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WO1997036605A1 - Inhibiteurs de farnesyl-proteine transferase - Google Patents

Inhibiteurs de farnesyl-proteine transferase Download PDF

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Publication number
WO1997036605A1
WO1997036605A1 PCT/US1997/004713 US9704713W WO9736605A1 WO 1997036605 A1 WO1997036605 A1 WO 1997036605A1 US 9704713 W US9704713 W US 9704713W WO 9736605 A1 WO9736605 A1 WO 9736605A1
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substituted
alkyl
aryl
unsubstituted
heterocycle
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PCT/US1997/004713
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English (en)
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Samuel L. Graham
Theresa M. Williams
John S. Wai
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Merck & Co., Inc.
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Priority claimed from GBGB9609667.2A external-priority patent/GB9609667D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to JP9535348A priority Critical patent/JP2000508631A/ja
Priority to EP97916942A priority patent/EP0897303A1/fr
Priority to AU25425/97A priority patent/AU717190B2/en
Publication of WO1997036605A1 publication Critical patent/WO1997036605A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • Ras proteins are part of a signalling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation.
  • Biological and biochemical studies of Ras action indicate that Ras functions like a G-regulatory protein.
  • Ras In the inactive state, Ras is bound to GDP.
  • Ras Upon growth factor receptor activation Ras is induced to exchange GDP for GTP and undergoes a conformational change.
  • the GTP-bound form of Ras propagates the growth stimulatory signal until the signal is terminated by the intrinsic GTPase activity of Ras, which returns the protein to its inactive GDP bound form (D.R. Lowy and D.M.
  • Mutated ras genes (Ha-ras, Ki4a-ras, Ki4b-ras and N-ras) are found in many human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias. The protein products of these genes are defective in their GTPase activity and constitutively transmit a growth stimulatory signal.
  • Ras C-terminus contains a sequence motif termed a "CAAX” or "Cys-Aaa 1 -Aaa 2 -Xaa” box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al., Nature 310:583-586 (1984)).
  • this motif serves as a signal sequence for the enzymes farnesyl-protein transferase or geranylgeranyl-protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a C 1 5 or C20 isoprenoid, respectively.
  • the Ras protein is one of several proteins that are known to undergo post-translational farnesylation.
  • 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 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
  • Farnesyl-protein transferase utilizes famesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a farnesyl group (Reiss et al., Cell, 62:81 -88 (1990); Schaber et al., J. Biol. Chem., 265: 14701-14704 (1990); Schafer et al., Science, 249: 1 133-1 139 (1990); Manne et al., Proc. Natl. Acad. Sci USA , 87:7541 -7545 (1990)).
  • FPTase farnesyl-protein transferase
  • FPP farnesyl diphosphate
  • Ras protein substrates
  • the peptide derived inhibitors that have been described are generally cysteine containing molecules that are related to the CAAX motif that is the signal for protein prenylation. (Schaber et al., ibid; Reiss et. al., ibid; Reiss et al., PNAS, 88:132-136 (1991)).
  • 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.
  • transferase inhibitors are inhibitors of proliferation of vascular smooth muscle cells and are therefore useful in the prevention and therapy of arteriosclerosis and diabetic disturbance of blood vessels (JP H7- 1 12930).
  • the present invention comprises peptidomimetic
  • piperidinone-containing compounds which inhibit the farnesyl-protein transferase.
  • the instant compounds lack a thiol moiety and thus offer 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.
  • chemotherapeutic compositions containing these farnesyl transferase inhibitors and methods for their production.
  • the compounds of this invention are useful in the inhibition of farnesyl-protein transferase and the farnesylation of the oncogene protein Ras.
  • the inhibitors of farnesyl-protein transferase are illustrated by the formula A:
  • R 1 a and R 1 b are independently selected from:
  • substitutent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 10 O-,
  • R 2 and R 3 are independently selected from: H; unsubstituted or
  • 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 and R 5 are independently selected from H and CH 3 ; and any two of R 2 , R 3 , R 4 and R 5 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 and heteroaryl sulfonyl, 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 6a is selected from: C 1 -4 alkyl, C 3 -6 cycloalkyl, heterocycle and aryl, unsubstituted or substituted with:
  • R 8 is independently selected from:
  • cyanophenyl heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 O-,
  • 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
  • G 1 and G 2 are independently oxygen or absent, provided that at least one of G 1 and G 2 is oxygen;
  • G 3 is oxygen or H 2 ;
  • 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
  • substituted heterocycle wherein the substituted aryl or substituted heterocycle is substituted with one or more of:
  • n 0, 1 , 2, 3 or 4;
  • p 0, 1 , 2, 3 or 4;
  • q 1 or 2;
  • r is 0 to 5, provided that r is 0 when V is hydrogen;
  • s is 0 or 1 ;
  • t is 0 or 1 ;
  • u 4 or 5; or the pharmaceutically acceptable salts thereof.
