CN1036207A - 新的天冬氨酸转氨甲酰酶抑制剂 - Google Patents
新的天冬氨酸转氨甲酰酶抑制剂 Download PDFInfo
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- CN1036207A CN1036207A CN89100817A CN89100817A CN1036207A CN 1036207 A CN1036207 A CN 1036207A CN 89100817 A CN89100817 A CN 89100817A CN 89100817 A CN89100817 A CN 89100817A CN 1036207 A CN1036207 A CN 1036207A
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- 102000030907 Aspartate Carbamoyltransferase Human genes 0.000 title abstract description 4
- 108091000126 Dihydroorotase Proteins 0.000 title abstract description 4
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
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- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及具有抑制天冬氨酸转氨甲酰酶作用
的某些膦酸酯的卤代衍生物，因此，它们可用于治疗
某些癌症。
Description
本发明涉及能抑制天冬氨酸转氨甲酰酶的某些膦酸酯的囟代衍生物，并且它们可用于治疗某些癌症。
更具体地说，本发明涉及具有下式新的膦酸酯囟代衍生物或其药学上适用的盐。
式中：
Z是NH或CH2，Q是O，或者当Z是CH2时，那么Q也可以是（H，OH）。
X是H，F或Cl，Y是F或Cl，
R1和R2各自是H或C1-6低级烷基，及
R3和R4各自是H或C1-6低级烷基。
值得注意的是，上述化合物可以以对映体形式存在，因此，各个对映体以及对映体混合物被认为是本发明范围的一部分。
本发明化合物可以以游离碱的形式和其酸加成盐的形式应用。以酸加成盐形式使用更方便。实际上，使用的盐相当于使用的游离碱。术语“药学上适用的酸加成盐”是指式Ⅰ所示碱基化合物的任何无毒性的有机或无机酸加成盐。可生成合适盐的无机酸的例子包括：盐酸，氢溴酸，硫酸和磷酸，以及酸式金属盐例如磷酸一氢钠和硫酸氢钾。可生成合适盐的有机酸的例子包括：一元，二元，和三元羧酸。例如这种酸有：乙酸，羟基乙酸，乳酸，丙酮酸，丙二酸，丁二酸，戊二酸，富马酸，苹果酸，酒石酸，柠檬酸，抗坏血酸，马来酸，羟基马来酸，苯甲酸，羟基苯甲酸，苯基乙酸，肉桂酸，水杨酸和2-苯氧基苯甲酸。可生成合适盐的其他有机酸有磺酸，例如：甲磺酸和2-羟基乙磺酸。可以生成一酸盐或二酸盐，上述盐可以为水合物的形式，或实质上是无水的形式。酸式盐可以按标准的方法制备，例如，将游离碱溶于含有合适酸的水溶液或水一醇溶液或其它合适的溶剂中，蒸发溶液进行分离，或者在有机溶剂中与游离碱反应，在该情况下盐直接析出，或浓缩该溶液制得盐。一般说来，本发明化合物的酸加成盐是溶于水和各种亲水有机溶剂的结晶状物质，与其游离碱相比，该酸加成盐熔点更高，溶解度也增加了。
一般说来，式Ⅰ化合物可以用本领域已知的相似方法和技术制备。当然制备任一具体化合物的特定反应路线取决于许多因素（例如，原材料能否买到及其价格，保护基团以及熟练技术人员通常考虑的其它因素），但是一般说来，主要基于由Z限定的基团的定义，有两条合成路线是适用的。
根据下述反应路线，在Z是氮的情况下，使用膦酰基乙酸和天冬氨酸衍生物是方便的。
反应路线A
