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WO1997036587A1 - Methode de traitement du cancer - Google Patents

Methode de traitement du cancer Download PDF

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Publication number
WO1997036587A1
WO1997036587A1 PCT/US1997/005328 US9705328W WO9736587A1 WO 1997036587 A1 WO1997036587 A1 WO 1997036587A1 US 9705328 W US9705328 W US 9705328W WO 9736587 A1 WO9736587 A1 WO 9736587A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
glycyl
substituted
pyrrolidin
methionine
Prior art date
Application number
PCT/US1997/005328
Other languages
English (en)
Inventor
David C. Heimbrook
Allen I. Oliff
Steven M. Stirdivant
Original Assignee
Merck & Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9613599.1A external-priority patent/GB9613599D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to JP9535542A priority Critical patent/JP2000504023A/ja
Priority to EP97921085A priority patent/EP0906099A4/fr
Priority to AU27221/97A priority patent/AU727939B2/en
Publication of WO1997036587A1 publication Critical patent/WO1997036587A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a method of treating cancer using a combination of a compound which has Raf antagonist activity and a compound which has famesyl transferase inhibiting activity.
  • the Raf antagonist compounds used in the present invention demonstrate anti-cancer activity through antagonism of the kinase, Raf .
  • the raf genes code for a family of proteins which can be oncogenically activated through N-terminal fusion, truncation or point mutations.
  • Raf is a member of the MAP Kinase cascade, which also includes MEK's and MAP Kinase (ERK).
  • Raf can be activated and undergoes rapid phosphorylation in response to treatment of cells with PDGF, EGF, insulin, thrombin, endothelin, acidic FGF, CSF1 or TPA, as well as in response to oncoproteins v-fms, v-src, v-sis, Hras and polyoma middle T antigen.
  • Antisense constructs which reduce cellular levels of c-Raf, and hence Raf activity, inhibit the growth of oncogene-transformed rodent fibroblasts in soft agar, while exhibiting little or no general cytotoxicity. Since inhibition of growth in soft agar is highly predictive of tumor responsiveness in whole animals, these studies suggest that the antagonism of Raf is an effective means by which to treat cancers in which Raf plays a role.
  • Examples of cancers where Raf is implicated through overexpression include cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung. More particularly, such examples include histiocytic lymphoma, lung adenocarcinoma and small cell lung cancers. Additional examples include cancers in which overexpression or activation of Raf-activating oncogenes (e.g., K-ras, erb-B) is observed. More particularly, such cancers include pancreatic and breast carcinoma.
  • Raf-activating oncogenes e.g., K-ras, erb-B
  • the Ras protein is part of a signalling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation. Biological and biochemical studies of Ras action indicate that Ras functions like a G-regulatory protein. In the inactive state, Ras is bound to GDP. Upon growth factor receptor activation, Ras is induced to exchange GDP for GTP and undergoes a conformational change. The GTP -bound form of Ras propagates the growth stimulatory signal until the signal is terminated by the intrinsic GTPase activity of Ras, which returns the protein to its inactive GDP bound form (D.R. Lowy and D.M. Willumsen,
  • Ras Activation of Ras leads to activation of multiple intracellular signal transduction pathways, including the MAP Kinase pathway and the Rho/Rac pathway (Joneson et al., Science 271.-810-812).
  • 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 protein is one of several proteins that are known to undergo post-translational modification.
  • Famesyl-protein transferase utilizes famesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a famesyl group (Reiss et al. , Cell, 62:81 -88 (1990): Schaber et al. , J. Biol. Chem., 265: 14701 - 14704 ( 1990); Schafer et al. , Science, 249: 1 133-1 139 ( 1990); Marine et al., Proc. Natl Acad. Sci USA, 57:7541 -7545 (1990)).
  • Ras C-terminus contains a sequence motif termed a "CAAX” or "Cys-Aaa 1 -Aaa 2 -Xaa” box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al. , Nature 310:583-586 (1984)).
  • this motif serves as a signal sequence for the enzymes farn esyl-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.
  • farn esyl-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.
  • 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.
  • Inhibitors of famesyl-protein transferase have been described in two general classes.
