CN1234698C - 基于金属中心的一氧化氮供体 - Google Patents
基于金属中心的一氧化氮供体 Download PDFInfo
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- CN1234698C CN1234698C CNB028007549A CN02800754A CN1234698C CN 1234698 C CN1234698 C CN 1234698C CN B028007549 A CNB028007549 A CN B028007549A CN 02800754 A CN02800754 A CN 02800754A CN 1234698 C CN1234698 C CN 1234698C
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- metal complexes
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- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical class O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 title abstract description 9
- 239000002840 nitric oxide donor Substances 0.000 title abstract description 6
- 229910052751 metal Inorganic materials 0.000 claims abstract description 30
- 239000002184 metal Substances 0.000 claims abstract description 29
- 150000001875 compounds Chemical class 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 13
- 229910052723 transition metal Inorganic materials 0.000 claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims abstract description 10
- 150000003624 transition metals Chemical class 0.000 claims abstract description 10
- 239000011701 zinc Substances 0.000 claims abstract description 8
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229910052725 zinc Inorganic materials 0.000 claims abstract description 6
- 239000003446 ligand Substances 0.000 claims abstract description 5
- 230000003647 oxidation Effects 0.000 claims abstract description 3
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 3
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 48
- 150000003839 salts Chemical class 0.000 claims description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 150000002500 ions Chemical class 0.000 claims description 11
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- 125000000129 anionic group Chemical group 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
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- 125000003118 aryl group Chemical group 0.000 claims description 8
