AU715658B2 - Inhibitors of farnesyl-protein transferase - Google Patents
Inhibitors of farnesyl-protein transferase Download PDFInfo
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- AU715658B2 AU715658B2 AU26702/97A AU2670297A AU715658B2 AU 715658 B2 AU715658 B2 AU 715658B2 AU 26702/97 A AU26702/97 A AU 26702/97A AU 2670297 A AU2670297 A AU 2670297A AU 715658 B2 AU715658 B2 AU 715658B2
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Description
WO 97/36876 PCT/US97/06257 TITLE OF THE INVENTION INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE BACKGROUND OF THE INVENTION The present invention relates to compounds which inhibit farnesyl protein transferase, a protein which is implicated in the oncogenic pathway mediated by Ras. The Ras proteins (Ha-Ras, Ki4a- Ras, Ki4b-Ras and N-Ras) are part of a signalling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation. Biological and biochemical studies of Ras action indicate that Ras functions like a G-regulator protein. In the inactive state, Ras is bound to GDP. Upon growth factor receptor activation Ras is induced to exchange GDP for GTP and undergoes a conformational change. The GTP-bound form of Ras propagates the growth stimulatory signal until the signal is terminated by the intrinsic GTPase activity of Ras, which returns the protein to its inactive GDP bound form Lowy and D.M. Willumsen, Ann. Rev. Biochem.
62:851-891 (1993)). Mutated ras genes (Ha-ras, Ki4a-ras, Ki4b-ras and N-ras) are found in many human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias.
The protein products of these genes are defective in their GTPase activity and constitutively transmit a growth stimulatory signal.
Ras must be localized to the plasma membrane for both normal and oncogenic functions. At least 3 post-translational modifications are involved with Ras membrane localization, and all 3 modifications occur at the C-terminus of Ras. The Ras C-terminus contains a sequence motif termed a "CAAX" or "Cys-Aaal-Aaa 2 -Xaa" box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al., Nature 310:583-586 (1984)). Depending on the specific sequence, this motif serves as a signal sequence for the enzymes farnesyl-protein transferase or geranylgeranyl-protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a C15 or C2 0 isoprenoid, respectively. Clarke., WO 97/36876 PCT/US97/06257 -2- Ann. Rev. Biochem. 61:355-386 (1992); W.R. Schafer and J. Rine, Ann. Rev. Genetics 30:209-237 (1992)). Ras proteins are known to undergo post-translational farnesylation. Other faresylated proteins include the Ras-related GTP-binding proteins such as Rho, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin. James, et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisome associated protein Pxf which is also famesylated. James, et al., have also suggested that there are famesylated proteins of unknown structure and function in addition to those listed above.
Inhibition of famesyl-protein transferase has been shown to block the growth of Ras-transformed cells in soft agar and to modify other aspects of their transformed phenotype. It has also been demonstrated that certain inhibitors of famesyl-protein transferase selectively block the processing of the Ras oncoprotein intracellularly Kohl et al., Science, 260:1934-1937 (1993) and G.L. James et al., Science, 260:1937-1942 (1993). Recently, it has been shown that an inhibitor of farnesyl-protein transferase blocks the growth of rasdependent tumors in nude mice Kohl et al., Proc. Natl. Acad.
Sci 91:9141-9145 (1994) and induces regression of mammary and salivary carcinomas in ras transgenic mice Kohl et al., Nature Medicine, 1:792-797 (1995).
Indirect inhibition of farnesyl-protein transferase in vivo has been demonstrated with lovastatin (Merck Co., Rahway, NJ) and compactin (Hancock et al., ibid; Casey et al., ibid; Schafer et al., Science 245:379 (1989)). These drugs inhibit HMG-CoA reductase, the rate limiting enzyme for the production of polyisoprenoids including farnesyl pyrophosphate. Farnesyl-protein transferase utilizes faresyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a famesyl group (Reiss et al., Cell, 62:81-88 (1990); Schaber et al., J. Biol. Chem., 265:14701-14704 (1990); Schafer et al., Science, 249:1133-1139 (1990); Manne et al., Proc. Natl. Acad. Sci USA, 87:7541-7545 (1990)). Inhibition of faresyl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane WO 97/36876 PCT/US97/06257 -3localization in cultured cells. However, direct inhibition of farnesylprotein transferase would be more specific, and thus preferable.
Inhibitors of famesyl-protein transferase (FPTase) have been described in two general classes. The first are analogs of famesyl diphosphate (FPP), while the second class of inhibitors is related to the protein substrates Ras) for the enzyme. The peptide derived inhibitors that have been described are generally cysteine containing molecules that are related to the CAAX motif that is the signal for protein prenylation. (Schaber et al., ibid; Reiss et. al., ibid; Reiss et al., PNAS, 88:732-736 (1991)). Such inhibitors may inhibit protein prenylation while serving as alternate substrates for the farnesyl-protein transferase enzyme, or may be purely competitive inhibitors (U.S.
Patent 5,141,851, University of Texas; N.E. Kohl et al., Science, 260:1934-1937 (1993); Graham, et al., J. Med. Chem., 37, 725 (1994)).
It has recently been reported that FPT-ase inhibitors also inhibit the proliferation of vascular smooth muscle cells and are therefore useful in the prevention and treatment of arteriosclerosis and diabetic disturbance of blood vessels (JP H7-112930).
It has recently been disclosed that certain tricyclic compounds which optionally incorporate a piperidine moiety are inhibitors of FPTase (WO 95/10514, WO 95/10515 and WO 95/10516).
Imidazole-containing inhibitors of famesyl protein transferase have also been disclosed (WO 95/09001 and EP 0 675 112 Al).
SUMMARY OF THE INVENTION The present invention addresses a compound of formula I:
(R
6 )r
(CR
V A'(CRa2)nA(CR 1 b2)n W (CR 2
A
3 (CR2)p-X t or a pharmaceutically acceptable salt thereof, wherein: WO 97/36876 PCTIUS97/06257 -4- R I a, R b and R 2 are independently selected from the group consisting of: hydrogen, aryl, substituted aryl, heterocyclyl, C3-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R9O-, R 9 S(O)mwherein m is 0, 1 or 2, R 8
C(O)NR
8 CN, N02, (R 8 )2NC(NR 8
R
8 R80C(O)-, N3, -N(R 8
R
9 0C(O)NR- and C1-C6 alkyl, unsubstituted or substituted by 1-3 groups selected from the group consisting of: halo, aryl, heterocyclyl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 8
R
9
R
8
C(O)NR
8
CN,
(RS)2NC(NRS)-, R 8
R
8 N3, -N(R 8 )2 and
R
9 0C(O)NR 8
R
3 and R 4 are independently selected from the group consisting of: H, F, Cl, Br, -NR 8 2, CF3, N02, R 8
R
9 S(O)m-, CF3(CH2)n-O-, R 8 C(O)NH-, H2NC(NH)-, R 8
R
8 N3, CN, R 9 0C(O)NR 8 C1-C20 alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl;
A
3 is selected from: -R 8 C= CR8aryl, heteroaryl or a bond; provided that when A 3 is heteroaryl, attachment of A 3 the remainder of the molecule is through substitutable heteroaryl ring carbons; X represents aryl or heteroaryl; provided that when X is heteroaryl, attachment of X the remainder of the molecule is through substitutable heteroaryl ring carbons;
R
6 is independently selected from the group consisting of: hydrogen, aryl, heterocyclyl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-6 perfluoroalkyl, F, Cl, Br, R 8
R
9 S(O)m-,
R
8
C(O)NR
8 CN, N02, (R 8 )2NC(NR 8
R
8 R80C(O)-, N3,
-N(R
8
R
9 0C(O)NR- and C1-C6 alkyl unsubstituted or substituted by 1-3 groups selected from: aryl, heterocyclyl, C3-C10 cycloalkyl, WO 97/36876 WO 9736876PCTIUS97/06257 C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RS0-,
R
9
RSC(O)NR
8 CN, (R 8 )2NC(NR 8
R
8
RSOC(O)-,
N3, -N(R 8 )2 and R 9
OC(O)NRS-;
R
7 is independently selected from the group consisting of: hydrogen, aryl, heterocyclyl, C3-CIO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, CI-6 perfluoroalkyl, F, Cl, Br, R 9
R
9
R
8 C(O)NR8, CN, N02, (Rg)2NC(NR 8
R
8
R
8 N3, -N(R 8 )2,
R
9 OC(O)NR8- and C I -C6 alkyl unsubstituted or substituted by 1-3 groups selected from: aryl, heterocyclyl, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 8
R
9 S(O)m-, R8C(O)NR8-, CN, (R 8 )2NC(NRS)-, R 8 C(OY-, R 8 N3, -N(RS)2 and R 9
OC(O)NR
8 each R 8 is independently selected from hydrogen, C I -C6 alkyl, aryl and aralkyl; each R 9 is independently selected from C I -C6 alkyl and aryl; A I and A 2 are independently selected from the group consisting of: a bond, -CH=CH-, -C(O)NR 8
-NR
8
-N(R
8
-N(R
8 and S(O)m; V is selected from the group consisting of: hydrogen, heterocyclyl, aryl, C I -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from 0, S, and N, and C2-C20 alkenyl, provided that V is not hydrogen if A 1 I is S(O)m and V is not hydrogen if A I is a bond, n is 0 and A 2 is S(O)m; provided that when V is heterocyclyl, attachment of V to R6 and to Al is through a substitutable ring carbon; W represents heterocyclyl; WO 97/36876 PCT/US97/06257 -6each n and p independently represents 0, 1, 2, 3 or 4; r is 0 to 5, provided that r is 0 when V is hydrogen, and t is 1.
DETAILED DESCRIPTION OF THE INVENTION The compounds of this invention are useful in the inhibition of famesyl-protein transferase and the famesylation of the oncogene protein Ras, and thus are useful for the treatment of cancer.
The compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention.