  • the inhibitors of farnesyl-protein transferase are illustrated by the formula B:
  • R 1 a and R 1 b are independently selected from:
  • R 10 C(O)-, N 3 , -N(R 10 ) 2 , or R 1 1 OC(O)NR 10 -, and c) unsubstituted or substituted C 1 -C 6 alkyl wherein the
  • substitutent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 10 0-, R 1 1 S(O) m -, R 10 C(O)NR 10 -, (R 10 ) 2 NC(O)-, R 10 2 N- C(NR 10 )-, CN, R 10 C(O)-, N 3 , -N(R 10 ) 2 , and R 11 OC(O)- NR 10 -;
  • R 2 and R 3 are independently selected from: H; unsubstituted or
  • 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 and 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 6a is selected from: C 1 -4 alkyl, C 3 -6 cycloalkyl, heterocycle and aryl, unsubstituted or substituted with:
  • R 8 is independently selected from:
  • cyanophenyl heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 O-, R 1 1 S(O) m -, R 10 C(O)NH-, (R 10 ) 2 NC(O)-, R 10 2 N- C(NR 10 )-, CN, R 10 C(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;
  • G 1 and G 2 are independently oxygen or absent provided that at least one of G 1 and G 2 is oxygen;
  • 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 selected from:
  • heteroaryl arylmethyl, heteroarylmethyl, arylsulfonyl and heteroarylsulfonyl, wherein the substituted group is substituted with one or more of the following:
  • n 0, 1 , 2, 3 or 4;
  • p 0, 1 , 2, 3 or 4;
  • q 1 or 2;
  • r is 0 to 5, provided that r is 0 when V is hydrogen;
  • s is 0 or 1 ;
  • t is 0 or 1
  • u is 4 or 5; or the pharmaceutically acceptable salts thereof.
  • R 1 a and R 1 b are independently selected from:
  • substitutent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 10 O-, R 11 S(O) m -, R 10 C(O)NR 10 -, (R 10 ) 2 NC(O)-, R 10 2 N- C(NR 10 )-, CN, R 10 C(O)-, R 10 OC(O)-, N 3 , -N(R 10 ) 2 , and R 1 1 OC(O)-NR 10 - ;
  • R 2 and R 3 are independently selected from: H; unsubstituted or
  • 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 and 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 6a is selected from: C 1 -4 alkyl, C 3 -6 cycloalkyl, heterocycle and aryl, unsubstituted or substituted with:
  • R 8 is independently selected from:
  • cyanophenyl heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, perfluoroalkyl, F, Cl, Br, R 10 O-,
  • 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
  • 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 selected from: 1 ) a unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroaryImethyl, arylsulfonyl and heteroarylsulfonyl, wherein the substituted group is substituted with one or more of the following:
  • n 0, 1 , 2, 3 or 4;
  • r is 0 to 5, provided that r is 0 when V is hydrogen;
  • s 1 ;
  • t is 0 or 1 ;
  • u is 4 or 5; or the pharmaceutically acceptable salts thereof.
  • the inhibitors of farnesyl-protein transferase are illustrated by the formula B:
  • R 1 a is independently selected from: hydrogen and C 1 -C 6 alkyl
  • R 1 b is independently selected from:
  • substitutent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, cycloalkyl, alkenyl, R 10 O- and -N(R 10 ) 2 ;
  • R 3 and R 4 are independently selected from H and CH 3 ;
  • R 2 is H; or C 1 -5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
  • R 6 , R 7 and R 7a are independently selected from:
  • R 6a is selected from:
  • R 8 is independently selected from:
  • R 9 is selected from:
  • perfluoroalkyl F, Cl, 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)-, -N(R 10 ) 2 , or
  • R 1 1 OC(O)NR 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;
  • V is selected from:
  • heterocycle selected from pyrrolidinyl, imidazolyl,
  • 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 ;
  • G 1 is absent
  • G 2 is oxygen
  • W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl and
  • Z is selected from:
  • heteroaryl arylmethyl, heteroaryImethyl, arylsulfonyl and heteroarylsulfonyl, wherein the substituted group is 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 ;
  • u is 4 or 5; or the pharmaceutically acceptable salts thereof.
  • R 1 a is selected from: hydrogen and C 1 -C 6 alkyl; R 1 b is independently selected from:
  • heterocycle cycloalkyl, alkenyl, R 10 O-, or -N(R 10 ) 2 ;
  • R 3 and R 4 independently selected from H and CH 3 ;
  • R 2 is selected from H; and C 1 -5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
  • R 6 and R 7 are independently selected from:
  • R 6a is selected from:
  • R 8 is independently selected from:
  • perfluoroalkyl F, Cl, R 10 O-, R 10 C(O)NR 10 -, CN, NO 2 ,
  • R 9a is hydrogen or methyl
  • 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;
  • V is selected from:
  • heterocycle selected from pyrrolidinyl, imidazolyl,
  • 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 ;
  • Z is selected from:
  • heteroaryl arylmethyl, heteroarylmethyl, arylsulfonyl and heteroarylsulfonyl, wherein the substituted group is 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; or the pharmaceutically acceptable salts thereof.
