WO1997036891A1 - Inhibitors of farnesyl-protein transferase - Google Patents
Inhibitors of farnesyl-protein transferase Download PDFInfo
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- WO1997036891A1 WO1997036891A1 PCT/US1997/005707 US9705707W WO9736891A1 WO 1997036891 A1 WO1997036891 A1 WO 1997036891A1 US 9705707 W US9705707 W US 9705707W WO 9736891 A1 WO9736891 A1 WO 9736891A1
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- 0 CC*(CCC(C)(*)CCCC(C)(*)CC1)(C1C(*(C)*)=N)C([C@](C)(*)*C(C)=*)=* Chemical compound CC*(CCC(C)(*)CCCC(C)(*)CC1)(C1C(*(C)*)=N)C([C@](C)(*)*C(C)=*)=* 0.000 description 3
- XWHVUNSUTQQDKS-XTBBCBASSA-N CC[C@@H]1[C@@H](C(N(C)Cc2cc(Cl)ccc2)=O)N(CC(CCC2)N2C(CCc2cnc[nH]2)=O)CC1 Chemical compound CC[C@@H]1[C@@H](C(N(C)Cc2cc(Cl)ccc2)=O)N(CC(CCC2)N2C(CCc2cnc[nH]2)=O)CC1 XWHVUNSUTQQDKS-XTBBCBASSA-N 0.000 description 1
- WUGMBWNWSYSZBI-ODWGLMJVSA-N CC[C@@H]1[C@@H](C(NCc2cc(Cl)ccc2)=O)N(C[C@@H](CCC2)N2C(Cc2cnc[n]2CC2C=CC(C#N)=CC2)=O)CC1 Chemical compound CC[C@@H]1[C@@H](C(NCc2cc(Cl)ccc2)=O)N(C[C@@H](CCC2)N2C(Cc2cnc[n]2CC2C=CC(C#N)=CC2)=O)CC1 WUGMBWNWSYSZBI-ODWGLMJVSA-N 0.000 description 1
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Definitions
- Ras proteins Ha-Ras, Ki4a-Ras, Ki4b-Ras and
- N-Ras are part of a signaling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation.
- Ras functions like a G-regulatory protein.
- Ras In the inactive state, Ras is bound to GDP.
- Ras Upon growth factor receptor activation Ras is induced to exchange GDP for GTP and undergoes a conformational change.
- the GTP-bound form of Ras propagates the growth stimulatory signal until the signal is terminated by the intrinsic GTPase activity of Ras, which returns the protein to its inactive GDP bound form (D.R. Lowy and D.M. Willumsen, Ann. Rev. Biochem. 62:851-891 (1993)).
- Mutated ras genes are found in many human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias.
- the protein products of these genes are defective in their GTPase activity and constitutively transmit a growth stimulatory signal.
- Ras 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 570:583-586 (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
- the Ras protein is one of several proteins that are known to undergo post-translational farnesylation.
- Other farnesylated proteins include the Ras-related GTP-binding proteins such as Rho, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin.
- James, et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisome associated protein Pxf which is also farnesylated. James, et al., have also suggested that there are farnesylated proteins
- FPTase farnesyl-protein transferase
- FPP farnesyl diphosphate
- Ras protein substrates
- the peptide derived inhibitors that have been described are generally cysteine containing molecules that are related to the CAAX motif that is the signal for protein prenylation.
- Such inhibitors may inhibit protein prenylation while serving as altemate substrates for the farnesyl-protein transferase enzyme, or may be purely competitive inhibitors (U.S. Patent 5,141 ,851 , University of Texas; N.E. Kohl et al., Science, 260: 1934-1937 (1993); Graham, et al., J. Med. Chem., 37, 725 (1994)).
- deletion of the thiol from a CAAX derivative has been shown to dramatically reduce the inhibitory potency of the compound.
- the thiol group potentially places limitations on the therapeutic application of FPTase inhibitors with respect to pharmacokinetics, pharmacodynamics and toxicity. Therefore, a functional replacement for the thiol is desirable.
- 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 (JP H7-112930).
