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11. 发明授权

US5753668A Substituted benzyloxypyrimidines and their inactivation of O.sup.6 -alkylguanine-DNA alkyltransferase 失效
标题翻译：取代的苄氧基嘧啶及其灭活O6-烷基鸟嘌呤-DNA烷基转移酶
公开(公告)号：US5753668A
公开(公告)日：1998-05-19
申请号：US661923
申请日：1996-06-11
申请人： Robert C. Moschel , Anthony E. Pegg , M. Eileen Dolan , Mi-Young Chae
发明人： Robert C. Moschel , Anthony E. Pegg , M. Eileen Dolan , Mi-Young Chae
IPC分类号： A61K31/505 , A61K31/52 , A61K31/522 , A61K31/53 , A61P35/00 , A61P43/00 , C07D239/46 , C07D239/47 , C07D239/48 , C07D239/50 , C07D251/52 , C07D473/06 , C07D473/18 , C07D473/40 , C07D487/04 , C07D239/42
CPC分类号： C07D239/47 , C07D239/48 , C07D239/50 , C07D251/52 , C07D473/06 , C07D473/18 , C07D473/40 , C07D487/04 , Y10S514/922
摘要： The present invention provides certain novel nitro or nitroso substituted benzyloxy pyrimidines useful as AGT inactivators. An example of such a pyrimidine is a compound of the formula ##STR1## wherein R.sub.1, is NO.sub.2 or NO, and R.sub.2 is hydrogen, halo, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 hydroxyalkyl, thiol, C.sub.1 -C.sub.4 alkythio, trifluoromethoxy, oxymethanesulfonyl, oxytrifluoromethanesulfonyl, or C.sub.1 -C.sub.4 oxyacyl. The present invention further provides pharmaceutical compositions comprising these compounds, and a method of enhancing the chemotherapeutic treatment of tumor cells in a mammal with an antineoplastic alkylating agent which causes cytotoxic lesions at the O.sup.6 -position of guanine.
摘要翻译：本发明提供了可用作AGT灭活剂的某些新的硝基或亚硝基取代的苄氧基嘧啶。这种嘧啶的实例是下式的化合物，其中R1是NO2或NO，R2是氢，卤素，C1-C4烷基，C1-C4羟烷基，硫醇，C1-C4链炔基，三氟甲氧基，羟甲磺酰基，三氟甲磺酰基，或C 1 -C 4氧酰基。本发明进一步提供了包含这些化合物的药物组合物，以及一种增强哺乳动物肿瘤细胞化学治疗的方法，所述抗肿瘤药物在鸟嘌呤的O6位引起细胞毒性损伤。

12. 发明授权

US08188055B2 Inactivators of O6-alkylguanine-DNA alkyltransferase 有权
标题翻译： O6-烷基鸟嘌呤-DNA烷基转移酶的失活剂
公开(公告)号：US08188055B2
公开(公告)日：2012-05-29
申请号：US12597773
申请日：2008-03-12
申请人： Robert C. Moschel , Matthew Karl Moschel, legal representative , Anthony E. Pegg , Sahar Javanmard , Natalia Loktionova , Gary Pauly
发明人： Robert C. Moschel , Anthony E. Pegg , Sahar Javanmard , Natalia Loktionova , Gary Pauly
IPC分类号： A01N43/04 , A61K31/70 , C07H17/00
CPC分类号： C07H19/16 , C07H19/173
摘要： Disclosed are compounds that are AGT inactivators that include a folate residue, e.g., a compound of formula (I), wherein X1, X2, R1, and R2 are as described herein. Also disclosed is a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier. Also disclosed are methods of enhancing the chemotherapeutic treatment of tumor cells and inactivating AGT in a tumor cell. The methods comprise, inter alia, administering a compound or pharmaceutically acceptable salt of formula (I).
摘要翻译：公开的是包含叶酸残基的AGT灭活剂的化合物，例如式（I）化合物，其中X 1，X 2，R 1和R 2如本文所述。还公开了包含本发明化合物和药学上可接受的载体的药物组合物。还公开了增强肿瘤细胞的化学治疗和灭活肿瘤细胞中AGT的方法。所述方法特别包括施用式（I）的化合物或药学上可接受的盐。

