EP1009854A1 - Procede de traitement du cancer - Google Patents
Procede de traitement du cancerInfo
- Publication number
- EP1009854A1 EP1009854A1 EP98944537A EP98944537A EP1009854A1 EP 1009854 A1 EP1009854 A1 EP 1009854A1 EP 98944537 A EP98944537 A EP 98944537A EP 98944537 A EP98944537 A EP 98944537A EP 1009854 A1 EP1009854 A1 EP 1009854A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- protein
- geranylgeranyl
- seq
- protein transferase
- compound
- Prior art date
- Legal status (The legal status 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 status listed.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims abstract description 130
- 206010028980 Neoplasm Diseases 0.000 title abstract description 30
- 201000011510 cancer Diseases 0.000 title abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 200
- 102000004357 Transferases Human genes 0.000 claims abstract description 148
- 108090000992 Transferases Proteins 0.000 claims abstract description 148
- 150000001450 anions Chemical class 0.000 claims abstract description 102
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 99
- 238000000338 in vitro Methods 0.000 claims abstract description 68
- 238000003556 assay Methods 0.000 claims abstract description 62
- 239000003112 inhibitor Substances 0.000 claims abstract description 55
- 239000003558 transferase inhibitor Substances 0.000 claims abstract description 25
- 241000124008 Mammalia Species 0.000 claims abstract description 21
- 238000001727 in vivo Methods 0.000 claims abstract description 21
- 229940125436 dual inhibitor Drugs 0.000 claims abstract description 18
- 230000000694 effects Effects 0.000 claims abstract description 17
- 229940123468 Transferase inhibitor Drugs 0.000 claims abstract description 16
- 108090000623 proteins and genes Proteins 0.000 claims description 97
- 102000004169 proteins and genes Human genes 0.000 claims description 91
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 71
- 239000000758 substrate Substances 0.000 claims description 68
- -1 dithiophosphate Chemical compound 0.000 claims description 64
- 238000012546 transfer Methods 0.000 claims description 56
- 125000002686 geranylgeranyl group Chemical group [H]C([*])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 46
- 238000005259 measurement Methods 0.000 claims description 46
- 210000004027 cell Anatomy 0.000 claims description 39
- 150000003839 salts Chemical class 0.000 claims description 25
- ZKHQWZAMYRWXGA-KQYNXXCUSA-N Adenosine triphosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-N 0.000 claims description 23
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 claims description 23
- 229960001456 adenosine triphosphate Drugs 0.000 claims description 23
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 22
- 230000012010 growth Effects 0.000 claims description 22
- 125000004030 farnesyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 21
- 238000012360 testing method Methods 0.000 claims description 21
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 20
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 18
- 210000002950 fibroblast Anatomy 0.000 claims description 17
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 claims description 15
- 235000011180 diphosphates Nutrition 0.000 claims description 15
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- XKMLYUALXHKNFT-UUOKFMHZSA-N Guanosine-5'-triphosphate Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XKMLYUALXHKNFT-UUOKFMHZSA-N 0.000 claims description 11
- XKMLYUALXHKNFT-UHFFFAOYSA-N rGTP Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O XKMLYUALXHKNFT-UHFFFAOYSA-N 0.000 claims description 11
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 10
- 150000001408 amides Chemical class 0.000 claims description 9
- SUYVUBYJARFZHO-RRKCRQDMSA-N dATP Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@H]1C[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 SUYVUBYJARFZHO-RRKCRQDMSA-N 0.000 claims description 9
- HAAZLUGHYHWQIW-KVQBGUIXSA-N dGTP Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 HAAZLUGHYHWQIW-KVQBGUIXSA-N 0.000 claims description 9
- WKKCYLSCLQVWFD-UHFFFAOYSA-N 1,2-dihydropyrimidin-4-amine Chemical compound N=C1NCNC=C1 WKKCYLSCLQVWFD-UHFFFAOYSA-N 0.000 claims description 8
- MMWCIQZXVOZEGG-XJTPDSDZSA-N D-myo-Inositol 1,4,5-trisphosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](OP(O)(O)=O)[C@H](OP(O)(O)=O)[C@@H](O)[C@@H]1OP(O)(O)=O MMWCIQZXVOZEGG-XJTPDSDZSA-N 0.000 claims description 8
- PGAVKCOVUIYSFO-XVFCMESISA-N UTP Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N1C(=O)NC(=O)C=C1 PGAVKCOVUIYSFO-XVFCMESISA-N 0.000 claims description 8
- 230000005907 cancer growth Effects 0.000 claims description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 8
- 235000019832 sodium triphosphate Nutrition 0.000 claims description 8
- 239000001226 triphosphate Substances 0.000 claims description 8
- UNXRWKVEANCORM-UHFFFAOYSA-I triphosphate(5-) Chemical compound [O-]P([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O UNXRWKVEANCORM-UHFFFAOYSA-I 0.000 claims description 8
- PGAVKCOVUIYSFO-UHFFFAOYSA-N uridine-triphosphate Natural products OC1C(O)C(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)OC1N1C(=O)NC(=O)C=C1 PGAVKCOVUIYSFO-UHFFFAOYSA-N 0.000 claims description 8
- OINNEUNVOZHBOX-XBQSVVNOSA-N Geranylgeranyl diphosphate Natural products [P@](=O)(OP(=O)(O)O)(OC/C=C(\CC/C=C(\CC/C=C(\CC/C=C(\C)/C)/C)/C)/C)O OINNEUNVOZHBOX-XBQSVVNOSA-N 0.000 claims description 7
- PFMUCCYYAAFKTH-YFKPBYRVSA-N Gly-Met Chemical compound CSCC[C@@H](C(O)=O)NC(=O)CN PFMUCCYYAAFKTH-YFKPBYRVSA-N 0.000 claims description 7
- 229910019142 PO4 Inorganic materials 0.000 claims description 7
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 7
- 239000010452 phosphate Substances 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 6
- 239000004471 Glycine Substances 0.000 claims description 5
- LRANPJDWHYRCER-UHFFFAOYSA-N 1,2-diazepine Chemical compound N1C=CC=CC=N1 LRANPJDWHYRCER-UHFFFAOYSA-N 0.000 claims description 3
- BEALYENGMRDLRK-LKEWCRSYSA-N [hydroxy-[[(2s,4r,5r)-4-hydroxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy]phosphoryl] phosphono hydrogen phosphate Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1[C@H](O)C[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 BEALYENGMRDLRK-LKEWCRSYSA-N 0.000 claims description 3
- 150000002460 imidazoles Chemical class 0.000 claims description 3
- BJFPYGGTDAYECS-UHFFFAOYSA-N (3-chlorophenyl)methanamine Chemical compound NCC1=CC=CC(Cl)=C1 BJFPYGGTDAYECS-UHFFFAOYSA-N 0.000 claims description 2
- OINNEUNVOZHBOX-QIRCYJPOSA-K 2-trans,6-trans,10-trans-geranylgeranyl diphosphate(3-) Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\CC\C(C)=C\COP([O-])(=O)OP([O-])([O-])=O OINNEUNVOZHBOX-QIRCYJPOSA-K 0.000 claims description 2
- DJTWYNIHIMFJRU-UHFFFAOYSA-N 4-[[5-[(4-benzoylanilino)methyl]imidazol-1-yl]methyl]benzonitrile Chemical compound C=1C=C(NCC=2N(C=NC=2)CC=2C=CC(=CC=2)C#N)C=CC=1C(=O)C1=CC=CC=C1 DJTWYNIHIMFJRU-UHFFFAOYSA-N 0.000 claims description 2
- GDAQDTCKYVKPPC-PMERELPUSA-N benzyl n-[(3-chlorophenyl)methyl]-n-[(2s)-2-[[3-[(4-cyanophenyl)methyl]imidazol-4-yl]methylamino]-4-methylsulfonylbutyl]carbamate Chemical compound C([C@H](CCS(=O)(=O)C)NCC=1N(C=NC=1)CC=1C=CC(=CC=1)C#N)N(C(=O)OCC=1C=CC=CC=1)CC1=CC=CC(Cl)=C1 GDAQDTCKYVKPPC-PMERELPUSA-N 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 125000000336 imidazol-5-yl group Chemical group [H]N1C([H])=NC([H])=C1[*] 0.000 claims description 2
- RZCIEJXAILMSQK-JXOAFFINSA-N TTP Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 RZCIEJXAILMSQK-JXOAFFINSA-N 0.000 claims 5
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims 1
- 101000574352 Mus musculus Protein phosphatase 1 regulatory subunit 17 Proteins 0.000 claims 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims 1
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 95
- 125000003118 aryl group Chemical group 0.000 description 94
- 125000000623 heterocyclic group Chemical group 0.000 description 79
- 239000001257 hydrogen Substances 0.000 description 68
- 229910052739 hydrogen Inorganic materials 0.000 description 68
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 66
- 235000018102 proteins Nutrition 0.000 description 46
- 150000002431 hydrogen Chemical class 0.000 description 45
- 239000000543 intermediate Substances 0.000 description 43
- 239000000243 solution Substances 0.000 description 43
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 38
- 125000000217 alkyl group Chemical group 0.000 description 38
- 239000000203 mixture Substances 0.000 description 33
- 125000003107 substituted aryl group Chemical group 0.000 description 32
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 31
- 125000000753 cycloalkyl group Chemical group 0.000 description 31
- 239000000047 product Substances 0.000 description 31
- 108010014186 ras Proteins Proteins 0.000 description 31
- 125000005010 perfluoroalkyl group Chemical group 0.000 description 30
- 102000016914 ras Proteins Human genes 0.000 description 27
- 238000002360 preparation method Methods 0.000 description 23
- 125000001424 substituent group Chemical group 0.000 description 22
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 20
- 230000005764 inhibitory process Effects 0.000 description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 150000001299 aldehydes Chemical class 0.000 description 17
- 235000001014 amino acid Nutrition 0.000 description 17
- 229940024606 amino acid Drugs 0.000 description 17
- 229910052736 halogen Inorganic materials 0.000 description 17
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 17
- 101001043818 Mus musculus Interleukin-31 receptor subunit alpha Proteins 0.000 description 16
- 229910052799 carbon Inorganic materials 0.000 description 16
- 150000002367 halogens Chemical class 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 102000004190 Enzymes Human genes 0.000 description 15
- 108090000790 Enzymes Proteins 0.000 description 15
- 239000003814 drug Substances 0.000 description 15
- 229940088598 enzyme Drugs 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- 238000003786 synthesis reaction Methods 0.000 description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 14
- 125000003545 alkoxy group Chemical group 0.000 description 14
- 150000001413 amino acids Chemical class 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- 238000011282 treatment Methods 0.000 description 14
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 125000003342 alkenyl group Chemical group 0.000 description 13
- 102200160920 rs35304565 Human genes 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 12
- 229910052801 chlorine Inorganic materials 0.000 description 12
- 125000004122 cyclic group Chemical group 0.000 description 12
- 229910052731 fluorine Inorganic materials 0.000 description 12
- 125000005842 heteroatom Chemical group 0.000 description 12
- 125000006239 protecting group Chemical group 0.000 description 12
- VWFJDQUYCIWHTN-YFVJMOTDSA-N 2-trans,6-trans-farnesyl diphosphate Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\CO[P@](O)(=O)OP(O)(O)=O VWFJDQUYCIWHTN-YFVJMOTDSA-N 0.000 description 11
- 125000004432 carbon atom Chemical group C* 0.000 description 11
- 229940079593 drug Drugs 0.000 description 11
- 125000002883 imidazolyl group Chemical group 0.000 description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 150000001412 amines Chemical class 0.000 description 10
- 125000001072 heteroaryl group Chemical group 0.000 description 10
- 239000003921 oil Substances 0.000 description 10
- 235000019198 oils Nutrition 0.000 description 10
- 229910052760 oxygen Inorganic materials 0.000 description 10
- 125000004076 pyridyl group Chemical group 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 239000004480 active ingredient Substances 0.000 description 9
- 238000005804 alkylation reaction Methods 0.000 description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 9
- 239000012267 brine Substances 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 231100000252 nontoxic Toxicity 0.000 description 9
- 230000003000 nontoxic effect Effects 0.000 description 9
- 230000013823 prenylation Effects 0.000 description 9
- 238000005932 reductive alkylation reaction Methods 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- 229910052717 sulfur Inorganic materials 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- 102000006495 integrins Human genes 0.000 description 8
- 108010044426 integrins Proteins 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 8
- 108700042226 ras Genes Proteins 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 102100039788 GTPase NRas Human genes 0.000 description 7
- 101000744505 Homo sapiens GTPase NRas Proteins 0.000 description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 7
- 238000003776 cleavage reaction Methods 0.000 description 7
- 125000001041 indolyl group Chemical group 0.000 description 7
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 239000008194 pharmaceutical composition Substances 0.000 description 7
- 239000000546 pharmaceutical excipient Substances 0.000 description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 7
- 230000003389 potentiating effect Effects 0.000 description 7
- 125000005494 pyridonyl group Chemical group 0.000 description 7
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- 125000000335 thiazolyl group Chemical group 0.000 description 7
- 125000001544 thienyl group Chemical group 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 6
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- 101000581118 Homo sapiens Rho-related GTP-binding protein RhoC Proteins 0.000 description 6
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- 102100027610 Rho-related GTP-binding protein RhoC Human genes 0.000 description 6
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- GHRQXJHBXKYCLZ-UHFFFAOYSA-L beta-glycerolphosphate Chemical compound [Na+].[Na+].CC(CO)OOP([O-])([O-])=O GHRQXJHBXKYCLZ-UHFFFAOYSA-L 0.000 description 6
- 229940125904 compound 1 Drugs 0.000 description 6
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- 150000007522 mineralic acids Chemical class 0.000 description 6
- 150000007524 organic acids Chemical class 0.000 description 6
- IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical class O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 description 6
- 229920001223 polyethylene glycol Polymers 0.000 description 6
- 239000003528 protein farnesyltransferase inhibitor Substances 0.000 description 6
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- 239000003981 vehicle Substances 0.000 description 6
- 125000004637 2-oxopiperidinyl group Chemical group O=C1N(CCCC1)* 0.000 description 5
- VWFJDQUYCIWHTN-UHFFFAOYSA-N Farnesyl pyrophosphate Natural products CC(C)=CCCC(C)=CCCC(C)=CCOP(O)(=O)OP(O)(O)=O VWFJDQUYCIWHTN-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000002202 Polyethylene glycol Substances 0.000 description 5
- 239000002246 antineoplastic agent Substances 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000007859 condensation product Substances 0.000 description 5
- 238000010511 deprotection reaction Methods 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 150000004665 fatty acids Chemical class 0.000 description 5
- 125000001153 fluoro group Chemical group F* 0.000 description 5
- 239000012634 fragment Substances 0.000 description 5
- OINNEUNVOZHBOX-KGODAQDXSA-N geranylgeranyl diphosphate Chemical compound CC(C)=CCC\C(C)=C/CC\C(C)=C\CC\C(C)=C\CO[P@@](O)(=O)OP(O)(O)=O OINNEUNVOZHBOX-KGODAQDXSA-N 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000003755 preservative agent Substances 0.000 description 5
- 238000012545 processing Methods 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 5
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 5
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Classifications
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- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
- G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
- G01N33/5011—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing antineoplastic activity
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- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
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- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/48—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving transferase
Definitions
- the present invention relates to a method of treating cancer which utilizes prenyl-protein transferase inhibitors which are efficacious in vivo as inhibitors of geranylgeranyl-protein transferase type I (GGTase-I).
