+

WO1996010034A2 - Inhibiteurs de la transferase de proteines farnesylees exempts de thiol - Google Patents

Inhibiteurs de la transferase de proteines farnesylees exempts de thiol Download PDF

Info

Publication number
WO1996010034A2
WO1996010034A2 PCT/US1995/012224 US9512224W WO9610034A2 WO 1996010034 A2 WO1996010034 A2 WO 1996010034A2 US 9512224 W US9512224 W US 9512224W WO 9610034 A2 WO9610034 A2 WO 9610034A2
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
alkyl
unsubstituted
aryl
hydrogen
Prior art date
Application number
PCT/US1995/012224
Other languages
English (en)
Other versions
WO1996010034A3 (fr
Inventor
Neville J. Anthony
S. Jane Desolms
Robert P. Gomez
Samuel L. Graham
John H. Hutchinson
Gerald E. Stokker
Original Assignee
Merck & Co., Inc.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from US08/526,244 external-priority patent/US5652257A/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to EP95935104A priority Critical patent/EP0783517A2/fr
Priority to CA 2201348 priority patent/CA2201348A1/fr
Priority to AU37248/95A priority patent/AU700175B2/en
Priority to JP8511933A priority patent/JPH10508005A/ja
Publication of WO1996010034A2 publication Critical patent/WO1996010034A2/fr
Publication of WO1996010034A3 publication Critical patent/WO1996010034A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07K5/0205—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)3-C(=0)-, e.g. statine or derivatives thereof
    • 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
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • 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 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)).
  • 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-trans lational famesylation.
  • Other farnesylated proteins include the Ras-related GTP-binding proteins such as Rho, fungal mating factors, the nuclear lamins, and the gamma subunit of 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 inhibitors are inhibitors of proliferation of vascular smooth muscle cells and are therefore useful in the prevention and thereapy of arteriosclerosis and diabetic disturbance of blood vessels (JP H7- 112930).
  • FPTase farnesyl-protein transferase
  • FPP famesyl diphosphate
  • Ras protein substrates
  • the peptide derived inhibitors that have been described are generally cysteine containing molecules that are related to the CAAX motif that is the signal for protein prenylation.
  • 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
  • the present invention comprises analogs of the CAAX motif of the protein Ras that is modified by famesylation in vivo. These CAAX analogs inhibit the famesylation of Ras. Furthermore, these CAAX analogues differ from those previously described as inhibitors of Ras famesyl 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. Further contained in this invention are chemotherapeutic compositions containing these famesyl transferase inhibitors and methods for their production.
  • Ras famesyl transferase inhibitors are illustrated by the formula I:
  • R 1 is independently selected from:
  • R 2a and R 2b are independently selected from:
  • R 2a and R 2b are combined to form - (CH 2 ) s - ;
  • R 3 and R 4 are independently selected from:
  • R 3 and R 4 are combined to form - (CH 2 ) s - ;
  • R 5a and R 5b are independently selected from:
  • R 7a is selected from
  • R 7b is selected from
  • a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C 1 -C 6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl;
  • R 8 is independently selected from:
  • R 9 is selected from:
  • R 10 C(O)NR 10 -, CN, (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 - ;
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl and aryl;
  • R 1 1 is independently selected from C 1 -C 6 alkyl and aryl;
  • R 12 is independently selected from hydrogen and C 1 -C 6 alkyl
  • R 14 is independently selected from hydrogen, C 1 -C 6 alkyl and benzyl
  • R 15 is independently selected from hydrogen and C 1 -C 6 alkyl
  • 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 or a bond;
  • W is a heterocycle;
  • Z is independently H 2 or O;
  • n 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 is 3, 4 or 5; or the pharmaceutically acceptable salts thereof.
  • R 1 is independently selected from:
  • R 2a and R 2b are independently selected from:
  • substituent is selected from F, Cl, Br, NO 2 , R 10 O-, R 1 1 S(O) m -.
  • R 2a and R 2b are combined to form - (CH 2 ) s - ;
  • R 3 and R 4 are independently selected from:
  • substituent is selected from F, Cl, Br,
  • R 3 and R 4 are combined to form - (CH 2 ) s - ;
  • R 5a and R 5b are independently selected from:
  • substituent is selected from F, Cl, Br, N(R 10 ) 2 , NO 2 , R 10 O-, R 1 1 S(O) m -, R 10 C(O)NR 10 -,
  • 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.
  • R 5a or R 5b are combined with R 14 to form a ring such that
  • R 7a is selected from
  • R 7b is selected from
  • R 8 is independently selected from:
  • 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 l lOC(O)NH-;
  • R 9 is selected from:
  • R 10 C(O)NR 10 -, CN, (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 -;
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl and aryl;
  • R 1 1 is independently selected from C 1 -C 6 alkyl and aryl
  • R 12 is independently selected from' hydrogen and C 1 -C 6 alkyl
  • R 13 is independently selected from C 1 -C 6 alkyl
  • R 14 is independently selected from hydrogen,C 1 -C 6 alkyl and benzyl
  • 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 or a bond;
  • W is a heterocycle
  • Z is 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 is 3, 4 or 5; or the pharmaceutically acceptable salts thereof.
  • R 1 is independently selected from: a) hydrogen,
  • R 2a and R 2b are independently selected from:
  • R 2a and R 2b are combined to form - (CH 2 ) s - ;
  • R 3 and R 4 are independently selected from:
  • substituent is selected from F, Cl, Br, N(R 10 ) 2 , NO 2 , R 10 O-, R 1 1 S(O) m -, R 10 C(O)NR 10 -,
  • R 3 and R 4 are combined to form - (CH 2 ) s - .
  • X-Y is
  • R 7a is selected from
  • R 7b is selected from
