WO1997001275A1 - Combinaisons d'inhibiteurs de farnesyl-proteine transferase - Google Patents

Combinaisons d'inhibiteurs de farnesyl-proteine transferase Download PDF

Info

Publication number
WO1997001275A1
WO1997001275A1 PCT/US1996/011022 US9611022W WO9701275A1 WO 1997001275 A1 WO1997001275 A1 WO 1997001275A1 US 9611022 W US9611022 W US 9611022W WO 9701275 A1 WO9701275 A1 WO 9701275A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
unsubstituted
group
amino
alkyl
Prior art date
Application number
PCT/US1996/011022
Other languages
English (en)
Inventor
Charles T. Caskey
Susumu Nishimura
Mari Yonemoto
Original Assignee
Merck & Co., Inc.
Banyu Pharmaceutical Co., Ltd.
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 Merck & Co., Inc., Banyu Pharmaceutical Co., Ltd. filed Critical Merck & Co., Inc.
Priority to JP9504573A priority Critical patent/JP2000501063A/ja
Priority to AU63996/96A priority patent/AU714072B2/en
Priority to EP96923503A priority patent/EP0836383A1/fr
Publication of WO1997001275A1 publication Critical patent/WO1997001275A1/fr

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)).
  • Mutated ras genes are found in many human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias.
  • the protein products of these genes are defective in their GTPase activity and constitutively transmit a growth stimulatory signal.
  • Ras C-terminus contains a sequence motif termed a "CAAX” or "Cys-Aaa 1 -Aaa 2 -Xaa” box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al., Nature 310:583-586 (1984)).
  • this motif serves as a signal sequence for the enzymes farnesyl-protein transferase or geranylgeranyl-protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a 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
  • FPTase farnesyl-protein transferase
  • FPP famesyl diphosphate
  • Ras protein substrates
  • the protein substrate- competitive 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)).
  • protein substrate-competitive inhibitors that lack a thiol moiety have been described (WO 95/09000; WO 95/09001; WO 95/10514; WO 95/10515; WO 95/10516; WO 95/08542; WO 95/11917; and WO 95/12612).
  • Inhibitors of FPTase have recently been described that incorporate characteristics of both famesyl pyrophosphate and the CAAX motif (R.S. Bhide et al., Bioorg. Med. Chem. Lett., 4:2107-2112 (1994) and (V. Marine et al., Oncogene, 10:1763-1779 (1995)).
  • 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
  • a famesyl pyrophosphate-competitive inhibitor also referred to as a famesyl pyrophosphate-competitive inhibitor
  • 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, 1B and 1C In vivo Assessment of a Combination of Compound D and Compound E:
  • Figure 1A 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 1B 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.
  • 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.
  • 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.
  • a 1 an aliphatic amino acid
  • a 2 an aliphatic amino acid
  • X any amino acid; b) Cys - Xaa 1 - Xaa 2 - Xaa 3 - NRR 1 , wherein
  • Xaa 1 any amino acid in the natural L-isomer form
  • Xaa 2 any amino acid in the natural L-isomer form
  • Xaa 3 - NRR 1 an amide of any amino acid in the natural L- isomer form, wherein R and R 1 are independently selected from hydrogen, C 1 -C 12 alkyl, aralkyl, or unsubstituted or substituted aryl; c) Cys - Xaa 1 - Xaa 2 - Xaa 3 , wherein
  • Xaa 1 any amino acid
  • Xaa 2 the amino acid phenyl alanine or a p- fluorophenylalanine
  • Xaa 3 any amino acid; d) Cys - Xaa 1 _ dXaa 2 - Xaa 3 , wherein
  • Xaa 1 any amino acid in the natural L-isomer form
  • X, Y, and Z are independently H 2 or O, provided that at least one of these is H 2 ;
  • R 1 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 1 NH may be absent;
  • R 2 , R 3 and R 4 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 5 is H or a straight or branched chain aliphatic group, which may be substituted with an aromatic or heteroaromatic group; f) U.S. Pat. No. 5,340,828, incorporated herein by reference,
  • X and Y are independently H 2 or O, provided that at least one of these is H 2 ;