  • the first class includes analogs of famesyl diphosphate (FPP), while the second is related to protein substrates (e.g., Ras) for the enzyme.
  • the peptide derived inhibitors that have been described are generally cysteine containing molecules that are related to the CAAX motif that is the signal for protein prenylation. (Schaber et al, ibid; Reiss et. al, ibid; Reiss et al., PNAS, 88:132-136 (1991 )).
  • Such inhibitors may inhibit protein prenylation while serving as altemate substrates for the famesyl-protein transferase enzyme, or may be purely competitive inhibitors (U.S.
  • Patent 5,141 ,851 University of Texas; N.E. Kohl et al, Science,
  • biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane localization in cultured cells.
  • a Raf antagonist compound and a famesyl protein transferase inhibitor are used in the present invention to treat cancer, such as in tumor cells which are not particularly Raf or FPTase dependent.
  • the Raf antagonist compound and a famesyl protein transferase inhibiting compound are used in combination.
  • a method of treating cancer is disclosed which is comprised of administering to a mammalian patient in need of such treatment an effective amount of a Raf antagonist compound and an effective amount of a famesyl protein transferase inhibiting compound.
  • the present invention relates to a method of treating cancer which is comprised of admininstering to a mammalian patient in need of such treatment an effective amount of a Raf antagonist compound and an effective amount of a famesyl protein transferase inhibiting compound. Any compound which antagonizes Raf and any compound which inhibits famesyl protein transferase can be used.
  • Raf antagonist is used in the general sense to relate to compounds which antagonize, inhibit or counteract the activity of the raf gene or the protein produced in response thereto.
  • famesyl protein transferase inhibiting compound is likewise used in the general sense and refers to compounds which antagonize, inhibit or counteract the activity of the gene coding famesyl protein transferase or the protein produced in response thereto.
  • Cancers which are treatable in accordance with the invention described herein include cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx, liver and lung. More particularly, such cancers include histiocytic lymphoma, lung adenocarcinoma and small cell lung cancers. Additional examples include cancers in which overexpression or activation of Raf-activating oncogenes (e.g., K-ras, erb-B) is observed. More particularly, such cancers include pancreatic, mammary and salivary carcinomas, colorectal carcinoma, exocrine pancreatic carcinoma and myeloid leukemias.
  • Raf-activating oncogenes e.g., K-ras, erb-B
  • AR represents an aromatic group containing 6-10 atoms
  • X and X' each independently represent -(CH2)m-Y-(CH2)n -, wherein m and n represent integers within the range of from 0 - 4, such that the sum of m and n is from 0 - 6;
  • Y represents a member selected from the group consisting of: a direct bond: O; S(O)y, with y equal to 0, 1 or 2; NRq', with Rq' as defined below; C(O); OC(O); C(O)O; SO x NRq' with x equal to 1 or 2 and Rq' as defined below; NRq'SO x ; C(O)NRq' and NRq'C(O); represents a 4 to 10 membered non-aromatic heterocycle containing at least one N atom, and optionally containing 1-2 additional N atoms and 0-1 O or S atom;
  • R x represents H, C 1-6 alkyl(R q ) 3 , OC 1-6 alky
  • each R and R" independently represents a member selected from the group consisting of: halo; hydroxy; C 1-6 alkyl(Rq) 3 ;
  • each R' independently represents a member selected from the group consisting of: CONH 2 ; CONHC 1-6 alkyl(Rq) 3 ;
  • each R 5 and R 6 independently represents H, aryl, C 1 -6 alkyl(Rq) 3 , or each CR 5 R 6 taken in combination represents a 3, 4, 5 or 6 membered cycloalkyl or heterocyclyl group, an aryl group or a heteroaryl group, wherein when p equals 1 , at least one of j and k is 1 , 2 or 3; each R 7 and R 8 independently represents H, C 1 -6 alkyl or aryl;
