Imidazole derivatives and their use as farnesyl protein...

Details Imidazole derivatives and their use as farnesyl protein... Imidazole derivatives and their use as farnesyl protein...

2000-03-24

2002-06-25

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S253090, C514S256000, C514S326000, C514S397000, C514S402000, C544S238000, C544S333000, C544S366000, C546S210000, C548S202000, C548S214000, C548S255000, C548S262200

Reexamination Certificate

active

06410539

ABSTRACT:

This invention relates to compounds that inhibit farnesylation of mutant ras gene products through inhibition of the enzyme farnesyl-protein transferase (FPTase). The invention also relates to methods of manufacturing the compounds, pharmaceutical compositions and methods of treating diseases, especially cancer, which are mediated through farnesylation of ras.
Cancer is believed to involve alteration in expression or function of genes controlling cell growth and differentiation. Whilst not wishing to be bound by theoretical considerations the following text sets out the scientific background to ras in cancer. Ras genes are frequently mutated in tumours. Ras genes encode guanosine triphosphate (GTP) binding proteins which are believed to be involved in signal transduction, proliferation and malignant transformation. H-, K- and N-ras genes have been identified as mutant forms of ras (Barbacid M, Ann. Rev. Biochem. 1987, 56: 779-827). Post translational modification of ras protein is required for biological activity. Farnesylation of ras catalysed by FPTase is believed to be an essential step in ras processing. It occurs by transfer of the farnesyl group of farnesyl pyrophosphate (FPP) to a cysteine at the C-terminal tetrapeptide of ras in a structural motif called the CAAX box. After further post-translational modifications, including proteolytic cleavage at the cysteine residue of the CAAX box and methylation of the cysteine carboxyl, ras is able to attach to the cell membrane for relay of growth signals to the cell interior. In normal cells activated ras is believed to act in conjunction with growth factors to stimulate cell growth. In tumour cells it is believed that mutations in ras cause it to stimulate cell division even in the absence of growth factors (Travis J, Science 1993, 260: 1877-1878), possibly through being permanently in GTP activated form rather than cycled back to GDP inactivated form. Inhibition of farnesylation of mutant ras gene products will stop or reduce activation.
One class of known inhibitors of farnesyl transferase is based on farnesyl pyrophosphate analogues; see for example European patent application EP 534546 from Merck. Inhibitors of farnesyl tansferase based on mimicry of the CAAX box have been reported. Reiss (1990) in Cell 62, 81-8 disclosed tetrapeptides such as CVIM (Cys-Val-Ile-Met). James (1993) in Science 260 1937-1942 disclosed benzodiazepine based peptidomimetic compounds. Lerner (1995) in J. Biol. Chem. 270, 26802 and Eisai in International Patent Application WO 95/25086 disclosed further peptidomimetic compounds based on Cys as the first residue. Bristol-Myers Squibb in European Patent Application EP 696593 disclosed farnesyl transferase inhibitors having a 4-sulfanylpyrrolidine residue in the first position.
According to one aspect of the present invention there is provided a compound of Formula (1):
R
5
is hydrogen, C
1-4
alkyl, phenylC
1-4
alkyl;
R
6
is hydrogen, C
1-4
alkyl, hydroxyC
1-4
alkyl, haloC
1-4
alkyl, dihaloC
1-4
alkyl, C
1-4
alkoxy, C
1-4
alkoxyC
1-4
alkyl, sulfanylC
1-4
alkyl, aminoC
1-4
alkyl,
N
—(C
1-4
alkyl)aminoC
1-4
alkyl,
N,N
-di-(C
1-4
alkyl)aminoC
1-4
alkyl or phenylC
1-4
alkyl; m is 0,1 or 2;
R
1
is hydrogen, C
1-4
allyl or C
1-4
alkanoyl;
R
12
and R
13
are independently hydrogen or C
1-4
alkyl;
Ar
2
is phenyl or heteroaryl;
p is 0 or 1;
Ar
3
is of the formula:
wherein W, X, Y and Z are independently is CH or N, provided that at least two of W, X, Y and Z are CH and R
2
and —(CH
2
)
n
R
3
are attached to ring carbon atoms; R
2
is a group of the Formula (2):
wherein R
7
is hydrogen or C
1-4
alkyl, R
8
is —(CH
2
)
q
—R
10
wherein q is 0-4 and R
10
is C
1-4
