EP0836383A1 - Combinaisons d'inhibiteurs de farnesyl-proteine transferase - Google Patents

Combinaisons d'inhibiteurs de farnesyl-proteine transferase

Info

Publication number
EP0836383A1
EP0836383A1 EP96923503A EP96923503A EP0836383A1 EP 0836383 A1 EP0836383 A1 EP 0836383A1 EP 96923503 A EP96923503 A EP 96923503A EP 96923503 A EP96923503 A EP 96923503A EP 0836383 A1 EP0836383 A1 EP 0836383A1
Authority
EP
European Patent Office
Prior art keywords
substituted
group
unsubstituted
alkyl
amino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP96923503A
Other languages
German (de)
English (en)
Inventor
Charles T. Caskey
Susumu Nishimura
Mari Yonemoto
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
MSD KK
Merck and Co Inc
Original Assignee
Banyu Phamaceutical Co Ltd
Merck and 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 GBGB9603091.1A external-priority patent/GB9603091D0/en
Application filed by Banyu Phamaceutical Co Ltd, Merck and Co Inc filed Critical Banyu Phamaceutical Co Ltd
Publication of EP0836383A1 publication Critical patent/EP0836383A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/03—Peptides having up to 20 amino acids in an undefined or only partially defined sequence; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • 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