  • Rq represents a member selected from the group consisting of: R q' ; CN; CO 2 H; CO 2 C 1 -4 alkyl; C(O)C 1 -4 alkyl ; aryl(R a ) 3 ; NH 2 ; NHC 1 -6 alkyl(R a )3; N(C 1 -6 alkyl(R a ) 3 ) 2 ; heteroaryl(R a ) 3 ;
  • each R a independently represents a member selected from the group consisting of: H, C 1 -6 alkyl, OC 1 -6 alkyl, aralkyl, substituted aralkyl, heteroaralkyl, substituted heteroaralkyl, aralkoxy, substituted aralkoxy , halo, hydroxy, CN, CONH 2 , CONHC 1 -6 alkyl, CON(C 1 -6 alkyl) 2 , CO 2 H, CO 2 C 1 -6 alkyl, C(O)C 1 -6 alkyl, phenyl, CF 3 , SH, NO 2 , SO y C 1 -6 alkyl, with y as defined above; SO 2 NH 2
  • each R' independently represents a member selected from the group consisting of: hydroxy; C 1 -6 alkyl(Rq) 3 ;
  • R 5 and R 6 are independently H, aryl, C 1 -6 alkyl(Rq) 3 , or CR 5 R 6 in combination represents a 3, 4, 5 or 6 membered cycloalkyl or heterocyclyl group, an aryl group or a heteroaryl group; p represents 1 , 2 or 3, with the proviso that when p represents 1 , CR 5 R 6 represents a 3, 4, 5 or 6 membered cycloalkyl group or a heterocyclyl group, an aryl group or a heteroaryl group, and at least one of j and k is 1 , 2 or 3;
  • R 9 represents H, a negative charge balanced by a positively charged group or a protecting group
  • Rq represents a member selected from the group consisting of: Rq'; CN; CO 2 H; CO 2 C 1 -4 alkyl; C(O)C 1 -4 alkyl ; NH(Rq ") ;
  • Rq represents H, OH or OC 1-4 alkyl
  • R 1 is 4-pyridyl, pyrimidinyl, quinazolin-4-yl, quinolyl, isoquinolinyl, 1 -imidazolyl or 1-benzimidazolyl which is optionally substituted with one or two substituents each of which is independently selected from C 1-4 alkyl, halogen, C 1-4 alkoxy, C 1-4 alkylthio, NR 10 R 20 , or N- heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR 22 ;
  • R 2 is hydrogen, -(CR 10 R 20 ) n OR 12 , heterocyclyl, heterocyclyl C 1-10 alkyl, C 1-10 alkyl, halo-substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-10 alkyl,
  • arylalkyl heteroaryl, heteroarylalkyl, heterocyclyl or
  • heterocyclyalkyl moieties may be optionally substituted
  • n' is an integer having a value of 1 to 10;
  • n 0 or the integer 1 or 2;
  • R 3 is Q-(Y 1 ) t ;
  • Q is an aryl or heteroaryl group
  • t is a number having a value of 1 , 2 or 3;
  • Z is oxygen or sulfur
  • n is 0 or an integer from 1 to 10;
  • Y 1 is independently selected from hydrogen, C 1 -5 alkyl, halo- substituted C 1 -5 alkyl, halogen, or -(CR 10 R 20 ) n Y 2 ;
  • Y 2 is -OR 8 , -NO 2 , -S(O) m 'R 1 1 , -SR 8 , -S(O)) m 'OR 8 , -S(O) m NR 8 R 9 , -NR 8 R 9 , -O(CR 10 R 20 ) n NR 8 R 9 , -C(O)R 8 , -CO 2 R 8 ,
  • m' is a number having a value of 1 or 2;
  • R 4 is phenyl, naphth-1 -yl or naphth-2-yl which is optionally substituted by one or two substituents, each of which is independently selected, and which, for a 4-phenyl, 4-naphth-1 -yl or 5-naphth-1 -yl
  • substituent is halo, cyano,-C(Z)NR 7 R 17 , -C(Z)OR 23 ,
  • R 5 is hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl or NR 7 R 17 , excluding the moieties -SR 5 being -SNR 7 R 17 and -SOR 5 being -SOH;
  • R 6 is C 1-4 alkyl, halo-substituted-C 1-4 alkyl, C 1-4 alkenyl, C 2-4
  • R 7 and R 17 are each independently selected from hydrogen or C 1-4 alkyl, or R 7 and R 17 together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR 22 ;
  • R 8 is hydrogen, heterocyclyl, heterocyclylalkyl or R 11 ;
  • R 9 is hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-7
  • cycloalkyl C 5-7 cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl or R 8 and R 9 may together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR 12 ;
  • R 10 and R 20 are each independently selected from hydrogen and C 1-4 alkyl
  • R 11 is C 1-10 alkyl, halo-substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-7 cycloalkyl, C 5-7 cycloalkenyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;
