公开(公告)号：US06310082B1

公开(公告)日：2001-10-30

申请号：US09594776

申请日：2000-06-16

申请人： Roger J Griffin ,  Alan H Calvert ,  Nicola J Curtin ,  David R Newell ,  Bernard T Golding

发明人： Roger J Griffin ,  Alan H Calvert ,  Nicola J Curtin ,  David R Newell ,  Bernard T Golding

IPC分类号： A61K314184

CPC分类号： C07D235/06 ,  A61K31/4184 ,  A61K31/675 ,  C07D235/08 ,  C07D235/10 ,  C07D235/12 ,  C07D235/14 ,  C07D235/16 ,  C07D235/18

摘要： Benzimidazole-4-carboxamide compounds (I) which can act as potent inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase or PARP enzyme (EC 2.4.2.30), and which thereby can provide useful therapeutic compounds for use in conjunction with DNA-damaging cytotoxic drugs or radiotherapy to potentiate the effects of the latter. In formula (I), R and R′ may each be selected independently from hydrogen, alkyl, hydroxyalkyl (e.g. CH2CH2OH), acyl (e.g. acetyl or benzoyl) or an optionally substituted aryl (e.g. phenyl) or aralkyl (e.g. benzyl or carboxybenzyl) group. R is generally a substituted phenyl group in the most preferred compounds. The compounds may also be used in the form of pharmaceutically acceptable salts or pro-drugs.

摘要翻译： 苯并咪唑-4-甲酰胺化合物（I），其可以作为DNA修复酶聚（ADP-核糖）聚合酶或PARP酶（EC 2.4.2.30）的有效抑制剂，由此可以提供有用的治疗化合物，与 DNA损伤性细胞毒性药物或放射治疗以增强后者的作用。 在式（I）中，R和R'可各自独立地选自氢，烷基，羟基烷基（例如CH 2 CH 2 OH），酰基（例如乙酰基或苯甲酰基）或任选取代的芳基（例如苯基）或芳烷基（例如苄基或羧基苄基） 组。 R通常是最优选的化合物中的取代的苯基。 化合物也可以以药学上可接受的盐或前药的形式使用。

公开(公告)号：US06677345B1

公开(公告)日：2004-01-13

申请号：US09671676

申请日：2000-09-28

申请人： Roger J Griffin ,  Alan H Calvert ,  Nicola J Curtin ,  David R Newell ,  Bernard T Golding ,  Jane A Endicott ,  Martin E M Noble ,  Francis T Boyle ,  Philip J Jewsbury

发明人： Roger J Griffin ,  Alan H Calvert ,  Nicola J Curtin ,  David R Newell ,  Bernard T Golding ,  Jane A Endicott ,  Martin E M Noble ,  Francis T Boyle ,  Philip J Jewsbury

IPC分类号： A61K31505

CPC分类号： C07D239/48 ,  A61K31/505 ,  C07D239/02 ,  C07D239/50 ,  C07H19/167

摘要： A range is disclosed of pyrimidine derivatives (I) which can act as inhibitors of cyclin dependent kinases (CDK's) and which thereby can provide useful therapeutic compounds for use in treatment of tumours or other cell proliferation disorders. The compounds of this invention bind to CDK molecules in a manner that appears to differ from that of known CDK inhibitors such as olomoucine and roscovitine. In formula (I), X is O, S or CHRx where Rx is H or C1-4 alkyl; D is H or NZ1Z2 where Z1 and Z2 are each independently H, C1-4 alkyl, C1-4 hydroxyalkyl, optionally substituted aryl or optionally substituted aralkyl; A is selected from H, C1-4 alkyl, C1-4 alkoxy, hydroxy, CH2(CH2)nOH (n=1-4), and NRa1Ra2 where Ra1 and Ra2 are each independently H or C1-4 alkyl; Y is or includes an optionally substituted 4- to 8-membered carbocyclic or heterocyclic ring; D′ is H or NZ3Z4 where Z3 and Z4 are each independently H, C1-4 alkyl, C1-4 hydroxyalkyl, optionally substituted aryl or optionally-substituted aralkyl; E is selected from NO, NO2, N═N—Ar where Ar is an optionally substituted aryl or optionally substituted aralkyl, NRe1Re2 or Nre1Nre2Re3 (Re1, Re2 and Re3 each being independently H, C1-4 alkyl, C1-4 hydroxyalkyl, an optionally substituted aryl or an optionally substituted aralkyl), C(Re)═U (Re being hydrogen, C1-4 alkyl or substituted alkyl, e.g. hydroxyalkyl, or an unsubstituted or substituted aryl or aralkyl, e.g. benzyl, and U being selected from O, Nre′, NORe′ and N—NRe′Re″ where Re′ and Re″ are each independently H, C1-4 alkyl or CONH2), T, CH2T, CHT2 and CT3, where T is a halide I, Br, Cl or F.

