CN101362763B - 含有巯基吡咯烷的碳青霉烯衍生物 - Google Patents
含有巯基吡咯烷的碳青霉烯衍生物 Download PDFInfo
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- CN101362763B CN101362763B CN2008102104118A CN200810210411A CN101362763B CN 101362763 B CN101362763 B CN 101362763B CN 2008102104118 A CN2008102104118 A CN 2008102104118A CN 200810210411 A CN200810210411 A CN 200810210411A CN 101362763 B CN101362763 B CN 101362763B
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- methyl
- acceptable salt
- compound
- pharmacy acceptable
- ethyl
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- -1 sulfhydryl pyrrolidine Chemical compound 0.000 title claims abstract description 105
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 title abstract description 6
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 49
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- 150000003839 salts Chemical class 0.000 claims abstract description 20
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- 208000035473 Communicable disease Diseases 0.000 claims abstract description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 21
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- OTTZHAVKAVGASB-UHFFFAOYSA-N hept-2-ene Chemical compound CCCCC=CC OTTZHAVKAVGASB-UHFFFAOYSA-N 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
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- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
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- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 claims description 3
- 238000009472 formulation Methods 0.000 claims description 3
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 10
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
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- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 5
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- XAKBSHICSHRJCL-UHFFFAOYSA-N [CH2]C(=O)C1=CC=CC=C1 Chemical group [CH2]C(=O)C1=CC=CC=C1 XAKBSHICSHRJCL-UHFFFAOYSA-N 0.000 description 4
- 125000005907 alkyl ester group Chemical class 0.000 description 4
- 238000003810 ethyl acetate extraction Methods 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 4
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- 239000012074 organic phase Substances 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
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- 235000019698 starch Nutrition 0.000 description 4
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- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
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- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
- 230000000843 anti-fungal effect Effects 0.000 description 3
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- 230000003115 biocidal effect Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
本发明属于医药技术领域，具体涉及通式(I)所示的含有巯基吡咯烷的碳青霉烯衍生物、其药学上可接受的盐、其易水解的酯、其异构体：其中R1、R2、R3、R4和R5如说明书中所定义；本发明还涉及这些化合物的制备方法，含有这些化合物的药物组合物，以及这些化合物在制备治疗和/或预防感染性疾病的药物中的应用。
Description
1、技术领域
本发明属于医药技术领域，具体涉及含有巯基吡咯烷的碳青霉烯衍生物、其药学上可接受的盐、其易水解的酯、其异构体，这些化合物的制备方法，含有这些化合物的药物组合物，以及这些化合物在用于制备治疗和/或预防感染性疾病的药物中的用途。
2、背景技术
碳青霉烯类抗生素，因其抗菌谱广，抗菌活性强，并对β-内酰胺酶稳定，而备受关注。已应用于临床的有亚胺培南、美罗培南、帕尼培南、比阿培南以及多尼培南等。美罗培南是第一个上市的1β-甲基碳青霉烯类抗生素，其结构式如下：
美罗培南
美罗培南对革兰阳性菌、革兰阴性菌均敏感，尤对革兰阴性菌有良好的抗菌活性。对亚胺培南耐药菌也有效，对含丝氨酸位点的肾脱氢肽酶I(DHP-I)稳定，主要用于呼吸系统严重感染。
因此，急需研究开发具有较好的抗菌活性包括耐药菌，并且具有良好的化学稳定性和DHP-I稳定性的碳代青霉烯类抗生素。
3、发明内容
本发明的技术方案如下：
本发明提供了通式(I)所示的化合物、其药学上可接受的盐、其易水解的酯、其异构体：
其中，R1代表羧基，-COOR6或易水解的酯，所述的R6代表羧基保护基；
R2代表氢原子或低级烷基；
R3、R4分别独立的代表氢原子，被卤素原子、羟基、羧基或氨基取代或未被取代的低级烷基；
R5代表低级烷基，氨基保护基或易水解的酯。
优选的化合物为：
其中，R1代表羧基，-COOR6或易水解的酯，
所述的R6代表羧基保护基，选自甲基、甲氧基甲基、甲硫甲基、苄氧甲基、苯甲酰甲基、乙基、叔丁基、烯丙基、苄基、对硝基苄基、对甲氧基苄基或二苯基甲基，