  • R 8 is independently selected from:
  • 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 1 1 OC(O)NH-;
  • R 9 is selected from:
  • R 10 C(O)NR 10 -, CN, (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 -;
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl and aryl;
  • R 1 1 is independently selected from C 1 -C 6 alkyl and aryl
  • R 12 is independently selected from hydrogen and C 1 -C 6 alkyl
  • R 14 is independently selected from hydrogen,C 1 -C 6 alkyl and benzyl
  • 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 or a bond; W is a heterocycle;
  • Z is 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 is 4 or 5; or the pharmaceutically acceptable salts thereof.
  • R 1 is independently selected from: a) hydrogen,
  • R 10 O-, R 1 1 S(O) m -_ R 1O C(O)NR 10 -, CN, NO 2 ,
  • R 2a and R 2b are independently selected from:
  • R 2a and R 2b are combined to form - (CH 2 ) s - ;
  • R 3 and R 4 are independently selected from:
  • substituent is selected from F, Cl, Br, N(R 10 ) 2 , NO 2 , R 10 O-, R 1 1 S(O) m -, R 10 C(O)NR 10 -,
  • R 3 and R 4 are combined to form - (CH 2 ) s - ;
  • X-Y is
  • R 7a is selected from
  • R 7b is selected from
  • R 8 is independently selected from:
  • R 10 OC(O)-, N 3 , -N(R 10 ) 2 , or R 1 1 OC(O)NH-;
  • R 9 is selected from:
  • R 10 C(O)NR 10 -, CN, (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 -;
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl and aryl;
  • R 1 1 is independently selected from C 1 -C 6 alkyl and aryl
  • R 12 is independently selected from hydrogen and C 1 -C 6 alkyl
  • R 14 is independently selected from hydrogen,C 1 -C 6 alkyl and benzyl
  • 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 or a bond; W is a heterocycle;
  • Z is 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 is 4 or 5; or the pharmaceutically acceptable salts thereof.
  • Ras famesyl transferase inhibitors are illustrated by the formula I:
  • R 1 is independently selected from:
  • R 2a is selected from:
  • amino acid is selected from alanine, leucine, isoleucine and valine;
  • R 2b is selected from hydrogen and C 1 -C 6 alkyl
  • R 2a and R 2b are combined to form - (CH 2 ) s - ;
  • R 3 and R 4 are independently selected from:
  • R 5a is selected from:
  • amino acid is selected from:
  • R 5b is selected from:
  • R 5a or R 5b are combined with R 14 to form a ring such that
  • R 7a is selected from
  • heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl;
  • R 7b is selected from
  • a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C 1 -C 6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl;
  • heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl;
  • R 8 is selected from:
  • 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 12 is independently selected from hydrogen and C 1 -C 6 alkyl
  • R 14 is independently selected from hydrogen and C 1 -C 6 alkyl
  • R 15 is independently selected from hydrogen and C 1 -C 6 alkyl
  • V is selected from: a) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, b) 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 or a bond;
  • W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, piperidinyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl;
  • Z is 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 2;
  • s is 4 or 5;
  • t is 3, 4 or 5; or the pharmaceutically acceptable salts thereof.
  • R 1 is independently selected from:
  • R 2a is selected from:
  • amino acid is selected from alanine, leucine, isoleucine and valine;
  • C 1 -C 10 alkyl C 2 -C 10 alkenyl, C 3 -C 10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, NO 2 , R 10 0-, R 1 1 S(O) m -, R 10 C(O)NR 10 -, CN, (R 10 ) 2 N-C(NR 10 )-, R 10 C(O)-, R 10 OC(O)-, N 3 , -N(R 10 ) 2 , R 1 1 OC(O)NR 10 - and C 1 -C 20 alkyl, and c) C 1 -C 6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C 3 - C 10 cycloalkyl; and R 2b is selected from hydrogen and C 1 -C 6 alkyl; or
  • R 2a and R 2b are combined to form - (CH 2 ) s - ;
  • R 3 and R 4 are independently selected from:
  • R 5a is selected from:
  • amino acid is selected from:
  • R 5a is selected from: a) hydrogen
  • R 5a or R 5b are combined with R 14 to form a ring such that
  • R 7a is selected from
  • heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl;
  • R 7b is selected from
  • a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C 1 -C 6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl;
  • heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl;
  • R 8 is selected from:
  • R 10 OC(O)-, -N(R 10 ) 2 , or R 1 1 OC(O)NR 10 -;
  • R 9 is selected from:
  • R 1 1 is independently selected from C 1 -C 6 alkyl and aryl
  • R 12 is independently selected from hydrogen and C 1 -C 6 alkyl
  • R 13 is 1 ,1-dimethylethyl
  • R 14 is independently selected from hydrogen and C 1 -C 6 alkyl
  • R 15 is independently selected from hydrogen and C 1 -C 6 alkyl
  • V is selected from:
  • heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, b) 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 or a bond;
  • W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, piperidinyl, 2-oxopiperidinyl, indolyl,
  • Z is 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 2;
  • s is 4 or 5;
  • t 3, 4 or 5; or the pharmaceutically acceptable salts thereof.
  • the inhibitors of famesyl transferase are illustrated by the formula II I:
  • R 1 is independently selected from:
  • R 2a is selected from:
  • amino acid is selected from alanine, leucine, isoleucine and valine;
  • C 1 -C 10 alkyl C 2 -C 10 alkenyl, C 3 -C 10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, NO 2 , R 10 O-, R 1 1 S(O) m , R 10 C(O)NR 10 -, CN, (R 10 ) 2 N-C(NR 10 )-, R 10 C(O)-, R 10 OC(O)-, N 3 , -N(R 10 ) 2 , R 1 1 OC(O)NR 10 - and C 1 -C 20 alkyl, and c) C 1 -C 6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C 3 -
  • R 2b is selected from hydrogen and C 1 -C 6 alkyl
  • R 2a and R 2b are combined to form - (CH 2 ) s - ;
  • R 3 and R 4 are independently selected from:
  • R 7a is selected from
  • heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl;
  • R 7b is selected from
