WO1996031525A2 - Inhibiteurs de la farnesyl-proteine transferase - Google Patents

Inhibiteurs de la farnesyl-proteine transferase Download PDF

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Publication number
WO1996031525A2
WO1996031525A2 PCT/US1996/003974 US9603974W WO9631525A2 WO 1996031525 A2 WO1996031525 A2 WO 1996031525A2 US 9603974 W US9603974 W US 9603974W WO 9631525 A2 WO9631525 A2 WO 9631525A2
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Prior art keywords
alkyl
hydrogen
aryl
substituted
alkenyl
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PCT/US1996/003974
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English (en)
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WO1996031525A3 (fr
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S. Jane Desolms
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Merck & Co., Inc.
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Priority to EP96911382A priority Critical patent/EP0837857A4/fr
Priority to JP53033696A priority patent/JP2002504067A/ja
Priority to AU54285/96A priority patent/AU713698B2/en
Publication of WO1996031525A2 publication Critical patent/WO1996031525A2/fr
Publication of WO1996031525A3 publication Critical patent/WO1996031525A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0207—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)4-C(=0), e.g. 'isosters', replacing two amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • Ras proteins 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.
  • 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
  • Mutated ras genes 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 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 farnesyl-protein transferase or geranylgeranyl-protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a C 15 or C 20 isoprenoid, respectively.
  • the Ras protein is one of several proteins that are known to undergo post-translational famesylation.
  • Other famesylated proteins include the Ras-related GTP-binding proteins such as Rho, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin.
  • James, et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisome associated protein Pxf which is also famesylated.
  • James, et al. have also suggested that there are famesylated proteins of unknown structure and function in addition to those listed above.
  • 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 has been shown to dramatically reduce the inhibitory potency of the compound.
  • the thiol group
  • 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).
  • the present invention comprises analogs of the CA 1 A 2 X motif of the protein Ras that is modified by famesylation in vivo. These CA 1 A 2 X analogs inhibit the farnesylprotein transferase. Furthermore, these CA 1 A 2 X analogs differ from those previously described as inhibitors of farnesyl-protein transferase in that they do not have a thiol moiety. The lack of the thiol offers unique advantages in terms of improved pharmacokinetic behavior in animals, prevention of thiol- dependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity. The compounds of the instant invention also incorporate a cyclic amine moiety in the A 2 position of the motif. Further contained in this invention are chemotherapeutic compositions containing these farnesyl transferase inhibitors and methods for their production.
  • the compounds of this invention inhibit the famesyl-protein transferase.
  • the famesyl-protein transferase inhibitors are illustrated by the formula I:
  • R 1a and R 1b are independently selected from:
  • heterocyclic cycloalkyl, alkenyl, alkynyl, R10O-,
  • R 2 and R 3 are independently selected from:
  • R 2 and R 3 are combined to form - (CH 2 ) s - ", or
  • R 2 or R 3 are combined with R 6 to form a ring such that
  • R 4a , R 4b , R 7a and R 7b are independently selected from:
  • R 5a and R 5b are independently selected from:
  • amino acid which is:
  • R 5a and R 5b are combined to form - (CH 2 ) s - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O) m , -NC(O)-, and -N(COR 10 )- ;
  • R 6 is independently selected from hydrogen or C 1 -C 6 alkyl
  • R 8 is independently selected from:
  • perfluoroalkyl F, Cl, Br, R 10 O-, R 1 1 S(O) m -, R 10 C(O)NR 10 -, CN, NO 2 , R 10 2N-C(NR 10 )-, R 10 C(O)-, R 10 OC(O)-, N 3 , -N(R 10 ) 2 , or R 1 1 ⁇ C(O)NR 10 -, and c) C 1 -C 6 alkyl unsubstituted or substituted by aryl,