  • the inhibitors of farnesyl-protein transferase are illustrated by the formula E:
  • R 1 b is independently selected from:
  • heterocycle cycloalkyl, alkenyl, R 1 0 O-, or -N(R 10 ) 2 ;
  • R 3 and R 4 independently selected from H and CH 3 ;
  • R 2 is selected from H; and C 1 -5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
  • R 6 and R 7 are independently selected from:
  • R 6a is selected from:
  • R 8 is independently selected from:
  • perfluoroalkyl F, Cl, R 10 O-, R 10 C(O)NR 10 -, CN, NO 2 , (R 10 ) 2 N-C(NR 10 )-, R 10 C(O)-, -N(R 10 ) 2 , or R 1 1 OC(O)NR 10 -, and
  • heteroaryl arylmethyl, heteroarylmethyl, arylsulfonyl and heteroarylsulfonyl, wherein the substituted group is substituted with one or more of the following:
  • p is 0, 1 , 2, 3 or 4; or the pharmaceutically acceptable salts thereof.
  • the inhibitors of farnesyl-protein transferase are illustrated by the formula F:
  • R 1 b is independently selected from:
  • heterocycle cycloalkyl, alkenyl, R 10 O-, or -N(R 10 ) 2 ;
  • R 3 and R 4 independently selected from H and CH 3 ;
  • R 2 is selected from H; and C 1 -5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of:
  • R 6 and R 7 are independently selected from:
  • R 6a 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
  • Z is selected from:
  • heteroaryl arylmethyl, heteroarylmethyl, arylsulfonyl and heteroarylsulfonyl, wherein the substituted group is substituted with one or more of the following:
  • p is 0, 1 , 2, 3 or 4; or the pharmaceutically acceptable salts thereof.
  • Examples of the compounds of this invention are as follows: 4-[5-(4-Cyanobenzyl)imidazol-1-ylmethyl]-1 -phenyl-2-piperidinone
  • the compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention.
  • any variable e.g. aryl, heterocycle, R 1 , R 2 etc.
  • its definition on each occurence is independent at every other occurence.
  • combinations of substituents/or variables are permissible only if such combinations result in stable compounds.
  • alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; “alkoxy” represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge.
  • Halogen or “halo” as used herein means fluoro, chloro, bromo and iodo.
  • aryl is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
  • heterocycle or heterocyclic represents a stable 5- to 7-membered monocyclic or stable 8- to 11- membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl,
  • heteroaryl is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic and wherein from one to four carbon atoms are replaced by heteroatoms selected from the group consisting of N, O, and S.
  • heterocyclic elements include, but are not limited to, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl,
  • the substituted group intended to mean a substituted C 1 -8 alkyl, substituted C 2-8 alkenyl, substituted C 2-8 alkynyl, substituted aryl or substituted heterocycle from which the substitutent(s) R 2 and R 3 are selected.
  • the substituted C 1 -8 alkyl, substituted C 3-6 cycloalkyl, substituted aroyl, substituted aryl, substituted heteroaroyl, substituted arylsulfonyl, substituted heteroarylsulfonyl and substituted heterocycle include moieties containing from 1 to 3 substitutents in addition to the point of attachment to the rest of the compound.
  • substituted aryl includes moieties containing from 1 to 3 substitutents in addition to the point of attachment to the rest of the compound.
  • such substitutents are selected from the group which includes but is not limited to F, Cl, Br, CF 3 , NH 2 , N(C 1 -C 6 alkyl) 2 , NO 2 , CN, (C 1 -C 6 alkyl)O-, -OH, (C 1 -C 6 alkyl)S(O) m -, (C 1 -C 6 alkyl)C(O)NH-, H 2 N-C(NH)-, (C 1 -C 6 alkyl)C(O)-, (C 1 -C 6
  • cyclic moieties When R 2 and R 3 are combined to form - (CH 2 ) u -, cyclic moieties are formed. Examples of such cyclic moieties include, but are not limited to:
  • cyclic moieties may optionally include a heteroatom(s).
  • heteroatom-containing cyclic moieties include, but are not limited to:
  • substituents G 1 and/or G 2 are "absent," the ring carbons to which G 1 and/or G 2 are attached are understood to be substituted with two hydrogen atoms and are considered substitutable ring carbon atoms, and are therefore optionally substituted with a substituent selected from R 2 , R 3 , R 4 and R 5 .
  • R 1 a and R 1 b are independently selected from: hydrogen, -N(R 10 ) 2 , R 10 C(O)NR 10 - or unsubstituted or substituted C 1 -C 6 alkyl wherein the substituent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted phenyl, -N(R 10 ) 2 , R 10 O- and R 10 C(O)NR 10 -.
  • R 2 is selected from: H, and an unsubstituted or substituted group, the group selected from C 1 -8 alkyl, C 2-8 alkenyl and C 2-8 alkynyl;
  • substituted group is substituted with one or more of:
  • R 3 is selected from: hydrogen and C 1 -C 6 alkyl.
  • R 4 is hydrogen
  • R 6 , R 7 and R 7a is selected from: hydrogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted aryl and unsubstituted or substituted cycloalkyl.
  • R 6a is unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted aryl and unsubstituted or substituted cycloalkyl.
  • R 9 is hydrogen or methyl.
  • R a is hydrogen.
  • R 10 is selected from H, C 1 -C 6 alkyl and benzyl.
