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ZA200104277B - Combination chemotherapy. - Google Patents

Combination chemotherapy. Download PDF

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Publication number
ZA200104277B
ZA200104277B ZA200104277A ZA200104277A ZA200104277B ZA 200104277 B ZA200104277 B ZA 200104277B ZA 200104277 A ZA200104277 A ZA 200104277A ZA 200104277 A ZA200104277 A ZA 200104277A ZA 200104277 B ZA200104277 B ZA 200104277B
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South Africa
Prior art keywords
phenylamino
methyl
benzamide
iodo
difluoro
Prior art date
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ZA200104277A
Inventor
Richard Carleton Gowan
Judith Sebolt-Leopold
Original Assignee
Warner Lambert Co
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Publication of ZA200104277B publication Critical patent/ZA200104277B/en

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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Description

COMBINATION CHEMOTHERAPY
FIELD OF THE INVENTION
This invention relates to a method for treating cancer in a patient in need of such treatment, said method comprising the step of administering to the patient a mitotic inhibitor and the step of administering to the patient a MEK inhibitor. The invention also relates to compositions or packaged units comprising a mitotic inhibitor and a MEK inhibitor.
BACKGROUND OF THE INVENTION
Cancer chemotherapy can entail the use of a combination of agents, generally as a means to reduce the toxic effects of the individual agents when used alone, and in some instances because the combination has greater efficacy than when either agent is used alone.
Mitotic inhibitors are antineoplastic agents that adversely affect the microtubular network in cells that is essential for mitotic and interphase cellular function. Mitotic inhibitors generally bind to free tubulin in cells, promoting the assembly of tubulin into stable microtubules, and simultaneously inhibiting their disassembly. Thus stabilized, microtubules cannot function normally. which in turn results in the inhibition of interphase and mitotic functions in the cell.
Several mitotic inhibitors are now used clinically to treat a variety of cancers. For example, paclitaxel, a natural product, is an antimicrotubule agent that not only promotes the assembly of microtubules from tubulin dimers but also stabilizes microtubules by preventing depolymerization. In addition, paclitaxel induces abnormal arrays or bundles of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis. Paclitaxel is indicated primarily for ovarian carcinoma and breast cancer, although it is useful in treating other cancers such as lung cancer. Use of paclitaxel is generally accompanied by undesirable side effects, including hypersensitivity reactions, hypotension. bradycardia,
hypertension, nausea and vomiting, and injection-site reactions. Docetaxel. another mitotic inhibitor, acts much like paclitaxel in its ability to bind to microtubules. Other mitotic inhibitors include the vinca alkaloids, such as vinblastine, vincristine and vinorelbine. as well as denvatives of such compounds such as vinflunine.
MEK inhibitors are compounds which inhibit one or more of the family of mammalian enzymes known as MAP kinase kinases, which phosphorylate the
MAP kinase subfamily of enzymes (mitogen-associated protein kinase enzymes) referred to as MAP kinases or ERKs (extracellular signal-regulating enzymes such as ERK1 and ERK 2). These enzymes regulate phosphorylation of other enzymes and proteins within the mammalian body. MEK 1 and MEK 2, as well as ERK1 and ERK 2, are dual specificity kinases that are present in all cell types and play a critical role in the regulation of cell proliferation and differentiation in response to mitogens and a wide variety of growth factors and cytokines. Upon activation, these enzymes control a cascade that can phosphorylate a large number of substrates, including transcription factors, the EGF receptor, phospholipase A2, tyrosine hydroxylase, and cytoskeletal proteins. One selective MEK inhibitor has been shown to be useful to treat a number of proliferative disorders, including psoriasis, restenosis, and cancer, as described in US Patent No. 5,525,625, incorporated herein by reference. A whole series of MEK inhibitors have been described as useful to prevent and treat septic shock, see WO 98/37881.
The prior art fails to teach or suggest that any such selective MEK inhibitors can be combined with mitotic inhibitors according to this invention.
’ © WO 0037141 PCT/US99/30485 -
SUMMARY OF THE INVENTION
This invention features a method for treating a proliferative disease, said method including (a) the step of administering to a patient in need of such treatment a MEK inhibitor and (b) the step of administering to said patient a mitotic inhibitor, wherein the amount of the MEK inhibitor and the amount of the mitotic inhibitor are such that the combination of the agents is an effective anti- proliferative therapy. The administration of a mitotic inhibitor may be before, during, or after the administration of the MEK inhibitor. Simultaneous administration may be by the same (both actives by either local or systemic injection) or different routes (e.g., oral administration of a MEK inhibitor and intravenous administration of the mitotic inhibitor). The invention also encompasses the use of additional pharmaceutical agents, such as a second MEK inhibitor, an inhibitor of famesyl transferase (a ras inhibitor), a RAF inhibitor, a second mitotic inhibitor, an anti-angiogenesis agent, a steroid, or other anti-cancer agents, as well as adjuvants, enhancers, or other pharmaceutically active and pharmaceutically acceptable materials. Therefore, the invention provides a method for treating cancer by administering at least one (e.g., one, two, or three)
MEK inhibitors and at least one (e.g., one or two) mitotic inhibitors to the patient.
In one aspect, the amounts of each active may vary independently from each other over time. For example, a patient may receive a first MEK inhibitor with a mitotic agent for a period of time, and then the first MEK inhibitor may be replaced by a second MEK inhibitor.
The invention also features compositions, packaged units, and kits which include at least one MEK inhibitor and at least one mitotic inhibitor. For example, the invention encompasses: (a) a single formulation (whether tablet, solution, or suspension, for example) that includes both a mitotic inhibitor and a MEK inhibitor; (b) a blister pack containing separate formulations of each active, such as a tablet or capsule form of a MEK inhibitor and a capsule or ampoule of a solution of a mitotic inhibitor; and (c) a kit with separate formulations of each active packaged together in a box with instructions for combination
Selective MEK 1 or MEK 2 inhibitors are those compounds which inhibit the MEK 1 or MEK 2 enzymes without substantially inhibiting other enzymes such as MKK3, ERK, PKC, Cdk2A, phosphorylase kinase, EGF and PDGF receptor kinases, and C-src. In general. a selective MEK | or MEK Z inhibitor nas an ICso for MEK 1 or MEK 2 that is at least one-fifueth (1/50) that of 11s ICs, for one of the above-named other enzymes. Preferably, a selective inhibitor has an
ICs, that is at least 1/100, more preferably 1/500, and even more preferably 1/1000, 1/5000 or less than that of its ICsq for one or more of the above-named enzymes.
In a preferred embodiment, the combination to be used according to this invention comprises the mitotic inhibitor paclitaxel. In another embodiment, a mitotic inhibitor is used in combination with the MEK inhibitor 2-(2-amino- 3-methoxyphenyl)-4-oxo-4H-[1]benzopyran, which is described in US Patent No. 5,525,625. In another preferred embodiment, the mitotic inhibitor administered is selected from paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, and
According to one aspect of the invention, the mitotic inhibitor is administered in combination with a selective MEK inhibitor which is a phenyl amine derivative of Formula L 2 v4
R)
N or
Brorl Ry R,
In Formula (I), Ry is hydrogen, hydroxy, C1-Cg alkyl, C1-Cg alkoxy, halo, trifluoromethyl, or CN. Rj is hydrogen. R3, R4, and Rs are independently selected from hydrogen, hydroxy, halo, trifluoromethyl, C1-Cg alkyl,
C1-Cg alkoxy, nitro, CN, and «(0 or NH);~(CH2)n-Ro. Rg is hydrogen, hydroxy,
COOH, or NRjoR}j; nis 0-4; misOor 1.
Each of Rj and Ry] is independently selected from hydrogen and C}-Cg alkyl, or taken together with the nitrogen to which they are attached can complete a 3-10 member cyclic ring optionally containing 1, 2, or 3 additional heteroatoms selected from O, S, NH, or N«(C1-Cg alkyl). Z is COOR7, tetrazolyl, CONRgR7,
CONHNR0R]{, or CH2OR7. Rg and R7 independently are hydrogen,
C)-Cg alkyl, C>-Cg alkenyl, C2-Cg alkynyl, (CO)-C-Cg alkyl, aryl, heteroaryl,
C3-Cjg cycloalkyl, or C3-Cj¢ (cycloalkyl optionally containing one, two, or three heteroatoms selected from O, S, NH, or N alkyl); or Rg and R7 together with the nitrogen to which they are attached complete a 3-10 member cyclic ring optionally containing 1, 2, or 3 additional heteroatoms selected from O, S, NH, or N alkyl. In formula (I), any of the foregoing alkyl, alkenyl, aryl, heteroaryl, heterocyclic, and alkynyl groups can be unsubstituted or substituted by halo, hydroxy, C;-Ce alkoxy, amino, nitro, C;-C4 alkylamino, di(C;-C)alkylamino, C3-C¢ cycloalkyl, phenyl, phenoxy, C;-Cs heteroaryl or heterocyclic radical, or C3-Cs heteroaryloxy or heterocyclic radical-oxy. The invention also provides a pharmaceutically acceptable salt, ester, amide, or prodrug of each of the disclosed MEK inhibitors.
