The invention relates to the inhibition of histone deacetylase. The invention provides compounds and methods for inhibiting histone deacetylase enzymatic activity. The invention also provides compositions and methods for treating cell proliferative diseases and conditions.
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We claim: 1. A compound of structural formula (2a): or a pharmaceutically acceptable salt thereof, wherein Ara is phenyl or thienyl; R6 is H, or C1-C6-alkyl; Y and Z are--CH═; W is (V'-L4)t-V-L3-; L3 is a direct bond,--C1-C6-hydrocarbyl,--(C1-C3-hydrocarbyl)m1-X'--(C1-C3 -hydrocarbyl)m2,--N
We claim: 1. A compound of structural formula (2a): or a pharmaceutically acceptable salt thereof, wherein Ara is phenyl or thienyl; R6 is H, or C1-C6-alkyl; Y and Z are--CH═; W is (V'-L4)t-V-L3-; L3 is a direct bond,--C1-C6-hydrocarbyl,--(C1-C3-hydrocarbyl)m1-X'--(C1-C3 -hydrocarbyl)m2,--NH--(C0-C3-hydrocarbyl), (C1-C3-hydrocarbyl)-NH--, or--NH--(C1-C3-hydrocarbyl)-NH--; m1 and m2 are independently 0 or 1; X' is--N(R21)--,--C(O)N(R21)--, N(R21)C(O)--,--O--, or--S--; R21 is--H, V"--(C1-C6-hydrocarbyl)c; L4 is (C1-C6-hydrocarbyl)a-M-(C1-C6-hydrocarbyl)b; a and b are independently 0 or 1; M is--NH--,--NHC(O)--,--C(O)NH--,--C(O)--,--SO2--,--NHSO2--, or--SO2NH-- V, V', and V" are independently selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl; t is 0 or 1; or W, the annular C to which it is bound, and Y together form a monocyclic cycloalkyl, heterocyclyl, aryl, or heteroaryl; and wherein the A and Ara rings are optionally further substituted with from 1 to 3 substituents independently selected from methyl, hydroxy, methoxy, halo, and amino. 2. The compound according to claim 1 wherein: R6 is H; W is V-L3-; L3 is--NH--CH--or--CH--NH--; V is phenyl optionally substituted with from 1 to 3 moieties independently selected from halo, hydroxy, C1-C6-hydrocarbyl, C1-C6-hydrocarbyl-oxy or-thio (particularly methoxy or methylthio), wherein each of the hydrocarbyl moieties are optionally substituted with one or more moieties independently selected from halo, nitroso, amino, sulfonamido, and cyano; and Ara is phenyl and the amino moieties to which it is bound are ortho to each other. 3. The compound according to claim 1 wherein V is an optionally substituted ring moiety selected from the group consisting of the following: 4. The compound according to claim 1 wherein W is selected from the group consisting of the following: 5. The compound according to claim 1 wherein the A and Ara rings are not further substituted. 