  • heterocycle cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F,
  • R 10 OC(O)NH-;
  • R 9 is selected from:
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and aryl;
  • R 1 1 is independently selected from C 1 -C 6 alkyl and aryl
  • a 1 and A 2 are independently selected from: a bond, -CH-CH-, -C ⁇ C-,
  • Q is a substituted or unsubstituted nitrogen-containing C 6 -C 9 bicyclic ring system, wherein the non-nitrogen containing ring is selected from an aromatic ring and a heterocycle;
  • V is selected from:
  • 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 ;
  • W is a heterocycle
  • X, Y and Z are independently H 2 or O; m is 0, 1 or 2;
  • n 0, 1, 2, 3 or 4;
  • p 0, 1, 2, 3 or 4;
  • r is 0 to 5, provided that r is 0 when V is hydrogen;
  • s 4 or 5;
  • t 3, 4 or 5;
  • u is 0 or 1
  • R 1 a and R 1b are independently selected from:
  • heterocyclic cycloalkyl, alkenyl, alkynyl, R 10 O-,
  • R 2 and R 3 are independently selected from:
  • R 2 or R 3 are combined with R 6 to form a ring such that
  • R 4a , R 4b , R 7a and R 7b are independently selected from:
  • R 5a and R 5b are independently selected from:
  • R 5a and R 5b are combined to form - (CH 2 ) s - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O) m , -NC(O)-, and -N(COR 10 )- ;
  • R 6 is independently selected from hydrogen or C 1 -C 6 alkyl
  • R 8 is independently selected from:
  • perfluoroalkyl F, Cl, Br, R 10 O-, R 1 1 S(O) m -, R 10 C(O)NR 10 -, CN, NO 2 , R 10 2 N-C(NR 10 )-, R 10 C(O)-, R 10 OC(O)-, N 3 , -N(R 10 ) 2 , or R 1 1 ⁇ C(O)NR 10 -, and c) C 1 -C 6 alkyl unsubstituted or substituted by aryl,
  • heterocycle cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 10 O-, R 1 1 S(O) m -, R 10 C(O)NH-, CN, H 2 N- C(NH)-, R 10 C(O)-, R 10 OC(O)-, N 3 , -N(R 10 ) 2 , or
  • R 9 is selected from:
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and aryl;
  • R 1 1 is independently selected from C 1 -C 6 alkyl and aryl
  • R 13 is independently selected from hydrogen and C 1 -C 6 alkyl
  • R 14 is independently selected from C 1 -C 6 alkyl
  • a 1 and A 2 are independently selected from: a bond, -CH-CH-, -C ⁇ C-,
  • Q is a substituted or unsubstituted nitrogen-containing C 6 -C 9 bicyclic ring system, wherein the non-nitrogen containing ring is selected from an aromatic ring and a heterocycle;
  • V is selected from:
  • 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 ; W is a heterocycle;
  • X, Y and Z are independently H 2 or O; m is 0, 1 or 2;
  • n 0, 1, 2, 3 or 4;
  • p 0, 1, 2, 3 or 4;
  • r is 0 to 5, provided that r is 0 when V is hydrogen; s is 4 or 5;
  • t 3, 4 or 5;
  • u is 0 or 1 ;
  • R 1 a and R 1b are independently selected from:
  • heterocyclic cycloalkyl, alkenyl, alkynyl, R 10 O-,
  • R 2 and R 3 are independently selected from:
  • R 2 and R 3 are combined to form - (CH 2 ) s - ;
  • R 2 or R 3 are combined with R 6 to form a ring such that
  • R 4a , R 4b , R 7a and R 7b are independently selected from:
  • R 6 is independently selected from hydrogen or C 1 -C 6 alkyl;
  • R 8 is independently selected from:
  • perfluoroalkyl F, Cl, Br, R 10 O-, R 1 1 S(O) m -, R 10 C(O)NR 10 -, CN, NO 2 , R 10 2N-C(NR 10 )-, R 10 C(O)-, R 10 OC(O)-, N 3 , -N(R 10 ) 2 , or R 1 1 OC(O)NR 10 -, and c) C 1 -C 6 alkyl unsubstituted or substituted by aryl,
  • heterocycle cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 10 O-, R 1 1 S(O) m -, R 10 C(O)NH-, CN, H 2 N-
  • R 9 is selected from:
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and aryl;
  • R 1 1 is independently selected from C 1 -C 6 alkyl and aryl;
  • a 1 and A 2 are independently selected from: a bond, -CH-CH-, -C ⁇ C-,
  • Q is a substituted or unsubstituted nitrogen-containing C 6 -C 9 bicyclic ring system, wherein the non-nitrogen containing ring is selected from an aromatic ring and a heterocycle;
  • V is selected from:
  • 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 ; W is a heterocycle;
  • X, Y and Z are independently H 2 or O; m is 0, 1 or 2;
  • n 0, 1, 2, 3 or 4;
  • p 0, 1, 2, 3 or 4;
  • q 0, 1 or 2;
  • r is 0 to 5, provided that r is 0 when V is hydrogen;
  • s 4 or 5;
  • t 3, 4 or 5;
  • u is 0 or 1; or the pharmaceutically acceptable salts thereof.