  • a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C 1 -C 6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl;
  • heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl;
  • R 8 is selected from:
  • R 1 1 is independently selected from C 1 -C 6 alkyl and aryl
  • R 12 is independently selected from hydrogen and C 1 -C 6 alkyl
  • V is selected from:
  • heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, b) aryl, c) C 1 -C 20 alkyl wherein from 0 to 4 non-terminal carbon atoms are replaced with a heteroatom selected from O, S, and N, and
  • 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 or a bond;
  • W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, piperidinyl, 2-oxopiperidinyl, indolyl,
  • Z is 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 2;
  • s is 4 or 5; or the pharmaceutically acceptable salts thereof.
  • R 1 is independently selected from:
  • R 2a is selected from:
  • amino acid is selected from alanine, leucine, isoleucine and valine;
  • R 2a and R 2b are combined to form - (CH 2 ) s - ;
  • R 3 and R 4 are independently selected from:
  • R 7a is selected from
  • heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl;
  • R 7b is selected from
  • a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C 1 -C 6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl;
  • heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl;
  • R 8 is selected from:
  • R 9 is selected from:
  • R 1 1 is independently selected from C 1 -C 6 alkyl and aryl
  • R 12 is independently selected from hydrogen and C 1 -C 6 alkyl
  • R 14 is independently selected from hydrogen and C 1 -C 6 alkyl
  • V is selected from: a) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, b) 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 or a bond;
  • W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, piperidinyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl;
  • Z is 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 2;
  • s is 4 or 5; or the pharmaceutically acceptable salts thereof.
  • 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. Examples of alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl,
  • cyclopentenyl cyclohexenyl, 1-propenyl, 2-butenyl, 2-methyl-2- butenyl, isoprenyl, famesyl, 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,
  • heterocycle or heterocyclic represents a stable 5- to 7-membered monocyclic or stable 8- to 11- membered bicyclic or stable 11-15 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
  • heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl,
  • benzofurazanyl benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydro-benzothienyl, dihydrobenzothiopyranyl, dihydrobenzothio-pyranyl sulfone, furyl, imidazolidinyl,
  • substituted aryl substituted heterocycle
  • substituted cycloalkyl substituted cycloalkyl
  • cyclic group which is substituted with 1 or 2 substitutents selected from the group which includes but is not limited to F, Cl, Br, NH 2 , N( C 1 -C 6 alkyl) 2 , CF 3 , NO 2 ,
  • 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:
  • cyclic moieties are formed.
  • cyclic moieties include, but are not limited to:
  • cyclic moieties as described hereinabove for R 2a and R 2b and R 3 and R 4 are formed.
  • such cyclic moieties may optionally include a heteroatom(s). Examples of such heteroatom-containing cyclic moieties include, but are not limited to:
  • R 1 is selected from: hydrogen, and C 1 -C 6 alkyl.
  • R 2a and R 2b are independently selected from: a side chain of a naturally occurring amino acid and C 1 -C 6 alkyl unsubstituted or substituted with an aryl group.
  • R 3 and R 4 are independently selected from:
  • 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 .
  • X-Y is selected from:
  • R 7b C 1 -C 6 alkyl substituted with hydrogen or an unsubstituted or substituted aryl group.
  • R 8 is selected from: hydrogen, perfluoroalkyl, F, Cl, Br, R 10 O-, R 1 1 S(O) m -, CN, NO 2 , R 10 C(O)-, R 10 OC(O)-,
  • R 9 is hydrogen.
  • R 10 is selected from H, C 1 -C 6 alkyl and benzyl.
  • a 1 and A 2 are a bond.
  • 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 include the conventional non-toxic salts of the
  • such conventional non- toxic salts include those derived from inorganic acids such as
  • -N(R 10 ) 2 represents -NHH, -NHCH 3 , -NHC 2 H 5 , etc. It is intended that the definition of any substituent or variable (e.g., R 10 , Z, n, etc.) at a particular location in a molecule be independent of its definitions elsewhere in that molecule.
  • -N(R 10 ) 2 represents -NHH, -NHCH 3 , -NHC 2 H 5 , etc. It is
  • the pharmaceutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this invention which contain a basic moiety by conventional chemical methods. Generally, the salts are prepared 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 techniques, and the additional methods described below. Standard methods of peptide synthesis are disclosed, for example, in the following works: Schroeder et al, "The Peptides", Vol.
  • TFA Trifluoroacetic acid
  • THF Tetrahydrofuran
  • Reaction A Amide bond formation and protecting group cleavage using standard solution or solid phase methodologies.
  • Reaction B Preparation of a reduced peptide subunit by 1 reductive alkylation of an amine by an aldehyde using sodium cyanoborohydride or other reducing agents.
  • Reaction C Alkylation of a reduced peptide subunit with an alkyl or aralkyl halide or, alternatively, reductive alkylation of a reduced peptide subunit with an aldehyde using sodium
  • Reaction E Preparation of a reduced subunit by borane reduction of the amide moiety.
  • Reaction B Preparation of reduced peptide subunits by reductive alkylation
  • R A and R B are R 2a , R 2b , R 3 , R 4 , R 5a or R 5b as previously defined;
  • X L is a leaving group, e.g., Br- , I- or MsO-; and R C is defined such that R 7b is generated by the reductive alkylation
  • 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 Scheme F outlines the preparation of the alkene isosteres utilizing standard manipulations such as Weinreb amide formation, Grignard reaction, acetylation, ozonolysis, Wittig reaction, ester hydrolysis, peptide coupling reaction, mesylation, cleavage of peptide protecting groups, reductive alkylation, etc., as may be known in the literature or exemplified in the Experimental Procedure.