Preferred embodiments of Formula (I) have a structure wherein: (a) R, is hydrogen, methyl, methoxy, fluoro, chloro, or bromo; (b) Rz is hydrogen; (c) Rs,
Ry, and Rs independently are hydrogen, fluoro, chloro. bromo, iodo. methyl, methoxy, or nitro; (d) Rj and Ry; independently are hydrogen or methyl; (e) Zis
COOR3, tetrazolyl, CONRsR7, CONHNR oR 11, or CHOR7; R¢ and R+ independently are hydrogen, C 14 alkyl, heteroaryl, or C 3.5 cycloalkyl optionally containing one or two heteroatoms selected from O, S, or NH; or Rg and Ry together with the nitrogen to which they are attached complete a 5-6 member cyclic ring optionally containing 1 or 2 additional heteroatoms selected from O,
NH or N-alkyl; and wherein any of the foregoing alkyl or aryl groups can be unsubstituted or substituted by halo, hydroxy, methoxy, ethoxy, or heteroaryloxy (such as 2,3,4,5,6-pentaflucrophenyl); (f) Z is COORy; (g) R7 is H, pentafiuorophenyl, or tetrazolyl; (h) Rs, Ra, and Rs are independently H, fluoro, or chloro; (i) Rs is fluoro; (j) two of R3, Rs, and Rs are fluoro; (k) or combinations of the above. In another preferred embodiment of Formula (I), R; is methyl, fluoro, chloro, or bromo.
In a more preferred embodiment, the MEK inhibitor is selected from a compound in Formula (I) Compound Table below.
: © Wo o0037141 PCT/US99/30485 -
FORMULA (I) COMPOUND TABLE (page 1 of 10) [4-Chloro-2-(1H-tetrazol-5-yl)-phenyl-(4-iodo-2-methyl-phenyl)-amine (4-iodo-2-methyl-phenyl)-[2-(1H-tetrazol-5-yl)-phenylJamine [4-nitro-2-(1H-tetrazo}-5-yl)-phenyl-(4-iodo-2-methyl-phenyl)-amine 4-Fluoro-2-(4-iodo-2-methylphenylamino)benzoic acid 3 4,5-Trifluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid 5-Bromo-3 ,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid
Sodium 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoate 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-benzoic acid 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-benzoic acid 4-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid 2-(4-Iodo-2-methyl-phenylamino)-benzoic acid 5-Fluoro-2-(4-iodo-2-methy!-phenylamino)-benzoic acid 5-Jodo-2-(4-iodo-2-methyl-phenylamino)-benzoic acid 2,3,5-Trifluoro-4-(4-iodo-2-methyl-phenylamino)-benzoic acid 2-(4-Iodo-phenylamino)-5-methoxy-benzoic acid 5-Methyl-2-(4-iodo-2-methyl-phenylamino)-benzoic acid 2-(4-lodo-2-methyl-phenylamino)-4-nitro-benzoic acid 2-(4-Bromo-2-methyl-phenylamino)-4-fluoro-benzoic acid 2-(2-Bromo-4-iodo-phenylamino)-5-nitro-benzoic acid 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-benzoic acid 5-Chloro-N-(2-hydroxyethyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-benzamide
N-Ethyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl-benzamide 4-Fluoro-2~(4-iodo-2-methyl-phenylamino)-N~(1 H-tetrazol-5-yl)-benzamide
FORMULA (I) COMPOUND TABLE (continued, page 2 of 10) 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide 3 5-Chloro-2-(4-iodo-2-methyl-phenylamino -N.N-dimethyi-benzamide [5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoylamino]-acetic acid 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-propyl-benzamide 5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide
N,N-Diethyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 4-Fluoro-N-{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-propyl }-2-(4-iodo- 2-methyl-phenylamino)-benzamide
N,N-Diethyl-2-(4-iodo-2-methyl-phenylamino)-S-nitro-benzamide
N-Butyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Chloro-N ,N-diethyl-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl-benzamide 5-Bromo-3,4-difluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide
N-(2,3-Dihydroxy-propyl)-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-1- yl-ethyl)-benzamide 3,4-Difluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide
N-(2,3-Dihydroxy-propyl)-4-flucro-2-(4-iodo-2-methyl-phenylamino)- benzamide 3,4-Difluoro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-1- yl-ethyl)-benzamide 5-Bromo-3,4-difluoro-2<(4-iodo-2-methyl-phenylamino)-N-(2-pyridin-4-yl- ethyl)-benzamide —_—
woonna PCT/US99/30485 -
FORMULA (I) COMPOUND TABLE (continued, page 3 of 10) 2-Fluoro-N-(2-hydroxy-cthyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Bromo-N-(3-dimethylamino-propyl)-3,4-difluoro-2-(4-iodo- 2-methylphenylamino)-benzamide 5-Bromo-3 ,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4- yl-ethyl)-benzamide 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl-ethyl)- benzamide 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-1-yl-ethyl)- benzamide 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin-4-yl-ethyl)- benzamide
N-(3-Dimethylamino-propyl)-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide
N-Benzyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 2-(4-Bromo-2-methyl-phenylamino)-3 ,4-difluoro-N-(2-hydroxy-ethyl)- benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl-ethyl)- benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-1 -yl-propyl)- benzamide . 3 4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-1-yl-propyl)- benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-thiophen-2-yl-ethyl)- benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-1-yl-ethyl)- benzamide 2-(4-Bromo-2-methyl-phenylamino)-3 ,4-difluoro-N-(2-morpholin-4-yi- ethyl)-benzamide
FORMULA (I) COMPOUND TABLE (continued, page 4 of 10) 5-Bromo-3 4-difluoro-2-(4-iodo-2-methyl-phenylamino)- N-pyridin4- yimethyl-benzamide 3,4-Difluoro-2+4-iodo-2-methyl-phenylamino)-N-pyridin-4-yimethyi- benzamide 2-(4-Bromo-2-methyl-phenylamino)-N-(3-dimethylamino- propyl) -3,4-difluoro-benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethyl-enzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin-4-yl-ethyl)- benzamide 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-pyridin-4-yl-ethyl)- benzamide 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(3-hydroxy-propyl)- benzamide 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-pyrrolidin-1-yl- ethyl)-benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-phenethyl-benzamide 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N~(2-thiophen-2-yl-ethyl)- benzamide 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-pyridin-4-ylmethyl- benzamide 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-phenethyl-benzamide 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-piperidin- 1-yl-ethyl)- benzamide 5-Chloro-N-{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl}-propyl }-2-(4-iodo-2- methyl- phenylamino)- benzamide 5-Fluoro-N-{3-{4-(2-hydroxy-ethyl)-piperazin-1-y1}-propyl } -2-(4-iodo-2- methyl- phenylamino)- benzamide 2-(4-lodo-2-methyl-phenylamino)-5-nitro-N-pyridin-4-yl methyl-benzamide
Wo on7I41 PCT/US99/30485
FORMULA (I) COMPOUND TABLE (continued, page 5 of 10) 5-Bromo-N-{3-[4-(2-bydroxy-cthyl)-piperazin-1-y1]-propyl}-2-(4-iodo-2- methyl- phenylamino)- benzamide 5-Chloro-N-(2-diethylamino-ethyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-1 -yl-ethyl)- benzamide (3-Hydroxy-pyrrolidin-1-yl)-[5-nitro-2-(4-iodo-2-methyl-phenylamino)-phenyl}- methanone 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-1-yl-ethyl)- benzamide 5-Bromo-N-(2-diethylamino-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide
N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5 -chloro-2-(4-iodo-2-methyl- phenylamino)- benzamide
N-{2-[Bis~(2-hydroxy-ethyl)-amino]-ethyl}-5-bromo-2-(4-iodo-2-methyl- phenylamino)- benzamide
N-{3-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-propyl }-2-(4-iodo-2-methyl- phenylamino)- benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethyl- benzamide 5-Bromo-2-(4-iodo-2-ethyl-phenylamino)}-N-(2-pyrrolidin-1-yl-ethyl)- benzamide 5-Bromo-2-(4-iodo-2-methyi-phenylamino)-N-(2-piperidin-1-yl-ethyl)- benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-1-yl-ethyl)- benzamide 5-Chloro-N-(3-dimethylamino-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide
N-{2-[Bis~(2-hydroxy-ethyl)-amino}-ethyl } -5-fluoro-2-(4-iodo-2-methy}- phenyiamino)- benzamide