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- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 5
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- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 claims description 4
- 125000002091 cationic group Chemical group 0.000 claims description 4
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- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 claims description 2
- LSPHULWDVZXLIL-LDWIPMOCSA-N (?)-Camphoric acid Chemical compound CC1(C)[C@@H](C(O)=O)CC[C@@]1(C)C(O)=O LSPHULWDVZXLIL-LDWIPMOCSA-N 0.000 claims description 2
- NQBWNECTZUOWID-UHFFFAOYSA-N (E)-cinnamyl (E)-cinnamate Natural products C=1C=CC=CC=1C=CC(=O)OCC=CC1=CC=CC=C1 NQBWNECTZUOWID-UHFFFAOYSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 2
- 239000004380 Cholic acid Substances 0.000 claims description 2
- DSLZVSRJTYRBFB-UHFFFAOYSA-N Galactaric acid Natural products OC(=O)C(O)C(O)C(O)C(O)C(O)=O DSLZVSRJTYRBFB-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 claims description 2
- 239000005639 Lauric acid Substances 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- 229910010413 TiO 2 Inorganic materials 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 150000001449 anionic compounds Chemical class 0.000 claims description 2
- 125000005110 aryl thio group Chemical group 0.000 claims description 2
- 125000004104 aryloxy group Chemical group 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 2
- CUBCNYWQJHBXIY-UHFFFAOYSA-N benzoic acid;2-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1O CUBCNYWQJHBXIY-UHFFFAOYSA-N 0.000 claims description 2
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 claims description 2
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- 235000019416 cholic acid Nutrition 0.000 claims description 2
- NQBWNECTZUOWID-QSYVVUFSSA-N cinnamyl cinnamate Chemical compound C=1C=CC=CC=1\C=C/C(=O)OC\C=C\C1=CC=CC=C1 NQBWNECTZUOWID-QSYVVUFSSA-N 0.000 claims description 2
