EP1045843A1 - Inhibitoren der farnesyl-protein-transferase - Google Patents

Inhibitoren der farnesyl-protein-transferase

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Publication number
EP1045843A1
EP1045843A1 EP98960545A EP98960545A EP1045843A1 EP 1045843 A1 EP1045843 A1 EP 1045843A1 EP 98960545 A EP98960545 A EP 98960545A EP 98960545 A EP98960545 A EP 98960545A EP 1045843 A1 EP1045843 A1 EP 1045843A1
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European Patent Office
Prior art keywords
substituted
unsubstituted
alkyl
aryl
hydrogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP98960545A
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English (en)
French (fr)
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EP1045843A4 (de
Inventor
Terrence M. Ciccarone
Wasyl Halczenko
John H. Hutchinson
William C. Lumma, Jr.
Gerald E. Stokker
Craig A. Stump
Theresa M. Williams
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Merck and Co Inc
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Merck and Co Inc
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Priority claimed from US08/985,320 external-priority patent/US5977134A/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP1045843A1 publication Critical patent/EP1045843A1/de
Publication of EP1045843A4 publication Critical patent/EP1045843A4/de
Withdrawn legal-status Critical Current

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Definitions

  • Ras protein is 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.
  • Ras In the inactive state, Ras is bound to GDP.
  • Ras 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 (D.R. Lowy and D.M. Willumsen, Ann. Rev. Biochem. 62:851- 891 (1993)).
  • 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 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 farnesyl-protein transferase or geranylgeranyl-protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a C 15 or C20 isoprenoid, respectively.
  • farnesyl-protein transferase or geranylgeranyl-protein transferase which catalyze the alkylation of the cysteine residue of the CAAX motif with a C 15 or C20 isoprenoid, respectively.
  • 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.
  • Farnesyl-protein transferase utilizes farnesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a farnesyl 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, ⁇ 7:7541-7545 (1990)).
  • Inhibition of farnesyl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane localization in cultured cells.
  • direct inhibition of farnesyl- protein transferase would be more specific and attended by fewer side effects than would occur with the required dose of a general inhibitor of isoprene biosynthesis.
  • FPTase farnesyl-protein transferase
  • FPP farnesyl 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 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)).
  • deletion of the thiol from a CAAX derivative has been shown to dramatically reduce the inhibitory potency of the compound.
  • the thiol group potentially places limitations on the therapeutic application of FPTase inhibitors with respect to pharmacokinetics, pharmacodynamics and toxicity. Therefore, a functional replacement for the thiol is desirable.
  • farnesyl-protein transferase inhibitors are inhibitors of proliferation of vascular smooth muscle cells and are therefore useful in the prevention and therapy of arteriosclerosis and diabetic disturbance of blood vessels (JP H7- 112930). It has also recently been disclosed that certain 1,2,3,4- tetrahydroisoquinoline peptidomimetic compounds, some of which incorporate an imidazole moiety, are inhibitors of FPTase (U.S. Pat. No. 5,439,918, EP 0 618 221 A2 and EP 0 675 112 Al ).
  • the present invention comprises peptidomimetic 1,2,3,4- tetrahydroisoquinolines and homologous compounds which inhibit farnesyl-protein transferase. Furthermore, these compounds differ from such heterocyclic compounds previously described as inhibitors of farnesyl-protein transferase with respect to the alkyl or heteroatom containing linker between the tetrahydroisoquinoline nitrogen and the imidazolyl moiety, and with respect to the lack of a thiol moiety in the instant compounds. Further contained in this invention are chemotherapeutic compositions containing these famesyl transferase inhibitors and methods for their production.
  • the compounds of this invention are useful in the inhibition of farnesyl-protein transferase and the famesylation of the oncogene protein Ras.
  • the inhibitors of farnesyl-protein transferase are illustrated by the formula I:
  • Rla, Rib nd lc are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
  • R2a ? R2b' a n R ⁇ b" are independently hydrogen, NH2 or -(CR112) V A3(CR12 2 ) W R13; or R2b' and R ⁇ b" are combined as O;
  • R3a and R ⁇ b are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3- ClO cycloalkyl, unsubstituted or substituted C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl,
  • R4 is independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
  • R5 is independently selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, perfluoroalkyl, F, Cl, Br, R80-, R9s(0) m -, R S C(0)NR8-, CN, N02, (R8)2N-C-(NR8)-, R8C(0)-, R8 ⁇ C(0)-, N3, -N(R8)2, or R9 ⁇ C(0)NR8-, and c) C1-C6 alkyl, unsubstituted or substituted by perfluoroalkyl,
  • R is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2- trifluoroethyl and aryl;
  • R9 is independently selected from C1-C6 alkyl and aryl
  • R 10 is selected from: H; R 8 C(0)-; R9S(0) m -; unsubstituted or substituted Cl-4 alkyl, unsubstituted or substituted C3-6 cycloalkyl, unsubstituted or substituted heterocycle, unsubstituted or substituted aryl, substituted aroyl, unsubstituted or substituted heteroaroyl, substituted arylsulfonyl, unsubstituted or substituted heteroarylsulfonyl, wherein the substituted group is substituted with one or two substituents selected from: a) Cl-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO,
  • Rl 1 and Rl2 are independently selected from: a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by C2-C20 alkenyl,
  • Rl is selected from: a) hydrogen, b) substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3-C10 cycloalkyl, C2-C2O alkenyl, C2-C2O alkynyl, C1-C2O perfluoroalkyl, allyloxy, F, Cl, Br, R80-, R9S(0) m -, R 8 C(0)NR8-, CN, N02, R82N-C(NR8)-, R8C(0)-, N3, -N(R 8 )2, (R9)2NC(0)- or
  • R9 ⁇ C(0)NR8- and c) C1-C alkyl unsubstituted or substituted by substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3-C10 cycloalkyl, C2-C20 alkenyl, C2-C2O alkynyl, C2- C20 perfluoroalkyl, F, Cl, Br, R8O-, R9S(0) m -,
  • G, J, L and M are independently selected from: CHy or N;
  • T is selected from: N, CR 2 ' 0 r CR2b'R2b" ;
  • V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if Al is S(0)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(0)m; and provided that V is not imidazolyl;
  • W is a heterocycle
  • inhibitors of farnesyl-protein transferase are illustrated by the formula A:
  • Rla, Rib and Rl° are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
  • R9OC(0)NR8- c) C1-C alkyl unsubstituted or substituted by unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R8O-, R9S(0) m - .
  • R S C(0)NR8-,
  • R 2a , R 2 ' and R 2 b" are independently hydrogen or -(CRH2)VA3(CR1 2 2)WR 13 ; or R 2 ' and R 2 " are combined as O;
  • R3 and R3b are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3- ClO cycloalkyl, unsubstituted or substituted C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 9 0-, R9s(0)m-, R S C(0)NR8-, (R8)2NC(0)-,
  • R4 is independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
  • R 9 S(0)m-, R8C(0)NR8-, CN, NO2, R S 2N-C(NR8)-, R8C(0)-, R8 ⁇ C(0)-, N3, -N(R8)2, or R9 ⁇ C(0)NR8-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R80-, R9s(0) m -, R8C(0)NH-, CN, H2N-C(NH)-, R8C(0)-, R8 ⁇ C(0)-, N3, -N(R8)2, or R8 ⁇ C(0)NH-, provided that R4 is not unsubstituted or substituted imidazolyl;
  • R5 is independently selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, perfluoroalkyl, F, Cl, Br, R80-, R9S(0) m -, R S C(0)NR8-, CN, N ⁇ 2, (R8)2N-C-(NR8)-, R8C(0)-, R8 ⁇ C(0)-, N3, -N(R8)2, or R9 ⁇ C(0)NR8-, and c) C1-C6 alkyl, unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R80-, R9s(0) m -, R S C(0)NR8-, CN, (R8) 2 N-
  • R is independently selected from hydrogen, C1-C alkyl, benzyl, 2,2,2- trifluoroethyl and aryl;
  • R9 is independently selected from C1-C6 alkyl and aryl
  • RlO is selected from: H; R8C(0)-; R9s(0) m -. unsubstituted or substituted Cl-4 alkyl, unsubstituted or substituted C3-6 cycloalkyl, unsubstituted or substituted heterocycle, unsubstituted or substituted aryl, substituted aroyl, unsubstituted or substituted heteroaroyl, substituted arylsulfonyl, unsubstituted or substituted heteroarylsulfonyl, wherein the substituted group is substituted with one or two substituents selected from: a) Cl-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO,
  • Rl l and Rl2 are independently selected from: a) hydrogen, b) Cl-C6 alkyl unsubstituted or substituted by C2-C20 alkenyl, R 8 0-, R9s(0) m -, R8C(0)NR8-, CN, N3,