  • R 1 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 1 NH may be absent;
  • R 2 and R 3 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; g) U.S. Pat. No. 5,340,828, incorporated herein by reference,
  • X and Y are independently H 2 or O, provided that at least one of these is H 2 ;
  • R 1 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 1 NH may be absent;
  • R 2 and R 3 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;
  • X and Y are independently H 2 or O;
  • R 1 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;
  • R 3 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; i) U.S. Pat. No. 5,326,773; PCT Publication WO 94/10137 and U.S.
  • R 1 and R 5a are independently selected from:
  • R 2 , R 3 and R 4 are independently selected from:
  • R 5b is a C 1 -C 6 alkyl group, a C 1 -C 6 acyl group, an aroyl group, a
  • alkyl group and acyl group is optionally substituted with substituted or unsubstituted aryl or heterocycle
  • R 6 is a substituted or unsubstituted aliphatic, aryl or heterocyclic group, wherein the aliphatic substituent is optionally substituted with an aryl or heterocyclic ring
  • n is 0, 1 or 2
  • U.S. Pat. No. 5,504,212 incorporated herein by reference
  • R 1 is selected from:
  • R 2 , R 3 and R 4 are independently selected from:
  • R 6 is a substituted or unsubstituted aliphatic, aryl or heterocyclic group, wherein the aliphatic substituent is optionally substituted with an aryl or heterocyclic ring
  • n is 0, 1 or 2
  • R 1 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 , R 3 and R 5 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;
  • R 4 is hydrogen or an alkyl group, wherein the alkyl group comprises straight chain or branched chain hydrocarbons of 1 to 6 carbon atoms;
  • R 6 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;
  • T is O or S(O) m ;
  • n 0, 1 or 2;
  • n 0, 1 or 2;
  • X is O or H 2 ;
  • n 1 or 2;
  • n O or l
  • t 1 to 4.
  • R and R 1 are independently selected from H, C 1-4 alkyl, or aralkyl;
  • R 2 , R 3 , R 4 , and R 5 are independently selected from: H; C 1-8 alkyl, alkenyl, or
  • R 2 , R 3 , R 4 , and R 5 are optionally attached to the same carbon atom;
  • Y is aryl, heterocycle, unsubstituted or substituted with one or more of:
  • W is H 2 or O
  • Z is aryl, heteroaryl, arylmethyl, heteroarylmethyl
  • arylsulfonyl arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with one or more of the following:
  • R 6 , R 7 and R 8 are independently selected from: H; C 1-4 alkyl, C 3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
  • R 6 and R 7 may be joined in a ring
  • R 7 and R 8 may be joined in a ring
  • R 9 is C 1-4 alkyl or aralkyl; m) PCT Publication WO 96/09821 and U.S. Serial No. 08/315,059, incorporated herein by reference,
  • R 1 is selected from:
  • R 2a and R 2b are independently selected from:
  • R 9 OC(O)NR 8 -, and d) C 1 -C 6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C 3 - C 10 cycloalkyl;
  • R 3 and R 4 are independently selected from:
  • R 5a and R 5b are independently selected from:
  • R 5a and R 5b are combined to form - (CH 2 ) s - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O) m , -NC(O)-, and -N(COR 8 )- ; R 6 is
  • R 7a is selected from
  • R 7b is selected from
  • a sulfonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, cycloalkyl and C 1 -C 6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl;
  • R 8 is independently selected from hydrogen, C 1 -C 6 alkyl and aryl;
  • R 9 is independently selected from C 1 -C 6 alkyl and aryl;
  • R 10 is independently selected from hydrogen and C 1 -C 6 alkyl;
  • R 11 is independently selected from C 1 -C 6 alkyl;
  • Z 1 and Z 2 are independently H 2 or O, provided that Z 1 is not O when
  • X-Y is - C(O)N(R 7a )-; m is 0, 1 or 2;
  • q 0, 1 or 2;
  • s is 4 or 5;
  • t is 3, 4 or 5; n) PCT Publication WO 96/09820 and U.S. Serial No. 08/315,151, incorporated herein by reference,
  • R 1 is selected from:
  • R 2a and R 2b are independently selected from:
  • R 5 OC(O)-, N 3 , -N(R 5 ) 2 , or R 6 OC(O)NR 5 -, and c) aryl, heterocycle, cycloalkyl, alkenyl, R 5 O-, R 5 S(O) m -