所述的易水解的酯选自烷酰氧烷基酯、烷氧基酰氧烷基酯、环烷酰氧烷基酯、环烷氧基酰氧烷基酯或(5-甲基-2-氧代-1，3-间二氧杂环戊烯-4-基)甲酯；
R2代表氢原子或甲基；
R3、R4分别独立的代表氢原子，羟甲基，三氟甲基，甲基，乙基或丙基；
R5代表低级烷基，氨基保护基及其易水解的酯，
所述的氨基保护基选自苄基、甲酰基、乙酰基、烯丙氧基羰基、苯甲酰甲基、叔丁氧基羰基对硝基苄氧基羰基、对甲氧基苄氧基羰基、3-乙酰氧基丙基或重氮基，
所述的易水解的酯选自烷酰氧烷基酯、烷氧基酰氧烷基酯、环烷酰氧烷基酯、环烷氧基酰氧烷基酯或(5-甲基-2-氧代-1，3-间二氧杂环戊烯-4-基)甲酯。
进一步优选的化合物为：
其中，R1代表羧基；
R2代表甲基；
R3、R4分别独立的代表甲基，三氟甲基或乙基；
R5代表甲基。
本发明的部分化合物
| 化合物 | R1 | R2 | R3 | R4 | R5 |
| 1 | -COOH | -CH3 | -CH3 | -CH3 | -CH3 |
| 2 | -COOH | -CH3 | -CH3 | H | -CH3 |
| 3 | -COOH | -CH3 | -CH2CH3 | H | -CH3 |
| 4 | -COOH | -CH3 | -CH3 | H | -CH2CH3 |
| 5 | -COOH | -CH3 | H | H | -CH2CH3 |
| 6 | -COOH | -CH3 | -CH3 | H | -CH2CH2CH3 |
| 7 | -COOH | -CH3 | H | H | H |
| 8 | -COOH | -CH3 | -CH3 | H | H |
| 9 | -COOH | -CH3 | H | -CH3 | -CH2CH2CH3 |
| 10 | -COOH | -CH3 | -CH3 | -CH3 | H |
更进一步优选的化合物如下：
化学名称：(4R，5S，6S)-3-[(2S，4S)-2-(二甲胺基)亚甲基-1-甲基-吡咯烷-4-基]硫基-6-[(1R)-1-羟乙基]-4-甲基-7-氧-1-氮杂双环[3，2，0]庚-2-烯-2-羧酸，以下简称化合物A，结构式如下：
本发明所述“低级烷基”为C1-6直链或支链的烷基，如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、仲丁基、戊基、新戊基、己基等。
本发明所述“氨基保护基”指常规用于取代氨基酸性质子的保护基团，此类基团的实例包括：环丙甲基、1-甲基-1-环丙甲基、二异丙甲基、9-芴甲基、9-(2-硫代)芴甲基、2-呋喃甲基、2，2，2-三氯甲基、2-卤代甲基、2-碘乙基、2-三甲基甲硅烷基乙基、2-甲硫基乙基、2-甲磺酰基乙基、2-(对甲苯磺酰基)乙基、2-磷鎓基乙基、1，1-二甲基-3-(N，N-二甲基甲酰氨基)丙基、1，1-二苯基-3-(N，N-二乙氨基)丙基、1-甲基-1-(金刚烷基)乙基、1-甲基-1-苯乙基、1-甲基-1-(3，5-二甲氧苯基)乙基、1-甲基-1-(4-联苯基)乙基、1-甲基-1-(对苯偶氮基苯基)乙基、1，1-二甲基-2，2，2-三氯乙基、1，1-二甲基-2-氰乙基、环丁基、1-甲基环丁基、环戊基、环己基、1-甲基环己基、1-金刚烷基、异冰片基、乙烯基、烯丙基、肉桂基、苯基、2，4，6-三叔丁基苯基、间硝基苯基、S-苯基、8-喹啉基、N’-羟基哌啶基、4-(1，4-二甲基哌啶基)、4，5-二苯基-3-噁唑啉-2-酮、苄基、2，4，6-三甲基苄基，对甲氧基苄基、对甲氧基苄氧基羰基、3，5-二甲氧基苄基、对癸氧基苄基、对硝基苄基、对硝基苄氧基羰基、邻硝基苄基、3，4-二甲氧基-6-硝基苄基、对溴苄基、氯苄基、2，4-二氯苄基、对氰基苄基、邻(N，N-二甲基甲酰氨基)苄基、间-氯-对-酰氧基苄基、对(二羟基硼烷基)苄基、对(苯偶氮基)苄基、对(对甲氧基苯偶氮基)苄基、5-苯并异噁唑基甲基、9-蒽基甲基、二苯甲基、苯基(邻硝基苯基)甲基、二(2-吡啶基)甲基、1-甲基-1-(4-吡啶基)乙基、异烟碱基、S-苄基、N’-哌定基羰基、N’-对甲苯磺酰基氨基羰基及N’-苯氨基硫代羰基的氨基甲酸酯；甲酰基、乙酰基、乙酰基-吡啶鎓、(N’-二硫代苄氧羰基氨基)乙酰基、3-苯基丙酰基、3-(对羟苯基)丙