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1. 发明授权

US06333331B1 Substituted O6-benzylguanines 失效
标题翻译：取代的O6-苄基胍
公开(公告)号：US06333331B1
公开(公告)日：2001-12-25
申请号：US09333047
申请日：1999-06-15
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： C07D47318
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 such as substituted O6-benzylguanines of the formula 7- or 9-substituted 8-aza-O6-benzylguanines, 7,8-disubstituted O6-benzylguanines, 7,9-disubstituted O6-benzylguanines, 4(6)-substituted 2-amino-5-nitro-6(4)-benzyloxypyrimidines, and 4(6)-substituted 2-amino-5-nitroso-6(4)-benzyloxypyrimidines, 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, 2,4-diamino-6-benzyloxy-s-triazine, 5-substituted 2,4-diamino-6-benzyloxypyrimidines, or 8-aza-O6-benzylguanine, 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AGT灭活化合物，例如式7-或9-取代的8-氮杂-O6-苄基胍的取代的O6-苄基胍，7,8-二取代的O6-苄基胍，7,9-二取代的O6-苄基胍，4（6 ） - 取代的2-氨基-5-硝基-6（4） - 苄氧基嘧啶和4（6） - 取代的2-氨基-5-亚硝基-6（4） - 苄氧基嘧啶，以及包含这些化合物的药物组合物药学上可接受的载体。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， 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。

2. 发明授权

US06303604B1 Pharmaceutical composition comprising 2,4-diamino-6-benzyloxy-s-triazine and inactivation of O6-alkylguanine-DNA-alkyltransferase 失效
标题翻译：包含2,4-二氨基-6-苄氧基-s-三嗪和O6-烷基鸟嘌呤-DNA-烷基转移酶失活的药物组合物
公开(公告)号：US06303604B1
公开(公告)日：2001-10-16
申请号：US09590187
申请日：2000-06-09
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： A61K3153
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 O6-benzylguanine, 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 O6-position of quanine, 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-O6-benzylguanine, 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8-取代的O6-苄基鸟嘌呤，4（6） - 取代的2-氨基-5-硝基-6（4） - 苄氧基嘧啶和4（6） - 取代的2-氨基-5-亚硝基-6（4 已经被发现是有效的AGT灭活剂的苄氧基嘧啶衍生物，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。本发明进一步提供一种通过向哺乳动物施用有效量的上述衍生物之一，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对化学治疗性治疗药物的抗肿瘤烷化剂的方法，所述抗肿瘤性烷化剂通过在喹诺酮的O6位引起细胞毒性病变， 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。

3. 发明授权

US5916894A 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：US5916894A
公开(公告)日：1999-06-29
申请号：US927846
申请日：1997-09-11
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 , 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 -benzylguanine derivatives which have been found to be effective AGT inactivators, as well as pharmaceutical compositions comprising such derivatives along with a pharmaceutically acceptable carrier. Thus, for example, the present invention provides a compound of the formula ##STR1## wherein R.sub.1 is a substituent selected from the group consisting of amino, hydroxy, C.sub.1 -C.sub.4 alkylamino, C.sub.1 -C.sub.4 dialkylamino, and C.sub.1 -C.sub.4 acylamino, R.sub.2 is a substituent selected from the group consisting of C.sub.1 -C.sub.4 aminoalkyl, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 dialkylamino alkyl, and C.sub.1 -C.sub.4 pivaloylalkyl, and R.sub.3 is a C.sub.1 -C.sub.4 alkyl. 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 lessons at the O.sup.6 -position of guanine by administering to a mammal an effective amount of one of the aforesaid derivatives 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：本发明提供已被发现是有效的AGT灭活剂的8-取代的O6-苄基鸟嘌呤衍生物，以及包含这种衍生物以及药学上可接受的载体的药物组合物。因此，例如，本发明提供下式化合物其中R 1是选自氨基，羟基，C 1 -C 4烷基氨基，C 1 -C 4二烷基氨基和C 1 -C 4酰基氨基的取代基，R 2是选择的取代基由C 1 -C 4氨基烷基，C 1 -C 4烷基，C 1 -C 4二烷基氨基烷基和C 1 -C 4新戊酰基烷基组成的组，R 3为C 1 -C 4烷基。本发明进一步提供一种通过向哺乳动物施用有效量的上述衍生物之一并施用有效量的上述衍生物之一来增强哺乳动物中具有抗肿瘤性烷化剂的肿瘤细胞的化学治疗方法，所述抗肿瘤烷化剂在鸟嘌呤的O6位上引起细胞毒性课程向哺乳动物施用有效量的在鸟嘌呤的O6位上引起细胞毒性损伤的抗肿瘤性烷化剂。