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 claims description 2
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- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
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- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 125000004309 pyranyl group Chemical class O1C(C=CC=C1)* 0.000 description 1
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- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- FGVVTMRZYROCTH-UHFFFAOYSA-N pyridine-2-thiol N-oxide Chemical compound [O-][N+]1=CC=CC=C1S FGVVTMRZYROCTH-UHFFFAOYSA-N 0.000 description 1
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- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical compound OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/53—Nitrogen atoms
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Abstract
本发明涉及配体配合物,其特征在于存在哌嗪NONO盐残基和金属阳离子,所述的阳离子衍生自稳定氧化态的过渡金属和锌。这些配合物是一氧化氮供体,在冠状区域产生内皮保护作用,刺激内皮修复(re-endothelialization)和血管生成过程。本发明还包括所述化合物的制备方法和治疗用途。
Description
本发明涉及一类释放一氧化氮(NO)的金属配合物,其特征在于存在配位哌嗪NONO盐残基;本发明还涉及它们作为药剂的用途,所述的药剂能够诱导血管松弛,产生对冠状区域内皮的保护作用,并且刺激内皮修复(re-endothelialization)和血管生成过程。
本发明还涉及制备上述化合物的方法。
本发明进一步涉及含有一种或多种上述化合物的药物制剂。
本发明化合物的药理学活性通过它们在用去甲肾上腺素预处理的血管标本(兔主动脉环)中的松弛诱导效应评价(Amerini等人,J.Cardiovasc.Pharmacol.,28:82-88,1966)。所述化合物的内皮保护和前血管生成作用也已经在对微循环系统内皮细胞的增殖和迁移的研究中进行了评价(M.Ziche等人,J.Clin.Invest.94:2036-2044,1994)。
b 一氧化氮在多种生物学和生理学过程中作为血管扩张剂、神经递质和生物调节剂起重要作用,并且在防御免疫系统中也有涉及(NitricOxide:Principles and Action,J.Lancaster Jr.ed.,Academic Press,San Diego,CA 1996)。其在体内通过NO合成酶由氨基酸L-精氨酸酶催化生成(R.Iyengar,D.J.Stuehr和M.A.Marletta,Proc.Natl.Acad.Sci.USA 84,6369,1987),其以各种异构形式存在。一氧化氮的作用取决于其对鸟苷酸环化酶并以此诱导生成环状鸟苷酸的活化能力。NO合成酶的结构异构形式主要以内皮浓度存在并控制血管紧张(vasal tone)。其它类型的NO合成酶在活化的巨噬细胞和其它细胞中被诱导,合成作为肿瘤细胞和微生物的cyclotoxic试剂的NO。
NO不充分的生成决定了多种病症,因此必须从体外施用这种分子。但是,证明NO是一种寿命相对短暂的自由基分子,不能以其本身投药,而要通过前体。这些包括传统的硝基血管舒张剂,诸如硝化甘油、硝普酸钠、亚硝酸异戊酯和四硝酸季戊四醇酯,它们已经使用了一段时间,但是带来了许多问题,涉及到NO释放速度和程度的控制和副作用的产生。因此,得到能够释放生理上更适合的NO浓度而副作用更小的化合物对于有利的治疗很重要。
