WO1996034010A2 - Inhibiteurs de la farnesyle transferase - Google Patents

Inhibiteurs de la farnesyle transferase Download PDF

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Publication number
WO1996034010A2
WO1996034010A2 PCT/US1996/003975 US9603975W WO9634010A2 WO 1996034010 A2 WO1996034010 A2 WO 1996034010A2 US 9603975 W US9603975 W US 9603975W WO 9634010 A2 WO9634010 A2 WO 9634010A2
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Prior art keywords
alkyl
hydrogen
aryl
cycloalkyl
alkenyl
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PCT/US1996/003975
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WO1996034010A3 (fr
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S. Jane Desolms
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Merck & Co., Inc.
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Priority to AU68950/96A priority Critical patent/AU708620B2/en
Priority to JP8528692A priority patent/JPH11502822A/ja
Priority to EP96929648A priority patent/EP0837875A4/fr
Publication of WO1996034010A2 publication Critical patent/WO1996034010A2/fr
Publication of WO1996034010A3 publication Critical patent/WO1996034010A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • 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
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

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
  • 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.
  • the Ras C-terminus contains a sequence motif termed a "CAAX” or "Cys-Aaa 1 -Aaa 2 -Xaa” box (Cys is cysterine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al., Nature 310: 583-586 ( 1984)).
  • this motif serv es 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 farnesylation. Other farnesylated proteins include the Ras-related GTP-binding proteins such as Rho, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin. James, et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisome associated protein Pxf which is also farnesylated. James, et al., have also suggested that there are farnesylated proteins of unknown structure and function in addition to those listed above.
  • CAAX box with a farnesyl group (Reiss et al., Cell 62:81-88 (1990);
  • FPTase farnesyl-protein transferase
  • FPP farnesyl diphosphate
  • Ras protein substrates
  • the peptide derived inhibitors that have been described are generally cysteine containing molecules that are related to the CAAX motif that is the signal for protein prenylation.
  • Such inhibitors may inhibit protein prenylation while serving as alternate substrates for the farnesyl-protein transferase enzyme, or may be purely competitive inhibitors (U.S. Patent 5,141,851, University of Texas; N.E. Kohl et al., Science, 260:1934-1937 (1993); Graham, et al., J. Med. Chem., 37, 725 (1994)).
  • deletion of the thiol from a CAAX derivative has been shown to dramatically reduce the inhibitory potency of the compound.
  • the thiol group has been shown to dramatically reduce the inhibitory potency of the compound.
  • the thiol group
  • 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 H7-1 12930).
  • 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. 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 bv the formula I:
  • R 1a and R 1b are independently selected from:
  • R 11 S(O) m -, R 10 C(O)NR 10 -, CN, NO 2 , (R 10 ) 2 N- C(NR 10 )-, R 10 C(O)-, R 10 OC(O)-, N 3 , -N(R 10 ) 2 , or R 1 1 OC(O)NR 10 -,
  • heterocyclic cycloalkyl, alkenyl, alkynyl, R 10 O-,
  • R 2 and R 3 are independently selected from:
  • amino acid which is:
  • R 2 or R 3 are combined with R 6 to form a ring such that
  • R 4a , R 4b , R 7a and R 7b are independently selected from:
  • R 11 S(O) m -, R 10 C(O)NR 10 -, CN, NO 2 , (R 10 ) 2 N- C(NR 10 )-, R 10 C(O)-, R 10 OC(O)-, N 3 , -N(R 10 ) 2 , or R 1 1 OC(O)NR 10 -, and
  • R 5a and R 5b are independently selected from:
  • R 5a and R 5b are combined to form - (CH 2 ) s - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O) m , -NC(O)-, and -N(COR 10 )- ;
  • R 6 is independently selected from hydrogen or C 1 -C 6 alkyl