  • the prodrugs of compounds of formula III are illustrated by the formula IV:
  • R 1 a and R 1b are independently selected from:
  • heterocyclic cycloalkyl, alkenyl, alkynyl, R 10 O-,
  • R 2 and R 3 are independently selected from:
  • amino acid which is:
  • R 2 or R 3 are combined with R 6 to form a ring such that
  • R 4a , R 4b , R 7a and R 7b are independently selected from:
  • R 6 is independently selected from hydrogen or C 1 -C 6 alkyl
  • R 8 is independently selected from:
  • perfluoroalkyl F, Cl, Br, R 10 O-, R 1 1 S(O) m -, R 10 C(O)NR 10 -, CN, NO 2 , R 10 2 N-C(NR 10 )-, R 10 C(O)-, R 10 OC(O)-, N 3 , -N(R 10 ) 2 , or R 1 1 0C(O)NR 10 -, and c) C 1 -C 6 alkyl unsubstituted or substituted by aryl,
  • heterocycle cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F,
  • R 9 is selected from:
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and aryl;
  • R 1 1 is independently selected from C 1 -C 6 alkyl and aryl;
  • Q is a substituted or unsubstituted nitrogen-containing C 6 -C 9 bicyclic ring system, wherein the non-nitrogen containing ring is selected from an aromatic ring and a heterocycle;
  • V is selected from:
  • W is a heterocycle
  • X, Y and Z are independently H 2 or O; m is 0, 1 or 2;
  • n 0, 1, 2, 3 or 4;
  • p 0, 1, 2, 3 or 4;
  • q 0, 1 or 2;
  • r is 0 to 5, provided that r is 0 when V is hydrogen;
  • s 4 or 5;
  • t 3, 4 or 5;
  • u is 0 or 1; or the pharmaceutically acceptable salts thereof.
  • Ras farnesyl transferase inhibitors are illustrated by the Formula I:
  • R 1 a is independently selected from: hydrogen or C 1 -C 6 alkyl
  • R 1b is independently selected from:
  • R 2 and R 3 are independently selected from:
  • R 2 and R 3 are combined to form - (CH 2 ) s - ;
  • R 2 or R 3 are combined with R 6 to form a ring such that
  • R 4a and R 7a are independently selected from:
  • R 4b and R 7b are hydrogen
  • R 5a is selected from:
  • R 5b is selected from:
  • R 6 is independently selected from hydrogen or C 1 -C 6 alkyl;
  • R 8 is independently selected from:
  • perfluoroalkyl F, Cl, R 10 O-, R 10 C(O)NR 10 -, CN, NO 2 , (R 10 ) 2 N-C(NR 10 )-, R 10 C(O)-, R 10 OC(O)-, -N(R 10 ) 2 , or
  • R 9 is selected from:
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and aryl;
  • R 1 1 is independently selected from C 1 -C 6 alkyl and aryl;
  • Q is selected from:
  • heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl,
  • 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 ;
  • W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or
  • X, Y and Z are independently H 2 or O; m is 0, 1 or 2;
  • n 0, 1, 2, 3 or 4;
  • p 0, 1, 2, 3 or 4;
  • r is 0 to 5, provided that r is 0 when V is hydrogen;
  • t 3, 4 or 5;
  • u is 0 or 1; or the pharmaceutically acceptable salts thereof.
  • R 1 a is independently selected from: hydrogen or C 1 -C 6 alkyl
  • R 1b is independently selected from:
  • heterocycle cycloalkyl, alkenyl, R 10 O-, or -N(R 10 ) 2 ;
  • R 2 and R 3 are independently selected from:
  • R 2 and R 3 are combined to form - (CH 2 ) s - ; or R 2 or R 3 are combined with R 6 to form a ring such that
  • R 4a and R 7a are independently selected from:
  • R 4b and R 7b are hydrogen
  • R 5 a is selected from:
  • R 5b is selected from:
  • R 6 is independently selected from hydrogen or C 1 -C 6 alkyl
  • R 8 is independently selected from:
  • perfluoroalkyl F, Cl, R 10 O-, R 10 C(O)NR 10 -, CN, NO 2 , (R 10 ) 2 N-C(NR 10 )-, R 10 C(O)-, R 10 OC(O)-, -N(R 10 ) 2 , or
  • R 9 is selected from:
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and aryl;
  • R 1 1 is independently selected from C 1 -C 6 alkyl and aryl
  • R 12 is
  • R 13 is independently selected from hydrogen and C 1 -C 6 alkyl
  • R 14 is independently selected from C 1 -C 6 alkyl
  • Q is selected from:
  • V is selected from:
  • heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl,
  • 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 ;
  • W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or
  • n 0, 1, 2, 3 or 4;
  • p 0, 1, 2, 3 or 4;
  • r is 0 to 5, provided that r is 0 when V is hydrogen;
  • t 3, 4 or 5;
  • u is 0 or 1; or the pharmaceutically acceptable salts thereof.