摘要翻译： 公开了可以作为细胞周期蛋白依赖性激酶（CDK's）抑制剂的嘧啶衍生物（I）的范围，由此可以提供用于治疗肿瘤或其它细胞增殖病症的有用的治疗化合物。 本发明的化合物以与已知的CDK抑制剂如奥洛莫斯和罗斯考维胺似乎不同的方式结合CDK分子。 在式（I）中，X是O，S或CHR x，其中R x是H或C 1-4烷基; D是H或NZ 1 Z 2，其中Z 1和Z 2各自独立地为H，C 1-4烷基，C 1-4羟基烷基，任选取代的芳基或任选取代的芳烷基; A选自H，C 1-4烷基，C 1-4烷氧基，羟基，CH 2（CH 2）n OH（n = 1-4）和NR a R a 2，其中R 1a和R 2a各自独立地为H或C 1-4烷基; Y是或包括任选取代的4-至8-元碳环或杂环; D'是H或NZ 3 Z 4，其中Z 3和Z 4各自独立地为H，C 1-4烷基，C 1-4羟基烷基，任选取代的芳基或任选取代的芳烷基; E选自NO，NO2，N = N-Ar，其中Ar是任选取代的芳基或任选取代的芳烷基，NRe1Re2或Nre1Nre2Re3（Re1，Re2和Re3各自独立地为H，C1-4烷基，C1-4羟基烷基， 任选取代的芳基或任选取代的芳烷基），C（Re）= U（Re为氢，C 1-4烷基或取代烷基，例如羟烷基，或未取代或取代的芳基或芳烷基，例如苄基，U选自O ，Nre'，NORe'和N-NRe'Re“，其中Re'和Re'各自独立地为H，C 1-4烷基或CONH 2），T，CH 2 T，CHT 2和CT 3，其中T为卤化物I，Br ，Cl或F.

公开(公告)号：US06303618B1

公开(公告)日：2001-10-16

申请号：US09481708

申请日：2000-01-12

申请人： Roger J Griffin ,  Alan H Calvert ,  Nicola J Curtin ,  David R Newell ,  Bernard T Golding ,  Jane A Endicott ,  Martin E M Noble ,  Francis T Boyle ,  Philip J Jewsbury

发明人： Roger J Griffin ,  Alan H Calvert ,  Nicola J Curtin ,  David R Newell ,  Bernard T Golding ,  Jane A Endicott ,  Martin E M Noble ,  Francis T Boyle ,  Philip J Jewsbury

IPC分类号： A61K3152

CPC分类号： C07H15/26 ,  C07D473/18 ,  C07D473/30 ,  C07D473/40

摘要： Method of treating a tumour or other cell proliferation disorder which comprises administering an effective amount of a purine compound which inhibits cyclic dependent kinase activity. Novel purine compounds and pharmaceutical compositions are also disclosed.

