ZA200402088B

ZA200402088B - Cyclooxygenase-2 inhibitor/histone deacetylase inhibitor combination.

Info

Publication number: ZA200402088B
Application number: ZA200402088A
Authority: ZA
Inventors: Ying-Nan Pan Chen; Peter Lassota; Alexander Wallace Wood
Original assignee: Novartis Ag
Priority date: 2001-11-06
Filing date: 2004-03-16
Publication date: 2005-06-20
Also published as: SI1443967T1

Description

Cyclooxygenase-2 inhibitor / histone deacetylase inhibitor combination

The invention relates to a combination which comprises (a) a cyclooxygenase-2 inhibitor

N (“COX-2 inhibitor”) and (b) a histone deacetylase inhibitor ("HDAI") for simultaneous, concurrent, separate or sequential use, especially for use in the treatment of pre-malignant colon lesions or a colon cancer or other malignancies in a mammal, particularly a human.

The invention also relates to pharmaceutical compositions comprising such a combination and to a method of treating pre-malignant colon lesions (e.g. polyps) and colon cancer, as well as other malignancies, in a mammal, particularly a human, with such a combination. The present invention further also relates to a commercial package or product comprising such a combination.

The COX-2 inhibitors used in the combination of the present invention are typically those which have an ICs, for COX-2 inhibition of less than about 2 uM and an ICs, for COX-1 inhibition of greater than about 5 pM, e.g. when measured in the assays described by

Brideau et al., Inflamm. Res. 45:68-74 (1996). Preferably the COX-2 inhibitor has a selectivity ratio of at least 10, more preferably at least 40, for COX-2 inhibition over COX-1 inhibition.

Of the known COX-2 inhibitors, the 5-alkyl substituted 2-arylaminophenylacetic acids and derivatives are especially useful in the present invention. Such compounds, their use and preparation are disclosed in U.S. Patent No. 6,291,523 and are herein incorporated by reference.

Useful COX-2 inhibitors disclosed in U.S. Patent No. 6,291,523 are described by formula la

R* AQ CH,COOH

NH (1a)

R* R%

R*; R%

R*;

Co. wherein R* is methyl or ethyl; . R*, is chloro or fluoro;

R*; is hydrogen or fluoro; . R*; is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy or hydroxy;

R*; is hydrogen or fluoro; and

R*s is chloro, fluoro, trifluoromethyl or methyl; pharmaceutically acceptable salts or solvates thereof; and pharmaceutically acceptable prodrug esters thereof.

A particular embodiment of the invention relates to the compounds of formula la wherein R* is methyl or ethyl; R*; is chloro or fluoro; R*; is hydrogen; R*; is hydrogen, fluoro, chloro, methyl or hydroxy; R*, is hydrogen; and R*; is chloro, fluoro or methyl; pharmaceutically . acceptable salts thereof; and pharmaceutically acceptable prodrug esters thereof.

A preferred embodiment relates to the compounds of formula la wherein R* is methyl or ethyl; R* is fluoro; R*; is hydrogen; R*; is hydrogen, fluoro or hydroxy; R*, is hydrogen; and

R*s is chloro; pharmaceutically acceptable salts thereof; and pharmaceutically acceptable prodrug esters thereof.

Another preferred embodiment of the invention relates to compound of formula la wherein R* is ethyl or methyl; R*; is fluoro; R*; is hydrogen or fluoro; R*; is hydrogen, fluoro, ethoxy or hydroxy; R* is hydrogen or fluoro; and R*s is chloro, fluoro or methyl; pharmaceutically acceptable salts thereof; and pharmaceutically acceptable prodrug esters thereof.

Further preferred are said compounds wherein R* is methyl or ethyl; R*, is fluoro; R*,-R*, are hydrogen or fluoro; and R*s is chloro or fluoro; pharmaceutically acceptable salts thereof: and pharmaceutically acceptable prodrug esters thereof.

A further embodiment of the invention relates to the compounds of formula la wherein R* is ’ methyl or ethyl; R* is fluoro; R*; is fluoro; R*; is hydrogen, ethoxy or hydroxy; R*, is fluoro; and R*; is fluoro; pharmaceutically acceptable salts thereof; and pharmaceutically ’ acceptable prodrug esters thereof.

Another preferred embodiment of the invention relates to the compounds of formula la . wherein R* is methyl; R*; is fluoro; R*; is hydrogen; R*; is hydrogen or fluoro; R* is hydrogen; and R*; is chloro; pharmaceutically acceptable salts thereof; and pharmaceutically ‘ acceptable prodrug esters thereof. . Particular embodiments of the invention relate to compounds of formula la (a) wherein R* is methyl; R*; is fluoro; R*; is hydrogen; R*; is hydrogen; R*;is hydrogen; and R*s is chloro; pharmaceutically acceptable salts thereof; and pharmaceutically acceptable prodrug esters thereof; (b) wherein R* is methyl; R*, is fluoro; R*; is hydrogen; R*zis fluoro; R*4 is hydrogen; and R*s is chloro; pharmaceutically acceptable salts thereof; and pharmaceutically acceptable prodrug esters thereof, (c) wherein R* is ethyl; R*, is fluoro; R*; is fluoro; R*; is hydrogen; R*, is fluoro; and

R*s is fluoro; pharmaceutically acceptable salts thereof; and pharmaceutically acceptable prodrug esters thereof; and (d) wherein R* is ethyl; R*; is chloro; R*; is hydrogen; R*3 is chloro; R*, is hydrogen; and R*s is methyl; pharmaceutically acceptable salts thereof; and pharmaceutically acceptable prodrug esters thereof.

Pharmaceutically acceptable prodrug esters are ester derivatives which are convertible by solvolysis or under physiological conditions to the free carboxylic acids of formula la. Such esters are e.g. lower alkyl esters (such as the methyl or ethyl ester), carboxy-lower alkyl esters such as the carboxymethyl ester, nitrooxy-lower alkyl esters (such as the 4- nitrooxybutyl ester), and the like. Preferred are the 5-alkyl substituted 2- arylaminophenylacetoxyacetic acids of formula Ib

R* 19 CH,COOCH,COOH ha (Ib) . R*, R*;

R*; RY,

R*; wherein R* and R*-R*s have meaning as defined hereinabove for compounds of formula la; and pharmaceutically acceptable salts thereof.

Thus, COX-2 inhibitors useful for use in the present invention are compounds of formula

R* Tr CH,COR?*,

NH 0)

R* R's

R*; RY

R*, wherein R* is methyl or ethyl;

R*; is chloro or fluoro;

R*; is hydrogen or fluoro;

R*; is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy or hydroxy;

R*, is hydrogen or fluoro;

R*; is chloro, fluoro, trifluoromethyl or methyl; and

R* is hydroxy or -OCH,COOH; pharmaceutically acceptable salts or solvates thereof; and pharmaceutically acceptable prodrug esters thereof.

