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WO1997036876A1 - Inhibiteurs de la farnesyl-proteine transferase - Google Patents

Inhibiteurs de la farnesyl-proteine transferase Download PDF

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Publication number
WO1997036876A1
WO1997036876A1 PCT/US1997/006257 US9706257W WO9736876A1 WO 1997036876 A1 WO1997036876 A1 WO 1997036876A1 US 9706257 W US9706257 W US 9706257W WO 9736876 A1 WO9736876 A1 WO 9736876A1
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compound
accordance
hydrogen
alkyl
aryl
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PCT/US1997/006257
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Christopher Dinsmore
Neville Anthony
Gerald E. Stokker
Robert Gomez
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Merck & Co., Inc.
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Priority claimed from GBGB9613462.2A external-priority patent/GB9613462D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to US09/155,681 priority Critical patent/US6063930A/en
Priority to EP97918643A priority patent/EP0891334A1/fr
Priority to JP9535634A priority patent/JP2000507955A/ja
Priority to AU26702/97A priority patent/AU715658B2/en
Publication of WO1997036876A1 publication Critical patent/WO1997036876A1/fr

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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
    • C07D233/56—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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    • C07D—HETEROCYCLIC COMPOUNDS
    • 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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    • 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. The GTP-bound form of Ras propagates the growth
  • 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 (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-Aaa 1 -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)).
  • 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 C 1 5 or C 20 isoprenoid, respectively.
  • Ras proteins are known to undergo post-translational famesylation.
  • Other farnesylated proteins include the Ras-related GTP-binding proteins such as Rho, fungal mating factors, the nuclear lamins, and the gamma subunit of
  • famesyl-protein transferase Indirect inhibition of famesyl-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 245:319 (1989)). These drugs inhibit HMG-CoA reductase, the rate limiting enzyme for the production of polyisoprenoids including famesyl pyrophosphate.
  • Famesyl-protein transferase utilizes famesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a famesyl group (Reiss et al.
  • FPTase famesyl-protein transferase
  • FPP famesyl 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. (Schaber et al, ibid; Reiss et. al, ibid; Reiss et al, PNAS, 88:732-136 ( 1991)).
  • 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)).
  • 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 and R 2 are independently selected from the group consisting of: hydrogen, aryl, substituted aryl, heterocyclyl, C 3 -C 1 0 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 8 O-, R 9 S(O) m - wherein m is 0, 1 or 2, R 8 C(O)NR 8 -, CN, NO 2 , (R 8 ) 2 NC(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N 3 , -N(R 8 ) 2 , R 9 OC(O)NR 8 - and C 1 -C 6 alkyl, unsubstituted or substituted by 1 -3 groups selected from the group consisting of: halo, aryl, heterocyclyl, C 3 -C 1 0 cycloalkyl, C 2 -C
  • R 3 and R 4 are independently selected from the group consisting of: H, F, Cl, Br, -NR 8 2, CF 3 , NO 2 , R 8 O-, R 9 S(O) m -, CF 3 (CH 2 ) n -O-, R 8 C(O)NH-, H 2 NC(NH)-, R 8 C(O)-, R 8 OC(O)-, N 3 , CN, R 9 OC(O)NR 8 -, C 1 -C 20 alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl;
  • a 3 is selected from: -C ⁇ C—, — R 8 C CR 8 -- , -C(O)- , aryl, heteroaryl or a bond;
  • X represents aryl or heteroaryl
  • R 6 is independently selected from the group consisting of: hydrogen, aryl, heterocyclyl, C 3 -C 1 0 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -6 perfluoroalkyl, F, Cl, Br, R 8 O-, R 9 S(O) m -, R 8 C(O)NR 8 -, CN, NO 2 , (R 8 ) 2 NC(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N 3 , -N(R 8 ) 2 , R 9 OC(O)NR 8 - and C 1 -C 6 alkyl unsubstituted or substituted by 1-3 groups selected from: aryl, heterocyclyl, C 3 -C 1 0 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, perfluoroalkyl, F, Cl
  • R 9 OC(O)NR 8 - and C 1 -C 6 alkyl unsubstituted or substituted by 1 -3 groups selected from: aryl, heterocyclyl, C 3 -C 1 0 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, perfluoroalkyl, F, Cl, Br, R 8 O-, R 9 S(O) m -, R 8 C(O)NR 8 -, CN, (R 8) 2 NC(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N 3 , -N(R 8 ) 2 and R 9 OC(O)NR 8 -; each R 8 is independently selected from hydrogen, C 1 -C 6 alkyl, aryl and aralkyl; each R 9 is independently selected from C 1 -C 6 alkyl and aryl;
