哌嗪基]甲基噁唑烷-2-酮；3-[3-(1-N-BOC-咪基-4-哌嗪基)丙基]-5-[4-(3-羧丙基)哌嗪]甲基噁唑烷-2-酮；3-[4-(1-苄基-4-哌嗪基)丁基]-5-[4-(3-羧丙基)哌嗪基]甲基噁唑烷-2-酮；3-[4-(1-N-BOC-咪基-4-哌嗪基)丁基]-5-[4-(3-羧丙基)哌嗪基]甲基噁唑烷-2-酮；3-(1-甲基-4-哌啶基)-5-[4-(3-羧丙基)哌嗪基]甲基噁唑烷-2-酮；3-(1-异丙基-4-哌啶基)-5-[4-(3-羧丙基)哌嗪基]甲基噁唑烷-2-酮；3-(1-叔丁基-4-哌啶基甲基)-5-[4-(3-羧丙基)哌嗪基]甲基噁唑烷-2-酮；3-(1-乙基-4-哌啶基甲基)-5-[4-(3-羧丙基)哌嗪基]甲基噁唑烷-2-酮；3-[2-(1-异丙基-4-哌啶基)乙基]-5-[4-(3-羧丙基)哌嗪基]甲基噁唑烷-2-酮；3-[2-(1-环己基-4-哌啶基)乙基]-5-[4-(3-羧丙基)哌嗪基]甲基噁唑烷-2-酮；3-[3-(1-甲基-4-哌啶基)丙基]-5-[4-(3-羧丙基)哌嗪基]甲基噁唑烷-2-酮；3-[3-(1-环戊基-4-哌啶基)丙基]-5-[4-(3-羧丙基)哌嗪基]甲基噁唑烷-2-酮；3-[4-(1-叔丁基-4-哌啶基)丁基]-5-[4-(3-羧丙基)哌嗪基]甲基噁唑烷-2-酮；3-[4-(1-环丙基-4-哌啶基)丁基]-5-[4-(3-羧丙基)哌嗪基]甲基噁唑烷-2-酮；3-[2-(1-甲基-4-哌嗪基)乙基]-5-[4-(3-羧丙基)哌嗪基]甲基噁唑烷-2-酮；3-[2-(1-环丙基-4-哌嗪基)乙基]-5-[4-(3-羧丙基)哌嗪基]甲基噁唑烷-2-酮；3-[3-(1-乙基-4-哌嗪基)丙基]-5-[4-(3-羧丙基)哌嗪基]甲基噁唑烷-2-酮；3-[3-(1-异丙基-4-哌嗪基)丙基]-5-[4-(3-羧丙基)哌嗪基]甲基噁唑烷-2-酮；3-[4-(1-丙基-4-哌嗪基)丁基]-5-[4-(3-羧丙基)哌嗪基]甲基噁唑烷-2-酮；3-[4-(1-环己基-4-哌嗪基)丁基]-5-[4-(3-羧丙基)哌嗪基]甲基噁唑烷-2-酮；3-(4-哌啶基)-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮，m.p.217～218℃；3-(1-咪基-4-哌啶基)-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮，m.p.＞300℃；3-(1-咪基-4-哌啶基甲基)-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-[2-(1-咪基-4-哌啶基)乙基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-[3-(1-咪基-4-哌啶基)丙基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-[4-(1-咪基-4-哌啶基)丁基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-[2-(1-咪基-4-哌嗪基)乙基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-[3-(1-咪基-4-哌嗪基)丙基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-[4-(1-咪基-4-哌嗪基)丁基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮；3-(4-哌啶基)-5-[4-(羧甲基)哌嗪基]甲基噁唑烷-2-酮；3-(1-咪基-4-哌啶基)-5-[4-(羧甲基)哌嗪基]甲基噁唑烷-2-酮；3-(1-咪基-4-哌啶基甲基)-5-[4-(羧甲基)哌嗪基]甲基噁唑烷-2-酮；3-[2-(1-咪基-4-哌啶基)乙基]-5-[4-(羧甲基)哌嗪基]甲基噁唑烷-2-酮；3-[3-(1-咪基-4-哌啶基)丙基]-5-[4-(羧甲基)哌嗪基]甲基噁唑烷-2-酮；3-[4-(1-咪基-4-哌啶基)丁基]-5-[4-(羧甲基)哌嗪基]甲基噁唑烷-2-酮；3-[2-(1-咪基-4-哌嗪基)乙基]-5-[4-(羧甲基)哌嗪基]甲基噁唑烷-2-酮；3-[3-(1-咪基-4-哌嗪基)丙基]-5-[4-(羧甲基)哌嗪基]甲基噁唑烷-2-酮；3-[4-(1-咪基-4-哌嗪基)丁基]-5-[4-(羧甲基)哌嗪基]甲基噁唑烷-2-酮；3-(1-咪基-4-哌啶基)-5-[4-(3-(羧丙基)哌嗪基