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  • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
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  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

• 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-regulatory 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.
• Ras 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 (D.R. Lowy and D.M. Willumsen, Ann. Rev. Biochem. 62:851 -891 ( 1993)).
• Mutated ras genes ( a-ras, Ki4a- ⁇ w, Ki4b-ra.s 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-Aaa ⁇ -Aaa ⁇ -Xaa” box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al, Nature 370:583-586 ( 1984)).
• this motif serves as a signal sequence for the enzymes famesyl-protein transferase or geranylgeranyl-protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a C15 or C20 isoprenoid, respectively.
• Ras proteins are known to undergo post-translational famesylation.
• farnesylated 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 farnesylated. James, et al., have also suggested that there are farnesylated proteins of unknown structure and function in addition to those listed above.
• FPTase famesyl-protein transferase
• FPP fa esyl diphosphate
• Ras protein substrates
• 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.
• Such inhibitors may inhibit protein prenylation while serving as altemate substrates for the famesyl-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: 1934-1931 (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 H7-1 12930).
• R 1 a, R 1 b an£ j R2 are independently selected from the group consisting of: hydrogen, aryl, substituted aryl, heterocyclyl, C3-C 10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 0-, R 9 S(0) m - wherein m is 0, 1 or 2, R C(0)NR 8 -, CN, N ⁇ 2, (R 8 )2NC(NR 8 )-, R 8 C(0)-, R 8 OC(0)-, N3, -N(R 8 )2, R 9 OC(0)NR 8 - and C1 -C6 alkyl, unsubstituted or substituted by 1 -3 groups selected from the group consisting of: halo, aryl, heterocyclyl, C3-C10 cycloalkyl, C2-C
• R3 and R ⁇ are independently selected from the group consisting of: H, F, Cl, Br, -NR 8 2, CF3, N ⁇ 2, R 8 0-, R 9 S(0) m -, CF 3 (CH 2 ) n -0-, R 8 C(0)NH-, H2NC(NH)-, R C(0)-, R 8 OC(0)-, N3, CN, R 9 OC(0)NR 8 -, Cl -C20 alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl;
• a 3 is selected from: -C ⁇ C — , — R C CR ⁇ " , -C(O)- , aryl, heteroaryl or a bond; provided that when A ⁇ is heteroaryl, attachment of A ⁇ 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° is independently selected from the group consisting of: hydrogen, aryl, heterocyclyl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-6 perfluoroalkyl, F, Cl, Br, R 0-, R 9 S(0) m -, R 8 C(0)NR 8 -, CN, N ⁇ 2, (R 8 )2NC(NR 8 )-, R C(0)-, R 8 OC(0)-, 1 3, -N(R 8 )2, R 9 OC(0)NR 8 - and C1 -C6 alkyl unsubstituted or substituted by 1-3 groups selected from: aryl, heterocyclyl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 0-, R 9 S(0)m-, R 8 C(0)NR*-, CN, (R )2NC(NR
• R 7 is independently selected from the group consisting of: hydrogen, aryl, heterocyclyl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C ⁇ . 6 perfluoroalkyl, F, Cl, Br, R 9 0-, R 9 S(0) m -, R C(0)NR 8 , CN, N ⁇ 2, (R )2NC(NR 8 )-, R 8 C(0)-, R 8 OC(0)-, N3, -N(R )2, R 9 OC(0)NR 8 - and C1 -C6 alkyl unsubstituted or substituted by 1 -3 groups selected from: aryl, heterocyclyl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 8 0-, R 9 S(0)m-, R 8 C(0)NR*-, CN, (R >2
• each R 8 is independently selected from hydrogen, Cl -C6 alkyl, aryl and aralkyl;
• each R 9 is independently selected from C1-C alkyl and aryl
• V is selected from the group consisting of: hydrogen, heterocyclyl, aryl, C1 -C2O 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(0) 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 heterocyclyl, attachment of V to R6 and to A l 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.
• 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.
• 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.
• 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.
• aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
• a preferred aralkyl group is benzyl.
• heterocyclyl, heterocycle and heterocyclic mean a 5- to 7-membered monocyclic or 8- to 1 1 - membered 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 consisting of N, O, and S.
• 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.
• 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-
• 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, O and S.
• Examples include benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxal
• 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 0-, R 9 S(0) m -, R»C(0)NR «-, CN, (R «) 2 NC(NR «)-, R «C(0)-, R «OC(0)-, N3, -N(R 8 )2 and R ⁇ OC(0)NR x -.