- the invention also relates to a method for identifying such prenyl-protein transferase inhibitors.
- Prenylation of proteins by prenyl-protein transferases represents a class of post-translational modification (Glomset, J. A., Gelb, M. H., and Farnsworth, C. C. (1990), Trends Biochem. Sci. 15, 139-142; Maltese, W. A. (1990), FASEB J.
- Prenylated proteins share characteristic C-terminal sequences including CAAX (C, Cys; A, an aliphatic amino acid; X, another amino acid), XXCC, or XCXC.
- CAAX C, Cys; A, an aliphatic amino acid
- X another amino acid
- XCXC XCXC
- Three post-translational processing steps have been described for proteins having a C-terminal CAAX sequence: addition of either a 15 carbon (farnesyl) or 20 carbon (geranylgeranyl) isoprenoid to the Cys residue, proteolytic cleavage of the last 3 amino acids, and methylation of the new C-terminal carboxylate (Cox, A. D. and Der, C. J. (1992a), Critical Rev.
- FPTase farnesylates CAAX-containing proteins that end with Ser, Met, Cys, Gin or Ala.
- CAAX tetra- peptides comprise the minimum region required for interaction of the protein substrate with the enzyme.
- the prenylation reactions have been shown genetically to be essential for the function of a variety of proteins (Clarke, 1992; Cox and Der, 1992a; Gibbs, J. B. (1991). Cell 65: 1-4; Newman and Magee, 1993; Schafer and Rine, 1992). This requirement often is demonstrated by mutating the CAAX Cys acceptors so that the proteins can no longer be prenylated. The resulting proteins are devoid of their central biological activity. These studies provide a genetic "proof of principle" indicating that inhibitors of prenylation can alter the physiological responses regulated by prenylated proteins.
- the Ras protein is part of a signaling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation.
- Biological and biochemical studies of Ras action indicate that Ras functions like a G-regulatory protein.
- Ras In the inactive state, Ras is bound to GDP.
- Ras Upon growth factor receptor activation, Ras is induced to exchange GDP for GTP and undergoes a conformational change.
- the GTP-bound form of Ras propagates the growth stimulatory signal until the signal is terminated by the intrinsic GTPase activity of Ras, which returns the protein to its inactive GDP bound form (D.R. Lowy and D.M. Willumsen, Ann. Rev. Biochem. 62:851-891 (1993)).
- 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 277:810-812).
- 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.
- Farnesyl-protein transferase utilizes farnesyl pyrophosphate to covalently modify the Cys thiol group of the Ras CAAX box with a farnesyl group (Reiss et al, Cell, 62:81-88 (1990); Schaber et al, J. Biol. Chem., 265:14701-14704 (1990); Schafer et al, Science, 249:1133-1139 (1990); Manne et al., Proc. Natl. Acad. Sci USA, 57:7541-7545 (1990)).
- Ras must be localized to the plasma membrane for both normal and oncogenic functions. At least 3 post-translational modifications are involved with Ras membrane localization, and all 3 modifications occur at the C-terminus of Ras.
- the Ras C-terminus contains a sequence motif termed a "CAAX” or "Cys-Aaa-Aaa-Xaa” box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al., Nature 370:583-586 (1984)).
- this motif serves as a signal sequence for the enzymes farnesyl-protein transferase or geranylgeranyl-protein transferase, which catalyze the alkylation of the cysteine residue of the CAAX motif with a C 15 or C20 isoprenoid, respectively.
- farnesylated proteins include the Ras-related GTP-binding proteins such as RhoB, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin. James, et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisome associated protein Pxf which is also farnesylated. James, et al., have also suggested that there are farnesylated proteins of unknown structure and function in addition to those listed above.
- FPTase farnesyl-protein transferase
- the first class includes analogs of farnesyl diphosphate (FPP), while the second is related to protein substrates (e.g., Ras) for the enzyme.
- FPP farnesyl diphosphate
- 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 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: 1934-1931 (1993); Graham, et al., J. Med. Chem., 37, 725 (1994)).
- Mammalian cells express four types of Ras proteins (H-, N-, K4A-, and K4B-Ras) among which K4B-Ras is the most frequently mutated form of Ras in human cancers.
- the genes that encode these proteins are abbreviated -ras, N-ras , K.4A-ras and K4B- ras respectively.
- -ras is an abbreviation for Harvey-ras.
- K4A-ras and K4B-ras are abbreviations for the Kirsten splice variants of ras that contain the 4A and 4B exons, respectively.
- a composition which comprises such an inhibitor compound is used in the present invention to treat cancer.
- GGTase-I geranylgeranyl-protein transferase type I
- the instant invention provides for a method of inhibiting prenyl-protein transferases and treating cancer which comprises administering to a mammal a prenyl-protein transferase inhibitor which is efficacious in vivo as an inhibitor of geranylgeranyl- protein transferase type I (GGTase-I).
- the invention also provides for a method of inhibiting farnesyl-protein transferase and geranylgeranyl- protein transferase type I by administering a compound that is a dual inhibitor of both of those prenyl-protein transferases.
- the invention also provides for a method of identifying such a compound, the method comprising a modified inhibitory assay that incorporates a modulator anion that alters the in vitro potency of prenyl-protein transferase inhibitors in a way that predicts their potency in vivo, thus providing convenient identification of compounds that possess such in vivo activity.
- FIGURES 1A and IB Effect of ⁇ -glycerol phosphate on IC50 of
- the present invention relates to a method of inhibiting prenyl-protein transferases which comprises administering to a mammal in need thereof a pharmaceutically effective amount of a prenyl-protein transferase inhibitor which is efficacious in vivo as an inhibitor of geranylgeranyl-protein transferase type I (GGTase-I).
- a prenyl-protein transferase inhibitor which is efficacious in vivo as an inhibitor of geranylgeranyl-protein transferase type I (GGTase-I).
- Such an inhibitor is characterized by: a) an IC 50 (a measurement of in vitro inhibitory activity) of less than about 5 ⁇ M against transfer of a geranylgeranyl residue to a protein or peptide substrate comprising a CAAX motif by geranylgeranyl-protein transferase type I in the presence of a modulating anion.
- the inhibitor used in the instant method may be further characterized by one or both: b) an IC 50 (a measurement of in vitro inhibitory activity) of less than about 1 ⁇ M against transfer of a farnesyl residue to a protein or
- F peptide substrate comprising a CAAX motif by farnesyl-protein transferase; and c) an IC 50 (a measurement of in vitro inhibitory activity) of less than about 100 nM against the anchorage independent growth of H-ras- transformed mammalian fibroblasts.
- the inhibitor compounds useful in the instant method are also useful in the treatment of cancer and other proliferative disorders in mammals in need thereof.
- the inhibitor compounds have inhibitory concentrations (IC50) of less than about 1 ⁇ M against GGTase-I in the presence of a modulating anion.
- IC50 inhibitory concentrations
- such compounds have inhibitory concentrations (IC50) of less than about 500 nM against GGTase-I in the presence of a modulating anion.
- IC50 inhibitory concentrations
- IC50 inhibitory concentrations
- IC50 inhibitory concentrations
- IC50 inhibitory concentrations
- IC50 inhibitory concentrations
- a preferred cancer is one which is characterized by mutated K4B-Ras.
- the compound useful in the methods of the instant inventions is characterized by an IC 50 (a measurement of in vitro inhibitory activity) of less than about 500 nM, but greater than about 5 nM against transfer of a geranylgeranyl residue to a protein or peptide substrate comprising a CAAX motif by geranylgeranyl-protein transferase type I in the presence of a modulating anion.
- IC 50 a measurement of in vitro inhibitory activity
- the prenyl-protein transferases that are being inhibited by the instant method are both farnesyl-protein transferase and geranylgeranyl-protein transferase type I.
- the invention also relates to a method of identifying a prenyl-protein transferase inhibitor which is efficacious in vivo as an inhibitor of geranylgeranyl-protein transferase type I (GGTase-I).
- the instant method comprises the step of determining the inhibitory activity of a test compound against GGTase-I in a novel modified in vitro enzymatic assay.
- the modified GGTase-I inhibition assay of the instant invention comprises an anion at a concentration that modulates the in vitro GGTase-I inhibitory potency of the prenyl-protein transferase inhibitor.
- the prenyl-protein transferase inhibitor which is efficacious in vivo as an inhibitor of GGTase-I is characterized by an increased potency in vitro against GGTase-I in the instant modified assay when compared to its potency in the absence of the modulating anion.