  • R 8 is independently selected from:
  • perfluoroalkyl F, Cl, Br, R 10 O-, R 1 1 S(O) m -, R 10 C(O)NR 10 -, CN, NO 2, R 10 2 N-C(NR 10 )-, R 10 C(O)-, R 10 OC(O)-, N 3 , -N(R 10 ) 2 , or R 1 1 OC(O)NR 10 -, and c) C 1 -C 6 alkyl unsubstituted or substituted by aryl,
  • heterocycle cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 10 O-, R 11 S(O) m - ,R 10 C(O)NH-, CN, H 2 N- C(NH)-, R 10 C(O)-, R 10 OC(O)-, N 3 , -N(R 10 ) 2 , or
  • R 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
  • Q is a substituted or unsubstituted nitrogen-containing C 4 -C 9 mono or bicychc ring system, wherein the non-nitrogen containing ring may be a C 5 -C 7 saturated ring;
  • 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;
  • r is 0 to 5, provided that r is 0 when V is hydrogen;
  • s 4 or 5;
  • t 3, 4 or 5;
  • u is 0 or 1
  • R 1a and R 1b are independently selected from:
  • heterocyclic cycloalkyl, alkenyl, alkynyl, R 10 O-,
  • R 2 and R 3 are independently selected from:
  • amino acid which is:
  • R 2 and R 3 are combined to form - (CH 2 ) s - ;
  • R 2 or R 3 are combined with R 6 to form a ring such that
  • R 4a , R 4b , R 7a and R 7b are independently selected from:
  • R 11 S(O) m -, R 10 C(O)NR 10 -, CN. NO 2 , (R 10 ) 2 N- C(NR 10 )-, R 10 C(O)-, R 10 OC(O)-, N 3 , -N(R 10 ) 2 ,
  • R 5a and R 5b are independently selected from:
  • R 5a and R 5b are combined to form - (CH 2 ) s - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O) m , -NC(O)-, and -N(COR 10 )- ;
  • R 6 is independently selected from hydrogen or C 1 -C 6 alkyl;
  • R 8 is independently selected from:
  • perfluoroalkyl F, Cl, Br, R 10 O-, R 1 1 S(O) m -, R 10 C(O)NR 10 -, CN, NO 2 , R 10 2 N-C(NR 10 )-, R 10 C(O)-, R 10 OC(O)-, N 3 , -N(R 10 ) 2 , or R 1 1 OC(O)NR 10 -, and c) C 1 -C 6 alkyl unsubstituted or substituted by aryl,
  • heterocycle cycloalkyl, alkenyl. alkynyl, perfluoroalkyl, F, Cl, Br, R 10 O-, R 11 S(O) m -, R 10 C(O)NH-, CN, H 2 N-
  • R 9 is selected from: a) hydrogen
  • R 11 S(O) m -, R 10 C(O)NR 10 -, CN, NO 2 , (R 10 ) 2 N-C- (NR 10 )-, R 10 C(O)-, R 10 OC(O)-, N 3 , -N(R 10 ) 2 , or
  • R 10 is independently selected from hydrogen, C 1 -C 6 alkyl, benzyl and aryl;
  • R 1 1 is independently selected from C 1 -C 6 alkyl and aryl
  • R 12 is
  • R 1 3 is independently selected from hydrogen and C 1 -C 6 alkyl;
  • R 14 is independently selected from C 1 -C 6 alkyl:
  • Q is a substituted or unsubstituted nitrogen-containing C 4 -C 9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be a C 5 -C 7 saturated ring;
  • V is selected from:
  • V is not hydrogen if A 1 is S(O) m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O) m ;
  • W is a heterocycle
  • X, Y and Z are independently H 2 or O; m is 0, 1 or 2;
  • n 0, 1, 2, 3 or 4;
  • p 0, 1, 2, 3 or 4;
  • r is 0 to 5, provided that r is 0 when V is hydrogen;
  • s 4 or 5;
  • t 3, 4 or 5;
  • u is 0 or 1
  • R 1a and R 1b are independently selected from:
  • R 2 and R 3 are independently selected from:
  • amino acid which is:
  • 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 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 1 0 -, CN, NO 2 , R 10 2 N-C(NR 10 )-, R 10 C(O)- R 10 OC(O)-, N 3 , -N(R 10 ) 2 , or R 11 OC(O)NR 10 -, and c) C 1 -C 6 alkyl unsubstituted or substituted by aryl,
  • heterocycle cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 10 O-, R 11 S(O) m -, R 10 C(O)NH-, CN, H 2 N- C(NH)-, R 10 C(O)-, R 10 OC(O)-, N 3 , -N(R 10 ) 2 , or
  • R 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 C 5 -C 7 saturated ring;
  • V is selected from:
  • aryl d) C 1 -C 20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C 2 -C 20 alkenyl,
  • V is not hydrogen if A 1 is S(O) m and V is not hydrogen if A 1 is a bond, n is 0 and A 2 is S(O) m ;
  • W is a heterocycle
  • X, Y and Z are independently H 2 or O; m is 0, 1 or 2;
  • n 0, 1, 2, 3 or 4;
  • p 0, 1, 2, 3 or 4;
  • q 0, 1 or 2;
  • r is 0 to 5, provided that r is 0 when V is hydrogen;
  • s 4 or 5;
  • t 3, 4 or 5;
  • u is 0 or 1; or the pharmaceutically acceptable salts thereof.
