+

WO1997036897A1 - Inhibiteurs de la farnesyl-proteine transferase - Google Patents

Inhibiteurs de la farnesyl-proteine transferase Download PDF

Info

Publication number
WO1997036897A1
WO1997036897A1 PCT/US1997/005358 US9705358W WO9736897A1 WO 1997036897 A1 WO1997036897 A1 WO 1997036897A1 US 9705358 W US9705358 W US 9705358W WO 9736897 A1 WO9736897 A1 WO 9736897A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
alkyl
unsubstituted
aryl
hydrogen
Prior art date
Application number
PCT/US1997/005358
Other languages
English (en)
Inventor
Neville J. Anthony
Original Assignee
Merck & Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9613462.2A external-priority patent/GB9613462D0/en
Priority claimed from GBGB9617258.0A external-priority patent/GB9617258D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to EP97917781A priority Critical patent/EP0891356A1/fr
Priority to AU26021/97A priority patent/AU714851B2/en
Priority to JP9535547A priority patent/JP2000507592A/ja
Publication of WO1997036897A1 publication Critical patent/WO1997036897A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—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
    • 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
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • 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
    • C07D233/66—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/70—One oxygen atom
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

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
  • Ras must be localized to the plasma membrane for both normal and oncogenic functions. At least 3 post-translational modifications are involved with Ras membrane localization, and all 3 modifications occur at the C-terminus of Ras.
  • the Ras C-terminus contains a sequence motif termed a "CAAX” or "Cys-Aaa 1 -Aaa 2 -Xaa” box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al, Nature 37(9:583-586 (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 15 or C 20 isoprenoid, respectively.
  • the Ras protein is one of several proteins that are known to undergo post-translational farnesyl- ation.
  • farnesylated proteins include the Ras-related GTP-binding proteins such as Rho, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin. James, et al., J. Biol Chem. 269, 14182 (1994) have identified a peroxisome associated protein Pxf which is also farnesylated. James, et al., have also suggested that there are farnesylated proteins of unknown structure and function in addition to those listed above.
  • FPTase farnesyl-protein transferase
  • FPP farnesyl diphosphate
  • Ras protein substrates
  • Bisubstrate inhibitors and inhibitors of farnesyl-protein transferase that are non-competitive with the substrates have also been described.
  • the peptide derived inhibitors that have been described are generally cysteine containing molecules that are related to the CAAX motif that is the signal for protein prenylation.
  • Such inhibitors may inhibit protein prenylation while serving as alternate substrates for the farnesyl-protein transferase enzyme, or may be purely competitive inhibitors (U.S.
  • Patent 5,141 ,851 University of Texas; N.E. Kohl et al, Science,
  • farnesyl-protein 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
  • the present invention comprises biheteroary I -containing compounds which inhibit the farnesyl-protein transferase. Further contained in this invention are 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:
  • a is N or C; from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S; from 1-3 of f(s) are independently N or N->O, and the remaining fs are independently CR 6 ;
  • R 1 and R 2 are independently selected from:
  • substituent 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 3 , R 4 and R 5 are independently selected from:
  • substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 12 O-,
  • each R 6 is independently selected from:
  • substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 12 O-,
  • R 6 when R 6 is unsubstituted or substituted heterocycle, attachment of R 6 to 0 is through a substitutable ring carbon;
  • R 7 is selected from: H; C 1-4 alkyl, C 3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, 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 independently selected from:
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl,
  • R 1 1 is independently selected from C 1 -C 6 alkyl and aryl
  • R 1 2 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6
  • aralkyl C 1 -C 6 substituted aralkyl, C 1 -C 6 heteroaralkyl, C 1 -C 6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substitut. heteroaryl, C 1 -C 6 perfluoroalkyl, 2-aminoethyl and 2,_,2-trifluoroethyl;
  • V is selected from:
  • V is not hydrogen if Al 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 ;
  • V when V is heterocycle, attachment of V to R 8 and to Al is through a substitutable ring carbon;
  • W is a heterocycle
  • n is independently 0, 1 , 2, 3 or 4;
  • p is independently 0, 1 , 2, 3 or 4;
  • q 0, 1 , 2 or 3;
  • r is 0 to 5, provided that r is 0 when V is hydrogen; and t is 0 or 1 ; or the pharmaceutically acceptable salts thereof.
  • a is N or C; from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S; from 1 -3 of f(s) are independently N or N->O, and the remaining fs are independently CR 6 ;
  • R 1 is independently selected from: hydrogen, C 3 -C 10 cycloalkyl, R 1 0 O , -N( R 10 ) 2 , F or C 1 -C 6 alkyl;
  • R 2 is independently selected from:
  • substituent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, R 10 O- and -N( R 10 ) 2 ;
  • R 3 , R 4 and R 5 are independently selected from:
  • R 11 S(O) m R 10 C(O)N R 10 -, ( R 10 ) 2 NC(O)-, R 10 2 N- C(N R 10 )-, CN, NO 2 , R 10 C(O)-, N 3 , -N( R 10 ) 2 , or R 11 OC(O)N R 10 -,
  • substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 12 O-,
  • each R 6 is independently selected from:
  • R 11 S(O) m -, R 10 C(O)N R 10 -, ( R 10 ) 2 NC(O)-, R 10 2 N- C(N R 10 )-, CN, NO2, R 10 C(O)-, N 3 , -N( R 10 ) 2 , or
  • substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 12 O-,
  • R 6 when R 6 is unsubstituted or substituted heterocycle, attachment of R 6 to Q is through a substitutable ring carbon;
  • R 7 is selected from: H; C 1 -4 alkyl, C 3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
  • R 8 is independently selected from:
  • R 8 when R 8 is heterocycle, attachment of R 8 to V is through a substitutable ring carbon;
  • R 9 is selected from: a) hydrogen
  • R 10 perfluoroalkyl, F, Cl, R 10 O-, R 1 1 S(O) m -, R 10 C(O)N R 10 -, ( R 10 ) 2 NC(O)-, CN, ( R 10 ) 2 N-C(N R 10 )-, R 10 C(O)-, -N( R 10 ) 2 , or R 1 1 OC(O)N R 10 -;
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl,
  • R 1 1 is independently selected from C 1 -C 6 alkyl and aryl
  • R 1 2 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6
  • aralkyl C 1 -C 6 substituted aralkyl, C 1 -C 6 heteroaralkyl, C 1 -C 6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 1 -C 6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
  • 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 ;
  • V when V is heterocycle, attachment of V to R 8 and to A 1 is through a substitutable ring carbon;
  • W is a heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, triazolyl or
  • X isoquinolinyl
  • n is independently 0, 1 , 2, 3 or 4;
  • p is independently 0, 1 , 2, 3 or 4;
  • q 0, 1 , 2 or 3;
  • r is 0 to 5, provided that r is 0 when V is hydrogen; and t is 0 or 1 ; or the pharmaceutically acceptable salts thereof.
  • 1 a is N or C; from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S; from 1 -3 of f(s) are independently N or N->0, and the remaining f s are independently CR 6 ; R 1 is independently selected from: hydrogen, C 3 -C 10 cycloalkyl, R 10 O,