  • a 1 and A 2 are independently selected from: a bond, -C(O)NR 10 -, -NR 10 C(O)-, O, -N(R 10 )-, -S(O) 2 N(R 10 ). and- N(R 10 )S(O) 2 -.
  • V is selected from hydrogen, heterocycle and aryl. More preferably, V is phenyl.
  • Y is selected from unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, unsubstituted or
  • Y is unsubstituted or substituted phenyl.
  • Z is selected from unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, unsubstituted or
  • Z is unsubstituted or substituted phenyl.
  • W is selected from imidazolinyl, imidazolyl, oxazolyl, pyrazolyl, pyyrolidinyl, thiazolyl and pyridyl. More preferably, W is selected from imidazolyl and pyridyl.
  • G 1 is oxygen and G 2 is absent.
  • G 2 is oxygen and G 1 is absent.
  • G 1 is oxygen and G 2 is absent.
  • n and r are independently 0, 1 , or 2.
  • p is 1 , 2 or 3.
  • s is 0.
  • t is 1.
  • -N(R 10 ) 2 represents -NH 2 , -NHCH 3 , -NHC 2 H 5 , etc. It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials.
  • the pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as formed, e.g., from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like: and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
  • the pharmaceutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this invention which contain a basic moiety by conventional chemical methods.
  • the salts are prepared either by ion exchange
  • Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the Schemes 1-14, in addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures.
  • Substituents R and R a as shown in the Schemes, represent the substituents R 2 , R 3 , R 4 , and R 5 ; however their point of attachment to the ring is illustrative only and is not meant to be limiting.
  • the piperidone nitrogen may be arylated by employing a triaryl bismuth - copper coupling.
  • the resulting diester Va can then be converted to the acid VIa and the aldehyde VIIa by procedures well known in the art.
  • the aldehyde intermediates VII can undergo a Wittig coupling with a protected imidazole to provide compound IX, which can then be catalytically reduced to the intermediate X (Scheme 4).
  • Intermediate X can be deprotected to provide the instant compound XI or it can be further alkylated to eventually provide the instant compound XII.
  • Scheme 4a Synthesis of compounds of the invention that have an alternate connectivity of the piperidinon-4-ylethyl to the preferred imidazolyl moiety is illustrated in Scheme 4a.
  • the Scheme illustrates use of a suitably substituted protected piperidine XIII, which is either commercially avaiable or may be prepared by techniques known in the art, as the precursor to the 2-piperidinone XV.
  • the nitrogen of intermediate XV may then be functionalized and the suitably substituted imidazolyl moiety incorporated via nucleophilic displacement.
  • Schemes 4b and 4c illustrate syntheses of suitably substituted homologous 4-hydroxymethyl 2-piperidinones, that may be utilized in the reactions illustrated in Scheme 4a, starting with
  • Schemes 4d and 4e illustrate alternate syntheses of the homologous piperidinon-4-ylmethyl-1 -imidazolyl compounds starting with the previously described intermediate IV.
  • heterocyclic substitutent is a carbonyl.
  • the protected imidazolyl Grignard XVI is reacted with the key intermediate VII to provide the secondary alcohol, which can be oxidized and alkylated as illustrated above to provide the instant compound XVII.
  • Scheme 6 illustraaes the analogous synthesis of the instant compound XVIII wherein the heterocyclic moity is linked to the piperidone carbon by an acetyl linker.
  • the carboxylic acid VI can be converted to the phosphonium salt XIX which can then be coupled to a variety of aldehydes, such as XX, as shown in Scheme 7.
  • the aldehydes can be prepared by standard procedures, such as that described by O. P. Goel, U. Krolls, M. Stier and S. Kesten in Organic Syntheses, 1988, 67, 69- 75), from the appropriate amino acid.
  • the coupling reaction provides the unsaturated intermediate, which is catalytically reduced to the bisprotected diamine XXI.
  • the product XXI can be deprotected to give the instant compound XXII with trifluoroacetic acid in methylene chloride.
  • the final product XXII is isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others.
  • the product diamine XXII can further be selectively protected to obtain XXIII, which can subsequently be reductively alkylated with a second aldehyde to obtain XXIV. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole XXV can be accomplished by literature procedures.
  • the protecting groups can be subsequently removed to unmask the hydroxyl group (Schemes 8, 9).
  • the alcohol can be oxidized under standard conditions to e.g. an aldehyde, which can then be reacted with a variety of organometallic reagents such as Grignard reagents, to obtain secondary alcohols such as XXIX.
  • the fully deprotected amino alcohol XXX can be reductively alkylated (under conditions described previously) with a variety of aldehydes to obtain secondary amines, such as XXXI (Scheme 9), or tertiary amines.
  • the Boc protected amino alcohol XXVII can also be utilized to synthesize 2-aziridinylmethylpiperidones such as XXXII (Scheme 10). Treating XXVII with 1,1'-sulfonyldiimidazole and sodium hydride in a solvent such as dimethylformamide led to the formation of aziridine XXXII. The aziridine reacted in the presence of a nucleophile, such as a thiol, in the presence of base to yield the ring- opened product XXXIII.
  • a nucleophile such as a thiol
  • the phosphonium XVIII can be reacted with aldehydes derived from amino acids such as O-alkylated tyrosines, according to standard procedures, to obtain compounds such as XXXIII.
