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 must be localized to the plasma membrane for both normal and oncogenic functions. At least 3 post-translational modifications are involved with Ras membrane localization, and all 3 modifications occur at the C-terminus of Ras.
• the Ras C-terminus contains a sequence motif termed a "CAAX” or "Cys-Aaa ⁇ -Aaa- ⁇ -Xaa” box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al, Nature 370:583-586 (1984)).
• this motif serves as a signal sequence for the enzymes farnesyl-protein transferase or geranylgeranyl-protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a C15 or C20 isoprenoid, respectively.
• the Ras protein is one of several proteins that are known to undergo post-trans lational famesylation.
• farnesylated proteins include the Ras-related GTP-binding proteins such as Rho, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin. James, et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisome associated protein Pxf which is also farnesylated. James, et al., have also suggested that there are farnesylated proteins of unknown structure and function in addition to those listed above. Inhibition of farnesyl-protein transferase has been shown to block the growth of Ras-transformed cells in soft agar and to modify other aspects of their transformed phenotype.
• 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 potentially places limitations on the therapeutic application of FPTase inhibitors with respect to pharmacokinetics, pharmacodynamics and toxicity. Therefore, a functional replacement for the thiol is desirable.
• 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:
• Rl is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, RlOO-, Rl lS(0) m -, R10C(0)NR 0-, CN, N02,
• R2a and R2b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C 1 -C20 alkyl, C2-C2O alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, Rl°0-, Rl !S(0) m -, R10C(0)NR1 -, CN, (RlO) 2 N-C(NRlO)-, RlOC(O)-, RlO ⁇ C(O)-, N3, -N(Rl0)2, R 0C(0)NR10- and -C20 alkyl, and d) C1-C6 alkyl substituted with an
• R2a and R2b are combined to form - (CH2)s - ;
• R3 and R4 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted Ci -C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(Rl )2, N ⁇ 2, Rl°0-, Rl l S(0) m -, R10C(0)NR1 -, CN, (RlO) 2 N-C(NRlO)-, RlOc(O)-, R lO ⁇ C(O)-, N3, -N(R lO)2, Rl lOC(O)NRl0- and C1-C20 alkyl, and d) C1
• R3 and R4 are combined to form - (CH2)s - ;
• R5a and R5b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C20 alkyl, C 2 -C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N(RlO)2, N02, Rl°0-, Rl lS(0) m -, R !0C(O)NR10-, CN, (RlO) 2 N-C(NRlO)-, RlOC(O)-, RlO ⁇ C(O)-, N3, -N(RlO)2, Rl lOC(O)NRl -, -S ⁇ 2N(RlO)
• R ⁇ a and R5b are combined to form - (CH2)s - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(0)m, -NC(O)-, and -N(COR lO)- ; or
• R5a or R5b are combined with R 14 to form a ring such that
• R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl;
• R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstit
• R8 is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, R J lS(0) m -.
• R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, RlOC(0)NRl -, CN, N02, (Rl°)2N- C(NRlO)-, RlOC(O)-, RlO ⁇ C(O)-, N3, -N(RlO) 2 , or Rl lOC(O)NRl0-, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, Rl O-, Rl lS(0) m -, R10C(O)NR 10-, CN, (RlO)2N-C(NRl )., RIOC(O)-,
• RlO is independently selected from hydrogen, -C6 alkyl and aryl
• R 1 1 is independently selected from Cl -C alkyl and aryl
• Rl2 is independently selected from hydrogen and C1 -C6 alkyl
• Rl4 is independently selected from hydrogen,Cl -C6 alkyl and benzyl
• Rl5 is independently selected from hydrogen and -C6 alkyl
• V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 non-terminal carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl ; provided that V is not hydrogen if Al is S(0) and V is not hydrogen if A 1 is a bond, n is 0 and A is S(0)m or a bond;
• W is a heterocycle; Z is independently H2 or O; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 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; and t is 3, 4 or 5;
• Rl is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, RlOO-, Rl lS(0) m -, R10C(0)NR10-, CN, N02, (Rl )2N-C(NRlO)-, Rl C(O)-, RlO ⁇ C(O)-, N3, -N(RlO)2, or Rl l ⁇ C(O)NRl0-, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, RlOO-,
• R2a and R2b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C20 alkyl, C2-C2O alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, Rl°0-, R lS(0)m-.
• R2a and R2b are combined to form - (CH2)s - ;
• R4 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1 -C2O alkyl, C2-C2O alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br,
• R3 and R4 are combined to form - (CH2)s - .
• R5a and R5b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1-C20 alkyl, C2-C2O alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N(Rl0)2, N ⁇ 2, Rl°0-, Rl lS(0) m -, R10C(O)NR10-,
• R5a and R5b are combined to form - (CH2)s - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(0)m . -NC(O)-, and -N(COR l )- ; or
• R5a or R5b are combined with R 14 to form a ring such that
• R6 i is a) substituted or unsubstituted C1-C8 alkyl, wherein the substituent on the alkyl is selected from: D aryl, 4) -OR 10, or
• R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl;
• R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstit
• R8 is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, RlOC(0)NRlO-, CN, N ⁇ 2, Rl°2N-C(NRl )-, RlOC(O)-, RlO ⁇ C(O)-, N3, -N(RlO) 2 , or
• Rl l ⁇ C(O)NRl0- and c) C 1 -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl l S(0) m -, Rl C(0)NH-, CN, H2N-C(NH)-, RlOC(O)-, R lO ⁇ C(O)-, N3, -N(R l0)2, or R l l ⁇ C(0)NH-;
• R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, R l lS(0) m -, R l0C(O)NRl0-, CN, N02, (Rl°)2N- C(N lO)-, RlOc(O)-, RlO ⁇ C(O)-, N3, -N(RlO) 2 , or Rl lOC(O)NRl0-, and c) C l -C ⁇ alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RlOO-, Rl l S(0) m -, Rl0C(O)NRl0-, CN, (RlO) 2 N-C(NRlO)-, RlOC(O)-, RlO ⁇ C(O)-, N3, -N(R lO) 2 , or R
• RlO is independently selected from hydrogen, C1-C6 alkyl and aryl
• Rl 1 is independently selected from -C6 alkyl and aryl
• Rl2 is independently selected from' hydrogen and C1 -C6 alkyl
• R 3 is independently selected from Cl-C6 alkyl
• Rl4 is independently selected from hydrogen,Ci-C6 alkyl and benzyl
• Rl5 is independently selected from hydrogen and C1 -C6 alkyl
• V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 non-terminal carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl ; provided that V is not hydrogen if Al is S(0)m and V is not hydrogen if A 1 is a bond, n is 0 and A is S(0)m or a bond;
• W is a heterocycle
• Z is independently H2 or O
• n 0, 1 , 2, 3 or 4
• p 0, 1 , 2, 3 or 4
• r 0 to 5, provided that r is 0 when V is hydrogen; s is 4 or 5; and t is 3, 4 or 5;
• Rl is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, RlOO-, Rl lS(0) m -, R!0C(O)NR10-, CN, N02, (RlO)2N-C(NRlO)-, RlOC(O)-, R10OC(O , N3, -N(RlO)2, or Rl l ⁇ C(O)NRl0-, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, Rl ⁇ O-,
• R2a and R2b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted Cl -C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br,
• R2a and R2b are combined to form - (CH2)s - ;
• R3 and R4 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C1-C20 alkyl, C2-C2O alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(RlO)2, N02, Rl°0-, Rl lS(0) m -, R10C(O)NR10-,
• R3 and R4 are combined to form - (CH2)s - .