  • the inhibitors of farnesyl transferase are illustrated by the formula III: wherein: R 1 a is independently selected from: hydrogen or C 1 -C 6 alkyl;
  • R 1b is independently selected from:
  • heterocycle cycloalkyl, alkenyl, R 10 O-, or -N(R 10 ) 2 ;
  • R 2 and R 3 are independently selected from:
  • R 2 or R 3 are combined with R 6 to form a ring such that
  • R 4a and R 7a are independently selected from:
  • R 4b and R 7b are hydrogen;
  • R 6 is independently selected from hydrogen or C 1 -C 6 alkyl
  • R 8 is independently selected from:
  • perfluoroalkyl F, Cl, R 10 O-, R 10 C(O)NR 10 -, CN, NO 2 , (R 10 ) 2 N-C(NR 10 )-, R 10 C(O)-, R 10 OC(O)-, -N(R 10 ) 2 , or
  • R 1 1 OC(O)NR 10 - and c) C 1 -C 6 alkyl substituted by C 1 -C 6 perfluoroalkyl, R 10 O-, R 10 C(O)NR 10 -, (R 10 ) 2 N-C(NR 10 )-, R 10 C(O)-, R 10 OC(O)-, -N(R 10 ) 2 , or R 1 1 OC(O)NR 10 -;
  • R 9 is selected from:
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and aryl;
  • R 1 1 is independently selected from C 1 -C 6 alkyl and aryl;
  • Q is selected from:
  • V is selected from:
  • 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 ;
  • W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or
  • n 0, 1, 2, 3 or 4;
  • p 0, 1, 2, 3 or 4;
  • q 0, 1 or 2;
  • r is 0 to 5, provided that r is 0 when V is hydrogen;
  • t 3, 4 or 5;
  • u is 0 or 1; or the pharmaceutically acceptable salts thereof.
  • the prodrugs of the preferred compounds of Formula III are illustrated by the Formula IV: wherein: R 1 a is independently selected from: hydrogen or C 1 -C 6 alkyl;
  • R 1b is independently selected from:
  • heterocycle cycloalkyl, alkenyl, R 10 O-, or -N(R 10 ) 2 ;
  • R 2 and R 3 are independently selected from:
  • R 2 and R 3 are combined to form - (CH 2 ) s - ; or R 2 or R 3 are combined with R 6 to form a ring such that
  • R 4a and R 7a are independently selected from:
  • R 4b and R 7b are hydrogen
  • R 6 is independently selected from hydrogen or C 1 -C 6 alkyl
  • R 8 is independently selected from:
  • perfluoroalkyl F, Cl, R 10 O-, R 10 C(O)NR 10 -, CN, NO 2 , (R 10 ) 2 N-C(NR 10 )-, R 10 C(O)-, R 10 OC(O)-, -N(R 10 ) 2 , or
  • R 10 OC(O)-, -N(R 10 ) 2 , or R 1 1 OC(O)NR 10 -;
  • R 9 is selected from:
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and aryl;
  • R 1 1 is independently selected from C 1 -C 6 alkyl and aryl;
  • Q is selected from:
  • V is selected from:
  • heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl,
  • 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 ;
  • W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or
  • X, Y and Z are independently H 2 or O; m is 0, 1 or 2;
  • n 0, 1, 2, 3 or 4;
  • p 0, 1, 2, 3 or 4;
  • q 0, 1 or 2;
  • r is 0 to 5, provided that r is 0 when V is hydrogen;
  • t 3, 4 or 5;
  • u is 0 or 1; or the pharmaceutically acceptable salts thereof.
  • compounds of the invention are: N-[L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro- 3(S)-isoquinolinecarbonyl-methionine
  • amino acids which are disclosed are identified both by conventional 3 letter and single letter abbreviations as indicated below:
  • 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 is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • cycloalkyl is intended to include non- aromatic cyclic hydrocarbon groups having the specified number of carbon atoms.
  • examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • Alkenyl groups include those groups having the specified number of carbon atoms and having one or several double bonds.
  • alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, isoprenyl, farnesyl, geranyl, geranylgeranyl and the like.