  • R' is an aryl group
  • catalytic hydrogenation of XXXIII also unmasks the phenol, and the amine group is then deprotected with acid to produce XXXV.
  • XXXV is an O-alkylated phenolic amines.
  • the instant compounds are useful as pharmaceutical agents for mammals, especially for humans. These compounds may be administered to patients for use in the treatment of cancer. Examples of the type of cancer which may be treated with the compounds of this invention include, but are not limited to, colorectal carcinoma, exocrine pancreatic carcinoma, myeloid leukemias and neurological tumors.
  • Such tumors may arise by mutations in the ras genes themselves, mutations in the proteins that can regulate Ras activity (i.e.,
  • NF-1 neurofibromin
  • neu neu
  • scr abl
  • lck lck
  • fyn neurofibromin
  • the compounds of the instant invention inhibit farnesyl- protein transferase and the farnesylation of the oncogene protein Ras.
  • the instant compounds may also inhibit tumor angiogenesis, thereby affecting the growth of tumors (J. Rak et al. Cancer Research, 55:4575- 4580 (1995)).
  • the compounds of this invention are also useful for inhibiting other proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes (i.e., the Ras gene itself is not activated by mutation to an oncogenic form) with said inhibition being accomplished by the administration of an effective amount of the compounds of the invention to a mammal in need of such treatment.
  • a component of NF-1 is a benign proliferative disorder.
  • the instant compounds may also be useful in the treatment of certain viral infections, in particular in the treatment of hepatitis delta and related viruses (J.S. Glenn et al. Science, 256: 1331 - 1333 (1992).
  • the compounds of the instant invention are also useful in the prevention of restenosis after percutaneous transluminal coronary angioplasty by inhibiting neointimal formation (C. Indolfi et al. Nature medicine, 1 :541 -545(1995).
  • the instant compounds may also be useful in the treatment and prevention of polycystic kidney disease (D.L. Schaffner et al. American Journal of Pathology, 142:1051-1060 (1993) and B. Cowley, Jr. et al. FASEB Journal, 2:A3160 (1988)).
  • the instant compounds may also be useful for the treatment of fungal infections.
  • the compounds of this invention may be administered to mammals, preferably humans, either alone or, preferably, in
  • the compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
  • the selected compound may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension.
  • carriers which are commonly used include lactose and corn starch, and lubricating agents, such as magnesium stearate, are commonly added.
  • useful diluents include lactose and dried com starch.
  • the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents may be added.
  • sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered.
  • the total concentration of solutes should be controlled in order to render the preparation isotonic.
  • the compounds of the instant invention may also be co- administered with other well known therapeutic agents that are selected for their particular usefulness against the condition that is being treated.
  • the instant compounds may be useful in combination with known anti-cancer and cytotoxic agents.
  • the instant compounds may be useful in combination with known anti-cancer and cytotoxic agents.
  • compounds may be useful in combination with agents that are effective in the treatment and prevention of NF-1, restinosis, polycystic kidney disease, infections of hepatitis delta and related viruses and fungal infections.
  • the present invention also encompasses a pharmaceutical composition useful in the treatment of cancer, comprising the
  • compositions of this invention include aqueous solutions comprising compounds of this invention and pharmacologically acceptable carriers, e.g., saline, at a pH level, e.g., 7.4.
  • pharmacologically acceptable carriers e.g., saline
  • the solutions may be introduced into a patient's blood-stream by local bolus injection.
  • composition is intended to encompass a product comprising the specified ingredients in the specific amounts, as well as any product which results, directly or indirectly, from combination of the specific ingredients in the specified amounts.
  • the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms.
  • a suitable amount of compound is administered to a mammal undergoing treatment for cancer.
  • Administration occurs in an amount between about 0.1 mg/kg of body weight to about 60 mg/kg of body weight per day, preferably of between 0.5 mg/kg of body weight to about 40 mg/kg of body weight per day.
  • the compounds of the instant invention are also useful as a component in an assay to rapidly determine the presence and quantity of farnesyl-protein transferase (FPTase) in a composition.
  • FPTase farnesyl-protein transferase
  • mixtures which comprise a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and farnesyl pyrophosphate and, in one of the mixtures, a compound of the instant invention.
  • FPTase for example a tetrapeptide having a cysteine at the amine terminus
  • farnesyl pyrophosphate for example a tetrapeptide having a cysteine at the amine terminus
  • the chemical content of the assay mixtures may be determined by well known
  • inhibitors of FPTase absence or quantitative reduction of the amount of substrate in the assay mixture without the compound of the instant invention relative to the presence of the unchanged substrate in the assay containing the instant compound is indicative of the presence of FPTase in the composition to be tested.
  • potent inhibitor compounds of the instant invention may be used in an active site titration assay to determine the quantity of enzyme in the sample.
  • a series of samples composed of aliquots of a tissue extract containing an unknown amount of farnesyl-protein transferase, an excess amount of a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and farnesyl pyrophosphate are incubated for an appropriate period of time in the presence of varying concentrations of a compound of the instant invention.