  • R 2 is independently selected from:
  • substituent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, R 1 0 O- and -N( R 10 ) 2 ;
  • R 3 and R 4 are independently selected from:
  • substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 12 O-, R 11 S(O) m -, R 10 C(O)N R 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 -; each R 6 is independently selected from:
  • R 6 is unsubstituted or substituted heterocycle, attachment of R 6 to Q is through a substitutable ring carbon;
  • R 8 is independently selected from:
  • R 8 when R 8 is heterocycle, attachment of R 8 to V is through a substitutable ring carbon;
  • R 9a and R 9b are independently hydrogen, C 1 -C 6 alkyl, trifluoromethyl and halogen;
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl,
  • R 1 1 is independently selected from C 1 -C 6 alkyl and aryl;
  • R 1 2 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6
  • aralkyl C 1 -C 6 substituted aralkyl, C 1 -C 6 heteroaralkyl, C 1 -C 6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 1 -C 6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
  • 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 ;
  • V when V is heterocycle, attachment of V to R 8 and to A 1 is through a substitutable ring carbon;
  • X is not -C(O)N R 10 -, -NR 10 - or O; m is 0, 1 or 2;
  • n is independently 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.
  • a is N or C; from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S; from 1-3 of f(s) are independently N or N->O, and the remaining fs are independently CR 6 ;
  • R 1 is independently selected from: hydrogen, C 3 -C 10 cycloalkyl, R 10 O, -N(R 10 ) 2 , For C 1 -C 6 alkyl;
  • R 2 is independently selected from:
  • substituent on the substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, R 10 O- and -N( R 10 ) 2 ;
  • R 3 and R 4 are independently selected from:
  • R 11 S(O) m -, R 10 C(O)N R 10 -, CN(R 10 ) 2 NC(O)-, R 10 2 N- C(NR 10 )-, CN, NO 2 , R 10 C(O)-, N 3 , -N(R 10 ) 2 , or
  • substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 12 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)-, N 3 , -N(R 10 ) 2 , and R 11 OC(O)-
  • each R 6 is independently selected from:
  • R 11 S(O) m -, R 10 C(O)N R 10 -, CN(R 10 ) 2 NC(O)-, R 10 2N- C(NR 10 )-, CN, NO 2 , R 10 C(O)-, N 3 , -N(R 10 ) 2 , or
  • substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 12 O-,
  • R 6 when R 6 is unsubstituted or substituted heterocycle, attachment of R 6 to Q is through a substitutable ring carbon; ndependently selected from:
  • R 9a and R 9b are independently hydrogen, C 1 -C 6 alkyl, trifluoromethyl and halogen;
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl,
  • R 1 1 is independently selected from C 1 -C 6 alkyl and aryl
  • R 1 2 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6
  • 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 ;
  • V when V is heterocycle, attachment of V to R 8 and to A 1 is through a substitutable ring carbon;
  • n is independently 0, 1 , 2, 3 or 4;
  • p is 0, 1 , 2, 3 or 4, provided that p is not 0 if X is a bond
  • r is 0 to 5, provided that r is 0 when V is hydrogen; or the pharmaceutically acceptable salts thereof.
  • a is N or C; from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S; from 1 -3 of f(s) are independently N or N->O, and the remaining fs are independently CR 6 ;
  • R 1 is independently selected from: hydrogen, C 3 -C 10 cycloalkyl or C 1 -C 6 alkyl;
  • R 2 is independently selected from:
  • R3 is selected from:
  • R 11 S(O) m -, R 10 C(O)N R 10 -, ( R 10 ) 2 NC(O)-, C 10 2 N- C(NR 10 )-, CN, NO 2 , R 10 C(O)-, N 3 , -N(R 10 ) 2 , or
  • substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 12 O-, R 11 S(O) m -, R 10 C(O)N R 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)-
  • R 4 is selected from H, halogen, C 1 -C 6 alkyl and CF 3 ; each R 6 is independently selected from:
  • substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 12 O-,
  • R 6 is unsubstituted or substituted heterocycle, attachment of R 6 to Q is through a substitutable ring carbon;
  • R 8 is independently selected from:
  • R 9a and R 9b are independently hydrogen, halogen, CF 3 or methyl;
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl, 2,2,2-trifluoroethyl and aryl;
  • R 1 1 is independently selected from C 1 -C 6 alkyl and aryl
  • R 12 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6 aralkyl, C 1 -C 6 substituted aralkyl, C 1 -C 6 heteroaralkyl, C 1 -C 6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 1 -C 6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
  • a 1 is selected from: a bond, -C(O)-, O, -N( R 10 )-, or S(O) m ;
  • n 0, 1 or 2;
  • p 0, 1 , 2, 3 or 4; or the pharmaceutically acceptable salts thereof.
  • the inhibitors of farnesyl-protein transferase are illustrated by the formula E:
  • a is N or C; from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S; from 1-3 of f(s) are independently N or N->O, and the remaining fs are independently CR 6 ;
  • R 1 is independently selected from: hydrogen, R 10 O-, -N( R 10 ) 2 , F,
  • R 2 is independently selected from:
  • R 3 is selected from:
  • substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 12 O-, R 11 S(O) m -, R 10 C(O)N R 10 -, ( R 10 ) 2 NC(O)-, R 10 2 N-
  • R 4 is selected from H, halogen, C 1 -C 6 alkyl and CF 3 ; each R 6 is independently selected from:
  • R 11 S(O) m -, R 10 C(O)NR 10 -, (R 10 ) 2 NC(O)-, R 10 2 N- C(NR 10 )-, CN, NO 2 , R 10 C(O)-, N 3 ,-N( R 10 ) 2 , or
  • substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 12 O-, R 11 S(O) m -, R 10 C(O)N R 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)-
  • R 6 is unsubstituted or substituted heterocycle, attachment of R 6 to Q is through a substitutable ring carbon;
  • R 8 is independently selected from:
  • R 9a and R 9b are independently hydrogen, halogen, CF 3 or methyl;
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl,
  • R 1 1 is independently selected from C 1 -C 6 alkyl and aryl
  • R 1 2 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6
  • aralkyl C 1 -C 6 substituted aralkyl, C 1 -C 6 heteroaralkyl, C 1 -C 6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 1 -C 6 perfluoroalkyl,
  • n 0, 1 or 2;
  • p is 0, 1 , 2, 3 or 4, provided that p is not 0 if X is a bond or O; or the pharmaceutically acceptable salts thereof.
  • a is N or C; from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that if a is C, then at least one of b, c, d or e is independently N, NH, O or S; from 1 -3 of f(s) are independently N or N->0, and the remaining fs are independently CR 6 ;
  • R 1 is independently selected from: hydrogen, C 3 -C 10 cycloalkyl or C 1 -C 6 alkyl;
  • R 2 is independently selected from:
  • R 3 is selected from:
  • substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 12 O-,
  • R 4 is selected from H, halogen, CH 3 and CF 3 ; each R 6 is independently selected from:
  • R 6 when R 6 is unsubstituted or substituted heterocycle, attachment of R 6 to Q is through a substitutable ring carbon;
  • R 9a and R 9b are independently hydrogen, halogen, CF 3 or methyl;
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl,
  • R 11 is independently selected from C 1 -C 6 alkyl and aryl
  • R 12 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6
  • aralkyl C 1 -C 6 substituted aralkyl, C 1 -C 6 heteroaralkyl, C 1 -C 6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 1 -C 6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
  • X is not -C(O)NR 10 -, -NR 10 - or O; m is 0, 1 or 2;
  • a is C; from 0-4 of b, c, d and e are independently N, NH, O and S, and the remaining b, c, d and e atoms are independently CH, provided that at least one of b, c, d or e is independently N, NH, O or S; from 1-3 of f(s) are independently N or N->O, and the remaining f s are independently CR 6 ;