  • R 5 C(O)NR 5 -, CN, NO 2 , (R 5 ) 2 N-C(NR 5 )-, R 5 C(O)-, R 5 OC(O)-, N 3 , -N(R 5 ) 2 , or R 6 OC(O)NR 5 -, R 3 is selected from:
  • R 4a is selected from
  • R 4b is selected from
  • R 5 is independently selected from hydrogen, C 1 -C 6 alkyl and aryl
  • R 6 is independently selected from C 1 -C 6 alkyl and aryl
  • Z is independently H 2 or O
  • n 0, 1, 2, 3 or 4;
  • X and Y are independently O or H 2 ;
  • n 1 or 2;
  • n 0 or 1
  • p 1, 2 or 3;
  • q 0, 1 or 2;
  • t 1 to 4.
  • R, R 1 and R 2 are independently selected from: H, C 1-6 alkyl, or C 1-6 aralkyl;
  • R 3 and R 4 are independently selected from: a) hydrogen,
  • W is -CHR 9 - or -NR 9 - ;
  • Z is unsubstituted or substituted C 1-8 alkyl, unsubstituted or substituted C 2-8 alkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle;
  • substituted group is substituted with one or more of:
  • R 5 is C 1-4 alkyl or aralkyl
  • R 6 , R 7 and R 8 are independently selected from: H, C 1-4 alkyl, C 3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
  • R 6 and R 7 may be joined in a ring
  • R 7 and R 8 may be joined in a ring;
  • R 9 is selected from: H, C 1-4 alkyl, C 3-6 cycloalkyl, heterocycle and aryl, unsubstituted, monosubstituted or disubstituted with substituents independently selected from:
  • R 10 and R 1 1 are independently selected from hydrogen, C 1 -C 6 alkyl,
  • 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
  • IV R 1 is selected from:
  • R 2a and R 2b are independently selected from:
  • R 2a and R 2b are combined to form - (CH 2 ) s - ;
  • R 3 and R 4 are independently selected from:
  • R 5a and R 5b are independently selected from:
  • R 5a and R 5b are combined to form - (CH 2 ) s - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O) m , -NC(O)-, and -N(C0R 8 )- ; R 6 is
  • R 7a is selected from
  • R 7b is selected from
  • R 8 is independently selected from hydrogen, C 1 -C 6 alkyl and aryl
  • R 9 is independently selected from C 1 -C 6 alkyl and aryl
  • R 10 is independently selected from hydrogen and C 1 -C 6 alkyl
  • R 1 1 is independently selected from C 1 -C 6 alkyl
  • Z is independently H 2 or O; m is 0, 1 or 2;
  • n 0, 1 or 2;
  • V is CH 2 , O, S, HN, or R 7 N;
  • R 2 , R 3 , R 4 and R 5 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;
  • R 6 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 7 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;
  • Z is H 2 or O
  • n 0, 1 or 2;
  • n 0, 1 or 2;
  • o 0, 1, 2 or 3;
  • R 1a is selected from:
  • R 1b is independently selected from:
  • R 1b is not R 10 C(O)NR 10 - when R 1 a is alkenyl, V is hydrogen and X-Y is -C(O)NR 7a -;
  • R 2a and R 2b are independently selected from:
  • substituent is selected from F, Cl, Br, N(R 10 ) 2 , NO 2 , R 10 O-, R 1 1 S(O) m -, R 10 C(O)NR 10 -, CN, (R 10 ) 2 N-C(NR 10 )-, R 10 C(O)-, R 10 OC(O)-, N 3 , -N(R 10 ) 2 , R 1 1 OC(O)NR 10 - and C 1 -C 20 alkyl, and d) C 1 -C 6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C 3 - C 10 cycloalkyl; or R 3 and R 4 are combined to form - (CH 2 ) s - ; R 5a and R 5b independently selected from:
  • substituent is selected from F, Cl, Br,
  • R 5a and R 5b are combined to form - (CH 2 ) s - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O) m . -NC(O)-, and -N(COR 10 )- ; R 6 is
  • R 7a is selected from
  • R 7b is selected from
  • R 8 is independently selected from:
  • R 9 is selected from:
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, R 10 O-, R 1 1 S(O) m -, R 10 C(O)NR 10 -, CN, NO 2 , N 3 , -N(R 10 ) 2 , and R 1 1 OC(O)NR 10 -; provided that R 9 is not R 10 C(O)NR 10 - when R 1 a is alkenyl, V is hydrogen and X-Y is -C(O)NR 7a -; R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and
  • R 11 is independently selected from C 1 -C 6 alkyl and aryl
  • R 12 is independently selected from hydrogen and C 1 -C 6 alkyl
  • R 13 is C 1 -C 6 alkyl
  • V is selected from:
  • W is -S(O) m -, -O-, -NHC(O)-, -C(O)NH-, -NHSO 2 -, -SO 2 NH-,
  • Z is independently H 2 or O; m is 0, 1 or 2;
  • n 0, 1, 2, 3 or 4, provided that n ⁇ 0 when V is hydrogen and W is
  • p is 0, 1, 2, 3 or 4, provided that p ⁇ 0 when R 9 is not hydrogen or
  • q 0, 1 or 2;