  • R 12 is hydrogen. -C(Z)R 13 or optionally substituted C 1-4 alkyl,
  • R 13 is hydrogen, C 1-10 alkyl, C 3-7 cycloalkyl, heterocyclyl,
  • R 14 and R 24 is each independently selected from hydrogen, alkyl, nitro or cyano;
  • R 15 is hydrogen, cyano, C 1-4 alkyl, C 3-7 cycloalkyl or aryl;
  • R 16 and R 26 is each independently selected from hydrogen or
  • R 18 and R 19 is each independently selected from hydrogen, C 1-4 alkyl. substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl or together denote a oxygen or sulfur;
  • R 21 is hydrogen, a pharmaceutically acceptable cation, C 1-10 alkyl, C 3-7 cycloalkyl, aryl, aryl C 1-4 alkyl, heteroaryl, heteroarylalkyl, heterocyclyl, aroyl, or C 1-10 alkanoyl;
  • R 22 is R 10 or C(Z)-C 1-4 alkyl
  • R 23 is C 1-4 alkyl, halo-substituted-C 1-4 alkyl or C 3-5 cycloalkyl;
  • R 36 is hydrogen or R 23 ;
  • R 25 is C 1-10 alkyl, C 3-7 cycloalkyl, heterocyclyl, aryl, arylalkyl,
  • heterocyclyl heterocyclyl, heterocyclyl-C 1-10 alkyl, heteroaryl or
  • R 27 is hydrogen, cyano, C 1-4 alkyl, C 3-7 cycloalkyl or aryl; or a pharmaceutically acceptable salt thereof.
  • R 1a and R 1b are independently selected from:
  • heterocyclyl C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 10 O-, R 11 S(O) m -, R 10 C(O)NR 10 -, CN, (R 10 ) 2 N-C(NR 10 )-, R 10 C(O)-, R 10 OC(O)-, N 3 ,
  • R 2 and R 3 are independently selected from: H; unsubstituted or
  • substituted group is substituted with one or more of:
  • R 2 and R 3 are attached to the same C atom and are combined to form (CH 2 ) u - wherein one of the carbon atoms is optionally replaced by a moiety selected from: O, S(O) m , -NC(O)-, and -N(COR 10 )-; R 4 and R 5 are independently selected from H and CH 3 ; and any two of R 2 , R 3 , R 4 and R 5 are optionally attached to the same carbon atom;
  • R 6 , R 7 and R 7a are independently selected from: H; C 1-4 alkyl, C 3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
  • R 6 and R 7 may be joined in a ring
  • R 7 and R 7a may be joined in a ring;
  • R 8 is independently 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:
  • 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;
  • Y is aryl, heterocycle, unsubstituted or substituted with one or more of:
  • n 0, 1, 2, 3 or 4;
  • p 0, 1 , 2, 3 or 4;
  • r is 0 to 5, provided that r is 0 when V is hydrogen; s is 0 or 1 ;
  • t is 0 or 1
  • R 1a , R 1b , R 10 , R 11 , m, R 2 , R 3 , R 6 , R 7 , p, R 7a , u, R 8 , A 1 , A 2 , V, W, X, n, p, r, s, t and u are as defined above with respect to formula (Il-a);
  • R 4 is selected from H and CH 3 ; and any two of R 2 , R 3 and R 4 are optionally attached to the same carbon atom; R 9 is selected from:
  • alkenyl alkynyl, perfluoroalkyl, F, Cl, Br, R 10 O-,
  • G is H 2 or O;
  • Z is aryl, heteroaryl, arylmethyl, heteroarylmethyl,
  • arylsulfonyl arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with one or more of the following:
  • R 1 a , R 1 b , R 10 , R 11 , m, R 2 , R 3 , R 6 , R 7 , p, u, R 7a , R 8 , A 1 , A 2 , V, W, X, n, r and t are as defined above with respect to formula (Il-a);
  • R 4 is selected from H and CH 3 ; and any two of R 2 , R 3 and R 4 are optionally attached to the same carbon atom;
  • G is O;
  • Z is aryl, , heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with one or more of the following:
  • R 11 , V, W, m, n, p and r are as defined above with respect to formula (Il-a);
  • R 1a and R 1b are independently selected from:
  • heterocyclyl C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 10 O-, R 11 S(O) m -, R 10 C(O)NR 10 -, CN,
  • R 2a and R 2b are independently selected from:
  • R 3 and R 4 are independently selected from:
  • R 3 and R 4 are combined to form - (CH 2 ) s - ;
  • R 5a and R 5b are independently selected from:
  • substituent is selected from F, Cl, Br. CF 3 , N(R 1 0 ) 2 , NO 2 , R 1 0 O-, R 1 1 S(O) m -, R 10 C(O)NR 10 -, CN, (R 10 ) 2 N-C(NR 10 )-, R 10 C(O)-, R 10 OC(O)-, N 3 , -N(R 10 ) 2 , R 11 OC(O)NR 10 - and C 1 -C 20 alkyl,