Definitions

  • Ras protein is part of a signaling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation.
  • Biological and biochemical studies of Ras action indicate that Ras functions like a G-regulatory protein.
  • Ras In the inactive state, Ras is bound to GDP.
  • Ras Upon growth factor receptor activation Ras is induced to exchange GDP for GTP and undergoes a conformational change.
  • the GTP-bound form of Ras propagates the growth stimulatory signal until the signal is terminated by the intrinsic GTPase activity of Ras, which returns the protein to its inactive GDP bound form (D.R. Lowy and D.M. Willumsen, Ann. Rev. Biochem. 62:851-891 (1993)).
  • ras 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 1 -Aaa 2 -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-translational farnesylation. 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 utilizes famesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a famesyl group (Reiss et al, Cell, 62:81-88 (1990); Schaber et al, J. Biol. Chem., 265:14701-14704 (1990); Schafer et al, Science, 249:1133-1139 (1990); Manne et al, Proc. Natl. Acad. Sci USA, 57:7541-7545 (1990)).
  • Inhibition of famesyl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane localization in cultured cells.
  • FPTase farnesyl-protein transferase
  • FPP famesyl diphosphate
  • Ras protein substrates
  • 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)).
  • bisubstrate strategy addresses the unfavorable entropic effect that might exist in bringing two molecules together at the same enzyme protein.
  • the spatial requirements for accessing two enzymatic site interactions with a single compound may result in a bisubstrate inhibitor with a molecular weight and correspondingly poor pharmacokinetic properties.
  • the reported bisubstrate analogs have shown limited activity in cell-based assays.
  • compositions which comprise two different independent famesyl protein transferase inhibitors, one inhibitor which is a competitive inhibitor with respect to the protein substrate of FPTase and the other inhibitor which is a competitive inhibitor with respect to famesyl pyrophosphate. It is a further object of this invention to develop methods of inhibiting famesyl protein transferase and treating cancer utilizing these chemotherapeutic compositions.
  • the present invention relates to compositions comprising amounts of at least two therapeutic agents selected from a group consisting of a famesyl protein transferase inhibitor which is an effective inhibitor of the enzyme because it is competitive with respect to the protein substrate of the enzyme (also referred to as a protein substrate- competitive inhibitor) and a famesyl protein transferase inhibitor which is an effective inhibitor of the enzyme because it is competitive with respect to famesyl pyrophosphate (also referred to as a famesyl pyrophosphate- competitive inhibitor) .
  • a famesyl protein transferase inhibitor which is an effective inhibitor of the enzyme because it is competitive with respect to the protein substrate of the enzyme
  • a famesyl protein transferase inhibitor which is an effective inhibitor of the enzyme because it is competitive with respect to famesyl pyrophosphate
  • methods of inhibiting farnesyl-protein transferase and treating cancer in a mammal comprise administering to said mammal, either sequentially in any order or simultaneously, amounts of at least two therapeutic agents selected from a group consisting of a famesyl protein transferase inhibitor which is an effective inhibitor of the enzyme because it is a competitive inhibitor with respect to the protein substrate of the enzyme and a famesyl protein transferase inhibitor which is an effective inhibitor of the enzyme because it is a competitive inhibitor with respect to famesyl pyrophosphate, in amounts sufficient to achieve an additive or synergistic therapeutic effect.
  • a famesyl protein transferase inhibitor which is an effective inhibitor of the enzyme because it is a competitive inhibitor with respect to the protein substrate of the enzyme
  • a famesyl protein transferase inhibitor which is an effective inhibitor of the enzyme because it is a competitive inhibitor with respect to famesyl pyrophosphate
  • the additive or synergistic therapeutic effect of the instant compositions may be achieved with smaller amounts of either or both of the protein substrate-competitive inhibitor and famesyl pyrophosphate-competitive inhibitor than would be required if such a protein substrate-competitive inhibitor or famesyl pyrophosphate- competitive inhibitor were administered alone, thereby avoiding any non- mechanism-based adverse toxicity effects which might result from administration of an amount of the single protein substrate-competitive inhibitor or famesyl pyrophosphate-competitive inhibitor sufficient to achieve the same therapeutic effect.
  • FIGURES 1A, IB and 1C In vivo Assessment of a Combination of Compound D and Compound E:
  • Figure 1 A shows the partial densitometric scan of an autoradiograph of a Westem blot from the SDS-PAGE gel of the method described in Example 21 wherein the FPTase inhibitory compound was Compound D at a concentration of 30 ⁇ M.
  • Figure IB shows the partial densitometric scan of an autoradiograph of a Westem blot from the SDS-PAGE gel of the method described in Example 21 wherein the FPTase inhibitory compound was Compound E at a concentration of 0.3 ⁇ M.
  • Figure 1C shows the partial densitometric scan of an autoradiograph of a Westem blot from the SDS-PAGE gel of the method described in Example 21 wherein a combination of FPTase inhibitory compounds was utilized (Compound D at a concentration of 30 ⁇ M and Compound E at a concentration of 0.3 ⁇ M).
  • FIGURE 2A and 2B In vivo Assessment of a Combination of Compound C and Compound A:
  • Figure 2A graphically illustrates the data from a Westem blot from the SDS-PAGE gel of the method described in Example 21 wherein the FPTase inhibitory compound was Compound C at various concentrations.
  • Figure 2B graphically illustrates the data from a Westem blot from the SDS-PAGE gel of the method described in Example 21 wherein a combination of FPTase inhibitory compounds (Compound C at various concentrations and Compound A at a concentration of 0.03 ⁇ M) was utilized.
  • additive means that the effect achieved with the methods and compositions of this invention is equal to the sum of the effects that result from methods and compositions comprising the farnesyl-protein transferase inhibitors of this invention separately and in the amounts employed in the methods and compositions hereof.
  • additive it is now possible to achieve an additive or synergistic therapeutic effect in a mammal with amounts of a protein substrate-competitive inhibitor and famesyl pyrophosphate-competitive inhibitor which, if administered in said amounts singly, are not capable of achieving said effect.
  • the preferred therapeutic effects achieved according to this aspect of the invention are inhibition of farnesyl-protein transferase in a mammal in need of such inhibition and treatment of cancer.
  • the administration of the protein substrate-competitive inhibitor and famesyl pyrophosphate-competitive inhibitor can be sequential in time or simultaneous with the simultaneous method being preferred.
  • this invention provides particularly advantageous methods of achieving a therapeutic inhibition of farnesyl-protein transferase and treatment of cancer with less than therapeutic levels of a protein substrate-competitive inhibitor and/or a famesyl pyrophosphate-competitive inhibitor.
  • the present invention is not limited in any way by the specific protein substrate-competitive inhibitor and/or famesyl pyrophosphate-competitive inhibitor but is applicable to such protein substrate-competitive inhibitors and famesyl pyrophosphate-competitive inhibitors now known or subsequently discovered or developed.
  • Farnesyl-protein transferase inhibitors useful in the instant invention are described hereinbelow. It is the co-administration of a protein substrate- competitive inhibitor and a famesyl pyrophosphate-competitive inhibitor as taught by this invention and not the particular protein substrate- competitive inhibitor and/or famesyl pyrophosphate-competitive inhibitor which brings about the additive or synergistic effect of this invention. Nonetheless, the preferred protein substrate-competitive inhibitors for use in the methods an compositions of this invention and preferred famesyl pyrophosphate-competitive inhibitors are described hereinbelow.
