WO2000069830A1 - Diketodiazacyclic compounds, diazacyclic compounds and combinatorial libraries thereof - Google Patents
Diketodiazacyclic compounds, diazacyclic compounds and combinatorial libraries thereof Download PDFInfo
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- WO2000069830A1 WO2000069830A1 PCT/US2000/010841 US0010841W WO0069830A1 WO 2000069830 A1 WO2000069830 A1 WO 2000069830A1 US 0010841 W US0010841 W US 0010841W WO 0069830 A1 WO0069830 A1 WO 0069830A1
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- Prior art keywords
- fmoc
- group
- substituted
- phenyl
- phe
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 185
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 33
- -1 C2-C1Q alkenyl Chemical group 0.000 claims description 560
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 114
- 125000001145 hydrido group Chemical group *[H] 0.000 claims description 69
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 58
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 57
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 54
- 125000000217 alkyl group Chemical group 0.000 claims description 52
- 125000001424 substituent group Chemical group 0.000 claims description 49
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 44
- 125000004432 carbon atom Chemical group C* 0.000 claims description 40
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 38
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 36
- 229910052757 nitrogen Inorganic materials 0.000 claims description 35
- 125000001624 naphthyl group Chemical group 0.000 claims description 25
- 229920006395 saturated elastomer Polymers 0.000 claims description 25
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 24
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 24
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 23
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 21
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 21
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 21
- 125000005842 heteroatom Chemical group 0.000 claims description 20
- 229910052760 oxygen Inorganic materials 0.000 claims description 20
- 239000001301 oxygen Substances 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 20
- 229910052717 sulfur Inorganic materials 0.000 claims description 20
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 19
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 19
- 239000011593 sulfur Substances 0.000 claims description 19
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 18
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 17
- 125000002619 bicyclic group Chemical group 0.000 claims description 17
- 229910052799 carbon Inorganic materials 0.000 claims description 17
- 125000002950 monocyclic group Chemical group 0.000 claims description 17
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 15
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 15
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 claims description 14
- 125000003143 4-hydroxybenzyl group Chemical group [H]C([*])([H])C1=C([H])C([H])=C(O[H])C([H])=C1[H] 0.000 claims description 14
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 14
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- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- 125000003934 2-norbornylethyl group Chemical group [H]C([H])(*)C([H])([H])C1([H])C([H])([H])C2([H])C([H])([H])C([H])([H])C1([H])C2([H])[H] 0.000 claims description 7
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- 125000006352 iso-propylthiomethyl group Chemical group [H]C([H])([H])C([H])(SC([H])([H])*)C([H])([H])[H] 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- 125000006229 isopropoxyethyl group Chemical group [H]C([H])([H])C([H])(OC([H])([H])C([H])([H])*)C([H])([H])[H] 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 102000051367 mu Opioid Receptors Human genes 0.000 description 1
- FTQWRYSLUYAIRQ-UHFFFAOYSA-N n-[(octadecanoylamino)methyl]octadecanamide Chemical compound CCCCCCCCCCCCCCCCCC(=O)NCNC(=O)CCCCCCCCCCCCCCCCC FTQWRYSLUYAIRQ-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000006124 n-propyl sulfonyl group Chemical group 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000006501 nitrophenyl group Chemical group 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 229910003445 palladium oxide Inorganic materials 0.000 description 1
- JQPTYAILLJKUCY-UHFFFAOYSA-N palladium(ii) oxide Chemical compound [O-2].[Pd+2] JQPTYAILLJKUCY-UHFFFAOYSA-N 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 239000000816 peptidomimetic Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 108010073025 phenylalanylphenylalanine Proteins 0.000 description 1
- ASUOLLHGALPRFK-UHFFFAOYSA-N phenylphosphonoylbenzene Chemical group C=1C=CC=CC=1P(=O)C1=CC=CC=C1 ASUOLLHGALPRFK-UHFFFAOYSA-N 0.000 description 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000005544 phthalimido group Chemical group 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 230000001817 pituitary effect Effects 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- SXYFKXOFMCIXQW-UHFFFAOYSA-N propanedioyl dichloride Chemical compound ClC(=O)CC(Cl)=O SXYFKXOFMCIXQW-UHFFFAOYSA-N 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 229910052705 radium Inorganic materials 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001525 receptor binding assay Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 239000012508 resin bead Substances 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000007423 screening assay Methods 0.000 description 1
- 150000003334 secondary amides Chemical class 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- WSWCOQWTEOXDQX-MQQKCMAXSA-N sorbic acid group Chemical group C(\C=C\C=C\C)(=O)O WSWCOQWTEOXDQX-MQQKCMAXSA-N 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 125000004426 substituted alkynyl group Chemical group 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 125000003375 sulfoxide group Chemical group 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005329 tetralinyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000000101 thioether group Chemical group 0.000 description 1
- 125000005032 thiofuranyl group Chemical group S1C(=CC=C1)* 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 150000005671 trienes Chemical class 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 1
- 238000005533 tritiation Methods 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 108020001612 μ-opioid receptors Proteins 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/30—Oxygen or sulfur atoms
- C07D233/32—One oxygen atom
- C07D233/36—One oxygen atom with hydrocarbon radicals, substituted by nitrogen atoms, attached to ring nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/30—Oxygen or sulfur atoms
- C07D233/42—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
- C07D239/10—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/18—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D245/00—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms
- C07D245/04—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D245/00—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms
- C07D245/04—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
- C07D245/06—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems condensed with one six-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B40/00—Libraries per se, e.g. arrays, mixtures
- C40B40/04—Libraries containing only organic compounds
-
- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B50/00—Methods of creating libraries, e.g. combinatorial synthesis
- C40B50/14—Solid phase synthesis, i.e. wherein one or more library building blocks are bound to a solid support during library creation; Particular methods of cleavage from the solid support
-
- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B40/00—Libraries per se, e.g. arrays, mixtures
Definitions
- the invention relates to the synthesis of individual di- and tri-substituted-1, 4-diazacyclic compounds having 6- to 8-atoms in the cyclic ring, their corresponding 1 , 6-diketo-2 , 5-diazacyclic compounds and similar 1,4-diazacyclic ring compounds having one ring carbonyl gorup and 6-8 atoms in the ring, and libraries of such compounds.
- the present invention further relates to methods of preparing and using the libraries of compounds as well as individual compounds of the libraries.
- the process of discovering new therapeutically active compounds for a given indication involves the screening of all compounds from available compound collections. From the compounds tested one or more structure (s) is selected as a promising lead. A large number of related analogs are then synthesized in order to develop a structure-activity relationship and select one or more optimal compounds. With traditional one-at-a-time synthesis and biological testing of analogs, this optimization process is long and labor intensive. Adding significant numbers of new structures to the compound collections used in the initial screening step of the discovery and optimization process cannot be accomplished with traditional one-at-a-time synthesis methods, except over a time frame of months or even years. Faster methods are needed that allow the preparation of up to thousands of related compounds in a matter of days or a few weeks.