摘要翻译： 治疗肿瘤或其他细胞增殖病症的方法，其包括施用有效量的抑制环状依赖性激酶活性的嘌呤化合物。 还公开了新的嘌呤化合物和药物组合物。

公开(公告)号：US06297250B1

公开(公告)日：2001-10-02

申请号：US09410742

申请日：1999-10-01

申请人： Roger J Griffin ,  Nicola J Curtin ,  Bernard T Golding ,  Alan H. Calvert ,  David R. Newell

发明人： Roger J Griffin ,  Nicola J Curtin ,  Bernard T Golding ,  Alan H. Calvert ,  David R. Newell

IPC分类号： A61K31519

CPC分类号： C07D487/04

摘要： A range of dipyridamole analogues useful for inhibiting transport of nucleosides or purines across cell membranes, thereby to potentiate the activity of various cytotoxic antitumor drugs, is disclosed. These analogues comprise compounds having general structural formula (I) or pharmaceutically acceptable salts thereof; wherein R1 is chloro and R3 is diethanolamino, or R1 and R3 are identical and are selected from allyl, halo, diethanolamino, solketalo and a group having the formula: —O—Rz or —NHRz, Rz being selected from alkyl, hydroxyalkyl, alkoxyalkyl, dialkoxyalkyl and 2-oxo-alkyl wherein the or each alkyl and/or alkoxy moiety has less than six carbon atoms, and R2 and R4 are identical and are selected from piperidino, N-tetrahydroisoquinolyl, and a benzylamino group having structural formula (II) wherein R5 is H, or an optionally substituted alkyl or benzyl group, and R6 and R7 represent H or optional substituents in the aromatic nucleus selected from halo, alkyl, alkoxy, hydroxy, trifluoromethyl, azido, cyano, nitro, carboxyl, carboxylic ester, amino or a substituted amino NRxRy where Rx and Ry each represent hydrogen or alkyl, subject to the provisos that (a) if R1 and R3 are both chloro or diethanolamino, R2 and R4 are not both benzylamino, i.e. R2 and R4 do not correspond to structure II with R5, R6 and R7 each being hydrogen, and (b) if R2 and R4 are both piperidino, R1 and R3 are not both chloro, diethanolamino, solketalo or (2,3-dimethoxy)propoxy

摘要翻译： 公开了一系列可用于抑制核苷或嘌呤跨细胞膜转运的双嘧达莫类似物，从而增强各种细胞毒性抗肿瘤药物的活性。 这些类似物包括具有通式结构式（I）的化合物或其药学上可接受的盐; 其中R 1是氯并且R 3是二乙醇氨基，或者R 1和R 3是相同的并且选自烯丙基，卤素，二乙醇氨基，溶剂酮和具有下式的基团：-O-Rz或-NHRz，Rz选自烷基，羟基烷基，烷氧基烷基 ，二烷氧基烷基和2-氧代 - 烷基，其中烷基和/或烷氧基部分具有少于6个碳原子，并且R 2和R 4相同，并且选自具有结构式（II）的哌啶子基，N-四氢异喹啉基和苄基氨基 ）其中R 5是H或任选取代的烷基或苄基，R 6和R 7在选自卤素，烷基，烷氧基，羟基，三氟甲基，叠氮基，氰基，硝基，羧基，羧酸酯的芳香核中代表H或任选的取代基 ，氨基或取代氨基NRxRy，其中Rx和Ry各自表示氢或烷基，条件是（a）如果R1和R3都是氯或二乙醇氨基，则R2和R4不都是苄氨基，即R2和R4不对应 结构II与 R5，R6和R7各自为氢，和（b）如果R2和R4都是哌啶子基，则R1和R3不同时为氯，二乙醇氨基，溶剂酮或（2,3-二甲氧基）丙氧基

公开(公告)号：US4564616A

公开(公告)日：1986-01-14

申请号：US591566

申请日：1984-03-20

申请人： Terence R. Jones ,  Kenneth R. Harrap ,  Alan H. Calvert

发明人： Terence R. Jones ,  Kenneth R. Harrap ,  Alan H. Calvert

IPC分类号： C07D205/04 ,  C07D239/95 ,  A61K31/505 ,  C07D239/84

CPC分类号： C07D239/95 ,  C07D205/04

摘要： Quinazoline derivatives of formula: ##STR1## wherein R represents: (1) a straight or branched chain unsaturated hydrocarbon group, or(2) a straight or branched chain saturated or unsaturated hydrocarbon group which is substituted by at least one: heteroatom, the or each heteroatom being halogeno when R is a C.sub.1 hydrocarbon group; or saturated carbocyclic group; or group containing at least one heteroatom, the or each heteroatom being O, N or S when R contains a cyclic group; andn is O or an integer of 1-4;X or, when n is an integer of at least 2, each X independently, represents a halogeno, C.sub.1 -C.sub.4 alkyl, aryl or aralkyl group or a group including at least one heteroatom; andY represents a group of formula: ##STR2## wherein m.gtoreq.1 (poly-L-glutamates); and the pharmaceutically acceptable salts and esters thereof, which are suitable as anti-cancer agents.