- the ratio of the inhibitory activities in the presence vs the absence of the modulating anion may also provide useful mechanistic information on the interaction of the inhibitory compound with GGTase-I.
- the IC 50 (a measurement of in vitro inhibitory activity) of the compound against transfer of a geranylgeranyl residue to a protein or peptide substrate comprising a CAAX motif by geranylgeranyl-protein transferase type
- I in the presence of a modulating anion is greater than 5 fold lower than the IC50 against said transfer of a geranylgeranyl residue in the absence of a modulating anion. It is more preferred in this embodiment that the compound in the presence of a modulating anion has greater than 7 fold lower IC50. It is more preferred that the compound in the presence of a modulating anion has greater than 10 fold lower IC50- It is still more preferred in this embodiment that the compound in the presence of a modulating anion has greater than 25 fold lower IC50. It is most preferred in this embodiment that the compound in the presence of a modulating anion has greater than 150 fold lower IC50.
- the IC 50 (a measurement of in vitro inhibitory activity) of the compound against transfer of a geranylgeranyl residue to a protein or peptide substrate comprising a CAAX motif by geranylgeranyl-protein transferase type I in the presence of a modulating anion is 5 fold or less lower than the IC50 against said transfer of a geranylgeranyl residue in the absence of a modulating anion.
- the assay for identifying compounds that inhibit geranylgeranyl-protein transferase type I activity comprises the steps of: a) reacting a protein or peptide substrate comprising a CAAX motif with geranylgeranyl pyrophosphate and geranylgeranyl-protein transferase type I in the presence of a test compound and further in the presence of a modulating anion; b) detecting whether the geranylgeranyl residue is incorporated into the protein or peptide substrate, in which the ability of the test compound to inhibit geranylgeranyl-protein transferase type I activity is indicated by a decrease in the incorporation of the geranylgeranyl residue into the protein or peptide substrate as compared to the amount of the geranylgeranyl residue incorporated into the protein or peptide substrate in the absence of the test substance.
- the modulating anion may be selected from any type of molecule containing an anion moiety.
- the modulating anion is selected from a phosphate or sulfate containing anion.
- modulating anions useful in the instant GGTase-I inhibition assay include adenosine 5'-triphosphate (ATP), 2'-deoxyadenosine 5'-triphosphate (dATP), 2'-deoxycytosine 5'-triphosphate (dCTP), ⁇ -glycerol phosphate, pyrophosphate, guanosine 5'-triphosphate (GTP), 2'-deoxyguanosine 5'-triphosphate (dGTP), uridine 5'- triphosphate, dithiophosphate, 3'-deoxythymidine 5'-triphosphate, tripolyphosphate, D-myo-inositol 1 ,4,5-triphosphate, chloride, guanosine 5'-monophosphate, 2'-deoxy
- the modulating anion is selected from adenosine 5'-triphosphate, 2'-deoxyadenosine 5'-triphosphate, 2'-deoxycytosine 5'-triphosphate, ⁇ -glycerol phosphate, pyrophosphate, guanosine 5'-triphosphate, 2'-deoxy guanosine 5'-triphosphate, uridine 5'-triphosphate, dithiophosphate, 3'-deoxythymidine 5'-triphosphate, tripolyphosphate, D-myo-inositol 1,4,5-triphosphate and sulfate.
- the modulating anion is selected from adenosine 5'-triphosphate, ⁇ -glycerol phosphate, pyrophosphate, dithiophosphate and sulfate.
- the extent to which the in vitro GGTase-I inhibitory potency of the prenyl-protein transferase inhibitor is increased in the presence of the modulating anion is dependent on the amount of anion that is added to the buffered assay system and the nature of the modulating anion. Preferably from about 0.1 mM to about 100 mM of the modulating anion is added to the buffered assay system. Most preferably, from about 1 mM to about 10 mM of the modulating anion is added.
- the protein or peptide substrate utilized in the instant assay may incorporate any CAAX motif that is geranylgeranylated by GGTase-I.
- CAAX will refer to such motifs that may be geranylgeranylated by GGTase-I.
- motifs include (the corresponding human protein is in parentheses): CVIM (K4B-Ras) (SEQ.ID.: 1), CVLL (mutated H-Ras) (SEQ.ID.: 2), CVVM (N-Ras) (SEQ.ID.: 3), CUM (K4A-Ras) (SEQ.ID.: 4), CLLL (Rap-IA) (SEQ.ID.: 5), CQLL (Rap-IB) (SEQ.ID.: 6), CSIM (SEQ.ID.: 7), CAIM (SEQ.ID.: 8), CKVL (SEQ.ID.: 9), CLIM (PFX) (SEQ.ID.: 10) and CVIL (Rap-2B) (SEQ.ID.: 14).
- the CAAX motif is CVIM (K4B-Ras) (
- CAAX containing protein or peptide substrates may also be farnesylated by farnesyl-protein transferase.
- CAAX is used to designate a protein or peptide substrate that incorporates four amino acid
- CAAX motifs include (the corresponding human protein is in parentheses): CVLS (H-ras) (SEQ.ID.: 11), CVIM (K4B-
- Ras (SEQ.ID.: 1), CVVM (N-Ras) (SEQ.ID.: 3) and CNIQ (Rap-2A) (SEQ.ID.: 15). It is understood that certain of the "CAAX F " containing protein or peptide substrates may also be geranylgeranylated by GGTase-I.
- Ras protein When a particular Ras protein is referred to herein by a term such as "K4B-Ras”, “N-Ras”, “H-Ras” and the like, such a term represents both the protein arising from expression of the corresponding wild type ras gene and various proteins arising from expression of ras genes containing various point mutations.
- a particular ras gene is referred to herein by a term such as “K4B-r ⁇ 5'", “N-ras”, “H-ras” and the like, such a term represents both the wild type ras gene and ras genes containing various point mutations.
- the compound identified by the instant method is also a potent in vivo farnesyl-protein transferase inhibitor. It has been surprisingly found that such a potent dual inhibitor is particularly useful as an in vivo inhibitor of the growth of cancer cells, particularly those cancers characterized by a mutated K4B- Ras protein, at concentrations of inhibitor that do not cause mechanism based toxicity. Mechanism-based toxicity of farnesyl-protein transferase inhibitors can be anticipated in rapidly proliferating tissues, for example, the bone marrow.
- Such an inhibitor can be identified by the steps of: a) assessing a test compound for its in vitro inhibitory activity against transfer of a geranylgeranyl residue to a protein or peptide substrate comprising a CAAX motif by geranylgeranyl-protein transferase in the presence of a modulating anion; b) assessing a test compound for its in vitro inhibitory activity against transfer of a farnesyl residue to a protein or peptide substrate
- F comprising a CAAX motif by farnesyl-protein transferase; and c) assessing the test compound for its ability to inhibit the anchorage independent growth of H-ras-transformed mammalian fibroblasts.
- the potent dual inhibitor identified by the instant method has an IC50 of less than about 100 nM against the anchorage independent growth of H-ras-transformed mammalian fibroblasts in a cell culture assay (referred to herein as the SALSA assay).
- SALSA assay a cell culture assay
- Other methods of assessing the ability of a test compound to inhibit the anchorage independent growth of ras-transformed mammalian fibroblasts have been previously described (eg. N. E. Kohl et al. Science, 260:1934-1937 (1993)).
- the potent dual inhibitor identified by the instant method has an IC50 of less than about 20 nM in the SALSA assay.
- the potent dual inhibitor has an inhibitory concentration (IC50) of less than about 1 ⁇ M against GGTase-I in the modified in vitro GGTase-I assay. More preferably such compounds have inhibitory concentrations (IC50) of less than about 500 nM against GGTase-I in the presence of a modulating anion. Preferably the potent dual inhibitor has an inhibitory concentration (IC50) of less than about
- the instant inhibitor has an inhibitory concentration (IC50) of less than about 100 nM against FPTase in the in vitro FPTase assay. Still more preferably, the instant inhibitor has an inhibitory concentration (IC50) of less than about 10 nM against FPTase in the in vitro FPTase assay.
- the potent dual inhibitor identified by the instant method has an IC50 of less than about 1 ⁇ M against the anchorage independent growth of H-ras-transformed mammalian fibroblasts in a cell culture assay (referred to herein as the SALSA assay), an inhibitory concentration (IC50) of less than about 1 ⁇ M against GGTase-I in the modified in vitro GGTase-I assay and an inhibitory concentration (IC50) of less than about 500 nM against a cell culture assay (referred to herein as the SALSA assay), an inhibitory concentration (IC50) of less than about 1 ⁇ M against GGTase-I in the modified in vitro GGTase-I assay and an inhibitory concentration (IC50) of less than about 500 nM against a cell culture assay (referred to herein as the SALSA assay), an inhibitory concentration (IC50) of less than about 1 ⁇ M against GGTase-I in the modified in vitro GGTase-
- F substrate comprising a CAAX motif by farnesyl-protein transferase
- K ⁇ a (hereafter K ⁇ a ) (determined as described in Example 10) is greater than 0.002 and less than 5,000.
- the term "apparent enzymologic K,” represents either the only enzymologic K, exhibited by a compound in the assay and calculations or, if multiple enzymologic K,'s are exhibited by a compound in the assay and calculations, then the lowest enzymologic K .
- the ratio of K a to IC is greater than 0.1 and less than 500. Most preferably, ratio of K ⁇ a to K ⁇ a is greater than 1 and less than 100.
- GGTase-I or farnesyl-protein transferase inhibiting compound refers to compounds which antagonize, inhibit or counteract the activities of: the gene coding GGTase-I or farnesyl- protein transferase or the proteins encoded by these genes.
- the preferred therapeutic effect provided by the instant composition is the treatment of cancer and specifically the inhibition of cancerous tumor growth and/or the regression of cancerous tumors.
- Cancers which are treatable in accordance with the invention described herein include cancers of the brain, breast, colon, genitourinary tract, prostate, skin, lymphatic system, pancreas, rectum, stomach, larynx, liver and lung. More particularly, such cancers include histiocytic lymphoma, lung adenocarcinoma, pancreatic carcinoma, colo-rectal carcinoma, small cell lung cancers, bladder cancers, head and neck cancers, acute and chronic leukemias, melanomas, and neurological tumors.
- composition of this invention is 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 instant composition to a mammal in need of such treatment.
- the composition is useful in the treatment of neurofibromatosis, which is a benign proliferative disorder.
- the composition of the instant invention is 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 composition may also be useful in the treatment and prevention of polycystic kidney disease (D.L. Schaffner et al.
- the instant compounds may also inhibit tumor angio- genesis, thereby affecting the growth of tumors (J. Rak et al. Cancer Research, 55:4575-4580 (1995)). Such anti-angiogenesis properties of the instant compounds may also be useful in the treatment of certain forms of vision deficit related to retinal vascularization.
- 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 instant compounds may also be useful as inhibitors of proliferation of vascular smooth muscle cells and therefore useful in the prevention and therapy of arteriosclerosis and diabetic vascular pathologies.
- the compounds of this invention may be administered to mammals, preferably humans, either alone or, preferably, in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice.
- the compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
- the pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
- compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
- Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
- excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, microcrystalline cellulose, sodium crosscarmellose, corn starch, or alginic acid; binding agents, for example starch, gelatin, polyvinyl- pyrrolidone or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.
- the tablets may be uncoated or they may be coated by known techniques to mask the unpleasant taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
- a water soluble taste masking material such as hydroxypropylmethyl- cellulose or hydroxypropylcellulose, or a time delay material such as ethyl cellulose, cellulose acetate buryrate may be employed.
- Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
- Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
- excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl- cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan
- the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
- Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
- the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
- compositions may be preserved by the addition of an anti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.
- Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
- an anti-oxidant such as ascorbic acid.
- the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions.
- the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
- Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
- the emulsions may also contain sweetening, flavouring agents, preservatives and antioxidants.
- Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
- sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
- Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
- compositions may be in the form of a sterile injectable aqueous solutions.
- acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
- the sterile injectable preparation may also be a sterile injectable oil-in-water microemulsion where the active ingredient is dissolved in the oily phase.