其中，R′ 3和R′ 4是C1-6烷基，Pg是合适的保护基团，最好是苄基，甲基或乙基，但也包括C1-6低级烷基。
在碱（例如，二甲基氨基吡啶（DMAP），N-甲基吗啉（NMM），三乙胺（TEA））等存在下，在温度约为-30℃～30℃，最好是约为0℃，使用相当量的反应物相互接触，很容易地进行酰氯（3）与被适当保护的天冬氨酸衍生物（2）的初始缩合反应。反应在无水条件下在对质子惰性的极性溶剂（最好是二氯甲烷）中进行。当然，应用本领域熟知的标准方法，用合适的OR′ 3、OR′ 4膦酰基-X，Y-取代的乙酸衍生物，可以制备式3所示的酰氯衍生物。一般来说，按已知条件，在碱（如DMAP，NMM，TEA等）存在下，于约-10℃～20℃，最好为0℃，在惰性气流（最好是氩或氮气）和对质子呈惰性的极性溶剂中，于无水条件下，使上述酸与乙二酰氯反应。
进行上述缩合反应之后，按如下方法脱去保护基团R′ 3，R′ 4（即C1-6烷基，最好是甲基或乙基）;在无水的对质子呈惰性的极性溶剂（最好是CH2Cl2）中，于惰性气流（最好是氩或氮气）下，在0℃～室温，与三甲基硅烷基溴（TMSBr）反应，随后，用水进行水解，使所得产品通过氢解（最好在水中，于催化剂，例如钯-碳存在下，用氢处理），脱去保护基团（例如脱苄基）。如果保护基团（用Pg表示）是低级烷基，则通过碱性水解脱去保护基。
制备其中Z代表CH2基团的式Ⅰ化合物，可以通过合适的醛与X，Y-取代膦酸二甲酯的锂衍生物进行亲核加成反应，生成醇，醇可以被氧化成相应的酮。氧化反应后，按上述方法脱去羟基保护基因。整个程序通过下面的反应路线表示。
反应路线B
其中，Pg，X，Y，R′ 3和R′ 4同上述定义。
在1当量的溴化锂存在下，以THF/乙醚（3/1）作混合溶剂，在约-50℃～-110℃，最好是约-78℃的低温下，醛（6）与2当量的R′ 3，R′ 4，X，Y-取代的甲膦酸酯锂进行亲核加成反应。
反应最好在惰性气流下（优选氩或氮气），在无水的，对质子呈惰性的极性溶剂中进行。反应结束后，通常用氯化铵水溶液使反应骤冷，按标准方法分离所得产品，用本领域熟知的标准方法，例如，应用重铬酸吡啶嗡，Dess-Matin试剂，最好是应用Swern氧化反应，将得到的醇（8）氧化成相应的酮。在含有活化DMSO的试剂（比如草酰氯或三氟乙酐）存在下，于对质子呈惰性的无水溶剂中（应用二甲基亚砜（DMSO）），在惰性气流（优选氩或氮气）下进行Swern氧化反应，然后加入碱，最好是TEA。氧化反应后，用三甲基硅烷基溴处理，接着按反应路线A所述方法进行氢解，脱去式（9）所示化合物的羟基保护基团。若Pg是C1-6低级烷基（最好是甲基或乙基），则用碱水解脱去保护基团。当然，如果最终制得的化合物需要保留C1-6低级烷基（即：R1，R2，R3和R4不是H），那么不需要脱去这些基团。
按照Organic Sgnthesis Vol.64，A.S.Kende（编辑），pp.150～156，由R.E.Claus和S.L.Schreiber提出的方法中，应用气体臭氧使3-环戊烯-1-羧酸酯（苄酯，甲酯或乙酯）进行臭氧分解，可以容易地制备所需式6所示的醛。在该方法中，在醇存在下进行臭氧分解以便得到在端末含有醛基和甲氧基过氧化氢的化合物。（当然，如果使用苄基醇，那么将生成苄氧基过氧化氢而不是甲氧基过氧化氢，因此，最好使用在Swern氧化反应后最易于脱去的醇）。臭氧分解后，最好用乙酐在碱（最好为TEA）存在下在原位置进行脱水，从而提供所需起始原料（6）。
最好制备式Ⅰ所示化合物的左旋对映体，而通过使用左旋天冬氨酸衍生物（如在反应路线A所示），可以容易地制备该化合物。由反应路线B所制备的化合物是外消旋混合物，按本领域中熟知的方法可以容易地将它们分离。一般说来，最好分离式6所示醛的对映体，而不是在其转化成化合物（5）之后进行分离。
实际上，最好采用R′ 3和R′ 4是甲基或乙基的膦酰基酯。可以采用其它烷基酯的反应试剂，这些酯可以制备中间体（3）和（7）的类似方法制得。
下面实施例详细说明制备上述式Ⅰ所示化合物的方法。
实施例1
2-[（2，2-二氟-1-氧-2-膦酰基乙基）氨基]丁二酸的制备