• R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl;
• R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C 1 -C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and Cl-C6 alkyl substituted with hydrogen or an unsubstitute
• R 8 is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, Rl0C(O)NRl0-, CN, N02, R 10 2N-C(NR O)-, RlOC(O)-, Rl ⁇ C(O)-, N3, -N(RlO) 2 , or Rl lOC(O)NRl0-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -,
• R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0)m-, Rl°C(O)NRl0., CN, NO2, (Rl°)2N- C(NRl )., RlOc(O)-, RlO ⁇ C(O)-, N3, -N(RlO) 2 , or Rl lOC(O)NRl0-, and c) C 1 -C ⁇ alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, Rl0C(O)NRl0-, CN, (RlO) 2 N-C(NRlO)-, R lOc(O)-, RlO ⁇ C(O)-, N3, -N(R lO)2, or Rl lOC(O)
• RlO is independently selected from hydrogen, C1-C6 alkyl and aryl
• Rl 1 is independently selected from -C6 alkyl and aryl
• Rl2 is independently selected from hydrogen and C1 -C6 alkyl
• Rl4 is independently selected from hydrogen,C ⁇ -Q5 alkyl and benzyl
• V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) Cl -C20 alkyl wherein from 0 to 4 non-terminal carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl ; provided that V is not hydrogen if A 1 is S(0)m and V is not hydrogen if A 1 is a bond, n is 0 and A2 is S(0)m or a bond;
• W is a heterocycle
• Z is independently H2 or O
• 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; and s is 4 or 5;
• Rl is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, RlOo-, Rl lS(0)m-_ R 10 C(O)NRl0-, CN, N ⁇ 2, (RlO)2N-C(NRlO)-, RlOC(O)-, RlO ⁇ C(O)-, N3, -N(Rl0)2, or Rl lOC(O)NRl0-, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, Rl ⁇ O-,
• R2a and R2b are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C1 -C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br,
• R 10 C(O)NRl0-, CN, (Rl ) 2 N-C(NRlO)-, RlOc(O)-, RlO ⁇ C(O)-, N3, -N(Rl ) 2 , Rl l ⁇ C(O)NRl0- and C1 -C20 alkyl, and d) C1 -C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-
• Cio cycloalkyl or
• R2a and R2b are combined to form - (CH2)s - ;
• R3 and R4 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C1-C2O alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(RlO)2, N02, Rl°0-, Rl lS(0)m-, R1°C(0)NR 10.,
• R3 and R4 are combined to form - (CH2)s - ;
• R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl;
• R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstitute
• R8 is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R lOO-, Rl lS(0) m -, Rl0C(O)NRl0-, CN, N02, R1°2N-C(NR10)-, Rl C(O)-, Rl ⁇ C(O)-, N3, -N(Rl ) 2 , or Rl l ⁇ C(O)NRl0-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -,
• R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0)m-, R 10C(O)NR1 -, CN, N ⁇ 2, (Rl°)2N- C(NRlO)-, RlOC(O)-, RlO ⁇ C(O)-, N3, -N(Rl ) 2 , or Rl lOC(O)NRl0-, and c) C 1 -C ⁇ alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0) m -, Rl0C(O)NRl0-, CN, (RlO) 2 N-C(NRlO)-, RlOc(O)-, RlO ⁇ C(O)-, N3, -N(R l ) 2 , or R HOC(0)NR10-
• RlO is independently selected from hydrogen, C1-C6 alkyl and aryl
• Rl 1 is independently selected from -C6 alkyl and aryl
• Rl is independently selected from hydrogen and -C6 alkyl
• Rl4 is independently selected from hydrogen,Cl -C6 alkyl and benzyl
• V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 non-terminal carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl ; provided that V is not hydrogen if A 1 is S(0)m and V is not hydrogen if A 1 is a bond, n is 0 and A2 is S(0)m or a bond;
• W is a heterocycle
• Z is independently H2 or O
• 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; and s is 4 or 5;
• Ras famesyl transferase inhibitors are illustrated by the formula I:
• Rl is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, RlOO-, -N(RlO)2 or alkenyl, c) C1 -C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, RlOO-, or -N(RlO)2;
• R2a is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from alanine, leucine, isoleucine and valine; b) substituted or unsubstituted C l -C 10 alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, R 10 O-, Rl lS(0) m -, R 10 C(O)NRl0_.