  • aryl is intended to include any stable monocyclic, bicyclic or tricyclic carbon ring(s) of up to 7 members in each ring, wherein at least one ring is aromatic.
  • aryl groups include phenyl, naphthyl, anthracenyl, biphenyl, tetrahydronaphthyl, indanyl, phenanthrenyl and the like.
  • heterocycle or heterocyclic represents a stable 5- to 7-membered monocyclic or stable 8- to 11- membered bicyclic or stable 11-15 membered tricyclic heterocycle ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group
  • heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • heterocyclic elements include, but are not limited to, azepinyl,
  • substituted aryl As used herein, the terms “substituted aryl”, “substituted heterocycle” and “substituted cycloalkyl” are intended to include the cyclic group which is substituted with 1 or 2 substitutents selected from the group which includes but is not limited to F, Cl, Br, CF 3 , NH 2 , N(C 1 - C 6 alkyl) 2 , NO 2 , CN, (C 1 -C 6 alkyl)O-, -OH, (C 1 -C 6 alkyl)S(O) m -, (C 1 - C 6 alkyl)C(O)NH-, H 2 N-C(NH)-, (C 1 -C 6 alkyl)C(O)-, (C 1 -C 6
  • cyclic amine moiety having 5 or 6 members in the ring, such a cyclic amine which may be optionally fused to a phenyl or cyclohexyl ring.
  • a cyclic amine moiety include, but are not limited to, the following specific structures:
  • substitution on the cyclic amine moiety by R 8a and R 8b may be on different carbon atoms or on the same carbon atom.
  • cyclic moieties When R 3 and R 4 are combined to form - (CH 2 ) s -, cyclic moieties are formed. Examples of such cyclic moieties include, but are not limited to:
  • cyclic moieties as described hereinabove for R 3 and R 4 are formed.
  • cyclic moieties may optionally include a heteroatom(s). Examples of such heteroatom-containing cyclic moieties include, but are not limited to:
  • the phrase "nitrogen containing C 6 -C 9 bicyclic ring system wherein the non-nitrogen containing ring is selected from an aromatic ring and a heterocycle" which defines moiety "Q" of the instant invention includes but is not limited to the following ring systems:
  • 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, phenyl- acetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
  • -N(R 10 ) 2 represents -NHH, -NHCH 3 , -NHC 2 H 5 , etc. It is understood that substituents and substitution patterns 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.
  • R 1a and R 1b are independently selected from: hydrogen, -N(R 8 ) 2 , R 8 C(O)NR 8 - or C 1 -C 6 alkyl unsubstituted or substituted by -N(R 8 ) 2 , R 8 O- or R 8 C(O)NR 8 -.
  • R 2 is the sidechain of glycine (hydrogen).
  • R 3 is selected from:
  • substituent is selected from F, Cl, Br,
  • R 3 is combined with R 6 to form pyrrolidinyl ring.
  • R 4a , R 4b , R 7a and R 7b are independently selected from: hydrogen, C 1 -C 6 alkyl, aryl and benzyl.
  • R 5a and R 5b are independently selected from: a side chain of a naturally occurring amino acid, methionine sulfoxide, methionine sulfone and unsubstituted or substituted C 1 -C 6 alkyl .
  • R 6 is: hydrogen or is combined with R 3 to form pyrrolidinyl ring.
  • R 8 is selected from: hydrogen, perfluoroalkyl, F, Cl, Br, R 10 O-, R 1 1 S(O) m -, CN, NO 2 , R 10 2 N-C(NR 10 )-, R 10 C(O)-, R 10 OC(O)-, N 3 , -N(R 10 ) 2 , or R 1 1 OC(O)NR 10 - and C 1 -C 6 alkyl.
  • R 9 is hydrogen
  • R 10 is selected from H, C 1 -C 6 alkyl and benzyl.
  • R 12 is selected from C 1 -C 6 alkyl and benzyl.
  • a 1 and A 2 are independently selected from: a bond, -C(O)NR 10 -, -NR 10 C(O)-, O, -N(R 10 )-, -S(O) 2 N(R 10 )- and- N(R 10 )S(O) 2 -.
  • Q is a tetrahydroisoquinolinyl moiety.
  • V is selected from hydrogen, heterocycle and aryl.
  • n, p and r are independently 0, 1, or 2.
  • t is 3.
  • the pharmaceutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this invention which contain a basic moiety conventional chemical methods. Generally, the salts are prepared 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.
  • the compounds of the invention can be synthesized from their constituent amino acids by conventional peptide synthesis
  • Reaction C Deprotection of the reduced peptide subunit Reaction D Peptide bond formation and protecting group cleavage using standard solution or solid phase methodologies.