  • composition of the instant invention may comprise a protein substrate-competitive inhibitor that incorporates a cysteinyl or sulfhydryl containing moiety at the N-terminus of the molecule.
  • a protein substrate-competitive inhibitor that incorporates a cysteinyl or sulfhydryl containing moiety at the N-terminus of the molecule.
  • Al an aliphatic amino acid
  • A2 an aliphatic amino acid
  • X any amino acid
  • Xaal an y amino acid in the natural L-isomer form
  • Xaa 2 any amino acid in the natural L-isomer form
  • Xaa3 - NRRl an amide of any amino acid in the natural L- isomer form, wherein R and Rl are independently selected from hydrogen, Cl-Cl2 alkyl, aralkyl, or unsubstituted or substituted aryl; c) Cys - Xaal - Xaa 2 - Xaa3 , wherein
  • Xaal an y amino acid in the natural L-isomer form
  • dXaa 2 any amino acid in the natural L-isomer form
  • Xaa3 any amino acid in the natural L-isomer form
  • X, Y, and Z are independently H2 or O, provided that at least one of these is H2;
  • R! is H, an alkyl group, an acyl group, an alkylsulfonyl group or aryl sulfonyl group, wherein alkyl and acyl groups comprise straight chain or branched chain hydrocarbons of 1 to 6 carbon atoms, or in the alternative, RINH may be absent;
  • R 2 , R3 and R ⁇ are the side chains of naturally occurring amino acids, or in the alternative may be substituted or unsubstituted aliphatic, aromatic or heteroaromatic groups, such as allyl, cyclohexyl, phenyl, pyridyl, imidazolyl or saturated chains of 2 to 8 carbon atoms, wherein the aliphatic substitutents may be substituted iwth an aromatic or heteroaromatic ring; and
  • R is H or a straight or branched chain aliphatic group, which may be substituted with an aromatic or heteroaromatic group;
  • X and Y are independently H2 or O, provided that at least one of these is H2;
  • R! is H, an alkyl group, an acyl group, an alkylsulfonyl group or aryl sulfonyl group, wherein alkyl and acyl groups comprise straight chain or branched chain hydrocarbons of 1 to 6 carbon atoms, or in the alternative, R!NH may be absent;
  • R 2 and R3 are the side chains of naturally occurring amino acids, or in the alternative may be substituted or unsubstituted aliphatic, aromatic or heteroaromatic groups, such as allyl, cyclohexyl, phenyl, pyridyl, imidazolyl or saturated chains of 2 to 8 carbon atoms, wherein the.aliphatic substitutents may be substituted with an aromatic or heteroaromatic ring;
  • Z is O or S; and n is 0, 1 or 2;
  • X and Y are independently H2 or O, provided that at least one of these is H2;
  • R! is H, an alkyl group, an acyl group, an alkylsulfonyl group or aryl sulfonyl group, wherein alkyl and acyl groups comprise straight chain or branched chain hydrocarbons of 1 to 6 carbon atoms, or in the alternative, RINH may be absent;
  • R 2 and R3 are the side chains of naturally occurring amino acids, or in the alternative may be substituted or unsubstituted aliphatic, aromatic or heteroaromatic groups, such as allyl, cyclohexyl, phenyl, pyridyl, imidazolyl or saturated chains of 2 to 8 carbon atoms, wherein the aliphatic substitutents may be substituted with an aromatic or heteroaromatic ring;
  • Z is O or S
  • n 0, 1 or 2;
  • X and Y are independently H2 or O;
  • Rl is an alkyl group, hydrogen, an acyl group, an alkylsulfonyl group or arylsulfonyl group, wherein alkyl and acyl groups comprise straight chain or branched chain hydrocarbons of 1 to 6 carbons atoms, which alternatively may be substituted with an aryl group;
  • R 2 is the side chains of naturally occurring amino acids, or in the alternative may be substituted or unsubstituted aliphatic, aromatic or heterocyclic groups, such as allyl, cyclohexyl, phenyl, pyridyl, imidazolyl or saturated chains of 2 to 8 carbon atoms which may be branched or unbranched, wherein the aliphatic substituents may be substituted with an aromatic or heteroaromatic ring;
  • R3 is an aromatic or heteroaromatic ring or in the alternative an alkyl group or an aryl or heteroaryl substituted alkane, wherein the aromatic ring is unsubstituted or in the alternative, substituted with one or more groups which may be alkyl, halo, alkoxy, trifluoromethyl, or sulfamoyl groups, and which may be poly cyclic;
  • R! and R ⁇ a are independently selected from: hydrogen, a Cl-C6 alkyl group, a Cl-C6 acyl group, an aroyl group, a Cl-C6 alkylsulfonyl group, Cl-C6 aralkylsulfonyl group or arylsulfonyl group wherein the alkyl group and acyl group is optionally substituted with substituted or unsubstituted aryl or heterocycle;
  • R 2 , R3 and R ⁇ are independently selected from: a) a side chain of naturally occurring amino acids, b) an oxidized form of a side chain of naturally occurring amino acids selected from methionine sulfoxide and methionine sulfone, c) substituted or unsubstituted Cl-C8 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, aryl or heterocycle groups, wherein the aliphatic substituent is optionally substituted with an
  • R5b is a C1-C6 alkyl group, a C1-C6 acyl group, an aroyl group, a
  • R6 is a substituted or unsubstituted aliphatic, aryl or heterocyclic group, wherein the aliphatic substituent is optionally substituted with an aryl or heterocyclic ring;
  • n 0, 1 or 2;
  • R! is selected from: hydrogen, a C1-C6 alkyl group, a C1-C6 acyl group, an aroyl group, a C1-C6 alkylsulfonyl group, C1-C6 aralkylsulfonyl group or arylsulfonyl group wherein the alkyl group and acyl group is optionally substituted with substituted or unsubstituted aryl or heterocycle;
  • R 2 , R3 and R4 are independently selected from: a) a side chain of naturally occurring amino acids, b) an oxidized form of a side chain of naturally occurring amino acids selected from methionine sulfoxide and methionine sulfone, c) substituted or unsubstituted Cl-C8 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, aryl or heterocycle groups, wherein the aliphatic substituent is optionally substituted with an
  • R6 is a substituted or unsubstituted aliphatic, aryl or heterocyclic group, wherein the aliphatic substituent is optionally substituted with an aryl or heterocyclic ring;
  • n 0, 1 or 2;
  • Rl is hydrogen, an alkyl group, an aralkyl group, an acyl group, an aracyl group, an aroyl group, an alkylsulfonyl group, aralkylsulfonyl group or arylsulfonyl group, wherein alkyl and acyl groups comprise straight chain or branched chain hydrocarbons of 1 to 6 carbon atoms;
  • R 2 , R3 and R5 are the side chains of naturally occurring amino acids, including their oxidized forms which may be methionine sulfoxide or methionine sulfone, or in the alternative may be substituted or unsubstituted aliphatic, aromatic or heteroaromatic groups, such as allyl, cyclohexyl, phenyl, pyridyl, imidazolyl or saturated chains of 2 to 8 carbon atoms which may be branched or unbranched, wherein the aliphatic substituents may be substituted with an aromatic or heteroaromatic ring;
  • R4 is hydrogen or an alkyl group, wherein the alkyl group comprises straight chain or branched chain hydrocarbons of 1 to 6 carbon atoms;
  • R6 is a substituted or unsubstituted aliphatic, aromatic or heteroaromatic group such as saturated chains of 1 to 8 carbon atoms, which may be branched or unbranched, wherein the aliphatic substituent may be substituted with an aromatic or heteroaromatic ring;
  • R and R are independently selected from H, Cl-4 alkyl, or aralkyl;
  • R 2 , R3, R4, and R5 are independently selected from: H; Cl-8 alkyl, alkenyl,
  • R 2 , R3, R4, and R5 are optionally attached to the same carbon atom;
  • Y is aryl, heterocycle, unsubstituted or substituted with one or more of:
  • Cl-4 alkyl unsubstituted or substituted with: a) Cl-4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO, 2) aryl or heterocycle,
  • W is H2 or O
  • Z is aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with one or more of the following:
  • Cl-4 alkyl unsubstituted or substituted with: a) Cl-4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) aryl or heterocycle, or e) HO,