FORMULA (I) COMPOUND TABLE (continued, page 6 of 10) 5-Chioro-N<(3-bydroxy-propyl)-2(4-iodo-2-methyl-phenylamino)}- 3 benzamide 5-Chioro-N-(3-diethylamino-2-hydroxy-propyl)-2-(4-iodo-2-methyl- phenylamino)- benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-1 -yl-ethyl)- benzamide 5-Bromo-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-1-yl-propyl)- benzamide
N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl }-2-(4-iodo-2-methyl- phenylamino)-5-nitro- benzamide 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl-ethyl)- benzamide 5-Chloro-N-(3-diethylamino-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide 5-Chloro-N-(2-diisopropylamino-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide . 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-1-yl-propyl)- benzamide 2-(4-lodo-2-methyl-phenylamino)-5-nitro-N-(2-piperidin-1-yl-ethyl)- benzamide 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperazin- 1-yl-ethyl)- benzamide
N-(2-Dicthylamino-ethyl)-S-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide 5-Bromo-N-(3-dimethylamino-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide
N-(3-Hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide
: © wooonT41 PCT/US99/30485
FORMULA (I) COMPOUND TABLE (continued, page 7 of 10) 5-Fluoro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl phenylamino)- benzamide
N-(3-Diethylamino-propyl)-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide
N-(3-Diethylamino-propyl)-2-(4-iodo-2-methyl-phenylamino)-3-nitro- benzamide 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl-ethyl)- benzamide 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(3-piperidin-1-yl-propyl)- benzamide [5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]}-(2 or 3-hydroxy- pyrrolidin-1-yl)-methanone 5-Bromo-N-(2-diisopropylamino-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl-ethyl)- benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-1-yl-propyl)- benzamide [5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl}-4-(2-hydroxy-ethyl)- piperazin-1-yl)-methanone
N-(3-Diethylamino-2-hydroxy-propyl)-5-fluoro-2-(4-iodo-2-methyl- phenylamino)- benzamide
N-Cyclopropyl-5-fluorc-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide
N-Benzyloxy-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide
N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide
FORMULA (I) COMPOUND TABLE (continued, page 8 of 10) 3{(&lodo-2-methyl-phenylamino)-5-nitro-N-(4-sulfamoyl-benzyl- 3 benzamide 5-Bromo-N~2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino )-benzamide
N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide
N-(2-Hydroxy-ethyl)-2-(4-iodo-2-ethyl-phenylamino)-5-nitro-benzamide 2-(4-Iodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl-benzamide 5-Chloro-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl-benzamide
N-Allyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide
N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)- benzamide
N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylamino)-benzamide
N-Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-S5-nitro-benzamide 5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl-benzamide 5-Iodo-2~(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)- benzamide 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)- benzamide
N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide 2-(4-lodo-2-methyl-phenylamino)-5-nitro-N-(4-sulfamoyl-benzyl)- benzamide
N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)-benzamide
N-Cyclopropyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide
- © wo 00537141 PCT/US99/30485 -
FORMULA (I) COMPOUND TABLE (continued, page 9 of 10)
SBromo-2-(+-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl-benzamide
N-Benzyloxy-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide
N-Cyclohexyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide
N-Allyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)-benzamide 2-(4-Todo-2-methyl-phenylamino)-N-(3-methyl-benzyl)-5-nitro-benzamide 5-Iodo-2~(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl-benzamide
N-Cyclohexyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Chloro-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)-benzamide 5-Bromeo-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide
N-Cyclohexyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide
N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide
N-Benzyloxy-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide . 2-(4-Iodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl-benzamide 5-Chloro-2~(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl-benzamide
N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Chloro-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-benzamide
N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl-benzamide
FORMULA (I) COMPOUND TABLE (continued, page 10 of 10)
N(3-Hydroxv-ethyl)-2-(4-iodo-2-methyl-phenylamino -S-nitro-benzamide 5-Fluoro-N-(2-hydroxy-ethyl)-2«(4-iodo-2-methyl-phenylamino »-benzam:ae 5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino )-benzamide
N-Cyclopropyl-5 -fluoro-2~(4-iodo-2-methyl-phenylamino)-benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)- benzamide
N-Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide
N-Ally}-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide
N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide
N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)- benzamide
N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzyl alcohol [5-Chloro-2-(4-iodo-2-methyl-phenylamino)-phenyl}-methanol [2-(4-Todo-2-methyl-phenylamino)-5-nitro-phenyl]-methanol [5-Bromo-2-(4-iodo-2-methyl-phenylamino)-phenyl}-methanol : N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide. ee
In another preferred embodiment, the MEK inhibitor is a compound of Formula II § fo
Ri, fa C-N—0—Ry,
N nn
Tr
Brorl Ry, Ry
In Formula (II), R) a is hydrogen, hydroxy, C1-Cg alkyl, C1-Cg alkoxy, halo, trifluoromethyl, or CN. Ry, is hydrogen. Each of R3a, Raa, and Rs, is independently selected from hydrogen, hydroxy, halo, trifluoromethyl,
C;-Cg alkyl, C1-Cg alkoxy, nitro, CN, and (O or NH)m-(CH2)n-Roa. Roa is hydrogen, hydroxy, CO2H or NR0aR11a; nis 0-4; and mis 0 or 1. Each of
Ra and R114 is independently hydrogen or C1-Cg alkyl, or taken together with the nitrogen to which they are attached can complete a 3- to 10-member cyclic ring optionally containing one, two, or three additional heteroatoms selected from O, S,
NH, or N-(C}-Cg alkyl). Req is hydrogen, C1-Cg alkyl, (CO}-(C1-Cg alkyl), aryl, aralkyl, or C3-Cyq cycloalkyl. R7, is hydrogen, C1-Cg alkyl, C>-Cg alkenyl,
C»-Cg alkynyl, C3-C1¢ (cycloalkyl or cycloalkyl optionally containing a heteroatom selected from O, S, or NRg,). In Formula (II), any of the foregoingany of the foregoing alkyl, alkenyl, aryl, heteroaryl, heterocyclic, and alkynyl groups be unsubstituted or substituted by halo, hydroxy, C;-Cs alkoxy, amino, nitro,
C,-C, alkylamino, di(C;-C4)alkylamino, C;3-Cg cycloalkyl, phenyl, phenoxy, Cs-Cs heteroaryl or heterocyclic radical, or C3-Cs heteroaryloxy or heterocyclic radical- oxy; or Rg, and R7, taken together with the N to which they are attached can complete a 5- to 10-membered cyclic ring, optionally containing one, two, or three additional heteroatoms selected from O, S, or NR10aR] 1a. The invention also encompasses pharmaceutically acceptable salts, esters, amides or prodrugs of each of the disclosed compounds.
Preferred embodiments of Formula (II) are those structures wherein: (a) Rya is H, methyl, fluoro, or chloro; (b) Ra, is H; Ras, Raa, and Rsaare each H,
Cl, nitro, or F; (c) Re, is H; (d) R7 is methyl, ethyl, 2-propenyl, propyl, butyl, pentyl, hexyl, cyclopropylmethyl, cyclobutyl methyl, cyclopropylmethyl, or cyclopropylethyl; (¢) the 4° position is 1, rather than Br; (f) Rs is F at the 4 position, para to the CO-N-Re-OR3, group and meta to the bridging nitrogen; () Raa or Rs, is F; (g) at least one of Rye, Rug, and Rs, is F; (h) Ria is methyl or chloro; or (i) or a combination of the above.
In a more preferred embodiment the MEK inhibitor is a compound selected from Formula (I) Compound Table below.
