CN1125575A - 粘附受体拮抗剂 - Google Patents
粘附受体拮抗剂 Download PDFInfo
- Publication number
- CN1125575A CN1125575A CN95115286A CN95115286A CN1125575A CN 1125575 A CN1125575 A CN 1125575A CN 95115286 A CN95115286 A CN 95115286A CN 95115286 A CN95115286 A CN 95115286A CN 1125575 A CN1125575 A CN 1125575A
- Authority
- CN
- China
- Prior art keywords
- oxo
- phenyl
- acid
- oxazolidinyl
- formula
- 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
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- KLNPSZDUOUZSEN-FIWHBWSRSA-N tert-butyl (2r)-2-[[3-(4-cyanophenyl)-2-oxo-1,3-oxazolidine-5-carbonyl]amino]-3-phenylpropanoate Chemical compound C([C@H](C(=O)OC(C)(C)C)NC(=O)C1OC(=O)N(C1)C=1C=CC(=CC=1)C#N)C1=CC=CC=C1 KLNPSZDUOUZSEN-FIWHBWSRSA-N 0.000 description 1
- DIGHFXIWRPMGSA-LLVKDONJSA-N tert-butyl (2r)-2-amino-3-(4-hydroxyphenyl)propanoate Chemical compound CC(C)(C)OC(=O)[C@H](N)CC1=CC=C(O)C=C1 DIGHFXIWRPMGSA-LLVKDONJSA-N 0.000 description 1
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- QOISWWBTZMFUEL-NSHDSACASA-N tert-butyl (2s)-2-amino-3-phenylpropanoate Chemical compound CC(C)(C)OC(=O)[C@@H](N)CC1=CC=CC=C1 QOISWWBTZMFUEL-NSHDSACASA-N 0.000 description 1
- MTHSMXGRVYJXND-UHFFFAOYSA-N tert-butyl 2-(ethylamino)propanoate Chemical compound CCNC(C)C(=O)OC(C)(C)C MTHSMXGRVYJXND-UHFFFAOYSA-N 0.000 description 1
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- UBOXGVDOUJQMTN-UHFFFAOYSA-N trichloroethylene Natural products ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 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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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
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Abstract
本发明所涉及的式I化合物
(其中R1和X的定义详见说明书)及其可作药用的盐和/或溶剂化物能抑制纤维蛋白原与相应的受体结合,因而可用于治疗血栓形成、骨质疏松症、肿瘤疾病、血管成型术后再狭窄、心肌梗塞形成、炎症、动脉硬化和溶骨性疾病。
Description
本发明涉及式I的噁唑烷酮羧酸衍生物:其中R1 为NO2,NR6R7,CN,CONR6R7,CSNR6R7,C(=NH)SA,
C(=NH)OA,C(=NH)SAr,C(=NH)NHOH,C(=NH)NR6R7,
CH2NR6R7,CH2NHC(=NH)NR6R7,NHC(=NH)NR6R7,
CH2NHCO-alk-NR6R7,CH2NHCO-Ph-E,CH2NHCO-Ph-CH2NR6R7,CH2NHCONH-Ph-E或D,X 为OH,OA,AS, AS-AS’,
或
D 为
E 为-CN,-C(=NH)OA,-CSNH2,-C(=NH)SA或
-C(=NH)NH2,Y 为CH2,CHOR5或C=O,R2 为H,A,Ar,OH,OA,CF3,CCl3,NR6R7,-alk-NR6R7,
As或As’各自独立地为选自下列的氨基酸残基;Ala,β—Ala,Arg,Asn,Asp,Gln,Glu,Gly,Leu,Lys,Orn,Phe,Pro,Sar,Ser,Thr,Tyr,Tyr(OMe),Val,C—烯丙基—Gly,C—炔丙基—Gly,N—苄基—Gly,N—苯乙基—Gly,N—苄基—β—Ala,N—甲基—β—Ala和N—苯乙基—β—Ala,也可向游离的氨基或羧基上提供本身已知的常规保护基,
R5、R6和R7各自独立地为H或A,
m为1、2或3,
n为1、2、3或4,
p为0、1或2,
q为0或1,
r为1或2,
A为C1-6烷基,
—alk—为C1-6亚烷基,
Ar为苯基或苄基,且
ph为亚苯基,及其生理上可接受的盐和/或溶剂化物。
具有相似活性的化合物可从EP—A1—0381033中知晓。
本发明所基于的目的是要找到具有有用性质的新化合物,尤其是可用于制备药物的化合物。
这一目的已由本发明达到。已发现式I化合物及其溶剂化物和盐具有有用的药理性质,且能被很好地耐受。具体地,它们抑制纤维蛋白原、fibronectin和von willebrand因子与血小板纤维蛋白受体(糖蛋白IIb/IIIa)结合,以及抑制这些蛋白质及其它粘附蛋白,如vitronectin、胶原蛋白和laminin等与各类细胞表面的相应受体结合。因此这些化合物影响细胞—细胞和细胞—基质之间的相互反应,具体地,它们防止了血小板血栓的形成,因而可用于治疗血栓形成、卒中、心肌梗塞形成、发炎和动脉硬化。另外,这些化合物通过阻止形成转移瘤而对肿瘤细胞具有作用,因此,它们可被用作抗肿瘤剂。
而且,这些化合物适用于预防或治疗溶骨性疾病,尤其是骨质疏松症和血管成形术后再狭窄。另外,它们还具有抗血管形成性质。
另外,这些化合物还显示出抗微生物作用,因此它们还可用于治疗或预防所必需防止的微生物感染。
本发明化合物的这些性质可利用EP—A1—0462960中所述的方法加以证实。纤维蛋白原与其受体的结合的抑制作用可按EP—A1—0381033中所述的方法加以证实。对血小板凝集的抑制作用可通过Born的方法(Nature 4832,927—929,1962)在体外证实。对β3—整合蛋白受体与合适配位体相互作用的抑制可通过J·W·Smith等人的方法(J·Biol·Chem.265,12267—12271(1990))证实。
本发明涉及式I所述的化合物、其盐和溶剂化物,以及这些化合物的制备方法,其特征在于:
(a)通过用溶剂分解剂或氢解剂处理,使式I化合物从其一种功能性衍生物中释放出来,或,
R1的定义同上,且
L为Cl、Br、OH或反应性酯化OH基或一易于进行亲核取代的离去基团,
H—X’ III其中
(c)通过水解式I的酯或酯化式I的羧酸,将残基X转化为不同的残基X,或
(d)通过下式方式使残基R1转化为不同的残基R1:
—催化氢化NO2和/或CN基团,或
—通过与氨反应将腈基转化为C(=NH)—NH2基团,或
—将腈基转化为硫代氨基甲酰基,或
—将硫代氨基甲酰基转化为烷基硫酰亚氨基,或
—将氨基甲酰基转化为烷基亚氨基,或
—将甲基硫酰亚氨基转化为脒基,或
—通过与NH2OH反应将腈基转化为C(=NH)—NHOH基团,或
—将NH2基团转化为胍基,或
—将C(=NH)—NHOH基团转化为脒基,或
—将CH2NH2基团转化为烷酰氨基甲基、CH2NHC(=NH)NR6R7、CH2NHCO—ph—C(=NH)NH2、CH2NHCO—ph—CH2NR6R7或CH2NHCONH—ph—E基团,或
—将1,2,4—噁二唑或1,2,4—噁二唑酮转化为脒基,
(e)将下式IV化合物与反应性碳酸衍生物反应,其中
R1和X的定义同前,或
(g)通过用酸或碱处理使式I化合物转化为其一种盐。
上文和下文中给定的氨基酸残基的缩写表示下列的氨基酸残基:
Ala 丙氨酸
β—Ala β—丙氨酸
Arg 精氨酸
Asn 天冬酰胺
Asp 天冬氨酸