When any variable aryl, heterocycle, R1, R 2 etc.) occurs more than one time in any constituent, each definition is independent.
The term "alkyl" and the alkyl portion of alkoxy, aralkyl and similar terms, is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, or 1-6 carbon atoms if unspecified. Cycloalkyl means 1-2 carbocyclic rings which are saturated and contain from 3-10 atoms.
"Halogen" or "halo" as used herein means fluoro, chloro, bromo and iodo.
As used herein, "aryl" and the aryl portion of aralkyl, are intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl. A preferred aralkyl group is benzyl.
The terms heterocyclyl, heterocycle and heterocyclic, as used herein, mean a 5- to 7-membered monocyclic or 8- to 11membered bicyclic heterocyclic rings, either saturated or unsaturated, aromatic, partially aromatic or non-aromatic, and which consist of carbon atoms and from one to four heteroatoms selected from the group WO 97/36876 PCT/US97/06257 -7consisting of N, 0, and S. Thus, it includes any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
The ring or ring system may be attached at any heteroatom or carbon atom which results in a stable structure. It optionally contains 1-3 carbonyl groups. Examples of such heterocycles include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 2oxopyrrolidinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl, thiamorpholiny1 sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl and thienyl.
"Heteroaryl" is a subset of heterocyclic as defined above, and means a monocyclic or bicyclic ring system, with up to 7 members in each ring, wherein at least one ring is aromatic and wherein from one to four carbon atoms are replaced by heteroatoms selected from the group consisting of N, 0 and S. Examples include benzimidazolyl, benzisoxazoly1, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl. chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyrany1 suIfone, furyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiazolyl, thienofuryl, thienothienyl and thienyl.
WO 97/36876 PCT/US97/06257 Lines drawn into ring systems from substituents indicate that the bond may be attached to any of the substitutable ring carbon atoms.
Substituted alkyl, substituted aryl, substituted heterocyclyl and substituted cycloalkyl mean alkyl, aryl, heterocyclyl and cycloalkyl groups, respectively, having from 1-3 substituents which are selected from: halo, aryl, heterocyclyl, C3-10 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, R 8
R
9
R
8 C(O)NRS-, CN, (R8)2NC(NR 8
R
8
R
8 N3, -N(R 8 2 and R 9 OC(O)NRS-. When for example, a substituted alkyl group is substituted with a "substituted aryl group", the aryl portion is substituted with 1-3 groups as defined above.
Preferably 1-2 groups are present on substituted alkyl, substituted aryl, substituted heterocyclyl and substituted cycloalkyl, which are selected from: halo, aryl, R 8 CN, R 8 and -N(R 8 )2.
Preferably, Ria ,Rlb and R 2 are independently selected from: hydrogen, -N(R 8
R
8
C(O)NR
8 or unsubstituted or substituted C -C6 alkyl wherein the substituent on the substituted C -C6 alkyl is selected from unsubstituted or substituted aryl, -N(R 8
R
8 0and R 8
C(O)NR
8 Preferably, R 3 and R 4 are selected from: hydrogen, Cl-C6 alkyl, Br, Cl, F, R 8 and CF3.
In a preferred group of compounds, A 3 represents -CC- -CR8=CR8-, or a bond. A particularly preferred group of compounds within this subset includes compounds of formula I wherein A 3 represents -C C- or a bond.
Another preferred group of compounds includes the compounds of formula I wherein A 3 represents aryl or heteroaryl.
Preferably R 6 represents CN.
Preferably, R 7 represents hydrogen, unsubstituted or substituted Cl-C6 alkyl.
Preferably, R 8 represents H or C 1 -6 alkyl, and R 9 is C1-6 alkyl.
Preferably, Al and A 2 are independently selected from: WO 97/36876 PCT/US97/06257 -9a bond, -C(O)NR 8
-NR
8
-N(R
8 -S(0)2N(R 8 and-
N(R
8 Preferably, V is selected from hydrogen, heterocyclyl and aryl. More preferably V is phenyl.
Preferably, W is heterocyclyl selected from imidazolinyl, imidazolyl, oxazolyl, pyrazolyl, pyyrolidinyl, thiazolyl and pyridyl.
More preferably, W is selected from imidazolyl and pyridyl.
Preferably X represents aryl. In particular, X can represent phenyl.
Preferably, m is 0 or 2.
Preferably n and p are 0, 1, 2 or 3.
A subset of compounds of the invention is represented by formula Ia:
R
7 (R6 )r I N N V A (CRla 2 )nA 2 (CRb 2
R
3 (CR22)-A 3
(CR
2 2 )p-X la
R
4 wherein:
R
3
R
4
A
3 R8, R 9 X, m, n, p and r are as originally defined; each R 1a and R 2 is independently selected from hydrogen and CI-C6 alkyl; each R b is independently selected from: hydrogen, aryl, heterocyclyl, C3-10 cycloalkyl, C2-6 alkenyl, R 8
-N(R
8 )2 and C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclyl, cycloalkyl, alkenyl,
R
8 0- and -N(R 8 )2; WO 97/36876 WO 9736876PCTIUS97cI6257
R
6 is independently selected from: hydrogen, C I -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, ClI-C6 perfluoroalkyl, F, Cl, R 8 0-,
R
8 C(O)NRS-, CN, N02, (Rg)2N-C(NRS)-, R 8 RgOC(O)-,
-N(R
8 or R 9 OC(O)NRS-, and C I-C6 alkyl substituted by ClI-C6 perfluoroalkyl, R 8
R
8
C(O)NR
8
(R
8 )2N-C(NR 8
R
8
R
8
-N(R
8 )2 and R 9
OC(O)NR
8
R
7 represents H or C 1-6 alkyl; A and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NR 8 0, -N(R 8 and S(O)m; and V is selected from: hydrogen; aryl; heterocyclyl selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, indolyl, quinolinyl, isoquinolinyl and thienyl; C I -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from 0, S, and N, and C2-C20 alkenyl, provided that V is not hydrogen if A I is S (O)m and V is not hydrogen if A I is a bond and A 2 is S(O)m; provided that when V is heterocycle, attachment of V to R6 and to A 1 is through a substitutable ring carbon.
A second subset of compounds of the present invention is represented by formula 1b: (R )r
R
VAl(CRla 2 )nA (CRl2b9 N (CR 2 )p-R 8
C-CR
8 {CR 2 )x wherein: Ria, Rib, R 2 Al, A 2
R
3
R
4
R
6
R
8
R
9 X, mn, n, p and r are as originally defined;
R
7 is selected from: hydrogen and ClI-C6 alkyl; WO 97/36876 PCT/US97/06257 -11- V is selected from: hydrogen, heterocyclyl selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, indolyl, quinolinyl, isoquinolinyl and thienyl; aryl; C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and C2-C20 alkenyl, provided that V is not hydrogen if A 1 is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O)m; provided that when V is heterocycle, attachment of V to R 8 and to Al is through a substitutable ring carbon; and W represents heterocyclyl selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, indolyl, quinolinyl and isoquinolinyl.
A third subset of compounds of the present invention is represented by formula Ic:
(R
6 )r RR3 V A(CRla 2 )nA 2 (CR b2 W (CR2 2 )C-CC-(CR2 X 4 Ic wherein: RIa, Rib, R 2 Al, A 2
R
3
R
4
R
6 R8, R 9 X, m, n, p and r are as originally defined;
R
7 is selected from: hydrogen and Cl-C6 alkyl; V is selected from: hydrogen, heterocyclyl selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, aryl, C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and C2-C20 alkenyl, WO 97/36876 WO 9736876PCTIUS97106257 -12provided that V is not hydrogen if AI is S(O)m and V is not hydrogen if A I is a bond, n is 0 and A 2 is S(O)m; provided that when V is heterocycle, attachment of V to R 8 and to A I is through a substitutable ring carbon; and W represents heterocyclyl selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, indolyl, quinolinyl and isoquinolinyl.
A fourth embodiment of the invention is described in accordance with formula Id:
H
N
2 /(R 2 )p _A 3 R C 2
R
6 Id wherein: each R2 is independently selected from hydrogen and C I-C6 alkyl;
R
3
R
4
A
3 RS, R 9 X, mn and p are as originally defined; and R 6 is selected from the group consisting of: hydrogen, CI-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CI-C6 perfluoroalkyl, F, Cl, RS0-, RgC(O)NR 8 CN, N02, (R 8 )2N-C(NR 8
R
8
R
8
-N(R
8 or R 9
OC(O)NR
8 and C I-C6 alkyl substituted by Cj -C6 perfluoroalkyl, R 8
R
8
C(O)NR
8
(R
8 )2N.-C(NR 8
R
8
C(O),
R
8
-N(R
8 )2 or R 9
OC(O)NR
8 WO 97/36876 PCT/US97/06257 -13- A fifth subset of compounds of the invention is represented by formula Ie:
H
(CR22)p A 3 (CR22)p-X
S\R
4
NC
le wherein: X and A 3 are as originally defined; each R2 is independently selected from: hydrogen and C1-C6 alkyl;
R
3 and R 4 are independently selected from H, F, Cl, Br,
N(R
8 CF3, N02, (R 8
(R
9
(R
8 H2N-C(NH)-,
(R
8
(R
8 N3, CN, (R 9
)OC(O)NR
8 C1-C20 alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclyl; and R 8
R
9 m and p are as originally defined.
Specific examples of compounds of the invention are: Cl NC N-
CC
WO 97/36876 WO 9736876PCTIUS97/06257 -14-
CI
NC N CH-CH
N-
NC
-CN
NC N- CH CH
N
C'
NC HO
N
NC-( OH C'
N
HO
NC 2N -C N C
N
WO 97/36876 WO 9736876PCT/US97/06257 NC HO NC
NCH
2 -C C
N
NO
NN
NC
N O
/Z
N)
NN
NC WO 97/36876 PCT/US97/06257 -16and the pharmaceutically acceptable salts and isomers thereof.
The pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as formed, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like: and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
The pharmaceutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this invention which contain a basic moiety by conventional chemical methods. Generally, the salts are prepared either by ion exchange chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents.
Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the Schemes, in addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures. Substituents R' and R'CH2-, as shown in the Schemes, represent the substituents R 8
R
9 and others, depending on the compound of the instant invention that is being synthesized. The variable p' represents p-1.
These reactions may be employed in a linear sequence to provide the compounds of the invention or they may be used to synthesize fragments which are subsequently joined by the alkylation reactions described in the Schemes.
Synopsis of Schemes WO 97/36876 PCT/US97/06257 -17- The requisite intermediates are in some cases commercially available, or can be prepared according to literature procedures.
Schemes 1-2 illustrate the synthesis of one of the preferred embodiments of the instant invention, wherein the variable W is present as an imidazolyl moiety that is substituted with a suitably substituted benzyl group. Substituted protected imidazoles can be prepared by methods such as those described by F. Schneider, Z. Physiol. Chem., 3:206-210 (1961) and C.P. Stewart, Biochem. Journal, 17:130-133(1923).
Benzylation and deprotection of the imidazole alkanol provides intermediate III which can be oxidized to the corresponding aldehyde IV. Also, while X is shown as a phenyl ring, other aryl and heteroaryl groups can be substituted therein without departing from the invention.
The aldehyde whose synthesis is illustrated in Scheme 1 may be reacted with a suitably substituted aralkyne, to provide the intermediate compound V. Compound V can be selectively hydrogenated across the unsaturated bond under standard conditions, such as those illustrated, to provide Compound VI.
Schemes 3-10 illustrate syntheses of suitably substituted aldehydes useful in the syntheses of the instant compounds wherein the variable W is a pyridyl moiety. Similar synthetic strategies for preparing alkanols that incorporate other heterocyclic moieties for variable W can be discerned from the teachings herein.
Generally the aldehyde is reacted with an appropriately substituted aralkyne using n-BuLi, after which the triple bond can be reduced. As shown in Schemes 2, 4, 6 and 8 reduction of the alkyne triple bond using Pd/BaSO4 Iproduces the Z-olefin isomer almost exclusively. By substituting sodium bis(2-methoxyethoxy)aluminum hydride (RED-AL) in toluene, one can readily obtain the E-allylic alcohol from propargylic alkynes used in the present invention.
In the preparation methods described herein, reactive groups may remain blocked until the final product is prepared, essentially in protected form, after which a final deprotection step is conducted. These blocking groups are readily removable, they can be removed, if desired, by procedures which will not cause cleavage or WO 97/36876 PCT/US97/06257 -18other disruption of the remaining portions of the molecule. Such procedures include chemical and enzymatic hydrolysis, treatment with chemical reducing or oxidizing agents under mild conditions, treatment with fluoride ion, treatment with a transition metal catalyst and a nucleophile and catalytic hydrogenation.
Examples of suitable hydroxyl protecting groups are: t-butylmethoxyphenylsilyl, t-butoxydiphenylsilyl, trimethylsilyl, triethylsilyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, benzyloxycarbonyl, t-butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl and allyloxycarbonyl. Preferred hydroxyl protecting groups are trimethylsilyl and triethylsilyl.
Examples of suitable carboxyl protecting groups are: benzhydryl, o-nitrobenzyl, p-nitrobenzyl, 2-naphthylmethyl, allyl, 2-chloroallyl, benzyl, 2,2,2-trichloroethyl, trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, 2-(trimethylsilyl)ethyl, phenacyl, p-methoxybenzyl, acetonyl, p-methoxyphenyl, 4-pyridylmethyl and t-butyl. A preferred carboxyl protecting group is p-nitrobenzyl.
Many other suitable hydroxyl and carboxyl protecting groups are known in the art. See, T.W. Greene, Protective Groups in Organic Synthesis, John Wiley Sons, Inc., 1981 (Chapters 2 and WO 97/36876 WO 9736876PCTIUS97/06257 -19- SCHEME 1 ,(CR 2 )p'-CH 2
OH
N,
LN
H
ProtX, Et 3
N
DMF
Prot-, (22)pC20
N
Ila
AC
2 O, Py (CR 2 )p-C H 2 OAc Protl1-Nx,,N EtOAc 2. N-deprotect HBr N-Y,(CR
R
2 2 )p-CH 2
OH
LiOH THE, H 2 0 R 2 2 )p,-CHO
HO
SO
3 'Py, Et 3 N n-BuLi, THF
DMSO
WO 97/36876 WO 9736876PCTfUS97/06257 SCHEME 2
HO
1 -1
N
R
6
H
2 Pd/C MeGH, EtOAc
P
3
H
2 Pd/BaSO 4 MeOH, EtOAc
HO
CR 2 2 )p-CHCH 2
CH
2 Vib (predominantly Z isomer) Via WO 97/36876 WO 9736876PCT/JS97/06257 -21 SCHEME 3
OH
3
H
2 N" N 1) HNO 2 ,Br 2 2) KMnO 4 3) MeOH,H+ C0 2
CH
3 BrNY MgCI ZnC1 2 NiCI 2 Ph 3
P)
2 NaBH 4 (excess) .C02C H 3
,GH
2
OH
SO
3 Py, Et 3
N
DMSO
n-BuLi, THF
RH
4 WO 97/36876 WO 9736876PCTIUS97/06257 -22- SCHEME 4
H
2 Pd/BaSO 4 MeOH, EtOAc
H
2 Pd/C MeOH, EtOAc OH R 3 (peo innl Z Cisomer) j
N-
WO 97/36876 WO 9736876PCTIUS97/06257 -23- SCHEME 1. EtOC(=O)CI R 6 I MgCI ZnCuCN 3. S, xylene, heat
CO
2
CH
3
NI
NaBH 4 N (excess) C Brn ~CO 2
CH
3
NI
S0 3 'Py, EI 3
N
,CH
2 0H
DMSO
MgCI -C0 2
CH
3 ZnCI 2 NiCI 2 (Ph 3
P)
2 NaBH 4 (excess)
N
N-BuLi, THE
H_
SO
3 -Py, Et 3
N
,CH
2 OH ,CHO
DMSO
WO 97/36876 WO 9736876PCTIUS97/06257 -24- SCHEME 6
H
2 Pd/BaSO 4 MeOH, EtOAc OH R 3
OH.
IH-I-C
H
2 Pd/C MeCH, EtOAc (predominantly Z isomer) WO 97/36876 WO 9736876PCTIUS97/06257 SCHEME 7 1. LDA, CO 2 2. MeOH, HI MgCI
CI
ZnCI 2 NiCI 2 (Ph 3
P)
2 NaBH 4 (excess) R 6
OH
2 0H SO 3 -Py, Et 3
N
DMSO
R 6 n-BuLl, THF WO 97/36876 PTU9/65 PCT/US97/06257 -26- SCHEME 8
H
2 Pd/BaSO 4 MeOH, EtOAc
H
2 Pd/C MeGH, EtOAc (predominantly Z isomer) WO 97/36876 WO 9736876PCTIUS97/06257 -27a'IN Br SCHEME 9 1. LDA, 002 2. (0H 3 3 SiCHN 2
CO
2
CH
3 Br R Br Zn, NiCI 2 (Ph 3
P)
2 C0 2
CH
3 excess NaBH 4
CH
2 0H
SO
3 -Py, Et 3
N
DMSO
OH
n-BuLl, THF WO 97/36876 WO 9736876PCTIUS97/06257 -28- SCHEME
H
2 Pd/C R4 MeOH, EtOAc WO 97/36876 WO 9736876PCT/US97/06257 -29- SCHEME11 BocNHI BocNH CHO BocNH BocN H O H
NH
2 N H 2
OH
BocN H
NH
2 H
R-
n-BuLi, THF I R 3CF 3 0 2
H
CHCI
R~ 3 BoC2O R 4
(R
6
CHO
NaBH (GAo) 3 H Et 3 N, CICH 2
CH
2
CI
BocNH
R
3 (R 6 )r
NHR
4
-O
2
OH
WO 97/36876 WO 9736876PCTfJS97/06257 SCHUEME12 BocNH (R6r~c~ ~2
OH
C F 3 C0 2
H
CH
2
CI
2 NaHCO 3 R4AgCN A
OH
WO 97/36876 PCT/US97/06257 -31- SCHEME 13 Me
N
me
N:CHO
Boc
HH
n-BuLi, THF Me 0R 3 Me
N
Boc R 4 O H MeR3 MeX N Boc O-SiMe 2 (t-Bu) R
HO
K- R 3 BocNH
R\
0-Si Me 2 (t-Bu) 0 H BocNH
H
4 0-Si Me 2 Bu) t-Bu (Me) 2 S1-C I imidazole, DMF TsOH,
H
2 0 benzene
CICOCOCI
DMS0
CH
2
CI
2 (02 H 5 3
N
1. H'MgX
(C
2
H
5 2 0 2. TFA,
CH
2
CI
2 HO R'
H
2 N4 WO 97/36876 PTU9/65 PCT/IJS97/06257 -32- SCHEME 14
HO
BocNH4 0-S M e 2 t- Bu)
HO'-
RH
3
H
2 N lo4
OH
CF
3 00 2
H
CH
2
CI
2
ROCHO
NaB H(OAC) 3
CICH
2
CH
2
CI
HO
R'CH21..