]甲基噁唑烷-2-酮；3-(1-咪基-4-哌啶基甲基)-5-[4-(3-(羧丙基)哌嗪基]甲基噁唑烷-2-酮；3-[2-(1-咪基-4-哌啶基)乙基]-5-[4-(3-(羧丙基)哌嗪基]甲基噁唑烷-2-酮；3-[3-(1-咪基-4-哌啶基)丙基]-5-[4-(3-(羧丙基)哌嗪基]甲基噁唑烷-2-酮；3-[4-(1-咪基-4-哌啶基)丁基]-5-[4-(3-(羧丙基)哌嗪基]甲基噁唑烷-2-酮；3-[2-(1-咪基-4-哌嗪基)乙基]-5-[4-(3-(羧丙基)哌嗪基]甲基噁唑烷-2-酮；3-[3-(1-咪基-4-哌嗪基)丙基]-5-[4-(3-(羧丙基)哌嗪基]甲基噁唑烷-2-酮；3-[4-(1-咪基-4-哌嗪基)丁基]-5-[4-(3-(羧丙基)哌嗪基]甲基噁唑烷-2-酮。
实施例7
10ml 20％NaOH水溶液加至0.3g 3-(1-咪基-4-哌啶基)-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮与20ml四氢呋喃的溶液中，混合液在室温下搅拌24小时。除去溶剂，冷冻干燥，得到3-(1-咪基-4-哌啶基)-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮的钠盐。
下列化合物可以类似方法制得3-[2-(1-咪基-4-哌啶基)乙基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮的Na盐；3-[2-(1-苄基-4-哌啶基)乙基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮的Na盐；3-[2-(1-咪基-4-哌嗪基)乙基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮的钠盐；3-[3-(4-哌啶基)丙基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮的钠盐。
实施例8
1.13g 3-[2-(1-(5-氧代-1,2,4-噁唑烷-3-基)-4-哌嗪基)乙基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑啉-2-酮[按实施例1，由3-哌嗪基丙酸甲酯与3-[2-(1-(5-氧代-1,2,4-噁唑啉-3-基)-4-哌嗪基)乙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应及后来的水解反应制备而得]溶于50ml甲醇中，以Raney-Ni作催化剂进行氢化。反应混合物过滤，滤液减压浓缩，所得产物用20ml乙酸乙酯处理并加热，冷却后吸滤，得到3-[2-(1-咪基-4-哌嗪基)乙基-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮。
下列化合物可以由类似的方法，通过还原去除5-氧代-1,2,4-噁唑啉基而制得。用3-[3-(1-(5-氧代-1,2,4-噁唑啉-3-基)-4-哌嗪基)丙基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮
得3-[3-(1-咪基-4-哌嗪基)丙基]-5-[4-(2-
羧乙基)哌嗪基]甲基噁唑烷-2-酮；用3-[4-(1-(5-氧代-1,2,4-噁唑啉-3-基)-4-哌嗪基)丁基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮
得3-[4-(1-咪基-4-哌嗪基)丁基]-5-[4-(2-
羧乙基)哌嗪基]甲基噁唑烷-2-酮；用3-[2-(1-(5-氧代-1,2,4-噁唑啉-3-基)-4-哌嗪基)乙基]-5-[4-羧甲基哌嗪基]甲基噁唑烷-2-酮
得3-[2-(1-咪基-4-哌嗪基乙基]-5-[4-羧甲基
哌嗪基]甲基噁唑烷-2-酮；用3-[3-(1-(5-氧代-1,2,4-噁唑啉-3-基)-4-哌嗪基)丙基]-5-[4-羧甲基哌嗪基]甲基噁唑烷-2-酮
得3-[3-(1-咪基-4-哌嗪基)丙基]-5-[4-羧甲
基哌嗪基]甲基噁唑烷-2-酮；用3-[4-(1-(5-氧代-1,2,4-噁唑啉-3-基)-4-哌嗪基)丁基]-5-[4-羧甲基哌嗪基]甲基噁唑烷-2-酮
得3-[4-(1-咪基-4-哌嗪基)丁基]-5-[4-(羧
甲基)哌嗪基]甲基噁唑烷-2-酮；用3-[2-(1-(5-氧代-1,2,4-噁唑啉-3-基)-4-(哌嗪基)乙基]-5-[4-(3-羧丙基)哌嗪基]甲基噁唑烷-2-酮
得3-[2-(1-咪基-4-哌嗪基)乙基]-5-[4-羧丙