FORMULA (II) COMPOUND TABLE agelefh 4-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(methoxy)-benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N~(prop-2-ynyloxy)-benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-phenoxyethoxy)-benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-thienylmethoxy)-benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop-2-enyloxy)-benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N~(cyclopropylmethoxy)-benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclopentoxy)-benzamide 3 4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-furylmethoxy)-benzamide 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-ethoxy-benzamide 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(but-2-enyloxy)-benzamide 3 4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclopropylmethoxy)- benzamide 3 4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(1-methylprop-2-ynyloxy)- benzamide 3 4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-phenylprop-2-ynyloxy)- benzamide 3.4-Difluoro-2~(4-iodo-2-methyl-phenylamino)-N-(3-methyl-5-phenylpent-2-en- 4-ynyloxy)-benzamide 3 .4-Difluoro-2-(d-iodo-2-methyl-phenylamino)-N-(prop-2-ynyloxy)-benzamide 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(propoxy)-benzamide
FORMULA (I) COMPOUND TABLE (continued, page 2 of 7) 3 4-Difluoro-2-(4-10d0-2-methyl-phenylamino)-N-(cyclobutyloxy -benzamide 2 3.4-Difluoro-2-(4-iodo-2-methyi-phenyiamino »-N-(2-thienyimethoxy --benzamide 3 .4-Difluoro-2-(4-iodo-2-methyi-phenylamino)-N-(2-methyl-prop-- -envioxy » benzamide 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-phenoxyethoxy)-benzamide 3 4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(but-2-enyloxy)-benzamide 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(but-3-ynyloxy)-benzamide 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclopentyloxy)-benzamide 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-(2-fluorophenyl)-prop- 2-ynyloxy)-benzamide 5-Bromo-3 4-difluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(n-propoxy)- benzamide 5-Bromo-3 4-difluoro-N-(furan-3-ylmethoxy)-2-(4-iodo-2-methyl-phenylamino)- benzamide 5-Bromo-N-(but-2-enyloxy)-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide 5-Bromo-N-butoxy-3 4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 5.Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-but- 2-enyloxy)-benzamide 5-Bromo-3 4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-pent-2-en- 4-ynyloxy)-benzamide
© woosia PCT/US99/30485
FORMULA (II) COMPOUND TABLE (continued, page 3 of 7) 5-Bromo-3 4-difluoro-2-(d-iodo-2-methyl-benzyl)-N-[5-(3-methoxy-phenyl}- 3-methyl-pent-2-en-4-ynyloxy]-benzamide 5-Bromo-3 ,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop-2-ynyloxy)- benzamide 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-{3-(3-methoxy- phenyl)-prop-2-ynyloxy]-benzamide 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(thiopen- 2-ylmethoxy)-benzamide 5.Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(pyridin- 3-ylmethoxy)-benzamide 5-Bromo-3-4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-(2-flucrophenyl)- prop-2-ynyloxy)-benzamide 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyi-phenylamino)-N~(ethoxy)-benzamide 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (cyclopropylmethoxy)-benzamide 5-Bromo-3 ,4-diftuoro-2-(4-iodo-2-methyl-phenylamino)-N-(isopropoxy)- benzamide 5-Bromo-3,4-difluoro-2~(4-iodo-2-methyl-phenylamino)-N-but-3-ynyloxy)- benzamide 5-Chloro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(tetrahydro-pyran-2-yloxy)- benzamide 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methoxy-benzamide 4-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-phenyimethoxy-benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy-benzamide 5-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide 5.lodo-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy-benzamide 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N~(tetrahydropyran-2-yloxy)- benzamide
FORMULA (II) COMPOUND TABLE (continued, page 4 of 7) 3.4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(3-phenylprop-2-ynvicxy - 3 benzamide 3,4-Difluoro-2-(4-bromo-2-methyl-phenyiamino)-N-(3-furyimethoxy »-perzamige 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(2-thienylmethoxy)- benzamide 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(but-3-ynyloxy)-benzamide 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(2-methyl-prop-2-enyloxy)- benzamide 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(but-2-enyloxy)-benzamide 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(methoxy)-benzamide 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(ethoxy)-benzamide 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(cyclobutoxy)-benzamide 3 4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(isopropoxy)-benzamide 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(2-phenoxyethoxy)- benzamide 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(cyclopropylmethoxy)- benzamide 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(n-propoxy)-benzamide 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N~(1 -methyl-prop-2-ynyloxy)- benzamide 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(3-(3-fluorophenyl)-prop- 2-ynyloxy)-benzamide 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(4,4-dimethylpent- 2-ynyloxy)-benzamide
SE
FORMULA (i) COMPOUND TABLE (continued, page 5 of 7) 34 Difivoro-3-(4-bromo.3-methyl-phenylamino) N-(cyclopentoxy)-benzamide 3.4,5-Trifluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide 5.Chloro-3 4-difluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide 5-Bromo-3 _4-diftuoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy-benzamide
N-Hydroxy-2-(4-iodo-2-methyl-phenylamino)-4-nitro-benzamide 3 4,5-Trifluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy-benzamide 5-Chloro-3 4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy-benzamide 5-Bromo-2-(2-chloro-4-iodo-phenylamino)-3 4-difluoro-N-hydroxy-benzamide 2-(2-Fluoro-4-iodo-phenylamino)-N-hydroxy-4-nitro-benzamide 2-(2-Chloro-4-iodo-phenylamino)-3 4, 5-trifluoro-N-hydroxy-benzamide 5-Chloro-2-(2-chloro-4-iodo-phenylamino)-3 ,a-difluoro-N-hydroxy-benzamide 5-Bromo-2-(2-bromo-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy-benzamide 2-(2-Chloro-4-iodo-phenylamino)-N-hydroxy-4-methyl-benzamide 2-(2-Bromo-4-iodo-phenylamino)-3 4,5-trifluoro-N-hydroxy-benzamide 2-(2-Bromo-4-iodo-phenylamino)-5-chioro-3,4-difluoro-N-hydroxy-benzamide 2-(2-Bromo-4-iodo-phenylamino)-N-hydroxy-4-nitro-benzamide 4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy-benzamide 3,4-Difluoro-2-(2-fluoro—4-iodo-phenylamino)-N-hydroxy-benzamide 2-(2-Chloro-4-iodo-phenylamino)-4-fluoro-N-hydroxy-benzamide 2-(2-Chloro-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy-benzamide 2-(2-Bromo-4-iodo-phenylamino)-4-fluoro-N-hydroxy-benzamide 2-(2-Bromo-4-iodo-phenylamino)-3 .A-difluoro-N-hydroxy-benzamide
UE
’ iad
FORMULA (II) COMPOUND TABLE (continued, page 6 of 7)
N-Cyclopropylmethoxy-3,4,5-rifiuoro-2-{4-iodo-2-methyl-phenylamino)- 3 penzamide 5-Chioro-N-cyclopropylmethoxy-3 4-difluoro-2-{4-10d0-2-methvi-phenyiamino ~- benzamide 5-Bromo-N-cyclopropylmethoxy-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide
N-Cyclopropylmethoxy-2-(4-iodo-2-methyl-phenylamino)-4-nitro-benzamide
N-Cyclopropylmethoxy-3,4,5-trifluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide 5-Chloro-N-cyclopropylmethoxy-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide 5-Bromo-2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro- benzamide
N-Cyclopropylmethoxy-2-(2-fluoro-4-iodo-phenylamino)-4-nitro-benzamide 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3 ,4,5-trifluoro- benzamide 5-Chloro-2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro- benzamide 5-Bromo-2-(2-bromo-4-iodo-phenylamino)-N-ethoxy-3,4-difluoro-benzamide 2-(2-Chloro-4-iodo-phenylamino)-N-ethoxy-4-nitro-benzamide 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4,5-trifluoro- benzamide 2-(2-Bromo-4-iodo-phenylamino)-5-chloro-N-cyclopropylmethoxy-3,4-difluoro- benzamide 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropyimethoxy-4-nitro-benzamide
FORMULA (II) COMPOUND TABLE (continued, page 7 of 7)
N-Cyclopropylmethoxy4-fuoro-2-2-fiuoro—4-iodo-phenylamino)-benzamide
N-Cyclopropylmethoxy-3,4-difluoro-2-(2-fluoro-4-jodo-phenylamino)-benzamide 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-fluoro-benzamide 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3 ,4-difluoro-benzamide 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-fluoro-benzamide 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro- benzamide.
Co ———— ——tat—————
In a further preferred embodiment of this invention, a mitotic inhibitor is administered to a patient suffering from cancer and in need of treatment in combination with a selective MEK inhibitor selected from: 2-(2-Chloro- 4-iodophenylamino)-N-cyclopropylmethoxy-3 _4-difluorobenzamide (PD184352); 2-2 -Methyl-4-iodophenylamino)-N-hydroxy-4-fluorobenzamide (PD170611); 2-(2-Methyl-4-iodophenylamino)-N-hydroxy-3,4-difluoro-5-bromobenzamide (PD171984); 2-(2-Methyl-4-iodophenylamino)-N-cyclopropylmethoxy- 3,4~difluoro-5-bromobenzamide (PD177168); 2~(2-Methyl-4-iodophenylamino)-
N-cyclobutylmethoxy-3,4-difluoro-5-bromobenzamide (PD 180841); 2-(2-Chloro- 4-iodophenylamino)-N-cyclopropylmethoxy-3 _4-difluoro-5-bromobenzamide (PD 184161); 2-(2-Chloro-4-iodophenylamino)-N-hydroxy-3 4-difluoro- 5-bromobenzamide (PD 184386); 2-(2-Chloro-4-iodophenylamino)-N- cyclobutylmethoxy-3,4-difluorobenzamide (PD 185625); 2-(2-Chloro- 4-iodophenylamino)-N-hydroxy-4-fluorobenzamide (PD 185848); 2-(2-Methyl- 4-iodophenylamino)-N-hydroxy-3,4-difluorobenzamide (PD 188563); 2-(2-Methyl-4-iodophenylamino)-N-cyclopropylmethoxy- 3,4,5-trifluorobenzamide (PD 198306); and 2-(2-Chloro-4-iodophenylamino)-N- cyclopropylmethoxy-4-fluorobenzamide (PD 203311); and the benzoic acid derivatives thereof. For example, the benzoic acid derivative of PD 198306 is 2-(2-Methyl-4-iodophenylamino)-3,4,5-triflucrobenzoic acid.