- the active ingredient may be first dissolved in a mixture of soybean oil and lecithin. The oil solution then introduced into a water and glycerol mixture and processed to form a microemulation.
- the injectable solutions or microemulsions may be introduced into a patient's blood-stream by local bolus injection.
- a continuous intravenous delivery device may be utilized.
- An example of such a device is the Deltec CADD-PLUSTM model 5400 intravenous pump.
- the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension for intramuscular and subcutaneous administration.
- This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
- the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil may be employed including synthetic mono- or diglycerides.
- fatty acids such as oleic acid find use in the preparation of injectables.
- Compounds of Formula A may also be administered in the form of a suppositories for rectal administration of the drug.
- These compositions can be prepared by mixing the drug with a suitable non- irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
- suitable non- irritating excipient include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
- topical use creams, ointments, jellies, solutions or suspensions, etc., containing the compound of Formula A are employed. (For purposes of this application, topical application shall include mouth washes and gargles.)
- the compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles and delivery devices, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art.
- the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
- the term "composition" is intended to encompass a product comprising the specified ingredients in the specific amounts, as well as any product which results, directly or indirectly, from combination of the specific ingredients in the specified amounts.
- the compounds identified by the instant method may also be co-administered with other well known therapeutic agents that are selected for their particular usefulness against the condition that is being treated.
- the instant compounds may be useful in combination with known anti-cancer and cytotoxic agents.
- the instant compounds may be useful in combination with agents that are effective in the treatment and prevention of neuro- fibromatosis, restinosis, polycystic kidney disease, infections of hepatitis delta and related viruses and fungal infections.
- the instant compounds may also be useful in combination with other inhibitors of parts of the signaling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation.
- the instant compounds may be utilized in combination with farnesyl pyrophosphate competitive inhibitors of the activity of farnesyl-protein transferase or in combination with a compound which has Raf antagonist activity.
- the instant compounds may also be co- administered with compounds that are selective inhibitors of geranylgeranyl protein transferase or selective inhibitors of farnesyl- protein transferase.
- the compounds of the instant invention may also be co-administered with other well known cancer therapeutic agents that are selected for their particular usefulness against the condition that is being treated. Included in such combinations of therapeutic agents are combinations of the instant prenyl-protein transferase inhibitors and an antineoplastic agent. It is also understood that the instant combination of antineoplastic agent and inhibitor of prenyl-protein transferase may be used in conjunction with other methods of treating cancer and/or tumors, including radiation therapy and surgery. If formulated as a fixed dose, such combination products employ the combinations of this invention within the dosage range described below and the other pharmaceutically active agent(s) within its approved dosage range. Combinations of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a multiple combination formulation is inappropriate.
- Radiation therapy including x-rays or gamma rays which are delivered from either an externally applied beam or by implantation of tiny radioactive sources, may also be used in combination with an inhibitor of prenyl-protein transferase alone to treat cancer.
- compounds of the instant invention may also be useful as radiation sensitizers, as described in WO 97/38697, published on October 23, 1997, and herein incorporated by reference.
- the instant compounds may also be useful in combination with other inhibitors of parts of the signaling pathway that links cell surface growth factor receptors to nuclear signals initiating cellular proliferation.
- the instant compounds may be utilized in combination with farnesyl pyrophosphate competitive inhibitors of the activity of farnesyl-protein transferase or in combination with a compound which has Raf antagonist activity.
- the instant compounds may also be useful in combination with an integrin antagonist for the treatment of cancer, as described in U.S. Ser. No. 09/055,487, filed April 6, 1998, which is incorporated herein by reference.
- an integrin antagonist refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to an integrin(s) that is involved in the regulation of angiogenisis, or in the growth and invasiveness of tumor cells.
- the term refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the ⁇ v ⁇ 3 integrin, which selectively antagonize, inhibit or counteract binding of a physiological ligand to the ⁇ v ⁇ 5 integrin, which antagonize, inhibit or counteract binding of a physiological ligand to both the ⁇ v ⁇ 3 integrin and the v ⁇ 5 integrin, or which antagonize, inhibit or counteract the activity of the particular integrin(s) expressed on capillary endothelial cells.
- the term also refers to antagonists of the ⁇ v ⁇ 6, ⁇ v ⁇ 8, ⁇ l ⁇ l, 2 ⁇ l, ⁇ 5 ⁇ l, ⁇ 6 ⁇ l and ⁇ 6 ⁇ 4 integrins.
- the term also refers to antagonists of any combination of v ⁇ 3, ⁇ v ⁇ 5, ⁇ v ⁇ 6, ⁇ v ⁇ 8, ⁇ l ⁇ l, ⁇ 2 ⁇ l, ⁇ 5 ⁇ l, ⁇ 6 ⁇ l and ⁇ 6 ⁇ 4 integrins.
- the instant compounds may also be useful with other agents that inhibit angiogenisis and thereby inhibit the growth and invasiveness of tumor cells, including, but not limited to angiostatin and endostatin.
- a suitable amount of a prenyl-protein transferase inhibitor are administered to a mammal undergoing treatment for cancer. Administration occurs in an amount of each type of inhibitor of between about 0.1 mg/kg of body weight to about 60 mg/kg of body weight per day, preferably of between 0.5 mg/kg of body weight to about 40 mg/kg of body weight per day.
- a particular therapeutic dosage that comprises the instant composition includes from about 0.0 lmg to about lOOOmg of a prenyl-protein transferase inhibitor.
- the dosage comprises from about lmg to about lOOOmg of a prenyl-protein transferase inhibitor.
- antineoplastic agent examples include, in general, microtubule-stabilising agents (such as paclitaxel (also known as Taxol®), docetaxel (also known as Taxotere®), or their derivatives); alkylating agents, anti-metabolites; epidophyllotoxin; an antineoplastic enzyme; a topoisomerase inhibitor; procarbazine; mitoxantrone; platinum coordination complexes; biological response modifiers and growth inhibitors; hormonal/anti-hormonal therapeutic agents and haematopoietic growth factors.
- microtubule-stabilising agents such as paclitaxel (also known as Taxol®), docetaxel (also known as Taxotere®), or their derivatives)
- alkylating agents such as paclitaxel (also known as Taxol®), docetaxel (also known as Taxotere®), or their derivatives)
- alkylating agents such as paclitaxel (also known as Taxol®), docetaxel (
- Example classes of antineoplastic agents include, for example, the anthracycline family of drugs, the vinca drugs, the mitomycins, the bleomycins, the cytotoxic nucleosides, the taxanes, the epothilones, discodermolide, the pteridine family of drugs, diynenes and the podophyllotoxins.
- Particularly useful members of those classes include, for example, doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloro- methotrexate, mitomycin C, porfiromycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or podo-phyllotoxin derivatives such as etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine, leurosine, paclitaxel and the like.
- antineoplastic agents include estramustine, cisplatin, carboplatin, cyclophosphamide, bleomycin, gemcitibine, ifosamide, melphalan, hexamethyl melamine, thiotepa, cytarabin, idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT-11, topotecan, ara-C, bicalutamide, flutamide, leuprolide, pyridobenzoindole derivatives, interferons and interleukins.
- Rla is selected from: hydrogen or Cl-C6 alkyl
- Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, RlOO-, -N(R1°)2 or C2-C6 alkenyl, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, RlOO-, or -N(RlO)2;
- R 3 and R 4 selected from H and CH3;
- R2 is selected from H; unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl,
- R2 and R3 are optionally attached to the same carbon atom;
- R6 and R ⁇ are independently selected from:
- R6a is selected from:
- R8 is independently selected from: a) hydrogen, b) C 1 -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -C6 perfluoroalkyl, F, Cl, RlOO-, R10C(O)NR1°-, CN, N ⁇ 2, (R10)2N-C(NR10)-, RlOC(O)-, -N(RlO)2, or Rl l ⁇ C(O)NRl0-, and c) C1-C6 alkyl substituted by -C6 perfluoroalkyl, Rl°0-, Rl0C(O)NRl0-, (R10) 2 N-C(NR10)-, RlOC(O)-, -N(RlO)2, or Rl
- R ⁇ a is hydrogen or methyl
- RlO is independently selected from hydrogen, C1-C6 alkyl, C1-C6 perfluoroalkyl, 2,2,2-trifluoroethyl, benzyl and aryl;
- RU is independently selected from C1-C6 alkyl and aryl
- V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if Al is S(0) m and V is not hydrogen if A is a bond, n is 0 and A ⁇ is S(0)m;
- a unsubstituted or substituted group selected from aryl, heteroaryl, arylmethyl, heteroarylmethyl, arylsulfonyl, heteroarylsulfonyl, wherein the substituted group is substituted with one or more of the following: a) Cl-4 alkyl, unsubstituted or substituted with:
- Rla is selected from: hydrogen or Cl-C alkyl
- R b is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, RlOO-, -N(R1°)2 or C2-C6 alkenyl, c) Cl-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, heterocycle, cycloalkyl, alkenyl, RlOO-, or -N(RlO) 2 ;
- Rlc is selected from: a) hydrogen, b) unsubstituted or substituted Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RlOO-, Rl lS(0) m -, Rl°C(O)NRl0-, (Rl0) 2 N-C(O)-, CN, (RlO)2N-C(NRlO)-, RlOc(O)-, RlO ⁇ C(O)-, N3, -N(RlO)2, and RHOC(O)-NR10-, and c) unsubstituted or substituted aryl;
- R3 and R4 independently selected from H and CH3;
- R2 is selected from H; ORlO; NR 6 R 7
- NR 6 R 7 o and R , R3 and R4 are optionally attached to the same carbon atom;
- R6 and R7 are independently selected from: H; Cl-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle, unsubstituted or substituted with: a) Cl-4 alkoxy, b) halogen, or c) aryl or heterocycle;
- R6a is selected from:
- R8 is independently selected from: a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, RlOO-, R10C(O)NR10-, CN, N ⁇ 2,
- R9a is hydrogen or methyl
- RlO is independently selected from hydrogen, C1-C6 alkyl, C1-C6 perfluoroalkyl, 2,2,2-trifluoroethyl, benzyl and aryl;
- Rl 1 is independently selected from C1-C6 alkyl and aryl;
- Rl2 is selected from: H; unsubstituted or substituted Cl-8 alkyl, unsubstituted or substituted aryl or unsubstituted or substituted heterocycle, wherein the substituted alkyl, substituted aryl or substituted heterocycle is substituted with one or more of:
- halogen e) CN, f) aryl or heteroaryl, g) perfluoro-Cl-4 alkyl, h) SR6a S(0)R6a S ⁇ 2R 6a 2) C3-6 cycloalkyl,
- V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if A is S(0)m and V is not hydrogen if Al is a bond, n is 0 and A is S(0)m;