  • Rl3 is selected from: a) hydrogen, b) substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3-C10 cycloalkyl, C2-C2O alkenyl, C2-C2O alkynyl, C1-C2O perfluoroalkyl, allyloxy, F, Cl, Br, R80-, R9S(0) m -, R8C(0)NR8-, CN, NO2,
  • V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if Al is S(0)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(0)m; and provided that V is not imidazolyl; W is a heterocycle;
  • Rla and Rlc are independently selected from: hydrogen, C3-C10 cycloalkyl, R8O-, -N(R8) 2 , F or C1-C6 alkyl;
  • Ri is independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C6 cycloalkyl, R 0-, -N(R8) 2 or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, heterocycle, C3-C6 cycloalkyl, C2-C6 alkenyl, R80-, or -N(R8) 2 ;
  • R 2a and R 2 b' are independently selected from: H; C1-C6 alkyl,
  • R3a and R3b are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted C2-C alkenyl, C 2 -
  • R4 is independently selected from: a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R 0-, R8C(0)NR8-, CN, N02, (R8)2N-C(NR8)-, R8C(0)-, R8 ⁇ C(0)-, -N(R8)2, or R9 ⁇ C(0)NR8-, and c) C l -C6 alkyl substituted by C l -C6 perfluoroalkyl, R80- , R8C(0)NR8-, (R8) 2 N-C(NR8)-, R8C(0)-, R8 ⁇ C(0)-, -N(R8)2, or R9 ⁇ C(0)NR8-;
  • R5 is selected from: a) hydrogen, b) C2-C6 aikenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 perfluoroalkyl, F, Cl, R80-, R9s(0) m -, R S C(0)NR8-, CN, N02, (R8)2N-C(NR8)-, R8C(0)-, R8 ⁇ C(0)-, -N(R8) 2J or
  • R9 ⁇ C(0)NR8- and c) C1-C alkyl unsubstituted or substituted by C1-C6 perfluoroalkyl, F, Cl, R80-, R9S(0) m -, R S C(0)NR8-, CN, (R8)2N-C(NR8)-, R8C(0)-, R8 ⁇ C(0)-, -N(R8) 2 , or R90C(0)NR8- ;
  • R6 and R ⁇ are independently selected from:
  • R8 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2- trifluoroethyl and aryl;
  • R9 is independently selected from C1-C6 alkyl and aryl;
  • V is selected from: a) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, and b) aryl;
  • W is a heterocycle selected from pyrrolidinyl, triazolyl, imidazolyl, pyridinyl, thiazolyl, indolyl, quinolinyl, or isoquinolinyl;
  • the inhibitors of farnesyl-protein transferase are illustrated by the formula Al:
  • Rla and Rlc are independently selected from: hydrogen, C3-C10 cycloalkyl, R8O-, -N(R8) 2 , F or C1-C6 alkyl;
  • Rib is independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C6 cycloalkyl, R 8 0-, -N(R8) 2 or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, heterocycle, C3-C6 cycloalkyl, C2-C6 alkenyl, R8O-, or -N(R8) 2 ;
  • R 2 a is selected from: H; C1-C6 alkyl, NH2
  • R3 and R3b are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted C2-C6 alkenyl, C 2 - C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R9 ⁇ -, R 9 S(0) m -, R8C(0)NR8-, (R8)2NC(0)-, R9C(0)0-, R82N- C(NR8)-, CN, N ⁇ 2, R 8 C(0)-, N3, -N(R8) 2 ⁇ or
  • R9 ⁇ C(0)NR8- c) unsubstituted Cl-C alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 9 0-,
  • R 9 S(0) m -, R8C(0)NR8-, (R8)2NC(0)-, R8 2 N-C(NR8)-, CN, R8C(0)-, N3, -N(R8)2, and R9 ⁇ C(0)-NR8-;
  • R4 is independently selected from: a) hydrogen, b) C 1 -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -C6 perfluoroalkyl, F, Cl, R8O-, R C(0)NR8-, CN, N02, (R8)2N-C(NR8)-, R8C(0)-, R8 ⁇ C(0)-, -N(R8)2, or R9 ⁇ C(0)NR8-, and c) C1-C6 alkyl substituted by -C6 perfluoroalkyl, R 8 0-,
  • R5 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 perfluoroalkyl, F, Cl, R8O-, R9s(0) m -, R S C(0)NR8-, CN, N02, (R8)2N-C(NR8)-, R8C(0)-, R8 ⁇ C(0)-, -N(R8) 2 , or R9 ⁇ C(0)NR8-, and c) C1-C6 alkyl unsubstituted or substituted by C1-C6 perfluoroalkyl, F, Cl, R8O-, R9S(0) m -, R S C(0)NR8-, CN, (R8)2N-C(NR8)-, R8C(0)-, R8 ⁇ C(0)-, -N(R8)2, or R90C(0)NR8- ;
  • R6 and R ⁇ are independently selected from:
  • R8 is independently selected from hydrogen, C1-C6 alkyl, benzyl, 2,2,2- trifluoroethyl and aryl;
  • R9 is independently selected from C1-C6 alkyl and aryl
  • G and M are independently selected from: CHy or N;
  • V is selected from: a) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, and b) aryl;
  • W is a heterocycle selected from pyrrolidinyl, triazolyl, imidazolyl, pyridinyl, thiazolyl, indolyl, quinolinyl, or isoquinolinyl;
  • n 0, 1 or 2
  • n 0, 1, 2, 3 or 4
  • p is 1, 2 or 3
  • q is 0, 1 or 2, provided that q is not 0 or 1 if X is O
  • r is 0 to 5, provided that r is 0 when V is hydrogen
  • s is 1 or 2
  • t is 1
  • y is 1 or 2;
  • Rla and Rlc are independently selected from: hydrogen, C3-C10 cycloalkyl, R80-, -N(R8) 2 , F or C1-C6 alkyl;
  • R is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R 8 0-, -N(R8) 2 , F or C2-C6 alkenyl, c) unsubstituted or substituted C1-C alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R8Q ⁇ and -N(R8) 2 ; R 2a and R 2 b' are independently selected from selected from: H; Cl-
  • R3a and R3b are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted C2-C6 alkenyl, C 2 - C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R9 ⁇ -, R9s(0)m- .
  • R4 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R8O-, R8C(0)NR8-, CN, N02,
  • R*5a and R ⁇ b are independently hydrogen, Cl-C6 alkyl, cyclopropyl, trifluoromethyl and halogen;
  • R6 and R ⁇ are independently selected from: H; Cl-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with one or two: a) Cl-4 alkoxy, b) halogen, or c) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle;
  • R8 is independently selected from hydrogen, C1-C6 alkyl, 2,2,2- trifluoroethyl, benzyl and aryl;
  • R9 is independently selected from C1-C6 alkyl and aryl
  • V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d) C1-C2O alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C2O alkenyl, and provided that V is not hydrogen if A is S(0)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(0)m;
  • the inhibitors of famesyl-protein transferase are illustrated by the formula B 1 :
  • Rla and Rlc are independently selected from: hydrogen, C3-C10 cycloalkyl, R 0-, -N(R8) 2 , F or C1-C6 alkyl;
  • Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R 8 0-, -N(R 8 )2, F or C2-C6 alkenyl, c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R8O- and -N(R8) 2 ;
  • R 2a is selected from selected from: H; C1-C6 alkyl,
  • R3a and R3b are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted C2-C alkenyl, C2- C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 9 0-, R 9 S(0)m-, R8C(0)NR8-, (R8)2NC(0)-, R9C(0)0-, R8 2 N- C(NR8)-, CN, N02, R 8 C(0)-, N3, -N(R8)2, or R9 ⁇ C(0)NR8-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstit
  • R 9 S(0)m-, R8C(0)NR8-, (R8) 2 NC(0)-, R82N-C(NR8)-, CN, R8C(0)-, N3, -N(R8)2, and R9OC(0)-NR8-;
  • R4 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R80-, R8C(0)NR8-, CN, N02, (R8)2N-C(NR8)-, R8C(0)-, -N(R8) 2 , or R9 ⁇ C(0)NR8-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R80-, R8C(0)NR8-, (R8) 2 N-C(NR8)-, R8C(0)-, -N(R8)2, or R9 ⁇ C(0)NR8-;
  • R ⁇ a and R ⁇ b are independently hydrogen, C1-C6 alkyl, cyclopropyl, trifluoromethyl and halogen;
  • R6 and R7 are independently selected from:
  • R is independently selected from hydrogen, C1-C6 alkyl, 2,2,2- trifluoroethyl, benzyl and aryl;
  • R9 is independently selected from C1-C alkyl and aryl
  • V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d) C1-C2O alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C2O alkenyl, and provided that V is not hydrogen if A is S(0)m and V is not hydrogen
  • n 0, 1 or 2
  • n 0, 1, 2, 3 or 4
  • p is 1, 2 or 3
  • q is 0, 1 or 2, provided that q is not 0 or 1 if X is 0
  • r is 0 to 5, provided that r is 0 when V is hydrogen
  • y is 1 or 2;
  • Rla and Rlc are independently selected from: hydrogen, C3-C10 cycloalkyl, R8O-, -N(R8)2, F or C1-C6 alkyl;
  • Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R 8 0-, -N(R 8 )2, F or C2-C6 alkenyl, c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R8Q- and -N(R8) 2 ;
  • R 2a and R 2 b' are independently selected from selected from: H; Ci-
  • R3a and R3b are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted C2-C6 alkenyl, C2- C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 9 0-, R 9 S(0)m-, R8C(0)NR8-, (R8)2NC(0)-, R 9 C(0)0-, R82N- C(NR8)-, CN, N02, R 8 C(0)-, N3, -N(R8)2, or
  • R 9 OC(0)NR8-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic,
  • R is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R 8 0-, R8C(0)NR8-, CN, NO2, (R8)2N-C(NR8)-, R8C(0)-, -N(R8) 2 , or R 9 OC(0)NR8-, and c) C1-C6 alkyl substituted by -C6 perfluoroalkyl, R 8 0-, R8C(0)NR8-, (R8) 2 N-C(NR8)-, R8C(0)-, -N(R8) 2J or R 9 OC(0)NR8-;
  • R ⁇ and R ⁇ b are independently hydrogen, C1-C6 alkyl, cyclopropyl, trifluoromethyl and halogen;
  • R6 and R ⁇ are independently selected from:
  • R8 is independently selected from hydrogen, C1-C6 alkyl, 2,2,2- trifluoroethyl, benzyl and aryl;
  • R 9 is independently selected from C1-C6 alkyl and aryl
  • V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C2O alkenyl, and provided that V is not hydrogen if Al is S(0)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(0)m.