  • R6, R7 and R8 are independently selected from: H; Cl-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) Cl-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO, o
  • R6 and R7 may be joined in a ring, and R7 and R8 may be joined in a ring; and R9 is Cl-4 alkyl or aralkyl;
  • Rl is selected from: a) hydrogen, b) R8S(0)2-, R 8 C(0)-, (R8)2NC(0)- or R9 ⁇ C(0)-, and c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R80-, R 8 S(0)m-, R8C(0)NR8-, CN, (R8)2N-C(NR8)-, R8C(0)-, R8 ⁇ C(0)-, N3, -N(R8)2, or R9 ⁇ C(0)NR8-;
  • R 2 a and R 2 b are independently selected from: a) hydrogen, b) Cl-C6 alkyl unsubstituted or substituted by alkenyl, R80-, R8S(0) m -, R8C(0)NR8-, CN, (R8)2N-C(NR8)-, R8C(0)-, R80C(0)-, N3, -N(R8)2, or R9 ⁇ C(0)NR8-, c) aryl, heterocycle, cycloalkyl, alkenyl, R80-, R 8 S(0)m-.
  • 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-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(R8)2, N02, R8O-, R8S(0) m -. R8C(0)NR8-, CN, (R8)2N-C(NR8)-,
  • R3 and R 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 C 1 -C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N(R8)2, N02, R80-, R8S(0)m-.
  • R 8 C(0)NR8-, CN, (R8) 2 N-C(NR8)-, R8C(0)-, R8 ⁇ C(0)-, N3, -N(R8)2, R9 ⁇ C(0)NR8- and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3- ClO cycloalkyl; or 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(COR8)- ;
  • R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, and e) Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl;
  • R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted
  • R is independently selected from hydrogen, C1-C6 alkyl and aryl
  • R9 is independently selected from C1-C6 alkyl and aryl
  • RlO is independently selected from hydrogen and C1-C6 alkyl
  • R 1 is independently selected from C1-C6 alkyl
  • Zl and Z 2 are independently H2 or O, provided that Zl is not O when X-Y is - C(0)N(R7a)- ;
  • Rl is selected from: a) hydrogen, b) R5S(0)2-, R 5 C(0)-, (R5)2NC(0)- or R6 ⁇ C(0)-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R ⁇ O-,
  • R 2 a and R 2 b are independently selected from: a) hydrogen, b) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, R ⁇ O-, R5S(0)m ⁇ .
  • R5C(0)NR5- CN, N02, (R5)2N-C(NR5)-, R5C(0)-, R5 ⁇ C(0)-, N3, -N(R5)2, or R60C(0)NR5-,
  • R3 is selected from: a) unsubstituted or substituted aryl, b) unsubstituted or substituted heterocycle, c) unsubstituted or substituted cycloalkyl, and d) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl;
  • R4a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl;
  • R4b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1
  • R ⁇ is independently selected from hydrogen, C1-C6 alkyl and aryl
  • R6 is independently selected from C1-C6 alkyl and aryl
  • Z is independently H2 or O
  • X and Y are independently O or H2; m is 1 or 2; nis Oorl; pis 1,2 or 3; q is 0, 1 or 2; t is 1 to 4;
  • R, Rl and R 2 are independently selected from: H, Cl-6 alkyl, or Cl-6 aralkyl;
  • R3 and R are independently selected from: a) hydrogen, b) Cl-C6 alkyl unsubstituted or substituted by C2-C6 alkenyl, R°0-, R 5 S(0) q -, R7C(0)NR6-, CN, N3, ROOC(0)NR6-, R6R7N-C(NR6R8)-, R6C(0)-, R7R8NC(0)0-, R7R8NC(0)- , R6R7N-S(0)2-, -NR6S(0)2R 5 , R°OC(0)0-, -NR6R7, or
  • R7R8NC(0)NR6- c) unsubstituted or substituted cycloalkyl, alkenyl, R60-, R 5 S(0) q -, R6C(0)NR6-, CN, NO2, R6R7N-C(NR8)-, R6C(0)-, N3, -NR6R7, halogen or R7 ⁇ C(0)NR6-, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3-C10 cycloalkyl;
  • W is -CHR9- or -NR9- ;
  • Z is unsubstituted or substituted Cl-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle; wherein the substituted group is substituted with one or more of:
  • Cl-4 alkyl unsubstituted or substituted with: a) Cl-4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) aryl or heterocycle, e) HO,
  • R 5 is Cl-4 alkyl or aralkyl
  • R6, R7 and R8 are independently selected from: H, Cl-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) Cl-4 alkoxy, b) aryl or heterocycle, c) halogen, d) HO,
  • R6 and R7 may be joined in a ring, and R7 and R8 may be joined in a ring;
  • R9 is selected from: H, Cl-4 alkyl, C3-6 cycloalkyl, heterocycle and aryl, unsubstituted, monosubstituted or disubstituted with substituents independently selected from: a) Cl-4 alkyl, b) Cl-4 alkoxy, c) aryl or heterocycle, d) halogen, e) HO,
  • RlO and Rl 1 are independently selected from hydrogen, C1-C6 alkyl, C2-C4 alkenyl, benzyl and aryl;
  • composition of the instant invention may alternatively or in addition comprise a protein substrate-competitive inhibitor that does not incorporates a cysteinyl or sulfhydryl containing moiety at the N- terminus of the molecule.
  • a protein substrate-competitive inhibitor that does not incorporates a cysteinyl or sulfhydryl containing moiety at the N- terminus of the molecule.
  • the lack of a sulfhydryl offers unique advantages in terms of improved pharmacokinetic behavior in animals, prevention of thiol-dependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity.
  • the following compounds, well known in the art are also useful as protein substrate-competitive inhibitors in the instant invention:
  • Rl is selected from: a>heterocycle, and b) Cl-ClO alkyl, which is substituted with heterocycle and which is optionally substituted with one or more of C1-C4 alkyl, hydroxy or amino groups;
  • R 2 a and R 2 b 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-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br,
  • R S C(0)NR8-, CN, (R8)2N- C(NR8)-, R ⁇ C(O)-, R80C(0)-, N3, -N(R8) 2 , R9 ⁇ C(0)NR8- and C1-C2O alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-
  • R 2 and R 2 b 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 ⁇ ) methionine sulfone, and 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, N(R8)2, N ⁇ 2, R80-, R9S(0)m-.
  • R S C(0)NR8-, CN, (R8) 2 N-C(NR8)-, R8C(0)-, R8 ⁇ C(0)-, N3, -N(R8)2, R9 ⁇ C(0)NR8- and C1-C20 alkyl,, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3- ClO cycloalkyl; or
  • 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(R8)2, N02, R8O-, R9s(0)m-, R S C(0)NR8-, CN, (R8)2N-C(NR8)-, R8C(0)-, R8 ⁇ C(0)-, N3, -N(R8)2, R90C(0)NR8- and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from
  • R5 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(C0R8)- ;
  • R6 is a) substituted or unsubstituted Cl-C ⁇ alkyl, wherein the substituent on the alkyl is selected from: D aryl,
  • 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 hydrogen, C1-C6 alkyl and aryl
  • R9 is independently selected from C1-C6 alkyl and aryl
  • RlO is independently selected from hydrogen and C1-C6 alkyl
  • Rl 1 is independently selected from C1-C6 alkyl
  • Z is independently H2 or O; m is 0, 1 or 2; n is 0, 1 or 2; and s is 4 or 5;
  • R 2 , R3, R4 and R5 are independently the side chains of naturally occurring amino acids, including their oxidized forms which may be methionine sulfoxide or methionine sulfone, or in the alternative may be substituted or unsubstituted aliphatic, aromatic or heteroaromatic groups, such as allyl, cyclohexyl, phenyl, pyridyl, imidazolyl or saturated chains of 2 to 8 carbon atoms which may be branched or unbranched, wherein the aliphatic substituents may be substituted with an aromatic or heteroaromatic ring;
  • R6 is a substituted or unsubstituted aliphatic, aromatic or heteroaromatic group such as saturated chains of 1 to 8 carbon atoms, which may be branched or unbranched, wherein the aliphatic substituent may be substituted with an aromatic or heteroaromatic ring;
  • R7 is an alkyl group, wherein the alkyl group comprises straight chain or branched chain hydrocarbons of 1 to 6 carbon atoms, which may be substituted with an aromatic or heteroaromatic group;
  • Rla is selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, (RlO)2N-C(NRlO)-, RlOc(O)-, or RIOQC(O)-, and c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, RlOO-, Rl S(0) m -, Rl0C(O)NRl0-, CN, (R1 ) 2 N-C(NR10)-, RlOC(O)-, RlO ⁇ C(O)-, N3, -N(R10) 2 , or Rll ⁇ C(O)NRl0-;
  • Rib is independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, cycloalkyl, alkenyl, alkynyl, (R10) 2 N-C(NR10)-, RlOC(O)-, or RlO ⁇ C(O)-, and c) Cl-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, cycloalkyl, alkenyl, alkynyl, RlOO-, RHS(0) m -, R1°C(0)NR10-, CN, (RlO)2N-C(NRlO)-, Rl C(O)-, RlO ⁇ C(O)-, N3,
  • Rib is not R10C(O)NR10- when Rla is alkenyl, V is hydrogen and X-Y is -C(0)NR7a