- Y is selected from: a) hydrogen, b) RlOO-, Rl lS(0)m-, R 10 C(O)NRl0-, (R10) 2 N-C(O)-, CN, N ⁇ 2, (R1°)2N-C(NR10)-, R12C(0)-, RlO ⁇ C(O)-, N3, F, -N(RlO)2, or Rl l ⁇ C(O)NRl0-, c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, RlOO-, R!0C(O)NR10-, (Rl0)2N-C(O)-, RlOC(O)- and RlO ⁇ C(O)-;
- Z is an unsubstituted or substituted aryl, wherein the substituted aryl is substituted with one or more of the following: 1) Cl-4 alkyl, unsubstituted or substituted with: a) Cl-4 alkoxy, b) NR6R7 5 c) C3-6 cycloalkyl, d) aryl, substituted aryl or heterocycle, e) HO, f) -S(0) m R 6a , or g) -C(0)NR6R7,
- n 0, 1, 2, 3 or 4
- p 0, 1, 2, 3 or 4
- r 0 to 5, provided that r is 0 when V is hydrogen; and v is 0, 1 or 2;
- Rl is independently selected from: hydrogen or C1-C6 alkyl
- R is independently selected from: a) hydrogen, b) substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3-C10 cycloalkyl, RlOO- or C2-C6 alkenyl
- R3 is selected from: a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by
- R4 and R5 are independently selected from: a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by
- R6 is independently selected from: a) hydrogen, b) substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C1-C6 alkyl, C2-C6 alkenyl,
- R7 is independently selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, and e) C1-C alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, indolyl, quinolinyl, isoquinolinyl, and thienyl; R8 is selected from: a) hydrogen, b) C 1 -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -C6 perfluoroalkyl, F, Cl, RlOO-, R10C(O)NR10-, CN, N ⁇ 2,
- R9 is selected from: a) hydrogen, b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F,
- Rl l ⁇ C(O)NRl0- and c) C1-C6 alkyl unsubstituted or substituted by C1-C6 perfluoroalkyl, F, Cl, RlOO-, Rl lS(0) m -, R 10 C(O)NRl0 . , CN, (RlO)2N-C(NRlO)-, R10C(O)-, RlO ⁇ C(O)-, _N(R10) 2 , or Rl 10C(0)NR10- ;
- RlO is independently selected from hydrogen, C1-C6 alkyl, C1-C6 perfluoroalkyl, 2,2,2-trifluoroethyl, benzyl and aryl;
- Rl 1 is independently selected from C1-C alkyl and aryl
- R 2 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkyl substituted with C ⁇ 2Rl°, C1-C6 alkyl substituted with aryl, C1-C6 alkyl substituted with substituted aryl, -C6 alkyl substituted with heterocycle, C1-C6 alkyl substituted with substituted heterocycle, aryl and substituted aryl;
- A3 is selected from: a bond, -C(0)NR7-, -NR7C(0)-, -S(0)2NR7-,
- a 4 is selected from: a bond, O, -N(R 7 )- or S;
- V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, and provided that V is not hydrogen if Al is S(0)m and V is not hydrogen if Al is a bond, n is 0 and A is S(0) m ;
- Z is independently (Rl)2 or O
- n 0, 1, 2, 3 or 4
- p 0, 1, 2, 3 or 4
- q is 0 or 1
- r is 0 to 5, provided that r is 0 when V is hydrogen;
- Rla is selected from: hydrogen or Cl-C6 alkyl
- Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, Rl°0-, -N(R 10 )2 or C2-C6 alkenyl, c) C1-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, RlOO-, or -N(RlO)2;
- R2a, R2b and R3 are independently selected from: a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by C2-C6 alkenyl, RlOO-, Rl lS(0) m -, R 10 C(O)NRl0-, CN, N3,
- R5 is hydrogen
- R8 is selected from: a) hydrogen, b) C 1 -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -C6 perfluoroalkyl, F, Cl, RlOO-, R10C(O)NR10-, CN, N02,
- R9 is independently selected from C1-C6 alkyl and aryl
- RIO is independently selected from hydrogen, C1-C6 alkyl, C1-C perfluoroalkyl, 2,2,2-trifluoroethyl, benzyl and aryl;
- RU is independently selected from C1-C6 alkyl, benzyl and aryl;
- V is selected from: a) hydrogen, b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c) aryl, d) C1-C2O alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and e) C2-C20 alkenyl, provided that V is not hydrogen if Al is S(0) m and V is not hydrogen if Al is a bond, n is 0 and A2 is S(0)m; Z is H2 or O; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is independently 0, 1, 2, 3 or 4; and r is 0 to 5, provided that r is 0 when V is hydrogen;
- Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, RlOO-, -N(Rl°)2 or C2-C6 alkenyl, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, Rl°0-, or -N(R 10 )2;
- R2 is selected from H; unsubstituted or substituted aryl or C 1-5 alkyl, unbranched or branched, unsubstituted or substituted with one or more of: 1) aryl,
- SR6a is independently selected from: Cl-4 alkyl, aryl, and heteroaryl, unsubstituted or substituted with: a) Cl-4 alkoxy, b) halogen, c) perfluoro-C 1 -4 alkyl, or d) aryl or heteroaryl;
- R6a is selected from: Cl-4 alkyl, unsubstituted or substituted with: a) Cl_4 alkoxy, or b) aryl or heteroaryl;
- R8 is independently selected from: a) hydrogen, b) C 1 -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -C6 perfluoroalkyl, F, Cl, RlOO-, R10C(O)NR10-, CN, N ⁇ 2, (RlO) 2 N-C(NRlO)-, RlOC(O)-, -N(RlO)2, or Rl l ⁇ C(O)NRl0-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, RlOO-,
- RIO is independently selected from hydrogen, C1-C6 alkyl, C1-C perfluoroalkyl, 2,2,2-trifTuoroethyl, benzyl and aryl;
- RU is independently selected from C1-C6 alkyl and aryl
- Z is an unsubstituted or substituted group selected from aryl, arylmethyl and arylsulfonyl, wherein the substituted group is substituted with one or more of the following: a) Cl-4 alkyl, unsubstituted or substituted with: Cl-4 alkoxy, NR 6 R7, C3-6 cycloalkyl, unsubstituted or substituted aryl, heterocycle, HO, -S(0)mR ⁇ a , or
- inhibitors of farnesyl-protein transferase are illustrated by the formula Il-a:
- Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, RlOO-, -N(R 10 )2 or C2-C6 alkenyl, c) Cl-C6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, heterocycle, cycloalkyl, alkenyl, RlOO-, or -N(RlO) 2 ;
- Rlc is selected from: a) hydrogen, b) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, RlOO-, Rl lS(0)m-, Rl°C(O)NRl0-, (RlO)2N-C(0)-, CN, (RlO) 2 N-C(NRlO)-, RlOC(O)-, RlO ⁇ C(O)-, N3, -N(RlO)2, and Rl 1OC(O)-NR10-, and c) unsubstituted or substituted aryl;
- R6, R7 and R7 are independently selected from:
- R ⁇ a is selected from:
- R8 is independently selected from: a) hydrogen, b) C l -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -C6 perfluoroalkyl, F, Cl, RlOO-, R10C(O)NR10-, CN, NO2, (RlO)2N-C(NRlO)-, RlOc(O)-, -N(RlO)2, or
- RIO is independently selected from hydrogen, C1-C6 alkyl, C1-C6 perfluoroalkyl, 2,2,2-trifluoroethyl, benzyl and aryl;
- RU is independently selected from C1-C6 alkyl and substituted or unsubstituted aryl
- Rl2 is selected from: H; unsubstituted or substituted Cl-8 alkyl, unsubstituted or substituted aryl or unsubstituted or substituted heterocycle, wherein the substituted alkyl, substituted aryl or substituted heterocycle is substituted with one or more of:
- Y is selected from: a) hydrogen, b) RlOO-, Rl lS(0) ⁇ r, R 10 C(O)NRl0-, (R1°)2N-C(0)-, CN, N02, (R1°)2N-C(NR10)-, R12C(0)-, RlO ⁇ C(O)-, N3, F, -N(RlO)2, or Rl l ⁇ C(O)NRl0-, c) unsubstituted or substituted C1-C6 alkyl wherein the substituent on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, RlOO-, R1°C(O)NR10-, (RlO)2N-C(0)-, RlOC(O)- and RlO ⁇ C(O)-;
- Z is an unsubstituted or substituted aryl, wherein the substituted aryl is substituted with one or more of the following: 1) Cl-4 alkyl, unsubstituted or substituted with: a) Cl-4 alkoxy, b) NR6R7, c) C3-6 cycloalkyl, d) aryl, substituted aryl or heterocycle, e) HO, f) -S(0) m R6a or g) -C(0)NR6R7,
- inhibitors of farnesyl-protein transferase are illustrated by the formula Ill-a:
- R2 is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, RlOO-, -N(R1°)2 or C2-C6 alkenyl, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, RlOO-, or -N(RlO)2;
- R3 is selected from: a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by C2-C6 alkenyl, RlOO-, Rl lS(0) m -, R1°C(0)NR10-, CN, N3, (R10) 2 N-C(NR10)-, RlOc(O)-, -N(RlO)2, or R11OC(O)NR10-, c) substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3-C10 cycloalkyl,
- R4 and R5 are independently selected from: a) hydrogen, b) C1-C6 alkyl unsubstituted or substituted by Rl°0- c) substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C3-C10 cycloalkyl,
- R6 is independently selected from: a) hydrogen, b) substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, C1-C6 alkyl, C2-C6 alkenyl,
- R7 is independently selected from a) hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted or substituted heterocycle, d) unsubstituted or substituted cycloalkyl, and e) C1-C6 alkyl substituted with hydrogen or an unsubstituted or substituted group selected from aryl, heterocycle and cycloalkyl; wherein heterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, indolyl, quinolinyl, isoquinolinyl, and thienyl;
- R8 is independently selected from: a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C6 perfluoroalkyl, F, Cl, RlOO-, R10C(O)NR10-, CN, NO2, (RlO)2N-C(NRlO)-, RlOc(O)-, -N(RlO)2, or R11OC(O)NR10-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, Rl°0-, Rl0C(O)NRl0-, (R10) 2 N-C(NR10)-, RlOc(O)-, -N(RlO)2, or Rl l ⁇ C(O)NRl0- ;
- RlO is independently selected from hydrogen, C1-C alkyl, C1-C6 perfluoroalkyl, 2,2,2-trifluoroethyl, benzyl and aryl;
- RU is independently selected from C1-C6 alkyl and aryl
- Rl2 is independently selected from hydrogen, Cl-C ⁇ alkyl, C1-C6 alkyl substituted with CO2RIO, C1-C6 alkyl substituted with aryl, C1-C6 alkyl substituted with substituted aryl, C1-C6 alkyl substituted with heterocycle, C1-C6 alkyl substituted with substituted heterocycle, aryl and substituted aryl;
- A3 is selected from: a bond, -C(0)NR7-, -NR7C(0)-, -S(0)2NR7-,
- Rib is independently selected from: a) hydrogen, b) aryl, heterocycle, cycloalkyl, Rl°0-, -N(R1°)2 or C2-C6 alkenyl, c) Cl-C6 alkyl unsubstituted or substituted by aryl, heterocycle, cycloalkyl, alkenyl, RlOO-, or -N(RlO)2;
- R2a and R2b are independently selected from: a) hydrogen, b) Cl-C6 alkyl unsubstituted or substituted by
- R5 is hydrogen
- R is independently selected from: a) hydrogen, b) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl, RlOO-, R10C(O)NR10-, CN, N02, (RlO) 2 N-C(NRlO)-, RlOC(O)-, -N(RlO)2, or Rl l ⁇ C(O)NRl0-, and c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, Rl°0-,
- RlO is independently selected from hydrogen, Q-C6 alkyl, substituted or unsubstituted C1-C6 aralkyl and substituted or unsubstituted aryl;
- RU is independently selected from C1-C6 alkyl, benzyl and aryl;
- alkyl refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 15 carbon atoms unless otherwise defined. It may be straight, branched or cyclic. Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl. Preferred cycloalkyl groups include cyclopentyl and cyclohexyl.
- substituted alkyl refers to a straight, branched or cyclic alkyl group as defined above, substituted with 1-3 groups as defined with respect to each variable.
- Heteroalkyl refers to an alkyl group having from 2-15 carbon atoms, and interrupted by from 1-4 heteroatoms selected from O, S and N.
- alkenyl refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 15 carbon atoms and at least one carbon to carbon double bond. Preferably one carbon to carbon double bond is present, and up to four non- aromatic (non- resonating) carbon-carbon double bonds may be present. Examples of alkenyl groups include vinyl, allyl, iso-propenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,
- alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted when a substituted alkenyl group is provided.
- alkynyl refers to a hydrocarbon radical straight, branched or cyclic, containing from 2 to 15 carbon atoms and at least one carbon to carbon triple bond. Up to three carbon-carbon triple bonds may be present.
- Preferred alkynyl groups include ethynyl, propynyl and butynyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkynyl group may contain triple bonds and may be substituted when a substituted alkynyl group is provided.
- Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and like groups as well as rings which are fused, e.g., naphthyl and the like.