酰基、3-(邻硝基苯基)丙酰基、2-甲基-2-(邻硝基苯氧基)丙酰基、2-甲基-2-(邻苯偶氮基苯氧基)丙酰基、4-氯代丁酰基、异丁酰基、邻硝基肉桂酰基、吡啶甲酰基、N’-乙酰甲硫氨酰基、N’-苯甲酰基-苯基烷基、苯甲酰基、对苯基苯甲酰基、对甲氧基苯甲酰基、邻硝基苯甲酰基、邻(苯甲酰氧基甲基)苯甲酰基和对-P-苯甲酰基的酰胺；邻苯二甲酰基、2，3-二苯基马来酰基和二硫代琥珀酰基的环亚酰胺；叔丁氧基羰基、烯丙氧基羰基、苯甲酰甲基、3-乙酰氧基丙基、4-硝基-1-环己基-2-氧代-3-吡咯烷-3-基、季铵盐、甲氧基甲基、2-氯乙氧基甲基、苄氧基甲基、新戊酰基甲基、[1-(烷氧羰基氨基)]-2，2，2，三氟乙基、[1-三氟甲基-1-(对氯苯氧基甲氧基)2，2，2，-三氟]乙基、2-四氢吡喃基、2，4-二硝基苯基、苄基、3，4-二甲氧基苄基、邻硝基苄基、二(对甲氧苯基)甲基、三苯甲基、(对甲氧苯基)二苯基甲基、二苯 基-4-吡啶基甲基、2-吡啶甲基-N’-氧化物、5-二苯丙环庚烷基、N’，N’-二甲氨基亚甲基、N’-异亚丙基、亚苄基、对甲氧基亚苄基、对硝基亚苄基、亚水杨基、5-氯亚水杨基、二苯亚甲基、(5-氯-2-羟苯基)苯基亚甲基、(酰基乙烯基)、5，6-二甲基-3-氧代-1-环己烯基、硼烷、[苯基(五羰基铬或钨)]羰基、铜或锌螯合物、硝基、亚硝基、氧化物、二苯基膦基、二甲硫基氧膦基、二苯硫基氧膦基、二乙基磷酰基、二苄基磷酰基、二苯基磷酰基、磷酰基、三甲基甲硅烷基、苯硫基、邻硝基苯硫基、2，4-二硝基苯硫基、2-硝基-4-甲氧基苯硫基、三苯甲硫基、苯磺酰基、对甲氧基苯磺酰基、2，4，6-三甲基苯磺酰基、甲基磺酰基、苯甲磺酰基、对甲苯甲磺酰基、三氟甲基磺酰基、苯甲酰甲基磺酰基、重氮基等。
本发明所述的“羧基保护基”指常规用于取代羧酸酸性质子的保护基团。此基团的实例包括：甲氧基甲基、甲硫甲基、四氢吡喃基、四氢呋喃基、甲氧乙基甲基、苄氧甲基、苯甲酰甲基、烯丙基、对溴苯甲酰甲基、α-甲基苯甲酰甲基、对甲氧基苯甲酰甲基、二酰基甲基、N-邻苯二甲酰亚氨基甲基、甲基、乙基、二苯基甲基、2，2，2-三氯乙基、2-卤代乙基、ω-氯代烷基、2-(三甲基甲硅烷基)乙基、2-甲硫基乙基、2-(对硝基苯硫基)乙基、2-(对甲苯硫基)乙基、1-甲基-1-苯乙基、叔丁基、环戊基、环己基、二(邻硝基苯基)甲基、9-芴基甲基、2-(9，10-二氧代)芴基甲基、5-二苯硫基、苄基、2，4，6-三甲基苄基、对溴苄基、邻硝基苄基、对硝基苄基、对甲氧基苄基、胡椒基、4-吡啶甲基、三甲基甲硅烷基、三乙基甲硅烷基、叔丁基二甲基甲硅烷基、异丙基二甲基甲硅烷基、苯基二甲基甲硅烷基、S-叔丁基、S-苯基、S-2-吡啶基、N-羟基哌啶基、N-羟基琥珀酰亚氨基、N-羟基邻苯二甲酰亚氨基、N-羟基苯并三唑基、O-酰基肟、2，4-二硝基苯硫基、2-烷基-1，3-噁唑啉、4-烷基-5-氧代-1，3-噁唑烷、5-烷基-4-氧代-1，3-二噁烷、三乙基锡烷、三正丁基锡烷；N，N’-二异丙基酰肼等。
本发明还提供了上述化合物的制备方法，但不仅限于以下方法，反应方程式如下：
反应步骤：
步骤1化合物1的制备
于干燥反应瓶中加入二氧六环，然后加入无水氯化锌，硼氢化钾，室温搅拌后，加入原料1，搅拌下缓慢升温至回流反应。冷至室温，加入盐酸稀释，乙酸乙酯萃取。有机相用饱和盐水洗，干燥，浓缩得化合物1。
步骤2化合物2的制备
干燥反应瓶中，加入化合物1和硫代乙酸钾，然后加入DMF，搅拌加热至溶解后，保温反应冷却至室温后，加水稀释，乙酸乙酯萃取，有机相用水洗涤，干燥，浓缩，得化合物2。
步骤3化合物3的制备
于氮气保护下，加入化合物2，二氯甲烷，滴入TMSI，室温下剧烈搅拌反应4h，冰水浴冷却，搅拌，减压抽滤。滤饼用少量二氯甲烷洗涤，滤液收集在预冷的烧瓶中。于氮气保护下，向该溶液中滴加含原料2的四氢呋喃溶液，滴加完毕，反应，反应液脱色，抽滤，滤液减压浓缩至干，然后加入盐酸，搅拌反应，冷至室温，抽滤，干燥，，得化合物3。
步骤4化合物4的制备
于干燥反应瓶中，加入原料3的乙腈溶液冷却，加入二异丙基乙胺和化合物3的乙腈溶液，搅拌反应完毕后，加乙酸乙酯稀释，依次用水、饱和盐水洗，有机层干燥、浓缩，得化合物4。
步骤5化合物5的制备
