公开(公告)号：US20110245250A1

公开(公告)日：2011-10-06

申请号：US13054960

申请日：2009-07-20

申请人： Simon David Edwards ,  Meriel Ruth Kimberley ,  Richard Edward Armer ,  Nawaz Mohammed Khan

发明人： Simon David Edwards ,  Meriel Ruth Kimberley ,  Richard Edward Armer ,  Nawaz Mohammed Khan

IPC分类号： A61K31/165 ,  C07C237/20 ,  A61K31/198 ,  C07D295/13 ,  A61K31/5375 ,  C07D207/12 ,  A61K31/40 ,  C07D211/06 ,  A61K31/445 ,  C07D213/40 ,  A61K31/4402 ,  A61P25/22 ,  A61P3/00 ,  A61P27/02 ,  A61P9/00 ,  A61P9/06 ,  A61P1/00

CPC分类号： A61K31/165 ,  A61K31/198 ,  A61K31/40 ,  A61K31/4402 ,  A61K31/445 ,  A61K31/5375 ,  A61K45/06 ,  C07C237/20 ,  C07D213/40

摘要： Compounds of formula (I) and pharmacologically acceptable salts and pro-drugs thereof wherein: Ar1 and Ar2 are aryl or heteroaryl; a is 0 to 5; R1 is alkyl, halogen, haloalkyl, alkoxy, haloalkoxy, alkoxycarbonyl, carboxyl, hydroxyl, amino, monoalkylamino, dialkylamino, nitro, acylamino, alkoxycarbonylamino, alkylsulphonyl, alkylsulphonylamino or cyano and, where a is greater than 1, each substituent R1 may be the same or different; b is 0 to 5; R2 is alkyl, halogen, haloalkyl, haloalkoxy, alkoxy, alkoxycarbonyl, carboxyl, hydroxyl, amino, monoalkylamino, dialkylamino, nitro, acylamino, alkoxycarbonylamino, alkylsulphonyl, alkylsulphonylamino or cyano and where b is greater than 1, each substituent R2 may be the same or different; V is selected from the group consisting of (CR3aR3b)pCON(R3b)X and (CR3aR3b)pN(R3b)CO(X), wherein said groups are in the 3- (meta) or 4- (para) position with respect to the substituent Z; W is selected from the group consisting of NR4a, O, S, S═O, SO2 and C(R4aR4b)2; X is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, aryloxyalkyl, cycloalkyl, aryl, heteroaryl, polyalkylene glycol, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkyl that is substituted with a groups of formula of formula NR8R9 wherein R8 and R9 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated heterocyclic group, carboxyalkyl, alkoxycarbonylalkyl, haloalkoxycarbonylalkyl or aralkyloxycarbonylalkyl; Y and Z are the same or different and each is a substituent selected from the group consisting of (CR5aR5b)n1, C═O, SO2, C(═O)NR5a; C(═O)NR5aSO2 and C═O(R5aR5b)n2; R3a, R3b, R4a, R4b, R5a and R5b are the same or different and each is selected from the hydrogen, alkyl, cycloalkyl, aryl and heteroaryl; n1 and n2 are the same or different and each is 0 to 2; and p is 0 to 2; are potassium ion channel modulators, making them particularly useful in treating and preventing conditions such as pain, lower urinary tract disorders and the like.

公开(公告)号：US09464052B2

公开(公告)日：2016-10-11

申请号：US13054960

申请日：2009-07-20

申请人： Simon David Edwards ,  Meriel Ruth Kimberley ,  Richard Edward Armer ,  Nawaz Mohammed Khan

发明人： Simon David Edwards ,  Meriel Ruth Kimberley ,  Richard Edward Armer ,  Nawaz Mohammed Khan

IPC分类号： C07C237/20 ,  C07D213/40

CPC分类号： A61K31/165 ,  A61K31/198 ,  A61K31/40 ,  A61K31/4402 ,  A61K31/445 ,  A61K31/5375 ,  A61K45/06 ,  C07C237/20 ,  C07D213/40

