4-Mercaptopyrrolidine derivatives as farnesyl transferase...

Details 4-Mercaptopyrrolidine derivatives as farnesyl transferase... 4-Mercaptopyrrolidine derivatives as farnesyl transferase...

1998-02-03

2001-05-15

Ramsuer, Robert W. (Department: 1613)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C548S518000, C548S541000, C548S556000

Reexamination Certificate

active

06232338

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 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. After earliest priority date of the present invention 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. Also after the earliest priority date of the present invention Bristol-Myers Squibb in European Patent Application EP 696593 disclosed for the first time farnesyl transferase inhibitors having a 4-sulfanylpyrrolidine residue in the first position.
According to one aspect of the present invention there is provided a pharmaceutical composition comprising an inhibitor of ras farnesylation of Formula I:
wherein:
R
1
is selected from H; —C
1-4
alkyl; —C
1-3
alkylene-Ph optionally mono or di-substituted on Ph with substituents selected from C
1-4
alkyl, halogen, OH, C
1-4
alkoxy, 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, carbamoyl, C
1-4
alkoxycarbonyl, thiol, C
1-4
alkylsulfanyl, C
1-4
alkylsulfinyl,C
1-4
alkylsulfonyl and sulfonamido; —CO—C
1-4
alkyl; —CO—O—C
1-4
alkyl; —CO—O—C
2-4
alkenyl; —CO—O—(CH
2
)
n
Ph optionally substituted on Ph as defined for substitution on Ph in R
1
=—C
1-3
alkylene-Ph above and n=0-4; —C
1-4
alkylene-CONR
4
R
5
where R
4
& R
5
are independently selected from H and C
1-4
alkyl; and —C
1-4
alkylene-COOR
6
where R
6
is selected from H, C
1-4
alkyl;
R
2
is selected from H; —C
1-4
alkyl; —C
1-3
alkylene-Ph optionally substituted on Ph as defined for substitution on Ph in R
1
=—C
1-3
alkylene-Ph above; —COC
1-4
alkyl; and —COOC
1-4
alkyl;
R
3
is selected from H; OH; CN; CF
3
; NO
2
; —C
1-4
alkyl; —C
1-4
alkylene-R
7
where R
7
is selected from phenyl, naphthyl, a 5-10 membered monocyclic or bicyclic heteroaryl ring containing upto 5 heteroatoms selected from O,N and S and any aryl ring in R
7
is optionally substituted as defined for substitution on the Ph group in R
1
=—C
1-3
alkylene-Ph above; R
7
; C
2-4
alkenyl; halogen; —(CH
2
)
n
COOR
8
where n=0-3 and R
8
represents H, C
1-4
alkyl, or C
2-4
alkenyl; —CONR
9
R
10
where R
9
and R
10
independently represent H, C
1-4
alkyl, C
2-4
alkenyl, —O—C
1-4
alkyl, —O—C
2-4
alkenyl, —C
1-3
alkylenePh optionally substituted as defined for this group for R
1
above; —CON(R
11
)OR
12
where R
11
and R
12
independently represent H, C
1-4
alkyl and C
2-4
alkenyl; a group of Formula II, —CONR
13
—CHR
14
—COOR
17
, where R
13
is H or C
1-4
alkyl, R
17
is H or C
1-6
alkyl, R
14
is selected from the side chain of a lipophilic amino acid. carbamoylC
1-4
alkyl, N-(monoC
1-4
alkyl)carbamoylC
1-4
alkyl and N-(diC
1-4
alkyl)carbamoylC
1-4
alkyl, the group of Formula II having L or D configuration at the chiral alpha carbon in the corresponding free amino acid; a lactone of formula:
 C
1-4
alkyl monosubstituted on carbon with ═N—OH; a group of Formula —X—R
15
where X is selected from O, CO, CH
2
, S, SO, SO
2
and R
15
is selected from C
1-6
alkyl, phenyl, naphthyl, a 5-10 membered monocyclic or bicyclic heteroaryl ring containing upto 5 heteroatoms selected from O,N and S and any aryl ring in R
15
is optionally substituted as defined for the Ph group in R
1
=—C
1-3
alkylene-Ph;
p is 0-3 in which R
3
values can be the same or different;
L is a linking moiety selected from the following groups written from left to right in Formula I: —CO—NR
16
— where R
16
is selected from H, C
1-4
alkyl, C
1-4
alkylene-Z, —CO—C
1-4
alkylene-Z, —CO—C
1-6
alkyl, —COZ, Z and Z is selected from —O—C
1-4
alkyl, phenyl, naphthyl, a 5-10 membered monocyclic or bicyclic heteroaryl ring containing upto 5 heteroatoms selected from O, N and S and any aryl ring in R
16
is optionally substituted as defined for the Ph group in R
1
=—C
1-3
alkylene-Ph; —CH
2
—NR
18
— where R
18
represents any value defined for R
16
; —CH
2
S—; —CH
2
O—; —CH
2
—CHR
19
— where R
19
represents any value defined for R
16
; —CH═CR
20
— where R
20
represents any value defined for R
16
; —CH
2
NR
21
—T— where R
21
represents any value defined for R
16
, T represents —(CH
2
)
n
— where n is 1-4 and T is optionally monosubstituted with R
22
where R
22
represents any value for R
16
other than H; —CH
2
NR
23
—SO
2
— where R
23
represents any value defined for R
16
; —CH
2-
—NR
24
—CO—T— where R
24
represents any value defined for R
16
, T represents —(CH
2
)
n
— where n is 0-4 and T is optionally monosubstituted with R
29
where R
29
represents any value for R
16
other than H; —CO—NR
25
—T— where R
25
represents any value defined for R
16
, T represents —(CH
2
)
n
— where n is 1-4 and T is optionally monosubstituted with R
26
where R
26
represents any value for R
16
other than H; —CH
2
S—T— where T represents —(CH
2
)
n
— where n is 1-4 and T is optionally monosubstituted with R
27
where R
27
represents any value for R
16
other than H; —CH
2
O—T— where T represents —(CH
2
)
n
— where n is 1-4 and T is optionally monosubstituted with R
28
where R
28
represents any value for R
16
other than H;
A is selected from phenyl; naphthyl; a 5-10 membered monocyclic or bicyclic heteroaryl ring containing upto 5 heteroatoms where the heteroatoms are independently selected from O, N & S; or a —S—S— dimer thereof when R
2
═H; or a N-oxide thereof; or an enantiomer, diastereoisomer, pharmaceutically acceptable salt, prodrug or solvate thereof together with a pharmaceutically acceptable diluent or carrier.
Preferably R
1
is selected from H; —CO—O—(CH
2
)
n
Ph optionally substituted on Ph as defined for R
1
=—C
1-3
alkylene-Ph and n=0-4; —CO—O—C
2-4
al

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