- Aryl thus contains at least one ring having at least 6 atoms, with up to two such rings being present, containing up to 10 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms.
- the preferred aryl groups are phenyl and naphthyl.
- Aryl groups may likewise be substituted as defined below.
- Preferred substituted aryls include phenyl and naphthyl substituted with one or two groups.
- "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. Examples of aryl groups include phenyl, naphthyl, anthracenyl, biphenyl, tetrahydronaphthyl, indanyl, phenanthrenyl and the like.
- heteroaryl refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, O, S or N, in which a carbon or nitrogen atom is the point of attachment, and in which one additional carbon atom is optionally replaced by a heteroatom selected from O or S, and in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms.
- the heteroaryl group is optionally substituted with up to three groups. Heteroaryl thus includes aromatic and partially aromatic groups which contain one or more heteroatoms.
- Examples of this type are thiophene, purine, imidazopyridine, pyridine, oxazole, thiazole, oxazine, pyrazole, tetrazole, imidazole, pyridine, pyrimidine, pyrazine and triazine.
- Examples of partially aromatic groups are tetrahydro- imidazo[4,5-c]pyridine, phthalidyl and saccharinyl, as defined below.
- 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.
- heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydro-benzothienyl, dihydrobenzothiopyranyl, dihydrobenzothio-pyranyl sulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazoly
- heterocycle is selected from imidazolyl, 2-oxopyrrolidinyl, piperidyl, pyridyl and pyrrolidinyl.
- substituted aryl substituted heterocycle
- substituted cycloalkyl are intended to include the cyclic group which is substituted with 1 or 2 substituents selected from the group which includes but is not limited to F, Cl, Br, CF3, NH2, N(Ci-C6 alkyl)2, N ⁇ 2, CN, (C1-C6 alkyl)0-, -OH, (C1-C6 alkyl)S(0)m-, (Ci-C ⁇ alkyl)C(0)NH-, H2N-C(NH)-, (C1-C6 alkyl)C(O)-, (Ci-C6 alkyl)OC(O)-, N3,(Ci-C6 alkyl)OC(O) NH- and -C20 alkyl.
- amino acids which are disclosed are identified both by conventional 3 letter and single letter abbreviations as indicated below:
- CAAX the letter “A” represents an aliphatic amino acid and is not limited to alanine.
- the compounds used in the present method 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.
- named amino acids are understood to have the natural "L" stereoconfiguration
- cyclic moieties When R2 and R3 are combined to form - (CH2)u -, cyclic moieties are formed. Examples of such cyclic moieties include, but are not limited to:
- cyclic moieties may optionally include a heteroatom(s).
- heteroatom-containing cyclic moieties include, but are not limited to:
- cyclic moieties are formed.
- examples of such cyclic moieties include, but are not limited to:
- 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., RlO, Z, n, etc.
- -N(RlO)2 represents -NHH, -NHCH3, -NHC2H5, etc. It is understood that 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.
- the pharmaceutically acceptable salts of the compounds of this invention can be synthesized from the compounds of this invention which contain a basic moiety by conventional chemical methods. Generally, the salts are prepared 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.
- Peptidyl compounds useful in the instant methods can be synthesized from their constituent amino acids by conventional peptide synthesis techniques, and the additional methods described below. Standard methods of peptide synthesis are disclosed, for example, in the following works: Schroeder et al, "The Peptides", Vol. I, Academic Press 1965, or Bodanszky et al, “Peptide Synthesis", Interscience Publishers, 1966, or McOmie (ed.) "Protective Groups in Organic Chemistry” , Plenum Press, 1973, or Barany et al, "The Peptides: Analysis, Synthesis, Biology” 2, Chapter 1, Academic Press, 1980, or Stewart et al, "Solid Phase Peptide Synthesis", Second Edition, Pierce Chemical Company, 1984.
- compositions may be prepared from the active ingredients in combination with pharmaceutically acceptable carriers.
- Non-toxic salts include conventional non-toxic salts or quarternary ammonium salts formed, e.g., from non-toxic inorganic or organic acids.
- 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, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
- the pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt- forming inorganic or organic acid or base, in a suitable solvent or solvent combination.
- the prenyl transferase inhibitors of formula (I) can be synthesized in accordance with Schemes 1-11, in addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures.
- Substituents R, R a and Rb, as shown in the Schemes, represent the substituents R2, R3 ; R4 ? a nd R5; however their point of attachment to the ring is illustrative only and is not meant to be limiting.
- Piperazin-5-ones can be prepared as shown in Scheme 1.
- the protected suitably substituted amino acid IV can be converted to the corresponding aldehyde V by first forming the amide and then reducing it with LAH.
- Reductive amination of Boc-protected amino aldehydes V gives rise to compound VI.
- the intermediate VI can be converted to a piperazinone by acylation with chloroacetyl chloride to give VII, followed by base-induced cyclization to VIII.
- Deprotection, followed by reductive alkylation with a protected imidazole carboxalde- hyde leads to IX, which can be alkylated with an arylmethylhalide to give the imidazolium salt X.
- Final removal of protecting groups by either solvolysis with a lower alkyl alcohol, such as methanol, or treatment with triethylsilane in methylene chloride in the presence of trifluoroacetic acid gives the final product XI.
- the intermediate VIII can be reductively alkylated with a variety of aldehydes, such as XII.
- 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 (Scheme 2).
- the reductive alkylation can be accomplished at pH 5-7 with a variety of reducing agents, such as sodium triacetoxyborohydride or sodium cyanoborohydride in a solvent such as dichloroethane, methanol or dimethylformamide.
- the product XIII can be deprotected to give the final compounds XIV with trifluoroacetic acid in methylene chloride.
- the final product XIV is isolated in the salt form, for example, as a trifluoroacetate, hydrochloride or acetate salt, among others.
- the product diamine XIV can further be selectively protected to obtain XV, which can subsequently be reductively alkylated with a second aldehyde to obtain XVI. Removal of the protecting group, and conversion to cyclized products such as the dihydroimidazole XVII can be accomplished by literature procedures.
- the imidazole acetic acid XVIII can be converted to the acetate XIX by standard procedures, and XIX can be first reacted with an alkyl halide, then treated with refluxing methanol to provide the regiospecifically alkylated imidazole acetic acid ester XX (Scheme 3).
- Hydrolysis and reaction with piperazinone VIII in the presence of condensing reagents such as l-(3-dimethylaminopropyl)- 3-ethylcarbodiimide (EDC) leads to acylated products such as XXI.
- the piperazinone VIII is reductively alkylated with an aldehyde which also has a protected hydroxyl group, such as XXII in Scheme 4, the protecting groups can be subsequently removed to unmask the hydroxyl group (Schemes 4, 5).
- 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 XXIV.
- the fully deprotected amino alcohol XXV can be reductively alkylated (under conditions described previously) with a variety of aldehydes to obtain secondary amines, such as XXVI (Scheme 5), or tertiary amines.
- the Boc protected amino alcohol XXIII can also be utilized to synthesize 2-aziridinylmethylpiperazinones such as XXVII (Scheme 6). Treating XXIII with 1 , 1 '-sulfonyldiimidazole and sodium hydride in a solvent such as dimethylformamide led to the formation of aziridine XXVII. The aziridine reacted in the presence of a nucleophile, such as a thiol, in the presence of base to yield the ring-opened product XXVIII.
- a nucleophile such as a thiol
- piperazinone VIII can be reacted with aldehydes derived from amino acids such as O-alkylated tyrosines, according to standard procedures, to obtain compounds such as XXX (Scheme 7).
- 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.
- Scheme 8 illustrates the use of an optionally substituted homoserine lactone XXXIII to prepare a Boc-protected piperazinone XXXVII.
- Intermediate XXXVII may be deprotected and reductively alkylated or acylated as illustrated in the previous Schemes.
- the hydroxyl moiety of intermediate XXXVII may be mesylated and displaced by a suitable nucleophile, such as the sodium salt of ethane thiol, to provide an intermediate XXXVIII.
- Intermediate XXXVII may also be oxidized to provide the carboxylic acid on intermediate IXL, which can be utilized form an ester or amide moiety.
- N-Aralkyl-piperazin-5-ones can be prepared as shown in Scheme 9. Reductive amination of Boc-protected amino aldehydes V (prepared from III as described previously) gives rise to compound XL. This is then reacted with bromoacetyl bromide under Schotten-Baumann conditions; ring closure is effected with a base such as sodium hydride in a polar aprotic solvent such as dimethylformamide to give XLI. The carbamate protecting group is removed under acidic conditions such as trifluoroacetic acid in methylene chloride, or hydrogen chloride gas in methanol or ethyl acetate, and the resulting piperazine can then be carried on to final products as described in Schemes 1-7.
- the isomeric piperazin-3-ones can be prepared as described in Scheme 10.
- the imine formed from arylcarboxamides XLII and 2-aminoglycinal diethyl acetal (XLIII) can be reduced under a variety of conditions, including sodium triacetoxyborohydride in dichloroethane, to give the amine XLIV.
- Amino acids I can be coupled to amines XLIV under standard conditions, and the resulting amide XLV when treated with aqueous acid in tetrahydrofuran can cyclize to the unsaturated XLVI.
- Catalytic hydrogenation under standard conditions gives the requisite intermediate XL VII, which is elaborated to final products as described in Schemes 1-7.
- Amino acids of the general formula IL which have a sidechain not found in natural amino acids may be prepared by the reactions illustrated in Scheme 11 starting with the readily prepared imine XL VIII.
- Reactions used to generate the compounds of the formula (II) are prepared by employing reactions as shown in the Schemes 16- 37, in addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures.
- Substituents R a and Rb, as shown in the Schemes, represent the substituents R2, R3, R4 ? a nd R5; substituent "sub” represents a suitable substituent on the substituent Z.
- the point of attachment of such substituents to a ring is illustrative only and is not meant to be limiting.
- the protected piperidine intermediate LIII can be deprotected and reductively alkylated with aldehydes such as l-trityl-4-imidazolyl-carboxaldehyde or 1-trityl- 4-imidazolylacetaldehyde, to give products such as LVI.
- aldehydes such as l-trityl-4-imidazolyl-carboxaldehyde or 1-trityl- 4-imidazolylacetaldehyde
- the trityl protecting group can be removed from LVI to give LVII, or alternatively, LVI can first be treated with an alkyl halide then subsequently deprotected to give the alkylated imidazole LVIII.
- the deprotected intermediate LIII can also be reductively alkylated with a variety of other aldehydes and acids as shown above in Schemes 4-7.
- Scheme 18 An alternative synthesis of the hydroxymethyl intermediate LIV and utilization of that intermediate in the synthesis of the instant compounds which inco ⁇ orate the preferred imidazolyl moiety is illustrated in Scheme 18.
- Scheme 19 illustrates the reductive alkylation of intermediate LIV to provide a 4-cyanobenzylimidazolyl substituted piperidine.
- the cyano moiety may be selectively hydrolyzed with sodium borate to provide the corresponding amido compound of the instant invention.
- Scheme 20 alternative preparation of the methyl ether intermediate LV and the alkylation of LV with a suitably substituted imidazolylmethyl chloride to provide the instant compound.
- Preparation of the homologous l-(imidazolylethyl)piperidine is illustrated in Scheme 21.
- Scheme 24 illustrates the synthesis of the instant compounds wherein the moiety Z is attached directly to the piperidine ring.
- the piperidone LIX is treated with a suitably substituted phenyl Grignard reagent to provide the gem disubstituted piperidine LX.
- Deprotection provides the key intermediate LXI.
- Intermediate LXI may be acetylated as described above to provide the instant compound LXII (Scheme 25).
- the protected piperidine LX may be dehydrated and then hydroborated to provide the 3- hydroxypiperidine LXIII.
- This compound may be deprotected and further derivatized to provide compounds of the instant invention (as shown in Scheme 27) or the hydroxyl group may be alkylated, as shown in Scheme 26, prior to deprotection and further manipulation.
- the dehydration product may also be catalytically reduced to provide the des-hydroxy intermediate LXV, as shown in Scheme 28, which can be processed via the reactions illustrated in the previous Schemes.