  • the key reactions are: stereoselective reduction of the Boc-amino-enone to the
  • alkane analogs are prepared in a similar manner by including an additional catalytic hydrogenation step as outlined in Reaction Scheme G.
  • aminoalcohol H-1 is acylated with alpha-chloroacetyl chloride in the presence of trialkylamines to yield amide H-2.
  • a deprotonation reagent e.g., sodium hydride or potassium t-butoxide
  • THF ethereal solvent
  • X L is a leaving group such as Br, I- or Cl- in THF/DME (1,2-dimethoxyethane) in the presence of a suitable base, preferably NaHMDS [sodium bis(trimethylsilyl)amide], affords H-5, which is retreated with NaHMDS followed by either protonation or the addition of an alkyl halide R 4 ⁇ to give H-6a or H-6b.
  • a suitable base preferably NaHMDS [sodium bis(trimethylsilyl)amide]
  • H-6a can be prepared from H-4 via an aldol condensation approach. Namely, deprotonation of H-4 with NaHMDS followed by the addition of a carbonyl compound
  • R y R z CO gives the adduct H-7 (wherein R y and R z are selected such that R 3 is eventually provided.
  • Dehydration of H-7 can be effected by mesylation and subsequent elimination catalyzed by DBU (1 ,8- diazabicyclo[5.4.0]undec-7-ene) or the direct treatment of H-7 with phosphorus oxychloride in pyridine to give olefin H-8. Then, catalytic hydrogenation of H-8 yields H-6a. Direct hydrolysis of H-6 with lithium hydrogen peroxide in aqueous THF will produce acid H- 9b.
  • Hydrolysis of compounds H-14 to the corresponding hydroxy acids and acids, respectively, is accomplished by standard methods such as treatment with NaOH in alcoholic or aqueous milieux followed by careful acidifcation with dilute BCI .
  • thia, oxothia and dioxothia isostere compounds of this invention are prepared in accordance to the route depicted in Scheme I.
  • Aminoalcohol I-1 is derivatized with BOC 2 O to give l-15.
  • Mesylation of l-15 followed by reaction with methyl alpha- mercaptoacetate in the presence of cesium carbonate gives sulfide l- 16.
  • Removal of the BOC group in l-16 with TFA followed by neutralization with di-isopropylethylamine leads to lactam 1-17.
  • N- BOC derivative l-18 is obtained via the reaction of l-17 with BOC anhydride in THF catalyzed by DMAP.
  • the N-BOC group of either l-21 or l-22 is readily removed by treatment with gaseous hydrogen chloride.
  • the resultant amine hydrochloride l-23 undergoes reductive alkylation in the presence of an aldehyde R x CHO (l-12) and a reducing agent (e.g., sodium cyanoborohydride); or acylation in the presence of R x COOH (l-13) and a peptide coupling reagent to afford the products l-24 and l-25.
  • Reaction Schemes J - 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. These reactions may be employed in a linear sequence to provide the compounds of the invention or they may be used to synthesize fragments which are
  • aldehydes such as V, as shown in Reaction Scheme J.
  • 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 J).
  • 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 VI can be deprotected to give the final compounds VII with trifluoroacetic acid in methylene chloride.
  • the final product VII is isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others.
  • the product diamine VII can further be selectively protected to obtain VIII, which can
  • 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 XII (Reaction Scheme K).
  • the trityl protecting group can be removed from XII to give XIII, or alternatively, XII can first be treated with an alkyl halide then subsequently deprotected to give the alkylated imidazole XIV.
  • the dipeptidyl analog intermediate can be acylated or sulfonylated by standard techniques.
  • the imidazole acetic acid XV can be converted to the acetate XVII by standard procedures, and XVII can be first reacted with an alkyl halide, then treated with refluxing methanol to provide the regiospecifically alkylated imidazole acetic acid ester XVIII.
  • Hydrolysis and reaction with the protected dipeptidyl analog intermediate in the presence of condensing reagents such as 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide (EDC) leads to acylated products such as XIX.
  • M may be employed using other peptidyl analog intermediates such as those whose synthesis is illustrated in Reaction Schemes B - l.
  • the compounds of this invention inhibit Ras famesyl transferase which catalyzes the first step in the post-translational processing of Ras and the biosynthesis of functional Ras protein.
  • These 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 pancreatic carcinoma, and myeloid leukemias.
  • the compounds of this invention are also useful for inhibiting 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 benign proliferative disorder neurofibromatosis, or tumors in which the Ras is activated due to mutation or overexpression of tyrosine kinase oncogenes e.g., neu, src, abl, lck, and fyn
  • arteriosclerosis and diabetic disturbance of blood vessels may be prevented or treated by use of the instant
  • the compounds of this invention may be administered to mammals, preferably humans, either alone or, preferably, in
  • the compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
  • 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.
  • suspending agents are suspending agents. If desired, certain sweetening and/or flavoring agents may be added. For intramuscular, intraperitoneal,
  • 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
  • compositions 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.
  • 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 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 quantity of farnesyl-protein transferase (FPTase) in a composition.
  • FPTase farnesyl-protein transferase
  • composition to be tested may be divided and the two
  • mixtures which comprise a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and famesyl pyrophosphate and, in one of the mixtures, a compound of the instant invention.