  • R 2a and R 2 b 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-C20 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 10 C(O)NR 10 -, CN, (RlO) 2 N-C(NRl )-, R10C(O)-, RlO ⁇ C(O)-, N3,
  • RlO N(RlO)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- ClO cycloalkyl; or R 2 and R 2 b 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 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) ⁇ r.
  • R3 and R4 are combined to form - (CH2)s - ;
  • R5a and R5b 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,
  • R6 IS a) substituted or unsubstituted Cl-C ⁇ alkyl, wherein the substituent on the alkyl is selected from:
  • 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 -,
  • R9 is selected from: hydrogen , C1-C6 alkyl , RlOO-, Rl lS(0) m -, Rl0C(O)NRl0-, CN, N02, N3, -N(RlO) 2 , and Rl lOC(O)NRl0-; provided that R is not R!0C(O)NR10- when Rla is alkenyl, V is hydrogen and X-Y is -C(0)NR7a- ;
  • RlO is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
  • RU is independently selected from C1-C6 alkyl and aryl
  • Rl 2 is independently selected from hydrogen and C1-C6 alkyl
  • Rl3 is C1-C6 alkyl
  • V is selected from: a) aryl; b) heterocycle; or c) hydrogen;
  • W is -S(0)m-. -0-, -NHC(O)-, -C(0)NH-, -NHSO2-, -SO2NH-, -N(R7a). or -N[C(0)R7a]- ;
  • Z is independently H2 or O
  • n 0, 1, 2, 3 or 4, provided that n ⁇ 0 when V is hydrogen and W is -S(0) m - ;
  • p is 0, 1, 2, 3 or 4, provided that p ⁇ 0 when R9 is not hydrogen or
  • Rl is hydrogen, Cl-C6 alkyl or aryl
  • R 2 and R 2 b 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 heterocycle group, wherein the substituent is selected from F, Cl, Br, N02, R 9 0-, RlOS(0)m-, R9C(0)NR9-, CN, (R9)2N-
  • 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 C l -C20 alkyl, C2-C2O alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N ⁇ 2, R 9 0-, Rl0S(O)m-, R9C(0)NR9-, CN, (R9)2N- C(NR9)-, R9C(0)-, R9 ⁇ C(0)-, N3, -N(R9)2, Rl0 ⁇ C(O)NR9- and C1-C2O alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group
  • 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-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br, N02, R 9 0-, Rl0s(O)m-, R9C(0)NR9-, CN, (R9) N- C(NR9)-, R9C(0)-, R9 ⁇ C(0)-, N3, -N(R9)2, Rl0 ⁇ C(O)NR9- and C1-C2O alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from
  • R5a and R5b are combined to form - (CH2)s - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O,
  • R6 i is a) substituted or unsubstituted Cl-C ⁇ alkyl, wherein the substituent on the alkyl is selected from:
  • R7a is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, and e) Cl-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl;
  • R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted
  • R8a and R ⁇ b are independently selected from: hydrogen, F, Cl, Br, N ⁇ 2, R J lO-, Rl0S(O) m -. CN, R9C(0)NR9-, (R9) 2 N-C(NR9)-, R9C(0)-, R9 ⁇ C(0)-, N3, -N(R9)2, R!0OC(O)NR9-, C1-C20 alkyl, aryl, heterocycle or Cl-C20 alkyl substituted with aryl or heterocycle;
  • R is independently selected from hydrogen, C1-C6 alkyl and aryl
  • RlO is independently selected from C1-C6 alkyl and aryl
  • RU is independently selected from hydrogen, C1-C6 alkyl and aryl, provided R 1 is C1-C6 alkyl when n is 0;
  • R 2 is independently hydrogen or C1-C6 alkyl
  • Rl3 is C1-C6 alkyl
  • Z is independently H2 or O;
  • Rl is independently selected from: a) hydrogen, b) aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, Rl ⁇ O- , Rl lS(0)m-.
  • R 2 a and R 2 b 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-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br, N02, Rl°0-, Rl lS(0) ⁇ r.
  • R 2 a and R 2 b 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 C1-C20 alkyl, C2-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br,
  • R 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,
  • R 10 C(O)NRl0-, CN, (Rl )2N-C(NRlO)-, Rl ⁇ c( ⁇ )-, RlO ⁇ C(O)-, N3, -N(RlO)2, Rl l ⁇ C(O)NRl0- and C1-C2O alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-
  • 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(CORlO)- ;
  • R6 is a) substituted or unsubstituted Cl-C ⁇ alkyl, wherein the substituent on the alkyl is selected from: 1) aryl,
  • 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, cycloalky
  • R8 is independently selected from: a) hydrogen, b) 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, Rl O-, Rl lS(0)m-.
  • RlO is independently selected from hydrogen, C1-C6 alkyl and aryl
  • Rl 1 is independently selected from C1-C6 alkyl and aryl
  • Rl 2 is independently selected from hydrogen and C1-C6 alkyl
  • Rl is independently selected from 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 a heteroatom selected from O, S, and N, and e) C2-C2O alkenyl ; provided that V is not hydrogen if Al is S(0)m and V is not hydrogen if A is a bond, n is 0 and A 2 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;
  • Rla and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Rl O-, RHS(0) m -, R10C(O)NR10-, CN, N ⁇ 2, (RlO) 2 N-C(NRlO)-, RlOC(O)-, Rl ⁇ C(O)-, N3, -N(Rl )2, or RHOC(0)NR10-, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Rl O-, Rl lS(0) m -, R1°C(0)NR10-, CN,
  • R2a and R 2 b are independently selected from: a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by C2-C6 alkenyl, RIOO-, RllS(0) ⁇ r. R1°C(0)NR10-, CN, N3, (Rl°)2N- C(NRlO)-, RlOC(O)-, RlO ⁇ C(O)-, -N(Rl )2, or Rll ⁇ C(O)NRl0-, c) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, Rl°0-,
  • 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 C 1-C20 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-, RllS(0)m-, R 10 C(O)NRl0-, CN, (RlO) 2 N-C(NRlO)-, RlOC(O)-, Rl ⁇ C(O)-, N3, -N(RlO)2, R110C(0)NR10- and C1-C20 alkyl, and d) Cl-C6 alkyl substituted with an
  • 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-C2O alkyl, C2-C2O alkenyl, C3-C10 cycloalkyl, aryl or heterocycle group, wherein the substituent is selected from F, Cl, Br,
  • 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(CORlO)- ;
  • R6 _S a) substituted or unsubstituted Cl-C ⁇ alkyl, substituted or unsubstituted C5-C8 cycloalkyl, or substituted or unsubstituted cyclic amine, wherein the substituted alkyl, cycloalkyl or cyclic amine is substituted with 1 or 2 substituents independently selected from: 1) C1-C6 alkyl, 2) aryl,
  • R7b is selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-C 10 cycloalkyl, e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3- Cio cycloalkyl, f) a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3-C10 cycloalkyl and C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3-C10 cycloalkyl, and g) a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C3-C10 cycloalky
  • R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R OO-, R lS(0) m -, Rl0C(O)NRl0-, CN, NO2, R1°2N-C( R 0)-, RlOc(O)-,
  • R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOo-, Rl lS(0) m - .
  • R O is independently selected from H, C1-C6 alkyl, benzyl, substituted aryl and C1-C6 alkyl substituted with substituted aryl;
  • RU is independently selected from C1-C6 alkyl and aryl
  • Rl 2 is hydrogen or C 1-C6 alkyl
  • Rl is C1-C6 alkyl
  • V is not hydrogen if A 1 is S(0) m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(0)m;
  • W is a heterocycle
  • Z is independently H2 or O
  • Rla and R b are independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, Rl ⁇ O-, R ⁇ S(0) m - .
  • R 10 C(O)NRl0-, CN, N02, (Rl )2N-C(NRlO)-, RlOc(O)-, RlO ⁇ C(O)-, N3, -N(RlO)2, or RH ⁇ C(O)NRl0-, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, RlOO-, R ⁇ S(0) m -, Rl°C(O)NRl0-, CN, (R10)2N-C(NR10)-, RlOC(O)-, RlO ⁇ C(O)-, N3, -N(RlO)2,
  • R 2 a and R 2 b are independently selected from: a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by alkenyl, RlOO-, Rl lS(0)m- . Rl°C(O)NRl0-, CN, N3, (R 10 )2N-C(NRlO)-,
  • Rl°C(O)NRl0- CN, NO2, (R 10 )2N- C(NRl )-, RlOC(O)-, RlO ⁇ C(O)-, N3, -N(RlO)2, or RH ⁇ C(O)NRl0-, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C3- ClO cycloalkyl;
  • R3a and R3b 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 C 1-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-,
  • R3a and R3b 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(CORlO)- ;
  • R4 and R5 are independently selected from: a) hydrogen, and