- Diketopiperazines are conformationally constrained scaffolds that are quite common in nature, and many natural products containing a diketopiperazine structure have been isolated that encompass a wide range of biological activities. Included in such compounds are inhibitors of the mammalian cell cycle reported by Cui et al . , J “ . Antibiot., 47:1202 (1996), inhibitors of plasminogen activator-1, and topoisomerase reported by Charlton et al . , P. Thromb. Haeomast . , 75:808 (1996) and Funabashi et al . , J. Antibiot . , 47:1202 (1994).
- Diketopiperazines have been reported by Terret et al . , Tetrahedron, 51:8135 (1995) to be useful as ligands to the neurokinin-2 receptor. Barrow et al . , Bioorg. Med . Chem . Lett . , 5:377 (1996) found diketopiperazines to be competitive antagonists to Substance P at the neurokinin-1 receptor. Because, diketopiperazine moieties are found in many biologically active compounds and are known to have useful therapeutic implications, there is a need to further study and develop large numbers of 2 , 3-diketopiperazine compounds and their analogues of larger ring size. This invention satisfies these needs and provides related advantages as well .
- the invention provides a rapid synthesis of (1- substituted or 1, 2-disubstituted) - (4-aminoalkyl) -1, 4- diazacyclic compounds having 6- to 8-atoms in the cyclic ring and the corresponding 1, 6-diketo- (2- substituted or 2 , 3-disubstituted) - (5-aminoalkyl) -2, 5- diazacyclic compounds and related cyclic amino amides and cyclic keto diamines of Formula I, hereinafter, and further provides combinatorial libraries that contain those compounds .
- the naming system used herein is understood to not be in conformance with naming systems usually used in organic chemistry, and relies upon the structural features common to all of the contemplated compounds as is discussed below.
- the numbering system used for these ring compounds begins with one of the carbonyl groups (when present) and continues around the ring to the second carbonyl group (when present) via the two ring nitrogen atoms so the ring nitrogen atoms have the same relative position numbers for all of the compounds embraced by Formula I.
- the carbonyl groups are generically numbered to be at the 1- and 6-positions of the ring.
- the carbonyl groups and their amido nitrogen atoms of those compounds have the same numbers when the ring contains six atoms as in a diketopiperazine compound, even though the carbonyl groups of such a compound are assigned the 2- and 3 -positions in a more usual system of nomenclature .
- Usual organic naming rules are followed for specific componds or libraries such as the 1, 4, 5-trisubstituted-2, 3 -diketopiperazines discussed in the examples.
- a first of the ring nitrogen atoms of a compound of Formula I, below, is bonded to a C 1 .-C 7 alkyl group that contains an amine substituent at the 2- through 7-position from that first amine.
- That first ring nitrogen is at ring position 5.
- that same nitrogen is at the 4-position of the ring.
- the second ring nitrogen can also be bonded to a substituent group.
- the second amine is at the 2-position for the group of compounds having the carbonyl groups and is at the 1- position for those compounds without the carbonyl groups.
- Compounds also typically contain a ring substituent at the 3 -position of a dicarbonyl compound and at the 2-position of a cyclic diamine.
- Exemplary structural formulas of some particularly preferred contemplated compounds are provided below based on structural Formulas II or III, hereinafter. Those formulas show the numbering system that is generally used, and in which q is one, and R al and R a2 and R bl and R b2 are all hydrido and x and y are both one so that the ring positions are more easily seen.
- the present invention contemplates individual compounds and synthetic combinatorial libraries of those compounds in which the compounds have a structure corresponding to that shown in Formula I, below, or a pharmaceutically acceptable salt thereof:
- q is an integer having a value of 1-7;
- W is a saturated or unsaturated chain of 2-4 carbon atoms that are bonded at each terminus of the chain to the depicted nitrogen atoms, wherein (1) zero, one or two of those carbon atoms of the chain is doubly bonded to an oxygen atom, (2) (a) each of the remaining carbon atoms of the chain is independently bonded to one or two substituents selected from the group consisting of a hydrogen atom (hydrido) , C ⁇ -CIQ alkyl, C]_-C ⁇ o substituted alkyl, C ⁇ -Cio phenylalkyl, C 7 ⁇ C ⁇ g substituted phenyalkyl, phenyl, substituted phenyl, C 3 -C 7 cycloalkyl, and a
- R 1 is selected from the group consisting of a hydrido, alkyl, C ⁇ -C ⁇ o substituted alkyl, C ⁇ _- C]_o phenylalkyl, C ⁇ f - ⁇ substituted phenyalkyl, phenyl, substituted phenyl, C 3 -C 7 cycloalkyl, and a C3-C 7 substituted cycloalkyl group.
- R 2 is selected from the group consisting of a c l " c 1 0 alkyl, C2 ⁇ C o alkenyl, benzyl, substituted benzyl, naphthyl, or substituted naphthyl group and preferably is a methyl, ethyl, benzyl, allyl, or naphthylmethyl group, and more preferably is a 2- naphthylmethyl group.
- R 2 is most preferably a methyl or benzyl group.
- R is selected from the group consisting of a hydrogen atom (hydrido) , C ⁇ -C ⁇ _o alkyl, C ⁇ -C ⁇ o substituted alkyl, C ⁇ -C ⁇ g phenylalkyl, C 7 -C ⁇ _ substituted phenylalkyl, phenyl, substituted phenyl, C 3 -C 7 cycloalkyl, and a C 3 -C 7 substituted cycloalkyl group.
- R is selected from the group consisting of a hydrido, C]_-C ⁇ o alkyl, C 2 -C 10 alkenyl, substituted alkyl, C 3 -C 7 substituted cycloalkyl, C 7 - C]_g phenylalkyl, C 7 ⁇ C]_g phenylalkenyl, C 7 ⁇ C ⁇ g phenylalkenyl and a C ⁇ - i Q substituted phenyl-alkenyl group.
- R 5 is selected from the group consisting of a hydrido, alkylaminocarbonyl, C ] _-C I _ Q alkylthiocarbonyl, arylaminocarbonyl, and an arylthiocarbonyl group.
- Another aspect of the invention contemplates individual compounds and synthetic combinatorial libraries of those compounds in which the compounds have a structure corresponding to that shown in Formula II, below, or a pharmaceutically acceptable salt thereof:
- R al , R a2 , R bl and R b2 are independently selected from the group consisting of a hydrido, C ⁇ _-
- Another aspect of the invention contemplates individual compounds and synthetic combinatorial libraries of those compounds in which the compounds have a structure corresponding to that shown in
- R ⁇ 1 , R 1 , R 2 , R 3 , R 4 and R 5 have the meanings provided above .
