公开(公告)号：US06225463B1

公开(公告)日：2001-05-01

申请号：US09210591

申请日：1998-12-15

Applicant: Dick de Vos ,  Stephen Brown ,  Allan M. Jordan ,  Nicholas J. Lawrence ,  Alan Th. McGown

Inventor： Dick de Vos ,  Stephen Brown ,  Allan M. Jordan ,  Nicholas J. Lawrence ,  Alan Th. McGown

IPC: C07D20508

CPC classification number: C07D305/14 ,  C07C217/58 ,  C07D205/08

Abstract: The object of the present invention is the development of new chiral auxiliaries for improved &bgr;-lactam formation that control both the diastereoselectivity of &bgr;-lactam formation and which can be removed without destruction of the sensitive azetidinone ring, providing valuable intermediates for coupling to the C-13 hydroxyl group of anti-tumor taxanes, such as paclitaxel. Further, the object of the present invention is enantiomerically pure (S)-(−)-1-(p-methoxy-phenyl)propyl-1-amine.

Abstract translation: 本发明的目的是开发用于改善β-内酰胺形成的新手性助剂，其控制β-内酰胺形成的非对映选择性，并且可以在不破坏敏感的氮杂环丁酮环的情况下除去，提供用于偶联至C的有价值的中间体 -13羟基的抗肿瘤紫杉烷，如紫杉醇。 此外，本发明的目的是对映异构体纯的（S） - （ - ） - 1-（对甲氧基 - 苯基）丙基-1-胺。

公开(公告)号：US07223837B2

公开(公告)日：2007-05-29

申请号：US10472921

申请日：2002-03-25

Applicant: Franciscus Marinus Hendrikus De Groot ,  Patrick Henry Beusker ,  Johannes Wilhelm Scheeren ,  Dick De Vos ,  Leonardus Wilhelmus Adriaan Van Berkom ,  Guuske Frederike Busscher ,  Antoinette Eugenie Seelen ,  Ralph Koekkoek ,  Carsten Albrecht

Inventor： Franciscus Marinus Hendrikus De Groot ,  Patrick Henry Beusker ,  Johannes Wilhelm Scheeren ,  Dick De Vos ,  Leonardus Wilhelmus Adriaan Van Berkom ,  Guuske Frederike Busscher ,  Antoinette Eugenie Seelen ,  Ralph Koekkoek ,  Carsten Albrecht

IPC: C07K5/08

CPC classification number: B82Y5/00 ,  A61K47/65 ,  A61K47/67 ,  A61K47/6889 ,  A61K47/6899

Abstract: This invention is directed to prodrugs that can be activated at the preferred site of action in order to selectively deliver the corresponding therapeutic parent drugs to target cells or to the target site. This invention will therefore primarily but not exclusively relate to tumor cells as target cells. More specifically the prodrugs are compounds of the formula V—(W)k—(X)l—A—Z, wherein: V is a specifier; (W)k—(X)l—A is an elongated self-elimination spacer system; W and X are each a 1,(4+2n) electronic cascade spacer, being the same or different; A is either a spacer group of formula (Y)m wherein: Y is a 1,(4+2n) electronic cascade spacer, or a group of formula U being a cyclization elimination spacer; Z is a therapeutic drug; k, l and m are integers from 0 (included) to 5 (included); n is an integer of 0 (included) to 10 (included), with the provisos that: —when A is (Y)m: k+l+m≧1, and if k+l+m=1; —when A is U: k+l≧1.

Abstract translation: 本发明涉及可以在优选的作用位点被活化的前药，以便选择性地将相应的治疗性母体药物递送至靶细胞或靶位点。 因此，本发明主要但不完全涉及作为靶细胞的肿瘤细胞。 更具体地，前药是式V-（W） - （X）1-Z-Z的化合物，其中：V是说明符; （W） - （X）1 - A是细长的自消除间隔体系; W和X分别为1（4 + 2n）个电子级联间隔物，相同或不同; A是式（Y）的间隔基团其中：Y是1，（4 + 2n）电子级联间隔基，或者是一组式U是环化消除间隔基; Z是治疗药物; k，l和m是从0（包括）到5（包括）的整数; n是0（包括）到10（包括）的整数，条件是：当A是（Y）m：k + 1 + m> = 1时，如果k + 1 + m = 1; - 当A是U：k + l> = 1。