• Cio cycloalkyl Cio cycloalkyl
• R2b is selected from hydrogen and C1-C6 alkyl
• R2a and R2b are combined to form - (CH2)s - ;
• R3 and R4 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted Cj-Cio alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, Rl°0-, Rl lS(0) m -, RlOC(0)NRlO-, CN, (Rl ) 2 N-C(NRlO)., RlOc(O)-, RlO ⁇ C(O)-, N3, -N(RlO) 2 , Rl lOC(O)NRl0- and C1-C20 alkyl, and d) C1-C6 alkyl substitute
• R5a is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from methionine and glutamine, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted C 1 -C 10 alkyl, C2-C 10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, Rl°0-, Rl lS(0)m-, R1 C(O)NR10-, CN, (RlO) 2 N-C(NRlO)-, RlOc(O)-, RlO ⁇ C(O)-, N3, -N(Rl ) 2 , Rl lOC(O)NRl0-, -S ⁇ 2N(R
• Rl ISO2NRIO- and -C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3- C 10 cycloalkyl;
• R5b i selected from: a) hydrogen, and b) C ⁇ -C3 alkyl; or
• R5a or R5b are combined with R 14 to form a ring such that
• R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl;
• R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and Cl-C6 alkyl substituted with hydrogen or an unsubstituted or
• R8 is selected from: a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl -C6 perfluoroalkyl, F, Cl, RlOO-, R10C(O)NR10-, CN, N02, (RlO)2N-C(NRlO)-, R10C(O)-, RlO ⁇ C(O)-, -N(Rl )2, or Rl l ⁇ C(O)NRl0-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, RlOo-, Rl0c(O)NRl0., (RlO) 2 N-C(NRlO)-, RlOC(O)-, Rl ⁇ C(O)-, -N(RlO)2, or Rl l ⁇ C(O)NRl - ;
• R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, RlOO-, Rl lS(0) m -, R 1 C(O)NR10-, CN, NO2,
• RlO is independently selected from hydrogen, C1-C6 alkyl and aryl
• Rl 1 is independently selected from Cl -C ⁇ alkyl and aryl
• Rl2 is independently selected from hydrogen and -C6 alkyl
• Rl4 is independently selected from hydrogen and -C6 alkyl
• Rl5 is independently selected from hydrogen and C1-C6 alkyl
• V is selected from: a) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, b) aryl, c) C1-C20 alkyl wherein from 0 to 4 non-terminal carbon atoms are replaced with a heteroatom selected from O, S, and N, and d) C2-C20 alkenyl; provided that V is not hydrogen if A 1 is S(0)m and V is not hydrogen if A 1 is a bond, n is 0 and A2 is S(0)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 H2 or O
• n 0, 1, 2, 3 or 4
• p 0, 1, 2, 3 or 4
• r 0 to 2
• s is 4 or 5
• t 3, 4 or 5;
• the prodrugs of the preferred compounds of formula I are illustrated by the formula II: (R I 8 )r ⁇ Z R 2a R 2b Z R 5a R 5b
• Rl is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, R 10 ⁇ -, -N(R 10)2 or alkenyl, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, RlOO-, or -N(RlO)2;
• R2a is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from alanine, leucine, isoleucine and valine; b) substituted or unsubstituted Cl- o alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, Rl°0-, Rl lS(0) m -, R !0C(O)NR 10-, CN, (Rl ) 2 N-C(NRlO)-, RlOC(O)-, R lO ⁇ C(O)-, N3, -N(Rl )2, Rl l ⁇ C(O)NRl0- and C1-C20 alkyl, and c) C l -C ⁇ alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-
• R2b is selected from hydrogen and Cl-C ⁇ alkyl
• R2a and R2b are combined to form - (CH2)s - ;
• R3 and R4 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted Cl-ClO alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N ⁇ 2, Rl°0-, Rl lS(0)m-, R1°C(0)NR10-, CN, (Rl0)2N-C(NRl0)-, RlOC(O)-, RlOoC(O)-, N3, -N(R lO)2, Rl lOC(O)NRl0- and -C20 alkyl, and d) C1-C6 alkyl substituted with an unsub
• R5a is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from methionine and glutamine, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, and c) substituted or unsubstituted Cl -ClO alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br,
• R5a is selected from: a) hydrogen, and b) Cl-C3 alkyl; or
• R5a or R5b are combined with R 14 to form a ring such that
• heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl;
• R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C 1 -C ⁇ alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C 1 -C6 alkyl substituted with hydrogen or an unsub
• R8 is selected from: a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1 -C6 perfluoroalkyl, F, Cl, R l O-, R1 C(O)NR10-, CN, N02, (R1°)2N-C(NR10)-, RlOc(O)-, RlO ⁇ C(O)-, -N(RlO)2, or Rl l ⁇ C(O)NRl0-, and c) Cl-Cfe alkyl substituted by C1 -C6 perfluoroalkyl, Rl O-, Rl0C(O)NRl0-, (R 10) 2 N-C(NR10)-, RlOc(O)-,
• R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, Rl O-, Rl lS(0) m -, R!