  • Reaction E Preparation of a reduced subunit by borane reduction of the amide moiety.
  • Reaction Schemes A-E illustrate bond-forming and peptide modifying reactions incorporating acyclic peptide units. It is well understood that such reactions are equally useful when the - NHC(R A ) - moiety of the reagents and compounds illustrated is replaced with the following moiety:
  • Reaction Schemes F - M illustrate reactions wherein the non- sulfhydryl-containing moiety at the N-terminus of the compounds of the instant invention is attached to an acyclic peptide unit which may be further elaborated to provide the instant compounds.
  • aldehydes such as I, as shown in Reaction Scheme F.
  • 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, from the appropriate amino acid (Reaction Scheme F).
  • 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 product II can be deprotected to give the final compounds III with trifluoroacetic acid in methylene chloride.
  • the final product III is isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others.
  • the product diamine III can further be selectively protected to obtain IV, which can subsequently be reductively alkylated with a second aldehyde to obtain V. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole VII can be accomplished by literature procedures.
  • the protected dipeptidyl analog intermediate can be reductively alkylated with other aldehydes such as 1-trityl-4- carboxaldehyde or 1-trityl-4-imidazolylacetaldehyde, to give products such as VIII (Reaction Scheme G).
  • the trityl protecting group can be removed from VIII to give IX, or alternatively, VIII can first be treated with an alkyl halide then subsequently deprotected to give the alkylated imidazole X.
  • the dipeptidyl analog intermediate can be acylated or sulfonylated by standard techniques.
  • the imidazole acetic acid XI can be converted to the acetate
  • the protected dipeptidyl analog intermediate is reductively alkylated with an aldehyde which also has a protected hydroxyl group, such as XVI in Reaction Scheme I
  • the protecting groups can be subsequently removed to unmask the hydroxyl group (Reaction Schemes I, J).
  • the alcohol can be oxidized under standard conditions to e.g. an aldehyde, which can then be reacted with a variety of organometallic reagents such as Grignard reagents, to obtain secondary alcohols such as XX.
  • the fully deprotected amino alcohol XXI can be reductively alkylated (under conditions described previously) with a variety of aldehydes to obtain secondary amines, such as XXII (Reaction Scheme K), or tertiary amines.
  • the Boc protected amino alcohol XVIII can also be utilized to synthesize 2-aziridinylmethylpiperazines such as XXUI (Reaction Scheme L). Treating XVIII with lj'-sulfonyldiimidazole and sodium hydride in a solvent such as dimethylformamide led to the formation of aziridine XXUI . The aziridine reacted in the presence of a nucleophile, such as a thiol, in the presence of base to yield the ring-opened product XXIV .
  • a nucleophile such as a thiol
  • the protected dipeptidyl analog intermediate can be reacted with aldehydes derived from amino acids such as O-alkylated tyrosines, according to standard procedures, to obtain compounds such as XXX, as shown in Reaction Scheme M.
  • R' is an aryl group
  • XXX can first be hydrogenated to unmask the phenol, and the amine group deprotected with acid to produce XXXI.
  • the amine protecting group in XXX can be removed, and O-alkylated phenolic amines such as XXXII produced.
  • Reaction Schemes N-R illustrate syntheses of suitably substituted aldehydes useful in the syntheses of the instant compounds wherein the variable W is present as a pyridyl moiety. Similar synthetic strategies for preparing alkanols that incorporate other heterocyclic moieties for variable W are also well known in the art.
  • 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 formation (i.e., neurofibromin (NF-1), neu, scr, abl, lck, fyn) or by other mechanisms.
  • the compounds of the instant invention inhibit famesyl- 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)).
  • 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.
  • a component of NF- 1 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 al.FASEB Journal, 2: A3160 (1988)).
  • 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,
  • the selected compound may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or
  • 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.
  • 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
  • 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.
  • pharmacologically acceptable carriers e.g., saline
  • the solutions may be introduced into a patient's intramuscular blood-stream by local bolus injection.
  • 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.
  • Administration occurs in an amount between about 0.1 mg/kg of body weight to about 20 mg/kg of body weight per day, preferably of between 0.5 mg/kg of body weight to about 10 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
  • FPTase famesyl-protein transferase
  • 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.
  • FPTase for example a tetrapeptide having a cysteine at the amine terminus
  • farnesyl 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 immunological, radiochemical or chromatographic techniques.