Asp(OBut) 天冬氨酸β—丁基酯
Gln 谷氨酰胺
Glu 谷氨酸
Gly 甘氨酸
Leu 亮氨酸
Lys 赖氨酸
Orn 鸟氨酸
Phe 苯丙氨酸
Pro 腈氨酸
Sar 肌氨酸(N—甲基甘氨酸)
Ser 丝氨酸
Thr 苏氨酸
Tyr 酪氨酸
Tyr(OMe) 2—氨基—3—对甲氧苯基丙酸
Val 缬氨酸
此外,下面所用的缩写的含义如下:
BOC 叔丁氧基羰基
CBZ 苄氧基羰基
DCCI 二环己基碳化二亚胺
DMF 二甲基甲酰胺
EDCI N—乙基—N’—(3—二甲基氨基丙基)碳化二
亚胺盐酸盐
Et 基
Me 甲基
OMe 甲基酯
OEt 基酯
TFA 三氟乙酸
在上、下文中,残基R1和X的定义同式I中。当式I化合物具有一手性中心时,它可以多种对映体形式存在。所有这些形式及其混合物,尤其是其外消旋物,均包括在本发明中。
在上、下文中的通式中,基团A含有1—6个,优选1、2、3或4个碳原子。具体地,优选A为甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基或叔丁基,以及戊基、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—或3—甲基戊基。
X优选为—OH、—OCH3、—O—CH2—CH3、4—羧基哌啶子基、4—羧基烷基哌啶子基、4—羧基烷氧基哌啶子基及所述残基的相应烷基酯基团、4—烷氧羰基哌啶子基、4—羧甲基哌啶子基、4—羧乙基哌啶子基,尤其优选为氨基酸残基或通过酰胺键与羰基相连的二肽残基。如果x为氨基酸残基或二肽残基,则尤其优选下列基团:Ala,β—Ala,Gly,Arg和β—Ala—Asp,Phe,N—苯乙基甘氨酸,N—苯乙基—β—丙氨酸或Sar。
C—末端氨基酸残基同样可被连接到一常规保护基上。尤其适合的是酯化反应。
R1基团优选为—NH2、—C(=NH)—NH2、—CH2—NH2、—CH2—NH—CO—alk—NH2、—CH2—NH—CO—ph—C(=NH)—NH2、—CH2—NH—CO—Alk—C(=NH)—NH2、—CH2—NH—CO—ph—CH2—NH2、NO2或CN。另外,R1也优选为—C(=NH)—S—A、—CSNH2、—C(=NH)—NHOH或
残基Ar为未取代苄基或苯基。
参数m和n优选为1,但也优选为2或3。可变的P优选为0或1,q和r则优选为1。
优选的式I化合物为基中至少一种所述残基、基团和/或参数为所给出的优选含义之一的化合物。部分优选的化合物为式Ia—If化合物,它们对应于式I,只是:
在Ia中,R1为C(=NH)NH2,且X为OH或OA;
在Ib中,R1为C(=NH)NH2,且X为4—羧基哌啶子基、4—羧基烷基哌啶子基或4—羧基烷氧基哌啶子基;
在Ic中,R1为C(=NH)NH2,且X为β—Ala、Asp、Tyr、Tyr(OMe)、N—苯乙基—β—Ala或Phe及其相应的酯化衍生物;
在Id中,R1为(C=NH)NH2,X为4—烷氧羰基哌啶子基、4—烷氧羰基哌嗪子基、4—烷氧羰基烷基哌啶子基、4—烷氧羰基烷氧基哌嗪子基或4—烷氧羰基烷氧基哌啶子基;
在Ie中,R1为(C=NH)NH2,且X为4—羧基哌嗪子基或4—羧基烷基哌嗪子基;
在If中,R1为(C=NH)NHOH,且X为Ia—Ie中所提到的残基之一。
而且,本发明也包括所有其NH2基团均携带了本身已知的保护基的化合物。
式I化合物以及制备它们的起始物也可另外采用本身已知的方法,如文献中所述的方法制得(如见Houben—Weyl,Methodende organischen Chemic〔Methods for OrganicChemistry〕,Georg—Thieme—Verlag,Stuttgart等经典著作;及J.March,Adv.Org.Chem.,3rd.Ed.(1985),J.Wiley&Sons),尤其是在已知的适用于所述反应的反应条件下进行。在本文中,也可使用本身已知的而未详细提到的各种改进方法。
如果需要,起始物料也可就地形成,因此不必从反应混合物中将它们分离出来而是直接进一步反应产生式I的化合物。
式I化合物能用溶剂解,特别是水解,或是氢解的方法从它们的功能性衍生物释放出式I化合物来制备。
用于溶剂解或氢解的优选的起始物料是那些在其它方面对应于式I且含有,(替代一个或多个游离的氨基和/或羟基),相应地被保护着的氨基和/或羟基的化合物,优选地是那些含有,(替代连接于一个氮原子上的一个氢原子),一个氨基保护基的化合物,尤其是那些含有R’—N基团以代替HN基团(其中R’为氨基保护基)的化合物,和/或携带了羟基保护基以代替羟基中的氢原子的化合物,如对应于式I但以—COOR”团(其中R”为羟基保护基)代替了—COOH基团的化合物。
在起始物料的分子中也可能存在着两个或多个相同或不同的被保护的氨基和/或羧基,如果存在的保护基是彼此不同的,则在许多情况下它们可以被选择性地除去。
术语“氨基保护基”通常是已知的且涉及那些具有保护(封闭)一个氨基不参加化学反应的能力,但是在分子的其它部分所需要的化学反应实施完后能够很容易被除去的基团,具体地,这些基团代表性的例子是未被取代的或已被取代的酰基、芳基(如2,4—二硝基苯基(DNP))、芳烷氧基甲基(如苄氧甲基(BOM))或芳烷基(如苄基、4—硝基苄基或三苯甲基)。由于氨基保护基在所需要的反应(或反应序列)后被除去,它们的性质和尺寸并不太关键;但是,那些1—20,尤其是1—8个碳原子的保护基是优选的。在本发明的方法中,术语“酰基”应该被认为是最广泛意义上的,它包括从脂肪族、芳基脂肪族、芳香族或杂环羧酸或磺酸中衍生来的酰基,和,尤其是烷氧基羰基、芳氧基羰基和,特别是芳烷氧基羰基。这样的酰基的实例是烷酰基如乙酰基、丙酰基和丁酰基;芳烷酰基如苯乙酰基;芳酰基如苯甲酰基或甲苯基;芳氧基烷酰基如POA;烷氧基羰基如甲氧基羰基、乙氧基羰基、2,2,2—三氯乙氧基羰基、异丙氧基羰基、BOC和2—碘代乙氧基羰基;芳烷氧基羰基如CBZ(苄氧羰基)、4—甲氧基苄氧基羰基和Fmoc。优选的氨基保护基是BOC、DNP和BOM,还有CBZ、苄基和乙酰基。
术语“羟基保护基”同样是通常已知的且涉及那些具有保护羟基不参加化学反应能力的基团,但这些基团在分子其它部分的所需的化学反应实施完后很容易除去。这样的基团代表性的是上述未取代的或取代的芳基、芳基烷基或酰基,还有烷基。由于这些基团在所需要的化学反应或反应序列后又被除去,所以羟基保护基的性质和大小并不是关键;1—20,尤其是1—10个碳原子的羟基保护基是优选的。羟基保护基的实例包括叔丁基、苄基、对硝基苯甲酰基、对甲苯磺酰基和乙酰基,其中苄基和乙酰基是特别优选的。
被用作起始物料的式I化合物的功能性衍生物可以用常规的方法来制备,如在上述的权威著作和专利申请中所叙述的方法,例如通过对应于式II和式III但其中至少一种该化合物含有保护基团以代替氢原子的化合物的反应来制备。
从式I化合物的功能性衍生物中释放出式I的化合物的实施取决于所用的保护基的性质,例如用强酸,较有利地用TFA或高氯酸,或用其它的强无机酸如盐酸或硫酸,强的有机羧酸,如三氯乙酸,或磺酸如苯—或对—甲苯磺酸。额外存在一种惰性溶剂是可能的但不总是必需的。
适当的惰性溶剂较好是有机酸,例如羧酸如乙酸,醚如四氢呋喃或二噁烷,酰胺如DMF,卤代烃如二氯甲烷,和醇如甲醇、乙醇或异丙醇,还有水。上述溶剂的混合物也是适宜的。较好地是过量使用TFA而不需要加入其它溶剂,而高氯酸较好地是以乙酸和70%高氯酸的比率为9∶1的混合物的形式来使用。裂解的反应温度较有利地是在大约0℃至大约50℃,优选15至30℃(室温)。
例如,基团BOC可较有利地用40%TFA在二氯甲烷中除去或用3—5NHCl在二噁烷中于15—60℃下除去。实施除去Fmoc基团,例如,可用大约5—20%浓度的二甲胺、二乙胺或哌啶在DMF中的溶液于15—50℃来进行。DNP基团的除去可通过用约3—10%2—巯基乙醇的DMF/水溶液于15—30℃处理来完成。
能够被氢解除去的保护基(例如,BOM、CBZ或苄基)能够用,例如,氢在催化剂(例如,贵金属催化剂如钯,较有利地是载于活性炭上)存在下进行处理来除去。在这方面,适当的溶剂是那些上面所给定的,特别的是醇如甲醇或乙醇,或酰胺如DMF。氢解通常是在大约0—100℃的温度下和大约1—200巴的压力下,优选在20—30℃和1—10巴下实施,例如,CBZ基的氨解较有利地是于20—30℃用5—10%Pd—C在甲醇中完成。
也可通过催化氢化,完成1,2,4—噁二唑啉—5—酮—3—基或5—烷基—1,2,4—噁二唑—3—基的氢解转化,形成脒基。
优选通过将式II恶唑烷酮与式III化合物反应,也可获得式I化合物。在这种情况下,较有利的是使用本身已知的亲核取代方法和/或胺的N—烷基化方法或酰胺形成反应。
式II中的离去基团L优选为Cl、Br或OH,或由它们所衍生出的基团,如三氟甲磺酰氧基、甲苯磺酰氧基或甲磺酰氧基。
反应优选在一种附加碱存在下,于惰性溶剂中,及温度为约—10至200℃,优选0—120℃的条件下进行。所述碱的例子有碱金属或碱土金属氢氧化物或碳酸盐,如氢氧化钠、氢氧化钾或氢氧化钙、碳酸钠、碳酸钾或碳酸钙。所述惰性溶剂的例子有卤代烃如二氯甲烷,醚如THF或二噁烷,酰胺如DMF或二甲基乙酰胺,或腈如乙腈。加入碘化物如碘化钾可有利于反应的进行。