  • R 1 a and R 1 b are independently selected from:
  • heterocyclic cycloalkyl, alkenyl, alkynyl,R 10 O-,
  • R 11 S(O) m R 10 C(O)NR 10 -, CN, (R 10 ) 2 N-C(NR 10 )-, R 10 C(O)-, R 10 OC(O)-, N 3 , -N(R 10 ) 2 , or R 11 OC(O)- NR 10 -;
  • R 2 and R 3 are independently selected from:
  • amino acid which is:
  • R 2 and R 3 are combined to form - (CH 2 ) s - ;
  • R 2 or R 3 are combined with R 6 to form a ring such that
  • R 4a , R 4b , R 7a and R 7b are independently 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)-, R 10 OC(O)-, N 3 , -N(R 10 ) 2 , or R 11 OC(O)NR 10 -, and c) C 1 -C 6 alkyl unsubstituted or substituted by aryl,
  • heterocycle cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 10 O-, R 11 S(O) m -, R 10 C(O)NH-, CN, H 2 N-
  • R 9 is selected from:
  • R 11 S(O) m -, R 10 C(O)NR 10 -, CN. NO 2 , ( R 10 ) 2 N-C- (NR 10 )-, R 10 C(O)-, R 10 OC(O)-. N 3 , -N(R 10 ) 2 , or
  • R 11 OC(O)NR 10 -, and c) C 1 -C 6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R 10 O-, R 11 S(O) m -,R 10 C(O)NR 10 -, CN,
  • 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 bicychc ring system, wherein the non-nitrogen containing ring may be a C 5 -C 7 saturated ring;
  • 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:
  • q 0, 1 or 2;
  • r is 0 to 5, provided that r is 0 when V is hydrogen;
  • s 4 or 5;
  • t 3, 4 or 5;
  • u is 0 or 1; or the pharmaceutically acceptable salts thereof.
  • the Ras farnesyl transferase inhibitors are illustrated by the Formula I:
  • R 1a 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 andR 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 6 is independently selected from hydrogen or C 1 -C 6 alkyl;
  • 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)-, R 10 OC(O)-, -N(R 10 ) 2 , or R 11 OC(O)NR 10 -, and
  • 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,
  • aryl d) C 1 -C 20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and e) C 2 -C 20 alkenyl, and
  • 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; or the pharmaceutically acceptable salts thereof.
  • 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 andR 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 R6 to form a ring such mat
  • R 4a and R 7a are independently selected from:
  • C 1 -C 6 alkyl unsubstituted or substituted by alkenyl, R 10 O-, R 11 S(O) m -, R 10 C(O)NR 10 -, CN, N 3 , (R 10 ) 2 N-C(NR 10 )-, R 10 C(O)-, R 10 OC(O)-, -N(R 10 ) 2 , or R 11 OC(O)NR 10 -, c) aryl, heterocycle, cycloalkyl, alkenyl, R 10 O-,
  • R 4b and R 7b are hydrogen
  • R 5a is selected from:
  • R 5b is selected from:
  • R6 is independently selected from hydrogen or C 1 -C 6 alkyl
  • 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)-, R 10 OC(O)-, -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 11 is independently selected from C 1 -C 6 alkyl and aryl; R 12 is
  • R 13 is independently selected from hydrogen and C 1 -C 6 alkyl
  • R 14 is independently selected from C 1 -C 6 alkyl
  • Q is 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 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; or the pharmaceutically acceptable salts thereof.
  • R 1 a is independently selected from: hydrogen or C 1 -C 6 alkyl
  • R 1 b 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 R6 to form a ring such that
  • R 4a and R 7a are independently selected from:
  • R 4b and R 7b are hydrogen
  • R 6 is independently selected from hydrogen or C 1 -C 6 alkyl
  • 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)-, R 10 OC(O)-, -N(R 10 ) 2 , or R 11 OC(O)NR 10 -, and
  • R 9 is selected from:
  • R 10 is independently selected from hydrogen.
  • R 11 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, quinohnyl, 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;
  • q 0, 1 or 2;
  • r is 0 to 5, provided that r is 0 when V is hydrogen;
  • t 3, 4 or 5;
  • u is 0 or 1; or the pharmaceutically acceptable salts thereof.
  • the prodmgs of the preferred compounds of Formula III are illustrated by the Formula IV:
  • R 1a 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 R6 to form a ring such that
  • R 4a and R 7a are independently selected from:
  • R 4b and R 7b are hydrogen;
  • R 6 is independently selected from hydrogen or C 1 -C 6 alkyl;
  • 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)-, R 10 oC(O)-, -N(R 10 ) 2 , or R 11 OC(O)NR 10 -, and
  • 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 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 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 ;
  • 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;
  • q 0, 1 or 2;
  • r is 0 to 5, provided that r is 0 when V is hydrogen
  • t 3. 4 or 5:
  • u is 0 or 1 ; or the pharmaceutically acceptable salts thereof.
