WO1997036583A1 - Inhibiteurs de la farnesyle-proteine transferase - Google Patents

Inhibiteurs de la farnesyle-proteine transferase Download PDF

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WO1997036583A1
WO1997036583A1 PCT/US1997/005170 US9705170W WO9736583A1 WO 1997036583 A1 WO1997036583 A1 WO 1997036583A1 US 9705170 W US9705170 W US 9705170W WO 9736583 A1 WO9736583 A1 WO 9736583A1
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unsubstituted
substituted
alkyl
compound
hydrogen
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PCT/US1997/005170
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Jeffrey Bergman
Christopher Dinsmore
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Merck & Co., Inc.
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Priority claimed from GBGB9610654.7A external-priority patent/GB9610654D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU25968/97A priority Critical patent/AU715604B2/en
Priority to EP97917711A priority patent/EP0959883A4/fr
Priority to JP9535483A priority patent/JP2000507584A/ja
Publication of WO1997036583A1 publication Critical patent/WO1997036583A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/57—Nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Definitions

  • the present invention relates to compounds which inhibit farnesyl protein transferase, a protein which is implicated in the oncogenic pathway mediated by Ras.
  • the Ras proteins (Ha-Ras, Ki4a-Ras, Ki4b-Ras and N-Ras) 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. In the inactive state, Ras is bound to GDP. 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
  • Ras 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 (Ud' -ras, Ki4a-/ y, Ki4b-r ⁇ 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 must be localized to the plasma membrane for both normal and oncogenic functions.
  • Ras C-terminus contains a sequence motif termed a "CAAX” or "Cys-Aaa ⁇ -Aaa ⁇ -Xaa” box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al., Nature 370:583-586 (1984)).
  • this motif serves as a signal sequence for the enzymes famesyl-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.
  • Ras proteins are known to undergo post-translational famesylation.
  • famesylated 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 famesyl ⁇ ated. James, et al., have also suggested that there are famesylated proteins of unknown structure and function in addition to those listed above. Inhibition of famesyl-protein transferase has been shown to block the growth of Ras-transformed cells in soft agar and to modify other aspects of their transformed phenotype.
  • Famesyl-protein transferase utilizes farnesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a fa esyl 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 ai, Proc. Natl. Acad. Sci USA, 87:7541 -1545 ( 1990)).
  • Inhibition of famesyl pyrophosphate biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane localization in cultured cells. However, direct inhibition of famesyl-protein transferase would be more specific, and thus preferable.
  • FPTase famesyl-protein transferase
  • FPP famesyl diphosphate
  • Ras protein substrates
  • the peptide derived inhibitors that have been described are generally cysteine containing molecules that are related to the CAAX motif that is the signal for protein prenylation.
  • Such inhibitors may inhibit protein prenylation while serving as altemate substrates for the famesyl-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)).
  • FPT-ase inhibitors also inhibit the proliferation of vascular smooth muscle cells and are therefore useful in the prevention and treatment of arteriosclerosis and diabetic disturbance of blood vessels (JP H7-1 12930). It has recently been disclosed that certain tricyclic compounds which optionally incorporate a piperidine moiety are inhibitors of FPTase (WO 95/10514, WO 95/10515 and WO 95/10516). Imidazole-containing inhibitors of famesyl protein transferase have also been disclosed (WO 95/09001 and EP 0 675 1 12 Al ).
  • Rl a, R ib an d R2 are independently selected from the group consisting of: hydrogen, aryl, heterocyclyl, C3-C] 0 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 0-, R 9 S(0) m -,
