Inhibitors of farnesyl protein transferase

Details Inhibitors of farnesyl protein transferase Inhibitors of farnesyl protein transferase

2002-06-20

2004-08-17

Solola, Taofiq (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S541000

Reexamination Certificate

active

06777438

ABSTRACT:

This application is a 371 of PCT/GB00/04875 filed Dec. 18, 2000.
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.
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 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 transferase 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. EP 696593 and PCT/GB96/01810 disclose further farnesyl transferase inhibitors, including pyrrolidine derivatives.
The applicants have found that a particular substitution of the pyrrolidine provides particular advantages in terms of inhibition of farnesyl transferase.
According to one aspect of the present invention there is provided a compound of formula (I):
wherein:
R
1
and R
2
are independently selected from H or a prodrug moiety;
R
3
is hydrogen or halogen;
R
4
is hydrogen or halogen;
L is —CH═CH— or —CH
2
—Z— where Z is NH or O;
Y is S, S(O) or S(O)
2
;
or a salt thereof, provided that at least one of R
3
or R
4
is other than hydrogen.
As used herein, the term “alkyl” refers to straight or branched chain groups, which may, unless otherwise stated have from 1 to 20 and preferably from 1 to 6 carbon atoms. The term “aryl” includes phenyl. The term “halo” includes fluoro, chloro, bromo and iodo.
The term “heterocyclyl” or “heterocyclic” include groups having from 4 to 10 ring atoms, up to 5 of which are selected from oxygen, sulphur and nitrogen. The rings may be mono-, or bicyclic and each ring may be aromatic or non-aromatic in character. Nitrogen atoms may be substituted if the valency of the ring allows it, with either a hydrogen or substituent group, such as a alkyl substituent. Sulphur atoms in a heterocyclic ring may be oxidised to S(O) or S(O)
2
groups.
Examples of aromatic 5- or 6-membered heterocyclic ring systems include imidazole, triazole, pyrazine, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole and thiophene. A 9- or 10-membered bicyclic heteroaryl ring system is an aromatic bicyclic ring system comprising a 6-membered ring fused to either a 5 membered ring or another 6 membered ring. Examples of 5/6 and 6/6 bicyclic ring systems include benzofuran, benzimidazole, benzthiophene, benzthiazole, benzisothiazole, benzoxazole, benzisoxazole, pyridoimidazole, pyrimidoimidazole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline and naphthyridine.
Preferably monocyclic heteroaryl rings contain up to 3 heteroatoms and bicyclic heteroaryl rings contain up to 5 heteroatoms. Preferred heteroatoms are N and S, especially N. In general, attachment of heterocyclic rings to other groups is via carbon atoms. Suitable heterocyclic groups containing only N as the heteroatom are pyrrole, pyridine, indole, quinoline, isoquinoline, imidazole, pyrazine, pyrimidine, purine and pteridine.
Hydrogenated or other substituted forms of the above aromatic rings, (which are not aromatic), such as tetrahydropyridyl rings are examples of non-aromatic heterocyclic groups.
Various forms of prodrugs are known in the art. For examples of such prodrug derivatives, see:
a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985);
b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen;
c) H. Bundgaard, Chapter 5 “Design and Application of Prodrugs”, by H. Bundgaard p. 113-191 (1991);
d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);
e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); and
f) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984).
Suitable examples of groups R
1
are hydrogen or prodrug groups of formula R
5
C(O)—where R
5
is an optionally substituted aryl or heterocyclyl group. In particular R
5
is optionally substituted phenyl, optionally substituted pyridyl optionally substituted furyl, optionally substituted isoxazole, optionally substituted tetrahydropyridyl or optionally substituted tetrahydrofuryl.
Suitable substituents for R
5
include alkyl groups such as methyl, haloalkyl groups such as trifluoromethyl, hydroxy, alkoxy such as methoxy or cyano.
Preferably R
5
is phenyl, pyridyl or N-methyl-tetrahydropyridyl.
Examples of prodrugs groups for R
2
are in vivo cleavable ester groups of a pharmaceutically-acceptable ester which is cleaved in the human or animal body to produce the parent acid. Suitably R
2
together with the carboxy group to which it is attached forms a pharmaceutically-acceptable esters such as C
1-6
alkyl esters or C
1-6
cycloalkyl esters, for example methyl, ethyl, propyl, iso-propyl, n-butyl or cyclopentyl; C
1-6
alkoxymethyl esters, for example methoxymethyl; C
1-6
alkanoyloxymethyl esters, for example pivaloyloxymethyl; phthalidyl esters; C
3-8
cycloalkoxycarbonyloxyC
1-6
alkyl esters, for example 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolan-2-ylmethyl esters, for example 5-methyl-1,3-dioxolan-2-ylmethyl; C
1-6
alkoxycarbonyloxyethyl esters, for example 1-methoxycarbonyloxyethyl; aminocarbonylmethyl esters and mono- or di-N—(C
1-6
alkyl) versions thereof, for example N,N-dimethylaminocarbonylmethyl esters and N-ethylaminocarbonylmethyl esters, and pharmaceutically acceptable esters of optionally substituted heterocyclic groups.
Further examples of such prodrugs for R
2
are in vivo cleavable amides of a compound of the invention. Suitably R
2
together with the carboxy group to which it is attached forms a pharmaceutically-acceptable amide, preferably an N—C
1-6
alkylamide and an N,N-di-(C
1-6
alkyl)amide, such as N-methyl, N-ethyl, N-propyl, N,N-dimethyl, N-ethyl-N-methyl or N,N-diethylamide.
Thus in particular, R
2
is selected from hydrogen, a C
1-4
alkyl group such as isopropyl or cyclopentyl,

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