• a substituted alkyl group is substituted with a "substituted aryl group”
• the aryl portion is substituted with 1 -3 groups as defined above.
• Rla ? Rlb anc j R2 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 C1 -C6 alkyl is selected from unsubstituted or substituted aryl, -N(R )2, R 8 0- and R C(0)NR 8 -.
• R3 and R 4 are selected from: hydrogen, C 1 -C6 alkyl, Br, Cl, F, R «0-, and CF3.
• 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.
• R 6 represents CN.
• R ⁇ represents hydrogen, unsubstituted or substituted C l -C6 alkyl.
• R x represents H or Cj- 6 alkyl
• R 9 is Ci -6 alkyl
• a ⁇ and A 2 are independently selected from: a bond, -C(0)NR 8 -, -NR 8 C(0)-, -O-, -N(R 8 )-, -S(0)2N(R 8 )- and- N(R )S(0)2-.
• V is selected from hydrogen, heterocyclyl and aryl. More preferably V is phenyl.
• W is heterocyclyl selected from imidazolinyl, imidazolyl, oxazolyl, pyrazolyl, pyyrohdinyl, thiazolyl and pyridyl. More preferably, W is selected from imidazolyl and pyridyl.
• X represents aryl.
• X can represent phenyl.
• m is 0 or 2.
• n and p are 0, 1 , 2 or 3.
• a subset of compounds of the invention is represented by formula la:
• R 3 , R 4 , A 3 , RK, Ry, X, m, n, p and r are as originally defined;
• each R 1 a nd R2 is independently selected from hydrogen and Cl -C6 alkyl; each R l b is independently selected from: hydrogen, aryl, heterocyclyl, C3-10 cycloalkyl, C2-6 alkenyl, R 8 0-, -N(R 8 )2 and C1 -C6 alkyl unsubstituted or substituted by aryl, heterocyclyl, cycloalkyl, alkenyl,
• R6 is independently selected from: hydrogen, C1 -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1 -C6 perfluoroalkyl, F, Cl, R 0-, R C(0)NR 8 -, CN, N ⁇ 2, (R 8 )2N-C(NR 8 )-, R 8 C(0)-, R OC(0)-, -N(R )2, or R 9 OC(0)NR 8 -, and C1 -C6 alkyl substituted by -C6 perfluoroalkyl, R 8 0-, R C(0)NR 8 -, (R 8 )2N-C(NR 8 )-, R C(0)-, R OC(0)-, -N(R )2 and R 9 OC(0)NR 8 -;
• R 7 represents H or Ci - 6 alkyl
• a l and A 2 are independently selected from: a bond,
• -CH CH-, -C ⁇ C-, -C(O)-, -C(0)NR 8 -, O, -N(R 8 )- and S(0) m ;
• V is selected from: hydrogen; aryl; heterocyclyl selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, indolyl, quinolinyl, isoquinolinyl and thienyl; C1 -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and C2-C2O alkenyl, provided that V is not hydrogen if A 1 is S(0) m and V is not hydrogen if Al is a bond and A 2 is S(0) m; provided that when V is heterocycle, attachment of V to R6 and to A l is through a substitutable ring carbon.
• a second subset of compounds of the present invention is represented by formula lb:
• R 7 is selected from: hydrogen and C 1 -C 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,
• V is not hydrogen if Al is S(0)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 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 7 is selected from: hydrogen and C1 -C6 alkyl
• V is selected from: hydrogen, heterocyclyl selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, aryl, C1 -C2O 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(0)m and V is not hydrogen if A l 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 Al is through a substitutable ring carbon; and
• W represents heterocyclyl selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, indolyl, quinolinyl and isoquinolinyl.
• each R 2 is independently selected from hydrogen and C1 -C6 alkyl
• R3, R4, A 3 , RX, R9, X, m and p are as originally defined;
• R6 is selected from the group consisting of: hydrogen, C1 -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1 -C6 perfluoroalkyl, F, Cl, R 0-, R 8 C(0)NR 8 -, CN, NO2, (R 8 )2N-C(NR 8 )-, R 8 C(0)-, R 8 OC(0)-, -N(R )2, or R 9 OC(0)NR 8 - and C 1 -C6 alkyl substituted by C 1 -C6 perfluoroalkyl, R 8 0-, R C(0)NR 8 -, (R 8 )2N-C(NR 8 )-, R 8 C(0), R 8 OC(0)-, -N(R )2 or R OC(0)NR 8 -.