13. 发明授权

US07825096B2 O6-alkylguanine-DNA alkyltransferase inactivators and beta-glucuronidase cleavable prodrugs 失效
标题翻译： O6-烷基鸟嘌呤-DNA烷基转移酶灭活酶和β-葡糖苷酸酶可切割前药
公开(公告)号：US07825096B2
公开(公告)日：2010-11-02
申请号：US11683310
申请日：2007-03-07
申请人： Robert C. Moschel , Matthew Karl Moschel, legal representative , Natalia A. Loktionova , Anthony E. Pegg , Gary T. Pauly
发明人： Robert C. Moschel , Natalia A. Loktionova , Anthony E. Pegg , Gary T. Pauly
IPC分类号： A01N43/04 , A61K31/70
CPC分类号： C07D473/18
摘要： Disclosed are prodrugs of inactivators of O6-alkylguanine-DNA alkyltransferase (AGT). The prodrugs are cleavable by the β-glucuronidase enzyme, which is either administered to the patient or produced by necrotic tumor cells. The prodrugs are represented by the formula A-B-C, wherein A is a glucuronosyl residue linked through its 1-oxygen to the phenyl ring of B; B is a benzyloxycarbonyl group, optionally ring-substituted with one or more electron withdrawing groups; and C is an inactivator of AGT, e.g., a substituted or unsubstituted O6-benzylguanine or O6-benzyl-2′-deoxyguanosine. Also disclosed are additional inactivators of AGT, pharmaceutical compositions comprising an inactivator or prodrug and a pharmaceutically acceptable carrier, and a method of use of the inactivator or prodrug in enhancing the chemotherapeutic treatment of tumor cells in a mammal, e.g., a human, with an antineoplastic alkylating agent that causes cytotoxic lesions at the O6-position of guanine.
摘要翻译：公开了O6-烷基鸟嘌呤-DNA烷基转移酶（AGT）的灭活剂的前药。前药可以被葡萄糖醛酸酶酶切割，其可以施用于患者或由坏死的肿瘤细胞产生。前药由式A-B-C表示，其中A是通过其1-氧连接到B的苯环的葡萄糖醛酸残基; B是一个苄氧基羰基，任选被一个或多个吸电子基团取代; 和C是AGT的灭活剂，例如取代或未取代的O6-苄基鸟嘌呤或O6-苄基-2'-脱氧鸟苷。还公开了AGT的额外灭活剂，包含灭活剂或前药和药学上可接受的载体的药物组合物，以及使用灭活剂或前药在增强哺乳动物（例如人）中的肿瘤细胞的化学治疗治疗中的方法，其中在鸟嘌呤的O6位引起细胞毒性损伤的抗肿瘤性烷化剂。

14. 发明授权

US06436945B2 Substituted O6-benzyl-8-aza-guanines 失效
标题翻译：取代的O6-苄基-8-氮杂 - 鸟嘌呤
公开(公告)号：US06436945B2
公开(公告)日：2002-08-20
申请号：US09928410
申请日：2001-08-14
申请人： Robert C. Moschel , Anthony E. Pegg , M. Eileen Dolan , Mi-Young Chae
发明人： Robert C. Moschel , Anthony E. Pegg , M. Eileen Dolan , Mi-Young Chae
IPC分类号： C07D48704
CPC分类号： C07D239/47 , C07D239/48 , C07D239/50 , C07D251/52 , C07D473/06 , C07D473/18 , C07D473/40 , C07D487/04 , Y10S514/922
摘要： The present invention provides AGT inactivating compounds, for example, substituted O6-benzyl-8-aza-guanines of the formula wherein R, for example, is pivaloyloxymethyl as well as pharmaceutical compositions comprising such compounds along with a pharmaceutically acceptable carrier. The present invention further provides a method of enhancing the chemotherapeutic treatment of tumor cells in a mammal with an antineoplastic alkylating agent which causes cytotoxic lesions at the O6-position of guanine, by administering to a mammal an effective amount of one of the aforesaid compounds, and administering to the mammal an effective amount of an antineoplastic alkylating agent which causes cytotoxic lesions at the O6-position of guanine.
摘要翻译：本发明提供了AGT灭活化合物，例如式R的取代的O6-苄基-8-氮杂 - 鸟嘌呤，例如，新戊酰氧基甲基以及包含这些化合物以及药学上可接受的载体的药物组合物。本发明还提供了通过向哺乳动物施用有效量的上述化合物之一来增强哺乳动物中肿瘤细胞的化学治疗方法，所述抗肿瘤烷化剂通过在鸟嘌呤的O6位引起细胞毒性损伤，并向哺乳动物施用有效量的在鸟嘌呤的O6位引起细胞毒性病变的抗肿瘤性烷化剂。