  • the compounds of the instant invention are selective inhibitors of FPTase
  • absence or quantitative reduction of the amount of substrate in the assay mixture without the compound of the instant invention relative to the presence of the unchanged substrate in the assay containing the instant compound is indicative of the presence of FPTase in the composition to be tested.
  • potent inhibitor compounds of the instant invention may be used in an active site titration assay to determine the quantity of enzyme in the sample.
  • a series of samples composed of aliquots of a tissue extract containing an unknown amount of 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
  • the standard workup referred to in the examples refers to solvent extraction and washing the organic solution with 10% citric acid, 10% sodium bicarbonate and brine as appropriate. Solutions were dried over sodium sulfate and evaporated in vacuo on a rotary evaporator.
  • Step B N-[(2S)-(t-Butyloxycarbonylamino)-3(S)-methylpentyl)- 1,2,3,4-tetrahydro-3(S)-isoquinolinecarboxylic acid benzyl ester.
  • 1,2,3,4-tetrahydro-3(S)-isoquinolinecarboxylic acid benzyl ester (2.23 g, 0.0084 mol) were dissolved in MeOH (30 mL) at ambient temperature under nitrogen and treated with 3A molecular sieves (3 g) and sodium cyanoborohydride (0.66 g, 0.0105 mol) with stirring. After 18 h the mixture was filtered, concentrated, and the residue was partitioned between EtOAc (50 mL) and satd aq NaHC03 solution (50 mL). The basic layer was washed with EtOAc (3 x 30 mL), the organics combined, washed with brine, and dried (Na 2 SO 4 ).
  • Step C N-[(2S)-(t-Butyloxycarbonylamino)-3(S)-methylpentyl)-
  • Step D N-[2(S)-(t-Butyloxycarbonylamino-3(S)-methylpentyl]- 1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine methyl ester
  • Step E N-[2(S)-amino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)- isoquinolinecarbonyl-methionine methyl ester
  • Step F N-[(1H-imidazol-4-ylacetyl-2(S)-amino)-3(S)- methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl- methionine methyl ester trifluoroacetate
  • Step G N-[(1H-imidazol-4-ylacetyl)-2(S)-amino-3(S)- methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl- methionine trifluoroacetate
  • Step B 1-(Triphenylmethyl)-1H-imidazol-4-ylacetic acid methyl ester
  • the precipitated imidazolium salts were combined, suspended in methanol (100 ml) and heated to reflux for 30min. After this time, the solvent was removed in vacuo, the resulting residue was suspended in EtOAc (75ml) and the solid isolated by filtration and washed (EtOAc). The solid was treated with sat aq NaHCO 3 (300ml) and CH 2 CI 2 (300ml) and stirred at room temperature for 2 hr. The organic layer was
  • the aqueous solution was lyophilized to afford the title compound containing lithium chloride as a white solid.
  • Step E N-[(1-(4-Cyanobenzyl)-1H-imidazol-5-yl)acetyl]-2(S)- amino-3(S)-methylpentyl]-1,2,34-tetrahydro-3(S)- isoquinolinecarbonyl methionine methyl ester
  • Step F N-[(1-(4-Cyanobenzyl)-1H-imidazol-5-yl)acetyl]-2(S)- amino-3(S)-methylpentyl]-1,2,34-tetrahydro-3(S)- isoquinolinecarbonyl methionine
  • Step A N-[L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]-1,2,3,4- tetrahydro-3(S)-isoquinolinecarbonyl-methionine methyl ester trifluoroacetate
  • Step B N-[L-Pyroglutamyl-2(S)-amino-3(S)-methylpentyl]-1,2,3,4- tetrahydro-3(S)-isoquinolinecarbonyl-methionine trifluoroacetate
  • N-(4-Cyanobenzyl)-L-pyroglutamic acid methyl ester (0.875 g, 0.0034 mol) was dissolved in THF:H 2 O (3:1) (12 mL) and treated with LiOH (0.294 g, 0.007 mol) with stirring at ambient temperature. After stirring for 3 h, the solution was neutralized with 1 N HCl, and
  • Step D N-[N-(4-Cyanobenzyl)-L-Pyroglutamyl-2(S)-amino-3(S)- memylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl- methionine methyl ester
  • Step E N-[N-(4-Cyanobenzyl)-L-Pyroglutamyl-2(S)-amino-3(S)- methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl- methionine
  • 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 [3H]-farnesyl diphosphate ([3H]-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 harvestor, 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 [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.