式II起始化合物通常是已知的或者可按与已知化合物类似的方法制得。它们的制备方法可见例如DE3723797(EP300272)。例如,可按如下方法制得:将适当取代的苯胺与烯丙基氯反应,然后将双键转化为二醇,将该二醇与碳酸的反应性衍生物如碳酰氯、N—N—羰基二咪唑、碳酸二烷基酯或双光气反应,将产物氧化为5—噁唑烷酮羧酸,并根据需要,通过衍生酸基进行进一步的活化。
在式II化合物中,通过例如将OH基团(Y=OH)与SOCl2、SOBr2、甲磺酰氯或对—甲苯磺酰氯反应,可使残基L转化为不同的残基L。
或III化合物一般来说是已知的,且可从市场上买到。
式II恶唑烷酮与式III化合物的反应可按本身已知的方式进行,优选于20℃至溶剂沸点的温度下在质子传递或非质子传递极性惰性溶剂中进行。反应时间为10分钟至24小时,优选2小时至10小时。
合适的溶剂包括:醇,如甲醇、乙醇、异丙醇、正丁醇和叔丁醇;醚,如乙醚、二异丙醚、四氢呋喃(THF)和二噁烷;二元醇醚,如乙二醇单甲醚和单乙醚,及乙二醇二甲醚;酮,如丙酮和丁酮;腈,如乙腈;硝基化合物,如硝基甲烷和硝基苯;酯,如乙酸乙酯和六甲基磷三酰胺;亚砜,如二甲基亚砜(DMSO);氯代烃,如二氯甲烷、氯仿、三氯乙烯、1,2—二氯乙烷和四氯化碳;烃,如苯、甲苯和二甲苯。这些溶剂的相互混合物也是合适的。尤其合适的是N—甲基吡咯烷酮。
具有游离伯或仲氨基的衍生物较有利的是被转化为被保护形式。合适的保护基如前所述。
也可通过将残基X转化为不同的残基X而获得式I化合物。例如,游离酸基(X=OH)可被酯化(x=OA)或通过一肽键被连接至一氨基酸或二肽上。而且,也可将酸转化为酰胺。
另外,也可通过将式I化合物中的残基R1转化为不同的残基R1而得到式I化合物。
具体地,氰基可被还原为氨基甲基或转化为脒基,苄基可通过氢解除去,氨基甲基可被转化为胍基甲基,腈基可被转化为硫代氨基甲酰基。
氰基还原为氰基甲基较有利的是通过催化氢化完成,例如较有利的是在氨存在下,在阮内镍上,于温度为0—100℃,优选10—30℃、压力为1—200巴,优选大气压的条件下,在惰性溶剂,如甲醇或乙醇等低级醇中进行。如果该操作是在例如20℃及1巴条件下进行,则起始物中存在的苄基酯基或N—苄基被保留。如果需要通过氢解裂解它们,则较有利的是使用贵金属催化剂,优选Pd/炭,在这种情况下,可向溶液中加入酸(如乙酸)和水。
为了制备其中R1为胍基苯基的式I化合物,可用脒化剂处理相应的氨基苯基化合物。优选的脒化剂是1—脒基—3,5—二甲基吡唑,该试剂具体地是以其硝酸盐形式使用。该操作较有利的是于0—120℃,优选60—120℃,在惰性溶剂或溶剂混合物(如水/二噁烷)中,并在加入一种碱(如三乙胺或乙基二异丙胺)的条件下进行。
为了制备式I的脒,可向式I的腈中加入氨。该加入过程优选按本身已知的方式分两步或多步完成:a)用H2S转化腈为硫代酰胺,用烷化剂如CH3I将硫代酰胺转化为相应的S—烷基—硫代亚氨酯,再将其与NH3反应而产生脒,b)在HCl存在下用醇如乙醇将腈转化为相应的亚氨酯并用氨处理后者,或c)将腈与双(三甲基甲硅烷基)氨基化锂反应,然后水解产物。
类似地,通过按a)或b)的步骤进行操作,所不同的是用羟胺代替氨,可由腈获得相应的式I的N—羟基脒。
而且,通过与脂族碳酰氯反应,N—羟基脒可被转化为1,2,4—噁二唑或1,2,4—噁二唑啉酮,然后再通过催化氢化,例如在阮内镍、Pd/C或PtO2上,优选在MeOH、二噁烷、冰醋酸、冰醋酸/乙酸酐或DMF中,将后者转化为脒。
另外,式I化合物也可通过将式IV化合物与碳酸的反应性衍生物反应制得。碳酸的反应性衍生物可为例如前面提到的化合物,尤其优选的是光气和双光气以及N,N—羰基二咪唑。其它合适的碳酸衍生物具体地有二烷基碳酸酯如碳酸二乙酯,和氯代甲酸烷基酯如氯代甲酸乙酯。较有利的是过量使用的碳酸衍生物最好也被用作溶剂或悬浮介质。但是,也可能存在一种前面所述的溶剂,条件是它在该反应中为惰性。而且,加入一种碱,尤其是碱金属醇盐如叔丁醇钾,也是可取的。该反应在0—150℃,优选70—120℃进行较为有利。
式IV起始化合物通常是新的。它们可通过例如将环取代的苯胺与a—羟基—β—卤代羧酸反应获得。
而且,通过将式V二醇与过量的反应性羧酸衍生物反应也可获得式I化合物,该反应优选在前面所述的条件下进行。碳酸衍生物可从市场上买到,式V化合物可通过如下方法获得:将烯丙基氯与对—氨基苄腈反应,将双键转化为二羟基基团,并将所得化合物与羟胺反应。
用酸可将式I的碱转化成相应的酸加成盐,特别适用该反应的酸是那些能产生生理上可接受的盐的那些酸。例如,可被使用的无机酸的实例是硫酸、硝酸,氢卤酸如盐酸或氢溴酸,磷酸如正磷酸,氨基磺酸,和有机酸,特别是脂族、脂环,芳脂族,芳香族或杂环的单一或多元羧酸、磺酸或硫酸,例如,甲酸、乙酸、三氟乙酸、丙酸,新戊酸,二乙基乙酸、丙二酸、琥珀酸、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、烟酸、异烟酸、甲磺酸或乙磺酸、乙二磺酸、2—羟基乙磺酸、苯磺酸、对甲苯磺酸、萘—磺酸和萘二磺酸和月桂基硫酸。与生理上不能接受的酸形成的盐,例如苦味酸盐,能被用来分离和/或纯化式I化合物。
根据需要,可通过用强碱如氢氧化钠或氢氧化钾、碳酸钠或碳酸钾处理使式I的游离碱从其盐中释放出来。
也可通过与相应的碱反应将式I的羧酸转化为其金属盐或铵盐,如其钠盐、钾盐或钙盐。
式I化合物可能含有一个或多个手性中心,因此它们可能含以外消旋形式或旋光活性形式存在。所获得的外消旋混合物可通过本身已知的机械的或化学的方法分离成对映体。
非对映体优选通过将外消旋混合物与旋光活性的拆解试剂反应形成。合适的拆解试剂的例子包括旋光活性的酸,如D或L形式的酒石酸、二乙酰酒石酸、二苯甲酰酒石酸、扁桃酸、苹果酸、乳酸,或各种旋光活性的樟脑磺酸如β—樟脑磺酸。
较可取的方法也可以是利用旋光活性的拆解试剂(如二硝基苯甲酰基苯基甘氨酸)进行对映体的拆析。合适的洗脱剂是例如己烷/异丙醇/乙腈混合物。
当然,也可利用本身已为旋光活性的起始物(如式II化合物),按照前面所述的方法制备旋光活性的式I化合物。
式I的新的化合物,和它们的生理上可接受的盐通过将其与至少一种赋形剂或助剂一起和,如果需要,与一种或几种活性物质一起投入适宜的药剂形式中用于制备药物组合物。这样制得的组合物可被用作药物用于人体或兽医中。作为赋形剂的适宜的物质是那些适于肠道(例如,口服或直肠的),非肠道的或适于吸入剂喷雾形式服用的并且不与新的化合物反应的有机物或无机物,实例是水、植物油、苄基醇、聚乙二醇、甘油三乙酸和其它脂肪酸甘油酯、明胶、大豆卵磷酯、碳水化合物如乳糖或淀粉、硬脂酸镁、滑石和纤维素。口服形式特别是使用片剂、涂膜片剂、胶囊、糖浆或滴剂;带有抗胃液涂层或胶囊套的涂膜片剂和胶囊是特别受到注意的。栓剂能被用于直肠服用,而非肠道服用则使用溶液,优选油性或水溶液,还有悬浮液,乳状液或移植物。
对于吸入剂喷雾的服用方式来说,可以使用含有溶解于或悬浮于推进气混合物的活性物质的喷雾。在这种情况下活性物质很方便地以微粉化的形式被使用,可以存在有一种或多种外加的生理上可接受的溶剂,例如,乙醇。用通常的吸入器可服入吸入剂溶液。新的化合物可被冷冻干燥并且产生的冻干物能被用于,例如,制备注射用组合物。产生的组合物可以被消毒和/或可以含有助剂,如防腐剂、稳定剂和/或润湿剂,乳化剂,影响渗透压的盐,缓冲剂物质、着色剂和/或香味剂。如果需要,它们也可以含有一种或多种其它活性物质,例如一种或多种维生素。
根据本发明的物料通常按与其它已知的和商业上可得到的药品相类似的方法服用,特别是用与在EP—A—459256中所述的化合物相似的方法服用,优选的剂量是每剂量单位大约5mg—1g,特别是50—500mg。每天剂量优选大约0.1—20mg/kg体重,尤其是1—10mg/kg体重。但是,每个特定病人的特定剂量取决于许多因素,例如,所用的特定化合物的效力,年龄、体重、健康的一般状态、饮食、给药的时间及途径、排泄速度、药物的组合和各自病情的严重性。口服是优选的。
上下文中所用温度均为℃,在后面的实施例中“常规操作”是指:根据需要,加入水,根据终产物的组成,将pH调至2—8。用乙酸乙酯或二氯甲烷萃取,相分离,有机相用硫酸钠干燥,蒸发浓缩和在硅胶上色谱纯化和/或结晶纯化残余物。
当分子质量被示出时,常规的质量光谱质用“M”表示,快速原子轰击FAB值则用“M+1”表示。实施例1
于16℃,将1g 4—(2—氧代—5—羟甲基噁唑烷—3—基)苄腈〔可按EP300272获得〕溶于12ml乙腈,并加至3.6g磷酸二氢钠二水合物、3.9g偏高碘酸钠和36mg RuCl3的23ml水/2.3ml二氯甲烷溶液中。于室温下搅拌反应混合物12小时,过滤及进行常规操作。真空蒸发浓缩至干后,得到3—(4—氰基苯基)—2—氧代—5—噁唑烷羧酸,m.p.204℃。实施例2