• a fifth subset of compounds of the invention is represented by formula Ie:
• each R2 is independently selected from: hydrogen and C1-C6 alkyl
• R3 and R4 are independently selected from H, F, Cl, Br, N(R 8 )2, CF3, N02, (R 8 )0-, (R 9 )S(0) m -, (R 8 )C(0)NH-, H2N-C(NH)- (R )C(0)-, (R )OC(0)-, N3, CN, (R 9 )OC(0)NR 8 -, C1 -C2O alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclyl;
• R 8 , R 9 > m and p are as originally defined.
• the pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as formed, e.g., from non-toxic inorganic or organic acids.
• 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.
• 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.
• Schemes 1 -2 illustrate the synthesis of one of the preferred embodi ⁇ ments 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 HI which can be oxidized to the corresponding aldehyde IV.
• 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.
• blocking groups are readily removable, i.e., they can be removed, if desired, by procedures which will not cause cleavage or other disruption of the remaining portions of the molecule.
• 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.
• hydroxyl protecting groups examples include: t-butylmethoxyphenylsilyl, t-butoxydiphenylsilyl, trimethylsilyl, triethylsilyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, benzyloxycarbonyl, t-butyloxycarbonyl, 2,2,2-trichloroethyloxy- carbonyl and allyloxycarbonyl.
• Preferred hydroxyl protecting groups are trimethylsilyl and triethylsilyl.
• 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.
• 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 themselves, mutations in the proteins that can regulate Ras activity (i.e., neurofibromin (NF- 1 ), neu, scr, abl , lck, fyn) or by other mechanisms.
• NF- 1 neurofibromin
• the compounds of the instant invention inhibit famesyl- protein transferase and famesylation of the oncogene protein Ras.
• the instant compounds may also inhibit tumor angiogenesis, thereby affecting the growth of tumors (J. 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 (i.e., 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.
• 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 (J.S. 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 (C. 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 (D.L. Schaffner et al.
• 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 combina ⁇ tion 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.
• the compounds can be administered orally, topically, rectally. vaginally transdermally or parenterally, including the intravenous, intramuscular, intraperitoneal and subcutaneous routes of administration.
• the compound is administered, for example, in the form of tablets or capsules, or as a solution or suspension.
• carriers which are commonly used include lactose and corn starch; lubricating agents, such as magnesium stearate, are commonly added.
• diluents also include lactose and dried com starch.
• the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents may be added.
• sterile solutions of the active ingredient are usually prepared, the pH of the solution is suitably adjusted and the product is buffered.
• the total concentration is controlled to render the preparation substantially isotonic.
• 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.
• the instant compounds may be useful in combination with known anti- cancer and cytotoxic agents.
• 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.
• 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 instant 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.
• 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 famesyl-protein transferase (FPTase) in a composition.
• FPTase famesyl-protein transferase
• 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 famesyl pyrophosphate and, in one of the mixtures, a compound of the instant invention.
• the chemical content of the assay mixtures may be determined by well known immuno- logical, 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.
• 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 farnesyl - protein 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.
• concentration of a sufficiently potent inhibitor i.e., one that has a Ki substantially smaller than the concentration of enzyme in the assay vessel
• concentration of a sufficiently potent inhibitor i.e., one that has a Ki substantially smaller than the concentration of enzyme in the assay vessel
• Step B Preparation of l -triphenylmethyl-4-
• the filtrate was concentrated in vacuo to a volume 100 mL, reheated at 60°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°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-cyanobenzy l)-5-
• Step E Preparation of l-(4-cyanobenzyl)-5- imidazolecarboxaldehyde
• Step F Preparation of ( ⁇ )-l-(4-cyanobenzyl)-5-[( l-hydroxy-3- phenyl)-2-propynyllimidazole hydrochloride
• phenylacetylene (0.172 mL, 1.56 mmol)
• n-butyllithium 0.530 mL, 2.5 M in hexanes, 1.32 mmol.
• 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.
• Step A Preparation of 3-(4-cyanobenzyl)pyridin-4-carboxylic acid methyl ester
• 4-cyanobenzyl bromide 625 mg, 3.27 mmol
• dry THF 4mL
• activated Zn dust; 250 mg
• dry THF 2 mL
• the ice-bath was removed and the slurry was stirred at room temperature for a further 30 min.