  • R a and Rlc are independently selected from: hydrogen, C3-C10 cycloalkyl or C1-C6 alkyl; Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R80-, -N(R 8 )2, F or C2-C6 alkenyl, c) Cl-C ⁇ alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R 8 0-, or
  • R 2a and R 2 b' are independently selected from selected from: H; Cl-
  • R3a and R3b are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted C2-C6 alkenyl, C 2 - C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R 9 0-, R 9 S(0)m-, R8C(0)NR8-, (R8) 2 NC(0)-, R 9 C(0)0-, R8 2 N- C(NR8)-, CN, N02, R 8 C(0)-, N3, -N(R8) 2 , or
  • R90C(0)NR8- c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic,
  • R4 is independently selected from: a) hydrogen,
  • SUBST1TUTE SHEET (RULE 26) b) aryl, substituted aryl, heterocycle, substituted heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R 8 0-, R8C(0)NR8-, CN, N02, (R8)2N-C(NR8)-, R8C(0)-, -N(R8)2, or R9 ⁇ C(0)NR8-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R 0-, R8C(0)NR8-, (R8) 2 N-C(NR8)-, R8C(0)-, -N(R8) 2 , or R90C(0)NR8- ;
  • R ⁇ a and R ⁇ b are independently hydrogen, ethyl, cyclopropyl or methyl
  • R6 and R ⁇ are independently selected from:
  • R is independently selected from hydrogen, C1-C6 alkyl, 2,2,2- trifluoroethyl, benzyl and aryl;
  • R9 is independently selected from Cl-C ⁇ alkyl and aryl
  • Al is selected from: a bond, -C(O)-, O, -N(R8)-, or -S(0) m ;
  • n 0, 1 or 2; provided that n is not 0 or 1 if A is a bond, O, -N(R8)-, or S(0)m; m is 0, 1 or 2; p is 0, 1, 2, 3 or 4; q is 0, 1 or 2, provided that q is not 0 or 1 if X is O; r is 1 or 2; and u is independently 0 or 1 ;
  • the inhibitors of farnesyl-protein transferase are illustrated by the formula Dl:
  • Rla and Rlc are independently selected from: hydrogen, C3-C10 cycloalkyl or C1-C6 alkyl;
  • Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R 8 0-, -N(R 8 )2, F or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R 8 0-, or
  • R 2a is selected from selected from: H; C1-C6 alkyl, NH 2 ,
  • R3a and R3b are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted C2-C6 alkenyl, C2- C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R9 ⁇ -, R 9 S(0)m-, R8C(0)NR8-, (R8) 2 NC(0)-, R 9 C(0)0-, R 2 N- C(NR8)-, CN, NO2, R 8 C(0)-, N3, -N(R8) 2 , or R 9 OC(0)NR8-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubsti
  • R 9 S(0)m-, R8C(0)NR8-, (R8)2NC(0)-, R8 2 N-C(NR8)-, CN, R8C(0)-, N3, -N(R8)2, and R 9 OC(0)-NR8-;
  • R4 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R8O-, R8C(0)NR8-, CN, N02, (R8) 2 N-C(NR8)-, R ⁇ C(O)-, -N(R8) 2 , or R OC(0)NR8-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R s O-, R8C(0)NR8-, (R8) 2 N-C(NR8)-, R8C(0)-, -N(R8) 2 , or R90C(0)NR8-;
  • R ⁇ and R ⁇ b are independently hydrogen, ethyl, cyclopropyl or methyl
  • R6 and R ⁇ are independently selected from:
  • SUBS UTE SHEET (RULE 26) unsubstituted or substituted with one or two: a) Cl-4 alkoxy, b) halogen, or c) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle;
  • R is independently selected from hydrogen, C1-C6 alkyl, 2,2,2- trifluoroethyl, benzyl and aryl;
  • R9 is independently selected from C1-C6 alkyl and aryl
  • Al is selected from: a bond, -C(O)-, O, -N(R8)-, or -S(0) m ;
  • Z is selected from: CR 2a , or N; provided that at least Y or Z is N;
  • n 0, 1 or 2; provided that n is not 0 or 1 if A is a bond, 0, -N(R8)-, or S(0)m; m is 0, 1 or 2; p is 0, 1, 2, 3 or 4; q is 0, 1 or 2, provided that q is not 0 or 1 if X is O; r is 1 or 2; and y is 1 or 2;
  • the inhibitors of farnesyl-protein transferase are illustrated by the formula E:
  • Rla and Rlc are independently selected from: hydrogen, R O ⁇ , -N(R8)2, F, C3-C10 cycloalkyl or C1-C6 alkyl;
  • Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, R 8 0-, -N(R 8 )2, F or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R80-, or
  • R 2a and R 2 b' are independently selected from selected from: H; Cl-
  • R3a a nd R3b are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted C2-C6 alkenyl, C2- C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R9 ⁇ -, R 9 S(0)m-, R8C(0)NR8-, (R8) 2 NC(0)-, R 9 C(0)0-, R8 2 N- C(NR8)-, CN, N02, R 8 C(0)-, N3, -N(R8) 2 , or R9 ⁇ C(0)NR8-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted ary
  • R4 is independently selected from: a) hydrogen, b) aryl, substituted aryl, heterocycle, substituted heterocycle, C1-C6 alkyl, C 2 -C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, R80-, R8C(0)NR8-, CN, N ⁇ 2,
  • R*5a and R ⁇ b are independently hydrogen, ethyl, cyclopropyl or methyl
  • R6 and R ⁇ are independently selected from: H; Cl-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with one or two: a) Cl-4 alkoxy, b) halogen, or c) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle;
  • R8 is independently selected from hydrogen, C1-C6 alkyl, 2,2,2- trifluoroethyl, benzyl and aryl;
  • R9 is independently selected from -C6 alkyl and aryl;
  • n 0 or 1 ;
  • m is 0, 1 or 2;
  • p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond or O;
  • q is 0, 1 or 2, provided that q is not 0 or 1 if X is O;
  • r is 1 or 2; and
  • u is independently 0 or 1 ;
  • Rla and Rlc are independently selected from: hydrogen, C3-C10 cycloalkyl or C1-C6 alkyl;
  • Rib is independently selected from: a) hydrogen,
  • R 2a and R 2 b' are independently selected from selected from: H; Cl-
  • R a and R3b are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted C2-C6 alkenyl, C2- C alkynyl, halogen, C1-C6 perfluoroalkyl, R 9 0-, R 9 S(0)m-, R8C(0)NR8-, (R8) 2 NC(0)-, R 9 C(0)0-, R8 2 N- C(NR8)-, CN, N02, R 8 C(0)-, N3, -N(R8) 2 , or
  • R 9 OC(0)NR8-, c) unsubstituted C1-C6 alkyl, d) substituted C1-C6 alkyl wherein the substituent on the substituted C1-C alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic,
  • R ⁇ a and R ⁇ b are independently hydrogen, ethyl, cyclopropyl or methyl
  • R6 and R ⁇ are independently selected from:
  • R is independently selected from hydrogen, Cl-C6 alkyl, 2,2,2- trifluoroethyl, benzyl and aryl;
  • R 9 is independently selected from C1-C6 alkyl and aryl
  • Rla and Rlc are independently selected from: hydrogen, R80-, -N(R8)2, F, C3-C10 cycloalkyl or C1-C6 alkyl;
  • Rib is independently selected from: a) hydrogen, b) aryl, heterocycle or C3-C10 cycloalkyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R 8 0-, or
  • R 2a and R 2 b' are independently selected from selected from: H; Cl-
  • R3a and R3b are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted C 2 -C6 alkenyl, C2- C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R9 ⁇ -,
  • R*5a and R*5b are independently hydrogen, ethyl, cyclopropyl or methyl
  • R6 and R ⁇ are independently selected from: H; Cl-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with one or two: a) Cl-4 alkoxy, b) halogen, or c) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle;
  • R8 is independently selected from hydrogen, Cl-C alkyl, 2,2,2- trifluoroethyl, benzyl and aryl;
  • R 9 is independently selected from C1-C6 alkyl and aryl
  • a 1 is selected from: a bond, -C(O)-, O, -N(R8)-, or -S(0) m ;
  • n 0, 1 or 2; provided that n is not 0 if Al is a bond, O,
  • p is 1, 2 or 3
  • q is 0, 1 or 2, provided that q is not 0 or 1 if X is O
  • u is independently 0 or 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.
  • any variable e.g. aryl, heterocycle, Rla, R4 etc.
  • its definition on each occurence is independent at every other occurence.
  • combinations of substituents/or variables are permissible only if such combinations result in stable compounds.
  • alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; “alkoxy” represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge.
  • Halogen or “halo” as used herein means fluoro, chloro, bromo and iodo.
  • aryl is intended to mean any stable monocyclic, bicyclic or tricyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic.
  • monocyclic and bicyclic aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
  • tricyclic aryl elements include 10,11- dihydro-5H-dibenzo[a,d]cyclohepten-5-yl (which is also known as dibenzylsuberyl), 9-fluorenyl and 9,10-dihydroanthracen-9-yl.
  • "aryl” is a monocyclic or bicyclic carbon ring.
  • heterocycle or heterocyclic represents a stable 5- to 7-membered monocyclic or stable 8- to 11- membered bicyclic heterocyclic ring or stable 13- to 15-membered tricyclic heterocyclic ring, which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • Examples of monocyclic and bicyclic heterocyclic elements 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,
  • tricyclic heterocyclic elements include, but are not limited to, 6,l l-dihydro-5H- benzo[5,6]cyclohepta[l,2-b]pyridine, 9,10-dihydro-4H-3-thia- benzo[f]azulen-4-yl and 9-xanthenyl.
  • the 6,11 -dihydro-5H- benzo[5,6]cyclohepta[l,2-b]pyridine moiety has the following structure:
  • heterocyclic is a monocyclic or bicyclic moiety.
  • heteroaryl is intended to mean any stable monocyclic, bicyclic or tricyclic carbon ring of 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 of monocyclic and bicyclic heteroaryl elements include, but are not limited to, 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, pyrroly
  • tricyclic heteroaryl elements include, but are not limited to, 6,ll-dihydro-5H- benzo[5,6]cyclohepta[l,2-b]pyridine.
  • heteroaryl is a monocyclic or bicyclic moiety.
  • substituted aryl As used herein, the terms “substituted aryl”, “substituted heterocycle” and “substituted cycloalkyl” are intended to include the cyclic group containing from 1 to 3 substitutents in addition to the point of attachment to the rest of the compound.
  • Such substitutents are preferably selected from the group which includes but is not limited to F, Cl, Br, CF3, NH2, N(Cl-C6 alkyl) 2 , N ⁇ 2, CN, (C1-C6 alkyl)0-, - OH, (C1-C6 alkyl)S(0)m-, (Cl-C6 alkyl)C(0)NH-, H 2 N-C(NH)-, (Cl- C6 alkyl)C(O)-, (Ci-C6 alkyl)OC(O)-, N3,(Cl-C6 alkyl)OC(0)NH- and C1-C20 alkyl.
  • cyclic amine moieties are formed.
  • examples of such cyclic moieties include, but are not limited to:
  • Such cyclic moieties may optionally include another heteroatom(s).
  • heteroatom-containing cyclic amine moieties include, but are not limited to:
  • R 2 , R , R4 etc. indicate that the indicated bond may be attached to any of the substitutable ring carbon or nitrogen atoms.
  • Rla and Rib are independently selected from: hydrogen, -N(R8) 2 , R8c(0)NR8- or C1-C6 alkyl which is unsubstituted or substituted by -N(R8) 2 , R8Q- or R8C(0)NR -.
  • R 2 a is selected from:H;
  • R 2 b' and R 2 b" are independently selected from selected from: H or C1-C6 alkyl.
  • R3a and R3b are independently selected from: hydrogen, C1-C6 perfluoroalkyl, F, Cl, Br, R80-, R 9 S(0) m -, CN, R8C(0)-, -N(R8)2 and C1-C6 alkyl.
  • R4 is selected from: hydrogen, perfluoroalkyl, F, Cl, Br, R80-, R 9 S(0)m-, CN, N ⁇ 2, R 8 2N- C(NR8)-, R8C(0)-, N3, -N(R8)2, R9 ⁇ C(0)NR8- and C1-C6 alkyl.
  • R-5 is hydrogen or C1-C6 alkyl.
  • R is selected from H, C1-C6 alkyl and benzyl.
  • Al and A 2 are independently selected from: a bond, -C(0)NR8-, -NR8C(0)-, O, -N(R8)-, -S(0)2N(R8)- and-
  • V is selected from hydrogen, heterocycle and aryl.
  • W is imidazolyl.
  • n, p and r are independently 0, 1, or 2. More preferably, r is 1.
  • t is 1.
  • u is independently 0 or 1. Most preferably, u is 1.
  • 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.
  • any substituent or variable e.g., Rla, Z, n, etc.
  • - N(R8)2 represents -NH2, -NHCH3, -NHC2H5, etc.
  • substituents and substitution pattems on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials.
  • the pharmaceutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this invention
  • SUBST ⁇ UTE SHEET (RULE 26) 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.
  • Scheme 1 illustrates the synthesis of 1,2,3,4- tetrahydroisoquinolines essentially according to the method of Stokker in Tetrahedron Letts., 1996, 37, 5453.
  • phenethylamines such as
  • trifluoroacetate 2 may be converted to the corresponding trifluoroacetate 2 using, for example, trifluoroacetic anhydride and an organic base such as triethylamine in a suitable solvent such as dichloromethane.
  • Compound 8 may also be obtained from 5 using the well-known Bischler-Napieralski reaction. Reduction of the imine of 8 to 9 may be done with a reducing agent such as sodium borohydride in an alcoholic solvent (e.g. methanol) or, alternatively, asymmetric hydrogenation processes may be employed to give 9 in optically enriched form. Intermediate 9 may be coupled with a suitably substituted acid using standard amide bond formation methods to yield the instant compound 10.
  • Scheme 3 illustrates reactions wherein the preferred 4- cyanobenzylimidazolyl moiety is incorporated into the instant compounds.
  • Schemes 4-5 illustrate the syntheses of 1,2,3,4- tetrahydroisoquinolines of the instant invention wherein the "X" moiety is other than an alkyl bridge.
  • the reactions illustrated therein show the incorporation of sidechains which comprise the preferred 4- cyanobenzylimidazolyl moiety. It is understood that a person of ordinary skill in the art could readily modify such reaction sequences by using appropriate protecting groups and reagents well known to one skilled in the art to provide other compounds of the instant invention.
  • Scheme 4 illustrates the syntheses of compounds of the instant invention wherein "X" is -S-.
  • the intermediate aldehyde 11 is reduced to the alcohol 12, activated and treated with a suitable thioacetate to provide the thioester 13.
  • the thiol is then generated and alkylated with a suitable ester containing reagent, such as bromoacetic acid to provide intermediate 14.
  • a suitable ester containing reagent such as bromoacetic acid
  • Reduction of the ester moiety, followed by oxidation provides the corresponding aldehyde, which can be utilized to reductively alkylate the suitably substituted 1,2,3,4- tetrahydroisoquinoline to provide the instant compound 15.
  • Scheme 5 illustrates the syntheses of compounds of the instant invention wherein "X" is -0-.
  • a dihydroxyalkane such as ethylene glycol
  • Intermediate 16 can be utilized to reductively alkylate the suitably substituted 1,2,3,4-tetrahydroisoquinoline and the sidechain deprotected.
  • Intermediate 17 can then be alkylated with a suitable reagent to provide the instant compound 18 which incorporates the ether moiety.
  • the reagent utilized in the reductive alkylation of the 1,2,3,4-tetrahydroisoquinoline may altematively incorporate a leaving group which may subsequently react with a blocked imidazolyl reagent, such as 19 to provide compounds of the instant invention wherein "X" is a bond and the preferred imidazolyl is attached to the alkyl bridge via one of the ring nitrogens, as shown in Scheme 6.
  • Scheme 7 illustrates the syntheses of compounds of the instant invention comprising 3,4-dihydro-l(lH)-isoquinolinones, indoles and benzoimidazoles.
  • R ,S a d ⁇ is V - A 1 (CR 1a 2 ) n A 2 (CR 1a 2 ) n (CR 1b 2 ) F or a protected precursor thereof;
  • RSa. is R2a or a protected precusor thereof; and R$b- is R2b' ? R2b" or a protected precusor thereof; and
  • R- is a "substituent" or a protected precusor thereof.
  • the selectively protected intermediate 20 utilized in the synthesis illustrated in Scheme 8 can be reductively alkylated with a variety of aldehydes, such as 21.
  • the aldehydes can be prepared by standard procedures, such as that described by O. P. Goel, U. Krolls, M. Stier and S. Kesten in Organic Syntheses. 1988, 67, 69-75.
  • the reductive alkylation can be accomplished at pH 5-7 with a variety of reducing agents, such as sodium triacetoxyborohydride or sodium cyanoborohydride in a solvent such as dichloroethane, methanol or dimethylformamide.
  • the ester product 22 can be deprotected with trifluoroacetic acid in methylene chloride to give the substituted diamine 23. That diamine may be isolated in the salt form, for example, as a
  • the product diamine 23 can be further selectively protected and reductively alkylated with a second aldehyde to obtain an analogous tertiary amine. Altematively, the diamine 23 can be cyclized to obtain intermediates such as the dihydroimidazole 24 by procedures known in the literature. The ester 24 can then be utilized in a reaction such as illustrated in Scheme 3 hereinabove.
  • Scheme 9 illustrates a general preparation of aralkyl imidazolyl intermediates 31 that can be utilized in reactions such as illustrated in Scheme 3.
  • imidazole acetic acid 27 can be converted to the protected acetate 29 by standard procedures, and 29 can be first reacted with an alkyl halide, then treated with refluxing methanol to provide the regiospecifically alkylated imidazole acetic acid ester 30.