在53.4g碳酸钠存在下,将27.9g 3—(4—氰基苯基)—2—氧代—5—噁唑烷羧酸〔得自实施例1〕和26.4g氯化羟铵在750ml甲醇和30ml水的混合物中煮沸5小时。抽滤所形成的沉淀,用甲醇洗涤并干燥。用盐酸处理后得到3—〔4—(氨基(羟亚氨基)甲基)苯基〕—2—氧代—5—噁唑烷羧酸盐酸盐,m.p.205—208℃。实施例3
将13.9g 3—〔4—(氨基(羟亚氨基)甲基)苯基〕—2—氧代—5—噁唑烷羧酸〔可得自实施例2〕溶于210ml冰醋酸,加入11.3g氧甲酸三氯甲基酯,并将混合物煮沸3h。然后冷却至室温,并进行常规操作。得到3—〔4—(5—氧代—1,2,4—噁二唑啉—3—基)苯基〕—2—氧代—5—噁唑啉羧酸,m.p.250—253℃。实施例4
将3.03g N—甲基吗啉加至2.91g 3—〔4—(5—氧代—1,2,4—噁二唑啉—3—基)苯基〕—2—氧代—5—噁唑烷羧酸〔可得自实施例3〕、2.77g哌啶—4—羧酸叔丁酯、2.02g 1—羟基苯并三唑和2.86g N—(3—二甲基氨基丙基)—N’—乙基碳化二亚胺盐酸盐的20ml DMF溶液中,并将混合物于室温下搅拌5h。然后在密集搅拌下向其中滴加200ml水,分离出形成的沉淀,并溶入90ml二氯甲烷,将混合物于Na2SO4上干燥。真空浓缩溶液,用乙醚研磨产生的油,得到1—{3—〔4—(5—氧代—1,2,4—噁二唑啉—3—基)苯基〕—2—氧代—5—噁唑烷羰基}哌啶—4—羧酸叔丁酯,m.p.171—175℃。
类似地,通过将3—〔4—(5—氧代—1,2,4—噁二唑啉—3—基)苯基〕—2—氧代—5—噁唑烷羧酸与下列化合物反应可得到相应的产物:
与2—(哌啶—4—基)乙酸叔丁酯反应,得到:2—{1—〔3—(4—(5—氧代—1,2,4—噁二唑啉—3—基)苯基)—2—氧代—5—噁唑烷基羰基〕哌啶—4—基}乙酸叔丁酯;
与2—(哌啶—4—基)乙酸乙酯反应,得到:2—{1—〔3—(4—(5—氧代—1,2,4—噁二唑啉—3—基)苯基)—2—氧代—5—噁唑烷基羰基〕哌啶—4—基}乙酸乙酯;
与2—(哌啶—4—基—氧)乙酸叔丁酯反应,得到:2—{1—〔3—(4—(5—氧代—1,2,4—噁二唑啉—3—基)苯基)—2—氧代—5—噁唑烷基羰基〕哌啶—4—基—氧}乙酸叔丁酯;m.p.180—181℃ ;
与2—(哌啶—3—基—氧)乙酸叔丁酯反应,得到:2—{1—〔3—(4—(5—氧代—1,2,4—噁二唑啉—3—基)苯基)—2—氧代—5—噁唑烷基羰基〕哌啶—3—基—氧}乙酸叔丁酯;m.p.92—95℃;
与2—(2—氧代—哌嗪基)乙酸叔丁酯反应,得到:2—{4—〔3—(4—(5—氧代—1,2,4—噁二唑啉—3—基)苯基)—2—氧代—5—噁唑烷基羰基〕2—氧代—哌嗪基}乙酸叔丁酯;m.p.155—157℃;
与(2R)—2—氨基丙酸叔丁酯(H—Ala—OBut)反应,得到:(2R)—2—{3—〔4—(5—氧代—1,2,4—噁二唑啉—3—基)苯基〕—2—氧代—5—噁唑烷基羰基—氨基}丙酸叔丁酯;m.p.105—107℃;
与(2R)—2—氨基丙酸甲酯(H—Ala—OMe)反应,得到:(2R)—2—{3—〔4—(5—氧代—1,2,4—噁二唑啉—3—基)苯基〕—2—氧代—5—噁唑烷基羰基氨基}—丙酸甲酯;m.p.199—201℃;
与(2R)—2—氨基琥珀酸二叔丁酯(H—Asp(OBut)—OBut)反应,得到:(2R)—2—{3—〔4—(5—氧代—1,2,4—噁二唑啉—3—基)苯基〕—2—氧代—5—噁唑烷基羰基氨基}琥珀酸二—叔丁酯,m.p.175—176℃;
与3—氨基丙酸叔丁酯(H—βAla—OBut)反应,得到:3—{3—〔4—(5—氧代—1,2,4—噁二唑啉—3—基)苯基〕—2—氧代—5—噁唑烷羰基氨基}—丙酸叔丁酯,m.p.143—146℃;
与3—氨基丙酸甲酯(H—βAla—OMe)反应,得到:3—{3—〔4—(5—氧代—1,2,4—噁二唑啉—3—基)苯基〕—2—氧代—5—噁唑烷基羰基氨基}丙酸甲酯,m.p.230—232℃;
与(2R)—2—氨基—3—(4—羟苯基)丙酸叔丁酯(H—Tyr—OBut)反应,得到:(2R)—2—{3—〔4—(5—氧代—1,2,4—噁二唑啉—3—基)苯基〕—2—氧代—5—噁唑烷羰基氨基}—3—(4—羟基苯基)丙酸叔丁酯;
与(2R)—2—氨基—3—(4—甲氧苯基)丙酸叔丁酯(H—Tyr—(OMe)—OBut)反应,得到:(2R)—2—{3—〔4—(5—氧代—1,2,4—噁二唑啉—3—基)苯基〕—2—氧代—5—噁唑烷羰基氨基}—3—(4—甲氧苯基)丙酸叔丁酯;
与3—N—苯乙氨基丙酸叔丁酯反应,得到:3—{3—〔4—(5—氧代—1,2,4—噁二唑啉—3—基)苯基〕—2—氧代—5—噁唑烷羰基—(N—苯乙基)氨基}丙酸叔丁酯;
与2—哌嗪基乙酸苄酯反应,得到:2—{1—〔3—(4—(5—氧代—1,2,4—噁二唑啉—3—基)—苯基)—2—氧代—5—噁唑烷基羰基〕哌嗪—4—基}乙酸苄基酯,m.p.165—170℃;
与3—哌嗪基丙酸苄酯反应,得到:3—{1—〔3—(4—(5—氧代—1,2,4—噁二唑啉—3—基)苯基)—2—氧代—5—噁唑烷羰基〕哌嗪—4—基}丙酸苄酯,m.p.150—153℃;实施例5
将1.37g 1—{3—〔4—(5—氧代—1,2,4—噁二唑啉—3—基)苯基〕—2—氧代—5—噁唑烷羰基}哌啶—4—羧酸叔丁酯溶于50ml甲醇中,并在阮内镍上氢化。然后过滤反应混合物,并真空浓缩滤液。所得产物用20ml乙酸乙酯处理,加热,冷却后抽滤。得到1—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基}哌啶—4—基—羧酸叔丁酯,m.p.160℃。
类似地,通过对下列化合物的5—氧代—1,2,4—噁二唑啉基团进行还原性裂解,可得到相应产物:
由2—{1—〔3—(4—(5—氧代—1,2,4—噁二唑啉—3—基)苯基)—2—氧代—5—噁唑烷基羰基〕哌啶—3—基}乙酸叔丁酯,得到:2—{1—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基〕哌啶—4—基}乙酸叔丁酯;
由2—{1—〔3—(4—(5—氧代—1,2,4—噁二唑啉—3—基)苯基)—2—氧代—5—噁唑烷基羰基〕哌啶—4—基}乙酸乙酯,得到:2—{1—〔3—(4—脒基苯基)—2—氧代—5—氧代—5—噁唑烷基羰基〕哌啶—4—基}乙酸乙酯;m.p.210—211℃;
由2—{1—〔3—(4—(5—氧代—1,2,4—噁二唑啉—3—基)苯基)—2—氧代—5—噁唑烷基羰基〕哌啶—4—基—氧}乙酸叔丁酯,得到2—{1—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基〕哌啶—4—基—氧}乙酸叔丁酯,m.p.100℃;
由2—{1—〔3—(4—(5—氧代—1,2,4—噁二唑啉—3—基)苯基)—2—氧代—5—噁唑烷基羰基〕哌啶—3—基—氧}乙酸叔丁酯,得到2—{1—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基〕哌啶—3—基—氧基}乙酸叔丁酯,m.p.139—144℃;
由2—{4—〔3—(4—(5—氧代—1,2,4—噁二唑啉—3—基)苯基)—2—氧代—5—噁唑烷基羰基〕—2—氧代—哌嗪基}乙酸叔丁酯,得到2—{4—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基〕—2—氧代—哌嗪基}乙酸叔丁酯,m.p.165—167℃;
由(2R)—2—{3—〔4—(5—氧代—1,2,4—噁二唑啉—3—基)苯基〕—2—氧代—5—噁唑烷基羰基氨基}丙酸叔丁酯,得到(2R)—2—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基氨基〕丙酸叔丁酯,m.p.173—175℃;
由(2R)—2—{3—〔4—(5—氧代—1,2,4—噁二唑啉—3—基)苯基〕—2—氧代—5—噁唑烷基羰基氨基}丙酸甲酯,得到(2R)—2—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基氨基〕丙酸甲酯,乙酸盐,m.p.190—192℃;
由(2R)—2—{3—〔4—(5—氧代—1,2,4—噁二唑啉—3—基)苯基〕—2—氧代—5—噁唑烷羰基氨基}琥珀酸二叔丁基酯,得到(2R)—2—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基氨基〕琥珀酸二叔丁基酯,乙酸盐,m.p.242℃;
由3—{3—〔4—(5—氧代—1,2,4—噁二唑啉—3—基)苯基〕—2—氧代—5—恶唑烷基羰基氨基}丙酸叔丁酯,得到:3—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基氨基〕丙酸叔丁酯,m.p.164—167℃;
由3—{3—〔4—(5—氧代—1,2,4—噁二唑啉—3—基)苯基)—2—氧代—5—噁唑烷基羰基氨基}丙酸甲酯,得到:3—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基氨基〕丙酸甲酯,乙酸盐,m.p.207—209℃;