  • R 1 is independently selected from: hydrogen, R 1 0 O-, -N( R 10 ) 2 , F, C 3 -C 10 cycloalkyl or C 1 -C 6 alkyl;
  • R 2 is independently selected from:
  • R 3 is selected from:
  • substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 12 O-,
  • R 4 is selected from H, halogen, CH 3 and CF 3 ; each R 6 is independently selected from:
  • R 11 S(O) m -, R 10 C(O)NR 10 -, ( R 10 ) 2 NC(O)-, R 10 2 N- C(NR 10 )-, CN, NO 2 , R 10 C(O)-, N 3 , -N( R 10 ) 2, or
  • R 6 when R 6 is unsubstituted or substituted heterocycle, attachment of R 6 to Q is through a substitutable ring carbon;
  • R 9a and R 9b are independently hydrogen, halogen, CF 3 or methyl;
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl,
  • R 1 1 is independently selected from C 1 -C 6 alkyl and aryl
  • R 1 2 is independently selected from hydrogen, C 1 -C 6 alkyl, C 1 -C 6
  • aralkyl C 1 -C 6 substituted aralkyl, C 1 -C 6 heteroaralkyl, C 1 -C 6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 1 -C 6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
  • a 1 is selected from: a bond, -C(O)-, O, -N( R 10 )-, or S(O) m ; m is 0, 1 or 2; and
  • n 0 or 1 ; or the pharmaceutically acceptable salts thereof.
  • 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. Also, combinations of substituents/or variables are permissible only if such combinations result in stable compounds.
  • alkyl and the alkyl portion of aralkyl and similar terms, 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.
  • cycloalkyl is intended to include non- aromatic cyclic hydrocarbon groups having the specified number of carbon atoms.
  • examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • alkenyl groups include those groups having the specified number of carbon atoms and having one or several double bonds. Examples of alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyI, isoprenyl, farnesyl, geranyl, geranylgeranyl and the like.
  • Alkynyl groups include those groups having the specified number of carbon atoms and having one triple bonds. Examples of alkynyl groups include acetylene, 2-butynyl, 2-pentynyl, 3-pentynyl and the like.
  • Halogen or "halo” as used herein means fluoro, chloro, bromo and iodo.
  • aryl and the aryl portion of aroyl and aralkyl, 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.
  • 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
  • heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable stmcture. Examples of such 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 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 substituents in addition to the point of attachment to the rest of the compound.
  • substituted aryl substituted heterocycle
  • substituted cycloalkyl are intended to include the cyclic group which is substituted on a substitutable ring carbon atom with 1 or 2 substitutents 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 aIkyl)S(O) m -, (C 1 -C 6 alkyl)C(O)NH-, H2N-C(NH)-, (C 1 -C 6
  • the moiety designated by the following structure represents an aromatic 5-membered heterocyclic ring and includes the following ring systems:
  • aromatic 5-membered heterocyclic ring is selected from:
  • the moiety designated by the following structure represents an aromatic 6-membered heterocyclic ring and includes the following ring systems:
  • the aromatic 6-membered heterocyclic ring is a pyridyl group.
  • f(s) are independently N, and the remaining f s are independently CR 6 ;
  • R 1 and R 2 are independently selected from: hydrogen, R 1 1 C(O)O-, -N( R 10 ) 2 , R 10 C(O)N R 10 -, R 10 O. 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 1 0 O- and R 10 C(O)N R 10 -.
  • R 3 is selected from:
  • substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 1 2 O-,
  • R4 is selected from: hydrogen, halogen, trifluoromethyl, trifluoromethoxy and C 1 -C 6 alkyl.
  • R 5 is hydrogen
  • R 6 is independently selected from: a) hydrogen,
  • substituted C 1 -C 6 alkyl is selected from unsubstituted or substituted aryl, C 3 -C 10 cycloalkyl, R 12 O-, R 1 1 S(O) m -, R 10 C(O)- or -N( R 10 ) 2 ; or
  • R 8 is independently selected from: a) hydrogen, and
  • R 9 is hydrogen, halogen or methyl.
  • 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)N R 10 -, -N R 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.
  • W is selected from imidazolinyl, imidazolyl, oxazolyl, pyrazolyl, pyyrolidinyl, thiazolyl and pyridyl. More preferably, W is selected from imidazolyl and pyridyl.
  • n and r are independently 0, 1 , or 2.
  • s is 0.
  • t is 1.
  • any substituent or variable e.g., R 1 , R 2 , R 9 , n, etc.
  • -N( R 10 ) 2 represents -NHH, -NHCH 3 , -NHC 2 H 5 , etc.
  • 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 synthe- sized 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. Generally, 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 the Schemes 1-25, 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 3 , R 6 and R 8 as shown in the Schemes, represent the substituents R 3 , R 4 , R 5 , R 6 and R 8 ; although only one such R3, R 6 0r R 8 is present in the intermediates and products of the schemes, it is understood that the reactions shown are also applicable when such aryl or heteroaryl moieties contain multiple substituents.
  • Schemes 1 - 15 illustrate synthesis of the instant biheteroaryl compound which incorporate a preferred benzylimidazolyl sidechain.
  • a biheteroaryl intermediate that is not commercially available may be synthesized by methods known in the art.
  • a pyridyl boronic acid I may be reacted under Suzuki coupling conditions (Pure Appl.
  • Schemes 2-5 illustrate other methods of synthesizing the key alcohol intermediates, which can then be processed as described in Scheme 1.
  • Scheme 2 illustrates the analogous series of biheteroaryl alcohol forming reactions starting with the halogenated
  • Scheme 3 illustrates the reaction wherein the "terminal" heteroaryl moiety is employed in the Suzuki coupling as the halogenated reactant. Such a coupling reaction is also compatible when one of the reactants incorporates a suitably protected hydroxyl functionality as illustrated in Scheme 4.
  • Negishi chemistry (Org. Synth., 66:67 (1988)) may also be employed to form the biheteroaryl component of the instant compounds, as shown in Scheme 5.
  • a zinc bromide adduct such as 2 -pyridyl zinc bromide
  • the heteroaryl halide and the zinc bromide adduct may be selected based on the availability of the starting reagents.
  • the sequence of coupling reactions may be modified such that the heteroaryl -heteroaryl bond is formed last.
  • a suitably substituted imidazole may first be alkylated with a heteroarylmethyl halide to provide intermediate VII.
  • Scheme 7 illustrates the synthesis of a thiazole containing instant compound from the acyclic precursors. Similar strategies may be utilized to prepare other bisheteroatom moieties.
  • Schemes 8 and 9 illustrate synthetic strategies that utilize the nucleophilicity of an imidazolyl component of the biheteroaryl.
  • Scheme 10 illustrates synthesis of an instant compound wherein a non-hydrogen R9b is incorporated in the instant compound.
  • a readily available 4-substituted imidazole IX may be selectively iodinated to provide the 5-iodoimidazole X. That imidazole may then be protected and coupled to a suitably substituted benzyl moiety to provide intermediate XI. Intermediate XI can then undergo the alkylation reactions that were described hereinabove.
  • Scheme 1 1 illustrates synthesis of instant compounds that incorporate a preferred imidazolyl moiety connected to the biheteroaryl moiety via an alkyl amino, sulfonamide or amide linker.