  • the prefe ⁇ ed compounds of this invention are as follows:
  • 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.
  • alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • 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, cyclohexenyl, 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.
  • heterocycle or heterocyclic represents a stable 5- to 7-membered monocyclic or stable 8- to 11- membered bicyclic or stable 11-15 membered tricyclic heterocycle ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic elements include, but are not limited to, azepinyl,
  • benzimidazolyl benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofiiryl, 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, CF 3 , NH 2 , N(C 1 - C 6 alkyl) 2 , NO 2 , CN, ( 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:
  • cyclic moieties as described hereinabove for R 3 and R 4 are formed.
  • cyclic moieties may optionally include a heteroatom(s). Examples of such heteroatom-containing cyclic moieties include, but are not limited to:
  • the phrase "nitrogen containing C 4 -C 9 mono or bicychc 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, phenyl- acetic, 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 1a and R 1b are independently selected from: hydrogen, -N(R 8 ) 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:
  • substituent is selected from F, Cl, Br, N(R 10 ) 2 , NO 2 , R 10 O-, R 11 S(O) m , R 10 C(O)NR 10 -,
  • R3 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: a side chain of a naturally occurring amino acid, methionine sulfoxide, methionine sulfone and unsubstituted or substituted C 1 -C 6 alkyl .
  • R 6 is: hydrogen or is combined withR 3 to form pyrrolidinyl ring.
  • R 8 is selected from: hydrogen, perfluoroalkyl, F,
  • R 9 is hydrogen
  • R 10 is selected from H, C 1 -C 6 alkyl and benzyl.
  • R 12 is selected from C 1 -C 6 alkyl and benzyl.
  • a 1 and A 2 are independently selected from: a bond, -C(O)NR 10 -, -NR 10 C(O)-, O, -N(R 10 )-, -S(O) 2 N(R 10 )- and-
  • 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 pharmaceutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this invention which contain a basic moiety conventional chemical methods. Generally, the salts are prepared 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.
  • the compounds of the invention can be synthesized from their constituent amino acids by conventional peptide synthesis
  • Reaction C Deprotection of the reduced peptide subunit Reaction D Peptide bond formation and protecting group cleavage using standard solution or solid phase methodologies.
  • 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 inco ⁇ orating 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 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:
  • aldehydes such as I, as shown in Reaction Scheme F.
  • the aldehydes can be prepared by standard procedures, such as that described by O. P. Goel, U. Krolls, M. Stier and S. Kesten in Organic Syntheses, 1988, 67, 69-75, from the appropriate amino acid (Reaction Scheme F).
  • the reductive alkylation can be accomplished at pH 5-7 with a variety of reducing agents, such as sodium triacetoxyborohydride or sodium
  • the product II can be deprotected to give the final compounds II I with trifluoroacetic acid in methylene chloride.
  • the final product II I is isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others.
  • the product diamine ffl 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 protected dipeptidyl analog intermediate can be reductively alkylated with other aldehydes such as 1-trityl-4- carboxaldehyde or 1-trityl-4-imidazolylacetaldehyde, to give products such as V II I (Reaction Scheme G).
  • the trityl protecting group can be removed from V II I to give IX, or alternatively, V II I can first be treated with an alkyl halide then subsequently deprotected to give the alkylated imidazole X.
  • the dipeptidyl analog intermediate can be acylated or sulfonylated by standard techniques.
  • 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
  • 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 subsequendy 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 XVm can also be utilized to synthesize 2-aziridinylmethylpiperazines such as XXIII (Reaction Scheme L).
  • 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 .
  • the protected dipeptidyl analog intermediate can be reacted with aldehydes derived from amino acids such as O-alkylated tyrosines, according to standard procedures, to obtain compounds such as XXX, as shown in Reaction Scheme M.
  • R' is an aryl group
  • XXX can first be hydrogenated to unmask the phenol, and the amine group deprotected with acid to produce XXXI.
  • the amine protecting group in XXX can be removed, and O-alkylated phenolic amines such as XXXII produced.
  • Reaction Schemes F- M may be employed using other peptidyl analog intermediates such as those whose synthesis is illustrated in Reaction Schemes B - E.
  • 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)).
  • the compounds of this invention are also useful for inhibiting other proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes (i.e., the Ras gene itself is not activated by mutation to an oncogenic form) with said inhibition being accomplished by the administration of an effective amount of the compounds of the invention to a mammal in need of such treatment.
  • a component of NF-1 is a benign proliferative disorder.
  • the instant compounds may also be useful in the treatment of certain viral infections, in particular in the treatment of hepatitis delta and related viruses (J.S. Glenn et al. Science, 256: 1331-1333 (1992).