基哌嗪基]甲基噁唑烷-2-酮；用3-[3-(1-(5-氧代-1,2,4-噁唑啉-3-基)-4-哌嗪基)丙基]-5-[4-(3-羧丙基)哌嗪基]甲基噁唑烷-2-酮
得3-[3-(1-咪基-4-哌嗪基)丙基]-5-[4-(3-
羧丙基)哌嗪基]甲基噁唑烷-2-酮；用3-[4-(1-(5-氧代-1,2,4-噁唑啉-3-基)-4-哌嗪基)丁基]-5-[4-(3-羧丙基)哌嗪基]甲基噁唑烷-2-酮
得3-[4-(1-咪基-4-哌嗪基)丁基]-5-[4-(3-
羧丙基)哌嗪基]甲基噁唑烷-2-酮。
实施例9
类似于实施例8，以3-[2-(1-(5-氧代-1,2,4-噁唑啉-3-基)-4-哌啶基)乙基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮[按实施例1的方法，通过3-(1-哌嗪基)丙酸甲酯与3-[2-(1-(5-氧代-1,2,4-噁唑啉-3-基)-4-哌啶基)乙基]-5-甲磺酰氧基甲基噁唑烷-2-酮反应，随后产物水解而制备]为原料，催化氢化，得到3-[2-(1-咪基-4-哌啶基)乙基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮。
下列化合物可通过还原，除去5-氧代-1,2,4-噁唑啉而制得。用3-[3-(1-(5-氧代-1,2,4-噁唑啉-3-基)-4-哌啶基)丙基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮
得3-[3-(1-咪基-4-哌嗪基)丙基]-5-[4-(2-
羧乙基)哌嗪基]甲基噁唑烷-2-酮；用3-[4-(1-(5-氧代-1,2,4-噁唑啉-3-基)-4-哌啶基)丁基]-5-[4-(2-羧乙基)哌嗪基]甲基噁唑烷-2-酮
得3-[4-(1-咪基-4-哌啶基)丁基]-5-[4-(2-
羧乙基)哌嗪基]甲基噁唑烷-2-酮；用3-[2-(1-(5-氧代-1,2,4-噁唑啉-3-基)-4-哌啶基)乙基]-5-[4-(2-羧甲基)哌嗪基]甲基噁唑烷-2-酮
得3-[2-(1-咪基-4-哌啶基)乙基]-5-[4-(羧
甲基)哌嗪基]甲基噁唑烷-2-酮；用3-[3-(1-(5-氧代-1,2,4-噁唑啉-3-基)-4-哌啶基)丙基]-5-[4-(羧甲基)哌嗪基]甲基噁唑烷-2-酮
得3-[3-(1-咪基-4-哌啶基)丙基]-5-[4-(羧
甲基)哌嗪基]甲基噁唑烷-2-酮；用3-[4-(1-(5-氧代-1,2,4-噁唑啉-3-基)-4-哌啶基)丁基]-5-[4-(羧甲基)哌嗪基]甲基噁唑烷-2-酮
得3-[4-(1-咪基-4-哌啶基)丁基]-5-[4-(羧
甲基)哌嗪基]甲基噁唑烷-2-酮；用3-[2-(1-(5-氧代-1,2,4-噁唑啉-3-基)-4-哌啶基)乙基]-5-[4-(3-羧丙基)哌嗪基]甲基噁唑烷-2-酮
得3-[2-(1-咪基-4-哌啶基)乙基]-5-[4-(3-
羧丙基)哌嗪基]甲基噁唑烷-2-酮；用3-[3-(1-(5-氧代-1,2,4-噁唑啉-3-基)-4-哌啶基)丙基]-5-[4-(3-羧丙基)哌嗪基]甲基噁唑烷-2-酮
得3-[3-(1-咪基-4-哌啶基)丙基]-5-[4-(3-
羧丙基)哌嗪基]甲基噁唑烷-2-酮；用3-[4-(1-(5-氧代-1,2,4-噁唑啉-3-基)-4-哌啶基)丁基]-5-[4-(3-羧丙基)哌嗪基]甲基噁唑烷-2-酮
得3-[4-(1-咪基-4-哌啶基)丁基]-5-[4-(3-
羧丙基)哌嗪基]甲基噁唑烷-2-酮
下列实施例涉及药物剂型的制备：
实施例A小瓶注射剂
100g通式Ⅰ的活性化合物及5g磷酸氢二钠，加双蒸水至31，用2N盐酸调节pH至6.5无菌条件下过滤，滤液装入注射用瓶，无菌条件下冷冻干燥后封口，每一注射瓶内含有5mg药物。
实施例B：栓剂
通式Ⅰ的活性化合物20g，豆卵磷脂100g，可可脂1400g，上述三种的混合物熔化后，倒入模具中冷却，每一栓剂含有20mg活性化合物。
实施例C：溶液剂
1g通式Ⅰ的活性化合物，9.38g NaH2PO4·2H2O,28.48gNa2HPO4·12H2O及0.1g btnzalkomium Chloride，溶于940ml的双蒸水，所成溶液调节pH=6.8，加水至11，照射灭菌，所制溶液可用作滴眼剂。
实施例D：软膏剂
500mg通式Ⅰ的活性化合物与99.5g凡士林在无菌条件下混合制成
实施例E：片剂
1kg通式Ⅰ的活性化合物，与4kg乳糖，1.2kg土豆淀粉，0.2kg滑石粉及0.1kg硬脂酸镁混合，混合物按常规方法压片，每片含有10mg活性化合物。
实施例F：包衣片剂