  • 4-aminoalkylimidazole XII wherein the primary amine is protected as the phthalimide, is selectively alkylated then deprotected to provide the amine XIII.
  • the amine XIII may then react under conditions well known in the art with various activated biheteroaryl moieties to provide the instant compounds shown.
  • a 1 (CR 1 2)nA 2 (CR 1 2)n linker is oxygen may be synthesized by methods known in the art, for example as shown in Scheme 12.
  • the suitably substituted phenol XIV may be reacted with methyl N-(cyano)methanimidate to provide the 4-phenoxyimidazole XV.
  • the intermediate XVI can undergo alkylation reactions as described for the benzylimidazoles hereinabove.
  • Scheme 13 illustrates an analogous series of reactions wherein the (CR 2 2)pX(CR 2 2)p linker of the instant compounds is oxygen.
  • a suitably substituted haloheteroaryl alcohol such as , is reacted with methyl N-(cyano)methanimidate to provide intermediate XVI.
  • Intermediate XVI is then protected and, if desired to form a compound of a preferred embodiment, alkylated with a suitably protected benzyl.
  • the intermediate XVII can then be coupled to a second heteroaryl moiety by Suzuki chemistry to provide the instant compound.
  • the intermediates whose synthesis are illustrated in Schemes hereinabove and other biheteroaryl intermediates obtained commercially or readily synthesized can be coupled with a variety of aldehydes.
  • 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 Svntheses. 1988, 67, 69-75, from the appropriate amino acid (Scheme 16).
  • Metal halogen exchange chemistry (Scheme 15) may be employed when manipulating the aldehydes.
  • Grignard chemistry may be utilized, as shown in Scheme 16.
  • Suzuki coupling provides, for example, the pyrrole containing biheteroaryl XXI.
  • Reaction of the intermediate XXI with a Grignard reagent provides the N-pyrrylmagnesium derivative XXIa, which is then reacted with an aldehyde to provide the C-alkylated instant compound XXII.
  • the product XXII can be deoxygenated by methods known in the art, such as a catalytic hydrogention, then deprotected with trifluoroacetic acid in methylene chloride to give the final compound XXIla.
  • the final product XXII may be 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.
  • Scheme 17 illustrates the use of in situ formation of a lithium anion of a suitably substituted N-alkyl pyrrole to provide the C-alkylated compound of the instant invention.
  • an aldehyde which also has a protected hydroxyl group, such as XXVI in Scheme 18
  • the protecting groups can be subsequently removed to unmask the hydroxyl group (Schemes 18, 19).
  • 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 XXX.
  • the fully deprotected amino alcohol XXXI can be reductively alkylated (under conditions described previously) with a variety of aldehydes to obtain secondary amines, such as XXXII (Scheme 19), or tertiary amines.
  • the Boc protected amino alcohol XXVIII can also be utilized to synthesize 2-aziridinylmethyIbiheteroaryl such as XXXIII (Scheme 20). Treating XXVIII with 1 ,1'-sulfonyldiimidazole and sodium hydride in a solvent such as dimethylformamide led to the formation of aziridine XXXIII . The aziridine is reacted with a nucleophile, such as a thiol, in the presence of base to yield the ring- opened product XXXIV .
  • a nucleophile such as a thiol
  • the biheteroaryl subunit can be reacted with aldehydes derived from amino acids such as O-alkylated tyrosines, according to standard procedures, to obtain compounds such as XL, as shown in Scheme 21.
  • R' is an aryl group
  • XL can first be hydrogenated to unmask the phenol, and the amine group deprotected with acid to produce XLI.
  • the amine protecting group in XL can be removed, and O-alkylated phenolic amines such as XLII produced.
  • 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
  • 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 c ⁇ .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 combination with pharmaceutically acceptable carriers or diluents, optionally with known adjuvants, such as alum, in a pharmaceutical composition, according to standard pharmaceutical practice.
  • the compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
  • the selected compound may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension.
  • carriers which are commonly used include lactose and com starch, and lubricating agents, such as magnesium stearate, are commonly added.
  • useful diluents include lactose and dried com starch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents may be added.
  • sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered.
  • the total concentration of solutes should be controlled in order to render the preparation isotonic.
  • the 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.
  • Such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent(s) within its approved dosage range.
  • Compounds of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate.
  • 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 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
  • 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.
  • 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 B 5-(Pyrid-2-yl)-2-hydroxymethylthiophene
  • 1.0 M lithium aluminum hydride in tetrahydrofuran 12.0 mL, 12.0 mmol
  • the reaction is allowed to stir at ambient temperature for 3 hours.
  • the reaction is cooled to 0°C, and water (0.5 mL), 4 N aq. NaOH (0.5 mL), and water (1.5 mL) are added sequentially.
  • Step C 1 -(5-(Pyrid-2'-yl)-thien-2-ylmethyl)-5-(4- cyanobenzyl)imidazole trifluoroacetic acid salt
  • Step D 4-[5-(Aminocarbonylmethyl)imidazol-1 - ylmethyllbenzonitrile
  • Step E 1 -(4-Cyanobenzyl)-5-aminothiocarbonylmethyl-1 H- imidazole
  • Step F 2-Bromoacetylpyridine.
  • Step G 1 -(4-Cyanobenzyl)-5-[(4-pyrid-2'-yl)-thiazol-2-ylmethyl] imidazole
  • Bovine FPTase was assayed in a volume of 100 ⁇ l containing 100 mM N-(2- hydroxy ethyl) piperazine-jV'-(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.
  • 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 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 are tested for inhibitory activity against human FPTase by the assay described above.
  • the cell line used in this assay is a v-ras line derived from either Rat1 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% 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 NaCl) 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 farnesylated and nonfarnesylated ras proteins are compared to IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA/1 % Triton X- 100.0.5% deoxycholate/0.1 %/SDS/0.1 M NaCl) 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
  • 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. Photomicrographs are taken 16 days after the cultures are seeded and comparisons are made.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Urology & Nephrology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Virology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne des composés qui inhibent la farnésyl-protéine transférase (FTase) et la farnésylation de la protéine oncogène Ras. Elle concerne également des compositions chimiothérapiques contenant ces composés et des procédés permettant d'inhiber la farnésyl-protéine transférase, ainsi que la farnésylation de la protéine oncogène Ras.
PCT/US1997/005358 1996-04-03 1997-04-01 Inhibiteurs de la farnesyl-proteine transferase WO1997036897A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP97917781A EP0891356A1 (fr) 1996-04-03 1997-04-01 Inhibiteurs de la farnesyl-proteine transferase
AU26021/97A AU714851B2 (en) 1996-04-03 1997-04-01 Inhibitors of farnesyl-protein transferase
JP9535547A JP2000507592A (ja) 1996-04-03 1997-04-01 ファルネシル―タンパク質トランスフェラーゼ阻害剤