本发明的化合物是一类金属配合物,配体含有哌嗪NONO盐残基,在溶液中时,释放出NO,它们相应的碱是4-(羟基亚硝氨基)-1-哌嗪乙烷胺,一种已知化合物(J.A.Hrabie,J.R.Klose,D.A.Wink和L.K.Keefer,J.Org.Chem.58,1472,1993),其通过对原始方法改进后的方法制备。从在此要求保护的NONO盐衍生的配合物允许在结构、电荷和物理化学性质以及NO释放活性上有很大的变化。它们是具有下述通式结构的化合物:
其中:
a)R1和R2独立地表示氢;直链或支链(C1-C4)烷基,其可被选自下述的1-2个基团取代:羟基、(C1-C4)烷氧基、(C1-C4)烷硫基、氨基、(C1-C4)烷基氨基、二(C1-C4)烷基氨基、羧基、羰基(C1-C4)烷氧基、芳基、芳氧基、芳硫基;
或
b)R1和R2一起表示选自下述的基团:=CR3-芳基,其中R3表示氢,可被1-2个选自羟基、羧基、芳基的基团取代的直链或支链(C1-C4)烷基;
n表示2-4的整数,优选2或3;
M+表示过渡金属或锌阳离子;
x表示1-3的整数,表示过渡金属或锌阳离子与其稳定氧化态相关的电荷单位;
A-表示与NONO盐金属配合物形成稳定盐的无机或有机阴离子;
y表示1-3的整数,表示阴离子的电荷单元;
m表示包括0的整数或分数,表示平衡NONO盐金属配合物的正电荷所需的负电荷数,其与x、y、k和w通过下式关联:
其中w是在NONO盐配体物质中存在的可能的其它阴离子电荷单元数,k是可能的其它阳离子电荷数。
在说明书和权利要求书中,术语“芳基”表示苯或萘环,其可被1-3个选自下述的取代基取代:(C1-C4)烷基、羟基、氨基、(C1-C4)烷基氨基、二(C1-C4)烷基氨基、羧基、羰基(C1-C4)烷氧基、(C1-C4)烷氧基、硝基、氰基、卤素、苯氧基、巯基、(C1-C4)烷硫基;或是5-6元含有1或2个选自N、S、O的杂原子的杂环,其可被如上取代;以及它们完全或部分氢化的衍生物,可被氧代或硫代基取代。
5-6元含有1或2个杂原子的杂环的例子是:吡咯、呋喃、吡唑、咪唑、噁唑、异噁唑、噻吩、噻唑、异噻唑、吡啶、吡嗪、哒嗪、嘧啶、吡喃、1,4-噁嗪、1,4-噻嗪,它们可被如上取代;以及它们完全或部分氢化的衍生物,其在碳环部分可被氧代或硫代基取代,并在氮原子上可被(C1-C4)烷基取代,如果存在,是诸如1-(C1-C4)-烷基-2(1H)吡啶酮或1-(C1-C4)烷基-2(1H)吡啶硫酮。
术语“过渡金属阳离子”表示选自下述的金属衍生的阳离子:Ti、V、Cr、Mn、Fe、Co、Ni、Cu、Pd、Ru、Pt、Au。这类阳离子的例子是:Zn2+、TiO2+、VO2+、Cr3+、Mn2+、Fe3+、Co3+、Ni2+、Cu2+、Pd2+、Ru3+、Pt2+、Au3+。
术语“(C1-C4)烷基”和包括它的等价的基团(例如(C1-C4)烷氧基、(C1-C4)烷基氨基等)表示直链或支链烷基链,诸如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基和叔丁基。
在NONO盐的配体物质中可能存在的阴离子电荷单元可衍生自酸类型基团的电离,例如羧基、羟基、巯基,它们可能作为取代基存在于通式(I)R1和/或R2和/或R3表示的基团中。在这种情况下,上述取代基还包括各自的阴离子形式。通常,w是0-3的整数,优选0-2,更优选0或1。
在NONO盐的配体物质中可能存在的阳离子电荷单元可衍生自例如通式(I)中R1R2N-碱部分和碱性基团—例如氨基、(C1-C4)烷基氨基、二(C1-C4)烷基氨基—的质子化,后者可能作为取代基存在于R1和/或R2和/或R3表示的基团中。通常,k是0-3的整数,优选0-2,更优选0或1。
与NONO盐配合物形成稳定盐的无机或有机阳离子可衍生自一般的无机或有机酸。优选与药学可接受的酸形成的盐,这些酸是例如盐酸、氢溴酸、硫酸、高氯酸、磷酸、乙酸、丙酸、抗坏血酸、乳酸、琥珀酸、马来酸、富马酸、棕榈酸、胆酸、粘液酸、樟脑酸、戊二酸、乙醇酸、邻苯二甲酸、酒石酸、月桂酸、硬脂酸、水杨酸、甲磺酸、苯磺酸、萘磺酸、山梨酸、苦味酸、苯甲酸、肉桂酸、甲苯磺酸、三氟乙酸和三氟甲磺酸。
当(x+k)的和等与(1+w)的和,设m为0,则在式(I)化合物中的阴离子[Ay-]不存在。实际上,其没有必要存在,因为NONO盐金属配合物中阳离子电荷单元(x+k)完全被内部阴离子电荷单元(1+w)补偿。
通常,下式用作起始原料的1-(ω-氨基烷基)哌嗪:
(其中n=2-4)可通过相应的ω-溴代烷基邻苯二甲酰亚胺与哌嗪反应,然后水解邻苯二甲酰亚胺基制备。
4-(羟基亚硝氨基)-1-哌嗪乙烷胺可通过将1-(2-氨基乙基)哌嗪与NO按照上述J.A.Hrabie等人报道的方法反应制备,其中在5atm的压力和室温下使用NO;或通过在此使用的可能更简单的等价生产方法制备,其中在1atm下使用NO,反应在-25℃的低温恒温器中进行。式(III)的4-(羟基亚硝氨基)-1-(ω-氨基烷基)哌嗪同系物:
其中n表示3或4,可用类似的方法从相应的1-(ω-氨基烷基)哌嗪和NO开始制备。
4-(羟基亚硝氨基)-1-(一或二烷基-ω-氨基烷基)哌嗪的前体是得到其中R1和/或R2表示a)中除了氢以外的基团的式(I)金属配合物所必须的,其制备可从相应的1-(ω-氨基烷基)哌嗪—选择性地保护在哌嗪环的4位的仲氮原子—与适当的羰基衍生物缩合,所述羰基衍生物相应于将被引入的(C1-C4)烷基,同时有伯氨基位于烷基链上(根据羰基化合物的反应性通过在醇中简单加热或在苯中回流共沸除去水),然后在温和的条件下还原(例如用硼氢化钠或在Pd/C上用氢气),然后可以在ω-氨基中引入第二个(C1-C4)烷基,烷基可以被上述a)的基团取代。这种引入可通过常规的烷基化方法完成。然后,通过与NO在类似于其中R1和R2均为氢的前述相应化合物的条件下反应,消去哌嗪环4位上的仲氮的保护基后,得到相应的4-羟基亚硝氨基衍生物。
为了制备用于得到其中R1和R2一起表示上述b)基团的通式(I)配合物所必须的席夫碱,将4-(羟基亚硝氨基)-1-哌嗪乙烷胺或其中n表示3或4的式(III)的4-(羟基亚硝氨基)-1-(ω-氨基烷基)-哌嗪与式O=CR3-芳基的羰基化合物缩合,其中R3定义如上。
用于得到b)组金属配合物所必须的4-(羟基亚硝氨基)-1-(氨基烷基)哌嗪的席夫碱通常不用分离,因为制备它们需要可使哌嗪基失去NO的条件。用于制备席夫碱的羰基化合物是商品化合物或可通过文献中所述的方法得到。例如,通过J.Becher和E.G.Frandsen,Acta Chem.Scand.,Ser.B 30,863,1976文献中报道的方法可得到3-甲酰基-1-异丙基-2(1H)-吡啶硫酮和在环的1位有不同的烷基取代基的类似衍生物。
优选的本发明金属配合物由下述式(I)化合物组成,其中R1和R2均表示氢或一起表示=CR3-芳基,其中R3是氢,术语:芳基”表示苯环或吡啶环,可被羟基或巯基取代,优选是离子化的阴离子形式,或部分氢化并在氮原子上可被(C1-C4)烷基取代并在碳环部分被氧代基或硫代基取代;n表示2或3,优选2。
根据本发明制备的金属配合物的例子如下:
*铜(II)和4-(羟基亚硝氨基)-1-哌嗪乙烷胺阴离子形成的配合物,以高氯酸根作为反荷离子,
定义为[Cu(PipNONO)][ClO4],相应于通式(I),其中:R1=R2=氢;Mx+=Cu2+;Ay-=ClO4-;(x+k)=2;(1+w)=1;y=1;m=1。
*镍(II)和由水杨醛与4-(羟基亚硝氨基)-1-哌嗪乙烷胺形成的席夫碱的双阴离子形成的配合物,
定义为[Ni(SalPipNONO)],相应于通式(I),其中:R1+R2=[=CH-(2-(-O)C6H4)];Mx+=Ni2+;(x+k)=2;(1+w)=2;m=0。
*铜(II)和由3-甲酰基-1-异丙基-2(1H)-吡啶硫酮与4-(羟基亚硝氨基)-1-哌嗪乙烷胺形成的席夫碱的阴离子形成的配合物,以高氯酸根作为反荷离子,
定义为[Cu(PitPipNONO)][ClO4],相应于通式(I),其中:R1+R2=[=CH-(1-(2-丙基)-2(1H)-硫代基-3-吡啶基)];Mx+=Cu2+;Ay-=ClO4 -;(x+k)=2;(1+w)=1;y=1;m=1。
*镍(II)和由2-甲酰基吡啶与4-(羟基亚硝氨基)-1-哌嗪乙烷胺形成的席夫碱的阴离子形成的配合物,以高氯酸根作为反荷离子,
定义为[Ni(PiaPipNONO)][ClO4],相应于通式(I),其中:R1+R2=[=CH-(2-吡啶基)];Mx+=Ni2+;Ay-=ClO4 -;(x+k)=2;(1+w)=2;y=1;m=1。
根据本发明的衍生自4-(羟基亚硝氨基)-(氨基烷基)哌嗪或其席夫碱的金属配合物的制备方法是基于下述一般的方法和反应。
属于式(I)中a)组的4-(羟基亚硝氨基)-1-(ω-氨基烷基)-哌嗪与金属离子的配合物的制备是通过化学计量量的式(IV)配体与过渡金属或锌的盐在惰性有机溶剂中在等量强碱存在下反应,
其中R1和R2定义如式(I)的a)组,n表示2-4的整数,优选2或3。通常使用的惰性有机溶剂是1-4个碳原子的低级醇,优选乙醇和甲醇。使用的过渡金属或锌优选那些带有与得到的式(I)配合物成盐的阴离子[Ay]相同的阴离子。其中[Ay-]表示特定阴离子的式(I)配合物无论怎样都可通过简单的离子交换反应转化为其中[Ay-]表示不同阴离子的另一种式(I)配合物。作为产物的配合物通常在低级醇中很易溶,特别是在甲醇中,为了分离它们可能需要在反应溶液中加入乙醚,优选在冷却条件下。产物通过过滤或离心分离并用少量冷的甲醇-乙醚混合物或简单地用乙醚洗涤提纯。所述的工艺也适用于得到其中R1和R2一起表示=CR3-芳基,其中R3定义如上的b)组式(I)配合物。在这种情况下,使用的配体是式(IV)表示的产物,其中R1和R2定义如上述式(I)的b)组,n表示2-4的整数,优选2或3。所述配体可通过缩合上述式(III)的4-(羟基亚硝氨基)-1-(ω-氨基烷基)哌嗪和式O=CR3-芳基的羰基化合物制备,式(III)中的n是2-4的整数,优选2或3,羰基化合物中R3定义如式(I)的b)组。