  • the compounds of the instant invention are also useful in the prevention of restenosis after percutaneous transluminal coronary angioplasty by inhibiting neointimal formation (C. Indolfi et al. Nature medicine, 1 :541-545( 1995).
  • the instant compounds may also be useful in the treatment and prevention of polycystic kidney disease (D.L. Schaffner et al. American Journal of Pathology, 142:1051-1060 (1993) and B. Cowley, Jr. et al.FASEB Journal, 2:A3160 (1988)).
  • the 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,
  • the selected compound may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or
  • 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.
  • 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
  • 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 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.
  • Administration occurs in an amount between about 0.1 mg/kg of body weight to about 20 mg/kg of body weight per day, preferably of between 0.5 mg/kg of body weight to about 10 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
  • FPTase farnesyl-protein transferase
  • 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 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 sufficiendy potent inhibitor i.e., one that has a Ki substantially smaller than the concentration of enzyme in the assay vessel
  • concentration of a sufficiendy potent inhibitor required to inhibit the enzymatic activity of the sample by 50% is approximately equal to half of the concentration of the enzyme in that particular sample.
  • 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 A Preparation of Diethyl 1-acetyl-5-hydroxy-3- ethylpyrrolidine-2,2-dicarboxylate
  • Step D Preparation of N-[(tert-Butyloxy)carbonyl]-cis:trans-3- ethylproline methyl ester
  • 3-Ethylproline hydrochloride (Cis:Trans Mixture) (20 g, 0.11 mol) was dissolved in CH 3 OH (200 mL), and the solution was saturated with HCl gas, then stirred at 23°C for 24 h. Argon was bubbled through the solution to remove excess HCl. The solution was treated with NaHCO 3 (>84 g) to a pH of 8, then di-tert-butyl dicarbonate (25.1 g, 0.115 mol) dissolved in CH 3 OH (20 mL) was added slowly. After stirring for 18 h at 23°C, the mixture was filtered, the filtrate
  • Step E Preparation of N-[(tert -Butyloxy)carbonyl]-trans-3- ethylproline and N-[(tert-Butyloxy)carbonyl]-cis-3- ethylproline methyl ester
  • N-[(tert -Butyloxy)carbonyl]-cistrans - 3-ethylproline methyl ester (29.1 g, 0.1 13 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). The organic layers were combined, dried (MgSO 4 ), filtered, and concentrated to give 12.8 g of N-[(tert- Butyloxy)carbonyl]-cis-3-ethylproline methyl ester as an oil.
  • Step F Preparation of 3(S)-Ethyl-2(S) -proline hydrochloride
  • 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 sitrring 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 Q N-[(tert-Butyloxy)carbonyl-3(S )-ethyl-2(S )-prolinol
  • 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 (IM 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, satd NaHCO 3 , H 2 O, dried (MgSO 4 ). filtered and concentrated to give a viscous oil.
  • Step H N-[(tert -Butyloxy)carbonyl]-3(S )-ethyl-2(S)-prorinal
  • Step I N-[(tert-Butyloxy)carbonyl-3(S)-ethylpyrrolidin-2(S)- ylmethyl]-proline methyl ester
  • Step L N-[3(S)-Ethylpyrrolidin-2(S)-ylmethyl]-prolyl-methionine methyl ester hydrochloride
  • Step M N-[ 1-( 1H-Imidazol-4-ylacetyl)-3(S)-ethylpyrrolidin-2(S)- ylmethyl]-prolyl-methionine methyl ester N-[3(S)-Ethylpyrrolidin-2(S)-ylmethyl]-prolyl methionine methyl ester hydrochloride (0.075 g, 0.169 mmol), 1H-imidazol-4- ylacetic acid (0.052 g, 0.253 mmol), HOBT (0.34 g, 0.253 mmol), EDC (0.49 g, 0.253 mmol) and Et 3 N ( 0.176 mL, 1.27 mmol) were dissolved in DMF (4 mL) and stirred at 23°C for 18 h. The solvent was removed in vacuo, EtOAc (60 mL) was added, and the solution was washed sequentially with satd NaHCO 3 solution, H 2 O,
  • N-[1-(1H-Imidazol-4-ylacetyl)-3(S)-ethylpyrrolidin-2(S)- ylmethyl]-prolyl-methionine methyl ester (0.020 g, 0.042 mmol) was dissolved in CH 3 OH (2 mL) at 0°C and treated with 1N NaOH solution (0.167 mL, 0.167 mmol) with stirring. After 5 h at 23°C 1N HCl (0.167 mL, 0.167 mmol) was added and the mixture was purified by preparative RP HPLC on a Vydac column eluting with 0.1% TFA/CH 3 CN: 0.1% TFA/ H 2 O gradient to give the title compound.