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US1459296P 1996-04-03 1996-04-03
US60/014,592 1996-04-03
GBGB9613462.2A GB9613462D0 (en) 1996-06-27 1996-06-27 Inhibitors of farnesyl-protein transferase
US2255896P 1996-07-24 1996-07-24
US60/022,558 1996-07-24
GBGB9617258.0A GB9617258D0 (en) 1996-08-16 1996-08-16 Inhibitors of farnesyl-protein transferase
GB9613462.2 1996-08-16
GB9617258.0 1996-08-16

Publications (1)

Publication Number Publication Date
WO1997036897A1 true WO1997036897A1 (fr) 1997-10-09

Family

ID=27451472

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1997/005358 WO1997036897A1 (fr) 1996-04-03 1997-04-01 Inhibiteurs de la farnesyl-proteine transferase

Country Status (5)

Country Link
EP (1) EP0891356A1 (fr)
JP (1) JP2000507592A (fr)
AU (1) AU714851B2 (fr)
CA (1) CA2249665A1 (fr)
WO (1) WO1997036897A1 (fr)

Cited By (58)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5939439A (en) * 1996-12-30 1999-08-17 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
US6093737A (en) * 1996-12-30 2000-07-25 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
EP1035850A1 (fr) * 1997-12-04 2000-09-20 Merck & Co., Inc. Inhibiteurs de la transferase de la farnesyl-proteine
US6127390A (en) * 1997-10-02 2000-10-03 Merck & Co., Inc. Inhibitors of prenyl-protein transferase
EP1045843A1 (fr) * 1997-12-04 2000-10-25 Merck & Co., Inc. Inhibiteurs de la farnesyl-proteine transferase
WO2001036395A1 (fr) * 1999-11-15 2001-05-25 Janssen Pharmaceutica N.V. Triazoles utilises comme inhibiteurs de farnesyl transferase
US6627629B2 (en) 2000-06-30 2003-09-30 Bristol-Myers Squibb Pharma N-ureidoheterocycloalkyl-piperidines as modulators of chemokine receptor activity
US7211595B2 (en) 2000-11-30 2007-05-01 Abbott Laboratories Farnesyltransferase inhibitors
US7557131B2 (en) 2005-01-20 2009-07-07 Pfizer Inc Substituted triazole derivatives as oxytocin antagonists
US7622471B2 (en) 2003-02-07 2009-11-24 Daiichi Pharmaceutical Co., Ltd. Pyrazole derivatives having a pyridazine and pyridine functionality
US7745638B2 (en) 2003-07-22 2010-06-29 Astex Therapeutics Limited 3,4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinase and glycogen synthase kinase-3 modulators
WO2010080864A1 (fr) 2009-01-12 2010-07-15 Array Biopharma Inc. Composés contenant de la pipéridine et leurs utilisations
US7994185B2 (en) 2008-05-06 2011-08-09 Glaxo Smith Kline LLC Benzene sulfonamide thiazole and oxazole compounds
US8013163B2 (en) 2005-01-21 2011-09-06 Astex Therapeutics Limited 4-(2,6-dichloro-benzoylamino)-1H-pyrazole-3-carboxylic acid piperidin-4-ylamide acid addition salts as kinase inhibitors
US8404718B2 (en) 2005-01-21 2013-03-26 Astex Therapeutics Limited Combinations of pyrazole kinase inhibitors
US8410144B2 (en) 2009-03-31 2013-04-02 Arqule, Inc. Substituted indolo-pyridinone compounds
US8686007B2 (en) 2011-04-22 2014-04-01 Cytokinetics, Inc. Certain heterocycles, compositions thereof, and methods for their use
US8815271B2 (en) 2010-11-03 2014-08-26 Dow Agrosciences, Llc. Pesticidal compositions and processes related thereto
US8901153B2 (en) 2012-04-27 2014-12-02 Dow Agrosciences, Llc. Pesticidal compositions and processes related thereto
US8946278B2 (en) 2007-02-07 2015-02-03 Glaxosmithkline Llc Inhibitors of AkT activity
US9024031B1 (en) 2014-08-19 2015-05-05 Dow Agrosciences Llc Process for the preparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine
US9029554B1 (en) 2013-10-17 2015-05-12 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US9029555B1 (en) 2014-07-31 2015-05-12 Dow Agrosciences Llc Process for the preparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine
US9029556B1 (en) 2014-07-31 2015-05-12 Dow Argosciences Llc Process for the preparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine
US9044017B2 (en) 2013-10-17 2015-06-02 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US9085552B1 (en) 2014-09-12 2015-07-21 Dow Agrosciences Llc Process for the preparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine
US9085564B2 (en) 2013-10-17 2015-07-21 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US9102655B2 (en) 2013-10-17 2015-08-11 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US9102654B2 (en) 2013-10-17 2015-08-11 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US9108946B2 (en) 2013-10-17 2015-08-18 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US9137998B2 (en) 2013-10-22 2015-09-22 Dow Agrosciences Llc Pesticidal compositions and related methods
US9144241B2 (en) 2013-10-22 2015-09-29 Dow Agrosciences Llc Synergistic pesticidal compositions and related methods
US9149040B2 (en) 2013-10-22 2015-10-06 Dow Agrosciences Llc Synergistic pesticidal compositions and related methods
US9155304B2 (en) 2013-10-22 2015-10-13 Dow Agrosciences Llc Synergistic pesticidal compositions and related methods
US9174962B2 (en) 2013-10-17 2015-11-03 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US9199964B1 (en) 2014-07-31 2015-12-01 Dow Agrosciences Llc Process for the preparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine
US9282739B2 (en) 2012-04-27 2016-03-15 Dow Agrosciences Llc Pesticidal compositions and processes related thereto
US9282740B2 (en) 2013-10-22 2016-03-15 Dow Agrosciences Llc Synergistic pesticidal compositions and related methods
US9295260B2 (en) 2013-10-22 2016-03-29 Dow Agrosciences Llc Pesticidal compositions and related methods
US9295258B2 (en) 2013-10-22 2016-03-29 Dow Agrosciences Llc Synergistic pesticidal compositions and related methods
US9445597B2 (en) 2013-10-22 2016-09-20 Dow Agrosciences Llc Pesticidal compositions and related methods
US9474276B2 (en) 2013-10-22 2016-10-25 Dow Agrosciences Llc Synergistic pesticidal compositions and related methods
US9491944B2 (en) 2013-10-22 2016-11-15 Dow Agrosciences Llc Pesticidal compositions and related methods
US9497966B2 (en) 2013-10-22 2016-11-22 Dow Agrosciences Llc Pesticidal compositions and related methods
US9549560B2 (en) 2013-10-22 2017-01-24 Dow Agrosciences Llc Pesticidal compositions and related methods
US9604965B2 (en) 2010-04-23 2017-03-28 Cytokinetics, Inc. Substituted pyridazines as skeletal muscle modulators
US9655365B2 (en) 2011-10-26 2017-05-23 Dow Agrosciences Llc Pesticidal compositions and processes related thereto
US9708288B2 (en) 2012-04-27 2017-07-18 Dow Agrosciences Llc Pesticidal compositions and processes related thereto
US9730886B2 (en) 2010-04-23 2017-08-15 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
US9788545B2 (en) 2013-10-22 2017-10-17 Dow Agrosciences Llc Synergistic pesticidal compositions and related methods
US9788546B2 (en) 2013-10-22 2017-10-17 Dow Agrosciences Llc Synergistic pesticidal compositions and related methods
US9801383B2 (en) 2013-10-22 2017-10-31 Dow Agrosciences Llc Synergistic pesticidal compositions and related methods
US9801376B2 (en) 2013-10-22 2017-10-31 Dow Agrosciences Llc Synergistic pesticidal compositions and related methods
US9808008B2 (en) 2013-10-22 2017-11-07 Dow Agrosciences Llc Synergistic pesticidal compositions and related methods
US9834542B2 (en) 2013-03-15 2017-12-05 Bristo-Myers Squibb Company LXR modulators
US9994528B2 (en) 2010-04-23 2018-06-12 Cytokinetics, Inc. Certain amino-pyridines and amino-triazines, compositions thereof, and methods for their use
US10100033B2 (en) 2016-12-29 2018-10-16 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4713387A (en) * 1984-06-25 1987-12-15 Toyama Chemical Co., Ltd. Vasodilating and platelet aggregation inhibiting 1,4 dihydropyridines with an imidazolyl or pyridyl containing ester
US5428164A (en) * 1990-12-28 1995-06-27 Neurogen Corporation Certain 4-aryl substituted piperazinyl and piperidinylmethyl phenylimidazole derivatives; a new class of dopamine receptor subtype specific ligands
US5587390A (en) * 1992-08-07 1996-12-24 Istituto Luso Farmaco D'italia S.P.A. Imidazole derivatives having a II antagonist activity
US5633376A (en) * 1990-12-28 1997-05-27 Neurogen Corporation Certain aminomethyl phenylimidazole derivatives; and 4-aryl substituted piperazinyl and piperidinylmethyl phenylimidazole derivatives; a new class of dopamine receptor subtype ligands