Additional preferred compounds include 2-(2-chloro-4- iodophenylamino)-5-chloro-N-cyclopropylmethoxy -3,4-difluorobenzamide (PD 297189), 2-(4-iodophenyiamino }N-cyclopropylmethoxy-5-chioro-3.4- difluorobenzamide (PD 297190;. 2-(4-10dophenylamino ~3-chlore-> <- difluorobenzoic acid (PD 296771), 2«2-chloro-4-iodophenyiamino - 3-chioro- 3,4-difluorobenzoic acid (PD 296770), 5-chloro-3,4-difluoro-2~(4-10do-2- methylphenylamino)-benzoic acid (PD 296767); and 5-chloro-N- cyclopropylmethoxy -3,4-difluoro-2-(4-iodo-2-methylphenylamino)-benzamide (PD ).
The most preferred embodiment of this invention is a combination of paclitaxel and the MEK inhibitor 2-(2-chloro-4-iodophenylamino)-N- cyclopropylmethoxy-3,4-difluorobenzamide (PD184352).
The invention further provides methods of synthesis and synthetic intermediates.
Other features and advantages of the invention are apparent from the "figures, description, examples, and claims below.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 shows the effect on apoptosis in colon 26 carcinoma cells of paclitaxel (Taxol®, paclitaxel injection, Bristol-Meyers Squibb) alone, of 2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide (PD184352) alone, and of the combination of the two agents.
FIG. 2 shows a second experiment measuring the effect on apoptosis in colon 26 carcinoma cells of Taxol alone and of 2-(2-chloro-4-iodophenylamino)-
N-cyclopropylmethoxy-3,4-diflucrobenzamide (PD184352) alone, and the combination of the two agents.
FIG. 3 shows the effect on apoptosis in HT-29 colon carcinoma cells treated with Taxol alone, with 2-(2-chloro-4-iodophenylamino)-N- cyclopropylmethoxy-3,4-difluorobenzamide (PD184352) alone, and the combination of the two agents.

Claims (1)

  1. CLAIMS What is claimed is:
    1. An anticancer combination which comprises a mitotic inhibitor and a MEK inhibitor.
    2. The combination according to Claim 1 wherein the MEK inhibitor is 2-(2-amino-3-methoxyphenyl)-4-oxo-4H-[1]benzopyran.
    3. The combination according to Claim 1 wherein the mitotic inhibitor is selected from paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, and vinflunine.
    4. The combination according to Claim 1 wherein the MEK inhibitor is a phenyl amine compound of Formula I: fz z R; N Rs 1 Brorl R4 Ry wherein: Rj is hydrogen, hydroxy, C1-Cg alkyl, C1-Cg alkoxy, halo, trifluoromethyl, or CN; Ry is hydrogen; R3, Ry, and Rs independently are hydrogen, hydroxy, halo, trifluoromethyl, C1-Cg alkyl, C1-Cg alkoxy, nitro, CN, or +O or NH)y(CH2)n-Rg, where Rg is hydrogen, hydroxy, COOH, or NR10R11; nis 0-4; misOorl;
    Ryo and R]} independently are hydrogen or C1-Cg alkyl, or taken together with the nitrogen to which they are attached can complete a 3-10 member cyclic ring optionally containing 1, 2, or 3 additional heteroatoms selected from O, S, NH, or N-C|-Cg alkyl; Z is COOR7, tetrazolyl, CONRgR7, CONHNRoR]1, or CHoOR7; Rg and R7 independently are hydrogen, C1-Cg alkyl, C2-Cg alkenyl, C»-Cg alkynyl, (CO)-C1-Cg alkyl, aryl, heteroaryl, C3-Cj cycloalkyl, or C3-Cj (cycloalkyl optionally containing 1, 2, or 3 heteroatoms selected from O, S, NH, or N alkyl); or Rg and R7 together with the nitrogen to which they are attached complete a 3-10 member cyclic ring optionally containing 1, 2, or 3 additional heteroatoms selected from O, S, NH, or N alkyl; and wherein any of the foregoing alkyl, alkenyl, aryl, heteroaryl, heterocyclic, and alkynyl groups can be unsubstituted or substituted by halo, hydroxy, C,-C alkoxy, amino, nitro, C,-C4 alkylamino, di(C,-Cy)alkylamino, C3-C¢ cycloalkyl, phenyl, phenoxy, C3-Cs heteroaryl or heterocyclic radical, or C3-Cs heteroaryloxy or heterocyclic radical-oxy; or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
    s. The combination according to Claim 4 wherein the MEK inhibitor is a phenyl amine selected from: [4-Chloro-2-(1H-tetrazol-5-yl)-phenyl(4-iodo-2-methyl-phenyl)- amine; (4-Todo-2-methyl-phenyl)-[2-(1H-tetrazol-5-yl)-phenylJamine; [4-Nitro-2-(1H-tetrazol-5-yl)-phenyl-(4-iodo-2-methyl-phenyl)- amine; 4-Fluoro-2-(4-iodo-2-methylphenylamino)benzoic acid; 3,4,5-Trifluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid;
    5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid: Sodium 3-Chioro-Z -«+-1000-2-methyi-poenyiamine ~benzoats.
    3 5-Bromo-Z-i4-1000-2-methyi-pnenyiamino benzoic acid. 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-benzoic acid; 4-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; 2-(4-lodo-2-methyl-phenylamino)-benzoic acid; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid,
    5-Iodo-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; 2,3,5-Trifluoro-4-(4-iodo-2-methyl-phenylamino)-benzoic acid; 2-(4-Iodo-phenylamino)-5-methoxy-benzoic acid; 5-Methyl-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; 2-(4-lodo-2-methyl-phenylamino)-4-nitro-benzoic acid;
    2~(4-Bromo-2-methyl-phenylamino)-4-fluoro-benzoic acid; 2-(2-Bromo-4-iodo-phenylamino)-5-nitro-benzoic acid; 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-benzoic acid; 5-Chloro-N-(2-hydroxyethyl)-2-(4-iodo-2-methyl-phenylamino)-
    benzamide;
    4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-benzamide; N-Ethyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; 4-Fluoro-2-(4-todo-2-methyl-phenylamino)-N,N-dimethyl-
    benzamide;
    4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(1H-tetrazol-5-yl)-
    benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl- benzamide; } [5-Chloro-2+(4-iodo-2-methyl-phenylamino)-benzoylamino]-acetic acid; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-propyl-benzamide;
    : ) © wo 0037141 PCT/US99/30485 ° 5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; N,N-Diethyl-4-fluoro-2(4-iodo-2-methyl-phenylamino)- benzamide; 4-Fluoro-N-{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-propyl}- 2-(4-iodo-2-methyl-phenylamino)-benzamide; N,N-Diethyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide; N-Butyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Chloro-N,N-diethyl-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl- benzamide; 5-Bromo-3,4-difluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide; N-(2.3-Dihydroxy-propyl)-3.4-difluoro-2<(4-iodo-2-methyi- phenylamino)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (2-piperidin-1-yl-ethyl)-benzamide; 3,4-Difluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide; N-(2,3-Dihydroxy-propyl)-4-fluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide; 3,4-Difluoro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (2-pyrrolidin-1-yl-ethyl)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (2-pyridin-4-yl-ethyl)-benzamide; 4-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Bromo-N-(3-dimethylamino-propyl)-3,4-difluoro-2-(4-iodo- 2-methyl-phenylamino)-benzamide; 83 i
    5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (2-morpholin-4-yl-ethyl)-benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino}-N-(2-morphohn- 4-yl-ethyl)-benzamde; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino }-N-(Z-pyrroiidin- 1-yl-ethyl)-benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin-4-vl- ethyl)-benzamide; N-(3-Dimethylamino-propyl)-3,4-difluoro-2-(4-iodo-2-methyl-
    phenylamino)-benzamide; N-Benzyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-hydroxy-
    ethyl)-benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl-
    ethyl)-benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-1-yl-
    propyl)-benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin- 1-yl-propyl)-benzamide;
    4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-thiophen-2-yl-
    ethyl)-benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-1-yl-
    ethyl)-benzamide; 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-morpholin-
    4-yl-ethyl)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-
    pyridin-4-ylmethyl-benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin- 4-ylmethyl-benzamide;
    2-(4-Bromo-2-methyl-phenylamino)-N-(3-dimethylamino-
    propyl)-3,4-difluoro-benzamide;
    4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4-yimethyl- : benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin-4-yl- ethyl)-benzamide; 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-pyridin- 4-yl-ethyl)-benzamide; 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(3-hydroxy- propyl)-benzamide; 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-pyrrolidin- I-yl-cthyly-benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-phenethyl- benzamide; 2-(4-Bromo-2-methyl-phenylamino)-3,4-difiuoro-N-(2-thiophen- 2-yl-ethyl)-benzamide; 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-pyridin- 4-yimethyl-benzamide; 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-phenethyl- benzamide; 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-piperidin- 1-yl-ethyl)-benzamide; 5-Chioro-N-{3-[4-(2-hydroxy-ethyl}-piperazin-1-yi]-propyl}- 2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Fluoro-N-{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl}-propyl}- 2-(4-iodo-2-methyl-phenylamino)-benzamide; 2-(4-lodo-2-methyl-phenylamino)-5-nitro-N-pyridin-4-yl methyl- benzamide; 5-Bromo-N-{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl}-propyl}- 2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Chloro-N-(2-diethylamino-ethyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide; 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-1-yl- cthyl)-benzamide;