• R 1 is independently selected from hydrogen, C l -C6 alkyl and aryl;
• Rl 1 is independently selected from C1-C6 alkyl and aryl
• Rl2 is independently selected from hydrogen and Cl -C ⁇ alkyl
• Rl3 is 1 ,1-dimethylethyl
• Rl4 is independently selected from hydrogen and C1 -C6 alkyl
• Rl ⁇ is independently selected from hydrogen and Cl -C6 alkyl
• V is selected from: a) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, b) aryl, c) C 1 -C20 alkyl wherein from 0 to 4 non-terminal carbon atoms are replaced with a heteroatom selected from O, S, and N, and d) C2-C2O alkenyl; provided that V is not hydrogen if Al is S(0) m and V is not hydrogen if A 1 is a bond, n is 0 and A is S(0)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 H2 or O
• n 0, 1, 2, 3 or 4
• p 0, 1, 2, 3 or 4
• r 0 to 2
• s is 4 or 5
• t 3, 4 or 5;
• inhibitors of famesyl transferase are illustrated by the formula HI:
• R 1 is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, Rl O-, -N(R l )2 or alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, Rl O-, or -N(RlO)2;
• R2a is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from alanine, leucine, isoleucine and valine; b) substituted or unsubstituted Cl-ClO alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br,
• Cio cycloalkyl Cio cycloalkyl
• R2b is selected from hydrogen and C1 -C6 alkyl
• R a and R2b are combined to form - (CH2)s - ;
• R3 and R4 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted Cl-ClO alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br,
• R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl;
• R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and Cl-C6 alkyl substituted with hydrogen or an unsubstitute
• R8 is selected from: a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci -C ⁇ perfluoroalkyl, F, Cl, Rl O-, R1 C(0)NR _, CN,
• R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, RlOO-, Rl lS(0) m -, R!0C(O)NR1 -, CN, N02, (R10) 2 N-C(NR10)-, RlOc(O)-, RlO ⁇ C(O)-, -N(Rl )2, or Rl lOC(O)NRl0-, and c) C1-C6 alkyl unsubstituted or substituted by C1-C6 perfluoroalkyl, F, Cl, RlOO-, Rl !S(0)m-, Rl0c(O)NRl0-, CN, (RlO) 2 N-C(NRlO)-, R lOc(O)-, RlO ⁇ C(O)-, -N(Rl ) 2 , or Rl
• RlO is independently selected from hydrogen, C1 -C6 alkyl and aryl
• R l 1 is independently selected from C1-C6 alkyl and aryl;
• Rl2 is independently selected from hydrogen and Cl -C6 alkyl
• R l4 is independently selected from hydrogen and C1 -C6 alkyl
• V is selected from: a) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, b) aryl, c) C1-C20 alkyl wherein from 0 to 4 non-terminal carbon atoms are replaced with a heteroatom selected from O, S, and N, and d) C2-C20 alkenyl; provided that V is not hydrogen if Al is S(0)m and V is not hydrogen if A 1 is a bond, n is 0 and A2 is S(0)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 H2 or O
• 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;
• R1 is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, RlOO-, -N(R l0)2 or alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, RlOO-, or -N(RlO)2;
• R2a is selected from: a) a side chain of a naturally occurring amino acid, wherein the amino acid is selected from alanine, leucine, isoleucine and valine; b) substituted or unsubstituted Cl-ClO alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, RlOO-, Rl lS(0)m-. R1°C(0)NR10-, CN,
• R2b is selected from hydrogen and C1 -C6 alkyl
• R2a and R2b are combined to form - (CH2)s - .
• R3 and R4 are independently selected from: a) a side chain of a naturally occurring amino acid, b) an oxidized form of a side chain of a naturally occurring amino acid which is: i) methionine sulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted Cl-ClO alkyl, C2-C10 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N ⁇ 2, Rl°0-, Rl lS(0) ⁇ r, R1°C(0)NR10-, CN, (R10) N-C(NR10)-, RlOC(O)-, RlO ⁇ C(O)-, N3, -N(Rl ) 2 , Rl lOC(O)NRl0- and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstitute
• R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2- oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl;
• R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocyclic, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C l -C ⁇ alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocyclic and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocyclic, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsub
• R8 is selected from: a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1 -C6 perfluoroalkyl, F, Cl, RlOO-, R!0C(O)NR10-, CN, N ⁇ 2, (R10) 2 N-C(NR10)., RlOc(O)-, RlO ⁇ C(O)-, -N(RlO) 2 , or Rl l ⁇ C(O)NRl0_, and c) C 1 -C6 alkyl substituted by C 1 -C6 perfluoroalkyl,
• RIOQ. Rl0c(O)NRl0-, (R10)2N-C(NR10)-, Rl°C(0)-, Rl ⁇ C(O)-, -N(Rl ) 2 , or Rl 10C(0)NR 10-;
• R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, RlOO-, Rl lS(0)m-, R 1°C(0)NR 10-, CN, N02, (Rl0) 2 N-C(NRl0)-, Rl0c(O)-, RlO ⁇ C(O)-, -N(Rl ) 2 , or Rl OC(O)NRl0-, and c) C l -C6 alkyl unsubstituted or substituted by C 1 -C6 perfluoroalkyl, F, Cl, Rl O-, Rl l S(0) m -.
• Rl is independently selected from hydrogen, C1-C6 alkyl and aryl
• Rl is independently selected from C1-C6 alkyl and aryl
• Rl2 is independently selected from hydrogen and C1-C6 alkyl
• Rl4 is independently selected from hydrogen and C1-C6 alkyl
• V is selected from: a) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, b) aryl, c) C1-C20 alkyl wherein from 0 to 4 non-terminal carbon atoms are replaced with a heteroatom selected from O, S, and N, and d) C2-C20 alkenyl; provided that V is not hydrogen if Al is S(0)m and V is not hydrogen if A 1 is a bond, n is 0 and A2 is S(0)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 H2 or O
• 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;
• Representative compounds of the invention are:
• 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, 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 heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
• the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable stmcture.
• 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, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, mo ⁇ holinyl, naphthy ridinyl, oxadiazol
• 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, NH2, N(Cl -C6 alkyl)2, CF3, N02, (C1 -C6 alkyOO-, -OH, (C1-C6 alkyl)S(0) m -, (C1-C6 alkyl)C(0)NH-, H2N-C(NH)-, (C1-C6 alkyl)C(O)-, (C1-C6 alkyl)OC(O)-, N3, CN, (C1-C6 alkyl)OC(0)NH- and C1 -C2O alkyl.
• substitutents selected from the group which includes but is not limited to F, Cl, Br, NH2, N(
• 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. Examples of such cyclic moieties include, but are not limited to:
• cyclic moieties as described hereinabove for R2 and R2b and R3 and R4 are formed.
• such cyclic moieties may optionally include a heteroatom(s). Examples of such heteroatom-containing cyclic moieties include, but are not limited to:
• Rl is selected from: hydrogen, and C1-C6 alkyl.
• R2a and R2b are independently selected from: a side chain of a naturally occurring amino acid and C1-C6 alkyl unsubstituted or substituted with an aryl group.
• R3 and R4 are independently selected from: a side chain of a naturally occurring amino acid and C1-C6 alkyl unsubstituted or substituted with a group selected from aryl, heterocycle and C3-C10 cycloalkyl.
• R ⁇ and R ⁇ b are independently selected from: a side chain of a naturally occurring amino acid, methionine sulfoxide, methionine sulfone and unsubstituted or substituted C1-C6 alkyl .
• X-Y is selected from:
• R?b C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted aryl group.
• R8 is selected from: hydrogen, perfluoroalkyl, F, Cl, Br, R lOO-, Rl lS(0) m -, CN, N ⁇ 2, R 10 C(O)-, RlO ⁇ C(O)-, -N(Rl0) 2 , Rl 1OC(O)NR10- and -C6 alkyl.
• R9 is hydrogen.