摘要： Compounds of formula (I) and pharmacologically acceptable salts and pro-drugs thereof wherein: Ar1 and Ar2 are aryl or heteroaryl; a is 0 to 5; R1 is alkyl, halogen, haloalkyl, alkoxy, haloalkoxy, alkoxycarbonyl, carboxyl, hydroxyl, amino, monoalkylamino, dialkylamino, nitro, acylamino, alkoxycarbonylamino, alkylsulphonyl, alkylsulphonylamino or cyano and, where a is greater than 1, each substituent R1 may be the same or different; b is 0 to 5; R2 is alkyl, halogen, haloalkyl, haloalkoxy, alkoxy, alkoxycarbonyl, carboxyl, hydroxyl, amino, monoalkylamino, dialkylamino, nitro, acylamino, alkoxycarbonylamino, alkylsulphonyl, alkylsulphonylamino or cyano and where b is greater than 1, each substituent R2 may be the same or different; V is selected from the group consisting of (CR3aR3b)pCON(R3b)X and (CR3aR3b)pN(R3b)CO(X), wherein said groups are in the 3- (meta) or 4- (para) position with respect to the substituent Z; W is selected from the group consisting of NR4a, O, S, S═O, SO2 and C(R4aR4b)2; X is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, aryloxyalkyl, cycloalkyl, aryl, heteroaryl, polyalkylene glycol, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkyl that is substituted with a groups of formula of formula NR8R9 wherein R8 and R9 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated heterocyclic group, carboxyalkyl, alkoxycarbonylalkyl, haloalkoxycarbonylalkyl or aralkyloxycarbonylalkyl; Y and Z are the same or different and each is a substituent selected from the group consisting of (CR5aR5b)n1, C═O, SO2, C(═O)NR5a; C(═O)NR5aSO2 and C═O(R5aR5b)n2; R3a, R3b, R4a, R4b, R5a and R5b are the same or different and each is selected from the hydrogen, alkyl, cycloalkyl, aryl and heteroaryl; n1 and n2 are the same or different and each is 0 to 2; and p is 0 to 2; are potassium ion channel modulators, making them particularly useful in treating and preventing conditions such as pain, lower urinary tract disorders and the like.

公开(公告)号：US20120065270A1

公开(公告)日：2012-03-15

申请号：US12746524

申请日：2008-12-05

申请人： Simon David Edwards ,  Meriel Ruth Kimberly ,  Kanesalingam Suthaharan ,  Nawaz Mohammed Khan ,  Geoff Lawton

发明人： Simon David Edwards ,  Meriel Ruth Kimberly ,  Kanesalingam Suthaharan ,  Nawaz Mohammed Khan ,  Geoff Lawton

IPC分类号： A61K31/18 ,  A61P13/02 ,  A61P25/22 ,  A61P25/08 ,  A61P29/00 ,  A61P9/00 ,  A61P27/16 ,  A61P25/06 ,  A61P25/28 ,  A61P3/00 ,  A61P35/00 ,  A61P21/00 ,  A61P25/00 ,  A61P37/00 ,  C07C311/39 ,  C07C311/35