    (3-Hydroxy-pyrrolidin-1-yl)-[2-(4-iodo-2-methyl-phenylamino)- 5-nitro-phenyl]; 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin- 1-vi- ethyl)-benzamide; h 5-Bromo-N-(2-diethyiamino-ethyl y-2-(4-10do-2-methyi- phenylamino)-benzamide; N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl }-5-chloro-2-(4-iodo- 2-methyl-phenylamino)-benzamide; N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl }-5-bromo-2-(4-iodo- 2-methyl-phenylamino)-benzamide; N-{3-[4-(2-Hydroxy-ethyl)-piperazin-1-yl}-propyl }-2-(4-iodo- 2-methyl-phenylamino)-benzamide; 5-Fluoro-2-(4-iodo-2-methyi-phenylamino)-N-pyridin-4-ylmethyl- benzamide; 5-Bromo-2-(4-iodo-2-ethyl-phenylamino)-N-(2-pyrrolidin-1-yi- ethyl)-benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-1-yl- ethyl)-benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-1-yl- ethyl)-benzamide; 5-Chloro-N-(3-dimethylamino-propyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide; N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl } -5-fluoro-2-(4-iodo- 2-methyl-phenylamino)-benzamide; 5-Chloro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Chloro-N-(3-diethylamino-2-hydroxy-propyl)-2-(4-iodo- 2-methyl-phenylamino)-benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-1-yl- ethyl)-benzamide; 5-Bromo-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide;
    5-Bromo-2~(4-iodo-2-methyi-phenylamino)-N-(3 -piperidin-1-yl- propyl)-benzamide; N-{2-[Bis-(2-hydroxy-ethyl)-amino}-ethyl}-2-(4-iodo-2-methyl- phenylamino)-5-nitro-benzamide; 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl- ethyl)-benzamide; 5-Chloro-N-(3-diethylamino-propyl)-2~(4-iodo-2-methyl- phenylamino)-benzamide; 5-Chloro-N-(2-diisopropylamino-ethyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide; 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N~(3-piperidin-1-yl- propyl)-benzamide; 2-(4-Todo-2-methyl-phenylamino)-5-nitro-N-(2-piperidin-1-yl- ethyl)-benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenyiamino)-N~(2-piperazin-1-yi- ethyl)-benzamide; N-(2-Diethylamino-ethyl)-5-fluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide; 5-Bromo-N-(3-dimethylamino-propyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide; N-(3-Hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide; 5-Fluoro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; N-(3-Diethylamino-propyl)-5-fluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide; N-(3-Diethylamino-propyl)-2-(4-iodo-2-methyl-phenylamino)- 5-nitro-benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl- ethyl)-benzamide; 2-(4-Iodo-2-methyl-phenylamino)-S-nitro-N-(3-piperidin-1-yl- propyl)-benzamide;
    [5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl}-(3-hydroxy- pyrrolidin-1-yl)-methanone 5-Bromo-N-(2-diisopropylamino-ethyl)-2-(4-10do-2-methyl- phenyiamino)-benzamide; 3 5-Fluoro-2-(4-iodo-2-methyl-phenylamino )-N-{Z-morphoiin—-y:- ethyl)-benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-1-yl- propyl)-benzamide; [5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]- [4-(2-hydroxy-ethyl)-piperazin-1-yl}-methanone; N-(3-Diethylamino-2-hydroxy-propyl)-5-fluoro-2-(4-iodo- 2-methyl-phenylamino)-benzamide; N-Cyclopropyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; N-Benzyloxy-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide; N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-phenylamino)- benzamide; 2-(4-lodo-2-methyl-phenylamino)-5-nitro-N-(4-sulfamoyl-benzyl)- benzamide; 5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl-phenylamino)- benzamide; N-(2-Hydroxy-ethyl)-2-(4-iodo-2-ethyl-phenylamino)-5-nitro- benzamide; 2-(4-lodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl- benzamide;
    © Wo 00537141 PCT/US99/30485 - 5-Chloro-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide;
    N-Allyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-
    benzyl)-benzamide; N-Ally}-5-chloro-2~(4-iodo-2-methyl-phenylamino)-benzamide; N-Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide; 5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Chloro-2~(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide; 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)- benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- benzyl)-benzamide; N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide; 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(4-sulfamoyl-benzyl)- benzamide; N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide; N-Cyclopropyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide; N-Benzyloxy-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide;
    N-Cyclohexyl-5-iodo-2+4-iodo-2-methyl-phenylamino)- benzamide; N-Allyl-5-iodo-2-(4~-iodo-2-methyl-phenylamino)-benzamide: S-lodo-2-t 4-10do-- -methyi-phenvlamino }-N-(3-metnyi-oenzvi- benzamide; 2-(4-lodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)-5-mtro- benzamide; 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide; N-Cyclohexyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Chloro-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide; 5-Bromo-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide; N-Cyclohexyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide; N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-phenylamino)- benzamide; N-Benzyloxy-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; 2-(4-Iodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl- benzamide;
    : | "© WO 0037141 PCT/US99/30485 - 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide; N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Chloro-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- benzamide; N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide; N-(2-Hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide; 5-Fluoro-N-(2-hydroxy-ethyl)-2~(4-iodo-2-methyl-phenylamino)- benzamide; 5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- benzamide; N-Cyclopropyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- benzyl)-benzamide; N-Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide; N-Allyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; N-Benzyloxy-5-iodo-2-(4-iodo-2-methy}-phenylamino)-benzamide; N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- benzyl)-benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide; N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzyl alcohol; [5-Chloro-2-(4-iodo-2-methyl-phenylamino)-phenyl}-methanol; [2-(4-Iodo-2-methyl-phenylamino)-5-nitro-phenyl]-methanol;
    [5-Bromo-2-(4-iodo-2-methyl-phenylamino)-phenyl]-methanol; and N-Allyl-2-(4-iodo-2-methyl-phenylamino)- 3-nitro-benzamide.
    6. The combination according to Claim 1 wherein the selective MEK inhibitor is a phenyl amine of Formula II: iP fe Rr, 2s C—N—0—R,, jog Rsa Brorl RS, Ry, wherein: R|g is hydrogen, hydroxy, C}-Cg alkyl, C1-Cg alkoxy, halo, trifluoromethyl, or CN; Rp, is hydrogen;
    R3a, R4a, and Rs, independently are hydrogen, hydroxy, halo,
    trifluoromethyl, C1-Cg alkyl, C{-Cg alkoxy, nitro, CN, or (O or NH)~(CH2)p-Rgg, Where Rog is hydrogen, hydroxy, COoH or NR10aR11a:
    nis 0-4;
    misOorl;
    R104 and R] | 5 independently are hydrogen or C1-Cg alkyl, or taken together with the nitrogen to which they are attached can complete a 3- to 10-member cyclic ring optionally containing one, two, or three additional heteroatoms selected from O, S, NH, or N-C1-Cg alkyl;
    Rega is hydrogen, C1-Cg alkyl, (CO)-C1-Cg alkyl, aryl, aralkyl, or
    C3-Cj cycloalkyl;
    R7, is hydrogen, C1-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, C3-C1¢ (cycloalkyl or cycloalkyl optionally containing a heteroatom selected from O, S, or NRgy,);
    and wherein any of the foregoing alkyl, alkenyl, aryl. heteroaryl, heterocyclic. and alkynyl groups can be unsubstituted or substituted by halo. hydroxy. C;-Ce alkoxy. amino. nitro. C.-C, alkvlamino. di C1-Cyjaikyviaminc. Cz-Ce CYCIOIKY.. DNEDY.. PNENOX: _:-o. 3 heteroaryi or heterocychic radical. or C:-C« neteroarvioxy or heterocyclic radical-oxy; or Rg and R74 taken together with the N to which they are attached can complete a 5- to 10-membered cyclic ring, optionally containing one, two, or three additional heteroatoms selected from O, S, or NRj0aR11a: Ora pharmaceutically acceptable salt, ester, amide or prodrug thereof.
    7. The anticancer combination of claim 6, wherein the MEK inhibitor has a structure of Formula (II) wherein R,, is methyl, fluoro, or chloro; Raz. is H; R34, R4a, and Rs, are each H or F; Re, is H; R, is methyl, ethyl, 2- propenyl, propyl, butyl, pentyl, hexyl, cyclopropylmethyl, cyclobutyl methyl, cyclopropylmethyl, or cyclopropylethyl; and 4° position is I.