  • RK NC(0)-, R C(0)NR 8 -, CN, N02, (R 8 )2NC(NR 8 )-, R 8 C(0)-, R 8 OC(0)-, N3, -N(R )2, R 9 OC(0)NR 8 - and Cl -C6 alkyl, unsubstituted or substituted by 1 -3 groups selected from the group consisting of: halo, aryl, heterocyclyl, C3-C10 cycloalkyl, C2-C alkenyl, C2-C6 alkynyl, R 8 0-, R9s(0) m -, R 8 C(0)NR 8 -, CN, (R 8 )2NC(NR 8 )-, R 8 C(0)-, R 8 OC(0)-, N3, -N(R 8 )2 and R 9 OC(0)NR 8 -;
  • R3 and R ⁇ are independently selected from the group consisting of: H, F, Cl, Br, -NR 8 2, CF3. NO2, R 8 0-, R 9 S(0) m -, (R*) 2 NC(0)-, R 8 C(0)NH-, H2NC(NH)-, R 8 C(0)-, R 8 OC(0)-, N3, CN, R 9 0C(0)NR 8 -, C1 -C20 alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heterocyclyl;
  • A3 is selected from: -NR ⁇ S(0) m - or -S(0) m NR5-, with m equal to 0, 1 or 2, and R5 selected from the group consisting of: hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted C3-C10 cycloalkyl, and C1 -C6 alkyl, unsubstituted or substituted with 1 -3 members selected from the group consisting of: unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted C3-C 10 cycloalkyl, -N(R8)2, -CF3, -N ⁇ 2, (R 8 )0-, (R9)S(0) m -, (R 8 )C(0)NH-, H2NC(NH)- , (R 8 )C(0)-, (R 8 )OC(0)-, N3, CN and
  • R6 and R are independently selected from the group consisting of: hydrogen, aryl, heterocyclyl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci- 6 perfluoroalkyl, F, Cl, Br, R 8 0-, R9S(0) m -, R 8 C(0)NR 8 -, CN, N02, (R 8 )2NC(NR 8 )-, R 8 C(0)-, R OC(0)-, N3, -N(R 8 )2, R 9 OC(0)NR 8 - and C1 -C-6 alkyl unsubstituted or substituted by 1 -3 groups selected from: aryl, heterocyclyl, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R 8 0-, R 9 S(0) m -, R 8 C(0)NR*-, CN,
  • each R 8 is independently selected from hydrogen, C1 -C6 alkyl, aryl and aralkyl;
  • each R 9 is independently selected from C
  • X represents aryl or heteroaryl
  • V is selected from the group consisting of: hydrogen, heterocyclyl, aryl, C1 -C2O alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatoin selected from O, S, and N, and C2-C2O alkenyl, provided that V is not hydrogen if A* is S(0)m and V is not hydrogen if A is a bond, n is 0 and A 2 is S(0) m ;
  • W represents heterocyclyl
  • each n and p independently represents 0, 1 , 2, 3 or 4; r is 0 to 5, provided that r is 0 when V is hydrogen, and t is 0 or 1.
  • the compounds of this invention are useful in the inhibition of famesyl-protein transferase and the famesylation of the oncogene protein Ras, and thus are useful for the treatment of cancer.
  • 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, Rl , R ⁇ etc.
  • alkyl and the alkyl portion of alkoxy. aralkyl and similar terms, is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, or 1 -6 carbon atoms if unspecified. Cycloalkyl means 1 -2 cabocyclic rings which are saturated and contain from 3- 10 atoms.
  • Halogen or “halo” as used herein means fluoro, chloro, bromo and iodo.
  • aryl and the aryl portion of aralkyl are 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.
  • aryl elements examples include phenyl, naphthyl. tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
  • a preferred aralkyl group is benzyl.
  • heterocyclyl, heterocycle and heterocyclic mean a 5- to 7-membered monocyclic or 8- to 1 1 - membered bicyclic heterocyclic rings, either saturated or unsaturated, aromatic, partially aromatic or non-aromatic, and which consist of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S.
  • it includes any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the ring or ring system may be attached at any heteroatom or carbon atom which results in a stable structure, and may contain 1 -3 carbonyl groups.
  • heterocycles include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl. benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl.
  • Heteroaryl is a subset of heterocyclic, and means a monocyclic or bicyclic ring system, with 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.
  • Examples include benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindohnyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxal
  • substituted alkyl, substituted aryl, substituted heterocyclyl and substituted cycloalkyl mean alkyl, aryl, heterocyclyl and cycloalkyl groups, respectively, having from 1 -3 substituents which are selected from: halo, aryl, heterocyclyl, C3- 10 cycloalkyl, Ci - 6 alkyl, C 2 - 6 alkenyl, C 2 -6 alkynyl, R*0-, R 9 S(0) m -, R*C(0)NR*-, CN, (R*) 2 NC(NR*K R «C(0)-, R «OC(0)-, N3.
  • 1 -2 groups are present on substituted alkyl, substituted aryl, substituted heterocyclyl and substituted cycloalkyl, which are selected from: halo, aryl, R*0-, CN, R*C(0)- and -N(R*) 2 .
  • R l a , R ⁇ and R 2 are independently selected from: hydrogen, -N(R 8 )2, R 8 C(0)NR 8 - or unsubstituted or substituted Cl -C6 alkyl wherein the substituent on the substituted Cl -C6 alkyl is selected from unsubstituted or substituted aryl, -N(R )2, R 0- and R 8 C(0)NR 8 -
  • R3 and R 4 are selected from: hydrogen and Cl -C6 alkyl.
  • a 3 represents NR 5 S(0) , wherein m represents
  • R ⁇ represents hydrogen
  • R° represents hydrogen, unsubstituted or substituted Cl -C6 alkyl.
  • R 7 represents H or unsubstituted Ci - alkyl.
  • R x represents H or Ci -6 alkyl, and R 9 is Ci - alkyl.
  • a ⁇ and A 2 are independently selected from: a bond, -C(0)NR 8 -, -NR 8 C(0)-, -0-, -N(R 8 )-, -S(0)2N(R 8 )- and-
  • N(R 8 )S(0)2- Preferably X represents aryl and most preferably phenyl.
  • V is selected from hydrogen, heterocyclyl and aryl. More preferably V is phenyl.
  • W is heterocyclyl selected from imidazolinyl, imidazolyl, oxazolyl, pyrazolyl, pyyrolidinyl, thiazolyl and pyridyl. More preferably, W is selected from imidazolyl and pyridyl. Preferably, m is 2.
  • n and p are independently 0, 1 , 2 or 3.
  • t is 1.
  • R3, R4, A 3 , RK, Ry, m, n, p and r are as originally defined;
  • each Rl a and R is independently selected from hydrogen and Cl -C6 alkyl
  • each Rib i independently selected from: hydrogen, aryl, heterocyclyl, C3- 1 0 cycloalkyl, C 2- 6 alkenyl, R&0-, -N(R 8 )2 and Cl -C6 alkyl unsubstituted or substituted by aryl, heterocyclyl, cycloalkyl, alkenyl, R 0- and -N(R )2;
  • R5 is selected from the group consisting of: hydrogen and C1 -C6 alkyl, unsubstituted or substituted with 1 -3 members selected from the group consisting of: unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted C3-C10 cycloalkyl, -N(R 8 )2, -CF3, -N ⁇ 2, (R 8 )0-, (R 9 )S(0) m -, (R )C(0)NH-, H2NC(NH)-, (R )C(0)-, (R )OC(0)-, N3, CN and (R 9 )OC(0)NR 8 -;
  • R6 is selected from: hydrogen, C ⁇ -C alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1 -C6 perfluoroalkyl, F, Cl, R 0-, R C(0)NR 8 -, CN, N02, (R 8 )2N-C(NR 8 )-, R C(0)-, R OC(0)-, -N(R )2, or R OC(0)NR 8 -, and Cl -C ⁇ alkyl substituted by Cl -C6 perfluoroalkyl, R 0-, R 8 C(0)NR 8 -, (R )2N-C(NR 8 )-, R C(0)-, R OC(0)-, -N(R )2 and R 9 OC(0)NR 8 -;
  • R 7 is hydrogen or unsubstituted C ⁇ _ 6 alkyl;
  • V is selected from: hydrogen; aryl; heterocyclyl selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl and thienyl; C1 -C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a hetero- atom selected from O, S, and N, and C2-C2O alkenyl, provided that V is not hydrogen if A ⁇ is S(0)m and V is not hydrogen if A ⁇ is a bond and A2 is S(0) m .
  • a second subset of compounds of the present invention is represented by formula lb:
  • R la, Rib, R2, A ' , A 2 , R3, R4, R5, 6, RH , R ) , m> n , p an d r are as originally defined;
  • R7 is selected from: hydrogen and unsubstituted C1 -C6 alkyl
  • V is selected from: hydrogen, heterocyclyl selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, aryl, C1 -C2O alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and C2-C2O alkenyl, provided that V is not hydrogen if A 1 is S(0)m and V is not hydrogen if A 1 is a bond, n is 0 and A2 is S(0) m ; and
  • W represents heterocyclyl selected from pyrrolidinyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl and isoquinolinyl.
  • each R is independently selected from hydrogen and
  • each R ⁇ is selected from: hydrogen and C] -C6 alkyl unsubstituted or substituted with 1 -3 groups selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted C3-C10 cycloalkyl, -N(R )2, -CF3, -N ⁇ 2, (R )0-, (R 9 )S(0) m -, (R 8 )C(0)NH-, H2NC(NH)-, (R )C(0)-, (R )OC(0)-, N3, -CN and (R 9 )OC(0)NR 8 -;