步骤A
2-[（2-二乙氧基氧膦基-2，2-二氟-1-氧-乙基）氨基]-丁二酸，双（苯基甲基）酯
在氩气流下，于0℃向二乙基膦酰基-二氟-乙酸（20mmol，4.64g）和2.02g N-甲基吗啉（20mmol）溶于50ml无水二氯甲烷的搅拌溶液中缓慢地加入1.75ml草酰氯（20mmol），将反应混合物冷却至0℃，向其中加入9.7g天冬氨酸甲苯磺酸酯（20mmol）和4.5gN-甲基吗啉（43mmol）溶于100ml无水二氯甲烷的溶液。在20℃下搅拌18小时后，反应混合物用饱和碳酸氢盐水溶液（30ml）水解，用1NHCl（30ml）、碳酸氢盐（30ml）和盐水（30ml）洗涤。有机层用Na2SO4干燥，过滤，经硅胶快速层析纯化，得4.8g2-[（2-二乙氧基氧膦基-2，2-二氟-1-氧-乙基）氨基]丁二酸，双（苯基甲基）酯。
步骤B
2-[（2，2-二氟-1-氧-2-膦酰基乙基）氨基]丁二酸，双（苯基甲基）酯
在氩气流下、于0℃向2-[（2-二乙氧基氧膦基-2，2-二氟-1-氧-乙基）氨基]丁二酸双[苯基甲基]酯（4g，7.5mmol）溶于50ml无水二氯甲烷的搅拌溶液中缓慢地加入10ml三甲基硅烷基溴（75mmol）。反应混合物在20℃下搅拌18小时，蒸发至干。将残余物溶解在25ml乙腈中并用1.5ml水进行水解。蒸发反应混合物至干，得到3.4g 2-[（2，2-二氟-1-氧-2-膦酰基乙基）氨基]丁二酸，双（苯基甲基）酯，不需要进一步提纯，可直接用于下一步。
步骤C
2-[（2，2-二氟-1-氧-2-膦酰基乙基）氨基]丁二酸
将3.4g 2-[（2，2-二氟-1-氧-2-膦酰基乙基）氨基]丁二酸，双（苯基甲基）酯（7.2mmol）溶于水（70ml）中，并在氢气压和0.6g钯-碳存在下进行搅拌。18小时后，过滤反应混合物，在THF（四氢呋喃）中结晶，得到2-[（2，2-二氟-1-氧-2-膦酰基乙基）氨基]丁二酸。
实施例2
（3，3-二氯-2-氧-3-膦酰基丙基）丁二酸的制备
步骤A
3，4-丁醛二羧酸，双（苯基甲基）酯
向装有玻璃管、氯化钙干燥管和玻璃塞的圆底烧瓶中加入20g 3-环戊烯-1-羧酸甲酯（158mmol），500ml二氯甲烷，100ml甲醇和4g无水碳酸氢钠。在-78℃下向该溶液通臭氧直至出现兰色为止。向该溶液通入氮气直至兰色消失，混合物在20℃下搅拌。过滤溶液，并加入150ml苯。将溶液蒸发使其体积减至约100ml。用450ml二氯甲烷稀释后，将烧瓶冷却至0℃，向其中滴入32ml三乙胺和43ml乙酐，并在氮气下将溶液搅拌30分钟。移去冰浴，继续搅拌4小时。溶液用150ml 0.1NHCl，10%NaOH水溶液和水洗涤。有机层用Na2SO4干燥，过滤，蒸发，得到25g粗产品，经硅胶快速层析纯化，得到18g 3，4-丁醛二羧酸，双（苯基甲基）酯。
步骤B
2-（3-二氧基氧膦基-3，3-二氯-2-羧丙基）-丁二酸，二甲酯
将三氯甲烷膦酸二乙酯（25.6g）和5g溴化锂在90ml乙醚和70mlTHF的溶液中加入装有搅拌器，加料漏斗、低温温度计和氮气插管的四口烧瓶中。在氮气流下，于-100℃在10分钟内滴加1.5N正-丁基锂溶液（72ml）。加完后，使混合物的温度提高到-85℃，保持10分钟。然后，向保持在-95℃～-110℃的反应混合物中缓缓加入10g 3，4-丁醛二羧酸，双（苯基甲基）酯在30mlTHF和20ml乙醚中的溶液。混合物在-110℃下搅拌30分钟，快速加入1NH2SO4进行水解，加温并用乙酸乙酯萃取（三次，100ml）。萃取液经0.1NH2SO4、盐水洗涤，用硫酸钠干燥，过滤并蒸发，所得残余物经硅胶快速层析纯化，得到11g 2-（3-二乙氧基氧膦基-3，3-二氯-2-羟丙基）-丁二酸，二甲酯。
步骤C
2-（3，3-二氯-3-二乙氧基氧膦基-2-氧-丙基）-丁二酸，二甲酯