- the present invention comprises analogs of the CA 1 A 2 X motif of the protein Ras that is modified by farnesylation in vivo. These CA 1 A 2 X analogs inhibit the farnesylprotein transferase. Furthermore, these CA 1 A 2 X analogs differ from those previously described as inhibitors of farnesyl-protein transferase in that they do not have a thiol moiety. The lack of the thiol offers unique advantages in terms of improved pharmacokinetic behavior in animals, prevention of thiol- dependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity. The compounds of the instant invention also incorporate a cyclic amine moiety in the A 2 position of the motif.
- the compounds of the instant invention also do not contain a carboxylic acid, and therefore do not require a prodrug ester for improved cell permeability. Further contained in this invention are chemotherapeutic compositions containing these farnesyl transferase inhibitors and methods for their production.
- the compounds of this invention inhibit the farnesyl-protein transferase.
- the farnesyl-protein transferase inhibitors are illustrated by the formula I: wherein:
- R 1 a and R 1b are independently selected from:
- R 10 O-, R 1 1 S(O) m -, R 10 C(O)NR 10 -, CN, NO 2 , (R 10 ) 2 N-C(NR 10 )-, R 10 C(O)-, CON(R 10 ) 2 -, N 3 ,
- heterocyclic cycloalkyl, alkenyl, alkynyl, R 10 O-,
- R 2 and R 3 are independently selected from:
- R 2 or R 3 are combined with R 6 to form a ring such that
- R 4a , R 4b , R 7a and R 7b are independently selected from:
- R 10 O-, R 1 1 S(O) m -, R 10 C(O)NR 10 -, CN, NO 2 , (R 10 ) 2 N- C(NR 10 )-, R 10 C(O)-, CON(R 10 ) 2 -, N 3 ,
- R 5a and R 5b are independently selected from:
- R 5a and R 5b are combined to form - (CH 2 ) s - wherein one of the carbon atoms is optionally replaced by a moiety selected from:
- R 6 is independently selected from hydrogen or C 1 -C 6 alkyl
- R 8 is independently selected from:
- perfluoroalkyl F, Cl, Br, R 10 O-, R 11 S(O) m -, R 10 C(O)NR 10 -, CN, NO 2 , R 10 2 N-C(NR 10 )-, R 10 C(O)-, CON(R 10 ) 2 -, N 3 , -N(R 10 ) 2 , or R 11 OC(O)NR 10 -, and c) C 1 -C 6 alkyl unsubstituted or substituted by aryl,
- R 9 is selected from:
- R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and aryl;
- R 11 is independently selected from C 1 -C 6 alkyl and aryl;
- Q is a substituted or unsubstituted nitrogen-containing C 4 -C 9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be a
- V is selected from:
- V is not hydrogen if A 1 is S(O) m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O) m ; W is a heterocycle;
- X, Y and Z are independently H 2 or O; m is 0, 1 or 2;
- p 0, 1 , 2, 3 or 4;
- r is 0 to 5, provided that r is 0 when V is hydrogen;
- s 4 or 5;
- Ras farnesyl transferase inhibitors are illustrated by the Formula I:
- R 1 a is independently selected from: hydrogen or C 1 -C 6 alkyl
- R 1b is independently selected from:
- heterocycle cycloalkyl, alkenyl, R 10 O-, or -N(R 10 ) 2 ;
- R 2 and R 3 are independently selected from:
- R 2 and R 3 are combined to form - (CH 2 ) s - ;
- R 2 or R 3 are combined with R 6 to form a ring such that
- R 4a and R 7a are independently selected from:
- R 4b and R 7b are hydrogen
- R 5a is selected from:
- R 5b is selected from:
- R 8 is independently selected from:
- perfluoroalkyl F, Cl, R 10 O-, R 10 C(O)NR 10 -, CN, NO 2 , (R 10 ) 2 N-C(NR 10 )-, R 10 C(O)-, CON(R 10 ) 2 -, -N(R 10 ) 2 , or R 11 OC(O)NR 10 -, and
- R 9 is selected from:
- R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and aryl;
- R 1 1 is independently selected from C 1 -C 6 alkyl and aryl; 0 is selected from:
- V is selected from:
- heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl,
- V is not hydrogen if A 1 is S(O) m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O) m ;
- W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or