  • R6 is selected from the group consisting of: hydrogen. C1 -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C
  • a fourth subset of compounds of the invention is represented by formula Id:
  • each R2 is independently selected from: hydrogen and Cl -C6 alkyl
  • R3 and R4 are independently selected from H, F, Cl, Br, N(R )2, CF3, N02, (R 8 )0-, (R 9 )S(0) m -, (R )C(0)NH-, H2N-C(NH)-, (R )C(0)-, (R )OC(0)-, N3, CN, (R 9 )OC(0)NR 8 -, C 1 -C20 alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclyl;
  • a 3 represents -NR5-S(0) m - or -S(0) m -NR5-
  • R5 is selected from: hydrogen and C 1 -C6 alkyl, unsubstituted or substituted witha group selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted C3-C10 cycloalkyl, N(R )2. CF3, NO2, (R 8 )0-, (R 9 )S(0) m -, (R )C(0)NH-, H2N-C(NH)-, (R )C(0)-, (R )OC(0)-, N3, CN (R 9 )OC(0)NR 8 -; and R 8 , R 9 > m and p are as originally defined.
  • 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 chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents.
  • Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in Schemes 1 - 7, 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 CH2-, as shown in the Schemes represent the substituents R 8 , R 9 and others, depending on the compound of the instant invention that is being synthesized.
  • the variable p' represents p-1.
  • the sulfinamide can be formed by converting a hydroxyl group to a sulfinyl chloride, and then reacting the sulfinyl chloride with the appropriately substituted amine.
  • the resulting sulfinamide can thereafter be oxidized with, e.g., periodate, to produce sulfonamides in accordance with formula I.
  • substitution on the sulfonamide nitrogen atom can be realized.
  • the instant compounds are useful in the treatment of cancer.
  • Cancers 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., neurofibromin (NF-1 ), neu. scr, abl , lck, fyn) or by other mechanisms.
  • the compounds of the instant invention inhibit farnesyl- protein transferase and famesylation 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)).
  • Such anti-angiogenic properties of the instant compounds may also be useful in the treatment of certain forms of blindness related to retinal vascularization.
  • the compounds of this invention are also useful for inhibiting other diseases where 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 viral infections, in particular in the treatment of hepatitis delta and related viruses (J.S. Glenn et al. Science, 256: 1331 - 1 33 ( 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 d ' l.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 combina- tion with pharmaceutically acceptable carriers or diluents, in the form of a pharmaceutical composition, which is comprised of a compound of formula I in combination with a pharmaceutically acceptable carrier.
  • the compounds can be administered orally, topically, rectally, vaginally transdermally or parenterally, including the intravenous, intramuscular, intraperitoneal and subcutaneous routes of administration.
  • the compound is administered, for example, in the form of tablets or capsules, or as a solution or suspension.
  • carriers which are commonly used include lactose and corn starch; lubricating agents, such as magnesium stearate, are commonly added.
  • diluents also include lactose and dried corn starch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents may be added.
  • sterile solutions of the active ingredient are usually prepared, the pH of the solution is suitably adjusted and the product is buffered.
  • the total concentration is controlled to render the preparation substantially 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 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. If formulated as a fixed dose, such combination products employ a compound of this invention substantially within the dosage range described below and other pharmaceutically active agent(s) typically within the acceptable dosage range.