4. 发明授权

US5691307A O.sup.6 -substituted guanine compositions and methods for depleting O.sup.6 失效
标题翻译： O6取代的鸟嘌呤组合物和用于消耗O6-烷基鸟嘌呤-DNA烷基转移酶的方法
公开(公告)号：US5691307A
公开(公告)日：1997-11-25
申请号：US255190
申请日：1994-06-07
申请人： Robert C. Moschel , M. Eileen Dolan , Anthony E. Pegg , Mark G. McDougall , Mi-Young Chae
发明人： Robert C. Moschel , M. Eileen Dolan , Anthony E. Pegg , Mark G. McDougall , Mi-Young Chae
IPC分类号： C07H19/16 , A61K31/54 , A61K31/52 , A61K31/535 , A61K31/70 , C07D403/02 , C07D403/12 , C07D473/18
CPC分类号： C07H19/16 , Y10S514/95
摘要： Novel O.sup.6 -substituted guanine compounds and pharmaceutical compositions thereof are useful for effectively reducing O.sup.6 -alkylguanine-DNA alkyltransferase (AGT). The novel compounds are useful for treating tumors and when used with anti-neoplastic alkylating agents enhance the chemotherapeutic treatment of tumor cells in a host.
摘要翻译：新型O6-取代的鸟嘌呤化合物及其药物组合物可用于有效还原O6-烷基鸟嘌呤-DNA烷基转移酶（AGT）。新型化合物可用于治疗肿瘤，并且当与抗肿瘤烷化剂一起使用时，可增强宿主中肿瘤细胞的化学治疗。

5. 发明申请

US20100204172A1 INACTIVATORS OF O6-ALKYLGUANINE-DNA ALKYLTRANSFERASE 有权
标题翻译： O6-谷氨酰胺-DNA烷基转移酶的灭活剂
公开(公告)号：US20100204172A1
公开(公告)日：2010-08-12
申请号：US12597773
申请日：2008-03-12
申请人： Robert C. Moschel , 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： A61K31/708 , C07H19/16 , C12N9/99 , C07D475/00 , A61K31/522 , A61P35/00
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。

6. 发明授权

US06172070B2 Substituted O6-benzyl-8-aza-guanines and 6(4)-benzyloxypyrimidines 失效
标题翻译：取代的O6-苄基-8-氮杂 - 鸟嘌呤和6（4） - 苄氧基嘧啶
公开(公告)号：US06172070B2
公开(公告)日：2001-01-09
申请号：US09318238
申请日：1999-05-25
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： A01N4354
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 O6-benzylguanine, 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 O6-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-O6-benzylguanine, 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8-取代的O6-苄基鸟嘌呤，4（6） - 取代的2-氨基-5-硝基-6（4） - 苄氧基嘧啶和4（6） - 取代的2-氨基-5-亚硝基-6（4 已经被发现是有效的AGT灭活剂的苄氧基嘧啶衍生物，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。

7. 发明授权

US5958932A Substitutes O.sup.6 -benzylguanines, compositions, and methods of using same 失效
标题翻译：代替O6-苄基胍，组合物及其使用方法
公开(公告)号：US5958932A
公开(公告)日：1999-09-28
申请号：US849223
申请日：1997-04-28
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 AGT inactivating compounds such as substituted O.sup.6 -benzylguanines of the formula ##STR1## wherein, for example, R.sub.1 is amino, hydroxy, or alkylamino, R.sub.2 is aminoalkyl, hydroxyalkyl, or alkylaminoalkyl, and R.sub.3 is halo, hydroxyalkyl, thiol or alkylthio, as well as pharmaceutical compositions comprising such compounds and 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 comprising 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 O.sup.6 -position of guanine.
摘要翻译： PCT No.PCT / US95 / 09702 Sec。 371日期1997年04月28日 102（e）日期1997年4月28日PCT提交1995年7月31日PCT公布。出版物WO96 / 04281 日本1996年2月15日本发明提供AGT灭活化合物，例如下式的取代的O6-苄基胍胺，其中例如R1是氨基，羟基或烷基氨基，R2是氨基烷基，羟基烷基或烷基氨基烷基，R3是卤素，，硫醇或烷硫基，以及包含这些化合物和药学上可接受的载体的药物组合物。本发明进一步提供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位引起细胞毒性病变，包括向哺乳动物施用有效量的上述化合物之一并施用向哺乳动物施用有效量的在鸟嘌呤的O6位上引起细胞毒性损伤的抗肿瘤性烷化剂。