- X, Y and Z are independently H 2 or O; m is 0, 1 or 2; n is 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;
- t 3, 4 or 5;
- u is 0 or 1 ;
- Ras farnesyl transferase inhibitors are illustrated by the Formula II:
- R 1a is independently selected from: hydrogen or C 1 -C 6 alkyl
- heterocycle cycloalkyl, alkenyl, R 10 O-, or -N(R 10 ) 2 ;
- R 2 or R 3 are combined with R 6 to form a ring such that
- R 4a is independently selected from: a) hydrogen,
- R 4b and R 7b are hydrogen; R 5a is selected from:
- R 5b is selected from:
- R 6 is independently selected from hydrogen or C 1 -C 6 alkyl
- R 8 is independently selected from:
- R 9 is selected from:
- R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and aryl;
- V is selected from:
- V is not hydrogen if A 1 is S(O) m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O) m ;
- W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or
- X, Y and Z are independently H 2 or O; m is 0, 1 or 2;
- n 0, 1 , 2, 3 or 4;
- p 0, 1 , 2, 3 or 4;
- r is 0 to 5, provided that r is 0 when V is hydrogen;
- t 3, 4 or 5;
- u is 0 or 1 ;
- Ras farnesyl transferase inhibitors are illustrated by the Formula IV:
- R 1 a is independently selected from: hydrogen or C 1 -C 6 alkyl
- heterocycle cycloalkyl, alkenyl, R 10 O-, or -N(R 10 ) 2 ;
- R 4a and R 7a are independently selected from:
- R 11 S(O) m -, R 10 C(O)NR 10 -, CN, NO 2 , (R 10 ) 2 N- C(NR 10 )-, R 10 C(O)-, CON(R 10 ) 2 -, N 3 ,
- R 5a is selected from:
- R 5b is selected from:
- R 8 is independently selected from:
- perfluoroalkyl F, Cl, R 10 O-, R 10 C(O)NR 10 -, CN, NO 2 , (R 10 ) 2 N-C(NR 10 )-, R 10 C(O)-, CON(R 10 ) 2 -, -N(R 10 ) 2 , or R 1 1 OC(O)NR 10 -, and
- R 9 is selected from:
- perfluoroalkyl F, Cl, R 10 O-, R 11 S(O) m -, R 10 C(O)NR 10 -, CN, (R 10 ) 2 N-C(NR 10 )-, R 10 C(O)-, CON(R 10 ) 2 -,
- R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and aryl;
- R 1 1 is independently selected from C 1 -C 6 alkyl and aryl;
- Q is selected from:
- V is selected from:
- heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl,
- V is not hydrogen if A 1 is S(O) m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O) m ;
- W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or
- Z is independently H 2 or O; m is 0, 1 or 2; n is 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;
- t 3, 4 or 5;
- u is 0 or 1 ;
- Ras farnesyl transferase inhibitors are illustrated by the Formula V:
- R 1 a is independently selected from: hydrogen or C 1 -C 6 alkyl
- heterocycle cycloalkyl, alkenyl, R 10 O-, or -N(R 10 ) 2 ;
- R 4a and R 7a are independently selected from:
- R 5a is selected from:
- R 8 is independently selected from:
- perfluoroalkyl F, Cl, R 10 O-, R 10 C(O)NR 10 -, CN, NO 2 , (R 10 ) 2 N-C(NR 10 )-, R 10 C(O)-, CON(R 10 ) 2 -, -N(R 1 0 ) 2 , or R 11 OC(O)NR 10 -, and
- R 9 is selected from:
- R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and aryl;
- R 11 is independently selected from C 1 -C 6 alkyl and aryl;
- V is selected from:
- heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl,
- V is not hydrogen if A 1 is S(O) m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O) m ;
- W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or
- n 0, 1 , 2, 3 or 4;
- t 3, 4 or 5;
- amino acids which are disclosed are identified both by conventional 3 letter and single letter abbreviations as indicated below:
- 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.
- 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.
- alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclo- hexenyl, 1 -propenyl, 2-butenyl, 2-methyl-2-butenyl, isoprenyl, farnesyl, geranyl, geranylgeranyl and the like.
- aryl is intended to include any stable monocyclic, bicyclic or tricyclic carbon ring(s) of up to 7 members in each ring, wherein at least one ring is aromatic.
- aryl groups include phenyl, naphthyl, anthracenyl, biphenyl, tetrahydronaphthyl, indanyl, phenanthrenyl and the like.
- heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl,
- substituted aryl As used herein, the terms “substituted aryl”, “substituted heterocycle” and “substituted cycloalkyl” are intended to include the cyclic group which is substituted with 1 or 2 substitutents selected from the group which includes but is not limited to F, Cl, Br, CF3, NH2, N(C 1 -C 6 alkyl) 2 , NO 2 , CN, (C 1 -C 6 alkyl)O-, -OH, (C 1 -C 6 alkyl)
- cyclic amine moiety having 5 or 6 members in the ring, such a cyclic amine which may be optionally fused to a phenyl or cyclohexyl ring.
- a cyclic amine moiety include, but are not limited to, the following specific structures:
- substitution on the cyclic amine moiety by R 8a and R 8b may be on different carbon atoms or on the same carbon atom.
- cyclic moieties When R 3 and R 4 are combined to form - (CH 2 ) s -, cyclic moieties are formed. Examples of such cyclic moieties include, but are not limited to:
- the phrase "nitrogen containing C 4 -C 9 mono or bicyclic ring system wherein the non-nitrogen containing ring may be a C 5 -C 7 saturated ring" which defines moiety "Q" of the instant invention includes but is not limited to the following ring systems:
- 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.
- any substituent or variable e.g., R 10 , Z, 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 readily synthesized by techniques known in the art as well as those methods set forth below.
- R 1 a and R 1 b are independently selected from: hydrogen, -N(R S ) 2 , R 8 C(O)NR 8 - or C 1 -C 6 alkyl unsubstituted or substituted by -N(R 8 ) 2 , R 8 O- or R 8 C(O)NR 8 -.
- R 2 is the sidechain of glycine (hydrogen).
- R 3 is selected from:
- R 3 is combined with R 6 to form pyrrolidinyl ring.
- R 4a , R 4b , R 7a and R 7b are independently selected from: hydrogen, C 1 -C 6 alkyl, aryl and benzyl.
- R 5a and R 5b are independently selected from: hydrogen, unsubstituted or substituted C 1 -C 6 alkyl, aryl, or C 1 -3 alkyl substituted with an unsubstituted or substituted group selected from aryl or heterocycle .
- R 6 is: hydrogen or is combined with R 3 to form pyrrolidinyl ring.
- R 8 is selected from: hydrogen, perfluoroalkyl,
- R 9 is hydrogen
- a 1 and A 2 are independently selected from: a bond, -C(O)NR 10 -, -NR 10 C(O)-, O, -N(R 10 )-, -S(O) 2 N(R 10 )- and
- Q is a pyrrolidinyl ring.
- V is selected from hydrogen, heterocycle and aryl.
- n, p and r are independently 0, 1 , or 2.
- t is 3.
- the compounds of the invention can be synthesized from their constituent amino acids by conventional peptide synthesis techniques, and the additional methods described below. Standard methods of peptide synthesis are disclosed, for example, in the following works: Schroeder et al., "The Peptides”, Vol. 1, Academic Press 1965, or Bodanszky et al., “Peptide Synthesis”, Interscience Publishers, 1966, or McOmie (ed.) "Protective Groups in Organic Chemistry", Plenum Press, 1973, or Barany et al., "The Peptides: Analysis, Synthesis, Biology” 2, Chapter 1 , Academic Press, 1980, or Stewart et al., “Solid Phase Peptide Synthesis", Second Edition, Pierce Chemical Company, 1984. The teachings of these works are hereby incorporated by reference.
- Reaction E Preparation of a reduced subunit by borane reduction of the amide moiety.
- Reaction Schemes A-E illustrate bond-forming and peptide modifying reactions incorporating acyclic peptide units. It is well understood that such reactions are equally useful when the - NHC(R A )- moiety of the reagents and compounds illustrated is replaced with the following moiety:
- Reaction B Preparation of reduced peptide subunits by reductive alkylation
- Reaction Schemes F - M illustrate reactions wherein the non-sulfhydryl-containing moiety at the N-terminus of the compounds of the instant invention is attached to an acyclic peptide unit which may be further elaborated to provide the instant compounds. It is well understood that such reactions are equally useful when the - NHC(R A ) - moiety of the reagents and compounds illustrated is replaced with the following moiety:
- the product II can be deprotected to give the final compounds III with trifluoroacetic acid in methylene chloride.