类似于实施例E，药片压好后按常规的方法包衣，包衣材料包括蔗糖、食用淀粉、滑石粉黄蓍胶者及着色剂。
实施例E胶囊
2kg通式Ⅰ的化合物，用常法填充到明胶囊壳中，每一胶囊含有20mg活性化合物。
实施例H：安瓿
1kg通式Ⅰ的活性化合物溶于601双蒸馏水中，所得溶液在无菌条件下过滤，分装，至安瓿中。无菌条件下冷却干燥，封口，每一安瓿有10mg活性化合物。
Claims (8)
1．通式Ⅰ的化合物以及它们的生理上可接受的相应盐类
其中
X为O,S,NH或NA
Y为氮丙啶基、氮杂环丁基、四氢吡咯基、哌啶子基、六氢氮杂基或哌嗪基，它们均有R2取代
R1为
R2为-CrH2r-COOR3
R3为H,A或Ar
A为含有1至6个碳原子的烷基
B为H,A，含有3至7个碳原子的环烷基，Ar-CkH2k-或脒基
Ar为无取代或被A,Cl,Br,I,NO2,CN,OA,OH,NH2,NHA和/或NA2单取代或二取代的苯基或苄基
k为1,2,3或4
m与r相互独立，为0,1,2,3,或4
n为2,3,或4。
2．根据权利要求1的通式Ⅰ的化合物的对映体。
3．权利要求1的通式Ⅰ的化合物，其游离氨基或脒基，可按常规的氨基保护方法部分或完全保护起来。
4．权利要求1的通式Ⅰ化合物，其中所述化合物选自：
(a)3-哌啶基-4-基-5-[4-(2-羧乙基)哌嗪基甲
基]噁唑烷-2-酮；
(b)3-(1-咪哌啶-4-基)-5-[4-(2-羧乙基)哌
嗪基甲基]噁唑烷-2-酮；
(c)3-(1-苄基哌啶-4-基)-5-[4-(2-甲氧羰乙
基)哌嗪基甲基]噁唑烷-2-酮；
(d)3-(1-苄基哌啶-4-基)-5-(2-苄氧羰乙基)哌
嗪基甲基]噁唑烷-2-酮；
(e)3-(2-哌啶-4-基乙基)-5-[4-(3-羧丙基)哌
嗪基甲基]噁唑烷-2-酮；
(f)3-(1-咪基哌啶-4-基甲基)-5-[(4-羧甲基)
哌嗪基甲基]噁唑烷-2-酮；
(g)3-[3-(1-咪基哌嗪-4-基)丙基]-5-(4-羧
甲基哌嗪基甲基)噁唑烷-2-酮
及它们的生理上可以接受的盐类。
5．权利要求1的通式Ⅰ化合物的制备方法，其特征在于：
(a)通式Ⅰ的化合物，通过溶剂解或氢解，从其功能衍生物
中释放出来，或在于
(b)通式Ⅱ的化合物：其中
R1和X如权利要求1中的定义及
Z为Cl,Br,I,OH,或一个活泼的脂化OH基，
与通式Ⅲ的化合物进行反应，
H-Y Ⅲ
其中
Y如权利要求1中定义，
或在于
(c)一种通式Ⅳ的化合物
R1-NH-CH2-CH(XH)-CH2-Y Ⅳ
其中
R1、X和Y如权利要求1中定义，与选自碳酸二烷基酯或氯甲酸烷基酯的碳酸活性衍生物反应，
或在于
(d)(a)项下基团R1与Y可以部分或两个都转变为另外的R1和/或Y，或在于
(e)通式Ⅰ的化合物可以通过用酸或碱处理使转变成它的一种盐。
6．权利要求6的方法，其中所述碳酸二烷基酯为碳酸二乙酯，氯甲酸烷基酯为氯甲酸乙酯。
7．药物制剂，其特征在于其含有至少一种权利要求1的通式Ⅰ的化合物或其生理上可接受的盐。
8．权利要求1的通式Ⅰ的化合物和/或它的生理上可接受的盐用于制备作为粘附受体拮抗剂的药物。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4439846A DE4439846A1 (de) | 1994-11-08 | 1994-11-08 | Adhäsionsrezeptor-Antagonisten |
| DEP4439846.8 | 1994-11-08 |
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| EP (1) | EP0711770A1 (zh) |
| JP (1) | JPH08208629A (zh) |
| KR (1) | KR100384978B1 (zh) |
| CN (1) | CN1069640C (zh) |
| AR (1) | AR002245A1 (zh) |
| AU (1) | AU704184B2 (zh) |
| BR (1) | BR9505109A (zh) |
| CA (1) | CA2162223A1 (zh) |
| CO (1) | CO4520229A1 (zh) |
| CZ (1) | CZ291049B6 (zh) |
| DE (1) | DE4439846A1 (zh) |
| FI (1) | FI955351A (zh) |
| HU (1) | HU217085B (zh) |
| NO (1) | NO306113B1 (zh) |
| PL (1) | PL183595B1 (zh) |