  • FPTase for example a tetrapeptide having a cysteine at the amine terminus
  • famesyl pyrophosphate for example a tetrapeptide having a cysteine at the amine terminus
  • the chemical content of the assay mixtures may be determined by well known immunological, radiochemical or chromatographic techniques.
  • 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 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 famesyl pyrophosphate are incubated for an appropriate period of time in the presence of varying concentrations of a compound of the instant invention.
  • concentration of a sufficiently potent inhibitor i.e., one that has a Ki substantially smaller than the concentration of enzyme in the assay vessel
  • concentration of a sufficiently potent inhibitor i.e., one that has a Ki substantially smaller than the concentration of enzyme in the assay vessel
  • 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.
  • Step B Preparation of 1 -(Phenylmethyl)-1H-imidazol-4-ylacetic acid methyl ester (2) and 1-(Phenylmethyl)-1H-imidazol-5- ylacetic acid methyl ester (3) (3:1 mixture)
  • sodium hydride 37.3 mg, 1.56 mmol
  • dimethylformamide 2 ml
  • cannula a solution of 1 (1 15 mg, 0.707 mmol) in dimethylformamide (3 ml). This suspension was allowed to stir at 0°C for 15 min.
  • Step C Preparation of 1-(Phenylmethyl)-1H-imidazol-4-ylacetic acid hydrochloride (4) and 1-(Phenylmethyl)-1H-imidazol- 5-ylacetic acid hydrochloride (5) (3: 1 mixture)
  • Step D Preparation of N-(2(S)-(t-butoxycarbonylamino)-3(S)- methylpentyl)glycine methyl ester (6)
  • Step E Preparation of N-[2(S)-(t-Butoxycarbonylamino)-3(S)- methylpentyn-N-(1 -naphthylmethyl)glycine methyl ester (7) N-[2(S)-(t-Butoxycarbonylamino)-3(S)-methyl-pentyl]- glycine methyl ester (6, 2.00 g, 6.97 mmol) was dissolved in 1,2- dichloroethane (56 ml) and 3A molecular sieves were added followed by 1 -naphthaldehyde (1.89 ml, 13.9 mmol) and sodium triacetoxy- borohydride (6.65 g, 31.4 mmol). The mixture was stirred at ambient temperature for 16 h, and filtered through glass fiber paper and
  • Step G Preparation of N-[2(S)-(t-Butoxycarbonylamino)-3(S)- methylpentyl]-N-(1 -naphthylmethyl)glycine-methionine methyl ester (9)
  • Step H Preparation of N-(2(S)-amino-3(S)-methylpentyl)-N-(1 - naphthylmethyl)-glycyl-methionine methyl ester hydrochloride (10) N-[2(S)-(t-Butoxycarbonylamino)-3(S)-methylpentyl]-N-(1 - naphthylmethyl)-glycyl-methionine methyl ester (9, 2.82 g, 5.04 mmol) was dissolved in EtOAc (50 mL) and cooled to -25°C. HCl was bubbled through the mixture until TLC (95:5 CH 2 CI 2 :MeOH) indicated complete reaction.
  • Step I Preparation of N-[2(S)-(1-(Phenylmethyl)-1H-imidazol-4- ylacetyl)amino-3(S)-methylpentyl]-N-1-naphthylmethyl - gylycyl-methionine methyl ester bis trifluoroacetate (11) and
  • the regioisomers were separated by Prep HPLC using a Nova Prep 5000 Semi preparative HPLC system and a Waters PrepPak cartridge (47 X 300mm, C18, 15 urn, , 100 A) eluting with 5 - 95% acetonitrile/water (0.1% TF A) at 100 ml/min (chromatography method A) to give after lyophilization pure 11 and 12.
  • Step J Preparation of N-[2(S)-(1-(Phenylmethyl)-1H-imidazol-4- ylacetyl)amino-3(S)-methylpentyl]-N-1-naphthylmethyl - glycyl-methionine bis trifluoroacetate (13) and N-[2(S)-(1 - (Phenylmethyl)-1H-imidazol-5-ylacetyl)amino-3(S)- methylpentyl]-N-1-naphthylmethyl-glycyl-methionine bis trifluoroacetate (14) To a solution of N-[2(S)-(1-(Phenylmethyl)-1H-imidazol-4- ylacetyl)amino-3(S)-methylpentyl]-N-1-naphthylmethyl-glycyl- methionine methyl ester bis trifluor
  • Step A Preparation of 1-(4-Nitrophenylmethyl)-1H-imidazol-4- ylacetic acid methyl ester (15) and 1 -(4-Nitrophenylmethyl)-
  • Step B Preparation of 1-(4-Nitropheny Imethyl)-1 H-imidazol-4- ylacetic acid hydrochloride (17) and 1-(4-Nitrophenyl- methyl)-1H-imidazol-5-ylacetic acid (18) (3:1 mixture )
  • Step C Preparation of N-[(2S)-(1-(4-Nitropheny Imethyl)-1H- imidazol-4-ylacetyl)amino-3(S)-methylpentyl]-N- 1 - naphthylmethyl-glycyl-methionine methyl ester bis trifluoroacetate (19) and N-[2(S)-(1-(4-Nitrophenyl-methyl)- 1 H-imidazol-5-ylacetyl)amino-3(S)-methylpentyl]-N- 1 - naphthylmethyl-glycyl-methionine methyl ester bis
  • Step D Preparation of N-[2(S)-(1 -(4-Nitropheny Imethyl)-1 H- imidazol-4-ylacetyl)amino-3(S)-methylpentyl]-N-1- naphthylmethyl-glycyl-methionine bis trifluoroacetate (21)
  • N-[2(S)-(1 -(4-nitrophenylmethyl)-1H- imidazol-4-ylacetyl)amino-3(S)-methylpentyl]-N-1-naphthylmethyl- glycyl-methionine methyl ester bis trifluoroacetate (19, 21 mg, 0.023 mmol) in methanol (1 ml ) at room temperature was added 1.0N lithium hydroxide (135 ⁇ l, 0.135 mmol).
  • Step E Preparation of N-[2(S)-(1-(4-NitrophenylmethyI)-1H- imidazol-5-ylacetyl)amino-3(S)-methylpentyl]-N-1 - naphthylmethyl-glycyl-methionine bis trifluoroacetate (22)
  • N- [2(S)-N'-(1 -(4-nitropheny Imethyl)-1 H- imidazol-5-ylacetyl)amino-3(S)-methylpentyl]-N-1-naphthylmethyl- glycyl-methionine methyl ester bis trifluoroacetate (20, 29 mg, 0.031 mmol) in methanol (1 ml ) was added 1.0N lithium hydroxide (187
  • Step B Preparation of 1-(4-Nitrophenylmethyl)-1H-imidazol-5- ylacetic acid methyl ester (16)
  • Step C Preparation of 1-(4-NitrophenyImethyl)-1H-imidazol-5 - ylacetic acid hydrochloride (18) 1-(4-Nitrophenylmethyl)-1H-imidazol-5-ylacetic acid methyl ester (0.115 g, 0.42 mmol ) was dissolved in 1.0N hydrochloric acid (10 ml ) and heated at 55°C for 3 h. The solution was evaporated in vacuo to give 18 as a white solid.
  • Step D Preparation of N-[2(S)-(1-(4-Nitropheny Imethyl)-1H- imidazol-5-ylacetyl)amino-3(S)-methylpentyl]-N- 1 - naphthylmethyl-glycyl-methionine methyl ester bis trifluoroacetate (20)
  • Step A Preparation of N-[2(S)-(1-(2-Naphthylmethyl)-1H-imidazol- 5-ylacetyl)amino-3(S)-methylpentyl]-N-1-naphthylmethyl- glycyl-methionine methyl ester bis trifluoroacetate
  • Step B Preparation of N-[2(S)-(1-(2-Naphthylmethyl)-1H- imidazol-5-ylacetyl)amino-3(S)-methylpentyl]-N-1- naphthylmethyl-glycyl-methionine bis trifluoroacetate
  • Step E but using the methyl ester prepared as described in Step A provided the titl e compound.