  • 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 7a is selected from a) hydrogen
  • R 7b is selected from
  • a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C 3 -C 1 0 cycloalkyl and C 1 -C 6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C 3 -C 1 0 cycloalkyl, and
  • R 8 is independently selected from:
  • R 1 1 OC(O)NR 10 -, and c) C 1 -C 6 alkyl unsubstituted or substituted by aryl,
  • R 10 is independently selected from H, C 1 -C 6 alkyl, benzyl, substituted aryl and C 1 -C 6 alkyl substituted with substituted aryl;
  • Z is independently H 2 or O;
  • s is 4 or 5:
  • t 3, 4 or 5;
  • R 11 , W, m, n, p and r are as defined above with respect to formula (II- a);
  • R 1a and R 1b are independently selected from:
  • heterocyclyl C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 10 O-, R 11 S(O) m -, R 10 C(O)NR 10 -, CN,
  • R 2a and R 2b are independently selected from:
  • R 3 and R 4 are independently selected from:
  • 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 7a is selected from
  • R 7a is selected from
  • a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C 3 -C 10 cycloalkyl and C 1 -C 6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C 3 -C 10 cycloalkyl, and
  • R 8 is 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 9 is selected from:
  • R 10 is independently selected from H, C 1 -C 6 alkyl, benzyl, substituted aryl and C 1 -C 6 alkyl substituted with substituted aryl;
  • R 12 is hydrogen or C 1 -C 6 alkyl
  • R 13 is C 1 -C 6 alkyl
  • Z is independently H 2 or O; s is 4 or 5;
  • t 3, 4 or 5;
  • u is 0 or 1; with respect to formula (Il-f):
  • R 11 , V, W, m, n, p and r are as defined above with respect to formula (Il-a); R 1a and R 1b are independently selected from:
  • heterocyclyl C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 10 O-, R 11 S(O) m -, R 10 C(O)NR 10 -, CN,
  • R 2a and R 2b are independently selected from:
  • R 3 and R 4 are independently selected from:
  • R 7a is selected from
  • R 7a is selected from
  • a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C 3 -C 1 0 cycloalkyl and C 1 -C 6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C 3 -C 1 0 cycloalkyl, and
  • R 8 is independently selected from:
  • R 1 1 OC(O)NR 1 0 -, and c) C 1 -C 6 alkyl unsubstituted or substituted by aryl,
  • R 9 is selected from:
  • R 10 is independently selected from H, C 1 -C 6 alkyl, benzyl, substituted aryl and C 1 -C 6 alkyl substituted with substituted aryl;
  • R 12 is hydrogen or C 1 -C 6 alkyl
  • R 13 is C 1 -C 6 alkyl;
  • Z is independently H 2 or O; q is 0, 1 or 2;
  • s 4 or 5;
  • t 3, 4 or 5;
  • u is 0 or 1; with respect to formula (Il-g):
  • R 11 , V, W, m, n, p and r are as previously defined with respect to formula (Il-a);
  • R 1a and R 1b are independently selected from:
  • R 2a and R 2b are independently selected from:
  • R 3 and R 4 are independently selected from:
  • R 7a is selected from
  • R 7a is selected from
  • a carbonyl group which is bonded to an unsubstituted or substituted group selected from aryl, heterocycle, C 3 -C 10 cycloalkyl and C 1 -C 6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and C 3 -C 10 cycloalkyl, and
  • R 8 is independently selected from:
  • 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 10 OC(O)NH-;
  • R 9 is selected from:
  • R 10 is independently selected from H, C 1 -C 6 alkyl, benzyl, substituted aryl and C 1 -C 6 alkyl substituted with substituted aryl;
  • R 12 is hydrogen or C 1 -C 6 alkyl
  • R 13 is C 1 -C 6 alkyl
  • Z is independently H 2 or O; qis 0, 1 or 2;
  • s 4 or 5;
  • u is 0 or 1
  • R 1a , R 1b , R 8 , R 9 , R 10 , R 11 , A 1 , A 2 , V, W, m, n, p and r are as previously defined with respect to formula (Il-a); 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 7a are independently selected from:
  • 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;
  • 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 an aromatic ring, a C 5 -C 7 saturated ring or a heterocycle;