Pharmaceutically acceptable salts represent metal salts, such as alkaline metal salts, e.g.

N sodium, potassium, magnesium or calcium salts, as well as ammonium salts, which are formed e.g. with ammonia and mono- or di-alkylamines, such as diethylammonium salts, and with amino acids, such as arginine and histidine salts.

The compound 5-methyl-2-(2'-chloro-6’-fluoro-anilino)-phenyl acetic acid, as well as its . pharmaceutically acceptable salts, is an especially useful COX-2 inhibitor for use in the present invention.

Also useful in the practice of the invention are the following COX-2-inhibiting compounds, derivatives thereof, or pharmaceutically acceptable salts thereof, or any hydrate thereof: rofecoxib, etoricoxib, celecoxib, valdecoxib, and parecoxib.

Another class of COX-2 inhibitors compounds for use in the invention is the methane sulfonanilide class of inhibitors, of which NS-398, flosulide, nimesulide and (i) are example members.

NHSO,CH, NHSO,CH, HSCs

A BON

1S F F

NO, NO, o

NS-398 Nimesulide (i), X=S

Flosulide, X=0

A further class of COX-2 inhibitors useful in the practice of the present invention is the tricyclic inhibitor class, which can be further divided into the sub-classes of tricyclic inhibitors with a central carbocyclic ring (examples include SC-57666, 1 and 2; those with a central monocyclic heterocyclic ring (examples include DuP697, SC-58125, SC-58635, SC-236 and 3, 4 and 5); and those with a central bicyclic heterocyclic ring (examples include 6, 7, 8, 9 and 10). Compounds 3, 4, and 5 are described in U.S. Pat. No. 5,474,995. The structure of the active agents identified hereinbefore or hereinafter by code nos., generic or trade names may be taken from the actual edition of the standard compendium “The Merck Index” or from } databases, e.g. Patents International (e.g. IMS World Publications).

CH,S0, NH,S0, CH,SO, ® pes ea ~

F F F

SC-57666 1 2

CH,SO, “OL “OL $ N —N

N— N

D—er N—cr, N—cF, oh

F F H,C

DuP697 SC-58125 SC-58635, celecoxib “CL CH,SO, B® CH,SO, ® _N

N 0

N—cr, ; 0

J 0 fo cl F

SC-236 8 4

CH,SO, CH,SO, CH,SO0,

Ola LJ, (0

B PS

0 I

N j 0) A . —

S | —_

F

6 7

CH,;SO, C “CL “CL —N 0] —N N

N \ ) CF,

CF, ® p CC

S

CH,0

F

8 9

A yet further class of COX-2 inhibitors can be referred to as those which are structurally modified nonsteroidal antiinflammatory drugs (NSAIDs), and includes 11a and structure 11b as exemplary members. The synthesis of compound 11b is described in US 5,622,948.

N

MT °

CH,O

N Za

Or CH, Cl : : Br 0) 11a 11b

In addition to these structural classes, sub-classes, and specific COX-2 inhibitor compound examples, examples of compounds which selectively inhibit cyclooxygenase-2 have also been described in the following patent publications and are herein incorporated by reference: . U.S. Pat. Nos. 5,344,991, 5,380,738, 5,393,790, 5,409,944, 5,434,178, 5,436,265, 5,466,823, 5,474,995, 5,510,368, 5,536,752, 5,550,142, 5,552,422, 5,604,253, 5,604,260, - 5,639,780; and International Patent Specification Nos. 94/13635, 94/15932, 94/20480, 94/26731, 94/27980, 95/00501, 95/15316, 96/03387, 96/03388, 96/06840; and International

Publication No.’s WO 94/20480, WO 96/21667, WO 96/31509, WO 96/36623, WO 97/14691, WO 97/16435.

Additional COX-2 inhibitor compounds, the use of which are included in the scope of this invention, include: 0 o \/ A/ \/

Xo SN @® Xo cl ~ 0 ) 0 x | 0 \ F

PN “0 9g o x o)

N

F

12 13 (etoricoxib) 14 o 0 \/ A / \/

No xo No \ \ \ 0] 0 Oo F (0) 0 lo] T 7 ae

F

\_/ . 15 16 17

0) (0)

SN A jo) g AN o Sa lo)

AN

. ) 0 o a Vd 0 PRGA 0 o J 0 Cl 18 19 20 o) Oo oO \/ \/ \/

Xo Xo ® Xo ° [)

Ny 0 0 o OH “No OH 21 22 23 fo) \/ 0

We \/ ~~ 0 Ss ~~ o

Cl 0 =

F «

OH TC N = ’ x

N

: 24 25

Some of the compounds above can also be identified by the following chemical names: } 3: 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone; 4: 3-(3,4-difluorophenyl)-4-(4-(methylsuifonyl)phenyl)-2-(5H)-faranone; . 5: 5,5-dimethyl-4-(4-(methylsulfonyl)phenyl)-3-(3-fluorophenyl)-H-furan-2-one; 12: 5,5- dimethyl-4-(4-(methylsulfonyl)phenyl)-3-(2-propoxy)-5H-furan-2-one; 13: 5-chloro-3-(4-(methylsulfonyl)phenyl)-2-(2-methyl-5-pyridinyl)pyridine; 14.:2-(3,5-difluorophenyl)-3-(4-(methylsulfonyl)phenyl)-2-cyclopenten-1-one; 15: 5(8)-5-ethyl-5-methyl-4-(4-methylsulfonyl)phenyl)-3-(2-propoxy)-5H-furan-2-one; 16: 5-ethyl-5-methyl-4-(4-(methylsulfonyl)phenyl)-3-(3,4-difluorophenyl)-5H-furan-2-one; 17: 3-((2-thiazolyl)methoxy)-4-(4-methyisulfonyl)phenyl)-5,5-dymethyl-5H-furan-2-one; 18: 3-propyloxy-4-(4-methyisulfonyl)phenyl)-5,5-dimethyl-5H-furan-2-one; 19: 3-(1-cyclopropylethoxy)- 5,5-dimethyl-4-(4-methylsulfonyl)phenyl)-5H-furan-2-one; 20: sodium 2-(4-chlorophenyl)-3-(4-methylisulfonyl)phenyl)-4-oxo-2-pentenoate; 21: 3-(cyclopropylmethoxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl)- SH-furan-2-one; 22: 3-(cyclopropylmethoxy)-5,5-dimethyl-4-(4-methylsulfonyl)phenyl)-2,5-dihydrofuran-2-ol; 23:3-isopropoxy-5,5-dimethyl-4-(4-methylsulfonyl)phenyl)-2,5-dihydrofuran-2-ol; 24: 5,5-dimethyl-3-(3-fluorophenyl)-2-hydroxy-4-(4-methylsulfonyl)phenyl)-2,5-dihydrofuran; 25: 5-Chloro-3-(4-methylsulfonyl)phenyl)-2-(3-pyridinyl)pyridine.