  • R6 is a) substituted or unsubstituted C1-C8 alkyl or substituted or unsubstituted C5-C8 cycloalkyl, wherein the substituent on the alkyl is selected from:
  • R7 is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R OO-, Rl lS(0) m -.
  • R8 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl lS(0)m-. Rl°C(O)NRl0-, CN, N02,
  • R O is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
  • Rl 1 is independently selected from C1-C6 alkyl and aryl
  • Rl 2 is independently selected from hydrogen and C1-C6 alkyl
  • Rl3 is independently selected from C1-C6 alkyl
  • V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C2O alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if A 1 is S(0) m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(0)m;
  • W is a heterocycle
  • Z is independently H2 or O
  • Rla and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, RlOO-, R n S(0)m-, Rl°C(O)NRl0-, CN, N02, (RlO) 2 N-C(NRlO)-, Rl0c(O)-, RlO ⁇ C(O)-, N3, -N(RlO)2, or Rl lOC(O)NRl -, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, Rl ⁇ O-, R ⁇ S(0) m -, RlOC(0)NRlO-, CN, (R10)2N-C(NR10)-, RlOC(O)-, RlO ⁇ C(O)-, N3, -N(RlO)2, or Rl l
  • R 2 and R 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-C20 alkenyl, C3-C10 cycloalkyl, aryl or heterocyclic group, wherein the substituent is selected from F, Cl, Br,
  • R 10 C(O)NRl0-, CN, (RlO)2N-C(NRlO)-, R10C(O)-, RlO ⁇ C(O)-, N3, -N(RlO)2, R110C(0)NR10- and C1-C20 alkyl, and d) C1-C6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C3-
  • R 2 and R3 are combined to form - (CH2)s - ;
  • R 2 or R3 are combined with R6 to form a ring such that
  • R4a, R4b, R7a and R7b are independently selected from: a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by alkenyl, R 1°0-,
  • 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-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 10 C(O)NR 10 -
  • R6 is independently selected from hydrogen or C1-C6 alkyl
  • R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, 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, Rl O-, Rl lS(0)m-, Rl°C(O)NRl0-, CN, NO2, (Rl°)2N-C- (NRlO)-, RlOC(O)-, RlO ⁇ C(O)-, N3, -N(RlO) 2 , or Rll ⁇ C(O)NRl0-, and c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl,
  • RlO is independently selected from hydrogen, Cl C6 alkyl, benzyl and aryl;
  • Rl 1 is independently selected from C1-C6 alkyl and aryl;
  • Rl 2 is a) substituted or unsubstituted Cl-C8 alkyl or substituted or unsubstituted C5-C8 cycloalkyl, wherein the substituent on the alkyl or cycloalkyl is selected from:
  • Rl3 is independently selected from hydrogen and C1-C6 alkyl
  • Rl4 is independently selected from C1-C6 alkyl
  • Q is a substituted or unsubstituted nitrogen-containing C4-C9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be an aromatic ring, a C5-C7 saturated ring or a heterocycle;
  • V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C2O alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if A is S(0)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(0)m; W is a heterocycle;
  • X, Y and Z are independently H2 or O;
  • Rla and Rib are independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RlOO-, Rl lS(0) m -. R1°C(0)NR10-, CN, N ⁇ 2, (R!0) 2 N-C(NR10)-, RlOc(O)-, RlO ⁇ C(O)-, N3, -N(RlO)2,
  • RHOC(O)NR10- c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RlOO-, RHS(0) m - .
  • R 2 and R3 are independently selected from: H; unsubstituted or substituted Cl-8 alkyl, unsubstituted or substituted C2-8 alkenyl, unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl, unsubstituted or
  • substituted heterocycle O O wherein the substituted group is substituted with one or more of: 1) aryl or heterocycle, unsubstituted or substituted with: a) Cl-4 alkyl,
  • R 2 and R3 are attached to the same C atom and are combined to form (CH2)u - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(0) m , -NC(O)-, and -N(COR O)- ;
  • R4 is selected from H and CH3;
  • R 2 , R3 and R4 are optionally attached to the same carbon atom;
  • R6, R7 and R ⁇ a are independently selected from: H; Cl-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with: a) Cl-4 alkoxy, b) aryl or heterocycle, c) halogen,
  • R6 and R? may be joined in a ring;
  • R7 and R ⁇ a may be joined in a ring;
  • R8 is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, RHS(0) m -.
  • R9 is selected from: a) hydrogen, b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 1 OO-, Rl lS(0)m- . R1°C(0)NR10-, CN, N02,
  • RlO is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
  • Rl 1 is independently selected from C1-C6 alkyl and aryl
  • G is H2 or O
  • V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if A 1 is S(0)m and V is not hydrogen if A is a bond, n is 0 and A 2 is S(0)m;
  • W is a heterocycle
  • Y is aryl, heterocycle, unsubstituted or substituted with one or more of:
  • u is 4 or 5;
  • Rla is independently selected from: a) hydrogen, b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C2O alkenyl, C2-
  • R 10 C(O)NRl0-, CN, (RlO)2N-C(NRl )-, RlOc(O)-, RlO ⁇ C(O)-, N3, -N(RlO)2, or Rl lOC(O)-NRl0-;
  • Rib is independently selected from: a) hydrogen, b) substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3-C10 cycloalkyl, C2-C20 alkenyl, C2-C20 alkynyl, RlOO-, Rl lS(0) m -, CN, N02, (R10)2N-C(NR10)-, RlOC(O)-, Rl0 ⁇ C(O)-, N3 or -N(Rl )2, c) Cl-C6 alkyl unsubstituted or substituted by substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic, C3-C10 cycloalkyl, C2-C20 alkenyl, C2-C2O alkynyl,
  • R 2 and R3 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, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heterocyclic group, wherein the substituent is selected from F, Cl, Br, N(RlO)2, N02, Rl°0-, Rl lS(0)m-, R1°C(0)NR10-,
  • R2 and R3 are combined to form - (CH2)s - ;
  • R 2 or R3 are combined with R ⁇ to form a ring such that
  • R4, R5, Rl3a and Rl3b are independently selected from: a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by C2-C20 alkenyl,
  • R6 is selected from: a) hydrogen, b) substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3-C10 cycloalkyl, C2-C2O alkenyl, C2-C20 alkynyl, C1-C2O perfluoroalkyl, allyloxy, F, Cl, Br, RlOO-, Rl lS(0) m -.
  • R7 is independently selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted C3-C10 cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C3- ClO cycloalkyl;
  • R8 is selected from: a) hydrogen, b) substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3-C10 cycloalkyl, C2-C20 alkenyl, C2-C2O alkynyl, C1-C20 perfluoroalkyl, allyloxy, F, Cl, Br, RlOO-, RllS(0)m-.
  • R9 is selected from: a) hydrogen, b) C2-C20 alkenyl, C2-C2O alkynyl, C2-C2O perfluoroalkyl, F, Cl, Br, RlOO-, R lS(0) m -, R1°C(0)NR10-, CN, N ⁇ 2,
  • R O is independently selected from hydrogen, C1-C6 alkyl, benzyl and aryl;
  • Rl 1 is independently selected from C1-C6 alkyl and aryl;
  • Rl 2 is independently selected from hydrogen, C1-C6 alkyl and aryl, or (Rl 2 )2 forms - (CH2)s - ;
  • V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C 1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if A 1 is S(0)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(0)m;
  • W is a heterocycle
  • Z is independently H2 or O
  • Rla and Rib are independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R80-, R9S(0) m -.
  • R S C(0)NR8-, CN, (R8)2N-C(NR8)-, R8C(0)-, R8 ⁇ C(0)-, N3, -N(R8)2, or R9 ⁇ C(0)-NR8- ;
  • R 2 a, R2b and R3 are independently selected from: a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by C2-C alkenyl, R80-, R 9 S(0)m- .
  • R4 and R ⁇ are independently selected from: a) hydrogen, and
  • R6 is independently selected from: a) hydrogen, b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, Br, R80-, R9S(0) m -, R8C(0)NR8-, CN, N ⁇ 2, R 8 2N-
  • R7 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C 1 -C6 perfluoroalkyl, F, Cl, Br, R80-, R9S(0)m-.
  • R8 is independently selected from hydrogen, C1-C6 alkyl, substituted or unsubstituted C 1-C6 aralkyl and substituted or unsubstituted aryl;
  • R9 is independently selected from C1-C6 alkyl and aryl
  • R O is independently selected from hydrogen, C1-C6 alkyl, substituted or unsubstituted C1-C6 aralkyl and substituted or unsubstituted aryl;
  • V is selected from: a) hydrogen, b) heterocycle, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if A 1 is S(0)m and V is not hydrogen if Al is a bond, n is 0 and A 2 is S(0)m;