  • X, Y and Z are independently H 2 or O; s is 4 or 5;
  • t 3, 4 or 5;
  • u is 0 or 1 ; with respect to formula (Il-i):
  • R 1 a , R 1 b , R 8 , R 9 , R 10 , R 1 1 , A 1 , A 2 , V, W, m, n, p and r are as previously defined with respect to formula (Il-a); R 2 and R 3 are independently selected from:
  • R 2 or R 3 are combined with R6 to form a ring such that
  • R 4a , R 4b , R 7a and R 7a are independently selected from:
  • 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 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 a substituted or unsubstituted nitrogen-containing C 4 -C 9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be an aromatic ring, a C 5 -C 7 saturated ring or a heterocycle;
  • X, Y and Z are independently H 2 or O; s is 4 or 5;
  • t 3, 4 or 5;
  • R 1 a , R 1 b , R 8 , R 9 , R 10 , R 1 1 , A 1 , A 2 , V, W, m, n, p and r are as previously defined with respect to formula (Il-a); 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 7a are independently selected from:
  • 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 ,
  • R 6 is independently selected from hydrogen or 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 an aromatic ring, a C 5 -C 7 saturated ring or a heterocycle;
  • X, Y and Z are independently H 2 or O; q is 0, 1 or 2;
  • s 4 or 5;
  • t 3, 4 or 5;
  • R 1 a , R 1 b , R 8 , R 9 , R 10 , R 1 1 , A 1 , A 2 , V, W, m, n, p, and r are as defined above with respect to formula (Il-a); 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 7a are independently selected from:
  • R 6 is independently selected from hydrogen or 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 an aromatic ring, a C 5 -C 7 saturated ring or a heterocycle;
  • X, Y and Z are independently H 2 or O; q is 0, 1 or 2;
  • s 4 or 5;
  • t 3, 4 or 5;
  • u is 0 or 1 ;
  • R 1 a , R 1 b , R 8 , R 9 , R 10 , R 1 1 , A 1 , A 2 , V, W, m, n, p and r are as defined above with respect to formula (Il-a); 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 7a are independently selected from:
  • 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 1 0 )- ;
  • R 6 is independently selected from hydrogen or C 1 -C 6 alkyl;
  • 0 is a substituted or unsubstituted nitrogen-containing C 4 -C 9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be an aromatic ring, a C 5 -C 7 saturated ring or a heterocycle;
  • X, Y and Z are independently H 2 or O; s is 4 or 5;
  • R 1a , R 1b , R 8 , R 9 , R 10 , R 11 , A 1 , A 2 , V, W, m, n, p and r are as defined above with respect to formula (Il-a); R 2 and R 3 are independently selected from:
  • R 4a , R 4b , R 7a and R 7a are independently selected from:
  • 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 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 an aromatic ring, a C 5 -C 7 saturated ring or a heterocycle;
  • X, Y and Z are independently H 2 or O;
  • s is 4 or 5;
  • t is 3, 4 or 5; and
  • u is 0 or 1; with respect to formula (Il-n):
  • R 1a , R 1b , R 8 , R 9 , R 10 , R 11 , A 1 , A 2 , V, W, m, n, p and r are as defined above with respect to formula (Il-a); 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 7a are independently selected from:
  • R 6 is independently selected from hydrogen or 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 an aromatic ring, a C 5 -C 7 saturated ring or a heterocycle;
  • X, Y and Z are independently H 2 or O; q is 0, 1 or 2;
  • s 4 or 5;
  • t 3, 4 or 5;
  • R 1a , R 1b , R 8 , R 9 , R 10 , R 11 , A 1 , A 2 , V, W, m, n, p and r are as defined above with respect to formula (Il-a); 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 7a are independently selected from:
  • R 6 is independently selected from hydrogen or 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 an aromatic ring, a C 5 -C 7 saturated ring or a heterocycle;
  • X, Y and Z are independently H 2 or O; q is 0, 1 or 2;
  • s 4 or 5;
  • t 3, 4 or 5;
  • u is 0 or 1.