  • Step A Preparation of N-[2( S)-(1-(1-Naphthylmethyl)-1H-imidazol- S-ylacetyl)ammo-3 -methylpentyl]-N-1-naphthylmethyl- glycyl-methionine methyl ester bis trifluoroacetate Following the procedure described in Example 3, Steps A-D, but using 1 -(bromomethyl)naphthlene in place of 4-nitrobenzylbromide provided the title compound.
  • Step B Preparation of N-[2(S)-(1-(1-Naphthylmethyl)-1H-imidazol- 5-ylacetyl)amino-3(S)-methylpentyl]-N-1-naphthylmethyl- glycyl-methionine bis trifluoroacetate
  • Step B Preparation of N-[2(S)-(1-(1-Farnesyl)-1H-imidazol-5- ylacetyl)amino-3(S)-methylpentyl]-N-1-naphthylmethyl - glycyl-methionine methyl ester bis trifluoroacetate
  • Step C Preparation of N-[2(S)-[1-(1-Famesyl)-1H-imidazol-5- ylacetyl]amino-3(S)-methylpentyl]-N-1-naphthylmethyl - glycyl-methionine bis trifluoroacetate
  • Step E but using the methyl ester prepared as described in Step B provided the title compound.
  • Step A Preparation of N-[2(S)-(1-Geranyl-1H-imidazol-5- ylacetyl)amino-3(S)-methylpentyl]-N-1-naphthylmethyl - glycyl-methionine methyl ester bis trifluoroacetate
  • Step B Preparation of N-[2(S)-(1-Geranyl-1H-imidazol-5- ylacetyl)amino-3(S)-methylpentyl]-N-1 -naphthylmethyl - glycyl-methionine bis trifluoroacetate
  • Step A Preparation of 1-(4-Pyridylmethyl)-1H-imidazol-4-ylacetic acid methyl ester (24) and 1 -(4-PyridyImethyl)-1H-imidazol-
  • Step B Preparation of N-[2(S)-(1-(4-Pyridylmethyl)-1H-imidazol-4- ylacetyl)amino-3(S)-methylpentyl]-N-1-naphthylmethyl- glycyl-methionine methyl ester tris trifluoroacetate (26) and N-[2(S)-(1-(4-Pyridylmethyl)-1H-imidazol-5- ylacetyl)amino-3(S)-methylpentyl]-N-1-naphthylmethyl- glycyl-methionine methyl ester tris trifluoroacetate (27) Following the procedure described in Example 2, Steps B-C, but using the mixture of pyridylmethylimidazolylacetic acid from Step A provided the title compounds after preparative HPLC.
  • Step C Preparation of N-[2(S)-(1 -(4-Pyridylmethyl)-1H-imidazol-4- ylacetyl)amino-3(S)-methylpentyl]-N-1-naphthylmethyl- glycyl-methionine methyl ester tris trifluoroacetate (28) Following the procedure described in Example 2, Step D, but using the methyl ester 26 prepared as described in Step B provided the title compound.
  • Step D Preparation of N-[2(S)--(1 -(4-PyridyImethyl)-1H-imidazol- 5-ylacetyl)amino-3(S)-methylpentyl]-N-1-naphthylmethyl- glycyl-methionine tris trifluoroacetate (29)
  • Step A Preparation of N-[2(S)-(1-(4-Cyanophenylmethyl)- 1 H- imidazol-5-ylacetyl)amino-3(S)-methylpentyl]-N-1- naphthylmethyl-glycyl-methionine methyl ester bis trifluoroacetate
  • Step B Preparation of N-[2(S)-(1-(4-Cyanophenylmethyl)-1H- imidazol-5-ylacetyl)amino-3(S)-methylpentyl]-N-1- naphthylmethyl-glycyl-methionine bis trifluoroacetate
  • Step A Preparation of N-[2(S)-(1-(4-Methoxyphenylmethyl)-1H-imidazol-5- ylacetyl)amino-3(S)-methylpentyl]-N-1-naphthylmethyl-glycyl- methionine bis trifluoroacetate
  • Step A Preparation of N-[2(S)-(1 -(4- Methoxyphenylmethyl)-1H- imidazol-5-yl)acetyl)amino-3(S)-methylpentyl]-N-1- naphthylmethyl-glycyl-methionine methyl ester bis trifluoroacetate
  • Step B Preparation of N-[2(S)-(1-(4-Methoxyphenylmethyl)-1H- imidazol-5-ylacetyl)amino-3(S)-methylpentyl]-N-1- naphthylmethyl-glycyl-methionine bis trifluoroacetate
  • Step A Preparation of N-[2(S)-(1-(4-Quinolinylmethyl)-1H-imidazol-5- ylacetyl)amino-3(S)-methylpentyl]-N-1-naphthylmethyl-glycyl- methionine bis trifluoroacetate
  • Step A Preparation of N-[2(S)-(1-(4-Quinolinylmethyl)-1H- imidazol-5-ylacetyl)amino-3(S)-methylpentyl]-N-1- naphthylmethyl-glycyl-methionine methyl ester bis trifluoroacetate
  • Step B Preparation of N-[2(S)-(1-(4-Quinolinylmethyl)-1H- imidazol-5-ylacetyl)amino-3(S)-methylpentyl]-N-1- naphthylmethyl-glycyl-methionine bis trifluoroacetate
  • Step A Preparation of N-[2(S)-(1-(2-Naphthylmethyl)-1H-imidazol- 5-ylacetyl)amino-3(S)-memylpentyl]-N-1-phenylmethyl- glycyl-methionine methyl ester bis trifluoroacetate
  • Step B Preparation of N-[2(S)-(1-(2-Naphthylmethyl)-1H-imidazol- 5-ylacetyl)amino-3(S)-methylpentyl]-N-1-phenylmethyl- glycyl-methionine bis trifluoroacetate
  • Step B 1 -(2-Naphthylmethyl)-1H-imidazol-5-ylacetaldehyde (30)
  • Step C Preparation of N-[2(S)-(1-(2-Naphthylmethyl)-1H-imidazol- 5-ylethyl)amino-3(S)-methylpentyl]-N-1-naphthylmethyl - glycyl-methionine methyl ester bis trifluoroacetate
  • Step D Preparation of N-[2(S)-(1-(2-Naphthylmethyl)-1H-imidazol- 5-ylethyl)ammo-3(S)-methylpentyl]-N-1-naphthylmethyl- glycyl-methionine bis trifluoroacetate
  • Step C Preparation of N-(tert-butoxycarbonyl)-5(S)-[1(S)- methyl]propyl-2,3,5,6-tetrahydro-4H-1,4-oxazin-3-one.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biochemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Animal Behavior & Ethology (AREA)
  • Molecular Biology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention porte sur des analogues du motif CAAX de la protéine Ras modifiés in vivo par farnésylation. Lesdits analogues, qui inhibent la farnésylation de la Ras, diffèrent par ailleurs de ceux précédemment décrits comme inhibiteurs de la Ras farnésyle transférase en ce qu'ils ne présentent pas de fraction thiol. Cette absence de thiol offre des avantages uniques en matière d'amélioration du comportement pharmacocinétique chez les animaux, de prévention des réactions chimiques liées aux thiols telles que la rapidité de l'auto-oxydation, la formation de bisulfures avec les thiols endogènes et une toxicité systémique réduite. L'invention porte également sur des compositions chimiothérapeutiques contenant les susdits inhibiteurs et sur leur procédé d'obtention.
PCT/US1995/012224 1994-09-29 1995-09-26 Inhibiteurs de la transferase de proteines farnesylees exempts de thiol WO1996010034A2 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP95935104A EP0783517A2 (fr) 1994-09-29 1995-09-26 Inhibiteurs de la transferase de proteines farnesylees exempts de thiol
CA 2201348 CA2201348A1 (fr) 1994-09-29 1995-09-26 Inhibiteurs de la transferase de proteines farnesylees exempts de thiol
AU37248/95A AU700175B2 (en) 1994-09-29 1995-09-26 Thiol-free inhibitors of farnesyl-protein transferase
JP8511933A JPH10508005A (ja) 1994-09-29 1995-09-26 チオールを有しないファルネシル−タンパク質トランスフェラーゼ阻害剤