H
H
4
OH
WO 97/36876 WO 9736876PCTfUS97/06257 -33- SCHEME HO -H BocNH
H
4 O-SiMe 2 (t-Bu) Boc-N -R 3 O-SiMe 2 (t-Bu)
H'S
-R
3 BocNH R 4 0-Si Me 2 Bu) H H 02 NaH, DMF OOC
R'SH
(C
2
H
5 3 N
A
CH
3 0H C F 3 C0 2
H
CH
2 C1 2
R'S
R H 3
H
2 N 4
R
4 WO 97136876 WO 9736876PCTIUS97/06257 -34- SCHEME 16
HO,
H
2 N- CO 2
H
LiAIH 4
THF
0-20 0
C
1) BoC 2 O, K 2 00 3
THF-H
2 0 2) 0H 2
N
2 EtOAc
HO
BocNH CH 2 0H
HO
BocNH
CO
2
CH
3
R'CHX
CS
2
CO
3
DMF
R'CH,
R'CH,
11J pyridine -SO 9
DMSO,
2
H
5 3
N
CH
2 OH2000
.CHO
WO 97/36876 PCT/US97/06257 SCHEME 16 (cont.) H R 3
R
4 n-BuLi, THF BocNH BocNH
H(
HCI
ETOAc
BF
3 *OEt 2 EtSH
CH
2
CI
2
H
2
N'
H
2
N
HO
The instant compounds are useful in the treatment of cancer. Cancers which may be treated with the compounds of this invention include, but are not limited to, colorectal carcinoma, exocrine pancreatic carcinoma, myeloid leukemias and neurological tumors. Such tumors may arise by mutations in the ras genes WO 97/36876 PCT/US97/06257 -36themselves, mutations in the proteins that can regulate Ras activity neurofibromin neu, scr, abl, Ick, fyn) or by other mechanisms.
The compounds of the instant invention inhibit faresylprotein transferase and faresylation of the oncogene protein Ras.
The instant compounds may also inhibit tumor angiogenesis, thereby affecting the growth of tumors Rak et al. Cancer Research, 55:4575- 4580 (1995)). Such anti-angiogenic properties of the instant compounds may also be useful in the treatment of certain forms of blindness related to retinal vascularization.
The compounds of this invention are also useful for inhibiting other diseases where Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes the Ras gene itself is not activated by mutation to an oncogenic form) with said inhibition being accomplished by the administration of an effective amount of the compounds of the invention to a mammal in need of such treatment.
For example, a component of NF-1 is a benign proliferative disorder.
The instant compounds may also be useful in the treatment of viral infections, in particular in the treatment of hepatitis delta and related viruses Glenn et al. Science, 256:1331-1333 (1992).
The compounds of the instant invention are also useful in the prevention of restenosis after percutaneous transluminal coronary angioplasty by inhibiting neointimal formation Indolfi et al. Nature medicine, 1:541-545(1995).
The instant compounds may also be useful in the treatment and prevention of polycystic kidney disease Schaffner et al.
American Journal of Pathology, 142:1051-1060 (1993) and B. Cowley, Jr. et al.FASEB Journal, 2:A3160 (1988)).
The instant compounds may also be useful for the treatment of fungal infections.
The compounds of this invention may be administered to mammals, preferably humans, either alone or, preferably, in combination with pharmaceutically acceptable carriers or diluents, in the form of a pharmaceutical composition, which is comprised of a compound of formula I in combination with a pharmaceutically acceptable carrier.
WO 97/36876 PCT/US97/06257 -37- The compounds can be administered orally, topically, rectally, vaginally transdermally or parenterally, including the intravenous, intramuscular, intraperitoneal and subcutaneous routes of administration.
For oral use, the compound is administered, for example, in the form of tablets or capsules, or as a solution or suspension. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch; lubricating agents, such as magnesium stearate, are commonly added. For oral administration in capsule form, diluents also include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents may be added. For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared, the pH of the solution is suitably adjusted and the product is buffered. For intravenous use, the total concentration is controlled to render the preparation substantially isotonic.
As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specific amounts, as well as any product which results, directly or indirectly, from combination of the specific ingredients in the specified amounts.
The compounds of the instant invention may also be co-administered in therapeutic compositions that also contain other well known therapeutic agents that are selected for their particular usefulness against the condition that is being treated. For example, the instant compounds may be useful in combination with known anticancer and cytotoxic agents. Similarly, the instant compounds may be useful in combination with agents that are effective in the treatment and prevention of NF- 1, restinosis, polycystic kidney disease, infections of hepatitis delta and related viruses and fungal infections.
If formulated as a fixed dose, such combination products employ a compound of this invention substantially within the dosage range described below and other pharmaceutically active agent(s) typically within the acceptable dosage range. Compounds of the WO 97/36876 PCT/US97/06257 -38instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate.
The daily dosage will normally be determined by the prescribing physician, who may vary the dosage according to the age, weight, and response of the individual patient, as well as the severity of the patient's condition.
In one exemplary application, a suitable amount of compound is administered to a mammal undergoing treatment for cancer. Administration occurs in an amount between about 0.1 mg/kg of body weight to about 60 mg/kg of body weight per day, preferably of between 0.5 mg/kg of body weight to about 40 mg/kg of body weight per day.
The compounds of the instant invention are also useful as a component in an assay to rapidly determine the presence and quantity of farnesyl-protein transferase (FPTase) in a composition.
Thus the composition to be tested may be divided and the two portions contacted with mixtures which comprise a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and farnesyl pyrophosphate and, in one of the mixtures, a compound of the instant invention. After the assay mixtures are incubated for an sufficient period of time, well known in the art, to allow the FPTase to farnesylate the substrate, the chemical content of the assay mixtures may be determined by well known immunological, radiochemical or chromatographic techniques. Because the compounds of the instant invention are selective inhibitors of FPTase, absence or quantitative reduction of the amount of substrate in the assay mixture without the compound of the instant invention relative to the presence of the unchanged substrate in the assay containing the instant compound is indicative of the presence of FPTase in the composition to be tested.
It would be readily apparent to one of ordinary skill in the art that such an assay as described above would be useful in identifying tissue samples which contain famrnesyl-protein transferase and quanti- WO 97/36876 PCT/US97/06257 -39tating the enzyme. Thus, potent inhibitor compounds of the instant invention may be used in an active site titration assay to determine the quantity of enzyme in the sample. A series of samples composed of aliquots of a tissue extract containing an unknown amount of faresylprotein transferase, an excess amount of a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and famesyl pyrophosphate are incubated for an appropriate period of time in the presence of varying concentrations of a compound of the instant invention. The concentration of a sufficiently potent inhibitor one that has a Ki substantially smaller than the concentration of enzyme in the assay vessel) required to inhibit the enzymatic activity of the sample by 50% is approximately equal to half of the concentration of the enzyme in that particular sample.
EXAMPLE 1 1-(4-CYANOBENZYL)-5-[(1-HYDROXY-3-PHENYL)-2- PROPYNYL1IMIDAZOLE HYDROCHLORIDE Step A: Preparation of 1-triphenylmethyl-4- (hydroxvmethyl)imidazole To a solution of 4-(hydroxymethyl)imidazole hydrochloride (35.0 g, 260 mmol) in 250 mL of dry DMF at room temperature was added triethylamine (90.6 mL, 650 mmol). A white solid precipitated from the solution. Chlorotriphenylmethane (76.1 g, 273 mmol) in 500 mL of DMF was added dropwise. The reaction mixture was stirred for 20 hours, poured over ice, filtered, and washed with ice water. The resulting product was slurried with cold dioxane, filtered, and dried in vacuo to provide the titled product as a white solid which was sufficiently pure for use in the next step.
Step B: Preparation of I-triphenylmethyl-4- (acetoxvmethvl)imidazole WO 97/36876 PCT/US97/06257 Alcohol from Step A (260 mmol, prepared above) was suspended in 500 mL of pyridine. Acetic anhydride (74 mL, 780 mmol) was added dropwise, and the reaction was stirred for 48 hours during which it became homogeneous. The solution was poured into 2 L of EtOAc, washed with water (3 x 1 5% aq. HCI soln. (2 x 1 L), sat. aq. NaHCO 3 and brine, then dried (Na 2
SO
4 filtered, and concentrated in vacuo to provide the crude product. The acetate was isolated as a white powder (85.8 g, 86% yield for two steps) which was sufficiently pure for use in the next reaction.
Step C: Preparation of 1-(4-cyanobenzyl)-5- (acetoxvmethyl)imidazole hydrobromide A solution of the product from Step B (85.8 g, 225 mmol) and a-bromo-p-tolunitrile (50.1 g, 232 mmol) in 500 mL of EtOAc was stirred at 60 °C for 20 hours, during which a pale yellow precipitate formed. The reaction was cooled to room temperature and filtered to provide the solid imidazolium bromide salt. The filtrate was concentrated in vacuo to a volume 200 mL, reheated at 60°C for two hours, cooled to room temperature, and filtered again. The filtrate was concentrated in vacuo to a volume 100 mL, reheated at 60 0 C for another two hours, cooled to room temperature, and concentrated in vacuo to provide a pale yellow solid. All of the solid material was combined, dissolved in 500 mL of methanol, and warmed to 60 0
C.
After two hours, the solution was reconcentrated in vacuo to provide a white solid which was triturated with hexane to remove soluble materials. Removal of residual solvents in vacuo provided the titled product hydrobromide as a white solid (50.4 g, 67% yield, 89% purity by HPLC) which was used in the next step without further purification.
Step D: Preparation of 1-(4-cyanobenzyl)-5- (hydroxvmethyl)imidazole To a solution of the acetate from Step C (50.4 g, 150 mmol) in 1.5 L of 3:1 THF/water at 0 oC was added lithium hydroxide monohydrate (18.9 g, 450 mmol). After one hour, the reaction was WO 97/36876 PCT/US97/06257 -41concentrated in vacuo, diluted with EtOAc (3 and washed with water, sat. aq. NaHCO 3 and brine. The solution was then dried (Na 2
SO
4 filtered, and concentrated in vacuo to provide the crude product (26.2 g, 82% yield) as a pale yellow fluffy solid which was sufficiently pure for use in the next step without further purification.