The following publications describe and/or provide methods for making the compounds as indicated: compounds 12, 15, 17, 18, 19 and 21, WO 97/14691; compounds 22, 23 and 24,

WO 97/16435; compound 20, WO 96/36623; compound 14, U.S. Pat. No. 5,536,752; compound 16, U.S. Pat. No. 5,474, 995; compounds 13 and 25, WO 98/03484.

Also incorporated herein by reference are those compounds described in WO 96/41645 as having structural formula ll, shown below, and the definition and preferred definitions and species described therein: 2 O 1 \ 285 z i 1) , // Ng 0)

Particulary preferred compounds of formula (11) include: 5-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyi]-3-(trifluoromethyl)pyrazole;

4-(4-fluorophenyl)-5-{4-(methylsulfonyl)phenyl}-1-phenyl-3-( trifluoromethyl)pyrazole;

. 4-(5-(4-chlorophenyl)-3-(4-methodoxyphenyl)-1H-pyrazol-1-yl)benzenesulfonamide; 4-(3,5-bis(4-methylphenyl)-1H-pyrazol-1-yi)benzenesulfonamide;

to 4-(5-(4-chlorophenyl)-3-phenyl-1H-pyrazol-1-yl)benzenesulfonamide;

4-(3,5-bis(4-methoxyphenyl)-1H-pyrazol-1-yl)benzenesulfonamide; 4-(5-(4-chlorophenyl)-3-(4-methylphenyl)-1H-pyrazol-1-yl) benzenesulfonamide; 4-(5-(4-chiorophenyl)-3-(4-nitrophenyl)-1H-pyrazol-1 -yh)benzenesulfonamide; 4-(5-(4-chlorophenyl)-3-(5-chloro-2-thienyl)-1H-pyrazol-1-yl)benzenesulfonamide; 4-(4-chloro-3,5-diphenyl-1H-pyrazol-1-yl) benzenesulfonamide; 4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; 4-(5-phenyl)-3-(trifluormethyl)-1H-pyrazol-1-yl)benzenesulfonamide; 4-(5-(4-fluorphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; 4-(5-(4-methoxyphenyl)-3-(trifluormethyl)-1H-pyrazol-1-yl)benzenesulfonamide; 4-(5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; 4-(5-(4-methylphenyl)-3-(trifluoromethy)-1H-pyrazol-1-yl)benzenesuifonamide; 4-(4-chloro-5-(4-chlorohenyl)-3-(trifluoromethyl}- 1H-pyrazol-1-yl)benzenesulfonamide; 4-(3-(difluoromethyl)-5-(4-methylphenyl)-1H-pyrazol-1-yl)benzenesulfonamide; 4-(3-(difluoromethyl)-5-phenyl-1H-pyrazol-1-yl)benzenesulfonamide; 4-(3-(difluoromethyl)-5-(4-methoxyphenyl)-1H-pyrazol-1-yl)benzenesulfonamide; 4-(3-cyano-5-(4-fluorophenyl)-1H-pyrazol-1-yl)benzenesulfonamide; 4-(3-(difluoromethyi)-5-(3-fluoro-4-methodoxyphenyl)- 1H-pyrazol-1-yl)benzenesulfonamide; 4-(5-(3-fluoro-4-methoxyphenyl)-3-(trifluormethyi)-1H-pyrazol-1-yl)benzenesulfonamide; 4-(4-chloro-5-phenyl-1H-pyrazol-1-yl)benzenesulfonamide; 4-(5-(4-chlorophenyl)-3-hydroxyphenyl)-1H-pyrazol-1-yl)benzenesulfonamide; 4-(5-(N,N-dimethylamino)phenyl)-3-(trifuoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; 5-(4-fluorophenyl)-6-(4-(methylsuifonyl)phenyl)spiro[2.4]hept-5-ene; 4-(6-(4-fluorophenyl)spiro[2.4]hept-5-en-5Syl)benzenesulfonamide; 6-(4-fluorophenyl)-7-(4-(methylsulfonyl)phenyl)spiro[3.4]oct-6-ene; 5-(3-chloro-4-methoxyphenyl)-6-(4-(methyisulfonyl)phenyl)spiro[2.4]hept-5-ene;

4-(6-(3-chloro-4methoxyphenyl)spiro[2.4]hept-5-en-5-yl)benzenesulfonamide; 5-(3,5-dichloro-4-methodoxyphenyl)-6-(4-(methylsulfonyl)phenyl)spiro[2.41hept-5-ene;

5-(3-chioro-4-fluorophenyl)-6-(4-(methylsulfonyl)phenyl)spiro[2.4jhept-5-ene; 4-(6-(3,4-dichlorophenyl)spiro[2.4]hept-5-en-5-yi)benzenesulfonamide; 2-(3-chloro-4-fluorophenyt)-4-(4-flucrophenyl)-5-(4-methylisulfonylphenyi)thiazole;

2-(2-chlorophenyl)-4-(4-fluorophenyl)-5-(4-methyisulfonylphenyl)thiazole;

] 5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-methylthiazole; 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-trifluormethyithiazole;

. 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(2-thienyl)thiazole; 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-benzenesulfonamide; 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(1-propylamino)thiazole; 2-((3,5-dichlorophenoxy)methyl)-4-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)thiazole; 5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-trifluoromethyithiazole; 1-methylsulfonyl-4-(1,1-dimethyl-4-(4-fluorophenyl)cyclopenta-2,4-dien-3-yl)benzene; 4-(4-(4-fluorophenyl-1,1-dimethylcyclopenta-2,4-dien-3-yl)benzenesulfonamide; 5-(4-fluorophenyl)-6-(4-(methylsulfonyl)phenyl)spiro[2.4]hepta-4,6-diene;