  • Specific compounds which antagonize Raf include the following: 4-[5-(4-fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl]-piperidine-1- carboxylic acid tert-butyl ester;
  • Examples of compounds which antagonize or inhibit famesyl protein transferase include the following:

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  • Proteomics, Peptides & Aminoacids (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Steroid Compounds (AREA)

Abstract

Cette invention porte sur une méthode de traitement du cancer consistant à administrer à un patient mammalien un composé inhibant Raf ainsi qu'un composé inhibant la farnésyl-protéine transférase.
PCT/US1997/005328 1996-04-03 1997-03-31 Methode de traitement du cancer WO1997036587A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP9535542A JP2000504023A (ja) 1996-04-03 1997-03-31 癌治療方法
EP97921085A EP0906099A4 (fr) 1996-04-03 1997-03-31 Methode de traitement du cancer
AU27221/97A AU727939B2 (en) 1996-04-03 1997-03-31 A method of treating cancer

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US1477396P 1996-04-03 1996-04-03
US60/014,773 1996-04-03
GB9613599.1 1996-06-28
GBGB9613599.1A GB9613599D0 (en) 1996-06-28 1996-06-28 A method of treating cancer

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FR2780892A1 (fr) * 1998-07-08 2000-01-14 Sod Conseils Rech Applic Utilisation d'inhibiteurs de prenyltransferases pour preparer un medicament destine a traiter les pathologies qui resultent de la fixation membranaire de la proteine g heterotrimerique
WO2000016778A1 (fr) * 1998-09-24 2000-03-30 Merck & Co., Inc. Procede de traitement du cancer
US6046208A (en) * 1996-01-11 2000-04-04 Smithkline Beecham Corporation Substituted imidazole compounds
WO2000061145A1 (fr) * 1999-04-09 2000-10-19 Schering Corporation Procedes pour l'induction de la mort de cellules cancereuses et la regression de tumeurs
US6251914B1 (en) 1997-07-02 2001-06-26 Smithkline Beecham Corporation Cycloalkyl substituted imidazoles
US6268370B1 (en) 1992-01-13 2001-07-31 Smithkline Beecham Corporation Compounds
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US6414150B1 (en) 1996-08-21 2002-07-02 Smithkline Beecham Corporation 4,5-disubstituted imidazole compounds
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US6268370B1 (en) 1992-01-13 2001-07-31 Smithkline Beecham Corporation Compounds
US7838512B2 (en) 1994-02-04 2010-11-23 Arch Development Corporation DNA damaging agents in combination with tyrosine kinase inhibitors
US7070968B2 (en) 1994-02-04 2006-07-04 Arch Development Corporation DNA damaging agents in combination with tyrosine kinase inhibitors
US6046208A (en) * 1996-01-11 2000-04-04 Smithkline Beecham Corporation Substituted imidazole compounds
US6414150B1 (en) 1996-08-21 2002-07-02 Smithkline Beecham Corporation 4,5-disubstituted imidazole compounds
US6774127B2 (en) 1997-06-13 2004-08-10 Smithkline Beecham Corporation Pyrazole and pyrazoline substituted compounds
US6610695B1 (en) 1997-06-19 2003-08-26 Smithkline Beecham Corporation Aryloxy substituted pyrimidine imidazole compounds
US7301021B2 (en) 1997-07-02 2007-11-27 Smithkline Beecham Corporation Substituted imidazole compounds