  • W is a heterocycle
  • composition of the instant invention may alternatively or in addition comprise a protein substrate-competitive inhibitor obtained by fermentation of cultures of novel organisms.
  • a protein substrate-competitive inhibitor obtained by fermentation of cultures of novel organisms.
  • the compounds disclosed in the following patents and publications may be useful as a protein substrate-competitive inhibitor component of the instant composition: U.S. Pat. No. 5,420,334; and 08/435,047. Those patents and publications are incorporated herein by reference.
  • protein substrate-competitive inhibitors useful in the compositions of the invention are:
  • protein substrate-competitive inhibitors useful in the compositions of the invention are:
  • Nicotinoyl-isoleucyl-phenylalanyl-methionine
  • Nicotinoyl-isoleucyl-phenylalanyl-methionine methyl ester Nicotinoyl-isoleucyl-phenylalanyl-methionine methyl ester
  • composition of the instant invention also comprises a famesyl pyrophosphate-competitive inhibitor.
  • a famesyl pyrophosphate-competitive inhibitor such as:
  • Rl and R 2 are each independently selected from: a) H; b) Cl-5 alkyl; c) Cl-5 alkyl substituted with a member of the group consisting of: i) phenyl; ii) phenyl substituted with methyl, methoxy, halogen
  • Rl and R 2 are each independently selected from: a) H; b) Cl-5 alkyl; c) Cl-5 alkyl substituted with a member of the group consisting of: i) phenyl; ii) phenyl substituted with methyl, methoxy, halogen
  • Rl and R 2 are each independently selected from: a) H; b) Cl-5 alkyl; c) Cl-5 alkyl substituted with a member of the group consisting of: i) phenyl; ii) phenyl substituted with methyl, methoxy, halogen
  • n 0 to 4
  • Rl and R3 independently are C ⁇ -4 alkyl, substituted with substituents selected from the group consisting of: a) aryl, which is defined as phenyl or naphthyl, unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of: i) F, ⁇ ) Cl, iii) Br, iv) nitro, v) cyano, vi) Cl-8 alkoxy, vii) Cl-8 alkylthio, viii) Cl-8 alkylsulfonyl, ix) sulfamoyl, or x) Cl-8 alkyl; or b) heteroaryl, which is defined as indolyl, imidazolyl or pyridyl, unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of:
  • R 2 is: C ⁇ -6 alkyl, which is unsubstituted or substituted with a substituent selected from the group consisting of: a) unsubstituted or substituted aryl, as defined in Rl(a), b) unsubstituted or substituted heteroaryl, as defined in R!(b), c) C3-8 cycloalkyl, d) Cl-8 alkylthio, e) Cl-8 alkylsulfonyl, f) Cl-8 alkoxy, or g) aryl Cl-8 alkyl sulfonyl; and
  • R 4 is: H
  • R is H, lower alkyl, or CH2CH2N+Me3A";
  • Rl is H, lower alkyl, or CH2CH2N+Me3A";
  • A is a pharmaceutically acceptable anion; m is 0, 1, 2, or 3; and n is 0, 1, 2, or 3;
  • A is a C2-8 saturated or unsaturated aliphatic hydrocarbon group which may have substituent(s) selected from the group consisting of a lower alkyl group, a hydroxyl group, a lower hydroxyalkyl group, a lower alkoxy group, a carboxyl group, a lower carboxyalkyl group, an aryl group and an aralkyl group; each of X and Y which are the same or different, is an oxygen atom, a sulfur atom, a carbonyl group or a group of the formula -CHR - (wherein R a is a hydrogen atom or a lower alkyl group) or -NRb (wherein Rb is a hydrogen atom or a lower alkyl group), or X and Y together represent a vinylene group or an ethynylene group; each of Rl, R 2 , R3, R8 and R which are
  • A is a C2-8 saturated or unsaturated aliphatic hydrocarbon group which may have substituent(s) selected from the group consisting of a lower alkyl group, a hydroxyl group, a lower hydroxyalkyl group, a lower alkoxy group, a carboxyl group, a lower carboxyalkyl group, an aryl group and an aralkyl group;
  • Q is a group of the formula -(CH2)m- (wherein m is an integer of from 1 to 6) or -(CH2)n-W- (CH2)p- (wherein W is an oxygen atom, a sulfur atom, a vinylene group or an ethynylene group; and each of n and p which are the same or different, is an integer of from 0 to 3);
  • Rl is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group
  • famesyl pyrophosphate-competitive inhibitors include:
  • a further embodiment of the specific famesyl pyrophosphate-competitive inhibitors includes: disodium (3RS.4RS)-4-[N- ⁇ (lRS,2RS,4E)-5-(2-benzoxazolyl)-l-methyl-
  • composition of the instant invention may alternatively or in addition comprise a famesyl pyrophosphate-competitive inhibitor obtained by fermentation of cultures of novel organisms.
  • the compounds disclosed in the following patents and publications may be useful as a famesyl pyrophosphate-competitive inhibitor component of the instant composition: U.S. Ser. Nos. 08/ 254,228 and 08/435,047. Those patents and publications are incorporated herein by reference.
  • compounds described in the following patents and publications may also be utilized as a famesyl pyrophosphate- competitive inhibitor component of the instant composition: European Pat. Publ. 0 537 008; European Pat. Publ. 0 540 782; PCT Pat. Publs. WO 94/1935; WO 95/12572 ; and WO 95/08546.
  • Those patents and publications are incorporated herein by reference.
  • the protein substrate-competitive inhibitors and famesyl pyrophosphate-competitive inhibitors 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.
  • named amino acids are understood to have the natural "L" stereoconfiguration.
  • 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 heterocycle ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • 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, morpholinyl, naphthyridinyl, oxadiazoly
  • 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, CF3, NH2, N(Cl-C6 alkyl)2, N02, CN, (C1-C6 alkyl)0-, -OH, (C1-C6 alkyl)S(0)m-, (C1-C6 alkyl)C(0)NH-, H2N-C(NH)-, (C1-C6 alkyl)C(O)-, (Cl-C-6 alkyl)OC(O)-, N3,(C ⁇ -C6 alkyl)OC(0)NH- and C1-C20 alkyl.
  • cyclic amine moiety having 5 or 6 members in the ring, such a cyclic amine which may be optionally fused to a phenyl or cyclohexyl ring.
  • a cyclic amine moiety include, but are not limited to, the following specific structures:
  • substitution on the cyclic amine moiety by R a , R b, R7a nd R7b ma y be on different carbon atoms or on the same carbon atom.
  • cyclic moieties are formed. Examples of such cyclic moieties include, but are not limited to:
  • cyclic moieties as described hereinabove for 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:
  • nitrogen containing C4-C9 mono or bicyclic ring system wherein the non-nitrogen containing ring may be a C6 aromatic ring, a C5-C7 saturated ring or a heterocycle which defines moiety "Q" of the instant invention includes but is not limited to the following ring systems:
  • any substituent or variable e.g., RlO, Z, n, etc.
  • -N(Rl )2 represents -NHH, -NHCH3, -NHC2H5, etc.
  • substituents and substitution patterns on the protein substrate- competitive inhibitors and famesyl pyrophosphate-competitive inhibitors of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth below.
  • the pharmaceutically acceptable salts of the protein substrate-competitive inhibitors and famesyl pyrophosphate-competitive inhibitors of this invention include the conventional non-toxic salts of the compounds of this invention as formed, e.g., from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like: and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenyl-acetic, glutamic, benzoic, salicylic, sulfanilic, 2- acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
  • organic acids such as acetic, propionic, succinic, glyco
  • the pharmaceutically acceptable salts of the protein substrate-competitive inhibitors and famesyl pyrophosphate-competitive inhibitors of this invention can be synthesized from the corresponding inhibitor of this invention which contain a basic moiety by conventional chemical methods.
  • 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 aryl group means a phenyl group, a naphthyl group or an anthryl group. A phenyl group or a naphthyl group is preferred.
  • the heteroaromatic ring group means a 5-membered or
  • a furyl group, a thienyl group, a pyridyl group, a pyrimidinyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, a benzofuranyl group, a benzothienyl group, a benzimidazolyl group, a benzoxazolyl group, a benzothiazolyl group or a quinolyl group is preferred.