- the final product III is isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others.
- the product diamine III can further be selectively protected to obtain IV, which can subsequently be reductively alkylated with a second aldehyde to obtain V. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole VII can be accomplished by literature procedures.
- the imidazole acetic acid XI can be converted to the acetate XIII by standard procedures, and XIII can be first reacted with an alkyl halide, then treated with refluxing methanol to provide the regiospecific- ally alkylated imidazole acetic acid ester XIV.
- Hydrolysis and reaction with the protected dipeptidyl analog intermediate in the presence of condensing reagents such as 1-(3-dimethylaminopropyl)-3-ethylcarbo- diimide (EDC) leads to acylated products such as XV.
- the protected dipeptidyl analog intermediate is reductively alkylated with an aldehyde which also has a protected hydroxyl group, such as XVI in Reaction Scheme I
- the protecting groups can be subsequently removed to unmask the hydroxyl group (Reaction Schemes I, J).
- 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 XX.
- the fully deprotected amino alcohol XXI can be reductively alkylated (under conditions described previously) with a variety of aldehydes to obtain secondary amines, such as XXII (Reaction Scheme K), or tertiary amines.
- the Boc protected amino alcohol XVIII can also be utilized to synthesize 2-aziridinylmethylpiperazines such as XXIII (Reaction Scheme L). Treating XVIII with 1 ,1 '-sulfonyldiimidazole and sodium hydride in a solvent such as dimethylformamide led to the formation of aziridine XXIII . The aziridine reacted in the presence of a nucleophile, such as a thiol, in the presence of base to yield the ring-opened product XXIV .
- a nucleophile such as a thiol
- Reaction Schemes N-R illustrate syntheses of suitably substituted aldehydes useful in the syntheses of the instant compounds wherein the variable W is present as a pyridyl moiety. Similar synthetic strategies for preparing alkanols that incorporate other heterocyclic moieties for variable W are also well known in the art.
- 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 formation (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 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)). Such anti-angiogenesis 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 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.
- 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.
- a chemotherapeutic compound according to this invention the selected compound may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension.
- carriers which are commonly used include lactose and corn starch, and lubricating agents, such as magnesium stearate, are commonly added.
- useful diluents include lactose and dried com starch.
- 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 present invention also encompasses a pharmaceutical composition useful in the treatment of cancer, comprising the administration of a therapeutically effective amount of the compounds of this invention, with or without pharmaceutically acceptable carriers or diluents.
- suitable 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.
- the solutions may be introduced into a patient's intramuscular blood-stream by local bolus injection.
- 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.
- 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 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 immunological, radiochemical or chromatographic techniques.
- 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 trans- ferase, 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
- the standard workup referred to in the examples refers to solvent extraction and washing the organic solution with 10% citric acid, 10% sodium bicarbonate and brine as appropriate. Solutions were dried over sodium sulfate and evaporated in vacuo on a rotary evaporator.
- Step D N-[(te r t-Butyloxy)carbonyl]-cis:trans-3-ethylproline methyl ester
- Step E N-[(tert-Butyloxy)carbonyl]-tran s-3-ethylproline and N- [(tery-Butyloxy)carbonyl]-cis-3-ethylproline methyl ester N-[(te rt-Butyloxy)carbonyl]-cis,trans-3-ethy]proline methyl ester (29.1 g, 0.113 mol) was dissolved in CH 3 OH (1 14 mL) with cooling to 0°C, then treated with 1 N NaOH (1 14 mL). After stirring for 20 h at 23°C, the solution was concentrated to remove the CH 3 OH and then extracted with EtOAc (3 x).
- N-[(tert-Butyloxy)carbonyl]-trans-3-ethylproline (15.5 g, 0.064 mol), S- ⁇ -methylbenzylamine (9.03 mL, 0.070 mol), HOBT (10.73 g, 0.70 mol), and N-methylmorpholine (8 mL, 0.076 mol) were dissolved in CH 2 CI 2 (150 mL) with stirring in an ice-H 2 O bath, treated with EDC (13.4 g, 0.070 mol) stirred at 23°C for 48 h.