  • Hydrolysis provides the acetic acid 31.
  • Schemes 10-13 illustrate syntheses of suitably substituted alkanols useful in the syntheses of the instant compounds wherein the variable W is present as a pyridyl moiety.
  • Scheme 15 illustrates synthesis of an instant compound wherein a non-hydrogen R ⁇ b i s incorporated in the instant compound.
  • a readily available 4-substituted imidazole 37 may be selectively iodinated to provide the 5-iodoimidazole 38. That imidazole may then be protected and coupled to a suitably substituted benzyl moiety to provide intermediate 39. Intermediate 39 can then undergo the alkylation reactions that were described hereinabove.
  • Al(CR a 2)nA (CRl a 2)n linker is oxygen may be synthesized by methods known in the art, for example as shown in Scheme 16.
  • the suitably substituted phenol 41 may be reacted with methyl N- (cyano)methanimidate to provide the 4-phenoxy imidazole 42.
  • the intermediate 43 can undergo alkylation reactions as described for the benzylimidazoles hereinabove.
  • the instant compounds are useful as pharmaceutical agents for mammals, especially for humans. These compounds may be administered to patients for use in the treatment of cancer.
  • Examples of the type of cancer 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, ser, abl, lck, fyn) or by other mechanisms.
  • the compounds of the instant invention inhibit farnesyl- protein transferase and the 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-angiogenesis 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 proliferative diseases, both benign and malignant, wherein 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.
  • the compounds are useful in the treatment of neurofibromatosis, which is a benign proliferative disorder.
  • the instant compounds may also be useful in the treatment of certain 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. American Journal of Pathology, 142:1051-1060 (1993) and B. Cowley, Jr. et s ⁇ .FASEB Journal, 2: A3160 (1988)).
  • the instant compounds may also be useful for the treatment of fungal infections.
  • the compounds of this instant invention are selective inhibitors of famesyl- protein transferase.
  • a compound is considered a selective inhibitor of famesyl-protein transferase, for example, when its in vitro famesyl- protein transferase inhibitory activity, as assessed by the assay described in Example 41, is at least 100 times greater than the in vitro activity of the same compound against geranylgeranyl-protein transferase-type I in the assay described in Example 42.
  • a selective compound exhibits at least 1000 times greater activity against one of the enzymatic activities when comparing geranylgeranyl-protein transferase-type I inhibition and farnesyl-protein transferase inhibition.
  • the compounds of this instant invention are dual inhibitors of farnesyl- protein transferase and geranylgeranyl-protein transferase type I. Such a dual inhibitor will exhibit certain characteristics when assessed in in vitro assays, which are dependent on the type of assay employed.
  • the dual inhibitor compound has an in vitro inhibitory activity (IC50) that is less than about 12 ⁇ M against K4B-Ras dependent activation of MAP kinases in cells. More preferably, the dual inhibitor compound has an in vitro inhibitory activity (IC50) against K4B-Ras dependent activation of MAP kinases in cells which is more than about 5 times lower than the inhibitory activity (IC50) against Myr-Ras dependent activation of MAP kinases in cells.
  • IC50 in vitro inhibitory activity
  • the dual inhibitor compound has an inhibitory activity (IC50) that is less than about 10 nM against H-Ras dependent activation of MAP kinases in cells.
  • IC50 inhibitory activity
  • the dual inhibitor compound has an in vitro inhibitory activity (IC50) that is less than about 5 ⁇ M against transfer of a geranylgeranyl residue to a protein or peptide substrate comprising a CAAXG motif by geranylgeranyl-protein transferase type I in the presence of a modulating anion.
  • the dual inhibitor compound has an in vitro inhibitory activity (IC50) that is less than about 1 ⁇ M against transfer of a geranylgeranyl residue to a protein or peptide substrate comprising a CAAXG motif by geranylgeranyl- protein transferase type I in the presence of a modulating anion.
  • IC50 in vitro inhibitory activity
  • the dual inhibitor compound has an in vitro inhibitory activity (IC50) in the in vitro assay as described in Example 41 that is less than about 1 ⁇ M against transfer of a famesyl residue to a protein or peptide substrate, comprising a CAAX-F motif, by farnesyl-protein transferase.
  • the dual inhibitor compound has an in vitro inhibitory activity (IC50) that is less than about lOOnM against transfer of a farnesyl residue to a protein or peptide substrate, comprising a CAAX* 7 motif, by farnesyl-protein transferase. Also preferably, the dual inhibitor compound has an in vitro inhibitory activity (IC50) in the in vitro assay as described in Example 44, that is less than about 100 nM against the anchorage independent growth of H- ras-transformed mammalian fibroblasts.
  • IC50 in vitro inhibitory activity
  • the protein or peptide substrate utilized in the instant assay may incorporate any CAAX motif that is geranylgeranylated by GGTase-I.
  • CAAX will refer to such motifs that may be geranylgeranylated by GGTase-I. It is understood that some of the
  • CAAX containing protein or peptide substrates may also be farnesylated by farnesyl-protein transferase.
  • farnesyl-protein transferase a protein or peptide substrates
  • CAAX motifs include (the corresponding human protein is in parentheses): CVIM (K4B-Ras) (SEQ.ID.NO.: 1), CVLL (mutated H- Ras) (SEQ.ID.NO.: 2), CVVM (N-Ras) (SEQ.ID.NO.: 3), CUM (K4A- Ras) (SEQ.ID.NO.: 4), CLLL (Rap-IA) (SEQ.ID.NO.: 5), CQLL (Rap- IB) (SEQ.ID.NO.: 6), CSIM (SEQ.ID.NO.: 7), CAIM (SEQ.ID.NO.: 8), CKVL (SEQ.ID.NO.: 9) and CLIM (PFX) (SEQ.ID.NO.: 10).
  • the CAAX motif is
  • CAAX is used to designate a protein or peptide substrate that incorporates four amino acid C- terminus motif that is farnesylated by famesyl-protein transferase. It is
  • CAAX containing protein or peptide substrates may also be geranylgeranylated by GGTase-I.
  • GGTase-I geranylgeranylated by GGTase-I.
  • CAAX motifs include (the corresponding human protein is in parentheses): CVLS (H-ras) (SEQ.ID.NO.: 11), CVIM (K4B-Ras) (SEQ.ID.NO.: 1) and CVVM (N-Ras) (SEQ.ID.NO.: 3).
  • the compounds of this invention may be administered to mammals, preferably humans, either alone or, preferably, in combination with pharmaceutically acceptable carriers or diluents, optionally with known adjuvants, such as alum, in a pharmaceutical composition, according to standard pharmaceutical practice.
  • the compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
  • a chemotherapeutic compound according to this invention the selected compound may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension.
  • carriers which are commonly used include lactose and com starch, and lubricating agents, such as magnesium stearate, are commonly added.
  • useful diluents 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, and the pH of the solutions should be suitably adjusted and buffered.
  • the total concentration of solutes should be controlled in order to render the preparation isotonic.
  • the present invention also encompasses a pharmaceutical composition useful in the treatment of cancer, comprising the administration of a therapeutically effective amount of the compounds of this invention, with or without pharmaceutically acceptable carriers or diluents.
  • suitable compositions of this invention include aqueous solutions comprising compounds of this invention and pharmacologically acceptable carriers, e.g., saline, at a pH level, e.g., 7.4.
  • the solutions may be introduced into a patient's intramuscular blood-stream by local bolus injection.
  • 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 daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms.
  • 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 farnesyl 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 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 famesyl-protein transferase and quantitating the enzyme.
  • 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 famesyl-protein transferase, an excess amount of a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and farnesyl 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 1 Preparation of l-triphenylmethyl-4-(hydroxymethyl)- imidazole To a solution of 4-(hydroxymethyl)imidazole hydrochloride (35 g) in 250 mL of dry DMF at room temperature was added triethylamine (90.6 mL). A white solid precipitated from the solution. Chlorotriphenylmethane (76.1 g) 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 title compound as a white solid which was sufficiently pure for use in the next step.
  • Step 2 Preparation of l-triphenylmethyl-4-(acetoxymethyl)- imidazole
  • Step 4 Preparation of l-(4-cyanobenzyl)-5-(hydroxymethyl)- imidazole
  • Step 5 Preparation of l-(4-cyanobenzyl)-5-imidazole- carboxaldehyde
  • Step 6 Preparation of 7-bromo-2-(l-(4-cyanobenzyl)-5- imidazolylmethyl)- 1.2.3.4-tetrahydroisoquinoline
  • Step 1 3(S)-Carboethoxy- 1.2.3.4-tetrahydroisoquinoline
  • the title compound was obtained from N-Boc-L-1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid (Bachem) using standard amino acid chemical procedures.
  • Step 2 3(S)-Carboethoxy-2-(l-(4-cyanobenzyl)imidazol-5- ylmethyl)- 1.2.3.4-tetrahydroisoquinoline dihydrochloride salt
  • Step 2 3 (R)-Carboethoxy-2- ( 1 - (4-cy anobenzyl)imidazol-5 - ylmethyl)- 1 ,2,3,4-tetrahydroisoquinoline dihydrochloride salt
  • Step 1 Preparation of 7-amino-2-trifluoroacetoxy- 1,2,3,4- tetrahydroisoquinoline
  • a solution of 7-nitro-2-trifluoroacetoxy- 1,2,3,4- tetrahydroisoquinoline (Stokker, Tetrahedron Letts., 1996, 37, 5453; 3.64 g, 13.3 mmol) in 100 mL EtOH at room temperature was was purged with argon and 10% palladium on carbon (300 mg) added. The mixture was then stirred under an atmosphere of hydrogen gas for 2 h. then filtered and the solvent removed in vacuo to yield a white solid which was sufficiently pure for use in the next step.