由(2R)—2—{3—〔4—(5—氧代—1,2,4—噁二唑啉—3—基)苯基)—2—氧代—5—噁唑烷基羰基氨基}—3—(4—羟苯基)丙酸叔丁酯,得到:(2R)—2—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基氨基〕—3—(4—羟苯基)丙酸叔丁酯;
由(2R)—2—{3—〔4—(5—氧代—1,2,4—噁二唑啉—3—基)苯基)—2—氧代—5—噁唑烷基羰基氨基}—3—(4—甲氧苯基)丙酸叔丁酯,得到(2R)—2—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基氨基〕—3—(4—甲氧苯基)丙酸叔丁酯;
由3—{3—〔4—(5—氧代—1,2,4—恶二唑啉—3—基)苯基)—2—氧代—5—噁唑烷基羰基—(N—苯乙基)氨基}丙酸叔丁酯,得到3—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基—(N—苯乙基)氨基〕丙酸叔丁酯;
由2—{1—〔3—(4—(5—氧代—1,2,4—噁二唑啉—3—基)苯基)—2—氧代—5—噁唑烷基羰基〕哌嗪—4—基}乙酸苄酯,得到2—{1—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基〕哌嗪—4—基}乙酸苄酯;
由3—{1—〔3—(4—(5—氧代—1,2,4—噁二唑啉—3—基)苯基)—2—氧代—5—噁唑烷基羰基〕哌嗪—4—基}丙酸苄酯,得到3—{1—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基〕哌嗪—4—基}丙酸苄酯。实施例6
于室温下将0.41g 1—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基}哌啶—4—基—羧酸叔丁酯于40ml乙醚的HCl溶液中搅拌2小时。抽滤出形成的沉淀,用20ml乙醚洗涤。然后将产物于60℃下用5ml乙腈处理10分钟,冷却至室温,抽滤出产物,用少量乙腈洗涤。得到1—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基〕哌啶—4—羧酸盐酸盐,m.p.184℃(分解)。
类似地,通过水解相应的酯可以得到下列产物:
由2—{1—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基〕哌啶—4—基}乙酸叔丁酯得到:
2—{1—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基〕哌啶—4—基}乙酸,盐酸盐;
由2—{1—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基〕哌啶—4—基—氧}乙酸叔丁酯得到:
2—{ 1—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基〕哌啶—4—基—氧}乙酸,盐酸盐;m.p.170—175℃(分解);
由2—{1—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基〕哌啶—3—基—氧}乙酸叔丁酯得到:
2—{1—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基〕哌啶—3—基—氧}乙酸,盐酸盐;m.p.127—129℃;
由2—{4—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基〕—2—氧代—哌嗪基}乙酸叔丁酯得到:
2—{ 4—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基〕—2—氧代—哌嗪基}乙酸,盐酸盐,m.p.68—70℃;
由(2R)—2—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基氨基丙酸叔丁酯得到:
(2R)—2—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基氨基丙酸,盐酸盐,m.p.190—204℃;
由(2R)—2—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基氨基〕琥珀酸二叔丁基酯得到:
(2R)—2—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基氨基〕琥珀酸,盐酸盐,m.p.308—310℃(分解);
由3—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基氨基〕丙酸叔丁酯得到:
3—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基氨基〕丙酸,盐酸盐,m.p.243—244℃(分解);
由(2R)—2—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基氨基〕—3—(4—羟苯基)丙酸叔丁酯得到:
(2R)—2—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基氨基〕—3—(4—羟苯基)丙酸,盐酸盐;
由(2R)—2—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基氨基〕—3—(4—甲氧苯基)丙酸叔丁酯得到:
(2R)—2—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基氨基〕—3—(4—甲氧苯基)丙酸,盐酸盐;
由(2R)—2—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基—(N—苯乙基)氨基〕丙酸叔丁酯得到:
(2R)—2—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基—(N—苯乙基)氨基〕丙酸,盐酸盐。实施例7
将1.0g 2—{1—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基〕哌嗪—4—基}乙酸苄基酯在100ml甲醇和50ml DMF的混合物中于披钯碳上催化氢化,直至氢气完全消耗。随后过滤反应混合物,并进行常规操作。用乙醚研磨粗产物并干燥,得到2—{1—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基〕—哌嗪—4—基}乙酸,m.p.220—225℃(分解)。
按类似方法可得到下列产物:
由3—{1—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基〕哌嗪—4—基}丙酸苄酯,得到:
3—{ 1—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基〕哌嗪—4—基}丙酸,m.p.255—258℃(分解)实施例8
与实施例4类似,将苯丙氨酸叔丁酯与3—(4—氰基苯基)—2—氧代—5—噁唑烷羧酸(得自实施例1)反应,得到(2R)—2—3—(4—氰基苯基)—2—氧代—5—噁唑烷基羰基氨基〕—3—苯基丙酸叔丁酯,m.p.72℃。
同样地,通过将3—(4—氰基苯基)—2—氧代—5—噁唑烷羧酸与哌啶—4—羧酸苄基酯反应,可得到:
1—〔3—(4—氰基苯基)—2—氧代—5—噁唑烷基羰基〕哌啶—4—羧酸苄基酯,FAB(M+1):434;与2—(4—哌啶氧基)乙酸叔丁酯反应,可得到:
2—{ 1—〔3—(4—氰基苯基)—2—氧代—5—噁唑烷基羰基—4—哌啶氧基}乙酸叔丁酯;m.p.126—127℃。实施例9
在室温及存在5ml三乙胺条件下,将2.3g 3—(4—氰基苯基)—2—氧代—5—噁唑烷碳酰氯(m.p.148—150℃;可通过酸与草酰氯反应获得)与1当量1—哌嗪基乙酸苄酯盐酸盐反应。经常规操作,得到2—{1—〔3—(4—氰基苯基)—2—氧代—5—噁唑烷基羰基〕—4—哌嗪基}乙酸苄酯,m.p.131—132℃。实施例10
将2.6g(2R)—2—〔3—(4—氰基苯基)—2—氧代—5—噁唑烷基羰基氨基〕—3—苯基丙酸叔丁酯〔可得自实施例8〕溶于由30ml吡啶和5ml三乙胺组成的溶剂混合物中,并在冰冷却下搅拌混合物1.5h,与此同时,连续向其中通入H2S气体。随后将反应混合物在室温下搅拌24小时。经蒸发浓缩和常规操作后,得到(2R)—2—〔3—(4—硫代氨基甲酰基苯基)—2—氧代—5—噁唑烷基羰基氨基〕—3—苯基丙酸叔丁酯,m.p.185—186℃。
同样地,可得到下列化合物:由1—〔3—(4—氰基苯基)—2—氧代—5—噁唑烷基羰基〕—哌啶—4—羧酸苄酯,得到:
1—〔3—(4—硫代氨基甲酰基苯基)—2—氧代—5—噁唑烷基羰基〕—哌啶—4—羧酸苄酯;