公开(公告)号：US08258175B2

公开(公告)日：2012-09-04

申请号：US11574531

申请日：2005-08-26

申请人： Hendrika Maria Gerarda Willems ,  Per Kallblad ,  Ian Robert Hardcastle ,  Roger John Griffin ,  Bernard Thomas Golding ,  John Lunec ,  Martin E. M. Noble ,  David R. Newell ,  Alan H. Calvert

发明人： Hendrika Maria Gerarda Willems ,  Per Kallblad ,  Ian Robert Hardcastle ,  Roger John Griffin ,  Bernard Thomas Golding ,  John Lunec ,  Martin E. M. Noble ,  David R. Newell ,  Alan H. Calvert

IPC分类号： A61K31/4015 ,  C07D209/46

CPC分类号： C07D209/50 ,  C07D209/48 ,  C07D401/12 ,  C07D403/06 ,  C07D403/12 ,  C07D405/06 ,  C07D405/12

摘要： A compound of formula or a prodrug and/or a pharmaceutically acceptable salt thereof, wherein X is O, N or S; R1 is hydrogen, halo, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylamine, alkoxy, substituted or unsubstituted aryl or heteroaryl, and substituted or unsubstituted aralkyl or heteroaralkyl; R2 is hydrogen, halo, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted hydroxyalkyl substituted or unsubstituted alkylamine, alkoxy, substituted or unsubstituted aryl or heteroaryl, and substituted or unsubstituted aralkyl or heteroalkyl; R3 is hydrogen, halo, hydroxy, substituted or unsubstituted alloy substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylamine alkoxy, substituted or unsubstituted aryl or heteroaryl, and substituted or unsubstituted aralkyl or heteroalkyl; and R4-R7, is used to represent groups R4, R5, R6 and R7 which are H, OH, alkyl, alkoxy, alkylamine, hydroxyalkyl, halo, CF3, NH2, NO2, COOH, C═O.

摘要翻译： 式或其前药和/或其药学上可接受的盐的化合物，其中X为O，N或S; 取代或未取代的烷基胺，烷氧基，取代或未取代的芳基或杂芳基，以及取代或未取代的芳烷基或杂芳烷基; R 1为氢，卤素，羟基， R2是氢，卤素，羟基，取代或未取代的烷基，取代或未取代的羟基烷基取代或未取代的烷基胺，烷氧基，取代或未取代的芳基或杂芳基，以及取代或未取代的芳烷基或杂烷基; 取代或未取代的烷基胺烷氧基，取代或未取代的芳基或杂芳基，以及取代或未取代的芳烷基或杂烷基; R 3为氢，卤素，羟基， H，OH，烷基，烷氧基，烷基胺，羟基烷基，卤素，CF 3，NH 2，NO 2，COOH，C = O的基团R 4，R 5，R 6和R 7。

公开(公告)号：US20080261917A1

公开(公告)日：2008-10-23

申请号：US11574531

申请日：2005-08-26

申请人： Hendrika Maria Gerarda Willems ,  Per Kallblad ,  Ian Robert Hardcastle ,  Robert John Griffin ,  Bernard Thomas Golding ,  John Lunec ,  Martin E.M. Noble ,  David R. Newell ,  Alan H. Calvert

发明人： Hendrika Maria Gerarda Willems ,  Per Kallblad ,  Ian Robert Hardcastle ,  Robert John Griffin ,  Bernard Thomas Golding ,  John Lunec ,  Martin E.M. Noble ,  David R. Newell ,  Alan H. Calvert

IPC分类号： A61K31/695 ,  C07D209/44 ,  A61K31/4035 ,  C07D213/02 ,  C07D295/00 ,  A61P35/00 ,  A61K31/496 ,  A61K31/4439 ,  C07D233/54 ,  A61K31/4164