- N-[(tert-Butyloxy)carbonyl-3(S)-ethyl- 2(S)-proline was dissolved in EtOAc (50 mL) and the solution was saturated with HCl gas with cooling in an ice-H 2 O bath. The solution was stoppered and stirred at 0°C. for 3 hr. Argon was bubbled through the solution to remove excess HCl, and the solution was concentrated to dryness to give 3(S)-ethyl-2(S)-proline hydrochloride.
- Step G N-[(t-Butyloxycarbonyl)-pyrrolidin-2(S)-ylmethyl]-3(S)- ethyl-proline
- 3(S)-Ethyl-2(S)-proline hydrochloride (from Example 1 , Step F) (2.33 g, 0.013 mol) was dissolved in CH 3 OH (20 mL), treated with 3 A molecular sieves (2 g) and KOAc (1.27 g, 0.013 mol) to adjust the pH of the reaction mixture to 4.5-5, then N-[(te rt-Butyloxy) carbonyl-prolinal (Pettit et al., J. Org. Chem. (1994) 59, [21] 6287-95) (3.36 g, 0.017 mol) was added, and the mixture was stirred for 16 hours at room temperature.
- reaction mixture was filtered, quenched with aqueous saturated NaHCO 3 (5 mL) and concentrated to dryness. The residue was extracted with CHCl 3 . The extract was dried (MgSO 4 ), filtered, and concentrated to give the title compound and inorganic salts.
- Step H N-[(t-Butyloxycarbonyl)-pyrrolidin-2(S)-ylmethyl]-3(S)- ethyl-proline-N-(3-chlorophenylmethyl) amide
- reaction mixture was stirred at 25 °C. for 2 h, then evaporated to dryness and partitioned between EtOAc and aqueous saturated NaHCO 3 solution. The organic layer was separated, washed with brine, dried (MgSO 4 ), filtered, and concentrated to dryness to give the title compound.
- N-[(t-Butyloxycarbonyl)-pyrrolidin-2(S)-ylmethyl]-3(S)- ethyl-proline-N-methyl-N-(3-chlorophenylmethyI) amide (0.150 g, 0.32 mmol) was dissolved in EtOAc (15 mL), cooled to -20°C. and saturated with HCl gas. The solution was stirred at 0°C. for 1 h, then at 25°C. for 1 hour, then concentrated to dryness to give pyrrolidin-2(S)-ylmethyl]- 3(S)-ethyl-proline-N-methyl-N-(3-chlorophenylmethyl) amide which was used without further purification.
- TFA/CH3CN 0.1 % TFA/H 2 O, 95:5 to 5:95 gradient
- lyophilization to give the title compound as the TFA salt.
- Step A N-[(tert-Butyloxy)carbonyl]-3(S)-ethyl-2(S)-prolinol
- N,N-diisopropylethylamine (2.2 mL, 0.0128 mol) and di-tert-butyl- dicarbonate (2.79 g, 0.0128 mol) were added and stirring was continued at 23°C for 48 h.
- the reaction mixture was partitioned between EtOAc (60 mL) and H 2 O (30 mL), the organic layer washed with 0.5N NaOH (2 x 40 mL), the aqueous layers combined and washed with EtOAc ( 30 mL) and this layer back-extracted with 0.5 N NaOH (30 mL). The aqueous layers were combined and carefully acidified at 0°C with 1N HCl to pH 2.
- N-[(tert-Butyloxy)carbonyl]-3(S)-ethyl-2(S)-proline (1.6 g, 6.58 mmol) was dissolved in dry THF (10 mL) and treated with borane (1 M in THF, 12.5 mL, 12.5 mmol) with stirring at 0 °C for 2 h, then 23°C for 1 h.
- the solution was cooled to 0°C, treated with H 2 O (20 mL), and extracted with EtOAc (2 x 30 mL). The organics were washed with brine, saturated NaHCO 3 , H 2 O, dried (MgSO4), filtered and concentrated to give a viscous oil.