• Rl is selected from H, -C6 alkyl and benzyl.
• Al and A2 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 compounds of this invention as formed, e.g., from non-toxic l o 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,
• variable e.g., R 10, Z, n, etc.
• -N(R10) 2 represents -NHH, -NHCH3, -NHC2H5, etc. It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of
• 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.
• 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 cyanoborohydride or other reducing agents.
• 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 B Preparation of reduced peptide subunits by reductive alkylation
• RA and RB are R2a, R2b, R3, R4, R5a or I#b as previously defined;
• XL is a leaving group, e.g., Br, I- or MsO-; and R s defined such that R7b is generated by the reductive alkylation process.
• Reaction Schemes A-E illustrate bond-forming and peptide modifying reactions inco ⁇ orating acyclic peptide units. It is well understood that such reactions are equally useful when the - NHC(RA) - 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 corresponding syn amino-alcohol (Scheme F, Step B, Part 1), and stereospecific boron triflouride or zinc chloride activated organo- magnesio, organo-lithio, or organo-zinc copper(l) cyanide SN ' displacement reaction (Scheme F, Step G).
• Scheme F stereoselective reduction of the Boc-amino-enone to the corresponding syn amino-alcohol
• stereospecific boron triflouride or zinc chloride activated organo- magnesio, organo-lithio, or organo-zinc copper(l) cyanide SN ' displacement reaction
• Step H of Scheme F R* is inco ⁇ orated using coupling reaction A and RlCOOH; the alkylation reaction C using R*CHO and a reducing agent; or alkylation reaction C using R*CH2XL.
• alkane analogs are prepared in a similar manner by including an additional catalytic hydrogenation step as outlined in Reaction Scheme G.
• Step C R 2a REACTION SCHEME F (CONT'D)
• the oxa isostere compounds of this invention are prepared according to the route outlined in Scheme H.
• An aminoalcohol H-l 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
• H-4 e.g., sodium hydride or potassium t-butoxide
• the N-Boc derivative H-4 is then obtained by the treatment of H_ ⁇ with BOC anhydride and DMAP (4- dimethylaminopyridine) in methylene chloride. Alkylation of H-4 with R3 ⁇ L.
• 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 RyRzCO gives the adduct H-7 (wherein Ry and R z are selected such that R3 is eventually provided.
• H-7 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. Sometimes, it is more efficient to carry out this conversion via a 2-step sequence, namely, hydrolysis of H-6 in hydrochloric acid to afford H-9a. which is then derivatized with BOC-ON or BOC anhydride to give H-9b.
• the thia, oxothia and dioxothia isostere compounds of this invention are prepared in accordance to the route depicted in Scheme I.
• Aminoalcohol . is derivatized with BOC2O to give 1-15.
• Mesylation of 1-15 followed by reaction with methyl alpha- mercaptoacetate in the presence of cesium carbonate gives sulfide Ii 16.
• Removal of the BOC group in 1-16 with TFA followed by neutralization with di-isopropylethylamine leads to lactam 1-17.
• N- BOC derivative 1-18 is obtained via the reaction of 1-17 with BOC anhydride in THF catalyzed by DMAP.
• the N-BOC group of either 1-21 or 1-22 is readily removed by treatment with gaseous hydrogen chloride.
• the resultant amine hydrochloride 1-23 undergoes reductive alkylation in the presence of an aldehyde RxCHO (1-12) and a reducing agent (e.g., sodium cyanoborohydride); or acylation in the presence of RxCOOH (1-13) and a peptide coupling reagent to afford the products 1-24 and 1-25.
• a reducing agent e.g., sodium cyanoborohydride
• L25 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 subsequently joined by the reactions described in Reaction Schemes A - E.
• the intermediates whose synthesis are illustrated in Reaction Schemes A and C can be reductively alkylated with a variety of 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 subsequently be reductively alkylated with a second aldehyde to obtain IX. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole XI 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 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 l-(3-dimethylaminopropyl)-3- ethylcarbodiimide (EDC) leads to acylated products such as XIX.
• condensing reagents such as l-(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 - 1.
• 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, 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
• 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 compounds to inhibit proliferation of vascular smooth muscle cells.
• the compounds of this invention may be administered to mammals, preferably humans, either alone or, preferably, in combination with pharmaceutically acceptable carriers or diluents, optionally with known adjuvants, such as alum, in a pharmaceutical composition, according to standard pharmaceutical practice.
• the compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
• the selected compound may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension.
• carriers which are commonly used include lactose and com starch, and lubricating agents, such as magnesium stearate, are commonly added.
• useful diluents include lactose and dried com starch.
• aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents may be added.
• sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered.
• the total concentration of solutes should be controlled in order to render the preparation isotonic.
• the present invention also encompasses a pharmaceutical composition useful in the treatment of cancer, comprising the administration of a therapeutically effective amount of the compounds of this invention, with or without pharmaceutically acceptable carriers or diluents.
• suitable compositions of this invention include aqueous solutions comprising compounds of this invention and pharmacologically acceptable carriers, e.g., saline, at a pH level, e.g., 7.4.
• the solutions may be introduced into a patient's intramuscular blood-stream by local bolus injection.
• 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 famesyl-protein transferase (FPTase) in a composition.
• FPTase famesyl-protein transferase
• the composition to be tested may be divided and the two portions contacted with mixtures which comprise a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and famesyl pyrophosphate and, in one of the mixtures, a compound of the instant invention.
• the chemical content of the assay mixtures may be determined by well known immunological, radiochemical or chromatographic techniques. Because the compounds of the instant invention are selective inhibitors of FPTase, absence or quantitative reduction of the amount of substrate in the assay mixture without the compound of the instant invention relative to the presence of the unchanged substrate in the assay containing the instant compound is indicative of the presence of FPTase in the composition to be tested.
• 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. Solutions were dried over sodium sulfate and evaporated in vacuo on a rotary evaporator.
• Step B Preparation of 1 -(Phenylmethyl)- 1 H-imidazol-4-ylacetic acid methyl ester (2) and 1 -(Phenylmethyl)- lH-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)- lH-imidazol-4-ylacetic acid hydrochloride (4) and 1 -(Phenylmethyl)- lH-imidazol- 5-ylacetic acid hydrochloride (5) (3: 1 mixture)
• Step E Preparation of N-[2(S)-(t-Butoxycarbonylamino)-3(S)- methylpentyn-N-(l -naphthylmethyl)glvcine 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).