CPC分类号： C07D209/50 ,  C07D209/48 ,  C07D401/12 ,  C07D403/06 ,  C07D403/12 ,  C07D405/06 ,  C07D405/12

摘要： A compound of formula or a prodrug and/or a pharmaceutically acceptable salt thereof, wherein X is O, N or S; R1 is hydrogen, halo, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylamine, alkoxy, substituted or unsubstituted aryl or heteroaryl, and substituted or unsubstituted aralkyl or heteroaralkyl; R2 is hydrogen, halo, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted hydroxyalkyl substituted or unsubstituted alkylamine, alkoxy, substituted or unsubstituted aryl or heteroaryl, and substituted or unsubstituted aralkyl or heteroalkyl; R3 is hydrogen, halo, hydroxy, substituted or unsubstituted alloy substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkylamine alkoxy, substituted or unsubstituted aryl or heteroaryl, and substituted or unsubstituted aralkyl or heteroalkyl; and R4-R7, is used to represent groups R4, R5, R6 and R7 which are H, OH, alkyl, alkoxy, alkylamine, hydroxyalkyl, halo, CF3, NH2, NO2, COOH, C=0.

摘要翻译： 式或其前药和/或其药学上可接受的盐的化合物，其中X为O，N或S; 取代或未取代的烷基，取代或未取代的烷基胺，烷氧基，取代或未经取代的芳基或杂芳基，以及取代或未取代的芳烷基或杂芳烷基; R 1是氢，卤素，羟基， R 2是氢，卤素，羟基，取代或未取代的烷基，取代或未取代的羟基烷基取代或未取代的烷基胺，烷氧基，取代或未取代的芳基或杂芳基，以及取代或未取代的芳烷基或杂烷基; 取代或未取代的烷基烷氧基，取代或未取代的芳基或杂芳基，以及取代或未取代的芳烷基或杂烷基; 和R 4〜R 7，用于表示R 4，R 5，R 5， 6和7是H，OH，烷基，烷氧基，烷基胺，羟基烷基，卤素，CF 3，NH 2， NO 2，COOH，C = 0。

公开(公告)号：US4447608A

公开(公告)日：1984-05-08

申请号：US435215

申请日：1982-10-19

申请人： Terence R. Jones ,  Kenneth R. Harrap ,  Alan H. Calvert

发明人： Terence R. Jones ,  Kenneth R. Harrap ,  Alan H. Calvert

IPC分类号： C07D205/04 ,  C07D239/95 ,  C07D239/84 ,  A61K31/505

CPC分类号： C07D239/95 ,  C07D205/04

摘要： Quinazoline derivatives of formula: ##STR1## wherein R represents: (1) a straight or branched chain unsaturated hydrocarbon group, or(2) a straight or branched chain saturated or unsaturated hydrocarbon group which is substituted by at least one: heteroatom, the or each heteroatom being halogeno when R is a C.sub.1 hydrocarbon group; or saturated carbocyclic group; or group containing at least one heteroatom, the or each heteroatom being O, N or S when R contains a cyclic group; andn is 0 or an integer of 1-4;X or, when n is an integer of at least 2, each X independently, represents a halogeno, C.sub.1 -C.sub.4 alkyl, aryl or aralkyl group or a group including at least one heteroatom; andY represents a group of formula: ##STR2## wherein m.gtoreq.1 (poly-L-glutamates); and the pharmaceutically acceptable salts and esters thereof, which are suitable as anti-cancer agents.

摘要翻译： 式（I）的喹唑啉衍生物其中R表示：（1）直链或支链不饱和烃基，或（2）直链或支链饱和或不饱和烃基，其被至少一个取代：杂原子 当R为C1烃基时，该杂原子或每个杂原子为卤素; 或饱和碳环基团; 或含有至少一个杂原子的基团，当R包含环状基团时，每个杂原子是O，N或S; 并且n为0或1-4的整数; X或当n是至少2的整数时，每个X独立地表示卤代，C 1 -C 4烷基，芳基或芳烷基或包含至少一个杂原子的基团; （a）图像（b）或图像（c）其中m≥1（聚-L-谷氨酸盐）; 和其药学上可接受的盐和酯，其适合作为抗癌剂。