  • the concentration of a sufficiently potent inhibitor i.e., one that has a Ki substantially smaller than the
  • concentration of enzyme in the assay vessel required to inhibit the enzymatic activity of the sample by 50% is approximately equal to half of the concentration of the enzyme in that particular sample.
  • Step A 1-Phenyl-2-piperidinone-4,4-dicarboxylic acid diethyl ester
  • 2-Piperidinone-4,4-dicarboxylic acid diethyl ester prepared as described in US 4,870,173, is dissolved in methylene chloride and treated with triphenylbismuth (1.5 equivalents), copper(II)acetate (1.5 equivalents) and triethylamine (1.5 equivalents) and stirred for 17 h at 20°C in dichloromethane (60 mL). The reaction mixture was adsorbed onto silica gel and chromatographed to provide the title compound.
  • Step B 1-Phenyl-2-piperidinone-4-carboxylic acid ethyl ester
  • Step C 1 -Phenyl-2-piperidinone-4-carboxylic acid
  • Step D 4-Hvdroxymethyl-1 -phenyl-2-piperidinone
  • Step F 4-[5-(4-Cyanobenzyl)imidazol-1 -ylmethyl]- 1 -phenyl-2- piperidinone hydrochloride
  • Step A 1 -tert-Butoxycarbonyl-4-hydroxyethylpiperidine
  • Step A The product from Step A (6.62 g, 28.90 mmol) was dissolved in methylene chloride (50 mL) containing pyridine (5.8 mL, 72.27 mmol). The reaction was cooled to 0°C under argon, and acetic anhydride added (3.3 mL, 34.68 mmol). The reaction was stirred overnight at room temperature. Saturated sodium bicarbonate solution was added, and the layers separated. The organic phase was washed with 10% aqueous hydrogen chloride, saturated sodium bicarbonate solution, and saturated brine. The organic phase was dried over magnesium sulfate. The title compound was obtained as an oil. Step C: 4-(2-Acetoxyethyl)-1-tert-butoxycarbonylpiperidin-2-one
  • Step E 4-(2-Acetoxyethyl)-1-phenylpiperidin-2-one
  • the product from Step D is dissolved in methylene chloride and treated with triphenylbismuth (1.5 equivalents), copper(II)acetate (1.5 equivalents) and triethylamine (1.5 equivalents) and stirred for 17 h at 20°C in dichloromethane (60 mL).
  • the reaction mixture is adsorbed onto silica gel and chromatographed to provide the title compound.
  • Step F 4-(2-Hydroxyethyl)-1-phenylpiperidin-2-one
  • Step E The product from Step E is hydrolyzed according to the procedure described in Example 1, Step C, giving the title compound.
  • Step G 4-[2- ⁇ 5-(4-Cyanobenzyl)imidazol- 1 -yl ⁇ ethyl]-1 - phenylpiperidin-2-one hydrochloride
  • Step F (1 eq) and the product from Example 1 , Step E (1 eq) were dissolved in methylene chloride containing diisopropylethylamine , cooled to -78°C under argon and treated with trifluoromethane sulfonic anhydride as described in
  • Example 1 Step F. After methanolysis, the title compound was isolated by chromatography on silica gel.
  • Step A 1-PhenyI-2-piperidinone-4,4-dicarboxylic acid diethyl ester
  • 2-Piperidinone-4,4-dicarboxylic acid diethyl ester prepared as described in US 4,870,173, is dissolved in methylene chloride and treated with triphenylbismuth (1.5 equivalents),
  • Step B 1 -Phenyl-2-piperidinone-4,4-dicarhoxylic acid
  • the product from Step A is dissolved in methanol and 5% aqueous sodium hydroxide added.
  • 6 N aqueous hydrochloric acid is added to obtain pH 1, and the solution extracted with ethyl acetate.
  • the organic phase is washed with saturated brine, dried over magnesium sulfate, filtered and concentrated to provide the title compound.
  • Step C 1 -Phenyl-2-piperidinone-4-carboxylic acid
  • step B The product from step B is dissolved in toluene and refluxed for 6 h. The reaction is cooled and concentrated to provide the title compound.
  • Step D 1-Phenyl-2-piperidinone-4-carboxylic acid methyl ester
  • the product from Step C is dissolved in 10 % methanol in toluene, and trimethylsilyldiazomethane added. The reaction is quenched with acetic acid and concentrated. The residue is partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic phase is washed with saturated brine, dried over magnesium sulfate, filtered and concentrated to provide the title compound.
  • Step D The product from Step D is dissolved in THF and cooled to -78°C under nitrogen. A solution of diisobutylaluminum hydride ( 1 eq.) in toluene is added dropwise. After 30 min, the reaction is quenched with saturated sodium potassium tartrate solution. The mixture is extracted with ethyl acetate, and the organic phase washed with saturated brine, and dried over MgSO 4 . Filtration and
  • Step F 4-Diethylphosphonomethyl-1 -triphenylmethy limidazole
  • Step I 4-[2- ⁇ 1-(Triphenylmethyl)-4-imidazolyl ⁇ ethenyl]-1 -phenyl- 2-piperidinone
  • Step I The product from Step I is dissolved in methanol and hydrogenated at 60 psi hydrogen with 10% palladium on carbon. When reaction is complete, the catalyst is filtered and the title compound obtained after evaporation of solvent.