Step E: Preparation of 1-(4-cyanobenzyl)-5imidazolecarboxaldehyde To a solution of the alcohol from Step D (21.5 g, 101 mmol) in 500 mL of DMSO at room temperature was added triethylamine (56 mL, 402 mmol), then S0 3 -pyridine complex (40.5 g, 254 mmol). After 45 minutes, the reaction was poured into 2.5 L of EtOAc, washed with water (4 x 1 L) and brine, dried (Na 2
SO
4 filtered, and concentrated in vacuo to provide the aldehyde (18.7 g, 88% yield) as a white powder which was sufficiently pure for use in the next step without further purification.
Step F: Preparation of -(4-cyanobenzyl)-5-[(1-hydroxy-3phenvl)-2-propynyllimidazole hydrochloride To a solution of phenylacetylene (0.172 mL, 1.56 mmol) in 5 mL of THF at 0 °C was added n-butyllithium (0.530 mL, 2.5 M in hexanes, 1.32 mmol). After 15 minutes, the aldehyde from Step E (254 mg, 1.20 mmol) was added, and the reaction was stirred for 30 minutes.
The reaction was quenched with sat. aq. NaHCO 3 poured into EtOAc, washed with sat. aq. NaHCO 3 and brine, dried (Na 2
SO
4 filtered, and concentrated in vacuo. The resulting product was purified by silica gel chromatography (35-50% acetone/CH 2
CI
2 to provide 187 mg of the desired alcohol. A portion of this was taken up in CH 2 C1 2 and treated with excess 1 M HCl/ether solution, and concentrated in vacuo. The titled product hydrochloride was isolated as a white solid.
FAB mass spectrum m/e 314 Analysis calculated for C 20
H
15
N
3 0 1.0 HCI 0.90 H 2 0: C, 65.63; H, 4.90; N, 11.48; WO 97/36876 PCT/US97/06257 -42- Found: C, 65.81; H, 4.98; N, 11.17.
EXAMPLE 2 -(4-CYANOBENZYL)-5-[( 1-HYDROXY-4-PHENYL)-3- BUTYNYL1IMIDAZOLE HYDROCHLORIDE To a solution of t-butyllithium in 1.5 mL of THF (0.78 mL of 1.7 M in pentane, 1.32 mmol) at -78 0 C was added tetramethylethylenediamine (0.199 mL, 1.32 mmol) and 1-phenyl-1-propyne (0.150 mL, 1.20 mmol). The solution was warmed to 0 °C for one hour, then cooled to -78 The aldehyde from Step E of Example 1 (225 mg, 1.07 mmol) on 1.0 mL THF was added, and the reaction allowed to warm to 0 OC. After 30 minutes, the reaction was quenched with sat.
aq. NaHCO 3 poured into EtOAc, washed with sat. aq. NaHCO 3 and brine, dried (Na 2
SO
4 filtered, and concentrated in vacuo. The product was purified by silica gel chromatography MeOH/CH 2 CI2), then taken up in CH 2 C1 2 and treated with excess 1 M HCl/ether solution, and concentrated in vacuo to provide the titled product hydrochloride (48 mg) as a pale yellow foam.
FAB mass spectrum m/e 328 Analysis calculated for C 21
H
17
N
3 0 1.10 HC1 0.10 Et 2 0: C, 68.56; H, 5.14; N, 11.21; Found: C, 68.30; H, 5.04; N, 11.06.
EXAMPLE 3 (f)-3-(4-CYANOBENZYL)-4-[( 1 -HYDROXY-3-PHENYL)-2- PROPYNYL1PYRIDINE HYDROCHLORIDE Step A: Preparation of 3-(4-cyanobenzyl)pyridin-4-carboxylic acid methyl ester WO 97/36876 PCT/US97/06257 -43- A solution of 4-cyanobenzyl bromide (625 mg, 3.27 mmol) in dry THF (4mL) was added slowly over -3 min. to a suspension of activated Zn (dust; 250 mg) in dry THF (2 mL) at 00 under an argon atmosphere. The ice-bath was removed and the slurry was stirred at room temperature for a further 30 min. Then 3-bromopyridin-4carboxylic acid methyl ester (540 mg. 2.5 mmol) followed by dichlorobis(triphenylphosphine)nickel (II) (50 mg). The resultant reddish-brown mixture was stirred for 3h at ~40-450C. The mixture was cooled and distributed between EtOAc (100 ml) and 5% aqueous citric acid (50 mL). The organic layer was washed with H20 (2X50 mL), dried with Na2SO4. After evaporation of the solvent the residue was purified on silica gel, eluting with 35% EtOAc in hexane to give 420 mg as a clear gum. FAB ms 253.
Step B: Preparation of 3-(4-cyanobenzyl)-4- (hydroxymethvl)pyridine The title compound was obtained by sodium borohydride (300 mg) reduction of the ester from Step A (415 mg) in methanol mL) at room temperature. After stirring for 4 h the solution was evaporated and the product was purified on silica gel, eluting with 2% methanol in chloroform to give the title compound. FAB ms (M+1) 225.
Step C: Preparation of 3-(4-cvanobenzyl)-4-pyridinal The title compound was obtained by activated manganese dioxide (1.Og) oxidation of the alcohol from Step B (240 mg, 1.07 mmol) in dioxane (10 mL) at reflux for 30 min. Filtration and evaporation of the solvent provided title compound, mp 80-830C.
Step D: Preparation of (±)-3-(4-cyanobenzyl)-4-[(1-hydroxy-3phenvl)-2-propynyl]pyridine hydrochloride The titled compound is prepared from the pyridinal from Step C using the procedured in Step F of Example 1. The product is purified by silica gel chromatography, then taken up in CH 2 C1 2 and WO 97/36876 PCT/US97/06257 -44treated with excess I M HCl/ether solution, and concentrated in vacuo to provide the titled product hydrochloride.
EXAMPLE 4 1-(4-BIPHENYLMETHYL)-5-(4-CYANOBENZYL)IMIDAZOLE HYDROCHLORIDE SALT Step A: 1-Tritvl-4-(4-Cyanobenzyl)-imidazole.
To a suspension of activated zinc dust (3.57g, 54.98mmol) in THF (50ml)was added dibromoethane (0.315ml, 3.60mmol) and the reaction stirred under argon at 20°C. The suspension was cooled to 0 C and a bromo-p-toluinitrile (9.33g, 47.6mmol) in THF (100ml) was added dropwise over a period of 10 min. The reaction was then allowed to stir at 20 0 C for 6hr and bis(triphenylphosphine)Nickel II chloride (2.4g, 3.64mmol) and 5 -iodotrityl imidazole (15.95g, 36.6mmol) was added in one portion.The resulting mixture was stirred 16hr at and then quenched by addition of saturated NH4Cl solution (100ml) and the mixture stirred for 2 hours. Saturated NaHCO3 solution was added to give a pH of 8 and the solution was extracted with EtOAc (2x250ml), dried MgSO4 and the solvent evaporated in vacuo. The residue was chromatographed (Si02, 0-20% EtOAc/CH2CI2 to afford the title compound as a white solid.
1H NMR 8 CDC13 (7.54 (2H, d, J=7.9Hz), 7.38(1H, 7.36-7.29 (11H, 7.15-7.09(6H, 6.58(1H, and 3.93(2H, s)ppm.
Step B: 1-(4-Biphenylmethyl)-5-(4-cyanobenzyl)imidazole hydochloride salt To l-Trityl-4-(4-Cyanobenzyl)-imidazole (608.8 mg 1.43 mmol) in acetonitrile (2 ml) was added 4-chloromethyl biphenyl (290mg, 1.43 mmol) and the mixture heated at 55 0 C for 16 hours. The residue was dissolved in methanol (30 ml) and heated at reflux for mins, cooled and evaporated to dryness. The residue was partitioned between saturated NaHCO3 solution and CH2C12. The organic layer WO 97/36876 PCT/US97/06257 was dried (MgSO4) and the solvent evaporated in vacuo. The residue was chromatographed (Si02, 5% methanol in CH2C12) to afford the imidazole which was converted to the HCI salt by treatment with one equivalent of HCI in aqueous acetonitrile. Evaporation of solvent in vacuo afforded the title compound as a white powder.
Anal. Calcd for C24H19N3* 1.00 HCI: C, 74.70; H, 5.22; N, 10.89.
Found: C, 74.70; H, 5.31; N, 10.77.
FAB MS 350 (MH+) 1 H NMR CD30D 5 9.03(1H, 7.65-7.50(5H, 7.44(2H, t, 7.39(1H, 7.35(1H, t, J=7.3Hz), 7.26(2H, d, J=8.1Hz), 7.20(2H, d, J=8.1Hz), 5.42(2H, and 4.17(2H, s) ppm.
EXAMPLE 1 -(4-CYANOBENZYL)IMIDAZOL-5-YL '-BIPHENYL -4-
YL)METHANOL
A Grignard reagent, freshly prepared from 4-bromo[1,1'biphenyl] (116 mg, 500 pmol) and magnesium turnings (18 mg, 730 pmol) in dry THF (500 pl) was added to a dry Argon-purged 3mL flask containing the aldehyde (105 mg, 500 pmol) in dry THF (200 pL) with vigorous stirring at room temperature. After 1 hour the reaction was quenched with sat. NH 4 CI (5 mL) and distributed between EtOAc mL) and H 2 0 (50 mL). The organic phase was evaporated and the residue was chromatographed on silica gel (CHCl 3 -MeOH to yield title (117 mg).
FAB ms 366.25.
Anal. Calc. for C 24
H
19
N
3 0-0.10 CHC1 3 -0.10 CH 3
OH;
C, 76.37 H, 5.16 N, 11.04.
Found: C, 76.13; H, 5:10; N, 10.76.
EXAMPLE 6 WO 97/36876 PCT/US97/06257 -46- [1 -(4-CYANOBENZYL)IMIDAZOL-5-YLI([ 1,1 '-BIPHENYL1-4-
YL)KETONE
The alcohol (Example 5) (105 mg, 228 pmol) was added to dioxane (3 mL) and activated MnO 2 (300 mg) and the black mixture was stirred at reflux for 2 hr. The mixture was filtered and the clear filtrate was evaporated and the residue was chromatographed on silica gel (CHC13-MeOH to yield title (35 mg).
