CN1277197A - 5－甲基四氢叶酸的稳定晶体盐 - Google Patents
5－甲基四氢叶酸的稳定晶体盐 Download PDFInfo
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- C07D475/02—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
本发明涉及稳定的5－甲基－(6R,S)－,－(6S)－和－(6R)－四氢叶酸结晶盐,制备这些盐的方法和它们作为制备药物的成分或作为食品添加剂的用途,以及含有这些盐的制剂。
Description
本发明涉及N-[4-[[(2-氨基-1，4，5，6，7，8-六氢-4-氧-5-甲基-(6S)，-(6R)-和(6R，S)-喋啶基)甲基]氨基]苯甲酰-L-谷氨酸晶体盐(以下称为5-甲基四氢叶酸盐)，涉及它们的用途和制备它们的方法。
四氢叶酸盐主要作为5-甲酰基四氢叶酸及其盐(甲酰四氢叶酸)或5-甲基四氢叶酸及其盐用于治疗由于缺乏叶酸引起的巨红细胞性贫血，作为解毒剂用于增强叶酸拮抗剂的相容性，特别是用于增强治疗癌症的氨喋呤和甲氨喋呤的相容性(“叶酸拮抗剂缓救(antifolate rescue)”)；用于增强氟化嘧啶的治疗效果；用于治疗例如牛皮癣和风湿性关节炎的自身免疫疾病；用于增强某些抗寄生虫药剂例如三甲氧苄二氨嘧啶-磺胺甲基异噁唑的相容性；和用于降低在化学治疗中二脱氮四氢叶酸(dideazatetrahydrofolates)的毒性。5-甲基四氢叶酸可特别用作药和食品添加剂，用作维生素制剂，用于预防神经管缺陷，用于治疗抑郁症，以及用于影响同型半胱氨酸的水平。
5-甲基四氢叶酸及其盐非常不稳定，特别对氧化高度敏感[见A.l.Fitzhugh，蝶啶(Pteridines)4(4)，187-191(1993)]，因此很难制得足够的纯度以用作药物活性成分和食品添加剂。
为了克服5-甲基四氢叶酸不稳定的缺点，已经采取了许多方法，例如尽可能完全去除氧或加入抗氧化剂例如抗坏血酸或还原型的L-谷胱甘肽。然而在使用当中很难完全去除氧，即使可以作到这一点，但成本也极其昂贵，同样地，加入抗氧化剂通常也并不可行。迄今为止，还没能找到商业上可行的办法来制备令人满意的稳定和高纯度的5-甲基四氢叶酸盐。
令人惊奇的是，已经发现在高于60℃温度下热处理溶液后，通过从这个极性溶液中结晶出相应的盐能够得到高化学纯度和优异稳定性的5-甲基四氢叶酸盐。在室温下，实际上没有限制的条件下，得到的高晶型5-甲基四氢叶酸盐是稳定的，它们适于用作生产药剂或食品添加剂的成分或起始原料。
因此本发明涉及5-甲基四氢叶酸的晶体盐，用于结晶的5-甲基四氢叶酸盐优选为碱土金属盐，特别是钙盐。这些5-甲基四氢叶酸晶体盐具有＞98％的纯度，到达迄今为止还没有过这样的纯度，同时具有高的稳定性，在温度为25℃，相对湿度为60％的空气中，将其存放6个月后，相对于原始数据到达了前所未有的＞98％纯度。 5-甲基-(6S)-四氢叶酸钙的晶体盐有4种不同的晶型(I型、II型、III型、IV型)，当进行粉末X-射线衍射测量时呈现出锐谱(参见图1到图4，和表1到表4)。不同晶型的选择性的2θ值为6.5，13.3，16.8和20.1(I型)；5.3，6.9，18.7和21.1(II型)；以及6.8，10.2，15.4和22.5(III型)；以及6.6，15.9，20.2和22.5(IV型)。在5-甲基四氢叶酸钙晶体盐中至少每当量5-甲基四氢叶酸含有一当量水的结晶水，这样在I型中含有≥3当量的水，在II型中含有≤2当量的水和III型和IV中含有≤5当量的水。
同样可以得到高结晶形式的5-甲基-(6R)-四氢叶酸盐和5-甲基-(6R，S)-四氢叶酸盐。
本发明进一步涉及制备5-甲基四氢叶酸高结晶盐的方法，其特征在于将相应的5-甲基四氢叶酸盐进行结晶。在本方法中，经过高于60℃，特别是高于85℃的热处理后，5-甲基四氢叶酸的晶体盐从极性介质中结晶出。
特别适合于作为板性介质的物质包括水或水和可与水混溶的有机溶剂的混合物，例如可溶于水的醇，例如甲醇、乙醇、正丙醇、异丙醇或乙二醇，低分子量的可溶于水的脂族族羧酸例如甲酸、乙酸或乳酸，或可溶于水的酰胺例如甲酰胺、二甲基甲酰胺、二甲基乙酰胺、1-甲基吡咯烷酮、2-甲基吡咯烷酮或2-哌啶酮。因为5-甲基四氢叶酸的晶体盐比相应的其无定型的溶解度低，所以对于所使用溶剂的类型和混合的比例没有严格的限制。
优选晶体从溶液中结晶出来，也可以从悬浮液中结晶出来。
通过进一步在高于60℃的温度下热处理，不同的晶型可以相互转化。这样，在经过高于60℃的热处理后从极性介质中生产的I型，可以在70℃真空干燥下转化为II型，可以经高于90℃的热处理转化为III型，以及可以经高于95℃的热处理转化为IV型。在90℃的湿度箱中可以用水处理II型，使其再次转变为I型。