  • Compounds of the instant invention may alternatively be used sequentially with known pharma ⁇ ceutically acceptable agent(s) when a combination formulation is inappropriate.
  • the daily dosage will normally be determined by the prescribing physician, who may vary the dosage according to the age, weight, and response of the individual patient, as well as the severity of the patient's condition.
  • 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 famesyl-protein transferase (FPTase) in a composition.
  • FPTase famesyl-protein transferase
  • the composition to be tested may be divided and the two portions contacted with mixtures which comprise a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and famesyl pyrophosphate and, in one of the mixtures, a compound of the instant invention.
  • the chemical content of the assay mixtures may be determined by well known immuno- logical, radiochemical or chromatographic techniques. Because the compounds of the instant invention are selective inhibitors of FPTase, absence or quantitative reduction of the amount of substrate in the assay mixture without the compound of the instant invention relative to the presence of the unchanged substrate in the assay containing the instant compound is indicative of the presence of FPTase in the composition to be tested.
  • potent inhibitor compounds of the instant invention may be used in an active site titration assay to determine the quantity of enzyme in the sample.
  • a series of samples composed of aliquots of a tissue extract containing an unknown amount of farnesyl- protein transferase, an excess amount of a known substrate of FPTase (for example a tetrapeptide having a cysteine at the amine terminus) and famesyl pyrophosphate are incubated for an appropriate period of time in the presence of varying concentrations of a compound of the instant invention.
  • concentration of a sufficiently potent inhibitor i.e., one that has a Ki substantially smaller than the concentration of enzyme in the assay vessel
  • concentration of a sufficiently potent inhibitor i.e., one that has a Ki substantially smaller than the concentration of enzyme in the assay vessel
  • Step A Preparation of l -triphenylmethyl-4-(hydroxymethyl)imidazole
  • Step C Preparation of l -(4-cyanobenzyl)-5-(acetoxymethyl)imidazole hydrobromide
  • a solution of -the product from Step B (85.8 g, 225 mmol) and ⁇ -bromo-/?-tolunitrile (50.1 g, 232 mmol) in 500 mL of EtOAc was stirred at 60°C for 20 hours, during which a pale yellow precipitate formed.
  • the reaction was cooled to room temperature and filtered to provide the solid imidazolium bromide salt.
  • the filtrate was concentrated in vacuo to a volume 200 mL, reheated at 60°C for two hours, cooled to room temperature, and filtered again.
  • the filtrate was concentrated in vacuo to a volume 100 mL, reheated at 60°C for another two hours, cooled to room temperature, and concentrated in vacuo to provide a pale yellow solid. All of the solid material was combined, dissolved in 500 mL of methanol, and warmed to 60 °C. After two hours, the solution was reconcentrated in vacuo to provide a white solid which was triturated with hexane to remove soluble materials. Removal of residual solvents in vacuo provided the titled product hydrobromide as a white solid (50.4 g, 67% yield, 89% purity by HPLC) which was used in the next step without further purification.
  • Step D Preparation of l -(4-cyanobenzyl)-5-(hydroxymethyl)imidazolc
  • Step E Preparation of l -(4-cyanobenzyl)-5-imidazolecarboxaldehyde To a solution of the alcohol from Step D (21.5 g, 101 mmol) in 500 mL of DMSO at room temperature was added triethyl ⁇ amine (56 mL, 402 mmol), then S ⁇ 3 -pyridine complex (40.5 g. 254 mmol).
  • Step F Preparation of l -(4-cyanobenzyl)-5-
  • Step I Preparation of N-[l -(4-cyanobenzyl)imidazolyl-5-methyl]- N-(methyl)-3-chlorobenzylsulfinamide To a 0° C solution of the sulfinyl chloride from Step H
  • Step J Preparation of N-[l -(4-cyanobenzyl)imidazolyl-5-methyJJ-
  • Step A Preparation of l -(4-chlorobenzyl)-5-imidazolylmethyl sulfinyl chloride