  • Step 2 Preparation of 7-iodo-2-trifluoroacetoxy- 1,2,3,4- tetrahydroisoquinoline
  • the aniline prepared above (3.34 g, 13.7 mmol) was suspended in 30 mL 3N HCI, cooled to 0°C and treated with a solution of NaN02 (1-04 g, 15.1 mmol) in 7 mL H2 ⁇ . After 30 minutes, a solution of KI (6.8 g, 41.1 mmol) in 10 mL H2O was added to the reaction mixture and stirring was continued for 45 minutes. The mixture was partitioned between CHCI3 and water, the organic layer was washed with aqueous NaHS ⁇ 3 then brine, dried and evaporated. Chromatography of the residue (hexane/EtOAc 5: 1) afforded the title compound as a colorless oil.
  • Step 4 7-iodo-2-(l-(4-cyanobenzyl)-5-imidazolylmethyl)-l,2,3,4- tetrahydroisoquinoline bis hydrochloride salt
  • Step 1 Preparation of 5-(4-cyanobenzyl)-2-trifluoroacetoxy- 1.2.3.4-tetrahydroisoquinoline
  • Step 1 Preparation of 5-(2-(3-tolyl)vinyl)-2-trifluoroacetoxy- 1.2.3.4-tetrahydroisoquinoline
  • Step 2 Preparation of 5-(3-tolyl)vinyl)- 1,2,3,4- tetrahydroisoquinoline
  • Step 1 Preparation of 5-(3-tolyl)ethyl)-l,2,3,4- tetrahydroisoquinoline
  • the stilbene from Example 13, Step 2 (242 mg, 1 mmol) was hydrogenated in 10 mL EtOH with 50 mg 10% palladium on carbon and hydrogen gas (balloon). Filtration through celite and removal of the solvent gave the title compound.
  • Step 2 5-(3-Tolyl)ethyl)-2-(l-(4-cyanobenzyl)-5- imidazolylmethyl)- 1.23.4-tetrahydroisoquinoline
  • Step 1 Preparation of 7-bromo-N-Boc- 1,2,3,4- tetrahydroisoquinoline
  • Step 2 Preparation of 7-phenyl-N-Boc- 1,2,3, 4- tetrahydroisoquinoline
  • Step 4 Preparation of 7-phenyl-2-(l-(4-cyanobenzyl)-5- imidazolylmethyl)- 1.2.3.4-tetrahydroisoquinoline Following the procedure described for Example 1, Step 6 but using 7-phenyl-l,2,3,4-tetrahydroisoquinoline the title compound was obtained as a white solid. Analysis for C27H24N4
  • Step 1 Preparation of 7 -bromo-N-Boc- 1,2,3,4- tetrahydroisoquinoline
  • Step 2 Preparation of 7-(2-tolyl)-N-Boc-l, 2,3,4- tetrahydroisoquinoline
  • Step 4 Preparation of 7-(2-tolyl)-2-(l-(4-cyanobenzyl)-5- imidazolylmethyl)- 1.2.3.4-tetrahydroisoquinoline
  • N-Boc-L-l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Bachem) was coupled with 2,3-dimethyl aniline using standard peptide coupling procedures.
  • the product was deprotected using TFA in CH2CI2 to give the title compound.
  • Step 2 Preparation of N-(2,3-dimethyl ⁇ henyl)-2-(l-(4- cyanobenzyl)-5-imidazolylmethyl)-l,2,3,4- tetrahydroisoquinoline-3(S)-carboxamide bis trifluoroacetate salt
  • Step 1 Preparation of N-(3-chlorobenzyl) 2-Boc- 1,2,3,4- tetrahydroisoquinoline-3(S)-carboxamide
  • N-Boc-L- 1 ,2,3 ,4-tetrahydroisoquinoline-3-carboxylic acid (Bachem) was coupled with 3-chlorobenzylamine using standard peptide coupling procedures to give the title compound.
  • Step 3 Preparation of N-(3-chlorobenzyl),N-Methyl 2-(l-(4- cyanobenzyl)-5-imidazolylmethyl)- 1 ,2,3,4- tetrahydroisoquinoline-3(S)-carboxamide bis trifluoroacetate salt Following the procedure described for Example 17 but using N-methyl 2-Boc-l,2,3,4-tetrahydroisoquinoline-3(S)- carboxamide, the title compound was obtained as a white solid.
  • Step 1 Preparation of 2-Boc-3(S)-carboethoxy-7-hydroxy- 1,2,3,4- tetrahydroisoquinoline
  • Step 2 Preparation of 2-Boc-3(S)-carboethoxy-7- trifluoromethylsulfonyloxy- 1.2.3.4-tetrahydroisoquinoline
  • Step 4 Preparation of 3(S)-carboethoxy-7-phenyl- 1,2,3,4- tetrahydroisoquinoline hydrochloride
  • Step 5 Preparation of 3(S)-carboethoxy-7-phenyl-2-(l-(4- cyanobenzyl)-5-imidazolylmethyl)- 1 ,2,3 ,4- tetrahydroisoquinoline dihydrochloride salt Following the procedure described for Example 1, Step 6 but using the product from Step 4 the title compound was obtained as a white solid.
  • Step 2 Preparation of 1 -n-buty 1-7 -bromo- 3.4-dihydroisoquinoline
  • Step 3 Preparation of l(R,S)-n-butyl-7-bromo- 1,2,3,4- tetrahydroisoquinoline
  • Step 4 Preparation of l(R,S)-n-butyl-7-bromo-2-(l-(4- cyanobenzyl)-5-imidazolylmethyl)- 1 ,2,3,4- tetrahydroisoquinoline dihydrochloride salt
  • Step 2 Preparation of l-(l-(4-cyanobenzyl)-5-imidazolylmethyl) indole
  • Step 1 Preparation of 4-phenylindole Following the procedure described for Example 21, Steps 2 and 3, 5-hydroxyindole (Aldrich) was converted into the title compound.
  • Step 1 Preparation of 6-Bromo-3.4-dihydro-l(TH)-isoquinolinone
  • 5-bromo-l-indanone Aldrich
  • H2SO4 38 mL
  • NaN3 NaN3 portionwise over 20 minutes.
  • the mixture was diluted EtOAc, washed with water then brine, dried and evaporated. Chromatography of the residue (silica gel; hexane/EtOAc 1:1) afforded the title compound as a solid.
  • Step 2 Preparation of 6-bromo-2-(l-(4-cyanobenzyl)-5- imidazolylmethyl)-3,4-dihydro- 1 (lH)-isoquinolinone hydrochloride salt
  • Step 2 Preparation of 6-Bromo-2-(l-(4-cyanobenzyl)-5- imidazolylmethyl)- 1.2.3.4-tetrahydroisoquinoline Following the procedure described for Example 1, Step 6 but using 6-bromo-l,2,3,4-tetrahydroisoquinoline from Step 1 the title compound was obtained. Analysis for C2lHl9N4Br Calcd. C, 61.92; H, 4.70; N, 13.76 found C, 61.59; H, 4.65; N, 13.49
  • Step 2 Preparation of 1 -(triphenylmethyl)- 1 H-imidazol-4-ylacetic acid methyl ester
  • Step 3 Preparation of [l-(4-cyanobenzyl)-lH-imidazol-5-yl]acetic acid methyl ester
  • 1 -(triphenylmethyl)- lH-imidazol-4- ylacetic acid methyl ester 8.00 g, 20.9 mmol
  • bromo-p-toluonitrile 4.10g, 20.92 mmol
  • the reaction was cooled to room temperature and the resulting imidazolium salt (white precipitate) was collected by filtration. The filtrate was heated at 55°C for 18 h.
  • Step 5 Preparation 7-bromo-2-(l-(4-cyanobenzyl)-5- imidazolylacetyl)- 1 ,2,3,4-tetrahydroisoquinoline hydrochloride
  • the acid from Step 4 0.575 g, 2 mmol
  • 7-bromo- 1,2,3,4- tetrahydroisoquinoline (0.424 g, 2 mmol) and HOBT 0.297 g, 2.2 mmol
  • DMF 15 mL
  • NMM (0.44 mL, 4 mmol
  • EDC 0.46 g, 2.4 mmol
  • Step 1 Preparation of 4-(3-bromo-phenyl)-4,5,6,7-tetrahydro-3H- imidazor4.5-clpyri.dine Histamine dihydrochloride (3.68 g, 0.02 mol), KOH (3.36 g, 0.06 mol), and 3-bromobenzaldehyde were dissolved in H 2 0 (250 mL) and EtOH(100 mL). The reaction mixture was heated for 24 h at
  • Step 2 Preparation of 4-(3-bromo-phenyl)-6,7-dihydro-4H- imidazo[4,5-c]pyridine-l,5-dicarboxylic acid di-tert-butyl ester 4-(3-Bromo-phenyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5- yridine (1.0 g, 3.6 mmol), Boc 2 0 (1.74 g, 7.9 mmol), and Et 3 N (1.1 mL, 7.9 mmol) were dissolved in CH 2 C1 2 (35 mL) and stirred overnight at room temperature under Ar. The reaction was washed with H 2 0, brine, and dried (N- ⁇ SO . Filtration, concentration, and silica gel chromatography (1:6 EtOAc/hexane) yielded the title compound.