6. The compound according to claim 1 selected from the group consisting of the following combinations, in which, unless expressly displayed otherwise, Ara is phenyl: Cpd W Y Z R6 481 CH CH H, 484 492 CH CH H, 493 CH CH H, 494 CH CH H, 495 CH CH H, 496 CH CH H, 497 CH CH H, 498 CH CH H, 499 CH CH H, 500 CH CH H, 501 CH CH H, 502 CH CH H, 503 CH CH H, 504 CH CH H, 505 CH CH H, 506 CH CH H, 507 CH CH H, 508 CH CH H, 509 CH CH H, 510 CH CH H, 511 CH CH H, 517 CH CH CH3, 518 CH CH CH3, 519 CH CH H, 520 CH CH H, 523 CH CH H, 526 CH CH H, 527 CH CH H, 528 CH CH H, 529 CH CH H, 530 CH CH H, 531 CH CH H, 532 CH CH H, 533 CH CH H, 534 CH CH H, 535 CH CH H, 536 CH CH H, 537 CH CH H, 538 CH CH H, 539 CH CH H, 540 CH CH H, 541 CH CH H, 542 CH CH H, 543 CH CH H, 544 CH CH H, 545 CH CH H, 546 CH CH H, 547 CH CH H, 548 CH CH H, 549 CH CH H, 550 CH CH H, 551 CH CH H, 552 CH CH H, 553 CH CH H, 554 CH CH H, 555 CH CH H, 556 CH CH H, 557 CH CH H, 558 CH CH H, 559 CH CH H, 560 561 562 CH CH H, 563 CH CH H, 564 565 CH CH H, 566 CH CH H, 567 568 and 570 7. The compound according to claim 6 wherein the amide nitrogen and the amino nitrogen bound to Ara are ortho to each other. 8. The compound of formula (3b): or pharmaceutically acceptable salt thereof, wherein Y and Z are CH and W is selected from the group consisting of: F, and 9. The compound according to claim 8 wherein Y, Z and W are one of the following combinations Cpd W Y Z 164 CH CH, 166 CH CH, 169 CH CH, 170 CH CH, 172 CH CH, 179 CH CH, 180 CH CH, 181 CH CH, 182 CH CH, or 183 CH CH. 10. The compound according to claim 8 wherein Y, Z and W are one of the following combinations Cpd W Y Z 187 CH CH, 188 CH CH, 189 CH CH, 190 CH CH, 193 CH CH, 194 CH CH, 195 CH CH, 196 CH CH, 320 CH CH, 321 CH CH, 322 CH CH, 323 CH CH, 325 CH CH, 326 CH CH, 327 CH CH, 328 CH CH, 329 CH CH, 330 CH CH, 331 CH CH, 332 CH CH, 333 CH CH, 334 CH CH, 335 CH CH, 336 CH CH, 337 CH CH, 338 CH CH, 339 CH CH, 340 CH CH, 341 CH CH, 342 CH CH, 343 CH CH, 344 CH CH, 345 CH CH, 346 CH CH, 347 CH CH, 348 CH CH, 349 CH CH, 350 CH CH, 351 CH CH, 356 CH CH, 357 CH CH, 358 CH CH, 359 CH CH, 360 CH CH, 361 CH CH, 362 CH CH, 363 CH CH, 364 CH CH, 365 CH CH, 366 CH CH, 368 CH CH, 369 CH CH, 370 CH CH, 375 CH CH, 377 CH CH, 378 CH CH, 379 CH CH, 381 CH CH, 382 CH CH, 383 CH CH, 384 CH CH, 385 CH CH, 386 CH CH, 387 CH CH, 388 CH CH, 389 CH CH, 390 CH CH, 391 CH CH, 392 CH CH, 393 CH CH, 394 CH CH, 395 CH CH, 396 CH CH, 397 CH CH, 399 CH CH, 400 CH CH, 401 CH CH, 402 CH CH, 403 CH CH, 404 CH CH, 405 CH CH, 406 CH CH, 407 CH CH, 408 CH CH, 409 CH CH, 410 CH CH, 411 CH CH, 412 CH CH, 413 CH CH, 414 CH CH, 415 CH CH, 416 CH CH, 417 CH CH, 418 CH CH, 419 CH CH, 420 CH CH, 421 CH CH, 422 CH CH, 423 CH CH, 424b CH CH, 425 CH CH, 426 CH CH, 427 CH CH, 428 CH CH, 429 CH CH, 430 CH CH, 431 CH CH, 432 CH CH, 433 CH CH, 434 CH CH, 435 CH CH, 436 CH CH, 437 CH CH, 438 CH CH, 439 CH CH, 440 CH CH, 441 CH CH, 442 CH CH, 443 CH CH, 444 CH CH, 447 CH CH, 448 CH CH, 449 CH CH, 450 CH CH, 451 F CH CH, 452 CH CH, 453 454 455 CH CH, 456 CH CH, 457 458 CH CH, 459 CH CH, 461 CH CH, 462 CH CH, 465 CH CH, 466 CH CH, 467 CH CH, or 468 CH CH. 11. A compound selected from the group consisting of the following and their pharmaceutically acceptable salts: 12. A histone deacetylase inhibitor selected from the group consisting of the following compounds and their pharmaceutically acceptable salts: N-(2-Amino-phenyl)-4-(quinolin-2- ylsulfanylmethyl)-benzamide, N-(2-Amino-phenyl)-4-(4,6-dimethyl- pyrimidin-2-ylsulfanylmethyl)-benzamide, N-(2-Amino-phenyl)-4-(4-trifluoromethyl- pyrimidin-2-ylsulfanylmethyl)-benzamide, Biphenyl-4,4'-dicarboxylic acid bis-[(2- amino-phenyl)-amide], N-(2-Amino-phenyl)-4-(2,4-dioxo-1,4- dihydro-2H-thieno[3,2-d]pyrimidin-3- ylmethyl)-benzamide, N-(2-Amino-phenyl)-4-[bis-(3- trifluoromethoxy-benzyl)-amino]- benzamide, and N-(2-Amino-phenyl)-3-(4-{[1-(3-benzyl- 7-chloro-4-oxo-3,4-dihydro-quinazolin-2- yl)-ethylamino]-methyl}-phenyl)- acrylamide. 13. A composition comprising a compound according to any one of claim 1-7 or 8-10 and a pharmaceutically acceptable carrier. 14. A method of treating or inhibiting colon cancer, the method comprising administering to a patient in need thereof a effective amount of a compound according to any one of claims 1-7 and 8-12, or a pharmaceutical composition thereof. 15. A method of treating or inhibiting colon cancer, the method comprising administering to a patient in need thereof an effective amount of a compound of structural formula (2a): or a pharmaceutically acceptable salt thereof, said compound optionally administered together with a pharmaceutically acceptable carrier, wherein Ara is phenyl or thienyl; R6 is H, or C1-C6-alkyl; Y and Z are--CH═; W is halo; or W, the annular C to which it is bound, and Y together form a monocyclic cycloalkyl, heterocyclyl, aryl, or heteroaryl; and wherein the A and Ara rings are optionally further substituted with from 1 to 3 substituents independently selected from methyl, hydroxy, methoxy, halo, and amino.
Bing-Yan Zhu ; Penglie Zhang ; Lingyan Wang ; Wenrong Huang ; Erick A. Goldman ; Wenhao Li ; Jingmei Zuckett ; Yonghong Song ; Robert M. Scarborough, Benzamides and related inhibitors of factor Xa.
Saunders, Jeffrey O.; Elbaum, Daniel; Novak, Perry M.; Naegele, Douglas; Bethiel, Randy S.; Ronkin, Steven M.; Badia, Michael C.; Frank, Catharine; Stamos, Dean P.; Walters, William; Pearlman, David, Inhibitors of IMPDH enzyme technical field of the invention.
Pederson Thoru (Worcester MA) Agrawal Sudhir (Shrewsbury MA) Mayrand Sandra (Shrewsbury MA) Zamecnik Paul C. (Shrewsbury MA), Method of site-specific alteration of RNA and production of encoded polypeptides.
Pederson Thoru (Worcester MA) Agrawal Sudhir (Shrewsbury MA) Mayrand Sandra (Shrewsbury MA) Zamecnik Paul C. (Shrewsbury MA), Method of site-specific alteration of RNA and production of encoded polypeptides.
Weiershausen Ute (Gundelfingen DEX) Satzinger Gerhard (Denzlingen DEX) Vollmer Karl-Otto (Freiburg DEX) Herrmann Wolfgang (Merzhausen DEX), N-(2′-aminophenyl)-benzamide derivatives process for the preparation thereof and pharmaceutical compositions containing.
Ajamian, Alain; Chantigny, Yves Andre; Vaisburg, Arkadii; Raeppel, Franck; Raeppel, Stephane; Deziel, Robert, Prodrugs of compounds that enhance antifungal activity and compositions of said prodrugs.
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