• Step F Preparation of N-[2(S)-(t-Butoxycarbonylamino)-3(S)- methylpentyl1-N-( 1 -naphthylmethvDglvcine (8)
• 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-(l - naphthylmethyl)-glycyl-methionine methyl ester (9, 2.82 g, 5.04 mmol) was dissolved in EtOAc (50 mL) and cooled to -25°C. HCI was bubbled through the mixture until TLC (95:5 CH2 ⁇ 2:MeOH) indicated complete reaction.
• Step I Preparation of N-[2(S)-(1 -(Phenylmethyl)- 1 H-imidazol-4- ylacetyl)amino-3(S)-methylpentyl]-N- 1 -naphthylmethyl - gylycyl-methionine methyl ester bis trifluoroacetate (11) and
• Step J Preparation of N-[2(S)-( 1 -(Phenylmethyl)- 1 H-imidazol-4- ylacetyl)amino-3(S)-methylpentyl] -N- 1 -naphthylmethyl - glycyl-methionine bis trifluoroacetate (13) and N-[2(S)-( 1 - (Phenylmethyl)- 1 H-imidazol-5-ylacetyl)amino-3(S)- methylpentyl]-N-l -naphthylmethyl-glycyl-methionine bis trifluoroacetate (14) To a solution of N-[2(S)-(1 -(Phenylmethyl)- 1 H-imidazol-4- ylacetyl)amino-3(S)-methylpentyl]-N- 1 -naphthylmethyl-glycyl-
• Step A Preparation of l-(4-Nitrophenylmethyl)-lH-imidazol-4- ylacetic acid methyl ester (15) and 1 -(4-Nitrophenylmethyl)- lH-imidazol-5-ylacetic acid methyl ester (16) (3:1 mixture)
• sodium hydride 60% in mineral oil, 99 mg, 2.5 mmol
• dimethylformamide 2 ml
• a solution of lH-imidazole-4-acetic acid methyl ester hydrochloride (1, 200 mg, 1.13 mmol) in dimethylformamide (3 ml).
• Step B Preparation of 1 -(4-Nitropheny Imethy 1)-1 H-imidazol-4- ylacetic acid hydrochloride (17) and l-(4-Nitrophenyl- methyl)-lH-imidazol-5-ylacetic acid (18) (3:l mixft ⁇ re)
• l-(4-Nitrophenylmethyl)-lH- imidazol-4-ylacetic acid methyl ester 15
• Step C Preparation of N-[(2S)-( 1 -(4-Nitropheny Imethyl)- 1 H- imidazol-4-ylacetyl)amino-3(S)-methylpentyl]-N- 1 - naphthylmethyl-glycyl-methionine methyl ester bis trifluoroacetate (19) and N-[2(S)-(l-(4-Nitrophenyl-methyl)- 1 H-imidazol-5-ylacetyl)amino-3(S)-methylpentyl]-N- 1 - 1 5 naphthylmethyl-glycyl-methionine methyl ester bis trifluoroacetate (20)
• Step D Preparation of N-[2(S)-(1 -(4-Nitropheny Imethy 1)-1 H- imidazol-4-ylacetyl)am o-3(S)-methylpentyl]-N-l- naphthylmethyl-glvcyl-methionine bis trifluoroacetate (21)
• N-[2(S)-(l -(4-nitrophenylmethyl)-lH- imidazol-4-ylacetyl)amino-3(S)-methylpentyl]-N- 1 -naphthylmethyl- glycy 1-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)-(l-(4-NitrophenylmethyI)-lH- imidazol-5-ylacetyl)amino-3(S)-methylpentyl]-N- 1 - naphthylmethyl-glvcyl-methionine bis trifluoroacetate (22)
• N- [2(S)-N'-(1 -(4-nitropheny Imethy 1)-1 H- imidazol-5-ylacetyl)amino-3(S)-methylpentyl]-N-l-naphthylmethyl- glycyl-methionine methyl ester bis trifluoroacetate (20, 29 mg, 0.031 mmol) in methanol (1 ml ) was added 1.0N lithium hydroxide (187 ⁇ l, 0.187 mmol ).
• Step B Preparation of l-(4-Nitrophenylmethyl)-lH-imidazol-5- ylacetic acid methyl ester (16)
• Step C Preparation of 1 -(4-Nitropheny Imethy 1)- 1 H-imidazol-5 - ylacetic acid hydrochloride (18) - 111 -
• Step D Preparation of N-[2(S)-( 1 -(4-Nitropheny Imethy 1)- 1 H- imidazol-5-ylacetyl)amino-3(S)-methylpentyl]-N- 1 - 10 naphthylmethyl-glycyl-methionine methyl ester bis trifluoroacetate (20)
• Step A Preparation of N-[2(S)-( 1 -(2-Naphthylmethy 1)- 1 H-imidazol- 5-ylacetyl)amino-3(S)-methylpentyl]-N- 1 -naphthylmethyl -
• Step B Preparation of N-[2(S)-(l-(2-Naphthylmethyl)-lH- imidazol-5-ylacetyl)amino-3(S)-methylpentyl]-N- 1 - naphthylmethyl-glvcyl-methionine bis trifluoroacetate
• Step A Preparation of N- ⁇ SMl-U-NaphthylmethyD-lH-imidazo S-ylacety ammo-S ⁇ -memylpentyll-N-l-naphthylmethyl- lycyl-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)- 1 H-imidazol- 5-ylacetyl)amino-3(S)-methylpentyl]-N- 1 -naphthylmethyl - lvcyl-methionine bis trifluoroacetate
• Step A Preparation of 1 -Famesyl- 1 H-imidazol-5-y lacetic acid methyl ester
• Step B Preparation of N-[2(S)-(l-(l-Farnesyl)-lH-imidazol-5- ylacetyl)amino-3(S)-methylpentyl]-N- 1 -naphthylmethyl - glvcyl-methionine methyl ester bis trifluoroacetate
• Step C Preparation of N-[2(S)-[ 1 -( 1 -Famesyl)- 1 H-imidazol-5- ylacetyl]amino-3(S)-methylpentyl]-N- 1 -naphthylmethyl - lycyl-methionine bis trifluoroacetate
• Step A Preparation of N-[2(S)-(1 -Geranyl- 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 -Geranyl- 1 H-imidazol-5- ylacetyl)amino-3(S)-methylpentyl]-N- 1 -naphthylmethyl - lycyl-methionine bis trifluoroacetate
• Step A Preparation of l-(4-Pyridylmethyl)-lH-imidazol-4-ylacetic i o acid methyl ester (24) and 1 -(4-Pyridy Imethyl)- 1 H-imidazol-
• Step B Preparation of N-[2(S)-( 1 -(4-Pyridylmethyl)- 1 H-imidazol-4- ylacetyl)amino-3(S)-methylpentyl]-N- 1 -naphthylmethyl - glycyl-methionine methyl ester tris trifluoroacetate (26) and N-[2(S)-(l-(4-Pyridylmethyl)-lH-imidazol-5- ylacetyl)amino-3(S)-methylpentyl]-N- 1 -naphthylmethyl- glvcyl-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)-lH-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)--(l -(4-Pyridy Imethyl)- lH-imidazol- 5-ylacetyl)amino-3(S)-methylpentyl]-N- 1 -naphthylmethyl - glvcyl-methionine tris trifluoroacetate (29) Following the procedure described in Example 2, Step E, but using the methyl ester 27 prepared as described in Step B provided the title compound.