5-甲基四氢叶酸盐的结晶可自然进行或通过引入相应的5-甲基四氢叶酸结晶盐晶种来进行。
优选的合适结晶的起始物质为纯的，无定型的或结晶的5-甲基(6S)-或-(6R)-四氢叶酸，5-甲基-(6R，S)四氢叶酸外消旋体也可以作为富含5-甲基(6S)-，-(6R)-或-(6R，S)-四氢叶酸而加以使用。
通过在此所述方法用无定型或部分结晶，光学纯的5-甲基四氢叶酸或其盐作为结晶的起始原料，可得到迄今为止尚未获得过的纯度和稳定性的5-甲基四氢叶酸的基本上为结晶的盐。
本发明还涉及高结晶的5-甲基四氢叶酸盐的用途，它可以作为生产药物或食品或生产其它的四氢叶酸衍生物的成分。由于其高稳定性的固体形式，5-甲基四氢叶酸结晶盐保持恒定不变的高质量，特别是对时间没有限制，质量保持不变。本发明还涉及含有5-甲基四氢叶酸的高度结晶盐的制剂，这些制剂可用已知的方法制备。它们的应用类似于已知四氢叶酸物质领域的用途，例如5-甲酰基四氢叶酸(甲酰四氢叶酸)。
不需要进一步描述，利用先前的说明，本领域的技术人员可以最大限度地实施本发明。下面优选的具体实施方案只是作为例证，无论如何不限制本发明所公开的内容。
上述和下述的实施例中，除非另有提示，所有的温度为未校正的摄氏温度，所有的份数和百分数都为重量份数和百分数。用于说明本发明的实施例
在实施例中5-甲基四氢叶酸盐的含量均用HPLC进行测量，并给出面积百分数，水的含量用Karl Fischer方法进行测量。实施例1[稳定性]
为了测定5-甲基四氢叶酸结晶盐的稳定性，在温度为25℃和相对湿度为60％的空气中，待测物与对照物一起贮存。定期间隔测量并给出与原始值对照的剩余5-甲基四氢叶酸盐的含量。
| 贮存月数 | ||||||
| 0 | 3 | 6 | 12 | 18 | 88 | |
| 5-甲基-(6S)-四氢叶酸结晶钙盐 | 100％ | 98.6％ | 98.7％ | 99.1％ | 99.0％ | 97.8％ |
| 5-甲基-(6S)-四氢叶酸无定型钙盐 | 100％ | 84.2％ | ||||
长时间贮存期后，5-甲基四氢叶酸结晶盐仍然具有很浅的颜色，与之相比，无定型样品迅速、明显地变色。实施例2[X-射线粉末衍射图]
为了表征5-甲基四氢叶酸结晶盐的结构性质(结晶变化)，记录这些待测物的X-射线粉末图(衍射图谱)。
5-甲基四氢叶酸结晶盐呈现出高分辨率的图谱，具有锐谱带和低背景谱，这说明了高的结晶成分。
实施例的图谱见图1(I型)，图2(II型)，图3(III型)和图4(IV型)，衍射数据见表1(I型)，表2(II型)，表3(III型)和表4(IV型)。为了进行比较，在类似条件下，也记录了无定型样品的图谱，参见图5(无定型)。选定的5-甲基-(6S)-四氢叶酸结晶钙盐的各种晶型变化体的2θ值列于下表：
实施例3[溶解度]
| 晶型 | 选定的2θ值 |
| I型II型III型IV型 | 6.5，13.3，16.8和20.15.3，6.9，8.7和21.16.8，10.2，15.4和22.56.6，15.9，20.2和22.5 |
5-甲基-(6S)-四氢叶酸结晶钙盐的溶解度列于下表：
实施例4[5-甲基-(6S)-四氢叶酸无定型钙盐]
| 晶型 | 在20℃下的溶解度 | |
| 0.9％NaCl | 水 | |
| I型II型III型 | 1.6％5.8％1.5％ | 1.1％3.8％1.0％ |
在室温下，将7.5克5-甲基-(6S)-四氢叶酸加入到75毫升的水中，同时通入氮气，用30％的氢氧化钠水溶液将其调节到pH值为12。用37％的盐酸将该澄清的溶液调到pH为7.5，然后用溶于11.7毫升水的7.15克六水氯化钙溶液处理，将形成的白色悬浮液搅拌5小时，在室温下吸滤，得到的固体用水洗涤，然后在45℃下真空干燥。
得到5.8克白色的5-甲基-(6S)-四氢叶酸无定型钙盐，它的含量为98.0％，6S成分相当于99.6％。
甚至在湿度箱中，在60℃下处理这些物质后，用偏光显微镜或X-射线衍射法进行测量，也检测不到结晶成分。实施例5[5-甲基-(6R，S)-四氢叶酸结晶钙盐]
在含有780毫升水的容器中，加入70克5-甲基-(6R，S)-四氢叶酸，用45.2g 30％的氢氧化钠将混合物调为pH为7.5。将澄清的、微带红色的溶液用溶于140毫升水中的62.7克六水氯化钙溶液处理，滤出固体，再用少量水处理。得到的粗品悬浮于水中，在90℃下处理24小时。
得到74.0克白色的5-甲基-(6R，S)-四氢叶酸结晶钙盐，含量为99.1％。实施例6[5-甲基-(6R)-四氢叶酸结晶钙盐]
在92℃下，在含有100毫升水的容器中，加入16.5克5-甲基-(6R)-四氢叶酸和50克六水氯化钙。在91℃下，将澄清的、微发黄的悬浮液搅拌10分钟，滤出固体，再用少量的水洗，并在35℃下进行真空干燥。