FAB ms 364.07.
Anal. Calc. for C 24
H
17
N
3 0-0.35 CHC1 3 C, 72.17; H, 4.32; N, 10.37.
Found: C, 71.87; H, 4.45; N, 10.29.
EXAMPLE 7 1l- [1-(4-CYANOBENZYL)- 1H-IMIDAZOL-5-YL1ETHYL 1-4- PHENYL IMIDAZOLE BIS HYDROCHLORIDE SALT
N
NNN
NC
Step A: 1H-Imidazole-4- acetic acid methyl ester hydrochloride A solution of 1H-imidazole-4-acetic acid hydrochloride (4.00g, 24.6 mmol) in methanol (100 ml) was saturated with gaseous hydrogen chloride. The resulting solution was allowed to stand at room temperature for 18 hrs. The solvent was evaporated in vacuo to afford the title compound as a white solid.
1 H NMR CDC13, 8 8.85(1H, 7.45(1H, 3.89(2H, s) and 3.75(3H, s) ppm.
WO 97/36876 PCT/US97/06257 -47- Step B: 1-(Triphenylmethyl)- 1H-imidazol-4-ylacetic acid methyl ester To a solution of the product from Step A (24.85g, 0.141mol) in DMF (115ml) was added triethylamine (57.2 ml, 0.412mol) and triphenylmethyl bromide (55.3g, 0.171mol) and the suspension was stirred for 24 hrs. After this time, the reaction mixture was diluted with EtOAc and water. The organic phase was washed with saturated aqueous NaHCO3, dried (Na2SO4) and the solvent evaporated in vacuo. The residue was purified by chromatography (SiO2, gradient elution, 0-100% EtOAc in hexanes; to provide the title compound as a white solid.
1H NMR CDC13, 6 7.35(1H, 7.31(9H, 7.22(6H, 6.76(IH, 3.68(3H, s) and 3.60(2H, s) ppm.
Step C: [1-(4-Cyanobenzyl)- H-imidazol-5-yl]acetic acid methyl ester.
To a solution of the product from Step B (8.00g, 20.9mmol) in acetonitrile (70 ml) was added 4-cyanobenzyl bromide (4.10g, 20.92 mmol) and heated at 55 0 C for 3 hr. After this time, the reaction was cooled to room temperature and the resulting imidazolium salt was collected by filtration. The filtrate was heated at 55°C for 18hrs. The reaction mixture was cooled to room temperature and evaporated in vacuo. To the residue was added EtOAc (70 ml) and the resulting precipitate collected by filtration. The precipitated imidazolium salts were combined, suspended in methanol (100 ml) and heated to reflux for 30 min. After this time, the solvent was removed in vacuo,. The resulting residue was suspended in EtOAc and the solid isolated by filtration and washed with EtOAc.
The solid was treated with saturated aqueous NaHCO3 solution (300ml) and CH2C12 (300ml) and stirred at room temperature for 2 hrs. The organic layer was separated, dried (MgSO4) and evaporated in vacuo to afford the title compound as a white solid 1 HNMR CDC13, 8 7.65(1H, d, J=8Hz), 7.53(1H, 7.15(1H, d, J=8Hz), 7.04(1H, 5.24(2H, 3.62(3H, s) and 3.45(2H, s) ppm.
WO 97/36876 PCT/US97/06257 -48- Step D: 5-[1-(4-cvanobenzyl)-1 H-imidazolyllethanol.
To a stirred solution of the ester from example step C, (1.50g, 5.88mmol), in methanol (20 ml) at 0°C, was added sodium borohydride (1.00g, 26.3mmol) portionwise over 5 min. The reaction was stirred at 0°C for 1 hr and then at room temperature for an additional 1 hr. The reaction was quenched by the addition of saturated NH4C1 solution and the methanol evaporated in vacuo.. The residue was partitioned between EtOAc and saturated NaHCO3 solution and the organic extracts dried, (MgSO4) and evaporated in vacuo. The residue was purified by chromatography (Si02, gradient elution, 4 to methanol in methylene chloride) to afford the title compound as a white solid.
1 H NMR CDCl3 6 7.64(2H, d, J=8.2Hz), 7.57(1H, 7.11(2H, d, J=8.2Hz), 6.97(1H, 5.23(2H, 3.79(2H, t, J=6.2Hz), 2.66(2H, t, J=6.2Hz) ppm.
Step E: -(4-Cvanobenzvl)-imidazolyl)ethylmethanesulfonate.
A solution of 5-[1-(4-cyanobenzyl)-1H-imidazolyl]ethanol (0.500 g, 2.20 mmol) in methylene chloride (6 ml) at 0°C was treated with Hunig's base (0.460ml, 2.64mmol) and methanesulfonyl chloride (0.204ml, 2.64mmol). After 2 hrs, the reaction was quenched by addition of saturated NaHCO3 solution (50ml) and the mixture extracted with methylene chloride (50ml), dried (MgSO4) and the solvent evaporated in vacuo. The title compound was used without furthur purification.
IH NMR CDCl3 5 7.69 (IH, s) 7.66(2H, d, J=8.2Hz), 7.15 (2H, d, J=8.2Hz), 7.04(1H, 5.24(2H, 4.31(2H, t, J=6.7Hz), 2.96(3H, s), and 2.88(2H, t, J=6.6Hz)ppm.
Step F: 1- [1 -(4-Cyanobenzyl)-1 H-imidazol-5-yl]ethyl -4-phenyl imidazole bis hydrochloride salt.
To a suspension of sodium hydride (14.2mg, dispersion in mineral oil, 0.356mmol) in DMF (0.30 ml) at 0°C was WO 97/36876 PCT/US97/06257 -49added 4-phenyl imidazole (48.8mg, 0.339mmol), and stirred for mins. A solution of the mesylate from step E (100mg, 0.339mmol) in DMF (0.50ml) was added to the solution and stirring continued at 0 C for 1 hr and then at room temperature for 16 hrs. The reaction was quenched with saturated ammonium chloride solution (0.10ml), and the the solvent evaporated in vacuo. The residue was purified by chromatography (SiO2, gradient elution, 2-5% ammonium hydoxide: acetonitrile. The resulting material was converted to the HCI salt by treating an EtOAc solution of the imidazole with gasseous HCI and evaporating the solvent in vacuo.
WO 97/36876 PCT/US97/06257 Anal. Calcd for C22H19N5-2.00HCl* .50H20: C, 58.29; H, 5.34; N, 15.45.
Found: C, 58.24; H, 5.47; N, 15.48.
FAB HRMS exact mass calcd for C22H20N5 354.171871 found 354.171948.
1H NMR CD30D 6 8.93 (1H, 8.75(1H, 7.86(1H, 7.76(2H, d, J=7.9Hz), 7.69(2H, d, 7.1Hz), 7.65-7.35(6H, 5.61(2H, s) and 4.53(2H,m)ppm.
In vitro inhibition of ras farnesyl transferase Assays offarnesyl-protein transferase.
Partially purified bovine FPTase and Ras peptides (Ras-CVLS, Ras-CVIM and Ras-CAIL) were prepared as described by Schaber et al., J. Biol. Chem. 265:14701-14704 (1990), Pompliano, et al., Biochemistry 31:3800 (1992) and Gibbs et al., PNAS U.S.A.
86:6630-6634 (1989), respectively. Bovine FPTase was assayed in a volume of 100 pl containing 100 mM N-(2-hydroxy ethyl) piperazine- N'-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgCI2, 5 mM dithiothreitol (DTT), 100 mM 3 H]-famesyl diphosphate 3 H]-FPP; 740 CBq/mmol, New England Nuclear), 650 nM Ras-CVLS and 10 tg/ml FPTase at 31 C for 60 min. Reactions were initiated with FPTase and stopped with 1 ml of 1.0 M HCL in ethanol. Precipitates were collected onto filter-mats using a TomTec Mach II cell harvestor, washed with 100% ethanol, dried and counted in an LKB P-plate counter. The assay was linear with respect to both substrates, FPTase levels and time; less than 10% of the 3 H]-FPP was utilized during the reaction period.
Purified compounds were dissolved in 100% dimethyl sulfoxide (DMSO) and were diluted 20-fold into the assay. Percentage inhibition is measured by the amount of incorporation of radioactivity in the presence of the test compound when compared to the amount of incorporation in the absence of the test compound.
Human FPTase was prepared as described by Omer et al., Biochemistry 32:5167-5176 (1993). Human FPTase activity was assayed as described above with the exception that 0.1% (w/v) WO 97/36876 PCT/US97/06257 -51polyethylene glycol 20,000, 10 gM ZnCI 2 and 100 nM Ras-CVIM were added to the reaction mixture. Reactions were performed for 30 min., stopped with 100 .l of 30% trichloroacetic acid (TCA) in ethanol and processed as described above for the bovine enzyme.
The compounds of the instant invention described in the above Examples 1-7 were tested for inhibitory activity against human FPTase by the assay described above and were found to have IC50 of gM.
In vivo ras farnesylation assay The cell line used in this assay is a v-ras line derived from either Ratl or NIH3T3 cells, which expressed viral Ha-ras p21.