4-(6-(4- fluorophenyl)spiro[2.4]hepta-4,6-dien-5-yl)benzenesulfonamide; 6-(4-fluorophenyl)-2-methoxy-5-(4-(methylsulfonyl)phenyl)-pyridine-3-carbonitrile; 2-bromo-6-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)-pyridine-3-carbonitrile; 6-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)-2-phenyl-pyridine-3-carbonitrile; 4-(2-(4-methylpyridin-2-yl)-4-(trifluoromethyl)- 1H-imidazol- 1-yl)benzenesulfonamide; 4-(2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl)benzenesulfonamide; 4-(2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)- 1H-imidazol- 1-yl)benzenesulfonamide; 3-(1-(4-(methylsulfonyl)phenyl)-4-(trifluoromethyl)- 1H-imidazol-2-yl)benzenesulfonamide; 2-(1-(4-(methylsulfonyl)phenyl)-4-(trifluoromethyl)- 1H-imidazol-2-yl)pyridine; 2-methyl-4-(1-(4-(methylsulfonyl)phenyl)-4-(trifluormethyl)- 1H-imidazol-2-yl)pyridine; 2-methyl-6-(1-(4-(methylsulfonyl)phenyl)-4-(trifluormethyl)-1H-imidazole-2-yl)pyridine; 4-(2-(6-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl)benzenesulfonamide; 2-(3,4-difluorophenyl)-1-(4-(methyisulfonyl)phenyl)-4-(trifluoromethyl)- 1H-imidazole; 4-(2-(4-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl)benzesulfonamide; 2-(4-chlorophenyl)-1-(4-methylsulfonyl)phenyl)-4-methyl-1H-imidazole; 2-(4-chiorophenyl)-1-(4-(methylsulfonyl)phenyl)-4-phenyl-1H-imidazole; 2-(4-chlorophenyl)-4-(4-fluorophenyl)- 1-(4-(methylsulfonyl)phenyl)-1H-imidazole; 2-(3-fluoro-4-methoxyphenyl)-1-(4-(methylsulfonyl)phenyl)-4-(trifluoromethyl)-1H-imidazole; ’ 1-(4-methylsulfonyl)phenyl)-2-phenyl-4-trifluoromethyl-1H-imidazole; 2-(4-methylphenyl)-1-(4-(methylsulfonyl)phenyl)-4-trifluoromethyl-1H-imidazole; 4-(2-(3-chloro-4-methylphenyl)-4-(trifluoromethyl-1H-imidazol-1-yl)benzenesulfonamide; 2-(3-fluoro-5-methylphenyl)-1-(4-methylsulfonyl)phenyl)-4-(trifluoromethyl)- 1H-imidazole; 4-(2-(3-fluoro-5-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl)benzenesulfonamide;

2-(3-methylphenyl)-1-(4-(methylsulfonyl)phenyl)-4-(trifluoromethyl)-1H-imidazole; 4-(2-(3-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl)benzenesulfonamide; 1-(4-(methylsulfonyl)phenyl)-2-(3-chlorophenyl)-4-(trifluoromethyl)-1H-imidazole; . 4-(2-(3-chlorophenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl)benzenesulfonamide; 4-(2-phenyl-4-(trifuoromethyl)-1H-imidazol-1-yl)benzenesulfonamide; 4-(2-(4-methodxy-3-chlorophenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl) benzenesulfonamide; 1-allyl-4-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-5-(trifluoromethyl)-1H-pyrazole; 4-(1-ethyl-4-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl)benzenesulfonamide;

N-phenyl-(4-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-5-(trifluoromethyl)- 1H-pyrazol-1- yl)acetamide; ethyl (4-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-5-(trifluoromethyi)-1H-pyrazol-1- yl)acetate; 4-(4-fluorophenyl)-3-(4-methylsulfonyl)phenyl)-1-(2-phenylethyl)-1H-pyrazole; 4-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-1-(2-phenylethyl)-5-(trifluoromethyl)pyrazole; 1-ethyl-4-(4-fluorophenyl)-3-(4-methyisulfonyl)phenyl)-5-(trifluoromethyl)-1H-pyrazole; 5-(4-fluorophenyl)-4-(4-methyisulfonyl)phenyl)-2-(trifluoromethyl)-1H-imidazole; 4-(4-methylsulfonyl)phenyl)-5-(2-thiophenyl)-2-(trifluoromethyl)-1H-imidazole; 5-(4-fluorophenyl)-2-methodoxy-4-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridine; 2-ethoxy-5-(4-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridine; 5-(4-fluorophenyl)-4-(4-(methylsulfonyl)phenyt)-2-(2-propynyloxy)-6-(trifluoromethyl)pyridine; 2-bromo-5-(4-fluorophenyl)-4-(4-methylsulfonyl)phenyl)-6-(trifluoromethyl)pyridine; 4-(2-(3-chloro-4-methoxyphenyl)-4,5-difluorophenyl)benzensulfonamide; 1-(4-fluorophenyl)-2-(4-methylsulfonyl)phenyl)benzene; 5-difluoromethyl-4-(4-methylsulfonyl)phenyl)-3-phenylisoxazole; 4-(3-ethyl-5-phenylisoxazol-4-yl)benzensulfonamid; 4-(5-difluoromethyl-3-phenylisoxazol-4-yl)benzenesulfonamide; 4-(5-hydroxymethyl-3-phenylisoxazol-4-yl)benzenesulfonamide; 4-(5-methyl-3-phenylisoxazol-4-yl)benzenesulfonamide; 1-(2-(4-fluorophenyl)cyclopenten-1-yi)-4-(methylsulfonyl)benzene; ’ 1-(2-(4-fluoro-2-methylphenyl)cyclopenten-1-yl)-4-(methyisulfonyl)benzene; 1-(2-(4-chlorophenyl)cyclopenten-1-yl)-4-(methylsulfonyl)benzene; ) 1-(2-(2,4-dichlorophenyl)cyclopenten-1-yl)-4-(methylsulfonyl)benzene; 1-(2-(4-trifluoromethylphenyl)cyclopenten-1-yl)-4-(methylsulfonyl)benzene; 1-(2-(4-methyithiophenyl)cyclopenten-1-yl)-4-(methylsulfonyl)benzene;

1-(2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1-yl)-4-(methylsulfonyl)benzene; . 4-(2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1-yl)benzesulfonamide; 1-(2-(4-chlorophenyl)-4,4- dimethylcyclopenten-1-yl)-4-(methylsulfonyl)benzene; “ 4-(2-(4-chlororophenyl)-4,4-dimethylcyclopenten-1-yl)benzenesulfonamide; 4-(2-(4-fluorophenyl)cyclopenten-1-yl)benzenesulfonamide; 4-(2-(4-chlorophenyl)cyclopenten-1-yl)benzenesulfonamide; 1-(2-(4-methoxyphenyl)cyclopenten-1-yl)-4-(methylsulfonyl)benzene; 1-(2-(2,3-difluorophenyl)cyclopenten-1-yi)-4-(methylsuifonyl)benzene; 4-(2-(3-fluoro-4methodyphenyl)cyclopenten-1-yl)benzenesulfonamide; 1-(2-(3-chloro-4-methoxyphenyl)cyclopenten-1-yi)-4-(methyisulfonyl)benzene; 4-(2-(3-chloro-4-fluorophenyl)cyclopenten-1-yl-benzenesulfonamide; 4-(2-(2-methylpyridin-5-yl)cyclopenten-1-yl)benzenesulfonamide; ethyl 2-(4-(4-fluorophenyl)-5-(4-methylsulfonyl)phenyl)oxazol-2-yl)-2-benzyl-accetate; 2-(4-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)oxazol-2-yl)acetic acid; 2-(tert-butyl)-4-(4-fluorophenyl)-5-(4-methylsulfonyl)phenyl)oxazole; 4-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)-2-phenyloxazole; 4-(4-fluorophenyl)-2-methyl-5-(4-methylsulfonyl)phenyl)oxazole; and 4-(5-(3-fluoro-4-methoxyphenyl)-2-trifluoromethyl-4-oxazolyl)benzenesulfonamide; or a pharmaceutically acceptable salt thereof.