• 3-bromopyridin-4- carboxylic acid methyl ester 540 mg. 2.5 mmol
• dichlorobis(triphenylphosphine)nickel II
• the title compound was obtained by sodium borohydride (300 mg) reduction of the ester from Step A (415 mg) in methanol (5 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.
• Step C Preparation of 3-(4-cyanobenzyl -4-pyridinal
• the title compound was obtained by activated manganese dioxide ( 1.0g) 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 80-83°C.
• Step D Preparation of ( ⁇ )-3-(4-cyanobenzyl)-4-[( l-hydroxy-3- phenvP-2-propynyllpyridine 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 CI 2 and treated with excess 1 M HCl/ether solution, and concentrated in vacuo to provide the titled product hydrochloride.
• Step A l -Trityl-4-(4-Cyanobenzyl)-imidazole.
• THF tetrahydrofuran
• dibromoethane 0.315ml, 3.60mmol
• oc bromo-p-toluinitrile 9.33g, 47.6mmol
• Step B l -(4-Biphenylmethyl)-5-(4-cyanobenzyl)imidazole hydochloride salt
• a Grignard reagent freshly prepared from 4-bromo[ l , l '- biphenyl] (1 16 mg, 500 ⁇ mol) and magnesium turnings (18 mg, 730 ⁇ mol) in dry THF (500 ⁇ l) was added to a dry Argon-purged 3mL flask containing the aldehyde (105 mg, 500 ⁇ mol) in dry THF (200 ⁇ L) with vigorous stirring at room temperature. After 1 hour the reaction was quenched with sat. NH CI (5 mL) and distributed between EtOAc (50 mL) and H 2 O (50 mL). The organic phase was evaporated and the residue was chromatographed on silica gel (CHCl 3 -MeOH (20: 1 )) to yield title (1 17 mg). FAB ms (M+l ) 366.25.
• Step A lH-Imidazole-4- acetic acid methyl ester hydrochloride A solution of lH-imidazole-4-acetic acid hydrochloride
• Step C [l-(4-Cyanobenzyl)-lH-imidazol-5-yl]acetic acid methyl ester.
• Step E 5-(- 1 -(4-Cyanobenzyl)-imidazolylkthylmethanesulfonate.
• a solution of 5-[l -(4-cyanobenzyl)- l H-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).
• Step F 1 - ⁇ [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl]ethyl ⁇ -4-phenyl imidazole bis hydrochloride salt.
• the residue was purified by chromatography (Si ⁇ 2, 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.
• Bovine FPTase was assayed in a volume of 100 ⁇ l containing 100 mM -(2-hydroxy ethyl) piperazine- N'-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgCl2, 5 mM dithiothreitol (DTT), 100 mM HJ-farnesyl diphosphate ([ 3 H]-FPP; 740 CBq/mmol, New England Nuclear), 650 nM Ras-CVLS and 10 ⁇ g/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 harvester, washed with 100% ethanol, dried and counted in an LKB ⁇ -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.
• DMSO dimethyl sulfoxide
• 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) polyethylene glycol 20,000, 10 ⁇ M ZnCl 2 and 100 nM Ras-CVIM were added to the reaction mixture. Reactions were performed for 30 min., stopped with 100 ⁇ l of 30% (v/v) trichloroacetic acid (TCA) in ethanol and processed as described above for the bovine enzyme.
• TCA trichloroacetic acid
• 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 50 ⁇ M.
• 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 ah, 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 0.1 %).
• the cells After 4 hours at 37°C, the cells are labelled in 3 ml methionine-free DMEM supple- meted with 10% regular DMEM, 2% fetal bovine serum and 400 mCi[35s]methionine (1000 Ci/mmol). After an additional 20 hours, the cells are lysed in 1 ml lysis buffer (1 % NP40/20 mM HEPES, pH 7.5/5 mM MgCl2/lmM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 mM PMSF) and the lysates cleared by centrifugation at 100,000 x g for 45 min.
• 1 ml lysis buffer (1 % NP40/20 mM HEPES, pH 7.5/5 mM MgCl2/lmM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 mM PMSF
• 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 NaCl) 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 famesylated and nonfamesylated ras proteins are compared to determine the percent inhibition of famesyl transfer to protein.
• IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA/1 % Triton X- 100.0.5% deoxycholate/0.1 %/SDS/0.1 M NaCl
• Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded at a density of 1 x 10 4 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 (0.6%). 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.

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