  • r is 0 or 1;
  • s is 4 or 5;
  • R 1 is hydrogen, C 1 -C 6 alkyl or aryl;
  • R 2a and R 2b are independently selected from:
  • substituent is selected from F, Cl, Br, NO 2 , R 9 O-, R 10 S(O) m -, R 9 C(O)NR 9 -, CN, (R 9 ) 2 N-
  • R 2a and R 2b are combined to form - (CH 2 ) s - ;
  • R 3 and R 4 are independently selected from:
  • substituent is selected from F, Cl, Br, NO 2 , R 9 O-, R 10 S(O) m -, R 9 C(O)NR 9 -, CN, (R 9 ) 2 N- C(NR 9 )-, R 9 C(O)-, R 9 OC(O)-, N 3 , -N(R 9 ) 2 , R 10 OC(O)NR 9 - and C 1 -C 20 alkyl, and
  • R 5a and R 5b are independently selected from:
  • substituent is selected from F, Cl, Br, NO 2 , R 9 O-, R 10 S(O) m -, R 9 C(O)NR 9 -, CN, (R 9 ) 2 N- C(NR 9 )-, R 9 C(O)-, R 9 OC(O)-, N 3 , -N(R 9 ) 2 , R 10 OC(O)NR 9 - and C 1 -C 20 alkyl, and
  • R 7a is selected from
  • R 7b is selected from
  • R 8a and R 8b are independently selected from:
  • R 9 is independently selected from hydrogen, C 1 -C 6 alkyl and aryl;
  • R 10 is independently selected from C 1 -C 6 alkyl and aryl;
  • R 11 is independently selected from hydrogen, C 1 -C 6 alkyl and aryl,
  • R 11 is C 1 -C 6 alkyl when n is 0;
  • R 12 is independently hydrogen or C 1 -C 6 alkyl;
  • R 13 is C 1 -C 6 alkyl; is aryl or 1,2,3,4-tetrahydronaphthyl;
  • Z is independently H 2 or O;
  • m is 0, 1 or 2;
  • n is independently 0 to 4.
  • p is 0 or 1 ;
  • q 0, 1 or 2;
  • R 1 is independently selected from:
  • R 2a and R 2b are independently selected from:
  • substituent is selected from F, Cl, Br, NO 2 , R 10 O-, R 1 1 S(O) m -, R 10 C(O)NR 10 -, CN, (R 10 ) 2 N-C(NR 10 )-, R 10 C(O)-, R 10 OC(O)-, N 3 , -N(R 10 ) 2 , R 11 OC(O)NR 10 - and C 1 -C 20 alkyl, and d) C 1 -C 6 alkyl substituted with an unsubstituted or
  • R 2a and R 2b are combined to form - (CH 2 ) s - ;
  • R 3 and R 4 are independently selected from:
  • substituent is selected from F, Cl, Br,
  • R 10 ) 2 N(R 10 ) 2 , NO 2 , R 10 O-, R 11 S(O) m -, R 10 C(O)NR 10 -, CN, (R 10 ) 2 N-C(NR 10 )-, R 10 C(O)-, R 10 OC(O)-, N 3 , -N(R 10 ) 2 , R 1 1 OC(O)NR 10 - and C 1 -C 20 alkyl, and d) C 1 -C 6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C 3 - C 10 cycloalkyl; or R 3 and R 4 are combined to form - (CH 2 ) s - ; R 5a and R 5b are independently selected from:
  • substituent is selected from F, Cl, Br,
  • R 10 is N(R 10 ) 2 , NO 2 , R 10 O-, R 1 1 S(O) m -, R 10 C(O)NR 10 -, CN, (R 10 ) 2 N-C(NR 10 )-, R 10 C(O)-, R 10 OC(O)-, N 3 , -N(R 10 ) 2 , R 11 OC(O)NR 10 - and C 1 -C 20 alkyl, and d) C 1 -C 6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C 3 - C 10 cycloalkyl; or R 5a and R 5b are combined to form - (CH 2 ) s - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O) m , -NC(O)-, and -N(COR 10 )- ; R 6 is
  • R 7a is selected from
  • R 7b is selected from
  • R 8 is independently selected from:
  • R 9 is selected from: a) hydrogen,
  • V is selected from:
  • V is not hydrogen if A 1 is S(O) m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O) m or a bond;
  • W is a heterocycle; Z is independently H 2 or O; m is 0, 1 or 2;
  • n 0, 1, 2, 3 or 4;
  • p 0, 1, 2, 3 or 4;
  • q 0, 1 or 2;
  • r is 0 to 5, provided that r is 0 when V is hydrogen;
  • R 1a and R 1b are independently selected from:
  • R 2a and R 2b are independently selected from:
  • R 3 and R 4 are independently selected from:
  • amino acid which is:
  • R 3 and R 4 are combined to form - (CH 2 ) s - ;
  • R 5a and R 5b are independently selected from:
  • R 5a and R 5b are combined to form - (CH 2 ) s - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O) m , -NC(O)-, and -N(COR 10 )- ;
  • R 6 is
  • R 7a is selected from
  • R 7b is selected from
  • R 8 is independently selected from:
  • R 10 is independently selected from H, C 1 -C 6 alkyl, benzyl, substituted aryl and C 1 -C 6 alkyl substituted with substituted aryl;
  • R 11 is independently selected from C 1 -C 6 alkyl and aryl;
  • R 12 is hydrogen or C 1 -C 6 alkyl;
  • R 13 is C 1 -C 6 alkyl;
  • V is not hydrogen if A 1 is S(O) m and V is not hydrogen if
  • a 1 is a bond, n is 0 and A 2 is S(O) m ;
  • W is a heterocycle
  • Z is independently H 2 or O; m is 0, 1 or 2;
  • n 0, 1, 2, 3 or 4;