HDAI compounds that are of particular interest for use in the combinations and methods of the invention are hydroxamate compounds described by the formula ll 0) R,

HO Y

Aaa I" R; R, (n)

X ny ny ny wherein : R; is H, halo, or a straight chain C4-Cs alkyl (especially methyl, ethyl or n-propyl, which methyl, ethyl and n-propy! substituents are unsubstituted or substituted by one or more substituents described below for alkyl substituents);

R; is selected from H, C,-C, alkyl, (preferably C,-Cs alkyl, e.g. methyl, ethyl or

-CH:CH,-OH), C4 — Cy cycloalkyl, C4; — Cy heterocycloalkyl, C4 — Co . heterocycloalkylalkyl, cycloalkylalkyl (e.g., cyclopropylmethyl), aryl, heteroaryl, arylalkyl (e.g. benzyl), heteroarylalkyl (e.g. pyridylmethyl), -(CH.),C(O)Rs, “ -(CH,),OC(O)Rs, amino acyl, HON-C(O)-CH=C(R;,)-aryl-alkyl- and -(CH,),Ry;

Ras and R, are the same or different and independently H, C4-C; alkyl, acyl or acylamino, or Rs; and R, together with the carbon to which they are bound represent C=0, C=S, or C=NRs, or R; together with the nitrogen to which it is bound and R; together with the carbon to which it is bound can form a C4 — C4 heterocycloalkyl, a heteroaryl, a polyheteroaryl, a non-aromatic polyheterocycle, or a mixed aryl and non-aryl polyheterocycle ring;

Rs is selected from H, C4-Cg alkyl, C4 — Cy cycloalkyl, C4 — Cy heterocycloalkyl, acyl, aryl, heteroaryl, arylalkyl (e.g. benzyl), heteroarylalkyl (e.g. pyridylmethyl), aromatic polycycles, non-aromatic polycycles, mixed aryl and non-aryl polycycles, polyheteroaryl, non-aromatic polyheterocycles, and mixed aryl and non-aryl polyheterocycles; n, nq, Nz and nz are the same or different and independently selected from 0 — 6, when n, is 1-6, each carbon atom can be optionally and independently substituted with Rs and/or Ry;

X and Y are the same or different and independently selected from H, halo, C,-C, alkyl, such as CHj and CF3, NO», C(O)R4, ORq, SRe, CN, and NR;,R1;

Re is selected from H, C4-C; alkyl, C, — C, cycloalkyl, C, — Cy heterocycloalkyl, cycloalkylalkyl (e.g., cyclopropylmethyl), aryl, heteroaryl, arylalkyl (e.g., benzyl, 2- phenylethenyl), heteroarylalkyl (e.g., pyridylmethyl), ORs, and NR13R14;

Ry is selected from ORs, SRy5, S(O)R1s, SO2R17, NR3R14, and NR1,SO,Rg;

Rs is selected from H, OR;s, NR43R44, C1-Cs alkyl, C4 — Cy cycloalkyl, Cs — Co heterocycloalkyl, aryl, heteroaryl, arylalkyl (e.g., benzyl), and heteroarylalkyl (e.g., pyridylmethyl);

Ry is selected from C, — C, alkyl, for example, CH; and CFs, C(O)-alkyl, for example

C(O)CHs;, and C(O)CF;; ‘ Rio and R44 are the same or different and independently selected from H, C,-C, alkyl, and -C(O)-alkyl; ’ Riz is selected from H, C,-C; alkyl, C4 — Co cycloalkyl, Cs — Co heterocycloalkyl, C, —- Cy heterocycloalkylalkyl, aryl, mixed aryl and non-aryl polycycle, heteroaryl, arylalkyl (e.g., benzyl), and heteroarylalkyl (e.g., pyridyimethyl);

Riz and R44 are the same or different and independently selected from H, C;-Cs alkyl, C, . — Cy cycloalkyl, C, — Co heterocycloalkyl, aryl, heteroaryl, arylalkyl (e.g., benzyl), heteroarylalkyl (e.g., pyridyimethyl), amino acyl, or Ry3 and Ry, together with the . nitrogen to which they are bound are C, — Cy heterocycloalkyl, heteroaryi, polyheteroaryl, non-aromatic polyheterocycle or mixed aryl and non-aryl polyheterocycle;

Ris is selected from H, C4-Cg alkyl, C4 — Cg cycloalkyl, C4 — Cq heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and (CH2)nZR12;

Rye is selected from C4-Cg alkyl, C4 — Cg cycloalkyl, C4 — Cg heterocycloalkyl, aryl, heteroaryl, polyheteroaryl, arylalkyl, heteroarylalkyl and (CH.),ZR12;

Riz is selected from C;-Cs alkyl, C, — Cg cycloalkyl, C4 — Cg heterocycloalkyl, aryl, aromatic polycycles, heteroaryl, arylalkyl, heteroarylalkyl, polyheteroaryl and NR13R14; m is an integer selected from 0 to 6; and

Z is selected from O, NR;3, S and S(O), or a pharmaceutically acceptable salt thereof.

As appropriate, unsubstituted means that there is no substituent or that the only substituents are hydrogen.

Halo substituents are selected from fluoro, chloro, bromo and iodo, preferably fluoro or chloro.

Alkyl substituents include straight and branched C,-Csalkyl, unless otherwise noted.

Examples of suitable straight and branched C,-Csalkyl substituents include methyl, ethyl, n- propyl, 2-propyl, n-butyl, sec-butyl, t-butyl, and the like. Unless otherwise noted, the alkyl substituents include both unsubstituted alkyl groups and alkyl groups that are substituted by one or more suitable substituents, including unsaturation (i.e. there are one or more double or triple C-C bonds), acyl, cycloalkyl, halo, oxyalkyl, alkylamino, aminoalkyl, acylamino and

ORs, for example, alkoxy. Preferred substituents for alkyl groups include halo, hydroxy, ) alkoxy, oxyalkyl, alkylamino, and aminoalkyl. ) Cycloalkyl substituents include C3-Cq cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, unless otherwise specified. Unless otherwise noted, cycloalkyl substituents include both unsubstituted cycloalkyl! groups and cycloalkyl groups that are substituted by one or more suitable substituents, including C4-Ce alkyl, halo, - hydroxy, aminoalkyl, oxyalkyl, alkylamino, and OR;s, such as alkoxy. Preferred substituents for cycloalkyl groups include halo, hydroxy, alkoxy, oxyalkyl, alkylamino and aminoalkyl.