  • Step K 4-[2- ⁇ 1-(4-Cyanobenzyl)-5-imidazolyl ⁇ ethyl]- 1-phenyl-2- piperidinone hydrochloride
  • Step A ( ⁇ )cis- and ( ⁇ )trans-3-Methyl-1-phenyl-4-[2- ⁇ 1 - triphenylmethyl)-4-imidazolyl ⁇ ethyl]-2-piperidinone
  • Step B ( ⁇ )cis- and ( ⁇ )trans-4-[2- ⁇ 1 -(4-Cyanobenzyl)-5- imidazolyl ⁇ ethyl]-3-methyl-1 -phenyl-2-piperidinone hydrochloride
  • Step A N-Methyl N-methoxy 1 -phenyl-2-piperidinone-4- carboxamide
  • Step B 1-Phenyl-4-[1-triphenyImethyl-4-imidazolyl ⁇ carbonyl]-2- piperidinone hydrochloride
  • the title compound is prepared according to the procedure described in Example 3, Step K, except using the product from Step B in place of 4-[2- ⁇ 1-(triphenylmethyl)-4-imidazolyl ⁇ ethyl]-1-phenyl-2- piperidinone.
  • the title compound is obtained after purification by silica gel chromatography, and conversion to the hydrochloride salt.
  • Step B Preparation of Ethyl N-tert-butoxycarbonyl-3-oxo-4-(3- methylbenzyl)piperidine-4-carboxylate
  • Step D Preparation of Ethyl 1-[3-(4-cyanobenzyl)-3H-imidazol-4- ylmethyl]-3-oxo-4-(3-methylbenzyl)piperidine-4- carboxylate trifluoroacetate salt
  • Bovine FPTase was assayed in a volume of 100 ⁇ l containing 100 mM N-(2- hydroxy ethyl) piperazine-N'-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgCl 2 , 5 mM dithiothreitol (DTT), 100 mM [ 3 H] -farnesyl diphosphate ([ 3 H]-FPP; 740 CBq/mmol, New England Nuclear), 650 nM Ras-CVLS and 10 ⁇ g/ml FPTase at 31 °C for 60 min. Reactions were initiated with FPTase and stopped with 1 ml of 1.0 M HCL in ethanol.
  • Precipitates were collected onto filter-mats using a TomTec Mach II cell harvestor, washed with 100% ethanol, dried and counted in an LKB ⁇ - plate counter.
  • the assay was linear with respect to both substrates, FPTase levels and time; less than 10% of the [ 3 H]-FPP was utilized during the reaction period.
  • Purified compounds were dissolved in 100% dimethyl sulfoxide (DMSO) and were diluted 20-fold into the assay. Percentage inhibition is measured by the amount of
  • polyethylene glycol 20,000, 10 ⁇ M ZnCl 2 and 100 nm Ras-CVIM were added to the reaction mixture. Reactions were performed for 30 min., stopped with 100 ⁇ l of 30% (v/v) trichloroacetic acid (TCA) in ethanol and processed as described above for the bovine enzyme.
  • TCA trichloroacetic acid
  • the compounds of the instant invention described in the above Examples are tested for inhibitory activity against human FPTase by the assay described above.
  • the compound of the instant invention described in Examples 1 and 6 were tested for inhibitory activity against human FPTase by the assay described above and were found to have IC 50 of ⁇ 10 ⁇ M.
  • the cell line used in this assay is a v-ras line derived from either Ratl or NIH3T3 cells, which expressed viral Ha-ras p21.
  • the assay is performed essentially as described in DeClue, J.E. et al., Cancer Research 51 :712-717, (1991). Cells in 10 cm dishes at 50-75%
  • the cells are labelled in 3 ml methionine-free DMEM supple- meted with 10% regular DMEM, 2% fetal bovine serum and 400 mCi[ 35 S]methionine (1000 Ci/mmol).
  • the cells are lysed in 1 ml lysis buffer (1% NP40/20 mM HEPES, pH 7.5/5 mM MgCl 2 /lmM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 mM PMSF) and the lysates cleared by centrifugation at 100,000 x g for 45 min. Aliquots of lysates containing equal numbers of acid-precipitable counts are bought to 1 ml with IP buffer (lysis buffer lacking DTT) and immunoprecipitated with the ras-specific monoclonal antibody Y 13-259 (Furth, M.E. et al., J. Virol.
  • Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded at a density of 1 x 10 4 cells per plate (35 mm in diameter) in a 0.3% top agarose layer in medium A (Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine semm) over a bottom agarose layer (0.6%). Both layers contain 0.1 % methanol or an appropriate concentration of the instant compound (dissolved in methanol at 1000 times the final concentration used in the assay).
  • the cells are fed twice weekly with 0.5 ml of medium A containing 0.1 % methanol or the concentration of the instant compound.
  • Photomicrographs are taken 16 days after the cultures are seeded and comparisons are made.