Landscapes

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

Abstract

L'invention concerne des compositions comprenant des quantités d'au moins deux agents thérapeutiques choisis dans un groupe constitué d'un inhibiteur de farnésyl-protéine transférase, lequel constitue un inhibiteur efficace de l'enzyme du fait qu'il se trouve en concurrence par rapport au substrat protéique de l'enzyme, et d'un inhibiteur de farnésyl-protéine transférase, lequel constitue un inhibiteur efficace de l'enzyme du fait qu'il se trouve en concurrence par rapport au farnésylpyrophosphate. L'invention concerne également des procédés d'inhibition de farnésyl-protéine transférase et de traitement du cancer chez un mammifère, lesquels procédés consistent à administrer audit mammifère, soit séquentiellement dans n'importe quel ordre soit simultanément, des doses d'au moins deux agents thérapeutiques choisis dans un groupe constitué d'un inhibiteur de farnésyl-protéine transférase, lequel constitue un inhibiteur efficace de l'enzyme du fait qu'il est un inhibiteur concurrentiel par rapport au substrat protéique de l'enzyme, et d'un inhibiteur de farnésyl-protéine transférase, lequel constitue un inhibiteur efficace de l'enzyme du fait qu'il est un inhibiteur concurrentiel par rapport au farnésyle pyrophosphate en des doses suffisantes pour obtenir un effet thérapeutique ou synergique. L'invention concerne en outre des procédés de préparation de ces compositions.
EP96923503A 1995-06-29 1996-06-26 Combinaisons d'inhibiteurs de farnesyl-proteine transferase Withdrawn EP0836383A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US225195P 1995-06-29 1995-06-29
US2251P 1995-06-29
GB9603091 1996-02-14
GBGB9603091.1A GB9603091D0 (en) 1996-02-14 1996-02-14 Combinations of inhibitors of farnesyl-protein transferase
PCT/US1996/011022 WO1997001275A1 (fr) 1995-06-29 1996-06-26 Combinaisons d'inhibiteurs de farnesyl-proteine transferase

Publications (1)

Publication Number Publication Date
EP0836383A1 true EP0836383A1 (fr) 1998-04-22

Family

ID=26308700

Family Applications (1)

Application Number Title Priority Date Filing Date
EP96923503A Withdrawn EP0836383A1 (fr) 1995-06-29 1996-06-26 Combinaisons d'inhibiteurs de farnesyl-proteine transferase

Country Status (5)

Country Link
EP (1) EP0836383A1 (fr)
JP (1) JP2000501063A (fr)
AU (1) AU714072B2 (fr)
CA (1) CA2225255A1 (fr)
WO (1) WO1997001275A1 (fr)

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU3192495A (en) * 1994-08-12 1996-03-07 Banyu Pharmaceutical Co., Ltd. N,n-disubstituted amic acid derivative
EP0856315B1 (fr) * 1995-08-09 2005-08-24 Banyu Pharmaceutical Co., Ltd. Inhibiteurs de la proteine farnesyltransferase en combinaison avec des inhibiteurs de hmgcoa-reductase pour le traitement de sida
EP0882701B1 (fr) * 1996-02-07 2002-07-24 Banyu Pharmaceutical Co., Ltd. Derives amides substitues
DE69714709T2 (de) * 1996-02-07 2003-04-10 Banyu Pharma Co Ltd Cyclische amic-säurederivate
AU1619497A (en) * 1996-02-07 1997-08-28 Banyu Pharmaceutical Co., Ltd. Substituted amide derivatives
EP0989114B1 (fr) * 1996-02-07 2002-07-24 Banyu Pharmaceutical Co., Ltd. Derives d'acides d'amides n,n-disubstitues
GB9801231D0 (en) 1997-06-05 1998-03-18 Merck & Co Inc A method of treating cancer
JP4091130B2 (ja) * 1997-06-09 2008-05-28 タカラバイオ株式会社 生理活性物質ｔｋｒ２４４９類、製造方法及び微生物
EP1159273A1 (fr) 1999-03-02 2001-12-05 Boehringer Ingelheim Pharmaceuticals Inc. Composes utiles en tant qu'inhibiteurs reversibles de la cathepsine s
US6420364B1 (en) 1999-09-13 2002-07-16 Boehringer Ingelheim Pharmaceuticals, Inc. Compound useful as reversible inhibitors of cysteine proteases
EP1261342A2 (fr) * 2000-02-29 2002-12-04 Janssen Pharmaceutica N.V. Combinaisons d'inhibiteur de farnesyl-proteine transferase
EP2124562B1 (fr) 2007-03-09 2016-04-20 Second Genome, Inc. Composés de bicyclohétéroaryle utilisés comme modulateurs de p2x7 et leurs utilisations
US20100227811A1 (en) * 2007-05-14 2010-09-09 University Of South Florida Farnesylamine derivatives and methods of use
CA2926950C (fr) 2013-10-10 2022-10-11 Eastern Virginia Medical School Derives de 4-((2-hydroxy-3-methoxybenzyl)amino) benzenesulfonamide commeinhibiteurs puissants et selectifs de 12-lipoxygenase
JO3637B1 (ar) 2015-04-28 2020-08-27 Janssen Sciences Ireland Uc مركبات بيرازولو- وترايازولو- بيريميدين مضادة للفيروسات rsv
TW201932470A (zh) 2017-11-29 2019-08-16 愛爾蘭商健生科學愛爾蘭無限公司 具有抗ｒｓｖ活性之吡唑并嘧啶
EP3746444B1 (fr) 2018-01-31 2023-09-27 Janssen Sciences Ireland Unlimited Company Pyrazolopyrimidines substituées de cycloalkyle présentant une activité contre le virus respiratoire syncytial
EA202092439A1 (ru) 2018-04-23 2021-03-05 Янссен Сайенсиз Айрлэнд Анлимитед Компани Гетероароматические соединения, обладающие активностью против rsv

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5298655A (en) * 1991-09-27 1994-03-29 Merck & Co., Inc. Farnesyl pyrophosphate analogs
US5340828A (en) * 1991-09-30 1994-08-23 Merck & Co., Inc. Inhibitors of farnesyl protein transferase
US5245061A (en) * 1991-12-16 1993-09-14 Merck & Co., Inc. Inhibitors of farnesyl protein transferase
US5352705A (en) * 1992-06-26 1994-10-04 Merck & Co., Inc. Inhibitors of farnesyl protein transferase
CA2165176A1 (fr) * 1993-06-18 1995-01-05 Samuel L. Graham Inhibiteurs de la farnesyl-proteine transferase
ATE188464T1 (de) * 1994-08-11 2000-01-15 Banyu Pharma Co Ltd Substituierte amidderivate

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9701275A1 *

Also Published As

Publication number Publication date
CA2225255A1 (fr) 1997-01-16
JP2000501063A (ja) 2000-02-02
WO1997001275A1 (fr) 1997-01-16
AU714072B2 (en) 1999-12-16
AU6399696A (en) 1997-01-30

Similar Documents

Publication Publication Date Title
EP0836383A1 (fr) Combinaisons d'inhibiteurs de farnesyl-proteine transferase
AU2802297A (en) A method of treating cancer
US6989383B1 (en) Method of treating cancer
JP3043815B2 (ja) ファルネシル蛋白トランスフェラーゼ阻害剤
US5736539A (en) Inhibitors of farnesyl-protein transferase
US5869682A (en) Inhibitors of farnesyl-protein transferase
AU701763B2 (en) Inhibitors of farnesyl protein transferase
KR19980703517A (ko) 파네실-단백질 트랜스퍼라제 억제제
JP2000504023A (ja) 癌治療方法
WO1998044797A1 (fr) Procede de traitement du cancer
AU5370196A (en) Inhibitors of farnesyl-protein transferase
WO1997036891A1 (fr) Inhibiteurs de la farnesyl-proteine transferase
WO1996034010A2 (fr) Inhibiteurs de la farnesyle transferase
WO1997036593A1 (fr) Inhibiteurs de la farnesyle-proteine transferase
US6160015A (en) Compounds useful in the treatment of neurofibromatosis
US5627202A (en) Inhibitors of farnesyl-protein transferase

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19980129

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU NL PT SE

RIN1 Information on inventor provided before grant (corrected)

Inventor name: YONEMOTO, MARI

Inventor name: NISHIMURA, SUSUMU

Inventor name: CASKEY, CHARLES, T.

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20020102