  • V is selected from the group consisting of: hydrogen, heterocyclyl, aryl, C 1 -C 20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and C 2 -C 20 alkenyl,
  • V is not hydrogen if A 1 is S(O) m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O) m ;
  • V is heterocyclyl, attachment of V to R 6 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.
  • 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,
  • pyridazinyl pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl 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, 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,
  • 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, C 3- 10 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, R 8 O-, R 9 S(O) m -, R 8 C(O)NR 8 -, CN, (R 8 ) 2 NC(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, N 3 , -N(R 8 ) 2 and R 9 OC(O)NR 8 -.
  • substituents which are selected from: halo, aryl, heterocyclyl, C 3- 10 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, R 8 O-, R 9 S(O) m -, R 8 C(O)NR 8 -, CN, (R 8 ) 2 NC(NR 8 )-, R 8 C(O)-, R 8
  • 1-2 groups are present on substituted alkyl, substituted aryl, substituted heterocyclyl and substituted cycloalkyl, which are selected from: halo, aryl, R 8 O-, CN, R 8 C(O)- and -N(R 8 ) 2 .
  • R 1 a ,R 1 b and R 2 are independently selected from: hydrogen, -N(R 8 ) 2 , R 8 C(O)NR 8 - or unsubstituted or
  • substituted C 1 -C 6 alkyl wherein the substituent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, -N(R 8 ) 2 , R 8 O- and R 8 C(O)NR 8 -.
  • R 3 and R 4 are selected from: hydrogen, C 1 -C 6 alkyl, Br, Cl, F, R 8 O-, and CF 3 .
  • a 3 represents
  • 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 1 -C 6 alkyl.
  • R 8 represents H or C 1 -6 alkyl
  • R 9 is C 1 -6 alkyl
  • a 1 and A 2 are independently selected from: a bond, -C(O)NR 8 -, -NR 8 C(O)-, -O-, -N(R 8 )-, -S(O) 2 N(R 8 )- and- N(R 8 )S(O) 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 , R 8 , R 9 , X, m, n, p and r are as originally defined; each R 1 a and R 2 is independently selected from hydrogen and C 1 -C 6 alkyl;
  • each R 1 b is independently selected from: hydrogen, aryl, heterocyclyl, C 3- 10 cycloalkyl, C 2-6 alkenyl, R 8 O-, -N(R 8 ) 2 and C 1 -C 6 alkyl unsubstituted or substituted by aryl, heterocyclyl, cycloalkyl, alkenyl,
  • R 8 O- and -N(R 8 ) 2 ;
  • R 6 is independently selected from: hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 perfluoroalkyl, F, Cl, R 8 O-, R 8 C(O)NR 8 -, CN, NO 2 , (R 8 ) 2 N-C(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, -N(R 8 ) 2 , or R 9 OC(O)NR 8 -, and C 1 -C 6 alkyl substituted by C 1 -C 6 perfluoroalkyl, R 8 O-, R 8 C(O)NR 8 -, (R 8 ) 2 N-C(NR 8 )-, R 8 C(O)-, R 8 OC(O)-, -N(R 8 ) 2 and R 9 OC(O)NR 8
  • R 7 represents H or C 1 -6 alkyl; A 1 and A 2 are independently selected from: a bond,
  • V is selected from: hydrogen; aryl; heterocyclyl selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, indolyl, quinolinyl, isoquinolinyl and thienyl; C 1 -C 20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and C 2 -C 20 alkenyl, provided that V is not hydrogen if A 1 is S(O) m and V is not hydrogen if A 1 is a bond and A 2 is S(O) m;
  • V when V is heterocycle, attachment of V to R 6 and to A 1 is through a substitutable ring carbon.
  • a second subset of compounds of the present invention is represented by formula lb:
  • R 1 a , R 1 b , R 2 , A 1 , 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 C 1 -C 6 alkyl
  • V is selected from: hydrogen, heterocyclyl selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, indolyl, quinolinyl, isoquinolinyl and thienyl; aryl; C 1 -C 20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and C 2 -C 20 alkenyl, provided that V is not hydrogen if A 1 is S(O) m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O) m ;
  • V when V is heterocycle, attachment of V to R 8 and to A 1 is through a substitutable ring carbon;
  • 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 1 a , R 1 b , R 2 , A 1 , 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 C 1 -C 6 alkyl
  • V is selected from: hydrogen, heterocyclyl selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, aryl, C 1 -C 20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and C 2 -C 20 alkenyl, provided that V is not hydrogen if A 1 is S(O) m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O) m ;
  • V when V is heterocycle, attachment of V to R 8 and to A 1 is through a substitutable ring carbon;
  • W represents heterocyclyl selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, indolyl, quinolinyl and isoquinolinyl.
  • each R 2 is independently selected from hydrogen and C 1 -C 6 alkyl
  • R 3 , R 4 , A 3 , R 8 , R 9 , X, m and p are as originally defined; and R 6 is selected from the group consisting of: hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 perfluoroalkyl, F, Cl, R 8 O-, R 8 C(O)NR 8 -, CN, NO 2 , (R 8 ) 2 N-C(NR 8 )-, R 8 C(O)-,
  • a fifth subset of compounds of the invention is represented by formula Ie:
  • X and A 3 are as originally defined;
  • each R 2 is independently selected from: hydrogen and C 1 -C 6 alkyl
  • R 3 and R 4 are independently selected from H, F, Cl, Br, N(R 8 ) 2 , CF 3 , NO 2 , (R 8 )O-, (R 9 )S(O) m -, (R 8 )C(O)NH-, H 2 N-C(NH)- (R 8 )C(O)-, (R 8 )OC(O)-, N 3 , CN, (R 9 )OC(O)NR 8 -, C 1 -C 20 alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclyl; and 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. 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' CH 2 -, 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 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).
  • 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.
  • 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, i.e., they caa be removed, if desired, by procedures which will not cause cleavage or other 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.
  • Suitable hydroxyl protecting groups are:
  • hydroxyl protecting groups are trimethylsilyl and triethylsilyl.
  • 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 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.
  • 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.
  • 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.
  • 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
  • composition to be tested may be divided and the two
  • 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.
  • FPTase for example a tetrapeptide having a cysteine at the amine terminus
  • famesyl pyrophosphate for example a tetrapeptide having a cysteine at the amine terminus
  • 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
  • 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 1 -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.
  • Step D Preparation of 1 -(4-cyanobenzyl)-5-
  • Step F Preparation of ( ⁇ )-1-(4-cyanobenzyl)-5-[( 1-hydroxy-3- phenyl)-2-propynyllimidazole hydrochloride
  • the resulting product was purified by silica gel chromatography (35-50% acetone/CH 2 Cl 2 ) to provide 187 mg of the desired alcohol. A portion of this was taken up in CH 2 CI 2 and treated with excess 1 M HCl/ether solution, and concentrated in vacuo. The titled product hydrochloride was isolated as a white solid.
  • 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 D Preparation of ( ⁇ )-3-(4-cyanobenzyl)-4-[( 1-hydroxy-3- phenyl)-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 CI 2 and treated with excess 1 M HCl/ether solution, and concentrated in vacuo to provide the titled product hydrochloride.
  • Step A 1 -Trityl-4-(4-Cyanobenzyl)-imidazole.
  • Step B 1 -(4-Biphenylmethyl)-5-(4-cyanobenzyl)imidazole
  • a Grignard reagent freshly prepared from 4-bromo[ 1 , 1 '- 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 4 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).
  • Example 5 The alcohol (Example 5) ( 105 mg, 228 ⁇ mol) 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 (CHCl 3 -MeOH (30: 1 )) to yield title (35 mg).
  • Step D 5-[ 1 -(4-cyanobenzyl)-1 H-imidazolyl]ethanol.
  • Step E 5-(-1 -(4-Cyanobenzyl)-imidazolyl)ethylmethanesulfonate.
  • Step F 1 - ⁇ [1 -(4-Cyanobenzyl)-1H-imidazol-5-yl]ethyl ⁇ -4-phenyl
  • 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 ⁇ l containing 100 mM N-(2-hydroxy ethyl) piperazine- N'-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgCl 2 , 5 mM dithiothreitol (DTT), 100 mM [ 3 H]-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.
  • DMSO dimethyl methyl 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 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[ 35 S]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 MgCl 2 /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 MgCl 2 /lmM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 m
  • 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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Abstract

Cette invention a trait à des composés inhibant la farnésyl-protéine transférase (FTase) et la farnélysation de la protéine oncogène Ras. Cette invention a trait, de surcroît, à des compositions à usage chimiothérapeutique contenant les composés selon cette invention ainsi qu'à des procédés visant à inhiber la farnésyl-protéine transférase et la farnélysation de la protéine oncogène Ras.
PCT/US1997/006257 1996-04-03 1997-04-01 Inhibiteurs de la farnesyl-proteine transferase WO1997036876A1 (fr)

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US09/155,681 US6063930A (en) 1996-04-03 1997-04-01 Substituted imidazole compounds useful as farnesyl-protein transferase inhibitors
EP97918643A EP0891334A1 (fr) 1996-04-03 1997-04-01 Inhibiteurs de la farnesyl-proteine transferase
JP9535634A JP2000507955A (ja) 1996-04-03 1997-04-01 ファルネシル―タンパク質転移酵素の阻害剤
AU26702/97A AU715658B2 (en) 1996-04-03 1997-04-01 Inhibitors of farnesyl-protein transferase

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GBGB9613462.2A GB9613462D0 (en) 1996-06-27 1996-06-27 Inhibitors of farnesyl-protein transferase
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