• 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)- 1 H- imidazol-5-y lacety l)amino-3(S)-methylpentyl]-N- 1 - naphthylmethyl-glvcyl-methionine bis trifluoroacetate
• N-[2(S)-(l-(4-cyanophenylmethyl)-lH- imidazol-5-ylacetyl)amino-3(S)-methylpentyl]-N- 1 -naphthylmethyl- glycyl-methionine methyl ester bis trifluoroacetate (25.6 mg, 0.028 mmol) in methanol (1 ml ) was added 1.0N sodium hydroxide (280 ⁇ l, 0.280 mmol) and stirred for 2 h.
• Step A Preparation of N-[2(S)-(1 -(4- Methoxyphenylmethyl)-lH- imidazol-5-yl)acetyl)amino-3(S)-methylpentyl]-N-l- naphthylmethyl-glycyl-methionine methyl ester bis trifluoroacetate
• Step B Preparation of N-[2(S)-(1 -(4-Methoxyphenylmethy 1)- 1 H- imidazol-5-ylacetyl)amino-3(S)-methylpentyl]-N- 1 - naphthylmethyl-glvcyl-methionine bis trifluoroacetate Following the procedure described in Example 9, Step B, but substituting the methyl ester from Step A provided the title compound.
• Step A Preparation of N-[2(S)-(1 -(4-Quinolinylmethyl)-lH- imidazol-5-ylacetyl)amino-3(S)-methylpentyl]-N-l- naphthylmethyl-glycyl-methionine methyl ester bis trifluoroacetate
• Step B Preparation of N-[2(S)-( 1 -(4-Quinolinylmethyl)- 1 H- imidazol-5-ylacetyl)amino-3(S)-methylpentyl]-N- 1 - naphthylmethyl-glvcyl-methionine bis trifluoroacetate
• Step A Preparation of N-[2(S)-(l-(2-Naphthylmethyl)-lH-imidazol- 5-ylacetyl)amino-3(S)-memylpentyl]-N-l-phenylmethyl- lvcyl-methionine methyl ester bis trifluoroacetate
• Step B Preparation of N-[2(S)-( 1 -(2-Naphthylmethyl)- 1 H-imidazol- 5-ylacetyl)amino-3(S)-methylpentyl]-N-l-phenylmethyl- lycyl-methionine bis trifluoroacetate 5 Following the procedure described in Example 9, Steps B, but substituting the methyl ester from Step A provided the title compound.
• Step B 1 -(2-NaphthylmethvD- 1 H-imidazol-5- ylacetaldehvde (30)
• Step C Preparation of N-[2(S)-(l-(2-Naphthylmethyl)-lH-imidazol- 5-ylethyl)amino-3(S)-methylpentyl]-N- 1 -naphthylmethyl - lvcyl-methionine methyl ester bis trifluoroacetate
• Step D Preparation of N-[2(S)-( 1 -(2-Naphthylmethy 1)- 1 H-imidazol- 5-ylethyl)ammo-3(S)-methylpentyl]-N-l-naphthylmethyl- lvcyl-methionine bis trifluoroacetate
• Step B Preparation of 5(S)-[1 (S)-methyl]propyl-2,3,5,6-tetra-hydro-
• Step C Preparation of N-(tert-butoxycarbonyl)-5(S)-[l (S)- methyllpropyl-2.3.5.6-tetrahydro-4H-1.4-oxazin-3-one. 5(S)-[l(S)-Methyl]propyl-2,3,5,6-tetrahydro 4H-l,4-oxazin-
• Step D Preparation of N-(tert-Butoxycarbonyl)-2(S)-benzyl-5(S)- [ 1 (S)-methyl]propyl-2,3,5,6-tetrahydro-4H-l ,4-oxazin-3- one
• Step F Preparation of N-(tert-Butoxycarbonyl)-2(S)-[2(S)-amino- 3(S)-methyl]-pentyloxy-3-phenyl-propionyl-methione sulfone methyl ester
• the title compound was prepared by EDC coupling of N- (tert-butoxycarbonyl)-2(S)-[2(S)-amino-3(S)-methyl]pentyloxy-3- phenylpropionic acid with methionine sulfone methyl ester.
• Step G Preparation of 2(S)-[2(S)-Amino-3(S)-methyl]pentyloxy-3- phenylpropionyl-methionine sulfone methyl ester hydrochloride N-(tert-butoxycarbonyl-2(S)-[2(S)-amino-3(S)- methyl]pentyloxy-3-phenylpropionyl-methionine sulfone methyl ester was treated with HCI gas in ethyl acetate and the solvent was evaporated in vacuo to afford the title compound.
