Methods of treating pain
The present invention provides compositions and methods for treating pain using a compound of general Formula I: wherein the substituents thereof are as described herein.
1 . A method for the treatment of pain comprising administering a therapeutically effective amount of at least one inhibitor of a cyclin-dependent kinase (CDK) to a subject in need thereof.
2 . The method of claim 1 , wherein said at least one inhibitor comprises at least one compound selected from the group consisting of a [4-(3-substituted-phenyl)-pyrimidin-2-yl]-phenyl-amine and a [4-(3-substituted-phenyl)-pyrimidin-2-yl]-(pyridine-3-yl)-amine.
3 . The method of claim 1 , wherein said at least one inhibitor of a cyclin-dependent kinase is characterized by general Formula I,
wherein:
Z is CR 10 or N;
one of R 1 and R 2 is selected from (CH 2 ) m R 11 , (CH 2 ) m R 12 , (CH 2 ) m NR 12 R 13 , (CH 2 ) m OR 12 , (CH 2 ) m NR 13 CO(CH 2 ) n R 11 , (CH 2 ) m NR 13 COR 12 , (CH 2 ) m CONR 13 (CH 2 )nR 11 , (CH 2 ) m CONR 12 R 13 , (CH 2 ) m CO(CH 2 ) n R 11 and (CH 2 )COR 12 ; where m is 0, 1, 2, 3 or 4, and n is 1, 2, 3 or 4;
the other of R 1 and R 2 is H or R 11 ;
R 3 and R 5 are both H;
R 4 is H or R 11 ;
R 6 is H or (CH 2 ) p R 11 , where p is 0 or 1;
R 7 , R 9 and R 10 are each independently H or R 11 ;
R 8 is selected from H, halogen, NO 2 , CN, OR 13 , NR 13 R 14 , NHCOR 13 , CF 3 , COR 13 , R 13 , CONR 13 R 15 , SO 2 NR 13 R 14 , SO 2 R 13 , NR 13 SO 2 R 14 , OCH 2 CH 2 OH, OCH 2 CH 2 OMe, morpholine, piperidine, and piperazine;
each R 11 is independently halogen, NO 2 , CN, (CH 2 ) q OR 13 , (CH 2 ) r NR 13 R 14 , NHCOR 13 , CF 3 , COR 13 , R 13 , CONR 13 R 14 , SO 2 NR 13 R 14 , SO 2 R 13 , OR 12 , NR 13 SO 2 R 14 , OCH 2 CH 2 OH, OCH 2 CH 2 OMe, NR 13 SO 2 R 13 , (CH 2 ) s NR 12 R 13 , morpholine, piperidine or piperazine, where q, r and s are each independently 0, 1, 2, 3 or 4;
each R 12 is independently a hydrocarbyl group optionally containing one or more heteroatoms and optionally substituted with one or more R 11 groups;
each R 13 and each R 14 is independently H or an alkyl group; and
R 15 is an alkyl group;
provided that:
when -Z is CR 10 and R 9 is H, then at least one of R 7 , R 8 and R 10 is other than OMe; and
when -Z is CR 10 and R 7 , R 8 , and R 9 are all H, then R 10 is other than OCF 2 CHF 2 ;
and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers, enantiomers, diastereomers thereof, and the pharmaceutically acceptable salts and solvates of such compounds.