  • DMSO dimethyl sulfoxide
  • Percentage inhibition is measured by the amount of incorporation of radioactivity in the presence of the test compound when compared to the amount of incorporation in the absence of the test compound.
  • Human FPTase was prepared as described by Omer et al, Biochemistry 32:5167-5176 (1993). Human FPTase activity was assayed as described above with the exception that 0.1% (w/v) 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
  • Examples 1, Step G, and Example 3, Step B, were tested for inhibitory activity against human FPTase by the assay described above and were found to have IC 50 of ⁇ 10 ⁇ M.
  • the cell line used in this assay is a v-ras line derived from either Ratl or N1H3T3 cells, which expressed viral Ha-ras p21.
  • the assay is performed essentially as described in DeClue, J.E. et al, Cancer Research 51:712-111, (1991). Cells in 10 cm dishes at 50-75%
  • 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.
  • the cells are lysed in 1 ml lysis buffer (1% NP40/20 mM HEPES, pH 7.5/5 mM MgCl 2 /1mM 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.
  • famesylated and nonfarnesylated ras proteins are compared to determine the percent inhibition of farnesyl transfer to protein.
  • Rat 1 cells transformed with either a v- ras, v-raf, or v-mos oncogene is tested.
  • Cells transformed by v-Raf and v-Mos maybe included in the analysis to evaluate the specificity of instant compounds for Ras-induced cell transformation.
  • Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded at a density of 1 x 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

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Abstract

La présente invention concerne des analogues du motif CA1A2X de la protéine Ras modifiés par farnesylation in vivo. Ces analogues CA1A2X ont un effet inhibiteur sur la farnésyl-protéine transférase et sur la farnesylation de certaines protéines. En outre, ces analogues CA1A2X diffèrent de ceux décrits antérieurement en tant qu'inhibiteurs de farnésyl-protéine transférase par le fait qu'ils ne comportent pas de fraction thiol. L'absence de thiol présente des avantages uniques en termes d'amélioration du comportement pharmacocinétique chez les animaux, de prévention de réactions chimiques dépendantes d'un thiol, telle que l'auto-oxidation rapide et les formations de bisulfure avec des thiols endogènes, et une toxicité systémique réduite. Les composants de cette invention renferment également une fraction amine cyclique à la position A2 du motif. Cette invention recouvre également des compositions chimiothérapeutiques renfermant de tels inhibiteurs de farnesyl transférase et leurs procédés de production.
PCT/US1996/003974 1995-03-29 1996-03-25 Inhibiteurs de la farnesyl-proteine transferase WO1996031525A2 (fr)

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EP96911382A EP0837857A4 (fr) 1995-03-29 1996-03-25 Inhibiteurs de la farnesyl-proteine transferase
JP53033696A JP2002504067A (ja) 1995-03-29 1996-03-25 ファルネシル−タンパク質トランスフェラーゼ阻害剤
AU54285/96A AU713698B2 (en) 1995-03-29 1996-03-25 Inhibitors of farnesyl-protein transferase

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5703241A (en) * 1995-10-16 1997-12-30 Merck & Co., Inc. Inhibitor of farnesyl-protein transferase
EP1045844A1 (fr) * 1997-12-04 2000-10-25 Merck & Co., Inc. Inhibiteurs de farnesyl-proteine transferase

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5238922A (en) * 1991-09-30 1993-08-24 Merck & Co., Inc. Inhibitors of farnesyl protein transferase
US5352705A (en) * 1992-06-26 1994-10-04 Merck & Co., Inc. Inhibitors of farnesyl protein transferase

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5238922A (en) * 1991-09-30 1993-08-24 Merck & Co., Inc. Inhibitors of farnesyl protein transferase
US5352705A (en) * 1992-06-26 1994-10-04 Merck & Co., Inc. Inhibitors of farnesyl protein transferase

Non-Patent Citations (2)

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Title
See also references of EP0837857A2 *
THE JOURNAL OF BIOLOGICAL CHEMISTRY, April 1993, Vol. 268, No. 11, GIBBS et al., "Selective Inhibition of Farresyl-Protein Transferase Blocks Ras Process in Vivo", pages 7617-7620. *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5703241A (en) * 1995-10-16 1997-12-30 Merck & Co., Inc. Inhibitor of farnesyl-protein transferase
EP1045844A1 (fr) * 1997-12-04 2000-10-25 Merck & Co., Inc. Inhibiteurs de farnesyl-proteine transferase
EP1045844A4 (fr) * 1997-12-04 2002-08-21 Merck & Co Inc Inhibiteurs de farnesyl-proteine transferase

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