alkylsulfanyl, C
1-4
alkylsulfinyl, C
1-4
alkylsulfonyl, hydroxy, C
1-4
alkoxy, carbamoyl,
N
—C
1-4
alkylcarbamoyl,
N,N
-(diCC
1-4
alkyl)carbamoyl, C
1-4
alkyl, phenyl, thienyl, or C
1-4
alkanoylamino; R
9
is hydroxy, C
1-6
-alkoxy, C
3-9
-cycloalkyloxy, heterocyclyloxy, heterocyclylC
1-4
alkoxy or —NH—SO
2
—R
11
wherein R
11
represents, trifluoromethyl, C
1-4
alkyl, phenyl, heteroaryl, arylC
1-4
alkyl or heteroarylC
1-4
alkyl; or R
2
represents a lactone of Formula (3)
the group of Formula (2) or (3) having L or D configuration at the chiral alpha carbon in the corresponding free amino acid;
n is 0, 1 or 2;
R
3
is phenyl or heteroaryl;
phenyl and heteroaryl rings in R
3
, R
5
, R
6
, R
9
, R
11
and Ar
2
are independently optionally substituted on ring carbon atoms by up to three substituents selected from C
1-4
alkyl, halogen, hydroxy, C
1-4
alkoxy, C
1-4
alkoxycarbonyl, C
1-4
alkanoyl, C
1-4
alkanoyloxy, amino, C
1-4
alkylamino, di(C
1-4
alkyl)amino, C
1-4
alkanoylamino, nitro, cyano, carboxy, thiol, C
1-4
alkylsulfanyl, C
1-4
alkylsulfinyl, C
1-4
alkylsulfonyl, C
1-4
alkanesulphonamido,
N
—(C
1-4
alkylsulphonyl)—
N
—C
1-4
alkylamino, aminosulfonyl,
N
—(C
1-4
alkyl)aminosulfonyl,
N,N
-di(C
1-4
alkyl)aminosulfonyl, carbamoyl,
N
-(C
1-4
alkyl)carbamoyl,
N,N
-(diC
1-4
alkyl)carbamoyl, carbamoylC
1-4
alkyl,
N
-(C
1-4
alkyl)carbamoylC
1-4
alkyl,
N,N
-(diC
1-4
alkyl)carbamoylC
1-4
alkyl, hydroxyC
1-4
alkyl and C
1-4
alkoxyC
1-4
alkyl and on ring NH groups by C
1-4
alkyl, C
1-4
alkanoyl, C
1-4
alkylsulfonyl, haloC
1-4
alkyl, difluoromethyl or trifluoromethyl;
provided that:
when n is 0, Ar
3
is substituted by R
2
in the 4-position and —(CH
2
)
n
R
3
in the 3- or 5-position; and when n is 1 or 2, Ar
3
is substituted by R
2
in the 3- or 5-position and —(CH
2
)
n
R
3
in the 4-position;
or a pharmaceutically-acceptable salt, prodrug or solvate thereof.
In this specification the generic term “alkyl” includes both straight-chain and branched-chain alkyl groups. However references to individual alkyl groups such as “propyl” are specific for the straight-chain version only and references to individual branched-chain alkyl groups such as “isopropyl” are specific for the branched-chain version only. An analogous convention applies to other generic terms.
It is to be understood that, insofar as certain of the compounds of Formula (1) defined above may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, the invention includes in its definition any such optically active or racemic form which possesses the property of inhibiting FTPase. The synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. Similarly, inhibitory properties against FTPase may be evaluated using the standard laboratory techniques referred to hereinafter.
The term “heterocyclyl” refers to a 5- or 6-membered monocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. The term “heteroaryl” refers to a 5-10 membered monocyclic heteroaryl ring containing upto 3 heteroatoms selected from nitrogen, oxygen and sulphur.
The term “halogen” refers to fluorine, chlorine, bromine and iodine. The term “carbamoyl” refers to —C(O)NH
2
. The term “BOC” refers to tert-butoxycarbonyl.
Examples of C
1-4
alkyl include methyl, ethyl, propyl isopropyl, sec-butyl and tert-butyl; examples of C
1-4
alkoxy include methoxy, ethoxy and propoxy; examples of C
1-4
akanoyl include formyl, acetyl and propionyl; examples of C
1-4
alkanoyloxy include acetyloxy and propionyloxy; examples of C
1-4
alkylamino include methylamino, ethylamino, propylamino, isopropylamino, sec-butylamino and tert-butylamino; examples of di-(C
1-4
alkyl)amino include di-methylamino, di-ethylamino and
N
-ethyl-
N
-methylamino; examples of C
1-4
alkanoylamino include acetamido and propionylamino; examples of C
1-4
alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; examples of C
1-4
alkylsulfanyl include methylsulfanyl, ethylsulfanyl, propylsulfanyl, isopropylsulfanyl, sec-butylsulfanyl and tert-butylsulfanyl; examples of C
1-4
alkylsulfinyl include methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, sec-butylsulfinyl and tert-butylsulfinyl; examples of

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