CPC分类号： C07C311/35 ,  C07C311/40

摘要： Compounds of formula (I) and pharmacologically acceptable salts and pro-drugs wherein: Ar1 and Ar2=aryl or heteroaryl; a=0 to 5; R1=alkyl, halogen, haloalkyl, alkoxy, alkoxycarbonyl, carboxyl, hydroxyl, amino, monalkylamino, dialkylamino, nitro, acylamino, alkoxycarbonylamino, alkylsulphonyl, alkylsulphonylamino and cyano and, where a is >1, each R1 is the same or different; b=0 to 5; R2=alkyl, halogen, haloalkyl, alkoxy, alkoxycarbonyl, carboxyl, hydroxyl, amino, monalkylamino, dialkylamino, nitro, acylamino, alkoxycarbonylamino, alkylsulphonyl, alkylsulphonylamino and cyano and where b is >1, each R2 is the same or different; V=(CR3aR3b)pSO2N(R3b)X and (CR3aR3b)pN(R3b)SO2(X); W=NR4a, O, S, S═O, SO2 and C(R4aR4b)2; X=hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, aryloxyalkyl, polyalkylene glycol residues, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl and alkyl groups substituted with ≧1 NR8R9 groups wherein R8 and R9+nitrogen atom form a saturated or partially unsaturated heterocyclic group which is optionally further substituted by ≧1 substituents selected from alkyl, halogen, haloalkyl, alkoxy, alkoxycarbonyl, carboxyl, nitro, amino, monoalkylamino, dialkylamino and hydroxyl; Y and Z each ═(CR5aR5b)n1, C═O, SO2, C(═O)NR5a, C(═O)NR5aSO2 or C═O(R5aR5b)n2; R3a, R3b, R4a, R4b, R5a and R5b each=hydrogen, alkyl, cycloalkyl, aryl or heteroaryl; n1 and n2 each =0 to 2; and p=0 to 2; are excellent selective modulators of potassium ion flux through KCNQ2, KCNQ3 and/or KCNQ2/3 channels, making them of use in treating and preventing a number of conditions including pain and lower urinary tract disorders.

摘要翻译： 式（I）化合物及其药理学上可接受的盐和前药，其中：Ar1和Ar2 =芳基或杂芳基; a = 0〜5; R 1 =烷基，卤素，卤代烷基，烷氧基，烷氧基羰基，羧基，羟基，氨基，单烷基氨基，二烷基氨基，硝基，酰氨基，烷氧基羰基氨基，烷基磺酰基，烷基磺酰基氨基和氰基，其中a≥1，每个R 1相同或不同; b = 0〜5; R 2 =烷基，卤素，卤代烷基，烷氧基，烷氧基羰基，羧基，羟基，氨基，单烷基氨基，二烷基氨基，硝基，酰氨基，烷氧基羰基氨基，烷基磺酰基，烷基磺酰基氨基和氰基，其中b≥1，各自相同或不同; V =（CR3aR3b）pSO2N（R3b）X和（CR3aR3b）pN（R3b）SO2（X）; W = NR4a，O，S，S = O，SO2和C（R4aR4b）2; X =羟基烷基，烷氧基烷基，卤代烷氧基烷基，芳氧基烷基，聚亚烷基二醇残基，氨基烷基，单烷基氨基烷基，二烷基氨基烷基和被1个NR8R9基团取代的烷基，其中R8和R9 +氮原子形成饱和或部分不饱和的杂环基，其任选进一步被≧ 1个选自烷基，卤素，卤代烷基，烷氧基，烷氧基羰基，羧基，硝基，氨基，单烷基氨基，二烷基氨基和羟基的取代基; Y和Z各自为（CR5aR5b）n1，C = O，SO2，C（= O）NR5a，C（= O）NR5aSO2或C = O（R5aR5b）n2; R3a，R3b，R4a，R4b，R5a和R5b各自为氢，烷基，环烷基，芳基或杂芳基; n1和n2各自= 0至2; 和p = 0至2; 是通过KCNQ2，KCNQ3和/或KCNQ2 / 3通道的钾离子通量的优异选择性调节剂，可用于治疗和预防许多病症，包括疼痛和下尿路疾病。

公开(公告)号：US08466201B2

公开(公告)日：2013-06-18

申请号：US12746524

申请日：2008-12-05

申请人： Simon David Edwards ,  Meriel Ruth Kimberly ,  Kanesalingam Suthaharan ,  Nawaz Mohammed Khan ,  Geoff Lawton

发明人： Simon David Edwards ,  Meriel Ruth Kimberly ,  Kanesalingam Suthaharan ,  Nawaz Mohammed Khan ,  Geoff Lawton