将化合物4溶于THF和水的混合液中，加入10％林德拉Pd-C，室温2MPa氢压下搅拌反应，滤除钯炭，滤液中加入THF，分层，收集水层。再向THF中加入5％氯化镁水溶液，静置，分出水层，重复操作1次。水相合并，慢慢滴入甲醇，搅拌，过滤，滤饼用丙酮重结晶，得化合物5。
以上反应方程式中的R2、R3、R4、R5代表的基团如前文所述，化合物5母核上的羧基也可以被羧基保护基保护，或者可以成体内易水解的酯。
本发明上述任一化合物药学上可接受的盐为有机酸盐、无机酸盐、有机碱盐或无机碱盐，其中有机酸包括乙酸、三氟乙酸、甲磺酸、甲苯磺酸、马来酸、琥珀酸、酒石酸、柠檬酸、富马酸；无机酸包括盐酸、氢溴酸、硝酸、硫酸、磷酸；有机碱包括葡甲胺、氨基葡萄糖； 无机碱包括钠、钾、钡、钙、镁、锌、锂的碱性化合物。
本发明要求保护的化合物易水解的酯，包括烷酰氧烷基酯，例如乙酰氧甲酯、丙酰氧甲酯、丁酰氧甲酯、异丙基甲酰氧甲酯、叔丁基甲酰氧甲酯、新戊基甲酰氧甲酯、异丁基甲酰氧甲酯、新戊乙酰氧甲酯、辛酰氧甲酯、癸酰氧甲酯等；烷氧羰氧基烷基酯，例如甲氧基甲酰氧甲酯、乙氧基甲酰氧甲酯、异丙氧基甲酰氧-1-乙酯、己氧基甲酰氧-1-乙酯、辛氧基甲酰氧-1-乙酯、癸氧基甲酰氧-1-乙酯、十二烷氧基甲酰氧-1-乙酯等；烷氧基甲酯，例如甲氧甲酯、1-异丙氧甲酯等；烷酰氨基甲酯，例如甲酰氨基甲酯、乙酰氨基甲酯等；环烷酰氧烷基酯，例如环己烷基甲酰氧甲酯、环己烷基甲酰氧-1-乙酯、1-甲基-环己烷基甲酰氧-1-乙酯、4-甲基-环己烷基甲酰氧甲酯等；环烷氧基酰氧烷基酯，例如环戊烷氧基甲酰氧-1-乙酯、环己烷氧基甲酰氧-1-乙酯等；(5-甲基-2-氧代-1，3-间二氧杂环戊烯-4-基)甲基酯，2-[(2-甲基丙氧基)羰基]-2-戊烯酯等。优选为丙酰氧甲基酯、丁酰氧甲基酯、叔丁基甲酰氧甲基酯、异丙氧甲酰氧甲基酯、异丙氧甲酰氧-1-乙基酯、环己烷氧甲酰氧-1-乙基酯、(5-甲基-2-氧代-1，3-间二氧杂环戊烯-4-基)甲基酯等。
本发明所述异构体是指其所有差向立体异构，非对映异构。当一个键用一个楔表示时，这表明在三维上该键将从纸面出来，而当一个键是阴影时，这表明在三维上该键将返入纸面中。式(I)化合物具有许多立体中心，即：在4-位上；在5-位上；在6-位上。
本发明进一步要求保护包括上面所述的任一化合物、其药学上可接受的盐、其易水解的酯、或其异构体与其它药用活性成分的药物组合物，如西司他丁及其钠盐、倍他米隆等。
本发明进一步要求保护包括上面所述的任一化合物、其药学上可接受的盐、其易水解的酯、或其异构体与一种或多种药用载体和/或稀释剂的药物组合物，为临床上或药学上可接受的任一剂型，优选为口服制剂或注射剂。其中含有生理有效量的通式(I)所示的化合物0.01g～5g，可以为0.01g、0.015g、0.02g、0.025g、0.03g、0.04g、0.05g、0.1g、0.125g、0.2g、0.25g、0.3g、0.4g、0.5g、0.6g、0.75g、1g、1.25g、1.5g、1.75g、2g、2.5g、3g、4g、5g等。
本发明任一化合物、其药学上可接受的盐、其易水解的酯、或其异构体，可以口服或肠胃外给药等方式施用于需要这种治疗的患者。
用于肠胃外给药时，可制成注射剂。注射剂系指药物制成的供注入体内的溶液、乳液或混悬液及供临用前配制或稀释成溶液或混悬液的粉末或浓溶液的无菌制剂，注射剂可分为注射液、注射用无菌粉末与注射用浓溶液。注射液系指药物制成的供注射入体内用的无菌溶液型注射液、乳液型注射液或混悬型注射液，可用于肌内注射、静脉注射、静脉滴注等；其规格有1ml、2ml、5ml、10ml、20ml、50ml、100ml、200ml、250ml、500ml等，其中供静脉滴注用的大体积(一般不小于100ml)注射液也称静脉输液。注射用无菌粉末系指药物制成的 供临用前用适宜的无菌溶液配制成澄清溶液或均匀混悬液的无菌粉末或无菌块状物，可用适宜的注射用溶剂配制后注射，也可用静脉输液配制后静脉滴注；无菌粉末用溶媒结晶法、喷雾干燥法或冷冻干燥法等制得。注射用浓溶液系指药物制成的供临用前稀释供静脉滴注用的无菌浓溶液。