The assay is performed essentially as described in DeClue, J.E. et al., Cancer Research 51:712-717, (1991). Cells in 10 cm dishes at 50-75% confluency are treated with the test compound (final concentration of solvent, methanol or dimethyl sulfoxide, is After 4 hours at 37 0 C, the cells are labelled in 3 ml methionine-free DMEM supplemeted with 10% regular DMEM, 2% fetal bovine serum and 400 mCi[ 3 5 S]methionine (1000 Ci/mmol). After an additional 20 hours, the cells are lysed in 1 ml lysis buffer NP40/20 mM HEPES, pH 7.5/5 mM MgCl2/1mM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml mM PMSF) and the lysates cleared by centrifugation at 100,000 x g for 45 min. Aliquots of lysates containing equal numbers of acid-precipitable counts are bought to 1 ml with IP buffer (lysis buffer lacking DTT) and immunoprecipitated with the ras-specific monoclonal antibody Y13-259 (Furth, M.E. et al., J. Virol. 43:294-304, (1982)). Following a 2 hour antibody incubation at 4°C, 200 ml of a suspension of protein A-Sepharose coated with rabbit anti rat IgG is added for 45 min. The immunoprecipitates are washed four times with IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA/1% Triton X- 100.0.5% deoxycholate/0.1%/SDS/0.1 M NaCI) boiled in SDS-PAGE sample buffer and loaded on 13% acrylamide gels. When the dye front reached the bottom, the gel is fixed, soaked in Enlightening, dried and autoradiographed. The intensities of the bands corresponding to WO 97/36876 PCT/US97/06257 -52famesylated and nonfarnesylated ras proteins are compared to determine the percent inhibition of farnesyl transfer to protein.
In vivo growth inhibition assay To determine the biological consequences of FPTase inhibition, the effect of the compounds of the instant invention on the anchorage-independent growth of Ratl cells transformed with either a v-ras, v-raf, or v-mos oncogene is tested. Cells transformed by v-Raf and v-Mos maybe included in the analysis to evaluate the specificity of instant compounds for Ras-induced cell transformation.
Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded at a density of 1 x 104 cells per plate (35 mm in diameter) in a 0.3% top agarose layer in medium A (Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum) over a bottom agarose layer Both layers contain 0.1% methanol or an appropriate concentration of the instant compound (dissolved in methanol at 1000 times the final concentration used in the assay).
The cells are fed twice weekly with 0.5 ml of medium A containing 0.1% methanol or the concentration of the instant compound.
Photomicrographs are taken 16 days after the cultures are seeded and comparisons are made.
Claims (42)
1. A compound represented by formula I: (R 6 )r 7 R 3 V A'(CRla 2 )nA 2 (CRlb 2 n (CR 2 A 3 (CR22)pX R 4 or a pharmaceutically acceptable salt thereof, wherein: R la, R b and R 2 are independently selected from the group consisting of: hydrogen, aryl, substituted aryl, heterocyclyl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 8 R 9 S(O)m- wherein m is 0, 1 or 2, R 8 C(O)NR 8 CN, N02, (R 8 )2NC(NRS)-, R 8 R 8 N3, -N(R 8 R 9 0C(O)NR 8 and CI-C6 alkyl, unsubstituted or substituted by 1-3 groups selected from the group consisting of: halo, aryl, heterocyclyl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 8 R 9 R 8 C(O)NR 8 CN, (R 8 )2NC(NR 8 R 8 R80C(O)-, N3, -N(R 8 )2 and R 9 0C(O)NR 8 R 3 and R 4 are independently selected from the group consisting of: H, F, Cl, Br, -NR 8 2, CF3, NO2, R 8 R 9 S(O)m-, R 8 C(O)NH-, H2NC(NH)-, R 8 R 8 N3, CN, R 9 0C(O)NR 8 C -C20 alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl; A 3 is selected from: -R 8 C-CR 8 aryl, heteroaryl, or a bond; provided that when A 3 is heteroaryl, attachment of A 3 the remainder of Sthe molecule is through substitutable heteroaryl ring carbons; X represents aryl or heteroaryl; WO 97/36876 WO 9736876PCT1US97/06257 -54- provided that when X is heteroaryl, attachment of X the remainder of the molecule is through substitutable heteroaryl ring carbons; R 6 is independently selected from the group consisting of: hydrogen, aryl, heterocyclyl, C3-ClO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 16 perfluoroalkyl, F, Cl, Br, R 8 R 9 R 8 C(O)NR 8 CN, N02, (Rg)2NC(NR 8 R 8 R 8 N3, -N(R 8 )2, R 9 OC(O)NR 8 and C I -C6 alkyl unsubstituted or substituted by 1-3 groups selected from: aryl, heterocyclyl, C3-ClO cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 8 R 9 S(O)m-, RgC(O)NR8-, CN, (R 8 )2NC(NR 8 RSC(O)-, R 8 N3, -N(R 8 )2 and R 9 OC(O)NR 8 R 7 is independently selected from the group consisting of: hydrogen, aryl, heterocyclyl, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, CI-6 perfluoroalkyl, F, Cl, Br, R 9 R 9 R 8 C(O)NR 8 CN, N02, (R 8 )2NC(NR 8 R 8 R 8 N3, -N(R 8 )2, R 9 OC(O)NR 8 and C1I-C6 alkyl unsubstituted or substituted by 1-3 groups selected from: aryl, heterocyclyl, C3-C1O cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 8 R 9 S(O)m-, R 8 C(O)NR8-, CN, (Rg)2NC(NR 8 R 8 R 8 N3, -N(Rg)2 and R 9 OC(O)NR 8 each R 8 is independently selected from hydrogen, C I -C6 alkyl, aryl and aralkyl; each R 9 is independently selected from C I-C6 alkyl and aryl; A1 and A 2 are independently selected from the group consisting of: a bond, -CH=CH-, -C(O)NR 8 NR 8 -N(R 8 -S(0)2N(R 8 -N(R 8 and S(O)m; WO 97/36876 PCT/US97/06257 V is selected from the group consisting of: hydrogen, heterocyclyl, aryl, C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and C2-C20 alkenyl, provided that V is not hydrogen if Al is S(O)m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(0)m; provided that when V is heterocycle, attachment of V to R 8 and to A 1 is through a substitutable ring carbon; W represents heterocyclyl; each n and p independently represents 0, 1, 2, 3 or 4; r is 0 to 5, provided that r is 0 when V is hydrogen, and t is 1.
2. A compound in accordance with claim 1 wherein Ria ,Rlb and R 2 are independently selected from: hydrogen, -N(R 8 )2, R 8 C(0)NR 8 or unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C] -C6 alkyl is selected from unsubstituted or substituted aryl, -N(RS)2, R 8 0- and R 8 C(0)NR 8
3. A compound in accordance with claim and R 4 are selected from: hydrogen, CI-C6 alkyl, Cl, Br, CF3.
4. A compound in accordance with claim represents -C -CR 8 =CRS-, or a bond.. 1 wherein R 3 F, R80- and 1 wherein A 3 represents A compound in accordance with claim 1 wherein A 3
6. A compound in accordance with claim represents aryl or heteroaryl. 1 wherein A 3 WO 97/36876 PCT/US97/06257 -56-
7. A compound in accordance with claim 1 wherein R 6 represents CN.
8. A compound in accordance with claim 1 wherein R 7 represents hydrogen, unsubstituted or substituted Ci-C6 alkyl.
9. A compound in accordance with claim 1 wherein R 8 represents H or C1-6 alkyl, and R 9 is Ci-6 alkyl.
10. A compound in accordance with claim 1 wherein A 1 and A 2 are independently selected from: a bond, -C(O)NR 8 -NR 8 -N(R 8 -S(0)2N(R 8 and-N(R 8
11. A compound in accordance with claim 1 wherein V is selected from hydrogen, heterocyclyl and aryl.
12. A compound in accordance with claim 11 wherein V is phenyl.
13. A compound in accordance with claim 1 wherein W is heterocyclyl selected from imidazolinyl, imidazolyl, oxazolyl, pyrazolyl, pyyrolidinyl, thiazolyl and pyridyl.
14. A compound in accordance is selected from imidazolyl and pyridyl. with claim 1 wherein W represents A compound in aryl.
16. A compound in phenyl.
17. A compound in heteroaryl. accordance with claim 1 wherein X accordance with claim 15 wherein X accordance with claim 1 wherein X represents represents
18. A compound in accordance with claim 17 wherein X represents pyridyl.
19. A compound in accordance with claim 1 wherein m is 0 or 2. A compound in accordance with claim 1 wherein n and p are 0, 1, 2 or 3.
21. A compound in accordance with claim 1 represented by formula la: 7 (R6)r 1 la 2 b3 V-A (CRa 2 nA (CR 1b 2 R (CR2 2 A3--(CR2 2 X la R 4 wherein: R 3 R 4 A 3 R 8 R9, X, m, n, p and r are as originally defined; each R l a and R 2 is independently selected from hydrogen and C1-C6 alkyl; each Rib is independently selected from: hydrogen, aryl, heterocyclyl, C 3 -10 cycloalkyl, C2-6 alkenyl, R 8 -N(R 8 )2 and C1-C 6 alkyl unsubstituted or substituted by aryl, heterocyclyl, cycloalkyl, alkenyl, R 8 0- and -N(R 8 2 a a O [R:LIBAA]07709.doc:tab -58- R 6 is independently selected from: hydrogen, ClI-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl, R 8 0-, R 8 C(O)NR 8 CN, N02, (Rg)2N-C(NRS)-, R 8 R 8 OC(O)-, -N(Rg)2, or R 9 OC(O)NR 8 and ClI-C6 alkyl substituted by ClI-C6 perfluoroalkyl, R 8 R 8 C(O)NR 8 (R 8 )2N-C(NR 8 R 8 R 8 -N(R 8 )2 and R 9 OC(O)NR8-; R 7 represents H or CI-6 alkyl; A and A 2 are independently selected from: a bond, -CH=CH-, -C(O)NRS-, 0, and S(O)m; and V is selected from: hydrogen; aryl; heterocyclyl selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, indolyl, quinolinyl, isoquinolinyl and thienyl; C I -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatomn selected from 0, S, and N, and C2-C20 alkenyl, provided that V is not hydrogen if A 1 is S (O)m and V is not hydrogen if AlI is a bond and A 2 is S(Om 20provided that when V is heterocycle, attachment of V to R 8 and to AlI is through a substitutable ring carbon.