The above discussion of alkyl and cycloalkyl substituents also applies to the alkyl portions of other substituents, such as without limitation, alkoxy, alkyl amines, alkyl ketones, arylalkyl, heteroarylalkyl, alkylsulfonyl and alkyl ester substituents and the like.

Heterocycloalkyl substituents include 3 to 9 membered aliphatic rings, such as 4 fo 7 membered aliphatic rings, containing from one to three heteroatoms selected from nitrogen, sulfur, oxygen. Examples of suitable heterocycloalkyl substituents include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morphilino, 1,3-diazapane, 1,4-diazapane, 1,4-oxazepane, and 1,4-oxathiapane. Unless otherwise noted, the rings are unsubstituted or substuted on the carbon atoms by one or more suitable substituents, including C4-C; alkyl, C4 — Co cycloalkyl, aryl, heteroaryl, arylalkyl (e.g., benzyl), and heteroarylalkyl (e.g., pyridylmethyl), halo, amino, alkyl amino and ORs, for example alkoxy. Unless otherwise noted, nitrogen heteroatoms are unsubstituted or substituted by H, C4-C; alkyl, arylalkyl (e.g., benzyl), and heteroarylalkyl (e.g., pyridylmethyl), acyl, aminoacyl, alkylsulfonyl, and aryisulfonyl.

Cycloalkylalkyl substituents include compounds of the formula —(CH,)s-cycloalkyl wherein n5 is a number from 1-6. Suitable alkylcycloalkyl substituents include cyclopentylmethyl-, cyclopentylethyl, cyclohexylmethyl and the like. Such substituents are unsubstituted or substituted in the alkyl! portion or in the cycloalkyl portion by a suitable substituent, including those listed above for alkyl and cycloalkyl.

Aryl substituents include unsubstituted phenyl and phenyl substituted by one or more suitable substituents, including C4-Cg alkyl, cycloalkylalkyl (e.g., cyclopropylmethyl),

O(CO)alkyl, oxyalkyl, halo, nitro, amino, alkylamino, aminoalkyl, alkyl ketones, nitrile, carboxyalkyl, alkylsulfonyl, aminosulfonyl, arylsulfonyl, and OR;s, such as alkoxy. Preferred substituents include including C4-Cs alkyl, cycloalkyl (e.g., cyclopropylmethyl), alkoxy, oxyalkyl, halo, nitro, amino, alkylamino, aminoalkyl, alkyl ketones, nitrile, carboxyalkyl, alkylsulfonyl, arylsulfonyl, and aminosulfonyl. Examples of suitable aryl groups include C-

C.alkylphenyl, C;-Cjalkoxyphenyl, trifluoromethylphenyl, methoxyphenyt,

Claims

What is claimed is:

1. A combination which comprises (a) a COX-2 inhibitor and (b) a histone deacetylase . inhibitor in which the active ingredients (a) and (b) are present in each case in free form or in the form of a pharmaceutically acceptable salt, for simultaneous, concurrent, separate or sequential use.

2. The combination of claim 1 wherein the COX-2 inhibitor is selected from a compound of formula R* x CH,COR*, R*, R*; R*; R%, R*, wherein R* is methyl or ethyl; R*; is chloro or fluoro; R*, is hydrogen or fluoro; R*; is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy or hydroxy; R*, is hydrogen or fluoro; R*s is chloro, fluoro, trifluoromethyl or methyl; and R*g is hydroxy or -OCH,COOH,; pharmaceutically acceptable salts or solvates thereof; and pharmaceutically acceptable prodrug esters thereof.

3. The combination of claim 2 wherein the COX-2 inhibitor is selected from a compound of . formula la

R* I CH,COOH NH (ta) R*; R*, R* wherein R* is methyl or ethyl; R*, is chloro or fluoro; R*; is hydrogen or fluoro; R*; is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy or hydroxy; R*, is hydrogen or fluoro; and Rs is chloro, fluoro, trifluoromethyl or methyl; pharmaceutically acceptable salts or solvates thereof; and pharmaceutically acceptable prodrug esters thereof.

4. The combination of claim 3 wherein the COX-2 inhibitor is 5-methyl-2-(2’-chloro-6’-fluoro- anilino)-phenyl acetic acid or a pharmaceutically acceptable salt thereof.

5. The combination of claim 1 wherein the COX-2 inhibitor is a COX-2 inhibitor which has an ICs for COX-2 inhibition of less than 2 pM and an ICs, for COX-1 inhibition of greater than uM.

6. The combination of claim 1 wherein the COX-2 inhibitor is selected from the group consisting of rofecoxib, etoricoxib, celecoxib, valdecoxib, parecoxib, a pharmaceutically acceptable salt thereof, and a hydrate thereof.

7. The combination of any one of claims 1-6 wherein the histone deacetylase inhibitor is a : compound of formula lI

0 R, ) HO Y aa«l k Rs R, an k n, Nn, Ng wherein R, is H, halo, or a straight chain C;-Cs alkyl; R; is selected from H, Ci-C,o alkyl, C4 — Cg cycloalkyl, C4 — Cg heterocycloalkyl, Cs — Co heterocycloalkylalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, -(CH2),C(O)Rs, -(CH,),OC(O)Rs, amino acyl, HON-C(O)-CH=C(R,)-aryl-alkyl- and -(CH2)Ry; Rs and R, are the same or different and independently H, C,-C; alkyl, acyl or acylamino, or R; and R, together with the carbon to which they are bound represent C=0, C=S, or C=NRs, or R; together with the nitrogen to which it is bound and R; together with the carbon to which itis bound can form a C; — Cy heterocycloalkyl, a heteroaryl, a polyheteroaryl, a non-aromatic polyheterocycle, or a mixed aryl and non-aryl polyheterocycle ring; Rs is selected from H, C-Cs alkyl, C4 — Co cycloalkyl, C4 — Co heterocycloalkyl, acyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, aromatic polycycle, non-aromatic polycycle, mixed aryl and non-aryl polycycle, polyheteroaryl, non-aromatic polyheterocycle, and mixed aryl and non-aryl polyheterocycle; n, Ny, N2 and n; are the same or different and independently selected from 0 — 6, when n, is 1-6, each carbon atom can be optionally and independently substituted with R; and/or Rg; X and Y are the same or different and independently selected from H, halo, C;-C, alkyl, NO,, C(O)R;, ORg, SRy, CN, and NR Rs; Rs is selected from H, C;-Cs alkyl, C4 — Co cycloalkyl, C, — Cy heterocycloalkyl,

. cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, OR,,, and NR13R14; R; is selected from ORs, SR1s, S(O)R16, SO2R17, NR13R14, and NR12SO;Rs; : Rs is selected from H, ORs, NR13R14, C4-Cg alkyl, C4 — Cs cycloalkyl, C4 — Co heterocycloalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; Rg is selected from C, — C4 alkyl and C(O)-alkyl;

Rio and Ry, are the same or different and independently selected from H, C,-C, alkyl, ) and -C(O)-alkyl; R12 is selected from H, C4-Cs alkyl, C4 — Co cycloalkyl, C4 — Cg heterocycloalkyl, C4 — Co . heterocycloalkylalkyl, aryl, mixed aryl and non-aryl polycycle, heteroaryl, arylalkyl, and heteroarylalkyl; Ris and R44 are the same or different and independently selected from H, C;-Cg alkyl, C4 — Co cycloalkyl, C4 — Cy heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, amino acyl, or Ry; and Ry4 together with the nitrogen to which they are bound are C4 — Cy heterocycloalkyl, heteroaryl, polyheteroaryl, non-aromatic polyheterocycle or mixed aryl and non-aryl polyheterocycle; Ris is selected from H, C;-Cs alkyl, C4 — Cy cycloalkyl, C4 — Cg heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and (CH;)nZR12; Rig is selected from C4-Cs alkyl, C4 — Cs cycloalkyl, C4 — Cg heterocycloalkyl, aryl, heteroaryl, polyheteroaryl, arylalkyl, heteroarylalkyl and (CHz)ZR12; R47 is selected from C4-Cs alkyl, C4 — Cg cycloalkyl, C, — Co heterocycloalkyl, aryl, aromatic polycycle, heteroaryl, arylalkyl, heteroarylalkyl, polyheteroaryl and NR3R4; m is an integer selected from 0 to 6; and : Z is selected from O, NRy3, S and S(O); or a pharmaceutically acceptable salt thereof.

8. The combination of claim 7 wherein the histone deacetylase inhibitor is a compound of formula (lI) of claim 7 wherein each of Ry, X, Y, Rs, and R, is H, or a pharmaceutically acceptable salt of such a compound.

9. The combination of claim 7 wherein the histone deacetylase inhibitor is a compound of formula (ll) of claim 7 wherein each of Ry, X, Y, Rs, and R, is H and one of n, and n; is zero and the other is 1, or a pharmaceutically acceptable salt of such a compound.

10. The combination of claim 7 wherein the histone deacetylase inhibitor is a compound of ‘ formula (Il) of claim 7 wherein each of Ry, X, Y, Rs, and R, is H, one of n, and n; is zero and the other is 1 and R; is H or —CH>-CH>-OH, or a pharmaceutically acceptable salt of such a compound.

11. The combination of claim 7 wherein the histone deacetylase inhibitor is a compound of the formula lla . . 0 HO Ny = Ra H (lla) Nr , n, s wherein ny is 0-3, R: is selected from H, C,-Cs alkyl, C, — Co cycloalkyl, C4, — Co heterocycloalkyl, alkylcycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalky!, -(CH_),C(O)Rs, amino acyl and -(CH,),R7; Rs’ is heteroaryl, heteroarylalkyl, an aromatic polycycle, a non-aromatic polycycle, a mixed ary! and non-aryl polycycle, polyheteroaryl, or a mixed aryl and non-aryl polyheterocycle or a pharmaceutically acceptable salt thereof.

12. The combination of claim 7 wherein the histone deacetylase inhibitor is a compound of the formula lib : 0)

HO . N = ¥ Rs (Ib) N ~ge wherein R'is selected from H, C4-Cs alkyl, C4,-Cs cycloalkyl, alkylcycloalkyl, and (CH,),4OR,, where Ry; is H, methyl, ethyl, propyl, or isopropyl, and ’ Rs” is unsubstituted or substituted 1H-indol-3-yl, benzofuran-3-yl or quinolin-3-yl or a pharmaceutically acceptable salt thereof.

13. The combination of claim 7 wherein the histone deacetylase inhibitor is a compound of the formula lle le R1 HO = 2 R18 } | N-R N 74 20 Y p q r A; wherein the variable substituents are as defined for a compound of formula (ll) of claim 7, or a pharmaceutically acceptable salt thereof.

14. The combination of claim 13 wherein the histone deacetylase inhibitor is a compound of formula (lle) of claim 13 wherein R18 is H, fluoro, chloro, bromo, a C,-C,alkyl group, a Ca- Cscycloalkyl group, phenyl or a heteroaryl ring, or a pharmaceutically acceptable salt of such a compound.

15. The combination of claim 13 wherein the histone deacetylase inhibitor is a compound of formula (lle) of claim 13 wherein R18 is H, fluoro, chloro, bromo, a C;-C4alkyl group, a Cs- Crcycloalkyl group, phenyl! or a heteroaryl ring, R; is H or -(CH,);CH,OH and s is 1-3, or a pharmaceutically acceptable salt of such a compound.

16. The combination of claim 13 wherein the histone deacetylase inhibitor is a compound of formula (lle) of claim 13 wherein R18 is H, fluoro, chloro, bromo, a C,-C,alkyl group, a Cs- Crcycloalkyl group, phenyl or a heteroaryl ring, R; is H or -(CH);sCH,OH, s is 1-3, Ry is H, X and Y are eachHand q is 1-3 and ris 0 or q is 0 and r is 1-3, or a pharmaceutically acceptable salt of such a compound.

17. The combination of claim 7 wherein the histone deacetylase inhibitor is selected from the group consisting of N-hydroxy-3-[4-[[(2-hydroxyethyi)[2-(1H-indol-3-yl)ethyl]- - aminojmethyl]phenyl]-2E-2-propenamide, N-hydroxy-3-[4-[[[2-(1H-indol-3-yl)ethyi]- amino]methyl]phenyl}-2E-2-propenamide and N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)- ) ethyl]-amino]methyl]phenyl]-2E-2-propenamide, and pharmaceutically acceptable salts thereof.

18. The combination of claim 17 wherein the histone deacetylase inhibitor is N-hydroxy-3-[4- ] [[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl}-amino]methyl]phenyl]-2E-2-propenamide or a pharmaceutically acceptable salt thereof.

19. The combination of any one of claims 1-18 for use in the treatment of a disease in a mammal.

20. The combination of claim 19 for use in the treatment of pre-malignant colon lesions or a colon cancer or other malignancies in a mammal.