在氩气流下于-78℃向草酰氯（2.1ml）在20ml无水二氯甲烷的搅拌溶液中加入DMSO（3.4ml）。反应混合物在-50℃下搅拌10分钟，并再冷却至-78℃，向其中滴加2-（3-二乙氧基氧膦基-3，3-二氯-2-羧丙基）丁二酸，二甲酯（8g）在30ml无水二氯甲烷中的溶液。在-40℃保持15分钟，在20℃保持1小时后，加入饱和氯化铵水溶液，分离有机层，水相用80ml二氯甲烷萃取两次，合并有机相，用盐水洗涤、干燥（Na2SO4），过滤并蒸发，得到8.7g粗产品，经硅胶快速层析纯化，得到6.7g 2-（3，3-二氯-3-二乙氧基氧膦基-2-氧-丙基）丁二酸，二甲酯。
步骤D
（3，3-二氯-2-氧-3-膦酰基丙基）丁二酸
在氩气流下、于0℃向2-（3，3-二氯-3-二乙氧基氧膦基-2-氧-丙基）丁二酸，二甲酯（6g）溶于75ml无水二氯甲烷的搅拌溶液中，缓慢地加入12ml三甲基甲硅烷基溴，反应混合物在20℃下搅拌18小时，然后蒸发至干。将残余物溶解在30ml乙腈中，并用2ml水进行水解。蒸发反应混合物至干，得到4.4g产品，所得产品溶解在MeOH（甲醇）（30ml）和水（10ml）中，在20℃下用0.5g LiOH（氢氧化锂）处理15小时。蒸发反应混合物至干。将残余物溶解在0.5NHCl（50ml）中，并浓缩成几毫升，用乙酸乙酯萃取5次。合并有机层，用盐水洗涤，干燥（Na2SO4），过滤，蒸发，得到4g（3，3-二氯-2-氧-3-膦酰基丙基）丁二酸，并在热的THF中重结晶。
实施例3
2-（3-二乙氧基氧膦基-3，3-二氟-2-羟丙基）-丁二酸，乙甲酯的制备
向33mmol二异丙胺（33.3g）在300ml无水THF的搅拌溶液中加入1.5N正丁基锂（30mmol）在己烷（200ml）中的溶液。反应混合物在0℃下搅拌30分钟，冷却至-78℃。在30分钟内，在-78℃和氩气流下加入52.5g二氟甲膦酸二乙酯在300ml冷THF的搅拌溶液中。然后在-78℃下，再加入丁醛-3，4-二羧酸双甲酯（34g）在250ml THF中的溶液，将反应混合物缓缓加温至20℃。将0.5L饱和氯化铵水溶液加到冷却至0℃的棕色溶液中，并用乙酸乙酯萃取，用0.5NHCl、盐水洗涤，干燥（Na2SO4），过滤，蒸发。粗产品经硅胶快速层析纯化，得到38g 2-（3-二乙氧基氧膦基-3，3-二氟-2-羟丙基）丁二酸，二甲酯。
实施例4
2-（3-二乙氧基氧膦基-3-氟-2-羟丙基）-丁二酸，二甲酯的制备
在-35℃向二异丙胺（21g）的200ml无水THF的搅拌溶液中加入1.5N正丁基锂（200mmol）的己烷（130ml）溶液。反应混合物在0℃下搅拌30分钟。向冷却至-78℃的溶液中滴加三氟甲膦酸二乙酯（34g）溶于60ml无水THF的溶液。搅拌15分钟后，在-78℃向该反应溶液中滴加丁醛-3，4-二羧酸，二甲酯（22g）溶于50mlTHF的溶液。将该反应混合物缓缓加温至20℃，加入饱和氯化铵水溶液使其骤冷，用乙酸乙酯萃取（3×250ml），用0.1NHCl和盐水洗涤，干燥（Na2SO4），过滤，蒸发。粗产品经硅胶快速层析纯化，得到20g 2-（3-二乙氧基氧膦基-3-氟-2-羟丙基）丁二酸，二甲酯。
按照上述方法，还可以制备以下化合物：
2-[（2，2-二氯-1-氧-2-膦酰基-乙基）氨基]丁二酸，
2-（氟-1-氧-2-膦酰基-乙基）氨基丁二酸，
2-（氯-1-氧-2-膦酰基-乙基）氨基丁二酸，
（3，3-二氟-2-氧-3-膦酰基-丙基）丁二酸，
（3-氟-2-氧-3-膦酰基-丙基）丁二酸，
（3-氯-2-氧-3-膦酰基-丙基）丁二酸。
合理设计有效的抗肿瘤剂一直是药物化学和生化药物学经典方法重要的辅助手段。确实，这一手段导致发现了临床上有效的抗肿瘤剂，如5-氟尿嘧啶，环磷酰胺和malphalan。除了这些成就以外，根据抗肿瘤剂可以作为天冬氨酸转氨甲酰酶（嘧啶核苷酸生物合成过程中的早期酶）的过渡态抑制剂的原理，人们尽了很大的努力寻找其它的抗肿瘤剂。这是一个非常理想的方法，因为已经证明能够抑制这一过程的一些药物可用于治疗许多类型人肿瘤。