4 . The method according to claim 1 , wherein said at least one inhibitor of a cyclin-dependent kinase is selected from the group consisting of:
4-[4-(3-Nitro-phenyl)-pyrimidin-2-ylamino]-phenol [1];
(4-Nitro-phenyl)-[4-(3-nitro-phenyl)-pyrimidin-2-yl]-amine [2];
[4-(3-Amino-phenyl)-pyrimidin-2-yl]-[4-(2-methoxy-ethoxy)-phenyl]-amine [3];
[4-(3-Amino-phenyl)-pyrimidin-2-yl]-(4-nitro-phenyl)-amine [4];
(3-Nitro-phenyl)-[4-(3-nitro-phenyl)-pyrimidin-2-yl]-amine [5];
(4-Fluoro-phenyl)-[4-(3-nitro-phenyl)-pyrimidin-2-yl]-amine [6];
[4-(3-Amino-phenyl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine [7];
N-[4-(3-Amino-phenyl)-pyrimidin-2-yl]-benzene-1,3-diamine [8];
N,N-Dimethyl-N′-[4-(3-nitro-phenyl)-pyrimidin-2-yl]-benzene-1,4-diamine [9];
N-Ethyl-N-{3-[2-(4-hydroxy-phenylamino)-pyrimidin-4-yl]-phenyl}-acetamide [10];
N-13-[2-(4-Hydroxy-phenylamino)-pyrimidin-4-yl]-phenyl-acetamide [11];
N-{3-[2-(4-Hydroxy-phenylamino)-pyrimidin-4-yl]-phenyl}-N-methyl-acetamide [12];
N-{3-[2-(4-Hydroxy-phenylamino)-pyrimidin-4-yl]-phenyl}-N-isobutyl-acetamide [13];
4-[4-(3-Methylamino-phenyl)-pyrimidin-2-ylamino]-phenol [14];
4-[4-(3-Amino-phenyl)-pyrimidin-2-ylamino]-phenol [15];
(4-Chloro-phenyl)-[4-(3-chloro-phenyl)-pyrimidin-2-yl]-amine [16];
4-[4-(3-Chloro-phenyl)-pyrimidin-2-ylamino]-phenol [17];
3-[4-(3-Chloro-phenyl)-pyrimidin-2-ylamino]-phenol [18];
[4-(3-Amino-phenyl)-pyrimidin-2-yl]-(3-nitro-phenyl)-amine [19];
N-[4-(3,4-Dichloro-phenyl)-pyrimidin-2-yl]-N′,N′-dimethyl-benzene-1,4-diamine [20];
4-[4-(3,4-Dichloro-phenyl)-pyrimidin-2-ylamino]-phenol [21];
3-[4-(3,4-Dichloro-phenyl)-pyrimidin-2-ylamino]-phenol [22];
N-Ethyl-N-{3-[2-(4-methoxy-phenylamino)-pyrimidin-4-yl]-phenyl}-acetamide [23];
N-Ethyl-N-13-[2-(4-nitro-phenylamino)-pyrimidin-4-yl]-phenyl-acetamide [24];
[4-(3-Ethylamino-phenyl)-pyrimidin-2-yl]-(4-methoxy-phenyl)-amine [25];
[4-(3-Ethylamino-phenyl)-pyrimidin-2-yl]-(4-nitro-phenyl)-amine [26];
{4-[3-(Benzylamino-methyl)-phenyl]-pyrimidin-2-yl}-(3-(3-nitro-phenyl)-amine [27];
3-{4-[3-(Benzylamino-methyl)-phenyl]-pyrimidin-2-ylamino}-phenol [28];
[4-(3-imidazol-1-ylmethyl-phenyl)-pyrimidin-2-yl]-(3-nitro-phenyl)-amine [29];
(3-Nitro-phenyl)-[4-(3-[1,2,4]triazol-1-ylmethyl-phenyl)-pyrimidin-2-yl]-amine [30];
[4-(3,4-Dichloro-phenyl)-pyrimidin-2-yl]-(3-nitro-phenyl)-amine [31];
(4-Morpholin-4-yl-phenyl)-[4-(3-[1,2,4]triazol-1-ylmethyl-phenyl)-pyrimidin-2-yl]-amine [32];
4-[4-(3-[1,2,4]Triazol-1-ylmethyl-phenyl)-pyrimidin-2-ylamino]-phenol [33];