IPC分类号： C07C311/35 ,  C07C311/40 ,  A61K31/18

CPC分类号： C07C311/35 ,  C07C311/40

摘要： Compounds of formula (I) and pharmacologically acceptable salts and pro-drugs wherein: Ar1 and Ar2=aryl or heteroaryl; a=0 to 5; R1=alkyl, halogen, haloalkyl, alkoxy, alkoxycarbonyl, carboxyl, hydroxyl, amino, monalkylamino, dialkylamino, nitro, acylamino, alkoxycarbonylamino, alkylsulphonyl, alkylsulphonylamino and cyano and, where a is >1, each R1 is the same or different; b=0 to 5; R2=alkyl, halogen, haloalkyl, alkoxy, alkoxycarbonyl, carboxyl, hydroxyl, amino, monalkylamino, dialkylamino, nitro, acylamino, alkoxycarbonylamino, alkylsulphonyl, alkylsulphonylamino and cyano and where b is >1, each R2 is the same or different; V=(CR3aR3b)pSO2N(R3b)X and (CR3aR3b)pN(R3b)SO2(X); W=NR4a, O, S, S═O, SO2 and C(R4aR4b)2; X=hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, aryloxyalkyl, polyalkylene glycol residues, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl and alkyl groups substituted with ≧1 NR8R9 groups wherein R8 and R9+nitrogen atom form a saturated or partially unsaturated heterocyclic group which is optionally further substituted by ≧1 substituents selected from alkyl, halogen, haloalkyl, alkoxy, alkoxycarbonyl, carboxyl, nitro, amino, monoalkylamino, dialkylamino and hydroxyl; Y and Z each ═(CR5aR5b)n1, C═O, SO2, C(═O)NR5a, C(═O)NR5aSO2 or C═O(R5aR5b)n2; R3a, R3b, R4a, R4b, R5a and R5b each=hydrogen, alkyl, cycloalkyl, aryl or heteroaryl; n1 and n2 each=0 to 2; and p=0 to 2; are excellent selective modulators of potassium ion flux through KCNQ2, KCNQ3 and/or KCNQ2/3 channels, making them of use in treating and preventing a number of conditions including pain and lower urinary tract disorders.

摘要翻译： 式（I）化合物及其药理学上可接受的盐和前药，其中：Ar1和Ar2 =芳基或杂芳基; a = 0〜5; R 1 =烷基，卤素，卤代烷基，烷氧基，烷氧基羰基，羧基，羟基，氨基，单烷基氨基，二烷基氨基，硝基，酰氨基，烷氧基羰基氨基，烷基磺酰基，烷基磺酰基氨基和氰基，其中a≥1，每个R 1相同或不同; b = 0〜5; R 2 =烷基，卤素，卤代烷基，烷氧基，烷氧基羰基，羧基，羟基，氨基，单烷基氨基，二烷基氨基，硝基，酰氨基，烷氧基羰基氨基，烷基磺酰基，烷基磺酰基氨基和氰基，其中b≥1，各自相同或不同; V =（CR3aR3b）pSO2N（R3b）X和（CR3aR3b）pN（R3b）SO2（X）; W = NR4a，O，S，S = O，SO2和C（R4aR4b）2; X =羟基烷基，烷氧基烷基，卤代烷氧基烷基，芳氧基烷基，聚亚烷基二醇残基，氨基烷基，单烷基氨基烷基，二烷基氨基烷基和被= = NR8R9基团取代的烷基，其中R8和R9 +氮原子形成饱和或部分不饱和的杂环基，其任选进一步被 > = 1个选自烷基，卤素，卤代烷基，烷氧基，烷氧基羰基，羧基，硝基，氨基，单烷基氨基，二烷基氨基和羟基的取代基。 Y和Z各自=（CR5aR5b）n1，C = O，SO2，C（= O）NR5a，C（= O）NR5aSO2或C = O（R5aR5b）n2; R3a，R3b，R4a，R4b，R5a和R5b各自为氢，烷基，环烷基，芳基或杂芳基; n1和n2各自= 0至2; 和p = 0至2; 是通过KCNQ2，KCNQ3和/或KCNQ2 / 3通道的钾离子通量的优异选择性调节剂，可用于治疗和预防许多病症，包括疼痛和下尿路疾病。