  • the titled compound is prepared from the alcohol from Step D of Example 1 by the methods described in Steps G and H of Example 1.
  • Step B Preparation of N-(3-chlorobenzyl)- l -[ (4-cyanobenzy!)-5- imidazoly 1 lmethylsulfinamide
  • Step C Preparation of N-(3-chlorobenzyl)-l-[(4-cyanobenzyl)-5- imidazolyllmethylsulfonamide hydrochloride
  • the sulfinamide from Step B is oxidized to the sulfonamide and converted to the HCI salt using the method described in Step J of Example 1.
  • Step A Preparation of 3-(4-cyanobenzyl)pyridin-4-carboxylic acid methyl ester
  • 4-cyanobenzyl bromide 625 mg, 3.27 mmol
  • dry THF 4mL
  • activated Zn dust; 250 mg
  • dry THF 2 mL
  • O 0 under an argon atmosphere
  • the ice-bath was removed and the slurry was stirred at room temperature for a further 30 min.
  • 3-bromopyridin-4- carboxylic acid methyl ester 540 mg. 2.5 mmol
  • dichlorobis(triphenylphos ⁇ hine)nickel II
  • Step B Preparation of 3-(4-cyanobenzy0-4-(hydroxymethy0pyridine The title compound was obtained by sodium borohydride
  • the title compound was obtained by activated manganese dioxide (l .Og) oxidation of the alcohol from Step B (240 mg, 1.07 mmol) in dioxane (10 mL) at reflux for 30 min. Filtration and evaporation of the solvent provided title compound, mp 80-83°C.
  • Step D Preparation of 3-(4-cyanobenzyl)-4- r(methyIamino)methyllpyridine
  • the titled compound is prepared from the pyridinal from
  • Step E Preparation of N-[3-(4-cyanobenzyl)pyridyl-4-methyl]-N- (methyl)-3-chlorobenzylsuIfonamide hydrochloride
  • the titled compound is prepared from the amine from Step D and the sulfinyl chloride from Step H of Example 1 using the procedures described in Steps I and J of Example 1.
  • Bovine FPTase was assayed in a volume of 100 ⁇ l containing 100 mM N-(2- hydroxy ethyl) piperazine-/V'-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgCl2, 5 mM dithiothreitol (DTT), 100 mM Hl-farnesyl diphosphate ( Hj-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 H j-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 incorporation of radioactivity in the presence of the test compound when compared to the amount of incorporation in the absence of the test compound.
  • DMSO dimethyl sulfoxide
  • Human FPTase was prepared as described by Omer et al.. Biochemistry 32:5167-5176 ( 1993). Human FPTase activity was assayed as described above with the exception that 0.1 % (w/v) polyethylene glycol 20,000, 10 ⁇ M ZnCI 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 cell line used in this assay is a v-ras line derived from either Rat l or NIH3T3 cells, which expressed viral Ha-ras p21.
  • the assay is performed essentially as described in DeClue, J.E. et ai., Cancer Research 51 :712-717, (1991). Cells in 10 cm dishes at 50-75% confluency are treated with the test compound (final concentration of solvent, methanol or dimethyl sulfoxide, is 0.1 %).
  • the cells After 4 hours at 37°C, the cells are labelled in 3 ml methionine-free DMEM supple- meted with 10% regular DMEM, 2% fetal bovine serum and 400 mCi[35S]methionine (1000 Ci/mmol). After an additional 20 hours, the cells are lysed in 1 ml lysis buffer (1 % NP40/20 mM HEPES, pH 7.5/5 mM MgCl2/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.
  • 1 ml lysis buffer (1 % NP40/20 mM HEPES, pH 7.5/5 mM MgCl2/lmM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 mM PMSF
  • the immunoprecipitates are washed four times with IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA/1 % Triton X- 100.0.5% deoxycholate/0.1 %/SDS/0.1 M NaCI) boiled in SDS-PAGE sample buffer and loaded on 13% acrylamide gels. When the dye front reached the bottom, the gel is fixed, soaked in Enlightening, dried and autoradiographed. The intensities of the bands corresponding to famesylated and nonfarnesylated ras proteins are compared to determine the percent inhibition of famesyl transfer to protein.
  • IP buffer 20 nM HEPES, pH 7.5/1 mM EDTA/1 % Triton X- 100.0.5% deoxycholate/0.1 %/SDS/0.1 M NaCI
  • 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 serum) 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. Photomicro ⁇ graphs are taken 16 days after the cultures are seeded and comparisons are made.