- Schemes 29 and 30 illustrate further chemical manipulations of the 4-carboxylic acid functionality to provide instant compounds wherein the substituent Y is an acetylamine or sulfonamide moiety.
- Scheme 31 illustrates inco ⁇ oration of a nitrile moiety in the 4-position of the piperidine of the compounds of formula II.
- the hydroxyl moiety of a suitably substituted 4-hydroxypiperidine is substituted with nitrile to provide intermediate LXVI, which can undergo reactions previously described in Schemes 17-21.
- Scheme 32 illustrates the preparation of several pyridyl intermediates that may be utilized with the piperidine intermediates such as compound LI in Scheme 16 to provide the instant compounds.
- Scheme 33 shows a generalized reaction sequence which utilizes such pyridyl intermediates.
- Scheme 36 illustrated preparation of compounds of the formula A wherein Y is hydrogen.
- suitably substituted isonipecotic acid may be treated with N,0-dimethylhydroxylamine and the intermediate LXXII reacted with a suitably substituted phenyl Grignard reagent to provide intermediate LXXIII. That intermediate may undergo the reactions previously described in Schemes 17-21 and may be further modified by reduction of the phenyl ketone to provide the alcohol LXXIV.
- R CH , CH 3 CH 2
- LXXIX sub Compounds of this invention of formula (III) are prepared by employing the reactions shown in the following Reaction Schemes 38-51, in addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures.
- Some key bond-forming and peptide modifying reactions are:
- Reaction B Preparation of a reduced peptide subunit by reductive alkylation of an amine by an aldehyde using sodium cyanoborohydride or other reducing agents.
- Reaction C Alkylation of a reduced peptide subunit with an alkyl or aralkyl halide or, alternatively, reductive alkylation of a reduced peptide subunit with an aldehyde using sodium cyanoborohydride or other reducing agents.
- Reaction E Preparation of a reduced subunit by borane reduction of the amide moiety.
- Reaction B Preparation of reduced peptide subunits by reductive alkylation
- R and RB are R2, R3 or R5 as previously defined; RC and RD are R7 or R 2; XL is a leaving group, e.g., Br, I- or MsO-; and Ry is defined such that R7 is generated by the reductive alkylation process.
- Reaction Scheme 43 illustrates inco ⁇ oration of the cyclic amine moiety, such as a reduced prolyl moiety, into the compounds of the formula III of the instant invention.
- Reduction of the azide LXXXI provides the amine LXXXII, which may be mono- or di-substituted using techniques described above.
- inco ⁇ oration of a naphthylmethyl group and an acetyl group is illustrated.
- Reaction Scheme 45 illustrates the use of protecting groups to prepare compounds of the instant invention wherein the cyclic amine contains an alkoxy moiety.
- the hydroxy moiety of key intermediate LXXXIVa may be further converted to a fluoro or phenoxy moiety, as shown in Reaction Scheme 46.
- Intermediates LXXXV and LXXXVI may then be further elaborated to provide the instant compounds.
- Reaction Scheme 474 illustrates syntheses of instant compounds wherein the variable -(CR ⁇ qA ⁇ CR ⁇ nR ⁇ is a suitably substituted ⁇ -hydroxybenzyl moiety.
- the protected intermediate aldehyde is treated with a suitably substituted phenyl Grignard reagent to provide the enantiomeric mixture LXXXVII.
- Treatment of the mixture with 2-picolinyl chloride allows chromatographic resolution of compounds LXXXVIII and IXC. Removal of the picolinoyl group followed by deprotection provides the optically pure intermediate XC which can be further processed as described hereinabove to yield the instant compounds.
- Reaction Scheme 50 illustrates the syntheses of imidazole-containing intermediates wherein the attachment point of the -(CR ⁇ 2)p-C(Z)- moiety to W (imidazolyl) is through an imidazole ring nitrogen.
- Reaction Scheme 51 illustrates the synthesis of an intermediate wherein an R2 substituent is a methyl.
- prenyl transferase inhibitors of formula (A) can be synthesized in accordance with Reaction Scheme below, in addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures. Some key reactions utilized to form the aminodiphenyl moiety of the instant compounds are shown.
- the reactions may be employed in a linear sequence to provide the compounds of the invention or they may be used to synthesize fragments which are subsequently joined by the alkylation reactions described in the Reaction Scheme.
- a method of forming the benzophenone intermediates is a Stille reaction with an aryl stannane. Such amine intermediates may then be reacted as illustrated hereinabove with a variety of aldehydes and esters/acids.
- 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 l-triphenylmethyl-4-(hydroxymethyl)- imidazole
- Step B Preparation of l-triphenylmethyl-4-(acetoxymethyl)- imidazole
- Step C Preparation of l-(4-cyanobenzyl)-5-(acetoxymethyl)- imidazole hydrobromide
- the filtrate was concentrated in vacuo to a volume 100 mL, reheated at 60°C for another two hours, cooled to room temperature, and concentrated in vacuo to provide a pale yellow solid. All of the solid material was combined, dissolved in 500 mL of methanol, and warmed to 60°C. After two hours, the solution was reconcentrated in vacuo to provide a white solid which was triturated with hexane to remove soluble materials. Removal of residual solvents in vacuo provided the titled product hydrobromide as a white solid which was used in the next step without further purification.
- Step D Preparation of l-(4-cyanobenzyl)-5-(hydroxymethyl)- imidazole
- Step E Preparation of l-(4-cyanobenzyl)-5- imidazolecarboxaldehyde
- the amine hydrochloride from Step F (ca. 282 mmol, crude material prepared above) was taken up in 500 mL of THF and 500 mL of sat. aq. NaHC ⁇ 3 soln., cooled to 0°C, and ⁇ i-tert- butylpyrocarbonate (61.6 g, 282 mmol) was added. After 30 h, the reaction was poured into EtOAc, washed with water and brine, dried (Na2S ⁇ 4), filtered, and concentrated in vacuo to provide the titled carbamate as a brown oil which was used in the next step without further purification.
- Step H Preparation of N-[2-(t -butoxycarbamoyl)ethyl]-N-(3- chlorophenyl)-2-chloroacetamide
- Step K Preparation of l-(3-chlorophenyl)-4-[l-(4- cyanobenzyl)imidazolylmethyl]-2-piperazinone dihydrochloride
- Examples 2-5 (Table 1) were prepared using the above protocol, which describes the synthesis of the structurally related compound 1 -(3-chlorophenyl)-4-[ 1 - (4-cy anobenzy l)-imidazolylmethyl] -2- piperazinone dihydrochloride.
- Step F the appropriately substituted aniline was used in place of 3-chloroaniline.
- Step G Preparation of l-(4-cyano-3-methoxybenzyl)-5-
- the titled product was prepared by reacting the bromide from Step F (21.7 g, 96 mmol) with the imidazole product from Step B of Example 1 (34.9 g, 91 mmol) using the procedure outlined in Step C of Example 1.
- the crude product was triturated with hexane to provide the titled product hydrobromide (19.43 g, 88% yield).
- Step H Preparation of l-(4-cyano-3-methoxybenzyl)-5-
- the titled product was prepared by hydrolysis of the acetate from Step G (19.43 g, 68.1 mmol) using the procedure outlined in Step D of Example 1.
- the crude titled product was isolated in modest yield (11 g, 66% yield). Concentration of the aqueous extracts provided solid material (ca. 100 g) which contained a significant quantity of the titled product , as judged by H NMR spectroscopy.
- Step I Preparation of l-(4-cyano-3-methoxybenzyl)-5- imidazolecarboxaldehyde
- Step J Preparation of l-(3-chlorophenyl)-4-[l-(4-cyano-3- methoxybenzyl)imidazolylmethyl]-2-piperazinone dihydrochloride
- the titled product was prepared by reductive alkylation of the aldehyde from Step I (859 mg, 3.56 mmol) and the amine (hydrochloride) from Step K of Example 1 (800 mg, 3.24 mmol) using the procedure outlined in Step H of Example 1. Purification by flash column chromatography through silica gel (50%-75% acetone CH 2 C1 2 ) and conversion of the resulting white foam to its dihydrochloride salt provided the titled product as a white powder
- l-(3-trifluoromethoxy-phenyl)-2-piperazinone hydrochloride was prepared from 3 -trifluoromethoxy aniline using Steps F-J of Example 1. This amine (1.75 g, 5.93 mmol) was coupled to the aldehyde from Step I of Example 6 (1.57 g, 6.52 mmol) using the procedure outlined in Step H of Example 1.
- the titled product was prepared by reductive alkylation of the aldehyde from Step E of Example 1 (124 mg, 0.588 mmol) and 4-aminobenzophenone (116 mg, 0.588 mmol) using the procedure outlined in Step K of Example 1. Purification by flash column chromatography through silica gel (2-6% MeOH/CH 2 Cl 2 ) and conversion to the hydrochloride salt provided the titled product as a white solid (126 mg, 50% yield). FAB ms (m+1) 393.11. Anal. Calc. for C25H2 ⁇ N5 ⁇ *1.40HCl « 0.40H2 ⁇ :
- Step B N-t-Butoxycarbonyl-4(R)-hvdroxyproline methyl ester
- Step C N-t-Butoxycarbonyl-4(R)-t-butyldimethylsilyloxy proline methyl ester
- Step D N-t-Butoxycarbonyl-4(R)-t-butyldimethylsilyloxy-2(S)- hydroxymethylpyrrolidine
- Step E N-t-Butoxycarbonyl-4(R)-t-butyldimethylsilylox methanesulfonyloxymethylpyrrolidine
- Step F Preparation of N-t-Butoxycarbonyl-4(R)-t- butyldimethylsilyloxy-2(S)-azidomethylpyrrolidine
- a solution of N-t-butoxycarbonyl-4(S)-t-butyldimethylsilyloxy-2(S)-methane- sulfonyloxy methyl pyrrolidine(10.40g, 25.39mmol) and tetrabutyl- ammonium azide (8.18g, 28.7mmol) in toluene (250ml) was stirred at 80°C for 5 hr.
- Step G Preparation of N-t-Butoxycarbonyl-4(R)-t- butyldimethylsilyloxy-2(S)-aminomethylpyrrolidine
- N-t-butoxycarbonyl-4(R)-t- butyldimethylsilyloxy-2(S)-azidomethylpyrrolidine 9.06g, 25.39mmol
- EtOAc 120ml
- argon argon
- 10% palladium on carbon (1.05g) added.
- the flask was evacuated and stirred under an atmosphere of hydrogen (49 psi) for 16hrs.
- the hydrogen was replaced by argon, the catalyst removed by filtration and the solvent evaporated in vacuo.
- Step H Preparation of N-t-Butoxycarbonyl-4(R)-t- butyldimethylsilyloxy-2(S)- ⁇ N'-3- chlorobenzyl ⁇ aminomethylpyrrolidine
- Step I Preparation of N-t-Butoxycarbonyl-4(R)-t- butyldimethylsilyloxy-2(S)- ⁇ N'-3-chlorobenzyl-N'- acetyl ⁇ - aminomethylpyrrolidine
- Step K N-t-Butoxycarbonyl-4(R)-benzyloxyoxy-2(S)- ⁇ N'- acetyl-N'-3-chlorobenzyl ⁇ aminomethylpyrrolidine
- Step M Preparation of lH-Imidazole-4- acetic acid methyl ester hydrochloride.
- Step N Preparation of l-(Triphenylmethyl)-lH-imidazol-4- ylacetic acid methyl ester.
- Step P Preparation of (l-(4-Cyanobenzyl)-lH-imidazol-5-yl)- ethanol
- Step 0 l-(4-Cyanobenzyl)-imidazol-5-yl-ethylmethanesulfonate
- Step R N ⁇ l-(4-Cyanobenzyl)-lH-imidazol-5-ylethyl ⁇ -4(R)- benzyloxyoxy-2(S)- ⁇ N'-acetyl-N'-3- chlorobenzy 1 ⁇ aminomethylpyrrolidine
- Prenyl-protein transferase activity assays are carried out at 30 °C unless noted otherwise.