公开(公告)号：US5760072A

公开(公告)日：1998-06-02

申请号：US722941

申请日：1996-09-30

Applicant: Hendricus B. A. de Bont ,  Ruben G. G. Leenders ,  Johan W. Scheeren ,  Hidde J. Haisma ,  Dick de Vos

Inventor： Hendricus B. A. de Bont ,  Ruben G. G. Leenders ,  Johan W. Scheeren ,  Hidde J. Haisma ,  Dick de Vos

IPC: C07D305/14 ,  A61K31/00 ,  A61K31/335 ,  A61K31/337 ,  A61K31/70 ,  A61K31/7024 ,  A61K38/46 ,  A61K39/395 ,  A61K47/48 ,  A61P35/00 ,  A61P43/00 ,  C07C263/12 ,  C07C265/00 ,  C07H13/12

CPC classification number: B82Y5/00 ,  A61K47/48761 ,  C07C263/12 ,  C07H13/12

Abstract: A paclitaxel prodrug has a paclitaxel portion coupled to a cleavable N-(aliphatic or aromatic)-O-glycosyl carbamate spacer group, and can be administered orally, topically or by injection to provide an anti-tumor effect, the prodrug being activated by a hydrolizing enzyme, an endogeneous enzyme or an exogeneous enzyme.

Abstract translation: 紫杉醇前药具有与可裂解N-（脂族或芳族）-O-糖基氨基甲酸酯间隔基团偶联的紫杉醇部分，并且可以口服，局部或通过注射给药以提供抗肿瘤作用，所述前药通过 水解酶，内源酶或外源酶。

公开(公告)号：US20090227617A1

公开(公告)日：2009-09-10

申请号：US12399569

申请日：2009-03-06

Applicant: Rene Wilhelmus Marie Aben ,  Johan Wilhelm Scheeren ,  Jeroen Johannes Lambertus Maria Cornelissen ,  Dick De Vos ,  Hidde Jacob Haisma

Inventor： Rene Wilhelmus Marie Aben ,  Johan Wilhelm Scheeren ,  Jeroen Johannes Lambertus Maria Cornelissen ,  Dick De Vos ,  Hidde Jacob Haisma

IPC: A61K31/4745 ,  C07C233/02 ,  A61K31/16 ,  C07D491/14

CPC classification number: C07H15/252

Abstract: The invention relates to novel esters and in particular to some novel esters of glucuronide prodrugs of anthracyclines having tunable water-solubility, their synthesis and use in tumor-selective chemotherapy. It appeared that in the final step in the synthesis of these prodrugs, i.e. the coupling of the glucuronide spacer moiety to the parent drug molecule, protection of the sugar hydroxyls is, surprisingly, no longer required. A process for the preparation of these unprotected sugar spacer moieties is also disclosed.

Abstract translation: 本发明涉及新的酯，特别涉及具有可调节的水溶性的蒽环类药物的葡糖苷酸前药的新型酯，它们在肿瘤选择性化疗中的合成和用途。 似乎在合成这些前药的最后步骤中，即葡糖苷酸间隔物部分与母体药物分子的偶合，令人惊奇的是不再需要保护糖羟基。 还公开了制备这些未保护的糖分隔体部分的方法。

公开(公告)号：US06407265B2

公开(公告)日：2002-06-18

申请号：US09770299

申请日：2001-01-29

Applicant: Marcel Gielen ,  Rudolph Willem ,  Monique Biesemans ,  Martine Kemmer ,  Dick de Vos

Inventor： Marcel Gielen ,  Rudolph Willem ,  Monique Biesemans ,  Martine Kemmer ,  Dick de Vos

IPC: C07D32100

CPC classification number: C07F7/2224

Abstract: Tin polyaalkanecarboxylates having the formula [(R1pR2qSn)rOs]t wherein R1 represents C1-C6 alkyl, branched or straight, substituted or not by one or more hydroxyl groups or halogen atoms, or a phenyl group, substituted or not by one or more hydroxyl groups or halogen atoms, R2 is carboxylic residue selected from (I), (II), (III) or (IV); and p, q, r, s and t have the following meanings: P=3, q=1, r=1, s=) and t=1, p=2, q=2, r=1, s=0, and t=1, p=2, q=1, r=2, s=1 and t=2, have anti-tumor activity.