研究证明，N-（膦酰基乙酰基）-L-天冬氨酸是天冬氨酸转氨甲酰酶的有效抑制剂，并且发现，与药物例如5-氟尿嘧啶（5-FU），1-β-D-阿糖呋喃胞嘧啶（ARA-C），氨甲蝶呤（MTX）（单独或与5-FU并用），异恶唑乙酸（单独或与5-FU并用）和4′-（9-吖啶基氨基）-甲磺酰基）-m-甲氧基苯胺（AMSA）一起同时使用可治疗癌症如结肠直肠癌，恶性黑素瘤，卵巢癌，神经纤维肉瘤，转移的腺癌，和脑瘤如脑膜瘤和成胶质细胞瘤。
在联合治疗癌症疾病中，N-（膦酰基乙酰基）-L-天冬氨酸（PALA）按约100mg/m2～3000mg/m2剂量（例如，每平方米身体表面用100毫克）给药是有效的，最好单次剂量为1～2g/m2或每天每次按0.5mg/m2连服5天（每隔两周重复一次）（同时服5-FU，ARA-C，MTX，异恶唑乙酸和AMSA）。例如，在使用上述剂量水平的PALA时，同时应用5-FU（如果静脉给药，每周一次，用药剂量在200～500mg/m2），ARA-C（如果静脉给用药，剂量为200～500mg/m2），AMSA（如果静脉给药，每月用药剂量为90～120mg/m2），联合用药治疗上述癌症疾病是有效的。
在与已知抗肿瘤剂（例如5-FU，ARA-C，MTX，异恶唑乙酸和AMSA）联合用药治疗时，如果与上述剂量的5-FU，ARA-C，MTX，异恶唑乙酸和AMSA联合用药进行治疗，可以按PALA剂量的1/5～1/1服用式Ⅰ所示化合物。
所服用的有效成份的量可以根据采用的具体剂量单位、治疗周期、患者的年龄和性别及其患病性质和程度在很大范围内变动。服用的有效成分的总量一般在1mg/kg～50mg/kg，最好为3mg/kg～25mg/kg。单位剂量可以含有25～500mg的有效成分，每天可服用一次或多次。式Ⅰ有效化合物与药用载体一起，以普通剂量单位形式口服、非经肠道给药或局部给药。
服药方式最好是口服。对于口服，化合物可以配制成固体或液体制剂，例如可以是胶囊剂，丸剂、片剂、锭剂、糖锭剂、粉剂、溶液剂、悬浮液剂或乳剂。固体单位剂量形式可以是胶囊剂，胶囊剂有硬明胶胶囊剂和软明胶胶囊剂，胶囊剂可含有例如表面活性剂，润滑剂和惰性填料（如乳糖、蔗糖、磷酸钙和玉米淀粉）。本发明化合物的另一实施例是与常用的片剂成份，例如乳糖和玉米淀粉以及粘合剂如阿拉伯胶，玉米淀粉或明胶;崩解剂（服药后能加速片剂的破裂和溶解），如土豆淀粉、澡酸、玉米淀粉和爪耳树胶;表面活性剂（意指可以改进片剂颗粒流动性并防止压制片剂的材料粘附在压片模子和冲子表面）如滑石、硬脂酸或硬脂酸镁，硬脂酸钙或锌;染料;着色剂和调味剂（意指增加片剂美观，使患者容易接受）一起压制成片剂。用于口服的液体剂型的合适的赋形剂包括稀释剂如水和醇，例如乙醇、苯甲醇和聚乙烯醇，可以加药学上适用的表面活性剂，悬浮剂或乳化剂，也可以不加。
本发明化合物也可以不经肠道给药，即，以生理上可以接受的稀释剂和药用载体将化合物配制成静脉或肌内给药的注射剂型，载体可以是无菌液体或多种液体（如水、盐水、葡萄糖水溶液和有关的糖溶液的混合液），也可以是醇（如乙醇、异丙醇、或十六烷基醇）;二元醇（如丙二醇，聚乙二醇），缩丙三醇（如2，2-二甲基-1，3-二氧戊环-4-甲醇）;醚（如聚乙烯二醇400）;油;脂肪酸;脂肪酸酯或甘油酯;乙酰脂肪酸甘油酯;可以加或不加药学上可以接受的表面活性剂（如肥皂或洗涤剂），悬浮剂（如果胶，聚羧乙烯，甲基纤维素，羟丙基甲基纤维素或羧甲基纤维素）或乳化剂和其它药用辅助剂。用于本发明非经肠道给药配方中油类的例子有石油产品，动物油，植物油或合成的油，例如：花生油，豆油，芝麻油，棉花籽油，玉米油，橄榄油，石油制品和矿物油。合适的脂肪酸酯有例如油酸乙酯，肉豆蔻酸异丙酯。合适的肥皂包括脂肪碱金属盐，铵盐和三乙醇胺盐。合适的洗涤剂包括阳离子洗涤剂（例如二甲基二烷基囟化铵，烷基囟化吡啶嗡和烷基胺乙酸盐），阴离子洗涤剂（例如烷基、芳基和链烯磺酸盐，烷基、链烯，醚和单甘油酯硫酸盐以及磺基丁二酸酯），非离子洗涤剂（例如脂肪胺氧化物，脂肪酸链烷醇酰胺和聚氧乙烯聚丙烯共聚物）和两性洗涤剂（例如烷基-β-氨基丙酸酯和2-烷基咪唑啉季铵盐，及其混合物）。本发明的非经肠道给药的组合物在溶液中一般含有0.5～25%（重量）的有效成分。最好也应用防腐剂和缓冲剂。为了减小或消除注射部位的疼痛，该组合物可以含具有约12～17亲水-亲脂平衡值（HLB）的非离子表面活性剂。配方中表面活性剂的量在约5～15%（重量）范围内。表面活性剂可以是有上述HLB值的单一成份或是有所需HLB值的两个或多个成分的混合物。用于非经肠道给药配方中表面活性剂的例子是聚乙烯脱水山梨醇脂肪酸酯类，例如脱水山梨醇-油酸酯以及环氧乙烷与亲水基质（由氧化丙烯和丙二醇缩合生成）的高分子量加成产物。