制成注射剂时，可采用现有制药领域中的常规方法生产，可选用水性溶剂或非水性溶剂。最常用的水性溶剂为注射用水，也可用0.9％氯化钠溶液或其他适宜的水溶液；常用的非水性溶剂为植物油，主要为供注射用大豆油，其他还有乙醇、丙二醇、聚乙二醇等的水溶液。配制注射剂时，可以不加入附加剂，也可根据药物的性质加入适宜的附加剂，如渗透压调节剂、pH值调节剂、增溶剂、填充剂、抗氧剂、抑菌剂、乳化剂、助悬剂等。常用的渗透压调节剂包括氯化钠、葡萄糖、氯化钾、氯化镁、氯化钙、山梨醇等，优选氯化钠或葡萄糖；常用的pH值调节剂包括醋酸-醋酸钠、乳酸、枸橼酸-枸橼酸钠、碳酸氢钠-碳酸钠等；常用的增溶剂包括聚山梨酯80、丙二醇、卵磷脂、聚氧乙烯蓖麻油等；常用的填充剂包括乳糖、甘露醇、山梨醇、右旋糖酐等；常用的抗氧剂有亚硫酸钠、亚硫酸氢钠、焦亚硫酸钠等；常用抑菌剂为苯酚、甲酚、三氯叔丁醇等。注射剂常用容器有玻璃安瓿、玻璃瓶、塑料安瓿、塑料瓶等。
用于口服时，可制成常规的固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等；也可制成口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。片剂系指药物与适宜的辅料混匀压制而成的圆片状或异形片状的固体制剂，以口服普通片为主，另有含片、舌下片、口腔贴片、咀嚼片、分散片、可溶片、泡腾片、缓释片、控释片与肠溶片等。胶囊剂系指药物或加有辅料充填于空心胶囊或密封于软质囊材中的固体制剂，依据其溶解与释放特性，可分为硬胶囊(通称为胶囊)、软胶囊(胶丸)、缓释胶囊、控释胶囊和肠溶胶囊等。丸剂系指药物与适宜的辅料均匀混合，以适当方法制成的球状或类球状固体制剂，包括滴丸、糖丸、小丸等。颗粒剂系指药物与适宜的辅料制成具有一定粒度的干燥颗粒状制剂，可分为可溶颗粒(通称为颗粒)、混悬颗粒、泡腾颗粒、肠溶颗粒、缓释颗粒和控释颗粒等。口服溶液剂系指药物溶解于适宜溶剂中制成供口服的澄清液体制剂。口服混悬剂系指难溶性固体药物，分散在液体介质中，制成供口服的混悬液体制剂，也包括干混悬剂或浓混悬液。糖浆剂系指含有药物的浓蔗糖水溶液。
制成口服制剂时，可以加入适宜的填充剂、粘合剂、崩解剂、润滑剂等。常用填充剂包括淀粉、糖粉、磷酸钙、硫酸钙二水物、糊精、微晶纤维素、乳糖、预胶化淀粉、甘露醇等；常用粘合剂包括羧甲基纤维素钠、PVP-K30、羟丙基纤维素、淀粉浆、甲基纤维素、乙基纤维素、羟丙甲纤维素、胶化淀粉等；常用崩解剂包括干淀粉、交联聚维酮、交联羧甲基纤维素钠、羧甲基淀粉钠、低取代羟丙基纤维素等；常用润滑剂包括硬脂酸镁、滑石粉、十二烷 基硫酸钠、微粉硅胶等。
本发明还提供了含有巯基吡咯烷的碳青霉烯衍生物在制备用于治疗和/或预防感染性疾病的药物中的用途。本发明的培南衍生物对革兰阳性和阴性、需氧和厌氧菌具有较好的抗菌活性，可用于治疗和/或预防由病原微生物引起的各种疾病，如呼吸道感染和泌尿道感染。
通常，已经发现碳青霉烯类对温血动物来说是无毒的，而这个通则也适用于本发明化合物。将本发明的优选化合物以能预防细菌感染所需要的过量剂量对小鼠给药，未观察到明显的中毒病兆或副作用。
本发明的含有巯基吡咯烷的碳青霉烯衍生物与最接近的现有技术相比，具有以下优点：
(1)本发明化合物具有优良的抗菌活性并且显示低毒性，能被安全的用于治疗和/或预防各种哺乳动物(包括人类)由敏感菌所引起的各种疾病；
(2)本发明进行了体内和体外的抗菌试验，表明本发明化合物对PBPs亲和力强，抗菌谱广，抗菌活性高，对革兰阳性和阴性、需氧和厌氧菌以及医院临床病原菌均有较好的抗菌活性，尤其对革兰阳性和阴性耐药菌显示出突出的抗菌活性；
(3)本发明化合物对β-内酰胺酶和DHP-1稳定的，可以单药给药；
(4)本发明化合物具有较长抗生素后效应，抗菌作用持久，用药方便；
(5)本发明化合物制备工艺简单，药品纯度高、收率高、质量稳定，易于进行大规模工业生产。
以下通过体外及体内抗菌实验进一步阐述本发明的含有巯基吡咯烷的碳青霉烯衍生物的有益效果，但不应将此理解为本发明的含有巯基吡咯烷的碳青霉烯衍生物仅具有下列有益效果。
实验例本发明化合物的体外抗菌活性
供试菌种：以下均为临床分离菌株，购于公众机构；耐甲氧西林金黄色葡萄球菌(MRSA)、对青霉素耐药的肺炎链球菌(PRSP)、肺炎克雷伯菌(产ESBLs)、铜绿假单胞菌。
供试品：美罗培南：注射用美罗培南，市购；本发明化合物A，自制，其化学名称和结构式见各化合物的制备实施例。
实验方法：琼脂稀释法，参考《药理试验方法学》P1659-1660，人民卫生出版社，主编：徐叔云等，版次：1982年8月第1版2002年1月第3版第5次印刷。