US6562832B1 (en) 1997-07-02 2003-05-13 Smithkline Beecham Corporation Substituted imidazole compounds
US6251914B1 (en) 1997-07-02 2001-06-26 Smithkline Beecham Corporation Cycloalkyl substituted imidazoles
US6362193B1 (en) 1997-10-08 2002-03-26 Smithkline Beecham Corporation Cycloalkenyl substituted compounds
US6730683B2 (en) 1997-12-19 2004-05-04 Smithkline Beecham Corporation Compounds of heteroaryl substituted imidazole, their pharmaceutical compositions and uses
WO1999038862A1 (fr) * 1998-02-02 1999-08-05 Lg Chemical Ltd. Inhibiteurs de farnesyl-transferases, ayant une structure piperidine, et procede de preparation correspondant
US6548520B1 (en) 1998-05-22 2003-04-15 Smithkline Beecham Corporation Substituted imidazoles having anti-cancer and cytokine inhibitory activity
US6858617B2 (en) 1998-05-26 2005-02-22 Smithkline Beecham Corporation Substituted imidazole compounds
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US6867284B1 (en) 1998-06-10 2005-03-15 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. Peptide inhibitors of hepatitis C virus NS3 protease
WO1999064442A1 (fr) * 1998-06-10 1999-12-16 Istituto Di Ricerche Di Biologia Molecolare P Angeletti S.P.A. Inhibiteurs peptides de la protease ns3 du virus de l'hepatite c
FR2780892A1 (fr) * 1998-07-08 2000-01-14 Sod Conseils Rech Applic Utilisation d'inhibiteurs de prenyltransferases pour preparer un medicament destine a traiter les pathologies qui resultent de la fixation membranaire de la proteine g heterotrimerique
WO2000016778A1 (fr) * 1998-09-24 2000-03-30 Merck & Co., Inc. Procede de traitement du cancer
US6548503B1 (en) 1998-11-04 2003-04-15 Smithkline Beecham Corporation Pyridin-4-yl or pyrimidin-4-yl substituted pyrazines
US6861417B2 (en) 1998-11-04 2005-03-01 Smithkline Beecham Corporation Pyridin-4-YL or pyrimidin-4-YL substituted pyrazines
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US6316462B1 (en) 1999-04-09 2001-11-13 Schering Corporation Methods of inducing cancer cell death and tumor regression
WO2000061145A1 (fr) * 1999-04-09 2000-10-19 Schering Corporation Procedes pour l'induction de la mort de cellules cancereuses et la regression de tumeurs
US7122666B2 (en) 1999-07-21 2006-10-17 Sankyo Company, Limited Heteroaryl-substituted pyrrole derivatives, their preparation and their therapeutic uses
US7189745B1 (en) 1999-11-22 2007-03-13 Smithkline Beecham Corporation Compounds
US7026336B1 (en) 1999-11-22 2006-04-11 Smithkline Beecham P.L.C. Compounds
US7053098B1 (en) 1999-11-23 2006-05-30 Smithkline Beecham Corporation 3,4-Dihydro-(1H) quinazolin-2-one compounds as CSBP/P38 kinase inhibitors
US6982270B1 (en) 1999-11-23 2006-01-03 Smithkline Beecham Corporation 3,4-dihydro-(1H)quinazolin-2-one compounds as CSBP/p38 kinase inhibitors
US6759410B1 (en) 1999-11-23 2004-07-06 Smithline Beecham Corporation 3,4-dihydro-(1H)-quinazolin-2-ones and their use as CSBP/p38 kinase inhibitors
US7235551B2 (en) 2000-03-02 2007-06-26 Smithkline Beecham Corporation 1,5-disubstituted-3,4-dihydro-1h-pyrimido[4,5-d]pyrimidin-2-one compounds and their use in treating csbp/p38 kinase mediated diseases
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