  • Step 3 Preparation of 4-(3-bromo-phenyl)-l,4,6,7-tetrahydro- imidazor4.5-c]pyridine-5-carboxylic acid tert-butyl ester 4-(3-Bromophenyl)-6,7-dihydro-4H- imidazo[4,5- c]pyridine-l,5-dicarboxylic acid di-tert-butyl ester (0.879 g, 1.83 mmol) and Zn(CN) 2 (0.323 g, 2.75 mmol) were stirred in anh. DMF (30 mL) at 80°C under Ar for 72 h. The solution was concentrated in vacuo, partitioned between CHC1 3 and sat. NaHC0 3 soln, dried (MgS0 4 ), filtered, and concentrated to yield the title compound without further purification.
  • Step 4 Preparation of 4-(3-bromo-phenyl)-l-[3-(4-cyano-benzyl)- H-imidazol-4-ylmethyl]- 1 ,4,6,7-tetrahydro-imidazo[4,5- clpyridine-5-carboxylic acid tert-butyl ester 4-(3-Bromo-phenyl)- 1 ,4,6,7-tetrahydro-imidazo[4,5- c]pyridine-5-carboxylic acid t ⁇ rz'-butyl ester (0.160 g, 0.422 mmol) and 5-(chloromethyl)-l-(4-cyanobenzyl)-imidazole hydrochloride, as described in Example 26, Step 1, (0.119 g, 0.444 mmol), were dissolved in DMF (6 mL).
  • Step 5 Preparation of 4- ⁇ 5-[4-(3-bromophenyl)-4,5,6,7- tetrahydroimidazo[4,5-c]pyridin- 1 -ylmethyljimidazol- 1- . ylmethyl ⁇ -benzonitrile
  • Step 1 Preparation of N-(2-phenethyl) 2-(3-methoxyphenethyl) amine
  • Step 2 Preparation of l-(2-phenethyl)-6-methoxy-3,4- dihydroisoquinoline
  • Step 3 Preparation of l(R,S)-(2-phenethyl)-6-methoxy-l,2,3,4- tetrahydroisoquinoline
  • Step 4 Preparation of l(R,S)-(2-Phenethyl)-6-methoxy-2-(l-(4- cy anobenzyl)-5-imidazolylmethyl)- 1,2,3 ,4- tetrahydroisoquinoline
  • Bovine FPTase was assayed in a volume of 100 ml containing 100 mM N-(2- hydroxy ethyl) piperazine-N'-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgCl2, 5 mM dithiothreitol (DTT), 100 mM [3H]-farnesyl diphosphate ([3HJ-FPP; 740 CBq/mmol, New England Nuclear), 650 nM Ras-CVLS and 10 mg/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 b- plate counter.
  • the assay was linear with respect to both substrates, FPTase levels and time; less than 10% of the [3H]-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 gly col 20,000, 10 mM ZnCl2 and 100 nM Ras-CVIM were added to the reaction mixture. Reactions were performed for 30 min., stopped with 100 ml of 30% (v/v) trichloroacetic acid (TCA) in ethanol and processed as described above for the bovine enzyme.
  • TCA trichloroacetic acid
  • the modified geranylgeranyl-protein transferase inhibition assay is carried out at room temperature.
  • a typical reaction contains (in a final volume of 50 mL): [ 3 H] geranylgeranyl diphosphate, biotinylated Ras peptide, 50 mM HEPES, pH 7.5, a modulating anion (for example 10 mM glycerophosphate or 5mM ATP), 5 mM MgCl 2 , 10 mM ZnCl 2 ,
  • the GGTase-type I enzyme employed in the assay is prepared as described in U.S. Pat. No. 5,470,832, incorporated by reference.
  • the Ras peptide is derived from the K4B-Ras protein and has the following sequence: biotinyl- GKKKKKKSKTKCVIM (single amino acid code) (SEQ.ID.NO.: 13).
  • Reactions are initiated by the addition of GGTase and stopped at timed intervals (typically 15 min) by the addition of 200 mL of a 3 mg/mL suspension of streptavidin SPA beads (Scintillation Proximity Assay beads, Amersham) in 0.2 M sodium phosphate, pH 4, containing 50 mM EDTA, and 0.5% BSA. The quenched reactions are allowed to stand for 2 hours before analysis on a Packard TopCount scintillation counter.
  • assays are mn as described above, except inhibitors are prepared as concentrated solutions in 100% dimethyl sulfoxide and then diluted 25-fold into the enzyme assay mixture.
  • IC 50 values are determined with Ras peptide near KM concentrations. Enzyme and nonsaturating substrate conditions for inhibitor IC 50 determinations are as follows: 75 pM GGTase-I, 1.6 mM Ras peptide, 100 nM geranylgeranyl diphosphate. EXAMPLE 43
  • the cell lines used in this assay consist of either Ratl or NIH3T3 cells transformed by either viral H-ras; an N-ras chimeric gene in which the C-terminal hypervariable region of viral-H-ras was substituted with the corresponding region from the N-ras gene; or ras-CVLL, a viral-H-ras mutant in which the C-terminal exon encodes leucine instead of serine, making the encoded protein a substrate for geranylgeranylation by GGTase-I.
  • the assay can also be performed using cell lines transformed with human H-ras, N-ras or K4B-ras.
  • 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(s) (final concentration of solvent, methanol or dimethyl sulfoxide, is 0.1%). After 4 hours at 37°C, the cells are labelled in 3 ml methionine-free DMEM supplemented with 10% regular DMEM, 2% fetal bovine serum, 400 mCi[35S)methionine (1000 Ci/mmol) and test compound(s).
  • lovastatin a compound that blocks Ras processing in cells by inhibiting the rate-limiting step in the isoprenoid biosynthetic pathway (Hancock, J.F. et al. Cell, 57: 1167 (1989); DeClue, J.E. et al. Cancer Res., 51:712 (1991); Sinensky, M. et al. /. Biol Chem., 265:19937 (1990)), serve as a positive control in this assay.
  • 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.
  • 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 prenylated and nonprenylated Ras proteins are compared to determine the percent inhibition of prenyl 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
  • SALSA Soft Agar-Like Surrogate Assay measures the inhibition of anchorage-independent growth by prenyl-transferase inhibitors. Only transformed cells are able to grow anchorage- independently in the SALSA format. Additionally, cells growing in the SALSA format grow in clumps, resembling the colonies formed in soft agar. SALSA may been used to measure the growth inhibition by prenyl-transferase inhibitors in a variety of transformed cell lines, including Ratl fibroblasts transformed with viral-H-ras (H-ras/ratl), as well as a panel of human tumor cell lines (HTL's).
  • H-ras/ratl Ratl fibroblasts transformed with viral-H-ras
  • HTL's human tumor cell lines
  • SALSA is performed in 96-well plates that are coated with a thin film of the polymer, PolyHEMA (Poly(2-hydroxyethyl methacrylate)), which prevents cells from attaching to the plate.
  • Ratl fibroblast cells transformed with v-Ha-ras (this cell line has been deposited in the ATCC on August 19, 1997 under the terms of the Budapest convention and has been given a designation of ATCC CRL 12387) are seeded at 5000 cells/well, grown for 4 hr, then vehicle or half-log dilutions of test compound (in either an 8 or 12 point titration) are added. The cells are then grown for 6 days at 37 degrees, without changing the growth media or adding fresh compound.
  • cell growth is assessed via a colorimetric assay that measures the cleavage of the tetrazolium dye, MTT, to an insoluble purple formazan, a reaction dependent upon mitochondrial dehydrogenases.
  • MTT tetrazolium dye
  • SDS is added to 9% w/v to lyse the cells and solubilize the insoluble MTT-formazan.
  • the amount of MTT metabolism is quantitated via spectrophotometric detection at 570 nM. Dose-inhibition curves and IC 50 's are determined.
  • the SEAP reporter plasmid, pDSElOO was constructed by ligating a restriction fragment containing the SEAP coding sequence into the plasmid pCMV-RE-AKI.
  • the SEAP gene is derived from the plasmid pSEAP2-Basic (Clontech, Palo Alto, CA).
  • the plasmid pCMV- RE-AKI was constructed by Deborah Jones (Merck) and contains 5 sequential copies of the 'dyad symmetry response element' cloned upstream of a 'CAT-TATA' sequence derived from the cytomegalovims immediate early promoter.
  • the plasmid also contains a bovine growth hormone poly-A sequence.
  • the plasmid, pDSElOO was constmcted as follows. A restriction fragment encoding the SEAP coding sequence was cut out of the plasmid pSEAP2-Basic using the restriction enzymes EcoRI and Hpal. The ends of the linear DNA fragments were filled in with the Klenow fragment of E. coli DNA Polymerase I. The 'blunt ended' DNA containing the SEAP gene was isolated by electrophoresing the digest in an agarose gel and cutting out the 1694 base pair fragment. The vector plasmid pCMV-RE-AKI was linearized with the restriction enzyme B gill and the ends filled in with Klenow DNA Polymerase I.