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Abstract

La présente invention concerne des composés inhibiteurs de la farnésyle-protéine transférase (FTase) et de la farnésylation de la protéine oncogène Ras. L'invention concerne également, non seulement des compositions chimiothérapiques contenant les composés de l'invention, mais aussi des procédés d'inhibition de la farnésyle-protéine transférase et de la farnésylation de la protéine oncogène Ras.
PCT/US1997/005170 1996-04-03 1997-03-31 Inhibiteurs de la farnesyle-proteine transferase WO1997036583A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU25968/97A AU715604B2 (en) 1996-04-03 1997-03-31 Inhibitors of farnesyl-protein transferase
EP97917711A EP0959883A4 (fr) 1996-04-03 1997-03-31 Inhibiteurs de la farnesyle-proteine transferase
JP9535483A JP2000507584A (ja) 1996-04-03 1997-03-31 ファルネシル―タンパク質転移酵素の阻害剤

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US1466896P 1996-04-03 1996-04-03
US60/014,668 1996-04-03
GBGB9610654.7A GB9610654D0 (en) 1996-05-21 1996-05-21 Inhibitors of farnesyl-protein transferase
GB9610654.7 1996-05-21

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0880320A1 (fr) * 1996-01-30 1998-12-02 Merck & Co., Inc. Inhibiteurs de la farnesyl-proteine transferase
EP0891335A1 (fr) * 1996-04-03 1999-01-20 Merck & Co., Inc. Inhibiteurs de transferase de farnesyl-proteine
JP2001526224A (ja) * 1997-12-22 2001-12-18 シェーリング コーポレイション 増殖性の疾患を処置するためのベンゾシクロヘプタピリジン化合物および抗腫瘍剤の組合せ
US6358985B1 (en) 1998-07-02 2002-03-19 Merck & Co., Inc. Inhibitors of prenyl-protein transferase
US6410534B1 (en) 1998-07-02 2002-06-25 Merck & Co., Inc. Inhibitors of prenyl-protein transferase
US7973078B2 (en) 2006-08-10 2011-07-05 Astellas Pharma Inc. Sulfonamide compound or salt thereof

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Publication number Priority date Publication date Assignee Title
WO1999059883A1 (fr) 1998-05-20 1999-11-25 Dai Nippon Printing Co., Ltd. Recipient isolant

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US4189592A (en) * 1978-04-03 1980-02-19 Basf Aktiengesellschaft Preparation of 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole dihydrochloride

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DE3219113A1 (de) * 1982-05-21 1983-11-24 Bayer Ag, 5090 Leverkusen Verwendung von n-substituierten 2,3-diaminocarbonsaeuren in arzneimitteln und ihre herstellung
US5447728A (en) * 1992-06-15 1995-09-05 Emisphere Technologies, Inc. Desferrioxamine oral delivery system
IL117580A0 (en) * 1995-03-29 1996-07-23 Merck & Co Inc Inhibitors of farnesyl-protein transferase and pharmaceutical compositions containing them
US5710171A (en) * 1995-05-24 1998-01-20 Merck & Co., Inc. Bisphenyl inhibitors of farnesyl-protein transferase
US5756528A (en) * 1995-06-06 1998-05-26 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
WO1997029092A1 (fr) * 1996-02-09 1997-08-14 James Black Foundation Limited Ligands du recepteur de l'histamine h¿3?

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0880320A1 (fr) * 1996-01-30 1998-12-02 Merck & Co., Inc. Inhibiteurs de la farnesyl-proteine transferase
EP0880320A4 (fr) * 1996-01-30 1999-06-16 Merck & Co Inc Inhibiteurs de la farnesyl-proteine transferase
EP0891335A1 (fr) * 1996-04-03 1999-01-20 Merck & Co., Inc. Inhibiteurs de transferase de farnesyl-proteine
EP0891335A4 (fr) * 1996-04-03 2001-08-16 Merck & Co Inc Inhibiteurs de transferase de farnesyl-proteine
JP2001526224A (ja) * 1997-12-22 2001-12-18 シェーリング コーポレイション 増殖性の疾患を処置するためのベンゾシクロヘプタピリジン化合物および抗腫瘍剤の組合せ
US6358985B1 (en) 1998-07-02 2002-03-19 Merck & Co., Inc. Inhibitors of prenyl-protein transferase
US6410534B1 (en) 1998-07-02 2002-06-25 Merck & Co., Inc. Inhibitors of prenyl-protein transferase
US7973078B2 (en) 2006-08-10 2011-07-05 Astellas Pharma Inc. Sulfonamide compound or salt thereof

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CA2250143A1 (fr) 1997-10-09
EP0959883A1 (fr) 1999-12-01
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JP2000507584A (ja) 2000-06-20
AU2596897A (en) 1997-10-22
AU715604B2 (en) 2000-02-03

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