    8. An anticancer combination comprising a mitotic inhibitor and a selective MEK 1 or MEK 2 inhibitor selected from: 4-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(methoxy)- benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop-2-ynyloxy)- benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-phenoxyethoxy)- benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-thienylmethoxy)- benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop-2-enyloxy)- benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- (cyclopropylmethoxy)-benzamide;
    : © Wo 0037141 PCT/US99/30485 - 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclopentoxy)- benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (3-furylmethoxy)-benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-ethoxy- benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(but-2-enyloxy)- benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclopropyl- methoxy)-benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(1-methylprop- 2-ynyloxy)-benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-phenylprop- 2-ynyloxy)-benzamide; 3,4-Difluoro-2-(4-iodo-2-metityi-phenylamino }-N-(3-methyl- 5-phenylpent-2-en-4-ynyloxy)-benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop- 2-ynyloxy)-benzamide; 3,4-Difluoro-2-(4-iodo-2-methyi-phenylamino)-N-(propoxy)- benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclobutyloxy)- benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (2-thienylmethoxy)-benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-methyl-prop- 2-enyloxy)-benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (2-phenoxyethoxy)-benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(but-2-enyloxy)- benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N~(but-3-ynyloxy)- benzamide;
    3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (cyclopentyloxy)-benzamide: 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino }-- ({3«(2-fluorophenyi -prop-Z-vnvioxy )-Denzamide. 3 5-Bromo-3,4-difluoro-N-hydroxy-Z-4-iodc-z-methy:- phenylamino)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (n-propoxy)-benzamide; 5-Bromo-3,4-difluoro-N-(furan-3-ylmethoxy)-2-(4-iodo-2-methyl- phenylamino)-benzamide; 5-Bromo-N-(but-2-enyloxy)-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide 5-Bromo-N-butoxy-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (3-methyl-but-2-enyloxy)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (3-methyl-pent-2-en-4-ynyloxy)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-benzyl)-N- [5-(3-methoxy-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop- 2-ynyloxy)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- [3-(3-methoxy-phenyl)-prop-2-ynyloxy]}-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (thiopen-2-ylmethoxy)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (pyridin-3-ylmethoxy)-benzamide; S-Bromo-3-4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (3-(2-fluorophenyl)-prop-2-ynyloxy)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (ethoxy)-benzamide;
    © wooo PCT/US99/30485 - 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (cyclopropylmethoxy)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (isopropoxy)-benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-but- 3-ynyloxy)-benzamide; 5-Chloro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(tetrahydro-pyran- 2-yloxy)-benzamide; 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methoxy- benzamide; 4-Bromo-2-(4-iodo-2-methyl-phenylamino)}-N-phenylmethoxy- benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy- benzamide; 5-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-lodo-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy- benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(tetrahydropyran- 2-yloxy)-benzamide; 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(3-phenyiprop- 2-ynyloxy)-benzamide; 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (3-furylmethoxy)-benzamide; 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (2-thienylmethoxy)-benzamide; 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(but- 3-ynyloxy)-benzamide; 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(2-methyl- prop-2-enyloxy)-benzamide; 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(but- 2-enyloxy)-benzamide;
    3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(methoxy )- benzamide:
    3.4-Difluoro-2+4-bromo-2-methyl-phenylamino -N-(etnoxy - penzamide: 3,4-Difluoro-2+4-bromo-Z-methyi-pnenylamino +N -i SVeiobutoxy » benzamide; 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-( isopropoxy)- benzamide; 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (2-phenoxyethoxy)-benzamide; 3 4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(cyclopropyl- methoxy)-benzamide; 3 4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(n-propoxy)- benzamide; 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N~(1 -methyl- prop-2-ynyloxy)-benzamide; 3 4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(3 -(3- fluorophenyl)-prop-2-ynyloxy)-benzamide; 3 4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(4,4- dimethylpent-2-ynyloxy)-benzamide; 3,4-Difluoro-2-(4-bromo-2-methy}-phenylamino)-N- (cyclopentoxy)-benzamide; 3 4,5-Trifluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Chloro-3,4-difluoro-N-hydroxy-2-(4-iodo-2-methyl- phenylamino)-benzamide; 5-Bromo-3,4-difluoro-2-(2-flucro-4-iodo-phenylamino)-N- hydroxy-benzamide; N-Hydroxy-2-(4-iodo-2-methyl-phenylamino)-4-nitro-benzamide; 3 4,5-Trifluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy- benzamide;
    - } "WoO 0037141 PCT/US99/30485 -
    5.Chloro-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N- hydroxy-benzamide; 5-Bromo-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N- hydroxy-benzamide; 2-(2-Fluoro-4-iodo-phenylamino)-N-hydroxy-4-nitro-benzamide; 2-(2-Chloro-4-iodo-phenylamino)-3,4,5-trifluoro-N-hydroxy- benzamide; 5-Chloro-2-(2-chloro4-iodo-phenylamino)-3,4-difluoro-N- hydroxy-benzamide; 5-Bromo-2-(2-bromo-4-iodo-phenylamino)-3,4-difluoro-N- hydroxy-benzamide; 2-(2-Chloro-4-iodo-phenylamino)-N-hydraxy-4-methyl-benzamide; 2-(2-Bromo-4-iodo-phenylamino)-3,4,5-trifluoro-N-hydroxy- benzamide; 2-(2-Bromo-4-iodo-phenyiammo }-3-chloro-3,4-difiuoro-N- hydroxy-benzamide; 2-(2-Bromo-4-iodo-phenylamino)-N-hydroxy-4-nitro-benzamide; 4-Fluoro-2-(2-flucro-4-iodo-phenylamino)-N-hydroxy-benzamide; 3 4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy- benzamide; 2-(2-Chloro-4-iodo-phenylamino)-4-fluoro-N-hydroxy-benzamide; 2-(2-Chloro-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy- benzamide; 2-(2-Bromo-4-iodo-phenylamino)-4-fluoro-N-hydroxy-benzamide; 2-(2-Bromo-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy- benzamide; N-Cyclopropylmethoxy-3,4,5-trifluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide; 5-Chloro-N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide; 5-Bromo-N-cyclopropylmethoxy-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide;
    N-Cyclopropylmethoxy-2-(4-iodo-2-methyl-phenylamino)-4-nitro- benzamide; N-Cyclopropylmethoxy-3.4.5-trifluoro-2-(2-fluoro-4-iodo- phenyiamino }-benzamiae. 3 5-Chloro-N-cyciopropyimetnoxy-3.4-difluore-2 - Z-fivoro—-ioac- phenylamino)-benzamide; 5-Bromo-2-(2-chloro-4-iodo-phenylamino)-N- cyclopropylmethoxy-3,4-difluoro-benzamide; N-Cyclopropylmethoxy-2-(2-fluoro-4-iodo-phenylamino)-4-nitro- benzamide; 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy- 3,4,5-triflucro-benzamide; 5-Chloro-2-(2-chloro-4-iodo-phenylamino)-N- cyclopropylmethoxy-3,4-difluoro-benzamide; 5-Bromo-2-(2-bromo-4-iodo-phenylamino)-N-ethoxy-3 ,4-difluoro- benzamide; 2-(2-Chloro-4-iodo-phenylamino)-N-ethoxy-4-nitro-benzamide; 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropyimethoxy- 3,4,5-trifluoro-benzamide; 2-(2-Bromo-4-iodo-phenylamino)-5-chloro-N- cyclopropylmethoxy-3,4-difluoro-benzamide 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-nitro- benzamide; N-Cyclopropyimethoxy-4-fluoro-2-(2-flucro-4-iodo-phenylamino)- benzamide; N-Cyclopropylmethoxy-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide; 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-fluoro- benzamide; 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy- 3,4-difluoro-benzamide;
    woosna PCT/US99/30485 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-fluoro- benzamide; or 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy- 3,4-difluoro-benzamide.
    8. The combination according to Claim 1 wherein the MEK inhibitor is a MEK or MEK 2 inhibitor selected from: 2-(2-chloro4-iodophenylamino)-N-cyclopropylmethoxy- 3,4-difluorobenzamide (PD184352); 2-(2-methyl-4-iodophenylamino)-N-hydroxy-4-fluorobenzamide (PD170611); 2-(2-methyl-4-iodophenylamino)-N-hydroxy-3.4-difluoro- 5-bromobenzamide (PD171984); 2-(2-methyl-4-iodophenylamino)-N-cyclopropylmethoxy- 3,4-difluoro-5-bromobenzamide (PD177168); 2-(2-methyl-4-iodophenylamino)-N-cyclobutyimethoxy- 3,4-difluoro-5-bromobenzamide (PD 180841); 2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy- 3,4-difluoro-S-bromobenzamide (PD 184161); 2-(2-chloro-4-iodophenylamino)-N-hydroxy-3 ,4-difluoro- S-bromobenzamide (PD184386); 2-(2-chloro-4-iodophenylamino)-N-cyclobutylmethoxy- 3,4-difluorobenzamide (PD 185625); 2-(2-chioro-4-iodophenylamino)-N-hydroxy-4-fluorobenzamide (PD 185848); 2-(2-methyl-4-iodophenylamino)-N-hydroxy-3,4- difluorobenzamide (PD 188563); 2-(2-methyl-4-iodophenylamino)-N-cyclopropyimethoxy- 3,4,5-rifluorobenzamide (PD 198306); and 2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy- 4-fluorobenzamide (PD 203311).