8. 发明授权

US5352669A O.sup.6 -benzylated guanine, guanosine and 2'-deoxyguanosine compounds possessing O.sup.6 -alkylguanine-DNA alkyltransferase depleting activity 失效
标题翻译： O6-苄基化鸟嘌呤，鸟苷和具有O6-烷基鸟嘌呤-DNA烷基转移酶消耗活性的2'-脱氧鸟苷化合物
公开(公告)号：US5352669A
公开(公告)日：1994-10-04
申请号：US616913
申请日：1990-11-21
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： A61K31/52 , A61K31/522 , A61K31/70 , A61K31/7042 , A61K31/7052 , A61K31/7064 , A61K31/7076 , A61K31/708 , A61K45/06 , A61P35/00 , A61P43/00 , C07D473/18 , C07H19/073 , C07H19/16 , C07H19/167 , C07H19/173 , C07H17/02
CPC分类号： C07H19/16
摘要： O.sup.6 -Benzylated guanine guanosine and 2'-deoxyguanosine compounds of the formula ##STR1## wherein Z is hydrogen, ##STR2## and 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： O6-苯甲酰鸟嘌呤鸟苷和2'-脱氧鸟苷化合物，其中Z是氢，IMA和R是苄基或取代的苄基，导致O6-烷基鸟嘌呤-DNA烷基转移酶（AGT）的消耗，哺乳动物细胞中的活性。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。

9. 发明授权

US5091430A 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：US5091430A
公开(公告)日：1992-02-25
申请号：US492468
申请日：1990-03-13
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
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。

10. 发明授权

US6060458A Oligodeoxyribonucleotides comprising O.sup.6 -benzylguanine and their use 失效
标题翻译：包含O6-苄基鸟嘌呤的寡脱氧核糖核苷酸及其用途
公开(公告)号：US6060458A
公开(公告)日：2000-05-09
申请号：US23726
申请日：1998-02-13
申请人： Robert C. Moschel , Gary T. Pauly , Anthony E. Pegg , M. Eileen Dolan
发明人： Robert C. Moschel , Gary T. Pauly , Anthony E. Pegg , M. Eileen Dolan
IPC分类号： C07H21/04 , A61K31/175 , A61K31/7115 , A61P35/00 , A61P43/00 , C07H21/00 , A61K31/70 , C12N5/06
CPC分类号： C07H21/00
摘要： The present invention provides a single-stranded oligodeoxyribonucleotide, which (i) comprises from about 5 to 11 bases, at least one of which is a substituted or an unsubstituted O.sup.6 -benzylguanine, and (ii) inactivates human AGT. The present invention also provides a single-stranded oligodeoxyribonucleotide, which can inactivate a mutant human AGT, which either is not inactivated by O.sup.6 -benzylguanine or is less inactivated by O.sup.6 -benzylguanine than by said single-stranded oligodeoxyribonucleotide. A phosphate of the single-stranded oligodeoxyribonucleotide can be replaced by a methylphosphonate or a phosphorothioate. The present invention also provides a composition comprising such an oligodeoxyribonucleotide. In addition, the present invention provides a method of enhancing the effect of an antineoplastic alkylating agent, which alkylates the O.sup.6 position of guanine residues in DNA, in the chemotherapeutic treatment of cancer in a mammal, which method comprises the co-administration to the mammal of a cancer-treatment effective amount of an antineoplastic alkylating agent and a chemotherapeutic treatment-enhancing amount of a present inventive oligodeoxyribonucleotide or composition thereof.
摘要翻译：本发明提供了单链寡脱氧核糖核苷酸，其（i）包含约5至11个碱基，其中至少一个是取代或未取代的O6-苄基鸟嘌呤，和（ii）使人AGT失活。本发明还提供了一种单链寡脱氧核糖核苷酸，其可以灭活突变型人AGT，其不被O6-苄基鸟嘌呤灭活，或者被O6-苄基鸟嘌呤灭活而不是所述单链寡脱氧核糖核苷酸失活。单链寡脱氧核糖核苷酸的磷酸酯可被甲基膦酸酯或硫代磷酸酯代替。本发明还提供了包含这种寡脱氧核糖核苷酸的组合物。此外，本发明提供了一种在哺乳动物的癌症的化学治疗中增强抗肿瘤性烷化剂的作用的方法，所述抗肿瘤性烷化剂使DNA中的鸟嘌呤残基的O6位置烷基化，该方法包括向哺乳动物共同施用癌症治疗有效量的抗肿瘤性烷化剂和化学治疗增强量的本发明的寡脱氧核糖核苷酸或其组合物。

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