  • p 0, 1, 2, 3 or 4;
  • q 0, 1 or 2;
  • r is 0 to 5, provided that r is 0 when V is hydrogen;
  • s 4 or 5;
  • t 3, 4 or 5;
  • u is 0 or 1
  • R 1 a and R 1b are independently selected from:
  • R 2a and R 2b are independently selected from:
  • R 3a and R 3b are independently selected from:
  • amino acid which is:
  • R 3a and R 3b are combined to form - (CH 2 ) s - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O) m, -NC(O)-, and -N(COR 10 )- ;
  • R 4 and R 5 are independently selected from:
  • R 7 is independently selected from:
  • perfluoroalkyl F, Cl, Br, R 10 O-, R 11 S(O) m -, R 10 C(O)NR 10 -, CN, NO 2 , R 10 2 N-C(NR 10 )-, R 10 C(O)-, R 10 OC(O)-, N 3 , -N(R 10 ) 2 , or R 11 OC(O)NR 10 -, and c) C 1 -C 6 alkyl unsubstituted or substituted by aryl,
  • heterocycle cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 10 O-, R 1 1 S(O) m -, R 10 C(O)NH-, CN, H 2 N- C(NH)-, R 10 C(O)-, R 10 OC(O)-, N 3 , -N(R 10 ) 2 , or
  • R 10 OC(O)NH-;
  • R 8 is selected from:
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and aryl; R 1 1 is independently selected from C 1 -C 6 alkyl and aryl; R 12 is independently selected from hydrogen and C 1 -C 6 alkyl; R 13 is independently selected from C 1 -C 6 alkyl;
  • V is selected from:
  • aryl d) C 1 -C 20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C 2 -C 20 alkenyl,
  • V is not hydrogen if A 1 is S(O) m and V is not hydrogen if
  • a 1 is a bond, n is 0 and A 2 is S(O) m ;
  • W is a heterocycle
  • Z is independently H 2 or O; m is 0, 1 or 2;
  • n 0, 1, 2, 3 or 4;
  • p 0, 1, 2, 3 or 4;
  • q 0, 1 or 2;
  • r is 0 to 5, provided that r is 0 when V is hydrogen;
  • s is 4 or 5;
  • u is 0 or 1
  • R 1a and R 1b are independently selected from: a) hydrogen,
  • R 2 and R 3 are independently selected from:
  • amino acid which is:
  • R 2 and R 3 are combined to form - (CH 2 ) s - ; or R 2 or R 3 are combined with R 6 to form a ring such that R 4a , R 4b , R 7a and R 7b are independently selected from:
  • R 11 S(O) m -, R 10 C(O)NR 10 -, CN, NO 2 , ( R 10 ) 2 N- C(NR 10 )-, R 10 C(O)-, R 10 OC(O)-, N 3 , -N(R 10 ) 2 , or R 1 1 OC(O)NR 10 -, and
  • R 5a and R 5b are independently selected from:
  • amino acid which is:
  • substituent is selected from F, Cl, Br, N(R 10 ) 2 , NO 2 , R 10 O-, R 1 1 S(O) m -, R 10 C(O)NR 10 -,
  • R 5a and R 5b are combined to form - (CH 2 ) s - wherein one of the carbon atoms is optionalljrreplaced by a moiety selected from: O, S(O) m, -NC(O)-, and -N(COR 10 )- ;
  • R 6 is independently selected from hydrogen or C 1 -C 6 alkyl;
  • R 8 is independently selected from:
  • perfluoroalkyl F, Cl, Br, R 10 O-, R 1 1 S(O) m -, R 10 C(O)NR 10 -, CN, NO 2 , R 10 2N-C(NR 10 )-, R 10 C(O)-, R 10 OC(O)-, N 3 , -N(R 10 ) 2 , or R 1 1 OC(O)NR 10 -, and c) C 1 -C 6 alkyl unsubstituted or substituted by aryl,
  • heterocycle cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 10 O-, R 1 1 S(O) m -, R 10 C(O)NH-, CN, H 2 N- C(NH)-, R 10 C(O)-, R 10 OC(O)-, N 3 , -N(R 10 ) 2 , or
  • R 10 OC(O)NH-;
  • R 9 is selected from:
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and aryl; R 1 1 is independently selected from C 1 -C 6 alkyl and aryl; R 12 is
  • R 13 is independently selected from hydrogen and C 1 -C 6 alkyl
  • R 14 is independently selected from C 1 -C 6 alkyl
  • Q is a substituted or unsubstituted nitrogen-containing C 4 -C 9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be an aromatic ring, a C 5 -C 7 saturated ring or a heterocycle;
  • V is selected from:
  • V is not hydrogen if A 1 is S(O) m and V is not hydrogen if
  • a 1 is a bond, n is 0 and A 2 is S(O) m ; W is a heterocycle;
  • X, Y and Z are independently H 2 or O; m is 0, 1 or 2;
  • n 0, 1, 2, 3 or 4;
  • p 0, 1, 2, 3 or 4;
  • q 0, 1 or 2;
  • r is 0 to 5, provided that r is 0 when V is hydrogen; s is 4 or 5;
  • t 3, 4 or 5;
  • u is 0 or 1
  • R 1 a and R 1b are independently selected from:
  • R 2 and R 3 are independently selected from: H; unsubstituted or substituted C 1-8 alkyl, unsubstituted or substituted C 2-8 alkenyl, unsubstituted or substituted C 2-8 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle,