由2—{1—〔3—(4—氰基苯基)—2—氧代—5—噁唑烷基羰基〕—4—哌啶氧基}乙酸叔丁酯,得到:
2—{1—〔3—(4—硫代氨基甲酰基苯基)—2—氧代—5—噁唑烷基羰基〕—4—哌啶氧基}乙酸叔丁酯;
由2—{1—〔3—(4—氰基苯基)—2—氧代—5—噁唑烷基羰基〕—4—哌嗪基}乙酸苄基酯,得到:
2—{1—〔3—(4—硫代氨基甲酰基苯基)—2—氧代—5—噁唑烷基羰基〕—4—哌嗪基}乙酸苄基酯;实施例11
将0.92g(2R)—2—〔3—(4—硫代氨基甲酰基苯基)—2—氧代—5—噁唑烷基羰基氨基〕—3—苯基丙酸叔丁酯(得自实施例10〕溶于15ml丙酮,并加入1.75ml甲基碘。于室温下搅拌溶液2h,并进行常规操作,得到(2R)—2—〔3—(4—亚氨基(甲硫基)甲基苯基)—2—氧代—5—噁唑烷基羰基氨基〕—3—苯基丙酸叔丁酯,盐酸盐,m.p.140℃。
类似地,可得到下列产物:由1—〔3—(4—硫代氨基甲酰基苯基)—2—氧代—5—噁唑烷基羰基〕—哌啶—4—羧酸苄酯,得到:1—〔3—(4—亚氨基—(甲硫基)甲基苯基)—2—氧代—5—噁唑烷基羰基〕—哌啶—4—羧酸苄酯,氢碘酸盐,m.p.86—91℃;由2—{1—〔3—(4—硫代氨基甲酰基苯基)—2—氧代—5—噁唑烷基羰基〕—4—哌啶氧基}乙酸叔丁酯,得到:2—{1—〔3—(4—亚氨基—(甲硫基)甲基苯基)—2—氧代—5—噁唑烷基羰基〕—4—哌啶氧基}乙酸叔丁酯,m.p.157℃;由2—{1—〔3—(4—硫代氨基甲酰基苯基)—2—氧代—5—噁唑烷基羰基〕—4—哌嗪基}乙酸苄酯,得到2—{ 1—〔3—(4—亚氨基(甲硫基)甲基苯基)—2—氧代—5—噁唑烷基羰基〕—4—哌嗪基}乙酸苄酯。实施例12
将0.45g(2R)—2—〔3—(4—亚氨基(甲硫基)甲基苯基)—2—氧代—5—噁唑烷基羰基氨基〕—3—苯基丙酸叔丁酯(可得自实施例11〕悬浮于5ml甲醇中,并加入0.47g乙酸铵,将混合物在室温下搅拌24小时。然后向反应混合物中加入10ml乙醚,过滤出形成的沉淀,蒸发浓缩,按常规操作,并用冰醋酸处理,得到(2R)—2—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基氨基〕—3—苯基丙酸叔丁酯,乙酸盐,m.p.191—192℃。
类似地,可得到下列化合物:由1—〔3—(4—亚氨基—(甲硫基)甲基苯基)—2—氧代—5—噁唑烷基羰基〕哌啶—4—羧酸苄酯,得到:1—〔3—(4—脒基(甲硫基)甲基苯基)—2—氧代—5—噁唑烷基羰基〕哌啶—4—羧酸苄酯,乙酸盐,m.p.197—199℃;由2—{1—〔3—(4—亚氨基—(甲硫基)甲基苯基)—2—氧代—5—噁唑烷基羰基〕—哌啶氧基}乙酸叔丁酯,得到:2—{1—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基〕—哌啶氧基}乙酸叔丁酯,乙酸盐,m.p.127—126℃;由2—{1—〔3—(4—亚氨基—(甲硫基)甲基苯基)—2—氧代—5—噁唑烷基羰基〕—4—哌嗪基}乙酸苄酯,得到:2—{1—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基〕—4—哌嗪基}乙酸苄酯,乙酸盐。实施例13
于室温下将0.25g(2R)—2—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基氨基)—3—苯基丙酸叔丁酯〔得自实施例12〕在10ml三氟乙酸中搅拌,直至完全水解。然后浓缩反应混合物,用甲苯反复洗涤残余物。再经乙酸乙酯处理后,得到(2R)—2—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基氨基〕—3—苯基丙酸,三氟乙酸盐,FAB(M+1):397。
同样地,通过水解实施例12的相应的酯,可得到下列产物:
1—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基〕哌啶—4—羧酸,三氟乙酸盐;
2—{1—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基〕—4—哌啶氧基}乙酸,三氟乙酸盐;
2—{1—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基〕—4—哌嗪基}乙酸,三氟乙酸盐。实施例14
将23.2g 3—(4—氰基苯基)—2—氧代—5—噁唑烷羧酸〔可得自实施例1〕与33.0g二碳酸二叔丁酯—起在1000ml甲醇和110ml 1N氢氧化钠溶液中在披钯碳上氢化,直至停止消耗氢气。然后真空浓缩溶液,再经常规操作,得到3—(4—叔丁氧羰基氨基甲苯基)—2—氧代—5—噁唑烷羧酸,m.p.166℃。实施例15
与实施例4类似,将3—(1—哌嗪基)丙酸苄酯与3—(4—叔丁氧基氨基苯基)—2—氧代—5—噁唑烷羧酸反应,得到3—{1—〔3—(4—叔丁氧羰基氨基甲苯基)—2—氧代—5—噁唑烷基羰基〕—4—哌嗪基}丙酸苄酯,m.p.128—130℃。
类似地,通过将3—(4—叔丁氧羰基氨基甲苯基)—2—氧代—5—噁唑烷羧酸与下列化合物反应,可得到相应产物:
与哌啶—4—羧酸苄基酯反应,得到:
1—〔3—(4—叔丁氧羰基氨基甲苯基)—2—氧代—5—噁唑烷基羰基〕—哌啶—4—羧酸苄酯;与2—(4—哌啶氧基)乙酸叔丁酯反应,得到:
2—{1—〔3—(4—叔丁氧羰基氨基甲苯基)—2—氧代—5—噁唑烷基羰基〕—4—哌啶氧基}乙酸叔丁酯,m.p.115—119℃;与2—(4—哌嗪基)乙酸苄酯反应,得到:
2—{1—〔3—(4—叔丁氧羰基氨基甲苯基)—2—氧代—5—噁唑烷基羰基〕—4—哌嗪基}乙酸苄酯,m.p.121℃;与4—哌啶羧酸叔丁酯反应,得到:
1—〔3—(4—叔丁氧羰基氨基甲苯基)—2—氧代—5—噁唑烷基羰基〕—4—哌啶羧酸叔丁酯,m.p.63.5℃;与(2R)—2—氨基—3—苯基丙酸叔丁酯反应,得到:
(2R)—2—〔3—(4—叔丁氧羰基氨基甲苯基)—2—氧代—5—噁唑烷基羰基氨基〕—3—苯基丙酸叔丁酯,m.p.68.69℃;实施例16
将1.5g 3—{1—〔3—(4—叔丁氧羰基氨基甲苯基)—2—氧代—5—噁唑烷基羰基〕—4—哌嗪基}丙酸苄酯在50ml DMF中于5%Pd/炭上氢化。经常规操作后,将粗产物溶于由二氯甲烷/甲醇/冰醋酸(70∶30∶2)组成的溶剂混合物中,并在硅胶上层析。用乙醚研磨产物,得到3—{1—〔3—(4—叔丁氧羰基氨基甲苯基)—2—氧代—5—噁唑烷基羰基〕—4—哌嗪基}丙酸,m.p.76—78℃。实施例17
于室温下将0.53g 2—{1—〔3—(4—叔丁氧羰基氨基甲苯基)—2—氧代—5—噁唑烷基羰基〕—4—哌啶氧基}乙酸叔丁酯在10ml三氟乙酸中搅拌。经常规操作后,用乙醚研制粗产物并干燥,得到2—{1—〔3—(4—氨基甲苯基)—2—氧代—5—噁唑烷基羰基〕—4—哌啶氧基}乙酸,三氟乙酸酯,FAB(M+1):378。
同样地,由(2R)—2—〔3—(4—叔丁氧羰基氨基甲苯基)—2—氧代—5—噁唑烷基羰基〕—3—苯基丙酸叔丁酯可制得:(2R)—2—〔3—(4—氨基甲苯基)—2—氧代—5—噁唑烷基羰基〕—3—苯基丙酸,三氟乙酸盐,m.p.178—185℃。实施例18
于室温下,将0.5g 1—〔3—(4—叔丁氧羰基氨基甲苯基)—2—氧代—5—噁唑烷基羰基〕哌啶—4—羧酸叔丁酯在10ml三氟乙酸中搅拌。真空浓缩溶液。随后用乙醚的盐酸处理粗产物,抽滤并干燥,得到1—〔3—(4—氨基甲苯基)—2—氧代—5—噁唑烷基羰基哌啶—4—羧酸,盐酸盐,m.p.256—258℃(分解)。实施例19
于室温下,将0.43g 3—{1—〔3—(4—叔丁氧羰基氨基甲苯基)—2—氧代—5—噁唑烷基羰基〕—4—哌嗪基}丙酸,乙酸盐在30ml乙醚的HCl溶液中搅拌。抽滤出形成的沉淀,用少量乙醚洗涤并干燥,得到3—{1—〔3—(4—氨基甲苯基)—2—氧代—5—噁唑烷基羰基〕—4—哌嗪基}丙酸,二盐酸盐,m.p.184—186℃。实施例20
于室温下,将0.74g 2—{1—〔3—(4—叔丁氧羰基氨基甲苯基)—2—氧代—5—噁唑烷基羰基〕—4—哌嗪基}乙酸苄酯在30mlHCl的乙酸乙酯溶液中搅拌。抽滤出形成的沉淀,用少许乙酸乙酯洗涤并干燥。得到2—{1—〔3—(4—氨基甲苯基)—2—氧代—5—噁唑烷基羰基〕—4—哌嗪基}乙酸苄酯,二盐酸盐,m.p.224—226℃。实施例21
将0.6g 2—{1—〔3—(4—氨基甲苯基)—2—氧代—5—噁唑烷基羰基〕—4—哌嗪基}乙酸苄酯二盐酸盐通过Pd/炭在30ml甲醇、5ml水和5ml冰醋酸的混合物中氢化。过滤反应混合物,并真空浓缩滤液。用乙酸乙酯研制粗产物,得到2—{1—〔3—(4—氨基甲苯基)—2—氧代—5—恶唑烷基羰基〕—4—哌嗪基}乙酸二盐酸盐,m.p.91℃(分解)。实施例22
将5.4g 3—(4—氨基甲苯基)—2—氧代—5—噁唑烷羧酸悬浮于70ml THF。搅拌下向其中滴加1N NaOH,然后滴加6.6g4—氰基苯甲酰氯的60ml THF溶液。通过加入1N NaOH维持溶液在pH9—10.5。反应发生后,用2NHCl酸化混合物至pH1。除去溶剂,抽滤出残余物,用水洗涤。得到3—(4—(4—氰基苯甲酰氨基甲基)苯基〕—2—氧代—5—噁唑烷羧酸,m.p.234℃。