如果存在金属离子,通过公知的模板效应,羰基化合物和式(III)的4-(羟基亚硝氨基)-1-(ω-氨基烷基)哌嗪的缩合会显著加速到一定程度,从而可在温和条件下,通过用羰基化合物、4-(羟基亚硝氨基)-1-(ω-氨基烷基)哌嗪和过渡金属或锌的盐在等量强碱存在下、在惰性有机溶剂—优选乙醇或甲醇—中、在室温或更低的温度下方便地得到这些亚氨基衍生物的配合物。通常在这些条件下配合物至少部分沉淀;加入乙醚可使沉淀完全。过滤或离心沉淀,用少量冷甲醇-乙醚混合物或仅用乙醚洗涤,这取决于沉淀的溶解性。
金属配合物通过元素分析(C,H,N)和IR、UV-Vis光谱和NMR(对于抗磁性配合物)表征。
下面的实施例非限制性地具体说明本发明。
实施例1:配合物[Cu(PipNONO)][ClO4]的合成
将50mg的4-(羟基亚硝氨基)-1-哌嗪乙烷胺(0.26mmol)溶于5ml含等摩尔量NaOH的甲醇溶液中。将等量的Cu(ClO4)26H2O溶于数毫升甲醇中,加入该溶液。在搅拌下保持冷溶液,可见到兰紫色产物沉淀,通过离心分离,用少量冷乙醚洗涤数次。然后在真空下干燥产物(产率33%)。分析数据证实了其组成。
实施例2:配合物[Ni(SalPipNONO)]的合成
将50mg的4-(羟基亚硝氨基)-1-哌嗪乙烷胺(0.26mmol)溶于5ml含等摩尔量NaOH的甲醇溶液中。将27.6μl水杨醛(0.26mmol)通过微移液管加入该溶液中,立刻得到黄色,然后在搅拌下加入34.2mg冷NiCl2。通过加入冷乙醚沉淀黄绿色的与席夫碱的配合物。然后离心,用少量冷乙醚洗涤,在真空下干燥(产率43%)。分析数据证实了其组成。
用于表征化合物释放NO活性的药理学试验是用去甲肾上腺素预处理的兔主动脉的松弛(Amerini等人,J.Cardiovasc.Pharmacol.,28:82-88,1996)。用ED50剂量的去甲肾上腺素预处理的血管样品用增加剂量的所研究配合物处理(1nM-100μM)。血管松弛效应与诸如硝普酸钠和精胺NONO盐的传统NO供体比较。
衍生自4-(羟基亚硝氨基)-1-(氨基烷基)哌嗪的根据本发明的配合物均能导致有力的血管松弛。例如,按照与硝普酸钠相比较的[Ni(SalPipNONO)]、[Cu(PipNONO)][ClO4]、[Cu(SalPipNONO)]的效能大小顺序,根据下述ED50值变化:[Ni(SalPipNONO)]30nM;[Cu(PipNONO)][ClO4]100nM;[Cu(SalPipNONO)]和硝普酸钠3μM。精胺NONO盐比哌嗪NONO盐配合物的效能低很多。配合物的生物效应的insurgence和持续的动力学高于用硝普酸钠得到的结果。
证明主动脉松弛效应是特定的并与NO释放相关的对照试验的进行是通过研究缺少结合在哌嗪核上的NONO盐残基的配合物[Ni(SalPipNONO)]类似物进行的;发现其完全没有活性。另外,ODQ{1H-[1,2,4]氧杂二唑并[4,3-a]喹喔啉-1-酮}—一种鸟苷酸环化酶的选择性抑制剂—的存在完全消除了[Ni(SalPipNONO)]的松弛效应。
通过测量对微循环系统内皮细胞上生长促进和迁移效应与其它NO供体比较评价本发明化合物的内皮保护和前血管生成作用。用Boyden室和在研究物质下暴露48小时后细胞总数评价细胞迁移和增殖。(M.ziche等人,J.Clin,Invest.94:2036-2044,1994)。
根据本发明衍生自4-(羟基亚硝氨基)-1-(ω-氨基烷基)哌嗪的配合物能够诱导内皮细胞增殖和迁移。对迁移的效应取决于剂量(1nM-1μM),最大活性在100nM和1μM之间。配合物也同样有活性,并且比硝普酸钠更为有力,其在100μM浓度表现出最大活性,而精胺NONO盐活性很小,对其它NO供体没有观察到最大效应。对增殖的效应用增加的化合物浓度(1nM-1μM)测定。在10和100nM的剂量观察到增加的细胞增殖,在较低的剂量,效应更大。在1μM,细胞的数量与对照相等。最优活性的配合物又是[Ni(SalPipNONO)]。发现那些缺少结合在哌嗪核上的NONO盐残基的该配合物的类似物根本没有活性。再次,在ODQ—一种鸟苷酸环化酶的选择性抑制剂—存在下,完全消除了配合物的增殖效应。