  • substituted group is substituted with one or more of:
  • R 2 and R 3 are attached to the same C atom and are combined to form (CH 2 ) u - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O) m , -NC(O)-, and -N(COR 10 )- ;
  • R 4 is selected from H and CH 3 ; and any two of R 2 , R 3 and R 4 are optionally attached to the same carbon atom;
  • R 6 , R 7 and R 7a are independently selected from: H; C 1-4 alkyl, C 3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
  • R 6 and R 7 may be joined in a ring
  • R 7 and R 7a may be joined in a ring;
  • R 8 is independently selected from:
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and aryl; R 1 1 is independently selected from C 1 -C 6 alkyl and aryl;
  • G is H 2 or O
  • V is selected from:
  • V is not hydrogen if A 1 is S(O) m and V is not hydrogen if
  • a 1 is a bond, n is 0 and A 2 is S(O) m ;
  • W is a heterocycle
  • Y is aryl, heterocycle, unsubstituted or substituted with one or more of:
  • Z is aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with one or more of the following:
  • n 0, 1, 2, 3 or 4;
  • p 0, 1, 2, 3 or 4;
  • r is 0 to 5, provided that r is 0 when V is hydrogen;
  • s is 0 or 1;
  • t is 0 or 1
  • R 1a is independently selected from:
  • R 1b is independently selected from:
  • R 2 and R 3 are independently selected from:
  • amino acid which is:
  • R 2 and R 3 are combined to form - (CH 2 ) s - ;
  • R 2 or R 3 are combined with R 7 to form a ring such that
  • R 4 , R 5 , R 13a and R 13b are independently selected from:
  • R 6 is selected from:
  • R 10 2 N-C(NR 10 )-, R 10 C(O)-, N 3 , -N(R 10 ) 2 , (R 12 ) 2 NC(O)- or R 1 1 OC(O)NR 10 -, and
  • R 7 is independently selected from
  • R 8 is selected from:
  • R 10 C(O)NH-, CN, H 2 N-C(NH)-, R 10 C(O)-, R 10 OC(O)-, N 3 , -N(R 10 ) 2 , or R 10 OC(O)NH-;
  • R 9 is selected from:
  • R 10 C(O)NR 10 -, CN, (R 10 ) 2 N-C(NR 10 )-, R 10 C(O)-, R 10 OC(O)-, N 3 , -N(R 10 ) 2 , or R 1 1 OC(O)NR 10 -;
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and aryl;
  • R 1 1 is independently selected from C 1 -C 6 alkyl and aryl;
  • R 12 is independently selected from hydrogen, C 1 -C 6 alkyl and aryl, or (R 12 ) 2 forms - (CH 2 ) s - ;
  • V is selected from:
  • V is not hydrogen if A 1 is S(O) m and V is not hydrogen if
  • a 1 is a bond, n is 0 and A 2 is S(O) m ;
  • W is a heterocycle
  • Z is independently H 2 or O; m is 0, 1 or 2;
  • n 0, 1, 2, 3 or 4;
  • p 0, 1, 2, 3 or 4;
  • q 0, 1, 2, 3 or 4;
  • r is 0 to 5, provided that r is 0 when V is hydrogen;
  • s is 4 or 5;
  • t is 3, 4 or 5; and aa) U.S. Serial No. 08/449,038, incorporated herein by reference,
  • R 1 a and R 1b are independently selected from:
  • R 2a , R 2b and R 3 are independently selected from:
  • R 4 and R 5 are independently selected from:
  • R 6 is independently selected from:
  • R 8 is independently selected from hydrogen, C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 aralkyl and substituted or unsubstituted aryl;
  • R 9 is independently selected from C 1 -C 6 alkyl and aryl;
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 aralkyl and substituted or unsubstituted aryl;
  • V is selected from:
  • V is not hydrogen if A 1 is S(O) m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O) m ;
  • n 0, 1, 2, 3 or 4;
  • p 0, 1, 2, 3 or 4;
  • r is 0 to 5, provided that r is 0 when V is hydrogen; and u is 0 or 1; or the pharmaceutically acceptable salts thereof.
  • 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: 5(S)-[2(R)-amino-3-merca ⁇ to ⁇ ropylamino]-6(S)-methyl-2(R)-n-propyl-3,4-E-octenoyl-homoserine, and the corresponding homoserine lactone,
  • homoserine lactone 5(S)-[2(R)-amino-3-mercaptopro ⁇ ylamino]-6(S)-methyl-2(R)-benzyl-3,4-E-octenoyl-homoserine, and the corresponding homoserine lactone,
  • N-(2(R)-Amino-3-mercaptopropyl)isoleucyl-phenylalanyl-homocysteine lactone N-[2(S)-(2(R)-Amino-3-mercapto ⁇ ropyl)-3(S)-methylpentyl]-isoleucyl-homoserine lactone, N-[N'-(2(R)-Amino-3-mercaptopropyl)isoleucyl-phenylalanyl]-3(S)-amino-tetrahydropyran-2-one,
  • Nicotinoyl-isoleucyl-phenylalanyl-methionine Nicotinoyl-isoleucyl-phenylalanyl-methionine methyl ester;