- R 5 is preferably hydrido in these compounds and libraries .
- the present invention relates to individual compounds and synthetic combinatorial libraries of those compounds, as well as the preparation and use of those compounds and libraries, in which the compounds have a structure corresponding to that shown in Formula I, below, or a pharmaceutically acceptable salt thereof :
- R 2 is selected from the group consisting of a ⁇ -C ⁇ o alkyl, C2-C1 0 alkenyl, benzyl, substituted benzyl, naphthyl, or substituted naphthyl group and preferably is a methyl, ethyl, benzyl, allyl, or naphthylmethyl group. More preferably, R 2 is a 2- naphthylmethyl group, and R 2 is most preferably a methyl or benzyl group.
- R 3 is selected from the group consisting of a hydrogen atom (hydrido), C ⁇ -C ⁇ o alkyl, CI-CJQ substituted alkyl, C ⁇ -C ⁇ g phenylalkyl, C 7 -C 1 5 substituted phenylalkyl, phenyl, substituted phenyl, C 3 -C 7 cycloalkyl, and a C 3 -C 7 substituted cycloalkyl group .
- That group can contain a chain of two, three or four carbon atoms, each of which can be substituted as described hereinafter.
- the terminal carbons of the chain are each bonded to one of the nitrogen atoms shown in Formula I so that the compound or library of compounds contains at least one ring that can contain six, seven or eight atoms in the ring.
- a more specific aspect of the invention contemplates individual compounds and synthetic combinatorial libraries of those compounds and their pharmaceutically acceptable salts in which the compounds have a structure corresponding to that shown in Formula II, below, or a pharmaceutically acceptable salt thereof:
- -R cl , -R c2 , -R c3 and -R c4 are independently selected from the group consisting of a hydrido, C ⁇ -C]_o alkyl, c l " c 10 substituted alkyl, phenylalkyl, C -CIQ substituted phenyalkyl, phenyl, substituted phenyl, C 3 -C 7 cycloalkyl, and a C 3 -C 7 substituted cycloalkyl group;
- x and y are independently zero or one, and the sum of x + y is zero, one or two;
- R a2 and R ⁇ 2 are absent when a double bond is present between the depicted carbon atoms.
- R ⁇ 1 are each also bonded to the same saturated or unsaturated mono or bicyclic ring.
- at least two fused rings are present, one is the ring shown in the formula and the second is bonded to R a ⁇ and R ⁇ 1 .
- That second ring can be monocyclic or bicyclic and can contain 5- to 8-members in each ring and zero to three heteroatoms in each ring that are independently oxygen, nitrogen or sulfur.
- Exemplary second rings include 1, 2-cyclohexylidene, 1,2- cyclooctylidene, o-phenylene, 3 , 4-furanylidene, 2,3- pyrazinylidene, and 2, 3-norbornenylidene.
- a double bond can also be present so that R a2 and R ⁇ 2 are both absent .
- Another aspect of the invention contemplates individual compounds and synthetic combinatorial libraries of those compounds and their pharmaceutically acceptable salts in which the compounds have a structure corresponding to that shown in Formula III, below, or a pharmaceutically acceptable salt thereof:
- q is an integer having a value of 1 through 7; x and y are independently zero or one, and the sum of x + y is zero, one or two;
- R l is selected from the group consisting of a hydrido, alkyl, C ⁇ _-C ⁇ o substituted alkyl, C ⁇ C ⁇ o phenylalkyl, C 7 -C ⁇ g substituted phenyalkyl, phenyl, substituted phenyl, C 3 -C 7 cycloalkyl, and a C 3 -C 7 substituted cycloalkyl group;
- R 3 is selected from the group consisting of a hydrido, C ⁇ -C ⁇ o alkyl, -CiQ substituted alkyl, C ⁇ Cig phenylalkyl, C 7 -C ⁇ g substituted phenylalkyl, phenyl, substituted phenyl, C 3 -C 7 cycloalkyl, and a C3-C7 substituted cycloalkyl group;
- R 4 is selected from the group consisting of C ] _- C ⁇ o alkyl, C 2 -C 10 alkenyl, Ci-C ⁇ g substituted alkyl, C 3 -C 7 substituted cycloalkyl, C 7 -C ⁇ phenylalkyl, C 7 - C ⁇ g phenylalkenyl, C 7 -C ] _g phenylalkenyl and a C 7 ⁇ C ⁇ substituted phenyl-alkenyl group; and
- the value of q is preferably one or two in each of the above Formulas, and is most preferably one.
- Exemplary compounds of each of those compound types of Formula I, and particularly for Formulas II and III, where q is one are shown below as Formulas IA, IIA and IIIA.
- R al and R ⁇ 1 when present as individual substituents, both be identical to minimize the presence of isomers. It is similarly preferred when R a ⁇ and R ⁇ l are present as bonds to a saturated or unsaturated carbocyclic or heterocyclic ring substituent that that substituent ring be symmetrically placed between the two ring nitrogen atoms .
- carbon atoms to which the R al and R ⁇ 1 groups are individually bonded can be bonded to each other via a single or double bond.
- Those two types of bonding are depicted in Formulas II and III by a single solid line, representing the single bond that must be minimally present, and one dotted line that represents another bond that can be present.
- R ⁇ 2 are both hydrido or are absent, R al and R* 31 are a before-described substituent or together form a ring structure and the other R groups are as described before.
- R 2 is selected from the group consisting of a hydrido, methyl, ethyl, allyl, benzyl, or a 2- naphthylmethyl substituent;
- R 2 is methyl
- R 3 is selected from the group consisting of a hydrido, methyl, benzyl, 3 -hydroxypropyl, 2 -butyl, 2- methylpropyl , methylsulfinylethyl , methylthioethyl, hydroxymethyl, 1-hydroxyethyl, 2-propyl, 4- hydroxybenzyl , propyl, butyl, cyclohexylmethyl, phenyl, and a 2-naphthylmethyl substituent;
- R 4 is selected from the group consisting of a 1- phenyl-1-cyclopropylmethyl, jn-tolylethyl , 3- fluorophenethyl , ( ⁇ , ⁇ , ⁇ -trifluoro-m-tolyl) ethyl, p- tolylethyl, 3 -methoxyphenethyl , 4-methoxyphenethyl,
- R 5 is hydrido.