| RU (1) | RU2155762C2 (zh) |
| SK (1) | SK281815B6 (zh) |
| TR (1) | TR199501389A2 (zh) |
| TW (1) | TW316903B (zh) |
| UA (1) | UA41928C2 (zh) |
| ZA (1) | ZA959434B (zh) |
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| ES2123889T3 (es) * | 1994-11-02 | 1999-01-16 | Merck Patent Gmbh | Antagonistas de receptores de adhesion. |
| US6046331A (en) * | 1998-12-17 | 2000-04-04 | Synaptic Pharmaceutical Corporation | Imidazolones and their use in treating benign prostatic hyperplasia and other disorders |
| BR9916518A (pt) | 1998-12-23 | 2002-01-29 | Searle & Co | Método para tratar ou prevenir um distúrbio de neoplasia em um mamìfero em necessidade de tal tratamento ou prevenção, e, combinação compreendendo um inibidor de ciclooxigenase-2 e um ou mais agentes anti-neoplásticos |
| AU4224699A (en) | 1999-01-27 | 2000-08-18 | Pharmacia & Upjohn Company | Assays for modulators of elongation factor p activity |
| WO2004032856A2 (en) * | 2002-10-07 | 2004-04-22 | Smithkline Beecham Corporation | Compounds |
| CN102796091A (zh) * | 2011-05-24 | 2012-11-28 | 北大方正集团有限公司 | 取代的噁唑烷酮化合物及其制备方法和应用 |
| PE20150775A1 (es) * | 2012-10-29 | 2015-05-21 | Hoffmann La Roche | Derivados de oxazolidinona 3,4-disustituidos y su uso como inhibidores del canal de potasio activado por calcio |
| CN104230915B (zh) * | 2014-08-29 | 2016-08-17 | 南京大学 | 含噻唑烷二酮的苯基哌嗪衍生物及其制备方法与用途 |
| WO2018236745A1 (en) | 2017-06-20 | 2018-12-27 | Carnot, Llc | COMPOSITIONS AND METHODS FOR INCREASING THE EFFICACY OF CARDIAC METABOLISM |
| US11530184B2 (en) | 2020-06-30 | 2022-12-20 | Imbria Pharmaceuticals, Inc. | Crystal forms of 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate |
| US11780811B2 (en) | 2020-06-30 | 2023-10-10 | Imbria Pharmaceuticals, Inc. | Methods of synthesizing 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate |
| US11883396B2 (en) | 2021-05-03 | 2024-01-30 | Imbria Pharmaceuticals, Inc. | Methods of treating kidney conditions using modified forms of trimetazidine |