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.
PCT/US1996/011022 1995-06-29 1996-06-26 Combinaisons d'inhibiteurs de farnesyl-proteine transferase WO1997001275A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP9504573A JP2000501063A (ja) 1995-06-29 1996-06-26 ファルネシル−タンパク質トランスフェラーゼ阻害剤の組み合わせ
AU63996/96A AU714072B2 (en) 1995-06-29 1996-06-26 Combinations of inhibitors of farnesyl-protein transferase
EP96923503A EP0836383A1 (fr) 1995-06-29 1996-06-26 Combinaisons d'inhibiteurs de farnesyl-proteine transferase

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US225195P 1995-06-29 1995-06-29
US60/002.251 1995-06-29
GB9603091.1 1996-02-14
GBGB9603091.1A GB9603091D0 (en) 1996-02-14 1996-02-14 Combinations of inhibitors of farnesyl-protein transferase

Publications (1)

Publication Number Publication Date
WO1997001275A1 true WO1997001275A1 (fr) 1997-01-16

Family

ID=26308700

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1996/011022 WO1997001275A1 (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)

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997029075A1 (fr) * 1996-02-07 1997-08-14 Banyu Pharmaceutical Co., Ltd. Derives d'amides substitues
EP0805154A1 (fr) * 1994-08-12 1997-11-05 Banyu Pharmaceutical Co., Ltd. Derive d'acide amique n,n-bisubstitue
EP0856315A1 (fr) * 1995-08-09 1998-08-05 Banyu Pharmaceutical Co., Ltd. Composition medicinale
EP0882701A1 (fr) * 1996-02-07 1998-12-09 Banyu Pharmaceutical Co., Ltd. Derives amides substitues
EP0882703A1 (fr) * 1996-02-07 1998-12-09 Banyu Pharmaceutical Co., Ltd. Derives d'acides d'amides cycliques
WO1998056755A1 (fr) * 1997-06-09 1998-12-17 Takara Shuzo Co., Ltd. Substances physiologiquement actives tkr2449, leur procede de preparation et micro-organisme
EP0989114A1 (fr) * 1996-02-07 2000-03-29 Banyu Pharmaceutical Co., Ltd. Derives d'acides d'amides n,n-disubstitues
WO2001064218A2 (fr) * 2000-02-29 2001-09-07 Janssen Pharmaceutica N.V. Combinaisons d'inhibiteur de farnesyl-proteine transferase
US6730671B2 (en) 1999-03-02 2004-05-04 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as reversible inhibitors of cathespin S
US6756372B2 (en) 1999-09-13 2004-06-29 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as reversible inhibitors of cysteine proteases
US6989383B1 (en) 1997-06-05 2006-01-24 Sloan-Kettering Institute For Cancer Research Method of treating cancer
US20100227811A1 (en) * 2007-05-14 2010-09-09 University Of South Florida Farnesylamine derivatives and methods of use
US8093265B2 (en) 2007-03-09 2012-01-10 Renovis, Inc. Bicycloheteroaryl compounds as P2X7 modulators and uses thereof
US10208048B2 (en) 2015-04-28 2019-02-19 Janssen Sciences Ireland Uc RSV antiviral pyrazolo- and triazolo-pyrimidine compounds
US10266488B2 (en) 2013-10-10 2019-04-23 Eastern Virginia Medical School 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide derivatives as potent and selective inhibitors of 12-lipoxygenase
US11339165B2 (en) 2017-11-29 2022-05-24 Janssen Sciences Ireland Unlimited Company Pyrazolopyrimidines having activity against the respiratory syncytial virus (RSV)
US11491157B2 (en) 2018-01-31 2022-11-08 Janssen Sciences Ireland Unlimited Company Co Cork, IE Cycloalkyl substituted pyrazolopyrimidines having activity against RSV
US11708369B2 (en) 2018-04-23 2023-07-25 Janssen Sciences Ireland Unlimited Company Heteroaromatic compounds having activity against RSV

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5340828A (en) * 1991-09-30 1994-08-23 Merck & Co., Inc. Inhibitors of farnesyl protein transferase
US5350867A (en) * 1991-12-16 1994-09-27 Merck & Co., Inc. Inhibitors of farnesyl protein transferase
US5352705A (en) * 1992-06-26 1994-10-04 Merck & Co., Inc. Inhibitors of farnesyl protein transferase
US5362906A (en) * 1991-09-27 1994-11-08 Merck & Co., Inc. Farnesyl pyrophosphate analogs
WO1995000497A1 (fr) * 1993-06-18 1995-01-05 Merck & Co., Inc. Inhibiteurs de farnesyle-proteine transferase
WO1996005168A1 (fr) * 1994-08-11 1996-02-22 Banyu Pharmaceutical Co., Ltd. Derive d'amide substitue

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5362906A (en) * 1991-09-27 1994-11-08 Merck & Co., Inc. Farnesyl pyrophosphate analogs
US5340828A (en) * 1991-09-30 1994-08-23 Merck & Co., Inc. Inhibitors of farnesyl protein transferase
US5350867A (en) * 1991-12-16 1994-09-27 Merck & Co., Inc. Inhibitors of farnesyl protein transferase
US5352705A (en) * 1992-06-26 1994-10-04 Merck & Co., Inc. Inhibitors of farnesyl protein transferase
WO1995000497A1 (fr) * 1993-06-18 1995-01-05 Merck & Co., Inc. Inhibiteurs de farnesyle-proteine transferase
WO1996005168A1 (fr) * 1994-08-11 1996-02-22 Banyu Pharmaceutical Co., Ltd. Derive d'amide substitue

Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5919786A (en) * 1994-08-12 1999-07-06 Banyu Pharmaceutical Co., Ltd. N,N-disubstituted amic acid derivatives
EP0805154A1 (fr) * 1994-08-12 1997-11-05 Banyu Pharmaceutical Co., Ltd. Derive d'acide amique n,n-bisubstitue
EP0805154A4 (fr) * 1994-08-12 1997-11-05
US6017956A (en) * 1994-08-12 2000-01-25 Banyu Pharmaceutical Co., Ltd. N,N-disubstituted amic acid derivatives
US5849747A (en) * 1994-08-12 1998-12-15 Banyu Pharmaceutical Co., Ltd. N, n-disubstituted amic acid derivatives
EP0856315A1 (fr) * 1995-08-09 1998-08-05 Banyu Pharmaceutical Co., Ltd. Composition medicinale
EP0856315A4 (fr) * 1995-08-09 2003-04-23 Banyu Pharma Co Ltd Composition medicinale
EP0882701A1 (fr) * 1996-02-07 1998-12-09 Banyu Pharmaceutical Co., Ltd. Derives amides substitues
EP0882703A1 (fr) * 1996-02-07 1998-12-09 Banyu Pharmaceutical Co., Ltd. Derives d'acides d'amides cycliques
EP0989114A1 (fr) * 1996-02-07 2000-03-29 Banyu Pharmaceutical Co., Ltd. Derives d'acides d'amides n,n-disubstitues
EP0989114A4 (fr) * 1996-02-07 2000-08-02 Banyu Pharma Co Ltd Derives d'acides d'amides n,n-disubstitues
EP0882701A4 (fr) * 1996-02-07 2000-08-02 Banyu Pharma Co Ltd Derives amides substitues
EP0882703A4 (fr) * 1996-02-07 2000-08-02 Banyu Pharma Co Ltd Derives d'acides d'amides cycliques
WO1997029075A1 (fr) * 1996-02-07 1997-08-14 Banyu Pharmaceutical Co., Ltd. Derives d'amides substitues
US6989383B1 (en) 1997-06-05 2006-01-24 Sloan-Kettering Institute For Cancer Research Method of treating cancer
WO1998056755A1 (fr) * 1997-06-09 1998-12-17 Takara Shuzo Co., Ltd. Substances physiologiquement actives tkr2449, leur procede de preparation et micro-organisme
US6303350B1 (en) 1997-06-09 2001-10-16 Takara Shuzo Co., Ltd. Physiologically active substances TKR2449, process for producing the same, and microorganism
US6730671B2 (en) 1999-03-02 2004-05-04 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as reversible inhibitors of cathespin S
US6756372B2 (en) 1999-09-13 2004-06-29 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as reversible inhibitors of cysteine proteases
WO2001064218A3 (fr) * 2000-02-29 2002-03-21 Janssen Pharmaceutica Nv Combinaisons d'inhibiteur de farnesyl-proteine transferase
WO2001064218A2 (fr) * 2000-02-29 2001-09-07 Janssen Pharmaceutica N.V. Combinaisons d'inhibiteur de farnesyl-proteine transferase
US8093265B2 (en) 2007-03-09 2012-01-10 Renovis, Inc. Bicycloheteroaryl compounds as P2X7 modulators and uses thereof
US20100227811A1 (en) * 2007-05-14 2010-09-09 University Of South Florida Farnesylamine derivatives and methods of use
US10266488B2 (en) 2013-10-10 2019-04-23 Eastern Virginia Medical School 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide derivatives as potent and selective inhibitors of 12-lipoxygenase
US10752581B2 (en) 2013-10-10 2020-08-25 Eastern Virginia Medical School 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide derivatives as potent and selective inhibitors of 12-lipoxygenase
US11274077B2 (en) 2013-10-10 2022-03-15 Eastern Virginia Medical School 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide derivatives as potent and selective inhibitors of 12-lipoxygenase
US10208048B2 (en) 2015-04-28 2019-02-19 Janssen Sciences Ireland Uc RSV antiviral pyrazolo- and triazolo-pyrimidine compounds
US10611769B2 (en) 2015-04-28 2020-04-07 Janssen Sciences Ireland Unlimited Company RSV antiviral pyrazolo- and triazolo-pyrimidine compounds
US11084826B2 (en) 2015-04-28 2021-08-10 Janssen Sciences Ireland Unlimited Company RSV antiviral pyrazolo- and triazolo-pyrimidine compounds
US11339165B2 (en) 2017-11-29 2022-05-24 Janssen Sciences Ireland Unlimited Company Pyrazolopyrimidines having activity against the respiratory syncytial virus (RSV)
US11491157B2 (en) 2018-01-31 2022-11-08 Janssen Sciences Ireland Unlimited Company Co Cork, IE Cycloalkyl substituted pyrazolopyrimidines having activity against RSV
US11708369B2 (en) 2018-04-23 2023-07-25 Janssen Sciences Ireland Unlimited Company Heteroaromatic compounds having activity against RSV

Also Published As

Publication number Publication date
CA2225255A1 (fr) 1997-01-16
JP2000501063A (ja) 2000-02-02
AU714072B2 (en) 1999-12-16
AU6399696A (en) 1997-01-30
EP0836383A1 (fr) 1998-04-22

Similar Documents

Publication Publication Date Title
WO1997001275A1 (fr) Combinaisons d'inhibiteurs de farnesyl-proteine transferase
AU2802297A (en) A 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
US6989383B1 (en) Method of treating cancer
US5736539A (en) Inhibitors of farnesyl-protein transferase
US5534537A (en) Prodrugs of inhibitors of farnesyl-protein transferase
US5869682A (en) Inhibitors of farnesyl-protein transferase
EP0821675A1 (fr) Nouveaux composes d'acides hydroxamiques et d'aminocarboxylates servant d'inhibiteurs des metalloproteases et du tnf
KR19980703517A (ko) 파네실-단백질 트랜스퍼라제 억제제
CZ176298A3 (cs) Sloučeniny inhibující proteázy retrovirů
WO1995029892A1 (fr) Derives d'acides hydroxamiques et d'acides amines et leur utilisation comme agents antiarthritiques
WO1997027852A1 (fr) Inhibiteurs de la farnesyle transferase
AU2722197A (en) A method of treating 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
US5523456A (en) Inhibitors of farnesyl-protein transferase
JP2001514011A (ja) 癌の治療方法

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

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

AL Designated countries for regional patents

Kind code of ref document: A1

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

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

Ref document number: 1996923503

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2225255

Country of ref document: CA

Ref country code: CA

Ref document number: 2225255

Kind code of ref document: A

Format of ref document f/p: F

ENP Entry into the national phase

Ref country code: JP

Ref document number: 1997 504573

Kind code of ref document: A

Format of ref document f/p: F

WWP Wipo information: published in national office

Ref document number: 1996923503

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1996923503

Country of ref document: EP