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US526,244 1990-05-18
US31497494A 1994-09-29 1994-09-29
US314,974 1994-09-29
US08/526,244 US5652257A (en) 1994-09-29 1995-09-21 Heterocycle-containing inhibitors of farnesyl-protein transferase

Publications (2)

Publication Number Publication Date
WO1996010034A2 true WO1996010034A2 (fr) 1996-04-04
WO1996010034A3 WO1996010034A3 (fr) 1996-05-09

Family

ID=26979651

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1995/012224 WO1996010034A2 (fr) 1994-09-29 1995-09-26 Inhibiteurs de la transferase de proteines farnesylees exempts de thiol

Country Status (5)

Country Link
EP (1) EP0783517A2 (fr)
JP (1) JPH10508005A (fr)
AU (1) AU700175B2 (fr)
IL (1) IL115471A0 (fr)
WO (1) WO1996010034A2 (fr)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0880320A4 (fr) * 1996-01-30 1999-06-16 Merck & Co Inc Inhibiteurs de la farnesyl-proteine transferase
US5932590A (en) * 1996-12-05 1999-08-03 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
EP0904080A4 (fr) * 1996-04-03 2001-08-01 Merck & Co Inc Inhibiteurs de farnesyle-proteine transferase
EP0891353A4 (fr) * 1996-04-03 2001-08-08 Merck & Co Inc Inhibiteurs de farnesyle-proteine transferase
EP0891352A4 (fr) * 1996-04-03 2001-08-16 Merck & Co Inc Inhibiteurs de la farnesyl-proteine transferase
EP0944388A4 (fr) * 1996-04-03 2001-08-16 Merck & Co Inc Inhibiteurs de la farnesyl-proteine transferase
EP0891335A4 (fr) * 1996-04-03 2001-08-16 Merck & Co Inc Inhibiteurs de transferase de farnesyl-proteine
EP1507549A4 (fr) * 2002-05-14 2009-07-01 Univ Leland Stanford Junior Pharmacotherapie destinee a une maladie coeliaque
US7776545B2 (en) 2002-11-20 2010-08-17 The Board Of Trustees Of The Leland Stanford Junior University Diagnostic method for Celiac Sprue
US7910541B2 (en) 2002-02-14 2011-03-22 The Board Of Trustees Of The Leland Stanford Junior University Enzyme treatment of foodstuffs for celiac sprue
US8143210B2 (en) 2002-02-14 2012-03-27 The Board Of Trustees Of The Leland Stanford Junior University Enzyme treatment of foodstuffs for celiac sprue
US8153593B2 (en) 2003-11-18 2012-04-10 The Board Of Trustees Of The Leland Stanford Junior University Transglutaminase inhibitors and methods of use thereof
US8778338B2 (en) 2007-03-16 2014-07-15 The Board Of Trustees Of The Leland Stanford Junior University Combination enzyme therapy for digestion of dietary gluten

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5141851A (en) * 1990-04-18 1992-08-25 Board Of Regents, The University Of Texas System Isolated farnesyl protein transferase enzyme
US5468733A (en) * 1993-09-30 1995-11-21 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
KR100362338B1 (ko) * 1993-11-05 2003-04-08 워너-램버트 캄파니 단백질:파르네실트랜스퍼라아제의치환디-및트리펩티드억제제