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4713387A (en) * 1984-06-25 1987-12-15 Toyama Chemical Co., Ltd. Vasodilating and platelet aggregation inhibiting 1,4 dihydropyridines with an imidazolyl or pyridyl containing ester
US5428164A (en) * 1990-12-28 1995-06-27 Neurogen Corporation Certain 4-aryl substituted piperazinyl and piperidinylmethyl phenylimidazole derivatives; a new class of dopamine receptor subtype specific ligands
US5633376A (en) * 1990-12-28 1997-05-27 Neurogen Corporation Certain aminomethyl phenylimidazole derivatives; and 4-aryl substituted piperazinyl and piperidinylmethyl phenylimidazole derivatives; a new class of dopamine receptor subtype ligands
US5587390A (en) * 1992-08-07 1996-12-24 Istituto Luso Farmaco D'italia S.P.A. Imidazole derivatives having a II antagonist activity

Cited By (126)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6077853A (en) * 1996-12-30 2000-06-20 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
US6093737A (en) * 1996-12-30 2000-07-25 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
US5939439A (en) * 1996-12-30 1999-08-17 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
US6127390A (en) * 1997-10-02 2000-10-03 Merck & Co., Inc. Inhibitors of prenyl-protein transferase
EP1045843A4 (fr) * 1997-12-04 2001-10-24 Merck & Co Inc Inhibiteurs de la farnesyl-proteine transferase
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
EP1035850A1 (fr) * 1997-12-04 2000-09-20 Merck & Co., Inc. Inhibiteurs de la transferase de la farnesyl-proteine
WO2001036395A1 (fr) * 1999-11-15 2001-05-25 Janssen Pharmaceutica N.V. Triazoles utilises comme inhibiteurs de farnesyl transferase
US7511061B2 (en) 1999-11-15 2009-03-31 Janssen Pharmaceutica N.V. Triazoles as farnesyl transferase inhibitors
US7592356B2 (en) 1999-11-15 2009-09-22 Janssen Pharmaceutica N.V. Triazoles as farnesyl transferase inhibitors
US6627629B2 (en) 2000-06-30 2003-09-30 Bristol-Myers Squibb Pharma N-ureidoheterocycloalkyl-piperidines as modulators of chemokine receptor activity
US6949546B2 (en) 2000-06-30 2005-09-27 Bristol-Myers Squibb Pharma Company N-ureidoheterocycloalkyl-piperidines as modulators of chemokine receptor activity
US7211595B2 (en) 2000-11-30 2007-05-01 Abbott Laboratories Farnesyltransferase inhibitors
US7323570B2 (en) 2000-11-30 2008-01-29 Abbott Laboratories Farnesyltransferase inhibitors
US7622471B2 (en) 2003-02-07 2009-11-24 Daiichi Pharmaceutical Co., Ltd. Pyrazole derivatives having a pyridazine and pyridine functionality
US8080666B2 (en) 2003-07-22 2011-12-20 Astex Therapeutics, Ltd. 3,4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinase and glycogen synthase kinase-3 modulators
US7745638B2 (en) 2003-07-22 2010-06-29 Astex Therapeutics Limited 3,4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinase and glycogen synthase kinase-3 modulators
US8779147B2 (en) 2003-07-22 2014-07-15 Astex Therapeutics, Ltd. 3,4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinase and glycogen synthase kinase-3 modulators
US9051278B2 (en) 2003-07-22 2015-06-09 Astex Therapeutics, Ltd. 3,4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinase and glycogen synthase kinase-3 modulators
US7557131B2 (en) 2005-01-20 2009-07-07 Pfizer Inc Substituted triazole derivatives as oxytocin antagonists
US9394278B2 (en) 2005-01-20 2016-07-19 Ixchelsis Limited Substituted triazole derivatives as oxytocin antagonists
US8207198B2 (en) 2005-01-20 2012-06-26 Pfizer Inc. Substituted triazole derivatives as oxytocin antagonists
US10150752B2 (en) 2005-01-20 2018-12-11 Ixchelsis Limited Substituted triazole derivatives as oxytocin antagonists
US9023872B2 (en) 2005-01-20 2015-05-05 Ixchelsis Limited Substituted triazole derivatives as oxytocin antagonists
US8013163B2 (en) 2005-01-21 2011-09-06 Astex Therapeutics Limited 4-(2,6-dichloro-benzoylamino)-1H-pyrazole-3-carboxylic acid piperidin-4-ylamide acid addition salts as kinase inhibitors
US8293767B2 (en) 2005-01-21 2012-10-23 Astex Therapeutics Limited 4-(2,6-dichloro-benzoylamino)-1H-pyrazole-3-carboxylic acid piperidin-4-ylamide acid addition salts as kinase inhibitors
US8404718B2 (en) 2005-01-21 2013-03-26 Astex Therapeutics Limited Combinations of pyrazole kinase inhibitors
US8946278B2 (en) 2007-02-07 2015-02-03 Glaxosmithkline Llc Inhibitors of AkT activity
US8642759B2 (en) 2008-05-06 2014-02-04 Glaxosmithkline Llc Benzene sulfonamide thiazole and oxazole compounds
US8415345B2 (en) 2008-05-06 2013-04-09 Glaxo SmithKline LLC Benzene sulfonamide thiazole and oxazole compounds
US7994185B2 (en) 2008-05-06 2011-08-09 Glaxo Smith Kline LLC Benzene sulfonamide thiazole and oxazole compounds
US9233956B2 (en) 2008-05-06 2016-01-12 Novartis Ag Benzene sulfonamide thiazole and oxazole compounds
US8809538B2 (en) 2009-01-12 2014-08-19 Array Biopharma Inc. Piperidine-containing compounds and use thereof
WO2010080864A1 (fr) 2009-01-12 2010-07-15 Array Biopharma Inc. Composés contenant de la pipéridine et leurs utilisations
US8410144B2 (en) 2009-03-31 2013-04-02 Arqule, Inc. Substituted indolo-pyridinone compounds
US10076519B2 (en) 2010-04-23 2018-09-18 Cytokinetics, Inc. Substituted pyridazines as skeletal muscle modulators
US9730886B2 (en) 2010-04-23 2017-08-15 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
US10272030B2 (en) 2010-04-23 2019-04-30 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
US11369565B2 (en) 2010-04-23 2022-06-28 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
US10765624B2 (en) 2010-04-23 2020-09-08 Cytokinetics, Inc. Amino-pyrimidine skeletal muscle modulators
US9994528B2 (en) 2010-04-23 2018-06-12 Cytokinetics, Inc. Certain amino-pyridines and amino-triazines, compositions thereof, and methods for their use
US9604965B2 (en) 2010-04-23 2017-03-28 Cytokinetics, Inc. Substituted pyridazines as skeletal muscle modulators
US8815271B2 (en) 2010-11-03 2014-08-26 Dow Agrosciences, Llc. Pesticidal compositions and processes related thereto
US9422278B2 (en) 2010-11-03 2016-08-23 Dow Agrosciences Llc Pesticidal compositions and processes related thereto
US8686007B2 (en) 2011-04-22 2014-04-01 Cytokinetics, Inc. Certain heterocycles, compositions thereof, and methods for their use
US8759380B2 (en) 2011-04-22 2014-06-24 Cytokinetics, Inc. Certain heterocycles, compositions thereof, and methods for their use
US9278962B2 (en) 2011-04-22 2016-03-08 Cytokinetics, Inc. Certain heterocycles, compositions thereof, and methods for their use
US9655365B2 (en) 2011-10-26 2017-05-23 Dow Agrosciences Llc Pesticidal compositions and processes related thereto
US10165775B2 (en) 2011-10-26 2019-01-01 Dow Agrosciences Llc Pesticidal compositions and processes related thereto
US9708288B2 (en) 2012-04-27 2017-07-18 Dow Agrosciences Llc Pesticidal compositions and processes related thereto
US9591857B2 (en) 2012-04-27 2017-03-14 Dow Agrosciences Llc Pesticidal compositions and processes related thereto
US8901153B2 (en) 2012-04-27 2014-12-02 Dow Agrosciences, Llc. Pesticidal compositions and processes related thereto
US9282739B2 (en) 2012-04-27 2016-03-15 Dow Agrosciences Llc Pesticidal compositions and processes related thereto
US9834542B2 (en) 2013-03-15 2017-12-05 Bristo-Myers Squibb Company LXR modulators