3-[4-(3-[1,2,4]Triazol-1-ylmethyl-phenyl)-pyrimidin-2-ylamino]-phenol [34];
(3-Methoxy-phenyl)-[4-(3-[1,2,4]triazol-1-ylmethyl-phenyl)-pyrimidin-2-yl]-amine [35];
3-[4-(3-[1,2,4]Triazol-1-ylmethyl-phenyl)-pyrimidin-2-ylamino]-benzonitrile [36];
Phenyl-(4-phenyl-pyrimidin-2-yl)-amine [37];
[4-(5-Fluoro-2-methoxy-phenyl)-pyrimidin-2-yl]-phenyl-amine [38];
[4-(3-Morpholin-4-ylmethyl-phenyl)-pyrimidin-2-yl]-(3-nitro-phenyl)-amine [39];
N-{3-[2-(3-Nitro-phenylamino)-pyrimidin-4-yl]-benzyl}-methanesulfonamide [40];
(4-Nitro-phenyl)-[4-(3-[1,2,4]triazol-1-ylmethyl-phenyl)-pyrimidin-2-yl]-amine [41];
(4-Methoxy-phenyl)-[4-(3-[1,2,4]triazol-1-ylmethyl-phenyl)-pyrimidin-2-yl]-amine [42];
N,N-Dimethyl-N′-[4-(3-[1,2,4]triazol-1-ylmethyl-phenyl)-pyrimidin-2-yl]-benzene-1,4-diamine [43];
[4-(2,5-Dimethoxy-phenyl)-pyrimidin-2-yl]-(3-nitro-phenyl)-amine [44];
4-[4-(2,5-Dimethoxy-phenyl)-pyrimidin-2-ylamino]-phenol [45];
(4-{3-[(Ethyl-isopropyl-amino)methyl]-phenyl}-pyrimidin-2-yl)-(3-nitro-phenyl)-amine [46];
[4-(4-Chloro-3-[1,2,4]triazol-1-ylmethyl-phenyl)-pyrimidin-2-yl]-(3-nitro-phenyl)-amine [47];
{4-[3-(Benzylamino-methyl)-phenyl]-pyrimidin-2-yl}-(6-chloro-pyridin-3-yl)-amine [48];
[4-(3,4-Dichloro-phenyl)-pyrimidin-2-yl]-(6-methoxy-pyridin-3-yl)-amine [49];
(6-Methoxy-pyridin-3-yl)-[4-(3-[1,2,4]triazol-1-ylmethyl-phenyl)-pyrimidin-2-yl]-amine [50];
3-[2-(6-Methoxy-pyridin-3-ylamino)-pyrimidin-4-yl]-benzonitrile [51];
[4-(2,5-Dimethoxy-phenyl)-pyrimidin-2-yl]-(6-methoxy-pyridin-3-yl)-amine [52];
(4-{3-[(Ethyl-isopropyl-amino)-methyl]-phenyl}-pyrimidin-2-yl)-(6-methoxy-pyridin-3-yl)-amine [53];
{4-[3-(4-Methyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-2-yl}-(3-nitro-phenyl)-amine [54];
3-[2-(3-Nitro-phenylamino)-pyrimidin-4-yl]-phenol [55];
[3-[2-(3-Hydroxy-phenylamino)-pyrimidin-4-yl]-phenol [56];
3-[2-(3-Fluoro-phenylamino)-pyrimidin-4-yl]-phenol [57];
(6-Methoxy-pyridin-3-yl)-{4-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-pyrimidin-2-yl}-amine [58];
[4-(3-Imidazol-1-ylmethyl-phenyl)-pyrimidin-2-yl]-(6-methoxy-pyridin-3-yl)-amine [59];
N-{3-[2-(3-Hydroxymethyl-phenylamino)-pyrimidin-4-yl]-phenyl}-acetamide [60];
[4-(2,5-Dimethyl-phenyl)-pyrimidin-2-yl]-(3-nitro-phenyl)-amine [61];
3-[4-(2,5-Dimethyl-phenyl)-pyrimidin-2-ylamino]-phenol [62];
[4-(2,5-Dimethyl-phenyl)-pyrimidin-2-yl]-(3-fluoro-phenyl)-amine [63];
3-[4-(3-Nitro-phenyl)-pyrimidin-2-ylamino]-phenol [64];
(3-Fluoro-phenyl)-[4-(3-nitro-phenyl)-pyrimidin-2-yl]-amine [65];