  • Step A N-[(t-Butyloxycarbonyl)-pyrrolidin-2(S)-ylmethyl]-3(S)- ethvl-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-[(tert- 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 hrs at room temperature.
  • Step B N-[(t-Butyloxycarbonyl)-pyrrolidin-2(S)-ylmethyl]-3(S)- ethyl-prolyl-methionine isopropyl ester
  • N-[(t-Butyloxycarbonyl)-pyrrohdin-2(S)-ylmethyl]-3(S)- ethyl-prolyl-methionine isopropyl ester (1.38 g, 0.0028 mol) was dissolved in EtOAc (40 mL), cooled to -20°C, saturated with HCl gas, and stirred at 0°C. for 1.25 hr, and room temperature for 0.25 hr.
  • Step D 1H-Imidazole-4- acetic acid methyl ester hydrochloride
  • Step E 1-(Triphenylmethyl)-1H-imidazol-4-ylacetic acid methyl ester
  • Step F [ 1 -(4-Cyanobenzyl)- 1 H-imidazol-5-yl]acetic acid methyl ester
  • 1-(Triphenylmethyl)-1H-imidazol-4- ylacetic acid methyl ester 8.00g, 20.9mmol
  • bromo-p-toluonitrile 4.10g, 20.92 mmol
  • the reaction was cooled to room temperature and the resulting imidazolium salt (white precipitate) was collected by filtration. The filtrate was heated at 55°C for 18hr.
  • Step H N-[ 1 -[1-(4-Cyanobenzyl)- 1H-imidazol-5-ylacetyl]- pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine isopropyl ester
  • reaction mixture was concentrated to remove most of the DMF, and the residue was partitioned between EtOAc and aq satd NaHCO 3 solution. The aq layer was washed with EtOAc, the organics combined, washed with brine and dried
  • Step A N-[1-[1-(4-Cyanobenzyl)-1H-imidazol-5-ylacetyl]- pyrtolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine methyl ester
  • Step B N-[1-[1-(4-Cyanoben zyl)-1H- midazol-5-1)acetyl]pyrrolidin- 2(S )-ylmethyl]-3(S )-ethyl-prolyl-methionine trifluoroacetate
  • Step A N-[2(S)-( 1H-Imidazol-4-ylacetyl-amino)-3(S)- methylpentyl]-prolyl-methionine methyl ester Following the methods outlined in Example 1, but substituting N-(t-Butyloxycarbonyl)-isoleucinal for N-[(t- Butyloxy)carbonyl]-3(S)-ethyl-2(S)-prolinal in Step I, the title compound was prepared.
  • Step B N-[2(S)-(1H-Imidazol-4-ylacetyl-amino)-3(S)- methylpentyl]-prolyl-methionine
  • Step A N-[1-(1H-Imidazol-4-ylacetyl)-pyrrolidin-2(S)-ylmethyl]- prolyl-methionine methyl ester
  • Step A 1 -(4-Nitrobenzyl)- 1 H-imidazol-4-ylacetic acid methyl ester and 1-(4-Nitrobenzyl)-1H-imidazol-5-ylacetic acid methyl ester (3:1 mixture)
  • Step B 1-(4-Nitrobenzyl)- 1 H-imidazol-4-ylacetic acid
  • Step C N-[1-(1-(4-Nitrobenzyl)-1H-imidazol-4-ylacetyl]pyrrolidin- 2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine methyl ester bis trifluoroacetate and N-[1-(1-(4-Nitrobenzyl)-1H-imidazol-5- ylacetyl]pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl methionine methyl ester bis trifluoroacetate
  • Step D N-[1-(1-(4-Nitrobenzyl)-1H-imidazol-4-ylacetyl]pyrrolidin - 2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine bis ttifluoroacetate
  • Step E N-[1-(1-(4-Nitrobenzyl)-1H-imidazol-5-ylacetyl]pyrrolidin- 2(S)-ylmethyl]-3(S)-ethyl-prolyl-methionine bis trifluoroacetate
  • Step B N-[1-(1-(1-Farnesyl)-1H-imidazol-5-ylacetyl)pyrrolidin- 2(S)-ylmethyl]-3(S)-ethyl-prolyl methionine methyl ester bis trifluoroacetate
  • Step C N-[1-(1-(1-Farnesyl)-1H-imidazol-5-ylacetyl)pyrrolidin- 2(S)-ylmethyl]-3(S)-ethyl-prolyl methionine bis trifluoroacetate
  • Step A N-[ 1-( 1 -( 1-Geranyl)- 1H-imidazol-5-ylacetyl)pyrrolidin-
  • Step B N-[1-(1-(1-Geranyl)-1H-imidazol-5- ylacetyl)pyrtolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl- methionine bis trifluoroacetate
  • Step A N-[1-(1-(4-Methoxybenzyl)-1H-imidazol-5- yl)acetyl)pyrrolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl- methionine methyl ester bis trifluoroacetate
  • Step B N-[1-(1-(4-Methoxybenzyl)-1H-imidazol-5- ylacetyl)pyrtolidin-2(S)-ylmethyl]-3(S)-ethyl-prolyl- methionine bis trifluoroacetate
  • Step A N-[ 1 -(1-(2-Naphthylmethyl)-1H-imidazol-5-ylacetyl]3(S)- ethylpyrrolidin -2(S)-ylmethyl]-prolyl-methionine methyl ester bis trifluoroacetate
  • Step B N-[ 1 -(1-(2-Naphthylmethyl)-1H-imidazol-5- ylacetyl]pyrrolidin-2(S)-ylmeth yl]-3(S)-ethyl-prolyl- methionine bis trifluoroacetate
  • Step A Methyl 2(S)- benzyloxycarbonylamino-3-amino propionate
  • Step B Methyl 2(S)-benzyloxycarbonylamino-3-acetylamino- propionate
  • pyridine 20 mL
  • acetic anhydride 5 mL
  • the residue was partitioned between ethyl acetate and water.