US9255083B2 (en) 2013-10-17 2016-02-09 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US9862702B2 (en) 2013-10-17 2018-01-09 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US9199942B2 (en) 2013-10-17 2015-12-01 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US9029554B1 (en) 2013-10-17 2015-05-12 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US10315999B2 (en) 2013-10-17 2019-06-11 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US9255082B2 (en) 2013-10-17 2016-02-09 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US9174962B2 (en) 2013-10-17 2015-11-03 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US9260396B2 (en) 2013-10-17 2016-02-16 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US9044017B2 (en) 2013-10-17 2015-06-02 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US9085564B2 (en) 2013-10-17 2015-07-21 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US9988356B2 (en) 2013-10-17 2018-06-05 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US9908864B2 (en) 2013-10-17 2018-03-06 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US9901095B2 (en) 2013-10-17 2018-02-27 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US9102655B2 (en) 2013-10-17 2015-08-11 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US9796682B2 (en) 2013-10-17 2017-10-24 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US9414594B2 (en) 2013-10-17 2016-08-16 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US9102654B2 (en) 2013-10-17 2015-08-11 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US9723839B2 (en) 2013-10-17 2017-08-08 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US9433215B2 (en) 2013-10-17 2016-09-06 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US9434712B2 (en) 2013-10-17 2016-09-06 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US9447048B2 (en) 2013-10-17 2016-09-20 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US9108946B2 (en) 2013-10-17 2015-08-18 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US9670164B2 (en) 2013-10-17 2017-06-06 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US9670178B2 (en) 2013-10-17 2017-06-06 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US9661849B2 (en) 2013-10-17 2017-05-30 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US9126974B2 (en) 2013-10-17 2015-09-08 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US9580405B2 (en) 2013-10-17 2017-02-28 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US9540342B2 (en) 2013-10-17 2017-01-10 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US9550751B2 (en) 2013-10-17 2017-01-24 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US9808008B2 (en) 2013-10-22 2017-11-07 Dow Agrosciences Llc Synergistic pesticidal compositions and related methods
US9801376B2 (en) 2013-10-22 2017-10-31 Dow Agrosciences Llc Synergistic pesticidal compositions and related methods
USRE48057E1 (en) 2013-10-22 2020-06-23 Dow Agrosciences Llc Pesticidal compositions and related methods
US9155304B2 (en) 2013-10-22 2015-10-13 Dow Agrosciences Llc Synergistic pesticidal compositions and related methods
US9137998B2 (en) 2013-10-22 2015-09-22 Dow Agrosciences Llc Pesticidal compositions and related methods
US9497967B2 (en) 2013-10-22 2016-11-22 Doe AgroSciences LLC Synergistic pesticidal compositions and related methods
US9549560B2 (en) 2013-10-22 2017-01-24 Dow Agrosciences Llc Pesticidal compositions and related methods
US9282740B2 (en) 2013-10-22 2016-03-15 Dow Agrosciences Llc Synergistic pesticidal compositions and related methods
US9497966B2 (en) 2013-10-22 2016-11-22 Dow Agrosciences Llc Pesticidal compositions and related methods
US9295260B2 (en) 2013-10-22 2016-03-29 Dow Agrosciences Llc Pesticidal compositions and related methods
US9491944B2 (en) 2013-10-22 2016-11-15 Dow Agrosciences Llc Pesticidal compositions and related methods
US9474276B2 (en) 2013-10-22 2016-10-25 Dow Agrosciences Llc Synergistic pesticidal compositions and related methods
US9445597B2 (en) 2013-10-22 2016-09-20 Dow Agrosciences Llc Pesticidal compositions and related methods
US9295258B2 (en) 2013-10-22 2016-03-29 Dow Agrosciences Llc Synergistic pesticidal compositions and related methods
US9144241B2 (en) 2013-10-22 2015-09-29 Dow Agrosciences Llc Synergistic pesticidal compositions and related methods
US9788545B2 (en) 2013-10-22 2017-10-17 Dow Agrosciences Llc Synergistic pesticidal compositions and related methods
US9788546B2 (en) 2013-10-22 2017-10-17 Dow Agrosciences Llc Synergistic pesticidal compositions and related methods
US9149040B2 (en) 2013-10-22 2015-10-06 Dow Agrosciences Llc Synergistic pesticidal compositions and related methods
US9801383B2 (en) 2013-10-22 2017-10-31 Dow Agrosciences Llc Synergistic pesticidal compositions and related methods
US10035786B2 (en) 2014-07-31 2018-07-31 Dow Agrosciences Llc Process for the preparation of 3-(3-chloro-1h-pyrazol-1-yl)pyridine
US9573931B2 (en) 2014-07-31 2017-02-21 Dow Agrosciences Llc Process for the preparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine
US9249122B1 (en) 2014-07-31 2016-02-02 Dow Agrosciences Llc Process for the preparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine
US9580403B2 (en) 2014-07-31 2017-02-28 Dow Agrosciences Llc Process for the preparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine
US9840490B2 (en) 2014-07-31 2017-12-12 Dow Agrosciences Llc Process for the preparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine
US9199964B1 (en) 2014-07-31 2015-12-01 Dow Agrosciences Llc Process for the preparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine
US9371310B2 (en) 2014-07-31 2016-06-21 Dow Agrosciences Llc Process for the preparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine
US9255081B1 (en) 2014-07-31 2016-02-09 Dow Agrosciences Llc Process for the preparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine
US9029555B1 (en) 2014-07-31 2015-05-12 Dow Agrosciences Llc Process for the preparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine
US9029556B1 (en) 2014-07-31 2015-05-12 Dow Argosciences Llc Process for the preparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine
US9611247B2 (en) 2014-07-31 2017-04-04 Dow Agrosciences Llc Process for the preparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine
US10005758B2 (en) 2014-08-19 2018-06-26 Dow Agrosciences Llc Process for the preparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine
US9522900B2 (en) 2014-08-19 2016-12-20 Dow Agrosciences Llc Process for the preparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine
US9115115B1 (en) 2014-08-19 2015-08-25 Dow Agrosciences Llc Process for the preparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine
US9809570B2 (en) 2014-08-19 2017-11-07 Dow Agrosciences Llc Process for the preparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine
US9024031B1 (en) 2014-08-19 2015-05-05 Dow Agrosciences Llc Process for the preparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine
US9156813B1 (en) 2014-09-12 2015-10-13 Dow Agrosciences Llc Process for the preparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine
US9085552B1 (en) 2014-09-12 2015-07-21 Dow Agrosciences Llc Process for the preparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine
US9663489B2 (en) 2014-09-12 2017-05-30 Dow Agrosciences Llc Process for the preparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine
US9422265B2 (en) 2014-09-12 2016-08-23 Dow Agrosciences Llc Process for the preparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine
US9896430B2 (en) 2014-09-12 2018-02-20 Dow Agrosciences Llc Process for the preparation of 3-(3-CHLORO-1H-pyrazol-1-yl)pyridine
US10100033B2 (en) 2016-12-29 2018-10-16 Dow Agrosciences Llc Processes for the preparation of pesticidal compounds
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof

Also Published As

Publication number Publication date
JP2000507592A (ja) 2000-06-20
AU2602197A (en) 1997-10-22
EP0891356A1 (fr) 1999-01-20
AU714851B2 (en) 2000-01-13
CA2249665A1 (fr) 1997-10-09

Similar Documents

Publication Publication Date Title
US5854265A (en) Biheteroaryl inhibitors of farnesyl-protein transferase
AU714851B2 (en) Inhibitors of farnesyl-protein transferase
US5859035A (en) Arylheteroaryl inhibitors of farnesyl-protein transferase
US6051574A (en) Inhibitors of farnesyl-protein transferase
US5854264A (en) Inhibitors of farnesyl-protein transferase
US5874452A (en) Biheteroaryl inhibitors of farnesyl-protein transferase
US5872136A (en) Arylheteroaryl inhibitors of farnesyl-protein transferase
US5939557A (en) Inhibitors of farnesyl-protein transferase
US5880140A (en) Biheteroaryl inhibitors of farnesyl-protein transferase
AU715603B2 (en) Inhibitors of farnesyl-protein transferase
AU716381B2 (en) Inhibitors of farnesyl-protein transferase
WO1997036901A1 (fr) Inhibiteurs de transferase de farnesyl-proteine
US5925651A (en) Inhibitors of farnesyl-protein transferase
WO1997036898A1 (fr) Inhibiteurs de la farnesyl-proteine transferase
AU2542597A (en) Inhibitors of farnesyl-protein transferase
AU706497B2 (en) Inhibitors of farnesyl-protein transferase
AU715667B2 (en) Inhibitors of farnesyl-protein transferase
WO1997036886A1 (fr) Inhibiteurs de la farnesyl-proteine transferase
AU704792B2 (en) Inhibitors of farnesyl-protein transferase
AU706314B2 (en) Inhibitors of farnesyl-protein transferase
AU703988B2 (en) Inhibitors of farnesyl-protein transferase
WO1997036591A1 (fr) Inhibiteurs de farnesyl-proteine transferase

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

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

AL Designated countries for regional patents

Kind code of ref document: A1

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

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

Ref document number: 2249665

Country of ref document: CA

Ref country code: CA

Ref document number: 2249665

Kind code of ref document: A

Format of ref document f/p: F

WWE Wipo information: entry into national phase

Ref document number: 1997917781

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1997917781

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1997917781

Country of ref document: EP

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载