服用的有效成分也可以是缓释制剂，因此在治疗期间通过载体的扩散，渗透或分解，从惰性的或易受生物侵蚀的（bioerodible）载体中使式Ⅰ所示化合物以可控制的均匀速率逐渐地释放。可控制的药物缓释系统可以是用于皮肤或颊部，舌下或鼻粘膜的小膏药或绷带形式，或是位于眼睛盲管的眼植入物形式，或是口服后逐渐侵蚀的片剂或胶囊剂，或是胃肠道蓄积剂的形式。服用上述缓释药物可以使身体组织连续长时间接受治疗或预防上有效剂量的式Ⅰ化合物。通过缓释系统接受的化合物单位剂量大约是有效日剂量乘以载体留待在宿主体表或体内最长的天数。缓释载体可以是固体或多孔基质的形式，或是蓄积剂的形式，并可由一种或多种天然的或合成的聚合物构成，这些聚合物包括改性或未改性的纤维素、淀粉、明胶、胶原、橡胶、聚烯烃、聚酰胺、聚丙烯酸酯、聚醇、聚醚、聚酯、聚氨基甲酸乙酯、聚砜、聚硅氧烷和聚酰亚胺，以及上述聚合物的混合物和共聚物。式Ⅰ所示化合物可以纯的形式掺在缓释载体中，或溶解在任何合适的液体赋形剂中，或分散在固体赋形剂中，所述赋形剂包括构成缓释载体的聚合物。
最好使用X和Y是氟或氯的化合物。如果X或Y之一是氢，那么另一个最好是氟。
Claims (14)
1、式I所示化合物或其药学上适用的盐，
其中Z是NH或CH2，Q是O，或若Z是CH2，Q也可是(H，OH)，
X是H，F或Cl，Y是F或Cl，
R1和R2各自是H或C1-6低级烷基，及R3和R4各自是H或C1-6低级烷基。
2、权利要求1所述的化合物，其中Q是氧。
3、权利要求2所述的化合物，其中Z是CH2。
4、权利要求2所述的化合物，其中Z是NH。
5、权利要求3所述的化合物，其中R1、R2、R3和R4是H。
6、权利要求4所述的化合物，其中R1、R2、R3和R4是H。
7、权利要求5所述的化合物，其中X和Y是F。
8、权利要求5所述的化合物，其中X和Y是Cl。
9、权利要求5所述的化合物，其中X是H，Y是F。
10、权利要求6所述的化合物，其中X和Y是F。
11、权利要求6所述的化合物，其中X和Y是Cl。
12、权利要求6所述的化合物，其中X是H，Y是F。
13、在适合于用化疗剂治疗癌症的方法中，化疗剂系选自5-氟尿嘧啶，1-β-D-阿糖呋喃胞嘧啶，氨甲蝶呤，异恶唑乙酸和4′-（9-吖啶基氨基）-甲磺酰基）-m-甲氧基苯胺，改进之处包括将上述化疗剂与权利要求1所述化合物联合用于治疗。
14、制备式Ⅰ所示化合物的方法，
该方法包括（a）在惰性气流中，于约0～室温下，在对质子呈惰性的极性无水溶剂中使三甲基硅烷基溴与式（Ⅱ）所示化合物反应，
然后用水进行水解，以便脱去R′ 3和R′ 4保护基团，及（b）将式Ⅱ所示化合物进行氢解或碱性水解，以便脱去Pg基团，该Pg是C1-6烷基或苄基保护基团，R′ 3和R′ 4是C1-6烷基，X是H、F或Cl，Y是Cl或F，Z是NH或CH2，Q是O，或当Z是CH2时，Q也可以是（H，OH）。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP88400348A EP0328834A1 (en) | 1988-02-16 | 1988-02-16 | Novel aspartate transcarbamylase inhibitors |