22. A compound in accordance with claim I represented by formula 1b: *R 6 V-Al(CRla 2 )A 2 (CRb 2 (0R 2 2 )pR C=CR 8 {R 2 R 4* wherein: Rla, Rib, R 2 Al, A 2 R 3 R 4 R 6 R 8 R 9 X, m, n, p and r are as originally defined; R 7 is selected from: hydrogen and ClI -C6 alkyl; -59- V is selected from: hydrogen, heterocyclyl selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, indolyl, quinolinyl, isoquinolinyl and thienyl; aryl; CI-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and C2-C20 alkenyl, provided that V is not hydrogen if A is S(O)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(O)m; provided that when V is heterocycle, attachment of V to R8 and to Al is through a substitutable ring carbon; and W represents heterocyclyl selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, indolyl, quinolinyl and isoquinolinyl.
23. A compound in accordance with claim 1 represented by formula Ic: (R 6 )r 7 .I R R 3 °V A'(CRa2)nA2(CR2) n (CR2-- R X R 4 Ic 20 wherein: Rla, Rlb, R 2 Al, A 2 R 3 R 4 R 6 R 8 R 9 X, m, n, p and r are as originally defined; R 7 is selected from: hydrogen and Cl-C6 alkyl; V is selected from: hydrogen, heterocyclyl selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, aryl, C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and C2-C20 alkenyl, provided that V is not hydrogen if A I is S(O)m and V is not hydrogen if A is a bond, n is 0 and A 2 is S(O)m; provided that when V is heterocycle, attachment of V to R8 and to A 1 is through a substitutable ring carbon; and W represents heterocyclyl selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, indolyl, quinolinyl and isoquinolinyl.
24. A compound in accordance with claim 1 represented by formula Id: H 2 (C 2 )P -A 3 2 (C 2 )-X R* 6 15 wherein: each R 2 is independently selected from hydrogen and C I-C6 alkyl; R 3 R 4 A 3 R8, R 9 X, mn and p are as originally defined; and R 6 is selected from the group consisting of: hydrogen, C I-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CI-C6 peffluoroalkyl, F, Cl, R 8 R 8 C(O)NRX-, CN, N02, (R 8 )2N-C(NR 8 R 8 R8OC(O)-, -N(R 8 or R 9 OC(O)NR 8 and CI-C6 alkyl substituted by C1I-C6 peffluoroalkyl, R90-, RgC(O)NR 8 8 )2N-C(NR 8 RgC(O)-, R 8 -N(R 8 )2 or R 9 OC(O)NR 8 -61- A compound in accordance with claim I represented by formula le: H NNy ,RN (CR 2 )p A 3 NC le wherein: X and A 3 are as originally defined; each R2 is independently selected from: hydrogen and C1I-C6 alkyl; :10 R 3 and R 4 are independently selected from H, F, Cl, Br, N(R 8 CF3, N02, (R 8 (R 9 (R 8 H2N-C(NH)-, (R 8 (R 8 N3, CN, (R 9 )OC(O)NRS-, C1 -C20 alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclyl; and R 8 R 9 m and p are as originally defined.
26. A compound in accordance with claim 1 represented by the formula: C1 NC N WO 97/36876 WO 9736876PCTfUS97/06257 -62- NC NC NC Ci -CH0 N-C C N CH--CH NC HO NC-C C N- NC OH CI N N NC HO NC -C -C N- NC CH 2 WO 97/36876 WO 9736876PCT1US97/06257 -63- C-C--O NO OH OH N N 0- ON or a pharmaceutically acceptable salt thereof. 6 S C 0 C C C 0 ego. em *C C C S S S
27. A compound which inhibits farnesyl-protein transferase, substantially as hereinbefore described with reference to any one of the examples.
28. A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of any one of claims 1 to 27.
29. A pharmaceutical composition made by combining the compound of any one of claims 1 to 27 and a pharmaceutically acceptable carrier. A process for making a pharmaceutical composition the process comprising combining a compound of any one of claims 1 to 27 and a pharmaceutically acceptable carrier.
31. A method for inhibiting farnesyl-protein transferase which method comprises administering to a mammal a therapeutically effective amount of a compound of any one of claims 1 to 27 or of a composition of claim 28 or claim 29.
32. A compound according to any one of claims 1 to 27 or a composition according to claim 28 or claim 29 when used in inhibiting farnesyl-protein transferase.
33. The use of a compound according to any one of claims 1 to 27 for the manufacture of a medicament for inhibiting farnesyl-protein transferase.
34. A method for treating cancer which method comprises administering to a mammal a therapeutically effective amount of a compound of any one of claims 1 to 27 or of a composition of claim 28 or claim 29.
35. A compound according to any one of claims 1 to 27 or a composition according to claim 20 28 or claim 29 when used in treating cancer.
36. The use of a compound according to any one of claims 1 to 27 for the manufacture of a medicament for treating cancer.
37. A method for treating neurofibromin benign proliferative disorder which method comprises administering to a mammal a therapeutically effective amount of a compound of any one of claims 1 to 27 or of a composition of claim 28 or claim 29.
38. A compound according to any one of claims 1 to 27 or a composition according to claim 28 or claim 29 when used in treating neurofibromin benign proliferative disorder.
39. The use of a compound according to any one of claims 1 to 27 for the manufacture of a medicament for treating neurofibromin benign proliferative disorder. 30 40. A method for treating blindness related to retinal vascularisation which method comprises administering to a mammal a therapeutically effective amount of a compound of any one of claims 1 to 27 or of a composition of claim 28 or claim 29.
41. A compound according to any one of claims 1 to 27 or a composition according to claim 28 or claim 29 when used in treating blindness related to retinal vascularisation.
42. The use of a compound according to any one of claims 1 to 27 for the manufacture of a Smedicament for treating blindness related to retinal vascularisation. [R:LIBAA]07709.doc:tab 32 RAI 3 3 ii
43. A method for treating infections from hepatitis delta and related viruses which method comprises administering to a mammal a therapeutically effective amount of a compound of any one of claims 1 to 27 or of a composition of claim 28 or claim 29.
44. A compound according to any one of claims 1 to 27 or a composition according to claim 28 or claim 29 when used in treating infections from hepatitis delta and related viruses. The use of a compound according to any one of claims 1 to 27 for the manufacture of a medicament for treating infections from hepatitis delta and related viruses.
46. A method for preventing restenosis which method comprises administering to a mammal a therapeutically effective amount of a compound of any one of claims 1 to 27 or of a composition of claim 28 or claim 29.
47. A compound according to any one of claims 1 to 27 or a composition according to claim 28 or claim 29 when used in preventing restenosis.
48. The use of a compound according to any one of claims 1 to 27 for the manufacture of a medicament for preventing restenosis. 15 49. A method for treating polycystic kidney disease which method comprises administering to o a mammal a therapeutically effective amount of a compound of any one of claims 1 to 27 or of a composition of claim 28 or claim 29. A compound according to any one of claims 1 to 27 or a composition according to claim :oo• 28 or claim 29 when used in treating polycystic kidney disease.
51. The use of a compound according to any one of claims 1 to 27 for the manufacture of a medicament for treating polycystic kidney disease. Dated 5 November, 1999 Merck Co., Inc. Patent Attorneys for the ApplicantlNominated Person 25 SPRUSON FERGUSON [R:\LIBAA]07709.doc'tab
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US1459296P | 1996-04-03 | 1996-04-03 | |
| US60/014592 | 1996-04-03 | ||
| GBGB9613462.2A GB9613462D0 (en) | 1996-06-27 | 1996-06-27 | Inhibitors of farnesyl-protein transferase |
| GB9613462 | 1996-06-27 | ||
| PCT/US1997/006257 WO1997036876A1 (en) | 1996-04-03 | 1997-04-01 | Inhibitors of farnesyl-protein transferase |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU2670297A AU2670297A (en) | 1997-10-22 |
| AU715658B2 true AU715658B2 (en) | 2000-02-10 |
Family
ID=26309577
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU26702/97A Ceased AU715658B2 (en) | 1996-04-03 | 1997-04-01 | Inhibitors of farnesyl-protein transferase |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0891334A1 (en) |
| JP (1) | JP2000507955A (en) |
| AU (1) | AU715658B2 (en) |
| CA (1) | CA2249615A1 (en) |
| WO (1) | WO1997036876A1 (en) |
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| WO1997027752A1 (en) * | 1996-01-30 | 1997-08-07 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
| US5932590A (en) * | 1996-12-05 | 1999-08-03 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
| KR100375421B1 (en) * | 1997-07-15 | 2003-05-12 | 주식회사 엘지생명과학 | Farnesyl transferase inhibitor having anti-tumor properties |
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| DE3813885A1 (en) | 1988-04-20 | 1989-11-02 | Schering Ag | 1-CHLORPYRIMIDINYL-1H-1,2,4-TRIAZOL-3-SULPHONIC ACID AMIDE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS AGENT WITH HERBICIDES, FUNGICIDES AND PLANT GROWTH REGULATING EFFECT |
| FR2657610A1 (en) | 1990-01-29 | 1991-08-02 | Rhone Poulenc Agrochimie | TRIAZOLOPYRIDINES HERBICIDES. |
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| JPH05201974A (en) | 1991-11-25 | 1993-08-10 | Sumitomo Chem Co Ltd | Heterocyclic compound and herbicide containing the compound as active component |
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-
1997
- 1997-04-01 AU AU26702/97A patent/AU715658B2/en not_active Ceased
- 1997-04-01 WO PCT/US1997/006257 patent/WO1997036876A1/en not_active Application Discontinuation
- 1997-04-01 CA CA002249615A patent/CA2249615A1/en not_active Abandoned
- 1997-04-01 JP JP9535634A patent/JP2000507955A/en active Pending
- 1997-04-01 EP EP97918643A patent/EP0891334A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| EP0891334A1 (en) | 1999-01-20 |
| JP2000507955A (en) | 2000-06-27 |
| CA2249615A1 (en) | 1997-10-09 |
| WO1997036876A1 (en) | 1997-10-09 |
| AU2670297A (en) | 1997-10-22 |
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