- a typical reaction contains (in a final volume of 50 ⁇ L): [ 3 H] farnesyl diphosphate or [ 3 H] geranylgeranyl diphosphate, Ras protein , 50 mM HEPES, pH 7.5, 5 mM MgCl 2 , 5 mM dithiothreitol, 10 ⁇ M ZnCl 2 , 0.1% poly ethylenegly col (PEG) (15,000-20,000 mw) and isoprenyl-protein transferase.
- PEG poly ethylenegly col
- the FPTase employed in the assay is prepared by recombinant expression as described in Omer, C.A., Krai, A.M., Diehl, R.E., Prendergast, G.C., Powers, S., Allen, CM., Gibbs, J.B. and Kohl, N.E. (1993) Biochemistry 32:5167-5176.
- the geranylgeranyl-protein transferase-type I employed in the assay is prepared as described in U.S. Pat. No. 5,470,832, incorporated by reference.
- reactions are initiated by the addition of isoprenyl-protein transferase and stopped at timed intervals (typically 15 min) by the addition of 1 M HCI in ethanol (1 mL). The quenched reactions are allowed to stand for 15 m (to complete the precipitation process). After adding 2 mL of 100% ethanol, the reactions are vacuum-filtered through Whatman GF/C filters. Filters are washed four times with 2 mL aliquots of 100% ethanol, mixed with scintillation fluid (10 mL) and then counted in a Beckman LS3801 scintillation counter.
- inhibitors are prepared as concentrated solutions in 100% dimethyl sulfoxide and then diluted 20-fold into the enzyme assay mixture.
- Substrate conditions for inhibitor IC50 determinations are as follows: FTase, 650 nM Ras-CVLS (SEQ.ID.NO.: 11), 100 nM farnesyl diphosphate; GGPTase-I, 500 nM Ras-CAIL (SEQ.ID.NO.: 12), 100 nM geranylgeranyl diphosphate.
- enzymologic K s values for inhibition of either FPTase or GGPTase-I can be determined using the methodology described by I. H. Segel ("Enzyme Kinetics", pages 342-345; Wiley and Sons, New York, N.Y. (1975) and references cited therein).
- the modified geranylgeranyl-protein transferase inhibition assay is carried out at room temperature.
- a typical reaction contains (in a final volume of 50 ⁇ L): [ 3 H] geranylgeranyl diphosphate, biotinylated Ras peptide, 50 mM HEPES, pH 7.5, a modulating anion (for example 10 mM glycerophosphate or 5mM ATP), 7 mM MgCl 2 , 10 ⁇ M ZnCl 2 ,
- the GGTase- type I enzyme employed in the assay is prepared as described in U.S. Pat. No. 5,470,832, inco ⁇ orated by reference.
- the Ras peptide is derived from the K4B-Ras protein and has the following sequence: biotinyl-GKKKKKKSKTKCVIM (single amino acid code) (SEQ.ID.NO.: 13).
- Reactions are initiated by the addition of GGTase and stopped at timed intervals (typically 15 min) by the addition of 200 ⁇ L of a 3 mg/mL suspension of streptavidin SPA beads (Scintillation Proximity Assay beads, Amersham) in 0.2 M sodium phosphate, pH 4, containing 50 mM EDTA, and 0.5% BSA. The quenched reactions are allowed to stand for 2 hours before analysis on a Packard TopCount scintillation counter.
- streptavidin SPA beads Scintillation Proximity Assay beads
- assays are run as described above, except inhibitors are prepared as concentrated solutions in 100% dimethyl sulfoxide and then diluted 25-fold into the enzyme assay mixture.
- GGTase and inhibitors are preincubated for one hour and reactions are initiated by the addition of peptide substrate, following methodology described by J.F. Morrison, CT. Walsh, Adv. Enzymol. & Related Areas Mol. Biol., 61 201-301 (1988).
- IC 5 o values are determined with Ras peptide near K M concentrations.
- Enzyme and substrate concentrations for inhibitor IC 50 determinations are as follows: 75 pM GGTase-I, 1.6 ⁇ M
- Ras peptide 100 nM geranylgeranyl diphosphate.
- enzymologic K values for inhibition of GGPTase-I can be determined using the methodology described by I. H. Segel ("Enzyme Kinetics", pages 342-345; Wiley and Sons, New York, N.Y. (1975) and references cited therein).
- the cell lines used in this assay consist of either Ratl or NIH3T3 cells transformed by either viral H-ras; an N-ras chimeric gene in which the C-terminal hypervariable region of viral-H-ras was substituted with the corresponding region from the N-ras gene; or ras-CVLL (SEQ.ID.NO.: 2), a viral-H-ras mutant in which the C- terminal exon encodes leucine instead of serine, making the encoded protein a substrate for geranylgeranylation by GGTase-I.
- the assay can also be performed using cell lines transformed with human H-ras, N-ras or K4B-ras.
- the assay is performed essentially as described in DeClue, J.E. et al., Cancer Research 51:712-717, (1991). Cells in 10 cm dishes at 50-75% confluency are treated with the test compound(s) (final concentration of solvent, methanol or dimethyl sulfoxide, is 0.1%). After 4 hours at 37°C, the cells are labeled in 3 ml methionine-free DMEM supplemented with 10% regular DMEM, 2% fetal bovine serum, 400 ⁇ Ci[35S]methionine (1000 Ci/mmol) and test compound(s).
- lovastatin a compound that blocks Ras processing in cells by inhibiting the rate-limiting step in the isoprenoid biosynthetic pathway (Hancock, J.F. et al. Cell, 57: 1167 (1989); DeClue, J.E. et al. Cancer Res., 51:712 (1991); Sinensky, M. et al. J. Biol. Chem., 265: 19937 (1990)), serve as a positive control in this assay.
- the cells are lysed in 1 ml lysis buffer (1% NP40/20 mM HEPES, pH 7.5/5 mM MgCl2/lmM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 mM PMSF) and the lysates cleared by centrifugation at 100,000 x g for 45 min.
- the media is removed, the cells washed, and 3 ml of media containing the same or a different test compound added. Following an additional 16 hour incubation, the lysis is carried out as above.
- the immunoprecipitates are washed four times with IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA/1% Triton X- 100.0.5% deoxycholate/0.1%/SDS/0.1 M NaCl) boiled in SDS-PAGE sample buffer and loaded on 13% acrylamide gels. When the dye front reached the bottom, the gel is fixed, soaked in Enlightening, dried and auto- radiographed. The intensities of the bands corresponding to prenylated and nonprenylated Ras proteins are compared to determine the percent inhibition of prenyl transfer to protein.
- IP buffer 20 nM HEPES, pH 7.5/1 mM EDTA/1% Triton X- 100.0.5% deoxycholate/0.1%/SDS/0.1 M NaCl
- SALSA Soft Agar-Like Surrogate Assay measures the inhibition of anchorage-independent growth by prenyl- transf erase inhibitors. Only transformed cells are able to grow anchorage-independently in the SALSA format. Additionally, cells growing in the SALSA format grow in clumps, resembling the colonies formed in soft agar. SALSA may been used to measure the growth inhibition by prenyl-transferase inhibitors in a variety of transformed cell lines, including Ratl fibroblasts transformed with viral-H-ras (H-ras/ratl), as well as a panel of human tumor cell lines (HTL's).
- SALSA is performed in 96-well plates that are coated with a thin film of the polymer, PolyHEMA (Poly(2-hydroxyethyl methacrylate)), which prevents cells from attaching to the plate.
- Ratl fibroblast cells transformed with v-Ha-ras (this cell line has been deposited in the ATCC on August 19, 1997 under the terms of the Budapest convention and has been given a designation of ATCC CRL-12387) are seeded at 5000 cells/well, grown for 4 hr, then vehicle or half-log dilutions of test compound (in either an 8 or 12 point titration) are added. The cells are then grown for 6 days at 37 degrees, without changing the growth media or adding fresh compound.
- cell growth is assessed via a colorimetric assay that measures the cleavage of the tetrazolium dye, MTT, to an insoluble pu ⁇ le formazan, a reaction dependent upon mitochondrial dehydrogenases.
- MTT tetrazolium dye
- the cells are incubated for 4 hr with 0.5 mg/ml MTT, and then SDS is added to 9% w/v to lyse the cells and solubilize the insoluble MTT-formazan.
- the amount of MTT metabolism is quantitated via spectrophotometric detection at 570 nM. Dose-inhibition curves and IC 50 's are determined.
- Rodent fibroblasts transformed with oncogenically mutated human Ha- ras or Ki-ras (10 6 cells/animal in 1 ml of DMEM salts) are injected subcutaneously into the left flank of 8-12 week old female nude mice (Harlan) on day 0.
- the mice in each oncogene group are randomly assigned to a vehicle, compound or combination treatment group. Animals are dosed subcutaneously starting on day 1 and daily for the duration of the experiment.
- the farnesyl-protein transferase inhibitor may be administered by a continuous infusion pump.
- Compound, compound combination or vehicle is delivered in a total volume of 0.1 ml. Tumors are excised and weighed when all of the vehicle-treated animals exhibited lesions of 0.5 - 1.0 cm in diameter, typically 11-15 days after the cells were injected. The average weight of the tumors in each treatment group for each cell line is calculated.
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Abstract
L'invention concerne un procédé pour inhiber les prényl-protéine-transférases et traiter le cancer, qui consiste à administrer à un mammifère un inhibiteur de prényl-protéine-transférase constituant un inhibiteur efficace in vivo de la géranylgéranyl-protéine-transférase de type I (GGTase-I). L'invention concerne aussi un procédé permettant d'inhiber la farnésyl-protéine-transférase et la géranylgéranyl-protéine-transférase de type I en administrant un composé qui est un double inhibiteur pour ces deux prényl-protéine-transférases. L'invention concerne en outre un procédé permettant d'identifier le composé susmentionné, qui consiste en un essai inhibiteur modifié comprenant un anion modulateur capable de modifier l'activité in vitro des inhibiteurs de prényl-protéine-transférase de manière à prévoir l'activité in vivo de ces inhibiteurs, moyennant quoi il est possible d'identifier aisément les composés possédant ladite activité in vivo.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
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US5734097P | 1997-08-27 | 1997-08-27 | |
US57340P | 1997-08-27 | ||
GBGB9724331.5A GB9724331D0 (en) | 1997-11-18 | 1997-11-18 | A method of treating cancer |
GB9724331 | 1997-11-18 | ||
PCT/US1998/017697 WO1999010523A1 (fr) | 1997-08-27 | 1998-08-26 | Procede de traitement du cancer |
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EP98944537A Withdrawn EP1009854A1 (fr) | 1997-08-27 | 1998-08-26 | Procede de traitement du cancer |
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EP (1) | EP1009854A1 (fr) |
JP (1) | JP2001518281A (fr) |
AU (1) | AU9205898A (fr) |
CA (1) | CA2301877A1 (fr) |
WO (1) | WO1999010523A1 (fr) |
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GB9809889D0 (en) | 1998-05-11 | 1998-07-08 | Univ Strathclyde | Prevention of restenosis |
WO2001066144A2 (fr) | 2000-03-08 | 2001-09-13 | Rhode Island Hospital, A Lifespan Partner | Therapie d'association de medicaments |
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US5185248A (en) * | 1990-05-08 | 1993-02-09 | E. R. Squibb & Sons, Inc. | Farnesyl-protein transferase assay for identifying compounds that block neoplastic transformation |
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1998
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- 1998-08-26 JP JP2000507831A patent/JP2001518281A/ja active Pending
- 1998-08-26 CA CA002301877A patent/CA2301877A1/fr not_active Abandoned
- 1998-08-26 EP EP98944537A patent/EP1009854A1/fr not_active Withdrawn
- 1998-08-26 WO PCT/US1998/017697 patent/WO1999010523A1/fr not_active Application Discontinuation
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CA2301877A1 (fr) | 1999-03-04 |
AU9205898A (en) | 1999-03-16 |
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