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Abstract

L'invention concerne des composés qui inhibent la farnésyl-protéine transférase (FTase) et la farnésylation de la protéine Ras oncogène. L'invention a en outre pour objet des compositions chimiothérapeutiques contenant les composés de cette invention et des procédés pour inhiber la farnésyl-protéine transférase et la farnésylation de la protéine Ras oncogène.
PCT/US1997/004713 1996-04-03 1997-03-27 Inhibiteurs de farnesyl-proteine transferase WO1997036605A1 (fr)

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CHEMICAL ABSTRACTS, Volume 112, No. 11, issued 12 March 1990, KIHARA et al., "Preparation of 1-(thio)carbamoyl- and 1-alkoxycarbonylimidazoles for Improvement of Brain Function", page 753, Abstract No. 98528g; & JP,A,01 203 366. *
See also references of EP0897303A4 *

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EP1035850A1 (fr) * 1997-12-04 2000-09-20 Merck & Co., Inc. Inhibiteurs de la transferase de la farnesyl-proteine
EP1045843A1 (fr) * 1997-12-04 2000-10-25 Merck & Co., Inc. Inhibiteurs de la farnesyl-proteine transferase
EP1035850A4 (fr) * 1997-12-04 2001-09-12 Merck & Co Inc Inhibiteurs de la transferase de la farnesyl-proteine
EP1045843A4 (fr) * 1997-12-04 2001-10-24 Merck & Co Inc Inhibiteurs de la farnesyl-proteine transferase
JP2002501024A (ja) * 1998-01-27 2002-01-15 アベンティス ファーマスーティカルズ プロダクツ インコーポレイテッド 置換オキソアザヘテロシクリルＸａ因子阻害剤
JP4676613B2 (ja) * 1998-01-27 2011-04-27 アベンティス・ファーマスーティカルズ・インコーポレイテツド 置換オキソアザヘテロシクリルＸａ因子阻害剤
FR2819509A1 (fr) * 2001-01-18 2002-07-19 Servier Lab Nouveaux composes cycloheptene, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
FR2819512A1 (fr) * 2001-01-18 2002-07-19 Servier Lab Nouveaux composes cyclo[d] azepane, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
FR2819510A1 (fr) * 2001-01-18 2002-07-19 Servier Lab Nouveaux composes cyclo[c] azepane, leur procede de preparation et les compositions pharmaceutiques qui le contiennent
EP1225170A2 (fr) * 2001-01-18 2002-07-24 Les Laboratoires Servier S.A. Composés cycloheptène, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
WO2002057258A1 (fr) * 2001-01-18 2002-07-25 Les Laboratoires Servier Derives de cyclo`d!azepane, utiles comme inhibiteurs de farnesyltransferase ainsi que leur procede de preparation
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WO2002057223A3 (fr) * 2001-01-18 2002-11-28 Servier Lab Composes azepane, leur procede de preparations et les compositions pharmaceutiques qui les contiennent
FR2819511A1 (fr) * 2001-01-18 2002-07-19 Servier Lab Nouveaux composes azepane, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
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US6861445B2 (en) 2001-08-24 2005-03-01 Wyeth Holdings Corporation 3-Substituted-3-(substitutedsulfonyl or sulfanyl)pyrrolidine-2,5-diones useful for inhibition of farnesyl-protein transferase
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WO2003018554A1 (fr) * 2001-08-24 2003-03-06 Wyeth Holdings Corporation 3-substitue-3-(substitue sulfonyl ou sulfanyl)pyrrolidine-2,5-diones utiles pour l'inhibition de la farnesyl-proteine transferase
US6974869B2 (en) 2001-09-18 2005-12-13 Bristol-Myers Squibb Pharma Company Piperizinones as modulators of chemokine receptor activity
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US8236953B2 (en) 2004-12-29 2012-08-07 Glaxo Group Limited Process for preparing piper azine derivatives
US8012981B2 (en) 2006-06-15 2011-09-06 Glaxo Group Limited Benzylpiperazine derivatives as motilin receptor agonists
US8835426B2 (en) 2007-02-26 2014-09-16 Vitae Pharmaceuticals, Inc. Cyclic urea and carbamate inhibitors of 11β-hydroxysteroid dehydrogenase 1
US9079861B2 (en) 2007-11-07 2015-07-14 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8748444B2 (en) 2007-12-11 2014-06-10 Vitae Pharmaceuticals, Inc. Cyclic urea inhibitors of 11β-hydroxysteroid dehydrogenase 1
US8754076B2 (en) 2008-07-25 2014-06-17 Vitae Pharmaceuticals, Inc./Boehringer-Ingelheim Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8846668B2 (en) 2008-07-25 2014-09-30 Vitae Pharmaceuticals, Inc. Inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8637505B2 (en) 2009-02-04 2014-01-28 Boehringer Ingelheim International Gmbh Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1
US8410144B2 (en) 2009-03-31 2013-04-02 Arqule, Inc. Substituted indolo-pyridinone compounds
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Also Published As

Publication number Publication date
AU717190B2 (en) 2000-03-23
JP2000508631A (ja) 2000-07-11
CA2249641A1 (fr) 1997-10-09
EP0897303A4 (fr) 1999-02-24
EP0897303A1 (fr) 1999-02-24
AU2542597A (en) 1997-10-22

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