- R groups are those defined immediately below:
- R 1 is selected from the group consisting of a hydrido, methyl, benzyl, 2 -butyl, N-methyl,N- benzylaminobutyl, N-methylaminobutyl, 2-methylpropyl, methylsulfinylethyl , methylthioethyl , hydroxymethyl , 1-hydroxyethyl, 2-propyl, 4-hydroxybenzyl, propyl, butyl, cyclohexylmethyl, phenyl, and a 2- naphthylmethyl substituent;
- R 2 is benzyl
- C2-C10 alkynyl denotes a radical such as ethynyl , propynyl , butynyl , pentynyl , hexynyl , heptynyl, decynyl and the like, as well as di- and triynes of straight and branched chains containing up to ten carbon atoms and at least one carbon-to-carbon (acetylenic) triple bond.
- C2-C10 substituted alkenyl and “C2-C10 substituted alkeynyl” denote that the above C ] _-C ] _ Q alkyl group and C2-C10 alkenyl and alkynyl groups are substituted by one or more, and preferably one or two, halogen, hydroxy, protected hydroxy, C 3 -C 7 cycloalkyl, C 3 -C 7 substituted cycloalkyl, naphthyl, substituted naphthyl, adamantyl , abietyl, thiofuranyl, indolyl, substituted indolyl, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, guanidino, (monosubstituted) guanidino, (disubstituted) guanidino, (disubstituted) guanidino, (tri
- Examples of the above substituted alkyl groups include the cyanomethyl, nitromethyl, chloromethyl, hydroxymethyl, tetrahydropyranyloxymethyl , trityloxymethyl, propionyloxymethyl, aminomethyl , carboxymethyl , allyloxycarbonylmethyl, allylcarbonyl- aminomethyl, carbamoyloxymethyl , methoxymethyl , ethoxymethyl , t-butoxymethyl , acetoxymethyl , chloromethyl, bromomethyl, iodomethyl , 6-hydroxy- hexyl, 2,4-dichloro (n-butyl) , 2-amino (isopropyl) , 2-carbamoyloxyethyl chloroethyl, bromoethyl, fluoroethyl, iodoethyl, chloropropyl, bromopropyl, fluoropropyl , iodopropyl and the like
- C 1 -C 4 alkoxy denotes groups that are ether groups containing up to four carbon atoms such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and like groups.
- a preferred C 1 -C 4 alkoxy group is methoxy.
- C3-C 7 cycloalkyl includes the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl rings.
- the substituent term "C 3 -C 7 substituted cycloalkyl” indicates an above cycloalkyl ring substituted by a halogen, hydroxy, protected hydroxy, phenyl, substituted phenyl, heterocycle, substituted heterocycle, C ⁇ -C ⁇ o alkyl, C 1 -C 4 alkoxy, carboxy, protected carboxy, amino, or protected amino .
- heterocyclic ring or “heterocycle” denotes an optionally substituted 5-membered or 6- membered ring that has 1 to 4 heteroatoms, such as oxygen, sulfur and/or nitrogen, in particular nitrogen either alone or in conjunction with sulfur or oxygen ring atoms.
- heteroatoms such as oxygen, sulfur and/or nitrogen, in particular nitrogen either alone or in conjunction with sulfur or oxygen ring atoms.
- C 7 -C 1 g phenylalkyl or "C 7 -C ⁇ g aralkyl” denotes a CI-CIQ alkyl group substituted at any position by a phenyl ring.
- Examples of such a group include benzyl, 2-phenylethyl, 3 -phenyl (n-prop- 1-yl) , 4-phenyl (hex-1-yl) , 3-phenyl (n-am-2-yl) , 3- phenyl (sec-butyl) , and the like.
- a preferred C 7 ⁇ C phenylalkyl group is the benzyl group.
- C 7 - Cig substituted phenylalkyl denotes an above C-J -C ⁇ Q phenylalkyl group substituted on C ⁇ -CIQ alkyl portion with one or more, and preferably one or two, groups chosen from halogen, hydroxy, protected hydroxy, keto, C 2 -C 3 cyclic ketal phenyl, amino, protected amino, C 1 -C 7 acyloxy, nitro, carboxy, protected carboxy, carbamoyl, carbarnoyloxy, cyano, N- (methyl- sulfonylamino) or C 1 -C 4 alkoxy, whose phenyl group can be substituted with 1 or 2 groups selecterd from the group consisting of halogen, hydroxy, protected hydroxy, nitro, C ⁇ -C ⁇ alkyl, C ⁇ -Cg substituted alkyl, C -C 4 alkoxy, carboxy, protected carboxy, carboxymethyl , protected carboxymethyl , hydroxy
- C 7 -C ⁇ g substituted phenylalkyl examples include groups such as 2 -phenyl-1-chloroethyl, 2- (4- methoxyphenyl) eth-l-yl, 2, 6-dihydroxy-4-phenyl (n-hex- 2-yl) , 5-cyano-3-methoxy-2-phenyl (n-pent-3-yl) , 3- (2, 6-dimethylphenyl) n-prop-1-yl, 4-chloro-3- aminobenzyl, 6- (4-methoxyphenyl) -3-carboxy (n-hex-1- yl) , 5- (4-aminomethyl-phenyl) -3- (aminomethyl) (n-pent- 2-yl), 5-phenyl-3-keto- (n-pent-1-yl) , 4- (4- aminophenyl) -4- (I .4-oxetanyl) (n-but-1-yl) , and the
- Substituents can the same as those as defined above in relation to C- -C ⁇ Q phenylalkyl and C 7 ⁇ C ⁇ g substituted phenylalkyl.
- a preferred C ⁇ -C- ⁇ , substituted phenylalkenyl is 3- (4-nitrophenyl) -2- propenyl .
- substituted phenyl specifies a phenyl group substituted at one or more positions, preferably at one or two positions, with moieties selected from the group consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, ⁇ -Cio alkyl, ⁇ -CIQ substituted alkyl, C 1 -C 4 alkoxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl , amino, protected anlino, (moaosubstituted) amino, protected (monosubstituted) amino, (disubstituted) amino, trifluoromethyl, N- (methylsulfonylamino) , or phenyl that is itself substituted or unsubstituted.
- substituted phenyl include a mono- or di (halo) phenyl group such as 4-chlorophenyl, 2,6- dichlorophenyl , 2 , 5-dichlorophenyl , 3,4- dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4- bromophenyl, 3 , 4-dibromophenyl, 3-chloro-4- fluorophenyl , 2 -fluorophenyl and the like; a mono or di (hydroxy) phenyl groups such as 4-hydroxyphenyl, 3- hydroxyphenyl, 2 , 4-dihydroxyphenyl , the protected hydroxy derivatives thereof and the like; a nitrophenyl group such as 3-or 4-nitrophenyl, a cyanophenyl group for example, 4-cyanopheny1 ; a mono- or di (lower alkyl) phenyl group such as 4-chlorophenyl, 2,6- dichlorophen
- substituted naphthyl specifies a naphthyl group substituted with one or more, and preferably one or two moieties selected from the group consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, ⁇ -CIQ alkyl, C 1 -C 4 alkoxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl , hydroxymethyl , protected hydroxymethyl, amino, protected amino, (monosubstituted) amino, protected
- substituted naphthyl examples include 2- (methoxy) naphthyl and 4- (methoxy) naphthyl .