21. The combination of claim 20 wherein the other malignancies to be treated are selected from the group consisting of breast cancer, lung cancer, ovarian cancer, lymphoma, head and neck cancer and cancer of the esophagus, stomach, bladder, prostrate, uterus and cervix.

22. The combination of claim 20 for use in the treatment of pre-malignant colon lesions or a colon cancer.

23. A combination which comprises (a) a pharmaceutically effective amount of 5-methyl-2- (2’-chloro-6’-fluoro-anilino)-phenyl acetic acid, or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically effective amount of N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol- 3-ylethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof, for use in the treatment of pre-malignant colon lesions or colon cancer in a mammal.

24. The combination of any one of claim 19-23 wherein the mammal to be treated is a human.

25. Use of a COX-2 inhibitor or a pharmaceutically acceptable salt thereof for the preparation of a medicament, for use in combination with a histone deacetylase inhibitor or a : pharmaceutically acceptable salt thereof, for the treatment of pre-malignant colon lesions or a colon cancer or other malignancies in a mammal.

26. Use of a histone deacetylase inhibitor or a pharmaceutically acceptable salt thereof for the preparation of a medicament, for use in combination with a COX-2 inhibitor or a pharmaceutically acceptable salt thereof, for the treatment of pre-malignant colon lesions or

. a colon cancer or other malignancies in a mammal. , 27. The use of claim 25 or 26 wherein the COX-2 inhibitor is a COX-2 inhibitor of any one of claims 2-6, or a pharmaceutically acceptable salt thereof, and the histone deacetylase inhibitor is a histone deacetylase inhibitor of any one of claims 7-18, or a pharmaceutically acceptable salt thereof.

28. A pharmaceutical composition which comprises (a) one or more unit dosage forms of a COX-2 inhibitor, or a pharmaceutically acceptable salt thereof, and (b) one or more unit dosage forms of a histone deacetylase inhibitor, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier.

29. The pharmaceutical composition of claim 28 which comprises (a) one or more unit dosage forms of a COX-2 inhibitor of any one of claims 2-6, or a pharmaceutically acceptable salt thereof, and (b) one or more unit dosage forms of a histone deacetylase inhibitor of any one of claims 7-18, or a pharmaceutically acceptable salt thereof.

30. The pharmaceutical composition of claim 28 or 29 wherein the COX-2 inhibitor is 5- methyl-2-(2’-chloro-6'-fluoro-anilino)-phenyl acetic acid, or a pharmaceutically acceptable salt thereof.

31. The pharmaceutical composition of claim 30 wherein the histone deacetylase inhibitor is selected from the group consisting of N-hydroxy-3-{4-[[(2-hydroxyethyl)[2-(1H-indol-3- yhethyl]-aminojmethyl]phenyl}-2E-2-propenamide, N-hydroxy-3-[4-[[[2-(1H-indo}-3-yl)ethyl]- amino]methyl]phenyl]-2E-2-propenamide and N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)- ethyl]-amino]methyl}phenyl]-2E-2-propenamide, and pharmaceutically acceptable salts thereof.

. 32. The pharmaceutical composition of claim 31 wherein the histone deacetylase inhibitor is N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2- ' propenamide or a pharmaceutically acceptable salt thereof.

33. Use of a combination according to any one of claims 1-18 and 23 for the preparation of . a pharmaceutical composition for the treatment of pre-malignant colon lesions or a colon cancer or other malignancies in a mammal.

34. A commercial package or product comprising (a) a COX-2 inhibitor, or a pharmaceutically acceptable salt thereof, and (b) a histone deacetylase inhibitor, or a pharmaceutically acceptable salt thereof, together with instructions for simultaneous, concurrent, separate or sequential use thereof in the treatment of a disease in a mammal.

35. The commercial package or product of claim 34 comprising (a) a COX-2 inhibitor of any one of claims 2-6, or a pharmaceutically acceptable salt thereof, and (b) a histone deacetylase inhibitor of any one of claims 7-18, or a pharmaceutically acceptable salt thereof.

36. A commercial package or product comprising a COX-2 inhibitor, or a pharmaceutically acceptable salt thereof, together with instructions for use in combination with a histone deacetylase inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of a disease in a mammal, or a commercial package or product comprising a histone deacetylase inhibitor, or a pharmaceutically acceptable salt thereof, together with instructions for use in combination with a COX-2 inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of a disease in a mammal.

37. The commercial package or product of claim 36 comprising a COX-2 inhibitor of any one of claims 2-6, or a pharmaceutically acceptable salt thereof, together with instructions for use in combination with a histone deacetylase inhibitor of any one of claims 7-18, or a pharmaceutically acceptable salt thereof, for the treatment of a disease in a mammal, or a commercial package or product comprising a histone deacetylase inhibitor of any one of claims 7-18, or a pharmaceutically acceptable salt thereof, together with instructions for use - in combination with a COX-2 inhibitor of any one of claims 2-6, or a pharmaceutically acceptable salt thereof, for the treatment of a disease in a mammal.

38. The commercial package or product of any one of claims 34-37 comprising instructions for use in the treatment of pre-malignant colon lesions or a colon cancer or other malignancies in a mammal.

39. A combination of (a) a COX-2 inhibitor, or a pharmaceutically acceptable salt thereof, and (b) a histone deacetylase inhibitor, or a pharmaceutically acceptable salt thereof, for use in treating pre-malignant colon lesions or a colon cancer or other malignancies in a mammal by administration of the combination simultaneously, concurrently, separately or sequentially.

40. The combination of claim 39 wherein the mammal is treated with pharmaceuticafly effective amounts of a combination according to any one of claims 1-18 and 28.

41. The combination of claim 40 wherein the other malignancies are selected from the group consisting of breast cancer, lung cancer, ovarian cancer, lymphoma, head and neck cancer and cancer of the esophagus, stomach, bladder, prostrate, uterus and cervix.

42. The combination of claim 40 for use in the treatment of pre-malignant colon lesions or a colon cancer.

43. Use of a combination of (a) a pharmaceutically effective amount of 5-methyl-2- (2’-chloro-6'-fluoro-anilino)-phenyl acetic acid, or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically effective amount of N-hydroxy-3-[4-[[(2- hydroxyethyl)[2-(1H-indol-3-yl)ethyl}-amino]methyl)phenyl}-2E-2-propenamide, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating pre-malignant colon lesions or colon cancer in a mammal.

44. The combination of any one of claims 39-42 or the use of claim 43, wherein the mammal is a human.

45. A combination according to claim 1 or claim 39, substantially as herein described and exemplified.

46. Use according to any one of claims 25, 26, 33 or 43, substantially as herein described and exemplified.

47. A pharmaceutical composition according to claim 28, substantially as herein described and exemplified.

48. A commercial package or product according to claim 34 or claim 36, substantially as herein described and exemplified. AMENDED SHEET