N-[3-(2-Phenylamino-pyrimidin-4-yl)-phenyl]-acetamide [66];
N-{3-[2-(3-Hydroxy-phenylamino)-pyrimidin-4-yl]-phenyl}-acetamide [67];
N-{3-[2-(3,5-Dimethoxy-phenylamino)-pyrimidin-4-yl]-phenyl}-acetamide [68];
N-{3-[2-(3-Nitro-phenylamino)-pyrimidin-4-yl]-phenyl}-acetamide [69];
N-{3-[2-(Pyridin-3-ylamino)-pyrimidin-4-yl]-phenyl}-acetamide [70];
[4-(3-Dimethylaminomethyl-phenyl)-pyrimidin-2-yl]-(3-nitro-phenyl)-amine [71];
3-[2-(3-Hydroxymethyl-phenylamino)-pyrimidin-4-yl]-phenol [72];
3-[2-(Pyridin-3-ylamino)-pyrimidin-4-yl]-phenol [73];
3-[2-(6-Methoxy-pyridin-3-ylamino)-pyrimidin-4-yl]-phenol [74];
3-[2-(3,5-Bis-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-phenol [75];
3-[4-(4-Methoxy-phenyl)-pyrimidin-2-ylamino]-phenol [76];
[4-(3-Methoxy-phenyl)-pyrimidin-2-yl]-(6-methoxy-pyridin-3-yl)-amine [77];
N-Isopropyl-N-3-[2-(3-nitro-phenylamino)-pyrimidin-4-yl]-benzyl}-acetamide [78];
(1-{3-[2-(3-Nitro-phenylamino)-pyrimidin-4-yl]-benzyl}-piperidin-2-yl)-methanol [79];
3-[4-(3-Dimethylaminomethyl-phenyl)-pyrimidin-2-ylamino]-phenol [80];
4-[4-(3-Dimethylaminomethyl-phenyl)-pyrimidin-2-ylamino]-phenol [81];
[4-(3-Dimethylaminomethyl-phenyl)-pyrimidin-2-yl]-(4-morpholin-4-yl-phenyl)-amine [82];
[4-(3-Dimethylaminomethyl-phenyl)-pyrimidin-2-yl]-(6-methoxy-pyridin-3-yl)-amine [83];
[4-(3-Diethylaminomethyl-phenyl)-pyrimidin-2-yl]-(3-nitro-phenyl)-amine [84];
N-Methyl-3-nitro-N-3-[2-(3-nitro-phenylamino)-pyrimidin-4-yl]-benzyl}benzenesulfonamide [85];
(3-Nitro-phenyl)-{4-[3-(2-phenylaminomethyl-pyrrolidin-1-ylmethyl)-phenyl]-pyrimidin-2-yl}-amine [86];
[4-(3-Methoxy-phenyl)-pyrimidin-2-yl]-(3-nitro-phenyl)-amine [87];
3-[4-(3-Methoxy-phenyl)-pyrimidin-2-ylamino]-phenol [88];
4-[4-(3,4-Dimethoxy-phenyl)-pyrimidin-2-ylamino]-phenol [89];
[4-(3,4-Dimethoxy-phenyl)-pyrimidin-2-yl]-(3-nitro-phenyl)-amine [90];
{3-[2-(3-Nitro-phenylamino)-pyrimidin-4-yl]-phenyl}-methanol [91];
3-[2-(3-Hydroxy-phenylamino)-pyrimidin-4-yl]-benzonitrile [92];
3-[2-(4-Hydroxy-phenylamino)-pyrimidin-4-yl]-benzonitrile [93];
[4-(4-Methoxy-phenyl)-pyrimidin-2-yl]-(3-nitro-phenyl)-amine [94];
3-[4-(3-Trifluoromethyl-phenyl)-pyrimidin-2-ylamino]-phenol [95];
4-[4-(3-Trifluoromethyl-phenyl)-pyrimidin-2-ylamino]-phenol [96];
(3-Nitro-phenyl)-[4-(3-trifluoromethyl-phenyl)-pyrimidin-2-yl]-amine [97];
4-[4-(3-Methoxy-phenyl)-pyrimidin-2-ylamino]-phenol [98];
1-{3-[2-(3-Nitro-phenylamino)-pyrimidin-4-yl]-benzyl}-piperidine-3-carboxylic acid amide [99];