- substituted indolyl specifies a indolyl group substituted, either at the nitrogen or carbon, or both, with one or more, and preferably one or two, moieties selected from the group consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, C 1 -C 10 alkyl, ⁇ -CIQ substituted alkyl, alkenyl, C 7 ⁇ C ⁇ phenylalkyl, 7 ⁇ C ⁇ g substituted phenylalkyl, Ci-C alkoxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, monosubstituted amino, or disubstituted amino.
- substituted indolyl includes such groups as 6-fluoro, 5-fluoro, 5-bromo,
- halo and halogen refer to the fluoro, chloro, bromo, or iodo groups.
- (monosubstituted) amino refers to an amino group with one substituent selected from the group consisting of phenyl, substituted phenyl, C]_-
- the (monosubstituted) amino can additionally have an amino-protecting group as encompassed by the term
- (disubstituted) amino refers to amino groups with two substituents selected from the group consisting of phenyl, substituted phenyl, C ⁇ -C ⁇ Q alkyl, and C 7 ⁇ C ⁇ arylalkyl wherein the latter three substituent terms are as described above.
- the two substituents can be the same or different.
- the terms " (monosubstituted) guanidino, " (disubstituted) guanidino. " and “ (trisubstituted) - guanidino” are used to mean that a guanidino group is substituted with one, two, or three substituents, respectively.
- the substituents can be any of those as defined above in relation to (monosubstituted) - amino and (disubstituted) amino and, where more than one substituent is present, the substituents can be the same or different
- amino-protecting group refers to one or more selectively removable substituents on the amino group commonly employed to block or protect the amino functionality.
- protected (monosubstituted) amino means there is an amino-protecting group on the monosubstituted amino nitrogen atom.
- protected carboxamide means there is an amino-protecting group present replacing the proton of the amido nitrogen so that there is no N-aLkylation.
- amino-protecting groups include the formyl ("For") group, the trityl group (Trt) , the phthalimido group, the trichloroacetyl group, the chloroacetyl , bromoacetyl , and iodoacetyl groups .
- Urethane blocking groups such as t-butoxy-carbonyl ("Boc"), 2- (4-biphenylyl) propyl (2) oxycarbonyl ("Bpoc”), 2- phenylpropyl (2) oxycarbonyl ( “Poc” ) , 2 - (4- xenyl) isopropoxycarbonyl, 1, 1-diphenylethyl (1) - oxycarbonyl , 1.1-diphenylpropyl (1) oxycarbonyl , 2- (3,5-dimethoxyphenyl) propyl (2) oxycarbonyl ( "Ddz” ) , 2-(p- 5 toluyl) propyl (2) oxycarbonyl, cyclopentanyl- oxycarbonyl, 1-methylcyclopentanyloxycarbonyl , cyclohexanyloxycarbonyl , 1-methylcyclohexanyl- oxycarbonyl, 2-methylcyclohexanyloxycarbonyl, 2- (4- toluy
- amino-protecting group employed is usually not critical so long as the derivatized amino group is stable to the conditions of the subsequent reactions and can be removed at the appropriate point without disrupting the remainder of the compound.
- Preferred amino-protecting groups are Boc and Fmoc.
- protected amino defines an amino group substituted with an amino-protecting group discussed above.
- carboxy-protecting group refers to one of the ester derivatives of the carboxylic acid group commonly employed to block or protect the carboxylic acid group while reactions are carried out on other functional groups on the compound.
- carboxylic acid protecting groups include 4-nitrobenzyl, 4-methoxy- benzyl, 3 , 4-dimethoxybenzyl, 2 , 4-dimethoxybenzyl, 2 , 4 , 6-trimethoxybenzyl , 2 , 4 , 6-trimethylbenzyl, pentamethylbenzyl, 3 , 4-methylene-dioxybenzyl, benzhydryl, 4, 4 ' -methoxytrityl, 4,4 I ,4''- trimethoxytrityl, 2-phenylprop-2-yl, trimethylsilyl, t-butyldimethylsilyl, 2,2, 2-trichloroethyl, ⁇ - (trimethylsilyl) ethyl, ⁇
- hydroxy-protecting group refers to readily cleavable groups bonded to hydroxyl groups, such as the tetrahydropyranyl, 2-methoxyprop-2-yl , 1- ethoxyeth-1-yl, methoxymethyl , ⁇ -methoxyethoxymethyl, methylthiomethyl, t-butyl, t-amyl, trityl, 4- methoxytrityl, 4 , 4 ' -dimethoxytrityl, 4, 4', 4"- trimethoxytrityl , benzyl, allyl, trimethylsilyl, (t- butyl) dimethylsilyl and 2 , 2 , 2-trichloroethoxycarbonyl groups, and the like.
- the species of hydroxy- protecting groups is also usually not critical so long as the derivatized hydroxyl group is stable to the conditions of subsequent reaction (s) and can be removed at the appropriate point without disrupting the remainder of the compound.
- C1-C 4 alkylthio refers to sulfide groups such as methylthio, ethylthio, n- propylthio, isopropylthio, -butylthio, t-butylthio and like groups.
- C1-C alkylsulfoxide indicates sulfoxide groups such as methylsulfoxide, ethylsulfoxide, ⁇ -propylsulfoxide, iso-propyl- sulfoxide, n-butylsulfoxide, sec-butylsulfoxide, and the like.
- C 1 -C 4 alkylsulfonyl encompasses groups such as methylsulfonyl , ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, ⁇ -butylsulfonyl , t-butylsulfonyl, and the like.
- Phenylthio, phenyl sulfoxide, and phenylsulfonyl compounds are known in the art and these have their art-recognized definitions.
- substituted phenylthio substituted phenyl sulfoxide
- substituted phenylsulfonyl is meant that the phenyl can be substituted as described above in relation to “substituted phenyl .
- substituted cyclic C2-C 10 alkylene "cyclic C 2 -C 10 heteroalkylene . " and “substituted cyclic 2 - 1 Q heteroakylene” defines a cyclic group bonded ("fused") to the phenyl radical.
- the cyclic group can be saturated or contain one or two double bonds.
- the cyclic group can have one or two methylene groups replaced by one or two oxygen, nitrogen or sulfur atoms.
- the cyclic alkylene or heteroalkylene group can be substituted once or twice by substituents selected from the group consisting of hydroxy, protected hydroxy, carboxy, protected carboxy, keto, ketal, C ] _-
- C 4 alkoxycarbonyl C 1 -C4 alkanoyl, C ⁇ -C ⁇ o alkyl, carbamoyl, C 1 -C 4 alkoxy, C 1 -C 4 , alkylthio, C 1 -C 4 alkylsulfoxide, C 1 -C 4 alkylsulfonyl, halo, amino, protected amino, hydroxymethyl and a protected hydroxymethyl group.