得到15.4克浅褐色的5-甲基-(6R)-四氢叶酸结晶钙盐，含量为97.9％，水的含量为7.8％。实施例7[I型]
将130千克的水放置在容器中，加入12.8千克5-甲基-(6S)-四氢叶酸，用30％的氢氧化钠大约9.1千克，将pH值调节为11.6，然后用大约1.9千克37％的盐酸调节pH为7.6。将含有0.3千克碳和0.3千克Cellflock的悬浮液加入到该澄清的溶液中。滤出固体并用13升水进行洗涤。滤液用含有8.3千克二水氯化钙的溶液处理，加热到90℃，并搅拌30分钟。产品趁热过滤，用2×20千克的水洗涤，得到的湿的粗产品在115升的水中形成浆液，并加热到90℃，立刻趁热过滤，用2×20千克的水洗涤，在40℃下进行真空干燥。
得到11.6千克白色的5-甲基-(6S)-四氢叶酸结晶钙盐(I型)，纯度为99.0％，水的含量为14.5％。实施例8(I型)
将1600毫升的水放置在容器中，加入194克5-甲基-(6S)-四氢叶酸，用约80毫升的30％氢氧化钠，将pH值调节为7.0，将悬浮于190毫升水中的20克碳和20克Cellflock的悬浮液加入到该澄清的溶液中。滤出固体，并用水洗涤，滤液用950毫升的5.5M的氯化钙溶液处理，加热至90℃并搅拌60分钟，产品趁热过滤，用水洗涤，在45℃下进行真空干燥。
得到156.2克白色的5-甲基-(6S)-四氢叶酸结晶钙盐(I型)，纯度为99.7％和99.9％的6S成分。实施例9[I型和转变为II型]
将554克的水放置在容器中，加入53.1克5-甲基-(6S)-四氢叶酸，用30％氢氧化钠，将pH值调节为7.5，然后将1.3克碳、1.3克Cellflock和19.5克水加入到该澄清的溶液中。过滤悬浮液，并用55毫升的水洗涤。滤液用溶于84.6克水中的52.0克六水氯化钙溶液处理，并加热到90℃，引入100毫克5-甲基四氢叶酸结晶钙盐作为晶种，结晶发生之后，在90℃下，趁热过滤，并用2×103克的水洗涤。得到的湿的粗产品在480毫升水中形成浆液，再加热到90℃，迅速热过滤，如上所述进行洗涤，在45℃下进行真空干燥。
得到47.5克白色的5-甲基-(6S)-四氢叶酸结晶钙盐(I型)，纯度为98.8％，水的含量为12.2％。
在70℃下真空干燥30分钟，可以将I型转变为含有5.0％水的II型。实施例10[III型]
将在140毫升水中的15.8克5-甲基-(6S)-四氢叶酸钙盐加热到95℃，同时通入氮气，在95℃下保持30分钟后，趁热抽吸过滤该白色悬浮液，用水洗涤固体，并在35℃下真空干燥。
得到14.0克白色的5-甲基-(6S)-四氢叶酸结晶钙盐(III型)，含量为98.9％和99.9％的6S成分。实施例11[IV型]
将在180毫升水中的20.0克5-甲基-(6S)-四氢叶酸钙盐加热到100℃，同时通入氮气，在100℃下保持30分钟后，趁热抽吸过滤该白色悬浮液，用水洗涤固体，并在25℃下真空干燥。
得到16.9克白色的5-甲基-(6S)-四氢叶酸结晶钙盐(IV型)，含量为98.3％，水的含量为9.9％。
在65℃下真空干燥，产品中水的含量可减少至5.5％，在这个过程中不会得到不同的结晶变化。表1：5-甲基-(6S)-四氢叶酸结晶钙盐(I型)衍射仪：透射式单色仪：Curved Ge(111)波长：1.540598 Cu检测器：Linear PSD扫描模式：Debye-Scherrer/Moving PSD/Fixed omega2θ扫描检测峰的参数：预计的半峰宽：0.150
显著水平：2.5
峰高标准：10峰值例表[范围1：2θ＝5.000 34.980 0.020 Imax＝765]！ D 2Theta I(rel) I(abs) FWHM h k l13.474630 6.5544 100.0 755 .22008.979750 9.8420 18.5 140 .16006.936035 12.7526 20.3 153 .16006.662427 13.2786 38.3 289 .08006.497896 13.6164 29.4 222 .12006.323596 13.9935 18.8 142 .02006.148863 14.3933 14.0 106 .04005.966675 14.8352 15.5 117 .12005.593548 15.8309 27.5 208 .22005.368022 16.5006 19.7 149 .11275.282104 16.7709 42.5 321 .20004.977751 17.8044 23.6 178 .18004.672452 18.9782 32.7 247 .28004.411916 20.1102 34.8 263 .08004.257688 20.8467 34.2 258 .26003.761157 23.6360 13.3 100 .04003.699455 24.0361 22.3 168 .14003.558431 25.0037 14.8 112 .10003.439070 25.8864 21.0 159 .14003.272550 27.2283 22.1 167 .28003.218939 27.6907 17.0 129 .14003.140884 28.3931 17.2 130 .08003.013536 29.6198 13.9 105 .10002.873482 31.0991 15.1 114 .02002.782802 32.1395 16.6 125 .02002.754830 32.4748 20.2 152 .06002.713309 32.8858 15.4 116 .1127表2：5-甲基-(6S)-四氢叶酸结晶钙盐(II型)衍射仪：透射式单色仪：Curved Ge(111)波长：1.540598 Cu检测器：Linear PSD扫描模式：Debye-Scherrer/Moving PSD/Fixed omega2θ扫描检测峰的参数：预计的半峰宽：0.150
显著水平：2.5
峰高标准：10峰值例表[范围1：2θ＝5.000 34.980 0.020 Imax＝526]！ D 2Theta I(rel) I(abs) FWHM h k l12.720530 6.9434 100.0 517 .26008.508053 10.3891 29.4 152 .24006.631466 13.3409 19.6 101 .12005.883504 15.0461 71.2 368 .22005.580025 15.8696 27.8 144 .08005.010988 17.6854 42.5 220 .14004.730443 18.7434 53.6 277 .14004.215807 21.0561 35.5 184 .04003.943879 22.5263 38.8 201 .36003.581969 24.8368 24.8 128 .02003.493985 25.4726 29.6 153 .04003.309171 26.9212 22.7 117 .0200表3：5-甲基-(6S)-四氢叶酸结晶钙盐(III型)衍射仪：透射式单色仪：Curved Ge(111)波长：1.540598 Cu检测器：Linear PSD扫描模式：Debye-Scherrer /Moving PSD / Fixed omega2θ扫描检测峰的参数：预计的半峰宽：0.150
显著水平：2.5
峰高标准：10峰值例表[范围1：2θ＝5.000 34.980 0.020 Imax＝817]！ D 2Theta I(rel) I(abs) FWHM h k l12.933490 6.8289 100.0 786 .120011.036740 8.0043 18.9 149 .04009.945525 8.8842 18.4 145 .10008.877709 9.9554 12.4 98 .07968.640580 10.2293 49.6 390 .10007.873330 11.2292 6.4 50 .10007.144004 12.3799 7.6 59 .08006.948557 12.7295 20.3 159 .10006.659956 13.2835 10.1 80 .04006.466239 13.6834 7.6 60 .02006.305060 14.0349 37.6 296 .10006.154434 14.3802 16.4 129 .04006.057193 14.6123 15.3 121 .06005.920458 14.9517 17.6 139 .10005.738533 15.4285 48.9 385 .10005.530167 16.0136 30.3 238 .10005.322477 16.6428 18.1 143 .06005.245302 16.8894 47.4 372 .08005.154604 17.1888 20.9 164 .07965.038273 17.5888 30.8 242 .10004.980502 17.7945 10.7 84 .07964.759336 18.6286 31.6 248 .12004.702846 18.8544 24.3 191 .07964.575841 19.3827 15.6 122 .08004.478961 19.8061 25.9 204 .10004.377158 20.2716 48.1 378 .10004.309006 20.5957 11.9 93 .07964.242777 20.9207 31.3 246 .08004.051441 