- Step B N-[(tert-ButyIoxy)carbonyl]-3(S)-ethyl-2(S)-prolinal
- Step C N-[(t-Butyloxycarbonyl)-3(S)-ethylpyrrolidin-2(S)- ylmethyl]-3(S)-ethyl-proline
- Step D N-[ 1 -(3-[ 1H-Imidazol-4-yl]propionyl)-3(S)-ethylpyrrolidin- 2(S)-ylmethyl]-3(S)-ethyl-proline-N-methyl-N-(3-chloro- phenylmethyl) amide
- Step B 1 -(Tribenzyl)- 1H-imidazol-4-ylacetic acid methyl ester
- reaction mixture was parti- tioned between EtOAc and 5% Na 2 CO 3 solution, the organic layer separated, washed with brine, dried (MgSO 4 ), filtered, and concentrated to dryness to give the title compound after preparative RP HPLC (Vydac column, 0.1 % TFA/CH 3 CN: 0.1 % TFA/H 2 O, 95:5 to 5:95 gradient) and lyophilization. to give the title compound as the TFA salt.
- Step B 1-[1 -(4-Cyanobenzyl)-1H-imidazol-5-ylacetyl]
- Step B 1 -(4-Nitrobenzyl)-1H-imidazol-4-ylacetic acid
- Step B 1 -(1 -(1-Famesyl)-1H-imidazol-5-ylacetyl)-pyrrolidin-
- Bovine FPTase was assayed in a volume of 100 ⁇ l containing 100 mM N-(2-hydroxy ethyl) piperazine-N '-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgCl 2 , 5 mM dithiothreitol (DTT), 100 mM [ 3 H]-farnesyl diphosphate ([ 3 H]-FPP; 740 CBq/mmol, New England Nuclear), 650 nM Ras-CVLS and 10 ⁇ g/ml FPTase at 31 °C for 60 min. Reactions were initiated with FPTase and stopped with 1 ml of 1.0 M HCL in ethanol.
- Precipitates were collected onto filter-mats using a TomTec Mach II cell harvestor, washed with 100% ethanol, dried and counted in an LKB ⁇ -plate counter.
- the assay was linear with respect to both substrates, FPTase levels and time; less than 10% of the [ 3 H]-FPP was utilized during the reaction period.
- Purified compounds were dissolved in 100% dimethyl sulfoxide (DMSO) and were diluted 20-fold into the assay. Percentage inhibition is measured by the amount of 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 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 were tested for inhibitory activity against human FPTase by the assay described above and were found to have IC 50 of ⁇ 10 ⁇ M.
- the cell line used in this assay is a v-ras line derived from either 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 are labeled in 3 ml methionine-free DMEM supple -meted with 10% regular DMEM, 2% fetal bovine serum and 400 mCi[ 35 s] methionine (1000 Ci/mmol). After an additional 20 hours, the cells are lysed in 1 ml lysis buffer (1% NP40/20 mM HEPES, pH 7.5/5 mM
- 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
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP97918520A EP0891352A4 (en) | 1996-04-03 | 1997-03-31 | Inhibitors of farnesyl-protein transferase |
JP9535615A JP2000507597A (en) | 1996-04-03 | 1997-03-31 | Farnesyl protein transferase inhibitor |
AU26607/97A AU717298B2 (en) | 1996-04-03 | 1997-03-31 | Inhibitors of farnesyl-protein transferase |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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US1477496P | 1996-04-03 | 1996-04-03 | |
US60/014,774 | 1996-04-03 | ||
GB9612291.6 | 1996-06-12 | ||
GBGB9612291.6A GB9612291D0 (en) | 1996-06-12 | 1996-06-12 | Inhibitors of farnesyl-protein transferase |
Publications (1)
Publication Number | Publication Date |
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WO1997036891A1 true WO1997036891A1 (en) | 1997-10-09 |
Family
ID=26309499
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PCT/US1997/005707 WO1997036891A1 (en) | 1996-04-03 | 1997-03-31 | Inhibitors of farnesyl-protein transferase |
Country Status (5)
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EP (1) | EP0891352A4 (en) |
JP (1) | JP2000507597A (en) |
AU (1) | AU717298B2 (en) |
CA (1) | CA2249617A1 (en) |
WO (1) | WO1997036891A1 (en) |
Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
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WO1999028315A1 (en) * | 1997-11-28 | 1999-06-10 | Lg Chemical Ltd. | Imidazole derivatives having an inhibitory activity for farnesyl transferase and process for preparation thereof |