    PCT/US/99/30485
    9. An anticancer combination comprising paclitaxel and the MEK inhibitor 2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy- 3,4-difluorobenzamide (PD 184352).
    10. Use of a mitotic inhibitor in the manufacture of a medicament for use with a MEK inhibitor for treating cancer in a patient, wherein the respective amounts of the mitotic inhibitor and the MEK inhibitor are such that the combination provides an effective anticancer therapy.
    11. Use of a MEK inhibitor in the manufacture of a medicament for use with a mitotic inhibitor for treating cancer in a patient, wherein the respective amounts of me Imulomc inmdior anc me MEK muidior are such that the combination is an effective anticancer therapy.
    12. Use of a mitotic inhibitor and a MEK inhibitor in the manufacture of a medicament for treating cancer in a patient, wherein the respective amounts of the mitotic inhibitor and the MEK inhibitor are such that the combination is an effective anticancer medicament.
    13. Use according to any one of Claims 10 to 12, by administering the mitotic inhibitor and the MEK inhibitor other than simultaneously.
    14. Use according to any one of Claims 10 to 12, wherein the MEK inhibitor is a phenyl amine of Formula I.
    15. Use according to any one of Claims 10 to 12, wherein the MEK inhibitor is a phenyl amine of Formula II. AMENDED SHEET
    PCT/US/99/30485
    16. Use according to any one of Claims 10 to 12, wherein the MEK inhibitor used in combination with a mitotic inhibitor is a selective MEK 1 or MEK 2 inhibitor.
    17. Use according to Claim 16. wherein the MEK inhibitor is a compound selected from: 2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4- difluorobenzamide (PD 184352); 2-(2-methyl-4-iodophenylamino)-N-hydroxy-3,4-flucrobenzamide (PD 170611): 2-(2-methyl-4-iodophenylamino)-N-hydroxy-3.4-difluoro- 5-bromobenzamide (PD 171984); 2-(2-methy :~+-10d0pheny 1amino -N-C3 CiOPropy MMemox} -3 .+-diiucro- 5-bromobenzamide (PD 177168); 2-(2-methyl-4-iodophenylamino)-N-cyclobutylmethoxy-3,4-difluoro- 5-bromobenzamide (PD 180841); 2-(2~chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluoro- 5-bromobenzamide (PD 184161): 2-(2-chloro-4-iodophenylamino)-N-hyvdroxy-3.4-difluoro- 5-bromobenzamide (PD 184386); 2-(2-chloro-4-iodophenylamino)-N-cyclobutylmethoxy-3,4-difluoro- benzamide (PD 185625); 2-(2-chloro-4-iodophenylamino)-N-hydroxy-4-fluorobenzamide (PD 185848); 2-(2-methyl-4-iodophenylamino)-N-hydroxy-3,4-difluorobenzamide (PD 188563); 2-(2-methyl-4-iodophenylamino)-N-cyclobutylmethoxy-3,4,5- trifluorobenzamide (PD 198306); and 2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy- 4-fluorobenzamide (PD 203311). AMENDED SHEET
    PCT/US/99/30485
    18. Use according to any one of Claims 10 to 12, wherein the mitotic inhibitor is selected from paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, and vinflunine.
    19. Use according to Claim 18. wherein the mitotic inhibitor is paclitaxel.
    20. Use according to Claim 18, wherein the mitotic inhibitor is docetaxel.
    21. Use according to Claim 18, wherein the mitotic inhibitor is vincristine.
    22. Use according to Claim 18, wherein the mitotic inhibitor is vinbiasune.
    23. Use according to Claim 18, wherein the mitotic inhibitor is vinorelbine.
    24. Use according to Claim 18, wherein the mitotic inhibitor is vinoflunine.
    25. Use according to Claim 18, wherein the MEK inhibitor is 2-(2-chloro4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide (PD 184352).
    26. Use according to Claim 17, wherein the mitotic inhibitor is paclitaxel, docetaxel, or vincristine.
    27. A substance or composition comprising a mitotic inhibior for use with a MEK inhibitor in a method for treating cancer in a patient, said method comprising administering said substance or composition to a patient and AMENDED SHEET
    PCT/US/99/30485 administering to said patient said MEK inhibitor, wherein the amount of the mitotic inhibitor and the amount of the MEK inhibitor are such that the combination is an effective anticancer therapy.
    28. A substance or composition comprising a MEK inhibitor for use with a mitotic inhibitor in a method for treating cancer in a patient, said method comprising administering to a patient said mitotic inhibitor and administering said substance or composition to said patient, wherein the amount of the mitotic inhibitor and the amount of the MEK inhibitor are such that the combination is an effective anticancer therapy.
    29. A substance or composition for use in a method for treating cancer in a patent. said substance Or COMPOSINON cOMPIISING & Mitotic imbItor and a MEK inhibitor, and said method comprising administering said substance or composition to a patient, wherein the amount of the mitotic inhibitor and the amount of the MEK inhibitor are such that the combination is an effective anticancer therapy.
    30. A substance or composition for use in a method of treatment according to any one of Claims 27 to 29 wherein the administration of the mitotic inhibitor and the administration of the MEK inhibitor are not simultaneous.
    31. A substance or composition for use in a method of treatment according to any one of Claims 27 to 29 wherein the MEK inhibitor is a phenyl amine of Formula I.
    32. A substance or composition for use in a method of treatment according to any one of Claims 27 to 29 wherein the MEK inhibitor is a phenyl amine of Formula II. AMENDED SHEET
    PCT/US/99/30485
    33. A substance or composition for use in a method of treatment according to any one of Claims 27 to 29 wherein the MEK inhibitor used in combination with a mitotic inhibitor is a selective MEK1 or MEK 2 inhibitor. :
    34. A substance or composition for use in a method of treatment according to Claim 33 wherein the MEK inhibitor is a compound as defined in Claim 17.
    35. A substance or composition for use in a method of treatment according to anv one of Claims 27 to 29 wherein the mitotic inhibitor is selected from paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, and vinfiunine.
    36. A substance or composition for use in a method of treatment according to Claim 35 wherein the mitotic inhibitor is paclitaxel.
    37. A substance or composition for use in a method of treatment according to Claim 35 wherein the mitotic inhibitor is docetaxel.
    38. A substance or composition for use in a method of treatment according to Claim 35 wherein the mitotic inhibitor is vincristine.
    39. A substance or composition for use in a method of treatment according to Claim 35 wherein the mitotic inhibitor is vinblastine.
    40. A substance or composition for use in a method of treatment according to Claim 35 wherein the mitotic inhibitor is vinorelbine.
    41. A substance or composition for use in a method of treatment AMENDED SHEET
    PCT/US/99/30485 according to Claim 35 wherein the mitotic inhibitor is vinflunine. :
    42. A substance or composition for use in a method of treatment according to Claim 35 wherein the MEK inhibitor is 2-(2-chloro-4- iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide (PD 184352).
    43. A substance or composition for use in a method of treatment according to Claim 34 wherein the mitotic inhibitor is paclitaxel, docetaxel, OT Vincristine.
    44. A combination according to Claim 1, substantially as herein described anc uiustratea
    45. Use according to any one of Claims 10, 11 or 12, substantially as herein described and illustrated.
    46. A substance or composition for use in a method of treatment according to anv one of Claims 27. 28 or 29. substantially as herein described and illustrated.
    47. A new combination; new use of a mitotic inhibitor; a MEK inhibitor, or a mitotic inhibitor and a MEK inhibitor; or a substance or composition for a new use in a method of treatment, substantially as herein described. AMENDED SHEET
ZA200104277A 1998-12-22 2001-05-24 Combination chemotherapy. ZA200104277B (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010068738A1 (en) 2008-12-10 2010-06-17 Dana-Farber Cancer Institute, Inc. Mek mutations conferring resistance to mek inhibitors
WO2011106298A1 (en) 2010-02-25 2011-09-01 Dana-Farber Cancer Institute, Inc. Braf mutations conferring resistance to braf inhibitors
WO2013169858A1 (en) 2012-05-08 2013-11-14 The Broad Institute, Inc. Diagnostic and treatment methods in patients having or at risk of developing resistance to cancer therapy

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010068738A1 (en) 2008-12-10 2010-06-17 Dana-Farber Cancer Institute, Inc. Mek mutations conferring resistance to mek inhibitors
WO2011106298A1 (en) 2010-02-25 2011-09-01 Dana-Farber Cancer Institute, Inc. Braf mutations conferring resistance to braf inhibitors
EP3028699A1 (en) 2010-02-25 2016-06-08 Dana-Farber Cancer Institute, Inc. Braf mutations conferring resistance to braf inhibitors
WO2013169858A1 (en) 2012-05-08 2013-11-14 The Broad Institute, Inc. Diagnostic and treatment methods in patients having or at risk of developing resistance to cancer therapy

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