21.9207 10.3 81 .02003.940356 22.5467 67.8 533 .12003.782452 23.5010 12.4 98 .04003.609291 24.6458 9.5 75 .02003.523157 25.2582 27.0 212 .20003.460874 25.7205 43.4 341 .08003.408545 26.1223 12.4 98 .07963.341048 26.6596 16.1 127 .20003.273575 27.2196 28.4 223 .14003.188038 27.9645 12.6 99 .02003.160310 28.2168 12.5 98 .04003.103472 28.7427 15.0 118 .08003.052658 29.2317 13.9 109 .06003.017419 29.5808 27.7 218 .14002.970195 30.0621 10.6 83 .12002.921067 30.5800 13.9 109 .02002.899222 30.8161 9.6 76 .07962.870572 31.1314 9.6 75 .04002.830661 31.5817 11.0 86 .02002.758126 32.4349 11.3 89 .04002.733265 32.7382 13.2 104 .06002.695836 33.2058 13.7 108 .08002.660160 33.6643 11.7 92 .10002.609572 34.3369 9.2 72 .0200表4：5-甲基-(6S)-四氢叶酸结晶钙盐(IV型)衍射仪：透射式单色仪：Curved Ge(111)波长：1.540598 Cu检测器：Linear PSD扫描模式：Debye-Scherrer/Moving PSD/Fixed omega2θ扫描检测峰的参数：预计的半峰宽：0.150
显著水平：2.5
峰高标准：10峰值例表[范围1：2θ＝5.000 34.980 0.020 Imax＝473]！ D 2Theta I(rel) I(abs) FWHM h k l13.398610 6.5916 97.7 446 .160012.930100 6.8307 100.0 457 .091511.033220 8.0069 19.2 88 .06009.952926 8.8776 16.7 76 .12008.912272 9.9167 25.5 116 .16008.626970 10.2455 48.9 223 .08006.931997 12.7600 37.4 171 .10006.651761 13.3000 39.7 181 .12006.499623 13.6127 32.8 150 .08006.309299 14.0254 47.0 215 .16006.161306 14.3641 25.1 115 .12005.917463 14.9593 27.0 124 .10005.736254 15.4347 49.8 227 .08005.544314 15.9724 36.7 168 .16005.255854 16.8553 62.1 284 .24005.172075 17.1303 29.5 135 .09155.035719 17.5978 37.0 169 .12004.978813 17.8006 31.3 143 .04004.758441 18.6321 40.7 186 .10004.688853 18.9112 46.0 210 .09154.577465 19.3757 29.5 135 .09154.479376 19.8043 35.5 162 .10004.383704 20.2410 63.6 290 .12004.246196 20.9037 59.5 272 .14004.088125 21.7216 19.7 90 .02003.941748 22.5386 62.9 288 .14003.778991 23.5229 27.9 128 .04003.696576 24.0551 30.5 139 .10003.523769 25.2537 35.6 163 .24003.459683 25.7295 44.7 204 .08003.338511 26.6803 28.7 131 .02003.273450 27.2206 45.5 208 .10003.135320 28.4446 23.6 108 .06003.108154 28.6985 25.9 118 .02003.018687 29.5681 34.4 157 .14002.923031 30.5589 21.9 100 .02002.844431 31.4249 18.4 84 .02002.749393 32.5408 28.5 130 .12002.713739 32.9804 25.6 117 .02002.663207 33.6246 19.6 90 .06002.613490 34.2838 17.4 80 .0200