实验结果和结论：上述试验结果表明，与美罗培南相比，本发明化合物对临床分离的MRSA、PRSP、肺炎克雷伯菌(产ESBLs)和铜绿假单胞菌均具有良好的抗菌活性，说明本发明化合物对革兰阳性菌、阴性菌及其临床耐药菌均具有强效抗菌作用，同最接近的现有技术相比，抗菌活性相当或更好，且抗菌谱广，具有很好的临床应用潜力。
表1本发明化合物对临床分离革兰阳性菌的抗菌活性
4、具体实施方式
以下通过实施例形式的具体实施方式，对本发明的上述内容作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下实施例。凡基于本发明上述内容所实现的技术均属于本发明的范围。以下实施例中各剂型的辅料可以用药学上可接受的辅料替换，或者减少、增加。
实施例1(2S，4R)-1-甲基-4-甲磺酰氧基吡咯烷-2-甲醇制备
于干燥反应瓶中，加入二氧六环100ml，然后加入无水氯化锌6.8g(50mmol)，硼氢化钾5.4g(100mmol)，室温搅拌2h后，加入(2S，4R)-1-甲基-4-甲磺酰氧基吡咯烷-2-甲酸甲酯8.1g(25mmol)。搅拌下缓慢升温至回流反应2h。冷至室温，加入1mol/L的盐酸100ml稀释，乙酸乙酯萃取。有机相用饱和盐水洗，干燥，浓缩得(2S，4R)-1-甲基-4-甲磺酰氧基吡咯烷-2-甲醇。
实施例2(2S，4R)-4-乙酰硫基-1-甲基-吡咯烷-2-甲醇的制备
干燥反应瓶中，加入(2S，4R)-1-甲基-4-甲磺酰氧基吡咯烷-2-甲醇11.8g(40mmol)和硫代乙酸钾9.2g(80mmol)，然后加入DMF150ml，搅拌加热至溶解后，保温反应10h。冷却至室温后，加水100ml稀释，乙酸乙酯萃取，有机相用水洗涤，干燥，浓缩，得固体6.6g，备用。
实施例3(2S，4S)-4-巯基-2-(二甲胺基)亚甲基-1-甲基-吡咯烷的制备
于氮气保护下，加入(2S，4R)-4-乙酰硫基-1-甲基吡咯烷-2-甲醇3.8g(20mmol)，二氯甲烷100ml，滴入TMSI 4ml(30mmol)，室温下剧烈搅拌反应4h，冰水浴冷却至0℃，搅拌30min，减压抽滤。滤饼用少量二氯甲烷洗涤，滤液收集在预冷的烧瓶中。于0℃氮气保护下，向该溶液中滴加含2.5mol/L二甲胺的四氢呋喃溶液20ml，滴加完毕，于0～5℃反应4h，反应液脱色，抽滤，滤液减压浓缩至干，然后加入5mol/L盐酸50ml，50℃搅拌反应1h，冷至室温，抽滤，干燥，得产物3.2g。
实施例4(4R，5S，6S)-3-[(2S，4S)-2-(二甲胺基)-亚甲基-1-甲基-吡咯烷-4-基]硫基-6-[(1R)-1-羟乙基]-4-甲基-7-氧-1-氮杂双环[3，2，0]庚-2-烯-2-羧酸对硝基苄酯的制备
干燥反应瓶中，加入(4R，5S，6S)-3-二苯氧磷酰氧基-6-[(1R)-1-羟乙基]-4-甲基-7-氧-1-氮杂双环[3，2，0]庚-2-烯-2-羧酸对硝基苄酯14.9g(25mmol)的乙腈溶液150ml，冷至-10℃以下，加 入二异丙基乙胺6ml和(2S，4S)-4-巯基-2-(二甲胺基)亚甲基-1-甲基-吡咯烷4.4g(25mmol)的乙腈100ml溶液，0℃搅拌15h。反应完毕后，加乙酸乙酯300ml稀释，依次用水、饱和盐水洗，有机层干燥，浓缩，得固体7.6g，收率：58.5％。
实施例5(4R，5S，6S)-3-[(2S，4S)-2-(二甲胺基)-亚甲基-1-甲基-吡咯烷-4-基]硫基-6-[(1R)-1-羟乙基]-4-甲基-7-氧-1-氮杂双环[3，2，0]庚-2-烯-2-羧酸(化合物A)的制备
将(4R，5S，6S)-3-[(2S，4S)-2-(二甲胺基)-亚甲基-1-甲基-吡咯烷-4-基]硫基-6-[(1R)-1-羟乙基]-4-甲基-7-氧-1-氮杂双环[3，2，0]庚-2-烯-2-羧酸对硝基苄酯10.4g(20mmol)溶于THF300ml和水30ml的混合液中，加入10％林德拉Pd-C 4g，室温2MPa氢压下搅拌反应2h，滤除钯炭，滤液中加入THF150ml，分层，收集水层。再向THF中加入5％氯化镁水溶液20ml，静置，分出水层，重复操作1次。水相合并，0℃慢慢滴入甲醇100ml，-10℃搅拌1h，过滤，滤饼用丙酮重结晶，得目标化合物4.1g，收率：53.5％。