| EP88400348.4 | 1988-02-16 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN90102278A Division CN1034832C (zh) | 1986-01-21 | 1987-01-21 | 工业炉窑供气预热装置的清洗系统和工作方法 |
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| CN1036207A true CN1036207A (zh) | 1989-10-11 |
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| Country | Link |
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| EP (2) | EP0328834A1 (zh) |
| JP (1) | JPH02149589A (zh) |
| CN (1) | CN1036207A (zh) |
| AU (1) | AU609942B2 (zh) |
| DK (1) | DK69489A (zh) |
| FI (1) | FI890695A (zh) |
| HU (1) | HUT49142A (zh) |
| IL (1) | IL89287A (zh) |
| NO (1) | NO890644L (zh) |
| NZ (1) | NZ227978A (zh) |
| PT (1) | PT89718B (zh) |
| ZA (1) | ZA891078B (zh) |
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| EP0465297B1 (en) * | 1990-07-04 | 1996-01-31 | Merrell Dow Pharmaceuticals Inc. | 9-Purinyl phosphonic acid derivatives |
| US5095007A (en) * | 1990-10-24 | 1992-03-10 | Ahluwalia Gurpreet S | Alteration of rate and character of hair growth |
| GB9200826D0 (en) * | 1992-01-15 | 1992-03-11 | Celltech Ltd | Peptidyl derivatives |
| US11104639B2 (en) | 2016-09-14 | 2021-08-31 | Daikin Industries, Ltd. | Branched fluorine-containing compound |
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| DE3425701A1 (de) * | 1984-07-12 | 1986-01-16 | Bayer Ag, 5090 Leverkusen | Verfahren zur herstellung von chlorierten phosphorylmethylcarbonyl-derivaten und neue zwischenprodukte zu ihrer herstellung |
| FR2590259B1 (fr) * | 1985-11-20 | 1989-05-12 | Roussel Uclaf | Procede de preparation de derives fluores de l'acide phosphonique, et produits obtenus par la mise en oeuvre de ce procede |