  • the ethyl acetate layer was extracted w/ 50 mL each of 2% potassium hydrogen sulfate, saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate and concentrated in vacuo.
  • Step D N-[1-(1H-Imidazol-4-ylacetyl)-pyrrolidin-2(S)-ylmethyl]- 3(S)-ethyl-prolyl-( ⁇ -acetylamino)alanine methyl ester trifluoroacetate
  • Step E N-[ 1 -( 1H-Imidazol-4-ylacetyl)-pyrrolidin-2(S)-ylmethyl]-
  • 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 [3H]-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 harvester, 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 [3H]-FPP was utilized during the reaction period.
  • Purified compounds were dissolved in 100% dimethyl sulfoxide (DMSO) and were diluted 20-fold into the assay.
  • DMSO dimethyl sulfoxide
  • 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.
  • 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 cell line used in this assay is a v-ras line derived from either Ratl or NIH 3 T3 cells, which expressed viral Ha-ras p21.
  • the assay is performed essentially as described in DeClue, J.E. et al., Cancer Research 51:112-111, (1991). Cells in 10 cm dishes at 50-75%
  • the cells are labelled in 3 ml methionine-free DMEM supple-meted with 10% regular DMEM, 2% fetal bovine serum and 400
  • mCi[ 3 5S]methionine 1000 Ci/mmol.
  • the cells are lysed in 1 ml lysis buffer (1% NP40/20 mM HEPES, pH 7.5/5 mM MgCl 2 /lmM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 mM PMSF) and the lysates cleared by centrifugation at
  • 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

La présente invention comporte des analogues du motif structural CA1A2X de la protéine Ras, laquelle est modifiée par farnésylation in vivo. Ces analogues de CA1A2X inhibent la farnésyle transférase ainsi que la farnésylation de certaines protéines. En outre, ces analogues de CA1A2X diffèrent de ceux précédemment décrits en tant qu'inhibiteurs de la farnésyle transférase, en ce qu'ils sont dépourvus d'une fraction thiol. Cette absence de fraction thiol offre des avantages uniques, en termes d'un meilleur comportement pharmacocinétique de ces analogues chez les animaux, d'une prévention de réactions chimiques dépendant des thiols, telles qu'une autoxydation rapide et une formation de disulfure avec les thiols endogènes, et d'une toxicité systématique réduite. Les composés selon l'invention comprennent également une fraction amine cyclique en position A2 du motif structural. On décrit encore dans cette invention des compositions chimiothérapeutiques contenant ces inhibiteurs de farnésyle transférase, ainsi que des procédés de production de ceux-ci.