15. 发明授权

US5525606A Substituted 06-benzylguanines and 6(4)-benzyloxypyrimidines 失效
标题翻译：取代的06-苄基胍和6（4） - 苄氧基嘧啶
公开(公告)号：US5525606A
公开(公告)日：1996-06-11
申请号：US283953
申请日：1994-08-01
申请人： Robert C. Moschel , Anthony E. Pegg , M. Eileen Dolan , Mi-Young Chae
发明人： Robert C. Moschel , Anthony E. Pegg , M. Eileen Dolan , Mi-Young Chae
IPC分类号： A61K31/505 , A61K31/52 , A61K31/522 , A61K31/53 , A61P35/00 , A61P43/00 , C07D239/46 , C07D239/47 , C07D239/48 , C07D239/50 , C07D251/52 , C07D473/06 , C07D473/18 , C07D473/40 , C07D487/04 , C07D473/04
CPC分类号： C07D239/47 , C07D239/48 , C07D239/50 , C07D251/52 , C07D473/06 , C07D473/18 , C07D473/40 , C07D487/04 , Y10S514/922
摘要： The present invention provides 8-substituted O.sup.6 -benzylguanines of the formula ##STR1## wherein R.sub.1, R.sub.2, and R.sub.3 are as defined in the specification, and 4(6)-substituted 2-amino-5-nitro-6(4)-benzyloxypyrimidine, and 4(6)-substituted 2-amino-5-nitroso-6(4)-benzyloxypyrimidine derivatives which have been found to be effective AGT inactivators, as well as pharmaceutical compositions comprising such derivatives along with a pharmaceutically acceptable carrier. The present invention further provides a method of enhancing the chemotherapeutic treatment of tumor cells in a mammal with an antineoplastic alkylating agent which causes cytotoxic lesions at the O.sup.6 -position of guanine, by administering to a mammal an effective amount of one of the aforesaid derivatives, 2,4-diamino-6-benzyloxy-s-triazine, 5-substituted 2,4-diamino-6-benzyloxypyrimidines, or 8-aza-O.sup.6 -benzylguanine, and administering to the mammal an effective amount of an antineoplastic alkylating agent which causes cytotoxic lesions at the O.sup.6 -position of guanine.
摘要翻译：本发明提供了式（I）的8-取代的O6-苄基胍，其中R1，R2和R3如说明书中所定义，和4（6） - 取代的2-氨基-5-硝基-6（4） - 苄氧基嘧啶和已被发现是有效的AGT灭活剂的4（6） - 取代的2-氨基-5-亚硝基-6（4） - 苄氧基嘧啶衍生物，以及包含这些衍生物以及药学上可接受的载体的药物组合物。本发明还提供了一种通过向哺乳动物施用有效量的上述衍生物之一来增强哺乳动物中肿瘤细胞的化学治疗方法，所述抗肿瘤烷化剂通过在鸟嘌呤的O6位引起细胞毒性损伤， 2,4-二氨基-6-苄氧基-s-三嗪，5-取代的2,4-二氨基-6-苄氧基嘧啶或8-氮杂-O6-苄基鸟嘌呤，并向哺乳动物施用有效量的抗肿瘤烷化剂，在鸟嘌呤的O6位引起细胞毒性病变。

16. 发明授权

US5358952A O.sup.6 -substituted guanine compounds and methods for depleting O.sup.6 -alkylguanine-DNA alkyltransferase levels 失效
标题翻译： O6取代的鸟嘌呤化合物和用于消耗O6-烷基鸟嘌呤-DNA烷基转移酶水平的方法
公开(公告)号：US5358952A
公开(公告)日：1994-10-25
申请号：US805634
申请日：1991-12-12
申请人： Robert C. Moschel , M. Eileen Dolan , Anthony E. Pegg
发明人： Robert C. Moschel , M. Eileen Dolan , Anthony E. Pegg
IPC分类号： C07H19/16 , A61K31/32 , C07D473/18
CPC分类号： C07H19/16
摘要： O.sup.6 -substituted guanine compounds of the formula ##STR1## wherein R is a benzyl group or a substituted benzyl group, cause a depletion of O.sup.6 -alkylguanine-DNA alkyltransferase (AGT) activity in mammalian cells. These compounds may be administered to a host so as to reduce AGT levels in tumor cells of the host in order to increase host responsiveness to anti-neoplastic alkylating agents, including chloroethylating agents, such as chloroethylnitrosoureas, for chemotherapeutic treatment of a number of neoplasms.
摘要翻译：其中R是苄基或取代的苄基的式“IMAGE”的O6取代的鸟嘌呤化合物导致哺乳动物细胞中O6-烷基鸟嘌呤-DNA烷基转移酶（AGT）活性的消耗。这些化合物可以施用于宿主以便降低宿主的肿瘤细胞中的AGT水平，以增加宿主对抗肿瘤性烷化剂（包括氯乙基化剂如氯乙基亚硝基脲）的反应性，用于许多肿瘤的化学治疗。

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