2-(1-{3-[2-(3-Nitro-phenylamino)-pyrimidin-4-yl]-benzyl}-piperidin-3-yl)-ethanol [100];
(1-{3-[2-(4-Morpholin-4-yl-phenylamino)-pyrimidin-4-yl]-benzyl}-piperidin-2-61)-methanol [101];
(1-{3-[2-(6-Methoxy-pyridin-3-ylamino)-pyrimidin-4-yl]-benzyl}-piperidin-2-yl)-methanol [102];
3-{4-[3-(2-Hydroxymethyl-piperidin-1-ylmethyl)-phenyl]-pyrimidin-2-ylamino}-phenol [103];
(3-Methanesulfonyl-phenyl)-[4-(3-[1,2,4]triazol-1-ylmethyl-phenyl)-pyrimidin-2-yl]-amine [104];
(1-{3-[2-(3-Nitro-phenylamino)-pyrimidin-4-yl]-benzyl}-piperidin-3-yl)-methanol [105];
4-{4-[3-(2-Hydroxymethyol-piperidin-1-ylmethyl)-phenyl]-pyrimidin-2-ylaminol}-phenol [106];
(1-{3-[2-(3,5-Bis-hydroxymethyl-phenylamino)-pyrimidin-4-yl]-benzyl}-piperidin-2-yl)-methanol [107];
(1-3-[2-(4-Methyl-3-nitro-phenylamino)-pyrimidin-4-yl]-benzyl}-piperidin-2-yl)-methanol [108];
3-[4-(4-Ethoxy-phenyl)-pyrimidin-2-ylamino]-phenol [109];
4-[4-(4-Methoxy-phenyl)-pyrimidin-2-ylamino]-phenol [110];
[4-(4-Methoxy-phenyl)-pyrimidin-2-yl]-(4-morpholin-4-yl-phenyl)-amine [111];
[4-(3-Chloro-phenyl)-pyrimidin-2-yl]-(3-nitro-phenyl)-amine [112];
4-[4-(3-Fluoro-phenyl)-pyrimidin-2-ylamino]-phenol [113];
3-[4-(2,5-Difluoro-phenyl)-pyrimidin-2-ylamino]-phenol [114];
3-[4-(3-Hydroxymethyl-phenyl)-pyrimidin-2-ylamino]-phenol [115];
{3-[2-(3-Fluoro-phenylamino)-pyrimidin-4-yl]-phenyl}-methanol [116];
{3-[2-(3,5-Dinitro-phenylamino)-pyrimidin-4-yl]-phenyl}-methanol [117];
(3-Fluoro-phenyl)-[4-(3-methoxy-phenyl)-pyrimidin-2-yl]-amine [118];
(3-Fluoro-phenyl)-[4-(4-methoxy-phenyl)-pyrimidin-2-yl]-amine [119];
3-[2-(3,5-Dimethoxy-phenylamino)-pyrimidin-4-yl]-phenol [121];
3-[2-(4-Hydroxy-phenylamino)-pyrimidin-4-yl]-phenol [122];
[4-(2,5-Difluoro-phenyl)-pyrimidin-2-yl]-(3-nitro-phenyl)-amine [123];
[4-(4-Methoxy-phenyl)-pyrimidin-2-yl]-(6-methoxy-pyridin-3-yl)-amine [124];
{3-[2-(6-Methoxy-pyridin-3-ylamino)-pyrimidin-4-yl]-phenyl}-methanol [125];
(3-Nitro-phenyl)-{4-[4-(2-[1,2,4]triazol-1-yl-ethyl)-phenyl]-pyrimidin-2-yl}-amine [126];
(1-4-[2-(3-Nitro-phenylamino)-pyrimidin-4-yl]-benzyl}-piperidin-2-yl)-methanol [127];
N-Methyl-N-{3-[2-(3-nitro-phenylamino)-pyrimidin-4-yl]-phenyl}-methanesulfonamide [129];
N-{3-[2-(3-Hydroxy-phenylamino)-pyrimidin-4-yl]-phenyl}-N-methylmethanesulfonamide [130];
N-{3-[2-(4-Hydroxy-phenylamino)-pyrimidin-4-yl]-phenyl}-N-methyl-methanesulfonamide [131]; and
N-{3-[2-(6-Methoxy-pyridin-3-ylamino)-pyrimidin-4-yl]-phenyl}-N-methyl-methanesulfonamide [132].