PCT/US1996/003975 1995-03-29 1996-03-25 Inhibiteurs de la farnesyle transferase WO1996034010A2 (fr)

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AU68950/96A AU708620B2 (en) 1995-03-29 1996-03-25 Inhibitors of farnesyl-protein transferase
JP8528692A JPH11502822A (ja) 1995-03-29 1996-03-25 ファルネシル−タンパク質トランスフェラーゼ阻害剤
EP96929648A EP0837875A4 (fr) 1995-03-29 1996-03-25 Inhibiteurs de la farnesyle transferase

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US41262695A 1995-03-29 1995-03-29
US41282895A 1995-03-29 1995-03-29
US08/412,626 1995-03-29
US08/412,828 1995-03-29
US441995P 1995-09-27 1995-09-27
US60/004,419 1995-09-27

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US5703241A (en) * 1995-10-16 1997-12-30 Merck & Co., Inc. Inhibitor of farnesyl-protein transferase
EP0891352A1 (fr) * 1996-04-03 1999-01-20 Merck & Co., Inc. Inhibiteurs de la farnesyl-proteine transferase
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
US9108951B2 (en) 2011-10-14 2015-08-18 Bristol-Myers Squibb Company Substituted 5,6,7,8-tetrahydro-1,6-naphthyridines as factor XIa inhibitors
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
US10081623B2 (en) 2014-09-04 2018-09-25 Bristol-Myers Squibb Company Diamide macrocycles that are FXIa inhibitors
US10273236B2 (en) 2014-01-31 2019-04-30 Bristol-Myers Squibb Macrocyclic factor XIa inhibitors bearing heterocyclic groups

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US5326773A (en) * 1992-10-29 1994-07-05 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
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NATURAL MEDICINE, August 1995, Vol. 1, No. 8, KOHL et al., "Inhibition of Farnesyltransferase Induces Regression of Mammary and Salivary Carcinomas in Ras Transgenic Mice", pages 792-797. *
See also references of EP0837875A2 *

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US5703241A (en) * 1995-10-16 1997-12-30 Merck & Co., Inc. Inhibitor of farnesyl-protein transferase
EP0891352A1 (fr) * 1996-04-03 1999-01-20 Merck & Co., Inc. Inhibiteurs de la farnesyl-proteine transferase
EP0891352A4 (fr) * 1996-04-03 2001-08-16 Merck & Co Inc Inhibiteurs de la farnesyl-proteine transferase
US9725435B2 (en) 2011-10-14 2017-08-08 Bristol-Myers Squibb Company Substituted 4,5,6,7-tetrahydropyrazolo[4,3-c]pyridines as factor XIa inhibitors
US9944625B2 (en) 2011-10-14 2018-04-17 Bristol-Myers Squibb Company Substituted tetrahydroisoquinoline compounds as factor XIa inhibitors
US9108951B2 (en) 2011-10-14 2015-08-18 Bristol-Myers Squibb Company Substituted 5,6,7,8-tetrahydro-1,6-naphthyridines as factor XIa inhibitors
US9192607B2 (en) 2011-10-14 2015-11-24 Bristol-Myers Squibb Company Substituted tetrahydroisoquinoline compounds as factor XIa inhibitors
US10906886B2 (en) 2011-10-14 2021-02-02 Bristol-Myers Squibb Company Substituted 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazines as factor xia inhibitors
US9394276B2 (en) 2011-10-14 2016-07-19 Bristol-Myers Squibb Company Substituted 1,2,3,4-tetrahydro-2,6-naphthyridines as factor XIa inhibitors
US9079929B2 (en) 2011-10-14 2015-07-14 Bristol-Myers Squibb Company Substituted tetrahydroisoquinoline compounds as factor XIa inhibitors
US9447110B2 (en) 2011-10-14 2016-09-20 Bristol-Myers Squibb Company Substituted tetrahydroisoquinoline compounds as factor XIa inhibitors
US10208021B2 (en) 2011-10-14 2019-02-19 Bristol-Myers Squibb Company Substituted tetrahydroisoquinoline compounds as factor XIa inhibitors
US9000172B2 (en) 2011-10-14 2015-04-07 Bristol-Myers Squibb Company Substituted tetrahydroisoquinoline compounds as factor XIa inhibitors
US10000466B2 (en) 2011-10-14 2018-06-19 Bristol-Myers Squibb Company Substituted 4,5,6,7-tetrahydropyrazolo[3,4-c]pyridines 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
US9920034B2 (en) 2012-10-12 2018-03-20 Bristol-Myers Squibb Company Crystalline forms of a factor XIa inhibitor
US9315519B2 (en) 2012-10-12 2016-04-19 Bristol-Myers Squibb Company Guanidine substituted tetrahydroisoquinoline compounds 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
US10273236B2 (en) 2014-01-31 2019-04-30 Bristol-Myers Squibb Macrocyclic factor XIa inhibitors bearing heterocyclic groups
US10081623B2 (en) 2014-09-04 2018-09-25 Bristol-Myers Squibb Company Diamide macrocycles that are FXIa inhibitors
US9453018B2 (en) 2014-10-01 2016-09-27 Bristol-Myers Squibb Company Pyrimidinones as factor XIa inhibitors
US10336754B2 (en) 2014-10-01 2019-07-02 Bristol-Myers Squibb Company Pyrimidinones as factor XIa inhibitors
US11053247B2 (en) 2014-10-01 2021-07-06 Bristol-Myers Squibb Company Pyrimidinones as factor XIA inhibitors

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