类似地,通过将3—(4—氨基甲苯基)—2—氧代—5—噁唑烷羧酸与下列化合物反应,可得到相应产物:与对—氯羰基氨基苄腈反应,得到3—{4—〔3—(4—氰基苯基)脲甲基〕苯基}—2—氧代—5—噁唑烷羧酸。实施例23
与实施例10类似,将3—〔4—(4—氰基苯甲酰氨基甲基)苯基〕—2—氧代—5—噁唑烷基羧酸与硫化氢反应,得到3—〔4—(4—硫基氨基甲酰基苯甲酰氨基甲基)苯基—2—氧代—5—噁唑烷羧酸,m.p.105—110℃。
类似地,通过将3—{4—〔3—(4—氰基苯基)脲基甲基〕—苯基}—2—氧代—5—噁唑烷基羧酸与硫化氢反应,可得到3—{4—〔3—(4—硫代氨基甲酰基苯基)脲基甲基〕苯基}—2—氧代—5—噁唑烷基羧酸。实施例24
与实施例11类似,将3—〔4—(4—硫代氨基甲酰基苯甲酰氨基甲基)苯基〕—2—氧代—5—噁唑烷基羧酸与甲基碘反应,得到3—〔4—(4—亚氨基(甲硫基)甲基苯甲酰氨基甲基)苯基〕—2—氧代—5—噁唑烷羧酸,氢磺酸盐,m.p.209℃。
类似地,通过3—{4—〔3—(4—硫代氨基甲酰基苯基)脲基甲基〕苯基}—2—氧代—5—噁唑烷—羧酸与甲基碘反应,得到3—{4—〔3—(4—亚氨基(甲硫基)甲苯基)脲甲基〕苯基}—2—氧代—5—噁唑烷羧酸苄酯。实施例25
与实例12类似,将3—〔4—(4—亚氨基(甲硫基)甲基苯甲酰氨基甲基)苯基〕—2—氧代—5—噁唑烷基羧酸与乙酸铵反应,得到3—〔4—(4—脒基苯甲酰氨基甲基)苯基〕—2—氧代—5—噁唑烷羧酸,乙酸盐,m.p.294℃。
同样地,通过3—{4—〔3—(4—亚氨基(甲硫基)甲苯基)脲甲基〕苯基}—2—氧代—5—噁唑烷羧酸苄酯与乙酸铵反应,得到3—{ 4—〔3—(4—脒基苯基)脲甲基〕苯基}—2—氧代—5—噁唑烷羧酸,乙酸盐。实施例26
与实施例21类似,由3—〔4—(4—脒基苯甲酰氨基甲基)苯基〕—2—氧代—5—噁唑烷羧酸苄酯中除去苄酯基,得到3—〔4—(4—脒基苯甲酰氨基甲基)苯基〕—2—氧代—5—噁唑烷羧酸。
同样地,由3—{4—〔3—(4—脒基苯基)脲基甲基〕苯基}—2—氧代—5—噁唑烷基羧酸苄酯除去苄酯基即得到3—{4—〔3—(4—脒基苯基)脲基甲基〕苯基}—2—氧代—5—噁唑烷基羧酸。实施例27
于室温下,将3.36g 3—(4—叔丁氧羰基氨基甲苯基)—2—氧代—5—噁唑烷羧酸〔可得自实施例14;m.p.166℃〕在已被HCl气体饱和的30ml乙醚和30ml二恶烷的混合物中搅拌1小时。抽滤出沉淀,并用乙醚洗涤。得到3—(4—氨基甲苯基)—2—氧代—5—噁唑烷羧酸,m.p.211—212℃。实施例28
于室温下将0.22g(2R)—2—〔3—(4—氰基苯基)—2—氧代—5—噁唑烷基羰基氨基—3—苯基丙酸叔丁酯〔可得自实施例8〕在5ml三氟乙酸中搅拌1小时。然后真空浓缩溶液,并用乙醚研制残余物。得到(2R)—2—〔3—(4—氰基苯基)—2—氧代—5—噁唑烷基羰基氨基〕—3—苯基丙酸,三氟乙酸盐。实施例29
将0.26g 3—〔4—氨基(羟亚氨基)甲苯基〕—2—氧代—5—噁唑烷羧酸(可得自实施例2)在10ml冰醋酸和10ml乙酸酐的混合物中煮沸2h。然后真空浓缩反应溶液,并将残余物在乙醚中重结晶。得到3—〔4—(5—甲基—1,2,4—恶二唑—3—基)苯基〕—2—氧代—5—噁唑烷羧酸,m.p.215—218℃。实施例30
将1.06g 3—〔4—氨基(羟亚氨基)甲苯基〕—2—氧代—5—噁唑烷羧酸〔可得自实施例2〕和1.47g氯代乙酰氯在20ml冰醋酸中煮沸2小时。真空浓缩反应溶液,并将残余物从乙醚中重结晶,得到3—〔4—(5—氯甲基—1,2,4—恶二唑—3—基)苯基〕—2—氧代—5—噁唑烷羧酸,m.p.178—181℃。实施例31
将1.32g 3—〔4—氨基(羟亚氨基)甲苯基)—2—氧代—5—恶唑烷羧酸〔可得自实施例2〕和4.44g N—(氯代羰甲基)邻苯二甲酰亚胺在20ml冰醋酸中煮沸2小时。然后冷却反应溶液至室温,并抽滤出沉淀,用乙醚和冰醋酸洗涤,并用乙醇重结晶。得到3—〔4—(5—邻苯二甲酰亚氨基甲基—1,2,4—噁二唑—3—基)苯基〕—2—氧代—5—噁唑烷7羧酸,m.p.130—135℃。实施例32
在加有13ml乙酸酐的370ml冰醋酸中,在披钯碳上氢化15g3—〔4—氨基(羟亚氨基)甲苯基)—2—氧代—5—噁唑烷羧酸(可得自实施例2),直至氢气消耗终止。过滤除去催化剂,并弃去滤液。然后用100ml 1N HCl溶液和200ml浓HCl溶液处理固体残余物,并过滤。真空浓缩含盐酸的滤液,并过滤出在此过程中析出的晶体残余物,用少量水洗涤并干燥,得到30(4—脒基苯基)—2—氧代—5—噁唑烷羧酸,盐酸盐,m.p.253—254℃。实施例33
在加有0.5ml水的12.5ml甲醇中,将0.87g 1—〔3—(4—氰基苯基)—2—氧代—5—噁唑烷基羰基〕哌啶—4—羧酸苄酯〔可得自实施例8〕、0.43g羟基氯化铵和0.89g碳酸钠煮沸3小时。随后将反应溶液进行常规操作。得到1—{3—〔4—氨基(羟亚氨基)甲苯基〕—2—氧代—5—噁唑烷基羰基}哌啶—4—羧酸苄酯,FAB(M+1):467和1—{3—〔4—氨基(羟亚氨基)甲苯基〕—2—氧代—5—噁唑烷基羰基}哌啶—4—羧酸甲酯,FAB(M+1):391的混合物。通过柱层析(硅胶∶二氧甲烷/甲醇93∶7)分离这两种物质。实施例34
于室温下,在加有1.35g碳酸钾的13.5ml水和30ml甲醇中,将1.12g 3—{3—〔4—(5—氧代—1,2,4—噁二唑啉—3—基)苯基〕—2—氧代—5—噁唑烷基羰基氨基}丙酸甲酯〔可得自实施例4〕搅拌3小时。然后进行常规操作。得到3—{3—〔4—(5—氧代—1,2,4—噁二唑啉—3—基)苯基〕—2—氧代—5—噁唑烷基羰基氨基)丙酸,m.p.221—223℃。
以下实施例涉及药物制剂:实施例A:注射小瓶
将100g式I活性化合物和5g磷酸氢二钠溶于3l双蒸馏水中,用2N盐酸调节其pH值至6.5,进行无菌过滤后分散至注射小瓶中,并在无菌条件下冷冻干燥,以无菌方式使注射小瓶封口。每一注射小瓶含有5mg活性化合物。实施例B:栓剂
将20g式I活性化合物和100g大豆卵磷脂及1400g可可油的混合物熔化,倒入模具中并冷却。每一栓剂含有20mg活性化合物。实施例C:溶液
将1g式I活性化合物、9.38g NaH2PO4·2H2O、28.48gNa2HPO4·12H2O和0.1g亚苄基麦芹属氯化物溶于940ml双蒸馏水中制成溶液。调节pH至6.8,并将溶液调节1升,并照射除菌。该溶液能以眼药水的形式使用。实施例D:软膏
在无菌条件下将500毫克的式I的活性物质与99.5克凡士林混合。实施例E:片剂
将1kg式I的活性物质、4kg乳糖、1.2kg土豆淀粉、0.2kg滑石和0.1kg硬脂酸镁的混合物以常规的方式压缩形成片剂,每片含有10毫克活性物质。实施例F:涂膜片剂
用与实施例E相类似的方法压成片剂,然后以常规的方式用含有蔗糖、土豆淀粉、滑石、黄蓍胶和着色剂的涂层进行涂膜。实施例G:胶囊
以常规的方式,用2kg式I的活性物质装填硬的明胶胶囊,使每个胶囊含有20毫克的活性物质。实施例H;安瓿
将1kg式I的活性物质在60升二次重蒸水中的溶液无菌过滤,分散于安瓿中和在无菌条件下冷冻干燥,并且在无菌条件下将安瓿封口,每个安瓿含有10毫克的活性物质。
Claims (9)
1.式I的恶唑烷酮羧酸衍生物:
其中
R1 为NO2,NR6R7,CN,CONR6R7,CSNR6R7,C(=NH)SA,
C(=NH)OA,C(=NH)SAr,C(=NH)NHOH,C(=NH)NR6R7,
CH2NR6R7,CH2NHC(=NH)NR6R7,NHC(=NH)NR6R7,
CH2NHCO-alk-NR6R7,CH2NHCO-Ph-E,CH2NHCO-Ph-CH2NR6R7,CH2NHCONH-Ph-E或D,
X 为OH,OA,AS,AS-AS’,
或
D 为
E 为-CN,-C(=NH)OA,-CSNH2,-C(=NH)SA或C(=NH)NH2,Y 为CH2,CHOR5或C=O,R2 为H,A,Ar,OH,OA,CF3,CCl3,NR6R7,-alk-NR6R7,
As或As’各自独立地为选自下列的氨基酸残基;Ala,β—Ala,Arg,Asn,Asp,Gln,Glu,Gly,Leu,Lys,Orn,Phe,Pro,Sar,Ser,Thr,Tyr,Tyr(OMe),Val,C—烯丙基—Gly,C—炔丙基—Gly,N—苄基—Gly,N—苯乙基—Gly,N—苄基—β—Ala,N—甲基—β—Ala和N—苯乙基—β—Ala,也可向游离的氨基或羧基上提供本身已知的常规保护基,
R5、R6和R7各自独立地为H或A,
m为1、2或3,
n为1、2、3或4,
P为0、1或2,
q为0或1,
r为1或2,
A为C1-6烷基,
—alk—为C1-6亚烷基,
Ar为苯基或苄基,且
ph为亚苯基,及其生理上可接受的盐和/或溶剂化物。