Claims (15)
1、5-甲基-(6R，S)-，-(6S)-和-(6R)-四氢叶酸结晶盐。
2、5-甲基-(6S)-和-(6R)-四氢叶酸结晶盐。
3、5-甲基-(6S)-和-(6R)-四氢叶酸结晶钙盐。
4、具有2θ值为6.5，13.3，16.8和20.1的5-甲基-(6S)-四氢叶酸结晶钙盐。
5、具有2θ值为5.3，6.9，18.7和21.1的5-甲基-(6S)-四氢叶酸结晶钙盐。
6、具有2θ值为6.8，10.2，15.4和22.5的5-甲基-(6S)-四氢叶酸结晶钙盐。
7、具有2θ值为6.6，15.9，20.2和22.5的5-甲基-(6S)-四氢叶酸结晶钙盐。
8、制备5-甲基-(6R，S)-，-(6S)-和5-甲基-(6R)-四氢叶酸结晶盐的方法，其特征在于，5-甲基-(6R，S)-，-(6S)-或-(6R)-四氢叶酸的盐经热处理后从极性介质中结晶出来。
9、根据权利要求8的方法，其特征在于在高于60℃的温度下热处理之后，进行结晶。
10、根据权利要求8的方法，其特征在于在高于85℃的温度下热处理之后，进行结晶。
11、根据权利要求8的方法，其特征在于在从溶液中进行结晶。
12、根据权利要求8的方法，其特征在于在从悬浮液中进行结晶。
13、根据权利要求11或12的方法，其特征在于，从水或水和与水可混溶的有机溶剂的混合物中结晶。
14、5-甲基-(6S)-或-(6R)-四氢叶酸结晶盐作为制备药物的成分或作为食品添加剂的用途。
15、含有5-甲基-(6S)-和-(6R)-四氢叶酸结晶盐的制剂。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH00695/99A CH693905A5 (de) | 1999-04-15 | 1999-04-15 | Stabile kristalline Salze von 5-Methyltetrahydrofolsäure. |
| CH695/1999 | 1999-04-15 |
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| Publication Number | Publication Date |
|---|---|
| CN1277197A true CN1277197A (zh) | 2000-12-20 |
| CN1154648C CN1154648C (zh) | 2004-06-23 |
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| Country | Link |
|---|---|
| US (1) | US6441168B1 (zh) |
| EP (5) | EP1695975A1 (zh) |
| JP (4) | JP5202774B2 (zh) |
| KR (2) | KR100774012B1 (zh) |
| CN (1) | CN1154648C (zh) |
| AT (2) | ATE451372T1 (zh) |
| AU (1) | AU782641B2 (zh) |
| CA (1) | CA2305926C (zh) |
| CH (1) | CH693905A5 (zh) |
| CY (2) | CY1109874T1 (zh) |
| DE (2) | DE50016064D1 (zh) |
| DK (4) | DK1044975T3 (zh) |
| ES (3) | ES2336190T3 (zh) |
| HU (1) | HU229423B1 (zh) |
| NO (1) | NO325495B1 (zh) |
| PT (4) | PT1044975E (zh) |
| RU (1) | RU2265605C2 (zh) |
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- 2000-04-08 EP EP06010738A patent/EP1695975A1/de not_active Withdrawn
- 2000-04-08 DE DE50016064T patent/DE50016064D1/de not_active Expired - Lifetime
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