5 . The method of claim 1 , wherein said pain comprises chronic pain, inflammatory pain, neuropathic pain, or a combination thereof.
6 . A pharmaceutical composition comprising at least one inhibitor of a cyclin-dependent kinase for the treatment of any type of pain, wherein said at least one inhibitor is characterized by general Formula I,
wherein:
Z is CR 10 or N;
one of R 1 and R 2 is selected from (CH 2 ) m R 11 , (CH 2 ) m R 12 , (CH 2 ) m NR 12 R 13 , (CH 2 ) m OR 12 , (CH 2 ) m NR 13 CO(CH 2 ) n R 11 , (CH 2 ) m NR 13 COR 12 , (CH 2 ) m CONR 13 (CH 2 )nR 11 , (CH 2 ) m CONR 12 R 13 , (CH 2 ) m CO(CH 2 ) n R 11 and (CH 2 )COR 12 ; where m is 0, 1, 2, 3 or 4, and n is 1, 2, 3 or 4;
the other of R 1 and R 2 is H or R 11 ;
R 3 and R 5 are both H;
R 4 is H or R 11 ;
R 6 is H or (CH 2 ) p R 11 , where p is 0 or 1;
R 7 , R 9 and R 10 are each independently H or R 11 ;
R 8 is selected from H, halogen, NO 2 , CN, OR 13 , NR 13 R 14 , NHCOR 13 , CF 3 , COR 13 , R 13 , CONR 13 R 15 , SO 2 NR 13 R 14 , SO 2 R 13 , NR 13 SO 2 R 14 , OCH 2 CH 2 OH, OCH 2 CH 2 OMe, morpholine, piperidine, and piperazine;
each R 11 is independently halogen, NO 2 , CN, (CH 2 ) q OR 13 , (CH 2 ) r NR 13 R 14 , NHCOR 13 , CF 3 , COR 14 , R 13 , CONR 13 R 14 , SO 2 NR 13 R 14 , SO 2 R 13 , OR 12 , NR 13 SO 2 R 14 , OCH 2 CH 2 OH, OCH 2 CH 2 OMe, NR 13 SO 2 R 13 , (CH 2 ) s NR 12 R 13 , morpholine, piperidine or piperazine, where q, r and s are each independently 0, 1, 2, 3 or 4;
each R 12 is independently a hydrocarbyl group optionally containing one or more heteroatoms and optionally substituted with one or more R 11 groups;
each R 13 and each R 14 is independently H or an alkyl group; and
R 15 is an alkyl group;
provided that:
when -Z is CR 10 and R 9 is H, then at least one of R 7 , R 8 and R 10 is other than OMe; and
when -Z is CR 10 and R 7 , R 8 , and R 9 are all H, then R 10 is other than OCF 2 CHF 2 ;
and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers, enantiomers, diastereomers thereof, and the pharmaceutically acceptable salts and solvates of such compounds.
7 . The pharmaceutical composition of claim 6 , wherein said pain comprises chronic pain, inflammatory pain, neuropathic pain, or a combination thereof.