2.权利要求1所述式I化合物的对映体或非对映异构体。
3.根据权利要求1所述的式I化合物,其中游离氨基、脒基或胍基部分或全部地被常规的氨基保护基保护。
4.(a)2—〔1—(3—(4—脒基苯基)—2—氧代—5—噁唑烷羰基)哌啶—4—基—氧〕乙酸;
(b)(2R)—2—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基氨基〕琥珀酸;
(c)3—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基氨基〕丙酸;
(d)1—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基〕哌啶—4—羧酸叔丁酯;
(e)(2R)—2—〔3—(4—脒基苯基)—2—氧代—5—噁唑烷基羰基氨基〕琥珀酸二叔丁基酯;
(f)1—〔3—(4—(5—氧代—1,2,4—噁二唑啉—3—基)苯基)—2—氧代—5—恶唑烷基〕哌啶—4—羧酸叔丁酯;
(g)3—〔4—(氨基(羟亚氨基)甲基)苯基〕—2—氧代—5—噁唑烷羧酸;
(h)(2R)—2—〔3—(4—氰基苯基)—2—氧代—5—噁唑烷基羰基氨基〕—3—苯基丙酸;
(i)3—〔3—(4—(5—氧代—1,2,4—噁唑烷—3—基)苯基)—2—氧代—5—噁唑烷基羰基氨基〕丙酸。
5.制备权利要求1所述的式I化合物的方法,其特征在于:
(a)通过用溶剂分解剂或氢解剂处理,使式I化合物从其一种功能性衍生物中释放出来,或,
R1的定义同上,且
L为Cl、Br、OH或反应性酯化OH基或一易于进行亲核取代的离去基团,
H—X’ III其中
(c)通过水解式I的酯或酯化式I的羧酸,将残基X转化为不同的残基X,或
(d)通过下式方式使残基R1转化为不同的残基R1:
—催化氢化NO2和/或CN基团,或
—通过与氨反应将腈基转化为C(=NH)—NH2基团,或
—将腈基转化为硫代氨基甲酰基,或
—将硫代氨基甲酰基转化为烷基硫酰亚氨基,或
—将氨基甲酰基转化为烷基亚氨基,或
—将甲基硫酰亚氨基转化为脒基,或
—通过与NH2OH反应将腈基转化为C(=NH)—NHOH基团,或
—将NH2基团转化为胍基,或
—将C(=NH)—NHOH基团转化为脒基,或
—将CH2NH2基团转化为烷酰氨基甲基、CH2NHC(=NH)NR6R7、CH2NHCO—ph—C(=NH)NR6R7、CH2NHCO—ph—CH2NR6R7或CH2NHCONH—ph—E基团,或
—将1,2,4—噁二唑或1,2,4—噁二唑酮转化为脒基,
(e)将下式IV化合物与反应性碳酸衍生物反应,其中
R1和X的定义同前,或
(g)通过用酸或碱处理使式I化合物转化为其一种盐。
6.一种制备药物制剂的方法,其特征在于将权利要求1的式I化合物和/或其一种生理上可接受的盐与至少一种固态、液态或半液态赋形剂或助剂一起制成合适的给药形式。
7.药物制剂,其特征在于它含有至少一种权利要求1的式I化合物和/或其生理上可接受的盐。
8.权利要求1所述的式I化合物和/或其一种可作药用的盐在控制疾病方面的应用。
9.权利要求1所述的式I化合物和/或其一种可作药用的盐在制备药物中的应用。
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US7049140B1 (en) * | 1999-04-29 | 2006-05-23 | Vanderbilt University | X-ray guided drug delivery |
DE19958153A1 (de) * | 1999-12-03 | 2001-06-07 | Yamanouchi Pharma Co Ltd | Oxazolidinon-Derivate |
DE10105989A1 (de) | 2001-02-09 | 2002-08-14 | Bayer Ag | Substituierte Oxazolidinone und ihre Verwendung |
US7306925B2 (en) | 2001-11-09 | 2007-12-11 | Vanderbilt University | Phage antibodies to radiation-inducible neoantigens |
US7906102B2 (en) | 2001-10-03 | 2011-03-15 | Vanderbilt University | Ligands to radiation-induced molecules |
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US7141588B2 (en) | 2002-02-25 | 2006-11-28 | Pfizer, Inc. | N-aryl-2-oxazolidinone-5-carboxamides and their derivatives |
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US20050107350A1 (en) * | 2003-08-22 | 2005-05-19 | Pharmacia Corporation | Method for the treatment or prevention of bone disorders with a cyclooxygenase-2 inhibitor alone and in combination with a bone disorder treatment agent and compositions therewith |
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US4866182A (en) * | 1988-02-18 | 1989-09-12 | Merrell Dow Pharmaceuticals Inc. | Cardiotonic alkanoyl and aroyl oxazolones |
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US5084466A (en) * | 1989-01-31 | 1992-01-28 | Hoffmann-La Roche Inc. | Novel carboxamide pyridine compounds which have useful pharmaceutical utility |
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CZ290984B6 (cs) | 2002-11-13 |
KR960007586A (ko) | 1996-03-22 |
KR100365870B1 (ko) | 2003-03-04 |
EP0697408A1 (de) | 1996-02-21 |
AU698412B2 (en) | 1998-10-29 |
PL310070A1 (en) | 1996-03-04 |
DE4429461A1 (de) | 1996-02-22 |
HU223844B1 (hu) | 2005-02-28 |
SK281754B6 (sk) | 2001-07-10 |
PL182615B1 (pl) | 2002-02-28 |
TW425392B (en) | 2001-03-11 |
HU9502431D0 (en) | 1996-05-28 |
HUT76790A (en) | 1997-11-28 |
DK0697408T3 (da) | 2002-04-15 |
CA2156360C (en) | 2011-01-11 |
UA35607C2 (uk) | 2001-04-16 |
CZ208795A3 (en) | 1996-06-12 |
ES2170114T3 (es) | 2002-08-01 |
NO953253D0 (no) | 1995-08-18 |
JP3810833B2 (ja) | 2006-08-16 |
ATE212339T1 (de) | 2002-02-15 |
CA2156360A1 (en) | 1996-02-20 |
NO305206B1 (no) | 1999-04-19 |
DE59510010D1 (de) | 2002-03-14 |
PT697408E (pt) | 2002-07-31 |
NO953253L (no) | 1996-02-20 |
AU2852295A (en) | 1996-02-29 |
ZA956929B (en) | 1996-03-29 |
EP0697408B1 (de) | 2002-01-23 |
US5614535A (en) | 1997-03-25 |
CN1204889C (zh) | 2005-06-08 |
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