| FR2596393B1 (fr) * | 1986-04-01 | 1988-06-03 | Sanofi Sa | Derives de l'acide hydroxy-3 dihydroxyoxophosphorio-4 butanoique, leur procede de preparation, leur application comme medicament et les compositions les renfermant |
-
1988
- 1988-02-16 EP EP88400348A patent/EP0328834A1/en not_active Withdrawn
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1989
- 1989-02-10 ZA ZA891078A patent/ZA891078B/xx unknown
- 1989-02-13 AU AU29904/89A patent/AU609942B2/en not_active Ceased
- 1989-02-14 FI FI890695A patent/FI890695A/fi not_active Application Discontinuation
- 1989-02-14 IL IL89287A patent/IL89287A/xx not_active IP Right Cessation
- 1989-02-14 NZ NZ227978A patent/NZ227978A/en unknown
- 1989-02-15 HU HU89767A patent/HUT49142A/hu unknown
- 1989-02-15 CN CN89100817A patent/CN1036207A/zh active Pending
- 1989-02-15 PT PT89718A patent/PT89718B/pt not_active IP Right Cessation
- 1989-02-15 EP EP89400420A patent/EP0331550A1/en not_active Ceased
- 1989-02-15 DK DK069489A patent/DK69489A/da not_active Application Discontinuation
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| Publication number | Publication date |
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| DK69489D0 (da) | 1989-02-15 |
| NO890644D0 (no) | 1989-02-15 |
| EP0331550A1 (en) | 1989-09-06 |
| HUT49142A (en) | 1989-08-28 |
| FI890695A0 (fi) | 1989-02-14 |
| ZA891078B (en) | 1989-10-25 |
| DK69489A (da) | 1989-08-17 |
| IL89287A0 (en) | 1989-09-10 |
| AU609942B2 (en) | 1991-05-09 |
| FI890695A (fi) | 1989-08-17 |
| JPH02149589A (ja) | 1990-06-08 |
| AU2990489A (en) | 1989-08-17 |
| PT89718B (pt) | 1994-03-31 |
| IL89287A (en) | 1993-02-21 |
| NZ227978A (en) | 1990-10-26 |
| NO890644L (no) | 1989-08-17 |
| PT89718A (pt) | 1989-10-04 |
| EP0328834A1 (en) | 1989-08-23 |
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