- a cyclic alkylene or heteroalkylene group fused onto the benzene radical can contain two to ten ring members, but it preferably contains four to six members.
- saturated cyclic groups include a bicyclic ring system that is a 2,3- dihydroindanyl or a tetralin ring.
- the cyclic groups are unsaturated, examples occur when the resultant bicyclic ring system is a naphthyl ring or indanyl.
- An example of a cyclic group which can be fused to a phenyl radical that has two oxygen atoms and that is fully saturated is dioxanyl .
- fused cyclic groups that each contain one oxygen atom and one or two double bonds occur when the phenyl ring is fused to a furo, pyrano, dihydrofurano or dihydropyrano ring.
- Cyclic groups that each have one nitrogen atom and contain one or two double more double bonds are illustrated where the phenyl is fused to a pyridino or pyrano ring.
- An example of a fused ring system having one nitrogen and two phenyl radicals is a carbozyl group.
- Examples of cyclic groups that each have one sulfur atom and contain one or two double bonds occur where the benzene ring is fused to a thieno, thiopyrano, dihydrothieno, or dihydrothiopyrano ring.
- Examples of cyclic groups that contain two heteroatoms selected from sulfur and nitrogen and one or two double bonds occur where the phenyl ring is fused to a thiazolo, isothiazolo, dihydrothiazolo or dihydroisothiazolo ring.
- Examples of cyclic groups that contain two heteroatoms selected from oxygen and nitrogen and one or two double bonds occur where the benzene ring is fused to an oxazole, isoxazole, dihydroxazole or dihydroisoxazole ring.
- Examples of cyclic groups that contain two nitrogen heteroatoms and one or two double bonds occur where the benzene ring is fused to a pyrazolo, imidazolo, dihydropyrazolo or dihydroimidazolo ring.
- One or more of the contemplated compounds within a given library can be present as a pharmaceutically- acceptable salt.
- pharmaceutically- acceptable salt encompasses those salts that form with carboxylate, phosphate or sulfonate anions and ammonium ions and include salts formed with the organic and inorganic cations discussed below.
- the term includes salts that form by standard acid-base reactions with basic groups (such as amino groups) and organic or inorganic acids.
- acids include hydrochloric, sulfuric, phosphoric, acetic, succinic, citric lactic, maleic, fumaric, palmitic, cholic, pamoic, mucic, D-glutamic, d-camphoric, glutaric, phthalic, tartaric, lauric, stearic, salicyclic, methanesulfonic, benzenesulfonic, sorbic, picric, benzoic, cinnamic, and like acids.
- organic or inorganic cation refers to counterions for the carboxylate, phosphate or sulfonate anion of a salt.
- the counter-ions are selected from the alkali and alkaline earth metals, (such as lithium, sodium, potassium, barium, magnesium and calcium) ammonium, and the organic cations such as dibenzylammonium, benzylammonium, 2- hydroxymet ylammonium, bis (2-hydroxyethyl) ammonium, phenylethylbenzylammonium, dibebenzylethylene- diammonium, and like cations.
- cations encompassed by the above term include the protonated form of procaine, quinine and N-methylglucosamine, and the protonated forms of basic amino acids such as glycine, ornithine, histidine, phenylglycine, lysine and arginine. Furthermore, any zwitterionic form of the instant compounds formed by a carboxylic acid and an amino group is referred to by this term.
- a preferred cation for a carboxylate anion is the sodium cation.
- the compounds of an above Formula can also exist as solvates and hydrates. Thus, these compounds can crystalize with, for example, waters of hydration, or one, a number of, or any fraction thereof of molecules of the mother liquor solvent.
- the solvates and hydrates of such compounds are included within the scope of this invention.
- One or more of the contemplated compounds can be in the biologically active ester form, such as the non-toxic, metabolically-labile ester-form. Such ester forms induce increased blood levels and prolong the efficacy of the corresponding non-esterified forms of the compounds .
- Ester groups that can be used include the lower alkoxymethyl groups (C 1 -C 4 alkoxymethyl) for example, me hoxymethyl , ethoxymethyl , isopropoxymethyl and the like; the ⁇ - (C1-C 4 ) alkoxyethyl groups, for example methoxyethyl, ethoxyethyl, propxyethyl, iso-propoxyethyl, and the like, the 2-oxo-l, 3-dioxolen-4-ylmethyl groups such as 5-methyl-2 -oxo-1, 3-dioxolen-4-ylmethyl, 5-phenyl- 2-oxo-l, 3-dioxolen-4-ylmethyl, and the like, the C ⁇ - C 3 alkylthiomethyl groups, for example methylthiomethyl, ethylthiomethyl, isopropylthiomethyl, and the like, the acyloxymethyl groups, for example pivaloyloxymethyl
- a chemical or combinatorial "library” is an intentionally created collection of differing molecules that can be prepared by the synthetic means provided below or otherwise herein and screened for biological activity in a variety of formats (e.g. libraries of soluble molecules) .
- the libraries can be screened in any variety of assays, such as those detailed below as well as others useful for assessing the biological activity of diketopiperazines.
- the libraries typically contain at least one active compound and are generally prepared in such that the compounds are in equimolar quantities.
- illustrative libraries were prepared, two trisubstituted diketopiperazines (one having R 2 as methyl and the other having R 2 as benzyl) .
- the diketopiperazine libraries and compounds of Formula I can be prepared according to the general Reaction Scheme shown in Scheme 1, below, and discussed in greater detail hereinafter.
- the compounds and libraries were prepared using solid-phase techniques.
- the solid-phase resin here is p-methylbenzhydryl-amine resin (p-MBHA) , is indicated in Scheme 1, below, by the large circle and dash. Compound preparation is illustrated first.
- Scheme 1 p-methylbenzhydryl-amine resin
- amino acids can be used with the present invention as described above to generate a vast array of compounds with different R 1 and R 3 groups.
- twenty-nine first amino acids were coupled to the resin, which amino acids contain R 1 .
- the twenty nine amino acids included Ala, Phe, Gly, lie, Leu, Nva, Ser(tBu), Thr(tBu), Val, Tyr(tBu), Nle, Cha, Nal, Phg, Lys (Boc), Me (O) , ala, phe, ile, leu, nva, ser(tBu), thr(tBu), val, tyr(tBu), nle, cha, nal, lys (Boc).
- R l and the twenty-seven of R 3 are described above and below, except in Table 1, in their modified form.
- a specific example of a modified lysine side is provided above.
- certain R 4 groups can be modified by the reduction procedure, as is well known.
- a tertiary amine such as diisopropylethylamine is typically also present when a diacid chloride or similar compound is used in these syntheses.