正如科学和/或专利文献中的大量参考所证实的,具有NO释放活性的化合物可用于许多治疗领域,这些文献中的一些引用如下作为例子:
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Geppetti P,Ledda E.,Nitric oxide mediates angiogenesis in vivo andendothelial cell growth and migration in vitro promoted by substance P.JClin Invest 1994;94(5):2036-44;
Ziche M,Morbidelli L,Masini E,Granger H,Geppetti P,Ledda E,.Nitricoxide promotes DNA systhesis and cyclic GMP formation in endothelialcells from postcapillary venules
Biochem Biophys Res Commun.1993;192(3):1198-203。
根据本发明的化合物因此可用于与下述相关的疾病和/或功能障碍的治疗:
a)心血管系统,诸如高血压、心绞痛、动脉粥样硬化、心肌缺血等;
b)女性生殖系统,诸如不孕症、痛经、早产、内分泌机能障碍、骨质疏松等;
c)男性生殖系统,诸如阳萎、男性更年期综合征、内分泌功能障碍、前列腺肥大等;
d)中枢神经系统,诸如神经和行为紊乱、癫痫、阿尔茨海默氏症等;
e)炎性过程,诸如自身免疫和免疫疾病、急性炎症、关节炎、移植反应;
f)内部器官功能,诸如肾(例如高血压、肾动脉狭窄)、胰腺(例如糖尿病)和膀胱(例如失禁);
g)皮肤系统,诸如湿疹、痤疮、创伤和烧伤;
h)肿瘤的生长和扩散。
本发明的化合物可使用其本身,或可与其它药物配合使用(例如非甾族抗炎剂,Del Soldato等人,TiPS,20:319-323,1999)。
剂量可根据年龄、给药方法和患者疾病状态变化。通常的有效剂量在0.015μg/kg至1.50mg/kg患者体重范围内变化,与患者状态、疾病和给药方式相关。
本发明的化合物可通过舌下、粘液渗透(transmucous)、吸入、口服、肌内、静脉内、透皮或局部给药。
药物剂型根据给药方式变化,通常用本领域已知的方法制备。
Claims (15)
1.下式哌嗪NONO盐衍生物的金属配合物,
其中:
a)R1和R2独立地表示:氢;直链或支链(C1-C4)烷基,其可被选自下述的1-2个基团取代:羟基、(C1-C4)烷氧基、(C1-C4)烷硫基、氨基、(C1-C4)烷基氨基、二(C1-C4)烷基氨基、羧基、羰基(C1-C4)烷氧基、芳基、芳氧基、芳硫基;
或
b)R1和R2一起表示选自下述的基团:=CR3-芳基,其中R3表示氢,可被1-2个选自羟基、羧基、芳基的基团取代的直链或支链(C1-C4)烷基;
n表示2-4的整数;
M+表示过渡金属或锌阳离子;
x表示1-3的整数,表示过渡金属或锌阳离子与其稳定氧化态相关的电荷单位;
A-表示与NONO盐金属配合物形成稳定盐的无机或有机阴离子;
y表示1-3的整数,表示阴离子的电荷单位;
m表示包括0的整数或分数,表示平衡NONO盐金属配合物的正电荷所需的负电荷数,其与x、y、k和w通过下式关联:
其中w是在NONO盐配体物质中存在的可能的其它阴离子电荷单位数,k是可能的其它阳离子电荷数。
2.权利要求1的金属配合物,其中n表示2或3的整数。
3.权利要求1的金属配合物,其中阳离子选自Zn2+、TiO2+、VO2+、Cr3+、Mn2+、Fe3+、Co3+、Ni2+、Cu2+、Pd2+、Ru3+、Pt2+和Au3+。
4.权利要求3的金属配合物,其中m是0,或者如果m不是0,阴离子[Ay-]是衍生自下述酸的阴离子:盐酸、氢溴酸、硫酸、高氯酸、磷酸、乙酸、丙酸、抗坏血酸、乳酸、琥珀酸、马来酸、富马酸、棕榈酸、胆酸、粘液酸、樟脑酸、戊二酸、乙醇酸、邻苯二甲酸、酒石酸、月桂酸、硬脂酸、水杨酸、甲磺酸、苯磺酸、萘磺酸、山梨酸、苦味酸、苯甲酸、肉桂酸、甲苯磺酸、三氟乙酸和三氟甲磺酸。
5.权利要求1、2、3或4的金属配合物,其中R1和R2均为氢,或者一起表示=CR3-芳基,其中R3是氢,术语“芳基”表示苯或吡啶环,其可被羟基或巯基取代,或是被部分氢化的吡啶环,其在氮原子上可被(C1-C4)烷基取代并在碳环部分被氧代基或硫代基取代;n表示2或3。
6.权利要求5的金属配合物,其中术语“芳基”表示苯或吡啶环,其被离子化的阴离子形式的羟基或巯基取代。
7.权利要求5的金属配合物,其中n表示2。
8.权利要求6的金属配合物,其中n表示2。
9.权利要求5的金属配合物,其中R1和R2均表示氢,或一起表示下面的基团:
或
阳离子Mx+选自Cu2+和Ni2+。
12.权利要求11的制备权利要求1式(I)哌嗪NONO盐金属配合物的方法,其中R1和R2具有b)组的含义,其它所有符号与权利要求1相同,包括将化学计量量的式(III)4-(羟基亚硝氨基)-1-(ω-氨基烷基)哌嗪与式O=CR3-芳基的羰基化合物,其中R3具有与权利要求1相同的含义,以及过渡金属或锌的盐在惰性有机溶剂中在等量强碱存在下反应,
其中n具有与权利要求1式(I)相同的含义。
13.权利要求11和12之一的方法,其中惰性有机溶剂是乙醇或甲醇,反应在室温或更低的温度进行。
14.权利要求1-10之一的哌嗪NONO盐衍生物的金属配合物作为治疗与心血管系统、女性生殖系统、男性生殖系统、中枢神经系统、炎性过程、内部器官功能、皮肤系统和/或肿瘤的生长和扩散相关的疾病和/或功能障碍的药物的用途。
15.权利要求1-10之一的哌嗪NONO盐衍生物的金属配合物在制备治疗与心血管系统、女性生殖系统、男性生殖系统、中枢神经系统、炎性过程、内部器官功能、皮肤系统和/或肿瘤的生长和扩散相关的疾病和/或功能障碍的药物中的用途。
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US7531505B2 (en) * | 2006-01-11 | 2009-05-12 | Affinergy, Inc. | Compositions and methods for promoting attachment of cells of endothelial cell lineage to medical devices |
US7807624B2 (en) * | 2006-01-11 | 2010-10-05 | Affinergy, Inc. | Methods and compositions for promoting attachment of cells of endothelial cell lineage to medical devices |
WO2007110084A1 (en) * | 2006-03-27 | 2007-10-04 | Salah Fathi Hussein | Pyrazinic acid copper (i) complex |
US20110136776A1 (en) * | 2008-07-22 | 2011-06-09 | Salah Fathiy Hussein Aly Ibraheim | Copper(1)Chloride Complex of Nicotinic Acid and Pharmaceutical Compositions Containing the Same |
CN102695528B (zh) | 2009-08-21 | 2016-07-13 | 诺万公司 | 创伤敷料、其使用方法及其形成方法 |
BR112012003792B1 (pt) | 2009-08-21 | 2020-05-19 | Novan Inc | composição tópica, e, uso da composição tópica |
US8591876B2 (en) | 2010-12-15 | 2013-11-26 | Novan, Inc. | Methods of decreasing sebum production in the skin |
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CN112266396B (zh) * | 2020-10-10 | 2021-08-20 | 中国药科大学 | 一种基于生物正交化学的整合型前药、制备方法及其医药用途 |
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HUP0302262A2 (hu) | 2003-10-28 |
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US6897218B2 (en) | 2005-05-24 |
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CN1458926A (zh) | 2003-11-26 |
ITMI20010426A1 (it) | 2002-09-01 |
US20040029854A1 (en) | 2004-02-12 |
DE60210428T2 (de) | 2006-11-23 |
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