  • the SEAP DNA fragment was blunt end ligated into the pCMV-RE-AKI vector and the ligation products were transformed into DH5-alpha E. coli cells (Gibco-BRL). Transformants were screened for the proper insert and then mapped for restriction fragment orientation. Properly oriented recombinant constructs were sequenced across the cloning junctions to verify the correct sequence. The resulting plasmid contains the SEAP coding sequence downstream of the DSE and CAT-TATA promoter elements and upstream of the BGH poly-A sequence. Cloning of a Myristylated viral-H-ms expression plasmid
  • a DNA fragment containing viral-H-ras can be PCRed from plasmid "H-l” (Ellis R. et al. J. Virol. 36, 408, 1980) using the following oligos.
  • Antisense 5'CACATCTAGATCAGGACAGCACAGACTTGCAGC 3'. (SEQ.ID.NO.: 15)
  • the sense strand oligo also optimizes the 'Kozak' translation initiation sequence immediately 5' to the ATG start site.
  • cysteine 186 would be mutated to a serine by substituting a G residue for a C residue in the C-terminal antisense oligo.
  • the PCR primer oligos introduce an Xhol site at the 5' end and a Xbal site at the 3 'end.
  • the Xhol-Xbal fragment can be ligated into the mammalian expression plasmid pCI (Promega) cut with Xhol and Xbal. This results in a plasmid in which the recombinant myr- viral-H-ras gene is constitutively transcribed from the CMV promoter of the pCI vector.
  • a viral-H-ras clone with a C-terminal sequence encoding the amino acids CVLL can be cloned from the plasmid "H-l" (Ellis R. et al. J. Virol. 36, 408, 1980) by PCR using the following oligos.
  • Sense strand
  • Antisense strand
  • the sense strand oligo optimizes the 'Kozak' sequence and adds an Xhol site.
  • the antisense strand mutates serine 189 to leucine and adds an
  • the PCR fragment can be trimmed with Xhol and Xbal and ligated into the Xhol-Xbal cut vector pCI (Promega). This results in a plasmid in which the mutated viral-H-ras-CVLL gene is constitutively transcribed from the CMV promoter of the pCI vector.
  • the human c-H-ras gene can be PCRed from a human cerebral cortex cDNA library (Clontech) using the following oligonucleotide primers.
  • Antisense strand
  • the primers will amplify a c-H-ras encoding DNA fragment with the primers contributing an optimized 'Kozak' translation start sequence, an EcoRI site at the N-terminus and a Sal I stite at the C-terminal end.
  • the c-H-ras fragment can be ligated ligated into an EcoRI -Sal I cut mutagenesis vector p Alter- 1 (Promega). Mutation of glutamine-61 to a leucine can be accomplished using the manufacturer' s protocols and the following oligonucleotide:
  • the mutated c-H-ras-Leu61 can be excised from the p Alter- 1 vector, using EcoRI and Sal I, and be directly ligated into the vector pCI (Promega) which has been digested with EcoRI and Sal I.
  • the new recombinant plasmid will constitutively transcribe c-H-ras-Leu61 from the CMV promoter of the pCI vector.
  • the human c-N-ras gene can be PCRed from a human cerebral cortex cDNA library (Clontech) using the following oligonucleotide primers.
  • Antisense strand
  • the primers will amplify a c-N-ras encoding DNA fragment with the primers contributing an optimized 'Kozak' translation start sequence, an
  • the c-N-ras fragment can be ligated into an EcoRI -Sal I cut mutagenesis vector p Alter- 1 (Promega). Mutation of glycine- 12 to a valine can be accomplished using the manufacturer's protocols and the following oligonucleotide: 5'-GTTGGAGCAGTTGGTGTTGGG-3' (SEQ.ID.NO.: 23)
  • the mutated c-N-r ⁇ s-Val-12 can be excised from the pAlter-1 vector, using EcoRI and Sal I, and be directly ligated into the vector pCI (Promega) which has been digested with EcoRI and Sal I.
  • the new recombinant plasmid will constitutively transcribe c-N-r ⁇ s- Val- 12 from the CMV promoter of the pCI vector.
  • the human c-K-r ⁇ s gene can be PCRed from a human cerebral cortex cDNA library (Clontech) using the following oligonucleotide primers.
  • Antisense strand 5 ' -CTCTGTCGACGTATTTAC ATAATTAC ACACTTTGTC-3 ' (SEQ.ID.NO.: 25)
  • the primers will amplify a c-K-r ⁇ s encoding DNA fragment with the primers contributing an optimized 'Kozak' translation start sequence, a Kpnl site at the N-terminus and a Sal I stite at the C-terminal end.
  • the c-K-r ⁇ s fragment can be ligated into a Kpnl -Sal I cut mutagenesis vector p Alter- 1 (Promega). Mutation of cysteine- 12 to a valine can be accomplished using the manufacturer's protocols and the following oligonucleotide:
  • the mutated c-K-ras-Val-12 can be excised from the p Alter- 1 vector, using Kpnl and Sal I, and be directly ligated into the vector pCI (Promega) which has been digested with Kpnl and Sal I.
  • the new recombinant plasmid will constitutively transcribe c-K-ras-Val-12 from the CMV promoter of the pCI vector.
  • Human C33A cells (human epitheial carcenoma - ATTC collection) are seeded in 10cm tissue culture plates in DMEM + 10% fetal calf semm + IX Pen/Strep + IX glutamine + IX NEAA. Cells are grown at 37°C in a 5% C02 atmosphere until they reach 50 -80% of conflunecy.
  • transient transfection is performed by the CaP04 method (Sambrook et al., 1989).
  • expression plasmids for H-ras, N-r ⁇ s, K-r ⁇ s, Myr-r ⁇ s or H-r ⁇ s-CVLL are co-precipitated with the DSE-SEAP reporter constmct.
  • 600ml of CaCl 2 -DNA solution is added dropwise while vortexing to 600ml of 2X HBS buffer to give 1.2ml of precipitate solution (see recipes below). This is allowed to sit at room temperature for 20 to 30 minutes. While the precipitate is forming, the media on the C33A cells is replaced with DMEM (minus phenol red; Gibco cat.
  • the cells are washed with PBS and trypsinized with 1ml of 0.05% trypsin.
  • the 1 ml of trypsinized cells is diluted into 10ml of phenol red free DMEM + 0.2% charcoal stripped calf semm + IX (Pen Strep, Glutamine and NEAA ).
  • Transfected cells are plated in a 96 well microtiter plate (100ml/ well) to which drug, diluted in media, has already been added in a volume of 100ml. The final volume per well is 200ml with each dmg concentration repeated in triplicate over a range of half-log steps.
  • the heat treated media is assayed for alkaline phosphatase by a luminescence assay using the luminescence reagent CSPD® (Tropix, Bedford, Mass.).
  • a volume of 50 ml media is combinRased with 200 ml of CSPD cocktail and incubated for 60 minutes at room temperature. Luminesence is monitored using an ML2200 microplate luminometer (Dynatech). Luminescence reflects the level of activation of the fos reporter construct stimulated by the transiently expressed protein.
  • Rodent fibroblasts transformed with oncogenically mutated human Ha-r ⁇ s or Ki-r ⁇ s are injected subcutaneously into the left flank of 8-12 week old female nude mice (Harlan) on day 0.
  • the mice in each oncogene group are randomly assigned to a vehicle, compound or combination treatment group. Animals are dosed subcutaneously starting on day 1 and daily for the duration of the experiment.
  • the farnesyl-protein transferase inhibitor may be administered by a continuous infusion pump.
  • Compound, compound combination or vehicle is delivered in a total volume of 0.1 ml. Tumors are excised and weighed when all of the vehicle-treated animals exhibited lesions of 0.5 - 1.0 cm in diameter, typically 11-15 days after the cells were injected. The average weight of the tumors in each treatment group for each cell line is calculated.

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EP98960545A 1997-12-04 1998-11-30 Inhibitoren der farnesyl-protein-transferase Withdrawn EP1045843A4 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US08/985,320 US5977134A (en) 1996-12-05 1997-12-04 Inhibitors of farnesyl-protein transferase
PCT/US1998/025352 WO1999028313A1 (en) 1996-12-05 1998-11-30 Inhibitors of farnesyl-protein transferase
US985320 2001-11-02

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0675112A1 (de) * 1994-03-31 1995-10-04 Bristol-Myers Squibb Company Imidazol-enthaltende Farnesyl-Protein-Transferase-Inhibitoren
WO1997036901A1 (en) * 1996-04-03 1997-10-09 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
WO1997036898A1 (en) * 1996-04-03 1997-10-09 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
WO1997036890A1 (en) * 1996-04-03 1997-10-09 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
WO1997036605A1 (en) * 1996-04-03 1997-10-09 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
WO1997036897A1 (en) * 1996-04-03 1997-10-09 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0675112A1 (de) * 1994-03-31 1995-10-04 Bristol-Myers Squibb Company Imidazol-enthaltende Farnesyl-Protein-Transferase-Inhibitoren
WO1997036901A1 (en) * 1996-04-03 1997-10-09 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
WO1997036898A1 (en) * 1996-04-03 1997-10-09 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
WO1997036890A1 (en) * 1996-04-03 1997-10-09 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
WO1997036605A1 (en) * 1996-04-03 1997-10-09 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
WO1997036897A1 (en) * 1996-04-03 1997-10-09 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO9928313A1 *

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