- Exemplary reactions are shown in Scheme 2, below, wherein only the ring-forming step is shown
- Bi- and tricyclic compounds can be prepared using the same general synthetic steps, but using a cyclic activated ⁇ , ⁇ -diacid as is illustrated in Scheme 3, below.
- Compounds and libraries containing a single amido carbonyl group can be prepared by several well- known synthetic methods. For example, a substituted or unsubstituted acryloyl halide can be reacted using a Michael addition to one amine of compound 5 and the acid halide used to form the amide bond with the second amine .
- the nonsupport-bound library mixtures were screened in solution in radio-receptor inhibition assays described in detail below. Deconvolution of highly active mixtures can then be carried out by iterative, or positional scanning methods. These techniques, the iterative approach or the positional scanning approach, can be utilized for finding other active compounds within the libraries of the present invention using any one of the below-described assays or others well known in the art.
- the optimum substituent at that position is determined, pointing to the optimum or at least a series of compounds having a maximum of the desired biological activity.
- the number of sublibraries for compounds with a single position defined is the number of different substituents desired at that position, and the number of all the compounds in each sublibrary is the product of the number of substituents at each of the other variables.
- a compound of the present invention is generally in a pharmaceutical composition so as to be administered to a subject in need of the medication at dosage levels of about 0.7 to about 7000 mg per day, and preferably about 1 to about 500 mg per day, for a normal human adult of approximately 70 kg of body weight, this translates into a dosage of about 0.01 to about 100 mg/kg of body weight per day.
- the specific dosages employed can be varied depending upon the requirements of the patient, the severity of the condition being treated, and the activity of the compound being employed. The determination of optimum dosages for a particular situation is within the skill of the art.
- inert, pharmaceutically acceptable carriers are used.
- the pharmaceutical carrier can be either solid or liquid.
- Solid form preparations include, for example, powders, tablets, dispersible granules, capsules, cachets, and suppositories.
- a solid carrier can be one or more substances that can also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material.
- the carrier is generally a finely divided solid which is in a mixture with the finely divided active component.
- the active compound is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
- a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture is then poured into convenient-sized molds and allowed to cool and solidify.
- Powders and tablets preferably contain between about 5% to about 70% by weight of the active ingredient.
- Suitable carriers include, for example, magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter and the like.
- compositions can include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier, which is thus in association with it.
- a carrier which is thus in association with it.
- cachets are also included. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.
- Liquid pharmaceutical compositions include, for example, solutions suitable for oral or parenteral administration, or suspensions, and emulsions suitable for oral administration.
- Sterile water solutions of the active component or sterile solutions of the active component in solvents comprising water, ethanol, or propylene glycol are examples of liquid compositions suitable for parenteral administration.
- Sterile solutions can be prepared by dissolving the active component in the desired solvent system, and then passing the resulting solution through a membrane filter to sterilize it or, alternatively, by dissolving the sterile compound in a previously sterilized solvent under sterile conditions.
- Aqueous solutions for oral administration can be prepared by dissolving the active compound in water and adding suitable flavorants, coloring agents, stabilizers, and thickening agents as desired.
- Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
- the pharmaceutical composition is in unit dosage form.
- the composition is divided into unit doses containing appropriate quantities of the active urea.
- the unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparation, for example, packeted tablets, capsules, and powders in vials or ampules.
- the unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms.
- the first amino acid (Fmoc-R 1 aa-OH, 6 eq) was coupled using the conventional reagents hydroxybenzotriazole (HOBt, 6 eq) and diisopropylcarbodiimide (DIC, 6 eq) in anhydrius DMF for 60 minutes. 2) Following removal of the protecting group with 25% piperidine in DMF (2 times, 2 x 10 minutes) and wash with DMF (8 times) , the amino acid was N- acylated with a carboxylic acid (10 eq) in the presence of DIC (10 eq) and HOBt (10 eq) overnight (about 18 hours) in anhydrous DMF. 3) Exhaustive reduction of the amide groups: The reduction was performed in 50 ml KimaxTM tubes under nitrogen. Boric acid (40x) and trimethyl borate
- N-alkylation was performed by treatment of the resin packet with 1 M lithium t-butoxide in THF (20 eq) during 10 minutes at room temperature . Excess base was removed by cannulation, followed by addition of the individual alkylating agent (20 eq) in anhydrous DMSO. The solution was vigorously shaken for 2 hours at room temperature .
- N-acylated dipeptide Upon removal of the trityl from the ⁇ -amino group with 2% TFA in DCM (2 x 10 min) , the resin packet was washed, neutralized with a solution of 5% DIEA in DCM, and the second amino acid (Fmoc-R 3 aa-OH) coupled in the same conditions as described before. Following removal of the Fmoc group, the dipeptide was N-acylated with a carboxylic acid (10 eq) in the presence of DIC (10 eq) and HOBt (10 eq) in anhydrous DMF.
- Trisubstituted diketopiperazine formation The cyclization occurred following treatment of the reduced acylated dipeptide overnight (about 18 hours) with oxalyldiimidazole (15 x) in DMF anhydrous. Following cleavage from the resin with anhydrous HF in the presence of anisole at 0°C for 6 hours [Houghten, R.A. et al . , Int . J. Pep . Pro. Res . , 1986, 27, 6763] , the desired product was extracted with acetonitrile/water (50:50) and lyophilized.
- Product Data Product Data:
- Fmoc-Phe Fmoc-Phe p-Tolylacetic Acid
- Fmoc-Phe Fmoc-Phe 3-Methoxyphenyl- acetic Acid
- N-Methyl- and N-Benzyl-1, 4 5- trisubstituted-2.3-diketopiperazines
- Libraries of N-methyl- and N-benzyl-1, 4, 5- trisubstituted-2, 3 -diketopiperazines were prepared.
- a single reagent was used to provide each of the R groups of the interemediates prepared in the syntheses of the individual compounds of Examples 1 and 2
- both single reactants and mixtures of reactants were used to provide the R 1 , R 3 and R 4 groups for the different library pools that were synthesiszed.
- 29 library pools were prepared in which R 1 was an individual amino acid side chain, and with R 3 and R 4 being separate mixtures of amino acid side chains
- a 0.5M solution of mixed Fmoc amino acids in DMF (1.2 mL) at a predetermined molar ratio (6X, 0.6 meq total), 1.2 mL 0.5M 1-hydroxybenzo- triazole (HOBt, 6X, 0.6 meq) in DMF, and 1.2 mL 0.5M diisopropylcarbodiimide (DIPCDI, 6X, 0.6 meq) in DMF were prereacted for 15 minutes for a final concentration of each of 0.167M.
- the resin packet was then added to the solution and permitted to react for 120 minutes. Following the reaction, the solution was decanted and the resin washed with DMF (3x5mL) .