Abstract translation: 具有式[（R1pR2qSn）rOs] t的锡多烷烃羧酸盐，其中R 1表示被一个或多个羟基或卤素原子支化或直链取代或不被一个或多个羟基或卤素原子取代或未被一个或多个羟基取代的苯基的C 1 -C 6烷基 基团或卤素原子，R 2是选自（I），（II），（III）或（IV）的羧酸残基; 并且p，q，r，s和t具有以下含义：P = 3，q = 1，r = 1，s =）和t = 1，p = 2，q = 2，r = 1，s = 0 ，t = 1，p = 2，q = 1，r = 2，s = 1和t = 2，具有抗肿瘤活性。

公开(公告)号：US5710135A

公开(公告)日：1998-01-20

申请号：US652940

申请日：1996-05-24

Applicant: Ruben G. G. Leenders ,  Eric W. P. Damen ,  Johan Wilhelm Scheeren ,  Hidde J. Haisma ,  Pieter H. J. Houba ,  Dick De Vos

Inventor： Ruben G. G. Leenders ,  Eric W. P. Damen ,  Johan Wilhelm Scheeren ,  Hidde J. Haisma ,  Pieter H. J. Houba ,  Dick De Vos

IPC: A61K31/70 ,  A61K31/7028 ,  A61K31/7034 ,  A61K31/704 ,  A61K39/395 ,  A61P35/00 ,  C07F7/18 ,  C07H15/203 ,  C07H15/252 ,  C07H15/24

CPC classification number: C07H15/203 ,  A61K31/70 ,  C07F7/18 ,  C07H15/252

Abstract: Anthracycline derivatives are disclosed which are coupled to an enzymatically cleavable N-phenyl-O-glycosyl carbamate spacer group, which derivatives are represented by the formula ##STR1## as well as the acid addition salts thereof. Further the synthesis of these derivatives and their use, alone or in combination with enzymes or antibody enzyme conjugates are disclosed.

Abstract translation: 公开了蒽环衍生物，其与酶促切割的N-苯基-O-糖基氨基甲酸酯间隔基团偶联，该衍生物由下式表示：R1 = H，OH，OMe R2 = H，OH R3 = H，CX3 ，NO 2，CN，X，Y，OY，NHY，S（O 2）Y，C（O）Y，C（O）OY R 4 = CH 2 OH，C（O）O-Z + X =卤素Y = C 1 -C 3烷基，芳基 Z = H，LI，Na，K及其酸加成盐。 此外，公开了这些衍生物的合成及其用途，单独或与酶或抗体酶缀合物组合。

公开(公告)号：US5559147A

公开(公告)日：1996-09-24

申请号：US519026

申请日：1995-08-24

Applicant: Marcel Gielen ,  Rudolph Willem ,  Abdeslam Bouhdid ,  Dick de Vos

Inventor： Marcel Gielen ,  Rudolph Willem ,  Abdeslam Bouhdid ,  Dick de Vos

IPC: C07F7/22 ,  A61K31/32

CPC classification number: C07F7/2256 ,  C07F7/2292

Abstract: The invention relates to novel aromatic fluorine-containing organotin compounds of the formula {(F.sub.5 C.sub.6 RCO.sub.2 SnBu.sub.2).sub.2 O}.sub.2 and {(F.sub.5 C.sub.6 RCO.sub.2).sub.2 SnBu.sub.2 } wherein R is CH.sub.2, CH.dbd.CH or a single bond between the phenyl ring and the CO.sub.2 group, and Bu is a butyl group; as well as to anti-tumour compositions containing as an active ingredient one or more of these compounds.

Abstract translation: 本发明涉及式{（F5C6RCO2SnBu2）2O} 2和{（F5C6RCO2）2SnBu2}的新型芳族含氟有机锡化合物，其中R是CH 2，CH = CH或苯环和CO 2基团之间的单键，以及 Bu是丁基; 以及含有这些化合物中的一种或多种作为活性成分的抗肿瘤组合物。

公开(公告)号：US06344571B2

公开(公告)日：2002-02-05

申请号：US09788344

申请日：2001-02-21

Applicant: Peter H. G. Wiegerinck ,  Duncan Sperling ,  Lesly Braamer ,  Eric W. P. Damen ,  Johan W. Scheeren ,  Dick de Vos

Inventor： Peter H. G. Wiegerinck ,  Duncan Sperling ,  Lesly Braamer ,  Eric W. P. Damen ,  Johan W. Scheeren ,  Dick de Vos

IPC: C07D30514

CPC classification number: C07D305/14

Abstract: The invention relates to water soluble antitumor analogs of paclitaxel of formula (I) wherein R1=C(O)CH2CH(OH)COOX, R2=H, C(O)CH2CH(OH)COOX, X=H, Li, Na or any other pharmaceutically acceptable counterion, as well as to a pharmaceutical composition comprising an antineoplastically effective amount of such analogs as an active ingredient.