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- 1995-11-07 US US08/551,743 patent/US5776937A/en not_active Expired - Fee Related
- 1995-11-07 KR KR1019950040017A patent/KR100384978B1/ko not_active IP Right Cessation
- 1995-11-07 FI FI955351A patent/FI955351A/fi not_active IP Right Cessation
- 1995-11-08 RU RU95119427/04A patent/RU2155762C2/ru not_active IP Right Cessation
- 1995-11-08 TR TR95/01389A patent/TR199501389A2/xx unknown
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| EP0443197A2 (de) * | 1990-02-21 | 1991-08-28 | MERCK PATENT GmbH | Oxazolidinone |
| EP0459256A1 (de) * | 1990-05-29 | 1991-12-04 | MERCK PATENT GmbH | Oxazolidinone mit ZNS-dämpfender Wirkung |
| DE4405633A1 (de) * | 1993-05-01 | 1994-11-03 | Merck Patent Gmbh | Adhäsionsrezeptor-Antagonisten |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH08208629A (ja) | 1996-08-13 |
| UA41928C2 (uk) | 2001-10-15 |
| NO954458D0 (no) | 1995-11-07 |
| HU9503191D0 (en) | 1996-01-29 |
| HUT76052A (en) | 1997-06-30 |
| HU217085B (hu) | 1999-11-29 |
| FI955351A (fi) | 1996-05-09 |
| ZA959434B (en) | 1996-05-15 |
| KR960017663A (ko) | 1996-06-17 |
| TR199501389A2 (tr) | 1996-07-21 |
| SK136895A3 (en) | 1996-06-05 |
| TW316903B (zh) | 1997-10-01 |
| CN1132201A (zh) | 1996-10-02 |
| NO954458L (no) | 1996-05-09 |
| EP0711770A1 (de) | 1996-05-15 |
| AR002245A1 (es) | 1998-03-11 |
| CZ288895A3 (en) | 1996-06-12 |
| FI955351A0 (fi) | 1995-11-07 |
| CZ291049B6 (cs) | 2002-12-11 |
| US5776937A (en) | 1998-07-07 |
| PL311257A1 (en) | 1996-05-13 |
| AU3661895A (en) | 1996-05-23 |
| SK281815B6 (sk) | 2001-08-06 |
| AU704184B2 (en) | 1999-04-15 |
| DE4439846A1 (de) | 1996-05-09 |
| KR100384978B1 (ko) | 2003-09-02 |
| NO306113B1 (no) | 1999-09-20 |
| BR9505109A (pt) | 1997-09-09 |
| RU2155762C2 (ru) | 2000-09-10 |
| CA2162223A1 (en) | 1996-05-09 |
| CO4520229A1 (es) | 1997-10-15 |
| PL183595B1 (pl) | 2002-06-28 |
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