- the resin packet was neutralized with 5% diisopropylethylamine (DIEA) in dichloromethane (DCM) (3x5mL) and then washed with DCM (3x5mL) .
- DIEA diisopropylethylamine
- a 0.5M solution of mixed Fmoc amino acids in DMF (1.2 mL) at a predetermined molar ratio (6X, 0.6 meq total), 1.2 mL 0.5M 1-hydroxy-benzotriazole (HOBt, 6X, 0.6 meq) in DMF, and 1.2 mL 0.5M diisopropylcarbodiimide (DIPCDI, 6X, 0.6 meq) in DMF were prereacted for 15 minutes for a final concentration of each of 0.167M.
- the resin packet was then added to the solution and permitted to react for 120 minutes. Following the reaction, the solution was decanted and the resin washed with DMF (3x5mL) .
- C Typical procedure for a carboxylic acid mixture coupling.
- the resin packet was neutralized with 5% diisopropylethylamine (DIEA) in dichloromethane (DCM) (3x5mL) and then washed with DCM (3x5mL) .
- DIEA diisopropylethylamine
- DCM dichloromethane
- DIEA diisopropylethylamine
- DCM dichloromethane
- the resin packet was then added to the solution and permitted to react for 120 minutes. Following the reaction, the solution was decanted and the resin washed with DMF (3x5mL) .
- N-Alkylations on the resin-bound peptides and peptide mixtures were carried out as described in Examples 1 and 2 for the individual compounds .
- Reductions of the resin-bound N-acylated and N- alkylated peptide mixtures were carried out as discussed in Examples 1 and 2 for the individual compounds. Cyclization reactions and cleavage of the compound libraries on and from the resin were also carried out as described in Examples 1 and 2 for the individual peptides.
- Example 4 Preparation of Individual N-Methyl- trisubstituted-5, 7-diketo-l, 4- diazacycloheptane Compounds and Library A series of individual N-methyl-trisubstituted- 5, 7-diketo-l, 4-diazacycloheptane compounds was prepared as discussed in Examples 1 and 2. The amino acids and carboxylic acids used to prepare these individual compounds are enumerated in Table 7, below. Table 7
- Fmoc-Phe Fmoc-Phe p-Tolylacetic Acid
- Fmoc-Phe Fmoc-Phe 3-Methoxyphenylacetic Acid
- a library of N-methyl-trisubstituted-5, 7-diketo- 1, 4-diazacycloheptane compounds was also prepared in a manner similar to that discussed for Example 3, except that malonyl dichloride as the ring-forming reagent.
- the amino acids and carboxylic acids used to prepare the compound pools of this library are shown in Table 8, below.
- Example 5 Preparation of Compounds with Additional Cyclizing Reagents A series of ninety-nine individual compounds was prepared using eleven reagents for forming N- methylamino-substituted cyclic bis-amide and bis- amine compounds. The cyclization reactions from common N-methylated indermediate compound 5 of Scheme 1 are illustrated in Schemes 6 and 7, below. The amino acids and carboxylic acids used to form the R 1 ,
- the diiodo- peptide (5 mg) , dissolved in 1 mL of N,N- dimethylformamide (DMF) , was exposed to tritium gas in the presence of 3 mg of palladium oxide. The reaction was allowed to proceed for two hours, after which the gas flow was discontinued and 2 mLs of methanol were added to the reaction mixture to exchange unreacted tritium. The resulting mixture was passed through Teflon filters (PTFE) , which were rinsed with 50% aqueous DMF. The eluent was lyophilized to dryness overnight (about 18 hours) . The tritiated peptide was purified by RP-HPLC. The radiolabeled peptide was found to have a specific activity of 33 Ci/mmole.
- PTFE Teflon filters
- Frozen rat brains (Harlan, Indianapolis, IN) were defrosted in Tris buffer [50 mM Tris, 2 mM EDTA,
- each assay tube contained a final concentration of 1.8 nM [ 3 H 2 ] -
- Orphanin FQ 1 mL of membrane suspension in a total volume of 1.1 mLs.
- the non-radiolabeled peptide (5 ⁇ M) was used to determine nonspecific binding.
- Assays were incubated at 25 C for time periods ranging from 5-30 minutes. The assay was performed twice. The reaction was terminated by filtration through GF-B filters using a Brandell Harvester (Gaithersberg, MA.) The filters had been previously soaked in 0.1% polyethyleneimine for one hour to reduce nonspecific binding. Filters were washed with
- Nonspecific binding was determined in the presence of 5 ⁇ M Orphanin FQ. Saturation studies were carried out using four replicates, and the assay was repeated three times. The reaction was terminated by filtration through GF-B filters, previously soaked in 0.1% polyethyleneimine, using a Tomtec 96 harvester (Orange, CT) . Filters were washed with 6 mL/sample Tris buffer at 4°C. Bound radioactivity was counted on a Pharmacia Biotech Beta-plate Liquid Scintillation Counter (Piscataway, NJ) and expressed in counts per minute. Competition assays were performed as described for saturation studies.
Abstract
Description
Claims
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EP00926259A EP1181279A4 (en) | 1999-05-12 | 2000-04-21 | Diketodiazacyclic compounds, diazacyclic compounds and combinatorial libraries thereof |
AU44818/00A AU774270C (en) | 1999-05-12 | 2000-04-21 | Diketodiazacyclic compounds, diazacyclic compounds and combinatorial libraries thereof |
CA002373590A CA2373590A1 (en) | 1999-05-12 | 2000-04-21 | Diketodiazacyclic compounds, diazacyclic compounds and combinatorial libraries thereof |
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US09/310,662 US6441172B1 (en) | 1996-11-07 | 1999-05-12 | Diketodiazacyclic compounds, diazacyclic compounds and combinatorial libraries thereof |
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US (3) | US6441172B1 (en) |
EP (1) | EP1181279A4 (en) |
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-
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- 2000-04-21 AU AU44818/00A patent/AU774270C/en not_active Ceased
- 2000-04-21 EP EP00926259A patent/EP1181279A4/en not_active Withdrawn
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2002
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EP3843779A4 (en) * | 2018-08-30 | 2022-06-08 | University of Central Florida Research Foundation, Inc. | Amino acid depletion agents as antiproliferative agents |
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AU4481800A (en) | 2000-12-05 |
US6809202B2 (en) | 2004-10-26 |
AU774270C (en) | 2007-03-29 |
EP1181279A1 (en) | 2002-02-27 |
AU774270B2 (en) | 2004-06-24 |
US20030120066A1 (en) | 2003-06-26 |
US6441172B1 (en) | 2002-08-27 |
EP1181279A4 (en) | 2002-09-25 |
CA2373590A1 (en) | 2000-11-23 |
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