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0880320A4 (fr) * 1996-01-30 1999-06-16 Merck & Co Inc Inhibiteurs de la farnesyl-proteine transferase
EP0904080A4 (fr) * 1996-04-03 2001-08-01 Merck & Co Inc Inhibiteurs de farnesyle-proteine transferase
EP0891353A4 (fr) * 1996-04-03 2001-08-08 Merck & Co Inc Inhibiteurs de farnesyle-proteine transferase
EP0891352A4 (fr) * 1996-04-03 2001-08-16 Merck & Co Inc Inhibiteurs de la farnesyl-proteine transferase
EP0944388A4 (fr) * 1996-04-03 2001-08-16 Merck & Co Inc Inhibiteurs de la farnesyl-proteine transferase
EP0891335A4 (fr) * 1996-04-03 2001-08-16 Merck & Co Inc Inhibiteurs de transferase de farnesyl-proteine
US5932590A (en) * 1996-12-05 1999-08-03 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
US7923532B2 (en) 2002-02-14 2011-04-12 The Board Of Trustees Of The Leland Stanford Junior University Methods for diagnosing celiac sprue and reagents useful therein
US8143210B2 (en) 2002-02-14 2012-03-27 The Board Of Trustees Of The Leland Stanford Junior University Enzyme treatment of foodstuffs for celiac sprue
US7910541B2 (en) 2002-02-14 2011-03-22 The Board Of Trustees Of The Leland Stanford Junior University Enzyme treatment of foodstuffs for celiac sprue
US8962545B2 (en) 2002-02-14 2015-02-24 The Board Of Trustees Of The Leland Stanford Junior University Enzyme treatment of foodstuffs for celiac sprue
US7928056B2 (en) 2002-02-14 2011-04-19 The Board Of Trustees Of The Leland Stanford Junior University Enzyme treatment of foodstuffs for Celiac Sprue
US7943312B2 (en) 2002-02-14 2011-05-17 The Board Of Trustees Of The Leland Stanford Junior University Enzyme treatment of foodstuffs for celiac sprue
US8796201B2 (en) 2002-02-14 2014-08-05 The Board Of Trustees Of The Leland Stanford Junior University Enzyme treatment of foodstuffs for celiac sprue
EP1507549A4 (fr) * 2002-05-14 2009-07-01 Univ Leland Stanford Junior Pharmacotherapie destinee a une maladie coeliaque
US7776545B2 (en) 2002-11-20 2010-08-17 The Board Of Trustees Of The Leland Stanford Junior University Diagnostic method for Celiac Sprue
US8426145B2 (en) 2002-11-20 2013-04-23 The Board Of Trustees Of The Leland Stanford Junior University Diagnostic method for celiac sprue
US8071316B2 (en) 2002-11-20 2011-12-06 The Board Of Trustees Of The Leland Stanford Junior University Diagnostic method for celiac sprue
US8153593B2 (en) 2003-11-18 2012-04-10 The Board Of Trustees Of The Leland Stanford Junior University Transglutaminase inhibitors and methods of use thereof
US8470782B2 (en) 2005-08-26 2013-06-25 The Board Of Trustees Of The Leland Stanford Junior University Transglutaminase inhibitors and methods of use thereof
US8871718B2 (en) 2005-08-26 2014-10-28 The Board Of Trustees Of The Leland Stanford Junior University Transglutaminase inhibitors and methods of use thereof
US8778338B2 (en) 2007-03-16 2014-07-15 The Board Of Trustees Of The Leland Stanford Junior University Combination enzyme therapy for digestion of dietary gluten

Also Published As

Publication number Publication date
AU700175B2 (en) 1998-12-24
JPH10508005A (ja) 1998-08-04
AU3724895A (en) 1996-04-19
WO1996010034A3 (fr) 1996-05-09
IL115471A0 (en) 1995-12-31
EP0783517A2 (fr) 1997-07-16

Similar Documents

Publication Publication Date Title
AU701763B2 (en) Inhibitors of farnesyl protein transferase
US5869682A (en) Inhibitors of farnesyl-protein transferase
US5578629A (en) Benzamide-containing inhibitors of farnesyl-protein transferase
US5585359A (en) Inhibitors of farnesyl-protein transferase
US5534537A (en) Prodrugs of inhibitors of farnesyl-protein transferase
US5576293A (en) Inhibitors of farnesyl-protein transferase
US5491164A (en) Inhibitors of farnesyl-protein transferase
WO1997038664A2 (fr) Methode de traitement de cancer
US5571835A (en) Inhibitors of farnesyl-protein transferase
US5624936A (en) Inhibitors of farnesyl-protein transferase
WO1996010034A2 (fr) Inhibiteurs de la transferase de proteines farnesylees exempts de thiol
AU2660797A (en) Inhibitors of farnesyl-protein transferase
WO1996034010A2 (fr) Inhibiteurs de la farnesyle transferase
US5523456A (en) Inhibitors of farnesyl-protein transferase
US5627202A (en) Inhibitors of farnesyl-protein transferase
US5652257A (en) Heterocycle-containing inhibitors of farnesyl-protein transferase
WO1996031525A2 (fr) Inhibiteurs de la farnesyl-proteine transferase
CA2201348A1 (fr) Inhibiteurs de la transferase de proteines farnesylees exempts de thiol
EP0837875A2 (fr) Inhibiteurs de la farnesyle transferase
EP0837857A2 (fr) Inhibiteurs de la farnesyl-proteine transferase
AU5428596A (en) Inhibitors of farnesyl-protein transferase
CA2201346A1 (fr) Inhibiteurs de farnesyle-proteine transferase
JPH11502822A (ja) ファルネシル−タンパク質トランスフェラーゼ阻害剤

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AM AU BB BG BR BY CA CN CZ EE FI GE HU IS JP KG KR KZ LK LR LT LV MD MG MK MN MX NO NZ PL RO RU SG SI SK TJ TM TT UA UG US US UZ

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): KE MW SD SZ UG AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 1995935104

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2201348

Country of ref document: CA

Ref country code: CA

Ref document number: 2201348

Kind code of ref document: A

Format of ref document f/p: F

WWP Wipo information: published in national office

Ref document number: 1995935104

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1995935104

Country of ref document: EP

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载