FR2780892A1 (en) * | 1998-07-08 | 2000-01-14 | Sod Conseils Rech Applic | USE OF PRENYLTRANSFERASE INHIBITORS FOR THE PREPARATION OF A MEDICINAL PRODUCT FOR TREATING CONDITIONS RESULTING FROM MEMBRANE FIXATION OF HETEROTRIMERIC PROTEIN |
KR100388791B1 (en) * | 1998-06-23 | 2003-10-10 | 주식회사 엘지생명과학 | Panesyltransferase inhibitors having a thiazole or oxazole structure and preparation method thereof |
US9000172B2 (en) | 2011-10-14 | 2015-04-07 | Bristol-Myers Squibb Company | Substituted tetrahydroisoquinoline compounds as factor XIa inhibitors |
US9079929B2 (en) | 2011-10-14 | 2015-07-14 | Bristol-Myers Squibb Company | Substituted tetrahydroisoquinoline compounds as factor XIa inhibitors |
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US9315519B2 (en) | 2012-10-12 | 2016-04-19 | Bristol-Myers Squibb Company | Guanidine substituted tetrahydroisoquinoline compounds as factor XIa inhibitors |
US9403774B2 (en) | 2012-10-12 | 2016-08-02 | Bristol-Myers Squibb Company | Guanidine and amine substituted tetrahydroisoquinoline compounds as factor xia inhibitors |
US9453018B2 (en) | 2014-10-01 | 2016-09-27 | Bristol-Myers Squibb Company | Pyrimidinones as factor XIa inhibitors |
US9738655B2 (en) | 2013-03-25 | 2017-08-22 | Bristol-Myers Squibb Company | Tetrahydroisoquinolines containing substituted azoles as factor XIa inhibitors |
US9777001B2 (en) | 2014-01-31 | 2017-10-03 | Bristol-Myers Squibb Company | Macrocycles with aromatic P2′ groups as factor xia inhibitors |
US9920034B2 (en) | 2012-10-12 | 2018-03-20 | Bristol-Myers Squibb Company | Crystalline forms of a factor XIa inhibitor |
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US10273236B2 (en) | 2014-01-31 | 2019-04-30 | Bristol-Myers Squibb | Macrocyclic factor XIa inhibitors bearing heterocyclic groups |
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EP0817630A4 (en) * | 1995-03-29 | 1999-01-27 | Merck & Co Inc | Inhibitors of farnesyl-protein transferase |
WO1996034010A2 (en) * | 1995-03-29 | 1996-10-31 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
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- 1997-03-31 EP EP97918520A patent/EP0891352A4/en not_active Withdrawn
- 1997-03-31 WO PCT/US1997/005707 patent/WO1997036891A1/en not_active Application Discontinuation
- 1997-03-31 JP JP9535615A patent/JP2000507597A/en active Pending
- 1997-03-31 CA CA002249617A patent/CA2249617A1/en not_active Abandoned
- 1997-03-31 AU AU26607/97A patent/AU717298B2/en not_active Ceased
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Cited By (27)
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WO1999028315A1 (en) * | 1997-11-28 | 1999-06-10 | Lg Chemical Ltd. | Imidazole derivatives having an inhibitory activity for farnesyl transferase and process for preparation thereof |
US6268363B1 (en) | 1997-11-28 | 2001-07-31 | Lg Chemical Ltd. | Imidazole derivatives having an inhibitory activity for farnesyl transferase and process for preparation thereof |
US6518429B2 (en) | 1997-11-28 | 2003-02-11 | Lg Chemical, Ltd. | Imidazole derivatives having an inhibitory activity for farnesyl transferase and process for preparation thereof |
US6472526B1 (en) | 1997-11-28 | 2002-10-29 | Lg Chemical Ltd. | Imidazole derivatives having an inhibitory activity for farnesyl transferase and process for preparation thereof |
KR100388791B1 (en) * | 1998-06-23 | 2003-10-10 | 주식회사 엘지생명과학 | Panesyltransferase inhibitors having a thiazole or oxazole structure and preparation method thereof |
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Also Published As
Publication number | Publication date |
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EP0891352A4 (en) | 2001-08-16 |
EP0891352A1 (en) | 1999-01-20 |
AU2660797A (en) | 1997-10-22 |
CA2249617A1 (en) | 1997-10-09 |
AU717298B2 (en) | 2000-03-23 |
JP2000507597A (en) | 2000-06-20 |
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