公开(公告)号：US20110166136A1

公开(公告)日：2011-07-07

申请号：US13002374

申请日：2009-07-03

申请人： Nawaz Mohammed Khan ,  Svenja Burckhardt ,  Julie Elaine Cansfield ,  Ngoc-Tri Vo ,  Richard Edward Armer ,  Raymond John Boffey

发明人： Nawaz Mohammed Khan ,  Svenja Burckhardt ,  Julie Elaine Cansfield ,  Ngoc-Tri Vo ,  Richard Edward Armer ,  Raymond John Boffey

IPC分类号： A61K31/5377 ,  C07D403/06 ,  A61K31/496 ,  C07D413/06 ,  C07D209/42 ,  A61K31/404 ,  A61P29/00 ,  A61P9/00 ,  A61P25/22 ,  A61P13/00 ,  A61P25/06 ,  A61P1/00 ,  A61P3/00

CPC分类号： C07D491/056 ,  A61K31/404 ,  C07D209/18 ,  C07D209/24 ,  C07D401/06

摘要： Compounds of formula (1), salts and pro-drugs wherein: R1, R2, R3 and R4 are hydrogen, alkyl, hydroxyalkyl, halogen, haloalkyl, alkoxy, haloalkoxy, alkoxycarbonyl, carboxyl, hydroxyl, nitro, amino, monalkylamino, dialkylamino, acylamino, alkoxycarbonylamino, alkylsulphonyl, arylsulphonyl, alkylsulphonylamino, arylsulphonylamino, aminosulphonyl or cyano, or any two of R1 to R4 that are adjacent on the ring may together represent the moiety —O—(CH2)n—O— wherein n is 1 to 3; R5 is hydrogen or alkyl; R6 is hydrogen or alkyl; and X is selected from the group consisting of: (a) groups of formula OR7 wherein R7 is hydrogen or alkyl which is optionally substituted with a substituent selected from alkylsulfonylalkyl, saturated or partially unsaturated heterocyclic, alkoxy, carboxyl, nitro, amino, monalkylamino, dialkylamino, halogen, and alkoxycarbonyl, provided that when R7 is hydrogen or ethyl, then R1, R2, R3 and R4 cannot be selected from hydrogen, halogen and alkyl; and (b) groups of formula NR8R9 wherein R8 and R9 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated heterocyclic group which optionally contains at least one more heteroatom selected from nitrogen, oxygen and sulphur atoms, said saturated or partially unsaturated heterocyclic group optionally further being substituted by one or more substituents selected from alkyl, halogen, haloalkyl, alkoxy, alkoxycarbonyl, carboxyl, nitro, amino, monalkylamino, dialkylamino and hydroxyl, provided that: (i) when R8+R9+N=piperazine, and ≧1 of R1 to R4 are hydrogen, hydroxyl, nitro, amino, alkylamino, dialkylamino, alkoxycarbonylamino, halogen, alkoxy or alkyl, the nitrogen atom at the 4-position of the piperazine is not alkyl substituted, (ii) when each of R1, R2, R3, R4, R5 and R6 is hydrogen, X is not unsubstituted piperazinyl or unsubstituted morpholino, (iii) when each of R1, R2, R4, R5 and R6 is hydrogen and R3 hydrogen, bromine or hydroxyl, X is not methoxy, (iv) when each of R2 and R3 is methoxy or they together represent —O—CH2—O— and each of R1, R4, R5 and R6 is hydrogen, X is not unsubstituted piperidine, are Cavx channel blockers and are of use in the treatment of various conditions including pain.