• Step H Preparation of 2(S)-[N-2(S)-( 1 -(2-Naphthy Imethyl)- 1 H- imidazol-5-ylacetyl)amino-3(S)-methyl]pentyloxy-3- phenylpropionyl-methionine sulfone methyl ester hydrochloride
• Step A Preparation of 2(S)-[2(S)-t-butoxycarbonylamino-3(S)- methyl]-pentyloxy-3-phenylpropionyl-methionine methyl ester
• the title compound was prepared in the same fashion as that described in Example 14 , Step F , using methionine methyl ester in place of methionine sulfone methyl ester.
• Step B Preparation of 2(S)-[2(S)-amino-3(S)-methyl]-pentyloxy-3- phenylpropionyl -methionine methyl ester hydrochloride
• the product of Step A was converted to the title compound using the method of Example 14, Step G.
• Step C Preparation of 2(S)-[N-2(S)-(l-(2-Naphthylmethyl)-l H- imidazol-5-ylethyl)amino-3(S)-methyl]pentyloxy-3- phenylpropionyl-methionine methyl ester bis trifluoroacetate Following the procedure described in Example 13, Step C, but substituting l-(2-naphthylmethyl)- lH-imidazol-5-ylacetaldehyde (30) and 2(S)-[2(S)-amino-3(S)-methyl]pentyloxy-3-phenylpropionyl- methionine methyl ester hydrochloride, the title compound was obtained.
• N-[2(S)-(1 -Methyl-4-imidazoleacetyl) amino-3(S)- methylpenty l]-N-( 1 -naphthylmethyl)-glycyl-methionine methyl ester (prepared in Example 18, 0.081 g, 0.139 mmol) was dissolved in MeOH (5 ml), cooled to 0°C, and IN NaOH (0.557 ml, 0.557 mmol) was added. The mixture was stirred at ambient temperature for 4 h and evaporated in vacuo. The resulting residue was dissolved in H2O (5 ml) and neutralized with IN HCI (0.557 ml, 0.557 mmol).
• Step A Preparation of N-[2(S)-t-Butoxycarbonylamino)-3- methylpentyll-N-(cvclopropylmethyl)glvcine methyl ester N-[2(S)-t-Butoxycarbonylamino)-3(S)-methylpentyl]glycine methyl ester (6, 287.8 mg, 0.9980 mmol) was dissolved in 1,2-dichloro- ethane (7.0 ml). 4A Molecular sieves (207 mg), cyclopropane- carboxaldehyde (75 ml, 1.0 mmol), and sodium triacetoxyborohydride (1.075 g, 5.072 mmol) were added.
• Step B Preparation of N-[2(S)-t-Butoxycarbonylamino)-3- methylpentyll-N-(cvclopropylmethyl)glvcine
• Step C Preparation of N-[2(S)-t-Butoxycarbonylamino)-3- methy lpenty 1] -N-(cyclopropy Imethy 1 )gly cy lmethi onine methyl ester
• Step D Preparation of N-[2(S)- Amino-3-methylpentyl)-N- (cyclopropylmethyl)glycylmethionine methyl ester hydrochloride
• Step E Preparation of N-[(2S)-l-(2-naphthylmethyl)-lH-imidazol- 5-ylacetyl]amino-(3S)-me ylpentyl]-N-cyclopropylmethyl)- glycylmethionine methyl ester bis trifluoroacetate salt
• the title compound was prepared in the same fashion as that described in Example 1 , Step I , but using the compound prepared in
• N-[2(S)-((4-Nitrobenzyl)pyroglutamyl)amino)-3(S)- methylpentyl]-N-(l-naphthylmethyl)-glycyl-methionine methyl ester (0.050 g, 0.071 mmol) was dissolved in MeOH (1 ml), cooled to 0°, and IN NaOH (0.283 ml, 0.283 mmol) was added. The mixture was stirred at ambient temperature for lh. The mixture was neutralized with IN HCI (0.283 ml, 0.283 mmol). The aqueous layer was washed with EtOAc (3x10 ml).
• Example 31 The product of Example 31 was converted to the title compound as described in Example 30.
• Step B Preparation of N-[2(S)- 1 -(4-Fluoropheny Imethy 1)-1 H- imidazol-5-ylacetyl)amino-3(S)-methylpentyl]-N- 1 -
• Step C Preparation of N-[2(S)- 1 -(4-Fluorophenylmethy 1)- 1 H- imidazol-5-ylacetyl)ammo-3(S)-methylpentyl]-N-l - naphthylmethyl-glvcyl-methionine bis trifluoroacetate.
• the title compound was prepared as the bis trifluoroacetate salt using the procedure described in Example 2 step D.
• Step A Preparation of lH-Imidazole-4- acetic acid methyl ester hydrochloride.
• Step B Preparation of 1 -(Triphenylmethyl)- 1 H-imidazol-4-ylacetic acid methyl ester.
• Step C Preparation of [ 1 -(4-cyanobenzyl)- 1 H-imidazol-5-yl]acetic acid methyl ester.
• Step D Preparation of [l-(4-cyanobenzyl)-lH-imidazol-5-yl]acetic acid.
• Step E Preparation of N-[2(S)-(amino)-3(S)-methylpentyl]-N-( 1 - naphthylmethvPglvcine methyl ester hydrochloride.
• a solution of N-[2(S)-(t-Butoxycarbonylamino)-3(S)- methylpentyl]N( 1 -naphthylmethyl) glycine methyl ester from example 1 step E (5.90g, 13.8 mmol) in EtOAc (100 ml) was saturated with gaseous hydrogen chloride. The resulting solution was allowed to stand at room temperature for lhr. The solvent was evaporated in vacuo to afford the title compound as a white solid.
• Step F Preparation of N-[2(S)-([ 1 -(4-cyanobenzy 1)- 1 H-imidazol- 5- yl] acetylamino)-3(S)-methylpentyl]-N-(l- naphthylmethyl) glycine methyl ester.

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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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• 1995
  • 1995-09-26 JP JP8511933A patent/JPH10508005A/ja active Pending
  • 1995-09-26 EP EP95935104A patent/EP0783517A2/de not_active Withdrawn
  • 1995-09-26 AU AU37248/95A patent/AU700175B2/en not_active Ceased
  • 1995-09-26 WO PCT/US1995/012224 patent/WO1996010034A2/en not_active Application Discontinuation
  • 1995-09-29 IL IL11547195A patent/IL115471A0/xx unknown

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