分子式：C18H29N3O4S
分子量：383.51
元素分析：
实测值：C，55.22％；H，7.86％；N，11.09％；S，8.18％
理论值：C，56.37％；H，7.62％；N，10.96％；S，8.36％
实施例6本发明化合物无菌粉针的制备
1、处方：
处方：
化合物A 250g
共制备 1000支
2、制备工艺：
(1)将制备所用的抗生素玻璃瓶、胶塞等进行无菌处理；
(2)按处方称取原料，将无菌粉末置于分装机中分装，随时检测装量；
(3)加塞，压盖，成品全检，包装入库。
实施例7本发明化合物片剂的制备
1、处方：
处方：
化合物A 250g
预胶化淀粉 80g
低取代羟丙基纤维素 50g
微晶纤维素 60g
2％HPMC水溶液 适量
微粉硅胶 6.0g
硬脂酸镁 5.0g
羧甲淀粉钠 3.0g
共制备1 000片
2、制备工艺：
(1)将原料粉碎过100目筛，其余辅料分别过100目筛，备用；
(2)按照处方量称取原料和辅料；
(3)将羟丙甲纤维素溶于水中制成2％的水溶液备用；
(4)将化合物A、预胶化淀粉、低取代羟丙基纤维素、微晶纤维素混合均匀，加入2％HPMC水溶液适量，搅拌均匀，制成适宜软材；
(5)过20目筛制颗粒；
(6)颗粒在60℃的条件下烘干；
(7)干燥好的颗粒加入硬脂酸镁、微粉硅胶和羧甲淀粉钠，过18目筛整粒，混合均匀；
(8)取样，半成品化验；
(9)按照化验确定的片重压片；
(10)成品全检，包装入库。
Claims (9)
1.通式(I)所示的化合物或其药学上可接受的盐：
其中，R1代表羧基；
R2代表氢原子或C1-6直链或支链的烷基；
R3、R4分别独立的代表氢原子，被卤素原子、羟基、羧基或氨基取代或未被取代的C1-6直链或支链的烷基；
R5代表C1-6直链或支链的烷基。
2.如权利要求1所述的化合物或其药学上可接受的盐：
其中，R1代表羧基；
R2代表氢原子或甲基；
R3、R4分别独立的代表氢原子，羟甲基，三氟甲基，甲基，乙基或丙基；
R5代表C1-6直链或支链的烷基。
3.如权利要求2所述的化合物或其药学上可接受的盐：
其中，R1代表羧基；
R2代表甲基；
R3、R4分别独立的代表甲基，三氟甲基或乙基；
R5代表甲基。
4.如权利要求3所述的化合物或其药学上可接受的盐，其所述化合物选自：
(4R，5S，6S)-3-[(2S，4S)-2-(二甲胺基)亚甲基-吡咯烷-4-基]硫基-6-[(1R)-1-羟乙基]-4-甲基-7-氧-1-氮杂双环[3，2，0]庚-2-烯-2-羧酸。
5.如权利要求1～4任一权利要求所述的化合物或其药学上可接受的盐，其药学上可接受的盐为有机酸盐、无机酸盐、有机碱盐或无机碱盐。
6.包括权利要求1～4任一权利要求所述的化合物或其药学上可接受的盐与一种或多种药用载体和/或稀释剂的药物组合物。
7.如权利要求6所述的药物组合物，为药学上可接受的任一剂型。
8.如权利要求6所述的药物组合物，含有权利要求1～4任一权利要求所述的化合物或其药学上可接受的盐0.01g～5g作为必需的活性成分。
9.如权利要求1～4任一权利要求所述的化合物或其药学上可接受的盐在用于制备治疗和/或预防感染性疾病的药物中的应用。
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992017480A1 (en) * | 1991-04-08 | 1992-10-15 | Zeneca Ltd. | Antibiotic carbapenem derivatives |
| CN1225636A (zh) * | 1996-07-12 | 1999-08-11 | 麦克公司 | 碳代青霉烯抗菌剂的合成方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO1992017480A1 (en) * | 1991-04-08 | 1992-10-15 | Zeneca Ltd. | Antibiotic carbapenem derivatives |
| CN1225636A (zh) * | 1996-07-12 | 1999-08-11 | 麦克公司 | 碳代青霉烯抗菌剂的合成方法 |
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