Abstract translation: 本发明涉及式（I）的紫杉醇的水溶性抗肿瘤类似物，其中R1 = C（O）CH2CH（OH）COOX，R2 = H，C（O）CH2CH（OH）COOX，X = H，Li，Na或 任何其它药学上可接受的抗衡离子，以及包含抗肿瘤有效量的这些类似物作为活性成分的药物组合物。

公开(公告)号：US5874595A

公开(公告)日：1999-02-23

申请号：US861053

申请日：1997-05-21

Applicant: Eric Wilhelmus Petrus Damen ,  Johan Wilhelm Scheeren ,  Dick de Vos

Inventor： Eric Wilhelmus Petrus Damen ,  Johan Wilhelm Scheeren ,  Dick de Vos

IPC: A61K31/335 ,  A61K31/337 ,  A61P35/00 ,  C07B61/00 ,  C07D305/14

CPC classification number: C07D305/14

Abstract: 10-Deacetylbaccatin III is selectively acylated to baccatin III and derivatives thereof in high yield with anhydrides (e.g. acetic anhydride), catalysed by Lewis acids. Extremely effective catalysts in this reaction are compounds of the formula ML.sub.x wherein M is a rare earth metal and L is a anion, preferably a strong electron withdrawing counterion such as triflate.

Abstract translation: 10-脱乙酰基浆果赤霉素III以路易斯酸催化的酸酐（如乙酸酐）以高收率选择性酰化成浆果赤霉素Ⅲ及其衍生物。 该反应中非常有效的催化剂是式MLx的化合物，其中M是稀土金属，L是阴离子，优选强吸电子抗衡离子如三氟甲磺酸酯。

公开(公告)号：US5874550A

公开(公告)日：1999-02-23

申请号：US985358

申请日：1997-12-04

Applicant: Marcel van der Rijst ,  Johan Wilhelm Scheeren ,  Dick de Vos

Inventor： Marcel van der Rijst ,  Johan Wilhelm Scheeren ,  Dick de Vos

IPC: C07H15/252 ,  C07H1/00 ,  C07H15/24

CPC classification number: C07H15/252 ,  Y02P20/55

Abstract: This invention relates to a novel method for the chemical preparation of epirubicin or acid addition salts thereof, in particular the HCl salt, from daunorubicin. This process avoids the disadvantages of the prior art. First daunorubicin is methanolized to obtain daunomycinone and daunosamine methyl ether in very high yields. Daunomycinone is converted to 14-acetoxy daunomycinone by bromination and acetoxylation, while daunosamine methyl ether is converted into an N-protected 4'-epi daunosamine. The choice of the protecting group of the amino group of the daunosamine methyl ether is important because it has to be removed after coupling the sugar with the aglycone without causing side reactions of the aglycone. Two protecting groups were selected: the trifluoroacetyl group and the allyloxycarbonyl group. After coupling the 14-acetoxy daunomycinone with the N-protected 4'-epi daunosamine, the obtained compound was converted to epirubicin; for the latter conversion two routes were developed, depending on the amino-protecting group.

Abstract translation: 本发明涉及从柔红霉素化学制备表柔比星或其酸加成盐，特别是HCl盐的新方法。 该过程避免了现有技术的缺点。 首先将柔红霉素甲醇化，以非常高的产率获得道诺霉素酮和柔红霉素甲醚。 道诺霉素通过溴化和乙酰氧化转化为14-乙酰氧基道诺霉素，而柔红霉素甲基醚转化为N-保护的4'-表柔比星诺酮胺。 道诺胺甲基醚的氨基保护基团的选择是重要的，因为必须在将糖与糖苷配基偶联之后除去，而不引起糖苷配基的副反应。 选择两个保护基团：三氟乙酰基和烯丙氧基羰基。 将14-乙酰氧基道诺霉素与N-保护的4'-表柔酮多糖结合后，将所得化合物转化为表柔比星; 对于后者的转化，根据氨基保护基团开发了两种途径。