WO2014007831A1 - Boron-containing small molecules - Google Patents
Boron-containing small molecules Download PDFInfo
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- WO2014007831A1 WO2014007831A1 PCT/US2012/045842 US2012045842W WO2014007831A1 WO 2014007831 A1 WO2014007831 A1 WO 2014007831A1 US 2012045842 W US2012045842 W US 2012045842W WO 2014007831 A1 WO2014007831 A1 WO 2014007831A1
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- WO
- WIPO (PCT)
- Prior art keywords
- compound
- substituted
- unsubstituted
- compounds
- exemplary embodiment
- Prior art date
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- 229910052796 boron Inorganic materials 0.000 title claims abstract description 26
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 150000003384 small molecules Chemical class 0.000 title 1
- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims description 217
- 150000003839 salts Chemical class 0.000 claims description 50
- 125000000217 alkyl group Chemical group 0.000 claims description 33
- 125000003118 aryl group Chemical group 0.000 claims description 28
- 125000001072 heteroaryl group Chemical group 0.000 claims description 23
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims description 15
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 9
- 206010028980 Neoplasm Diseases 0.000 claims description 6
- XOQABDOICLHPIS-UHFFFAOYSA-N 1-hydroxy-2,1-benzoxaborole Chemical compound C1=CC=C2B(O)OCC2=C1 XOQABDOICLHPIS-UHFFFAOYSA-N 0.000 abstract description 6
- 150000002993 phenylalanine derivatives Chemical class 0.000 abstract 1
- -1 carboxybenzyl Chemical group 0.000 description 68
- 239000000203 mixture Substances 0.000 description 59
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 46
- 125000001424 substituent group Chemical group 0.000 description 29
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 150000003254 radicals Chemical class 0.000 description 20
- 239000000243 solution Substances 0.000 description 19
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 14
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 13
- 125000005842 heteroatom Chemical group 0.000 description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- 239000000651 prodrug Substances 0.000 description 10
- 229940002612 prodrug Drugs 0.000 description 10
- 239000012453 solvate Substances 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 125000004429 atom Chemical group 0.000 description 9
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 8
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000013543 active substance Substances 0.000 description 6
- 125000002947 alkylene group Chemical group 0.000 description 6
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 239000012279 sodium borohydride Substances 0.000 description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 description 6
- 229910052717 sulfur Inorganic materials 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
- 150000001413 amino acids Chemical class 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 235000019439 ethyl acetate Nutrition 0.000 description 5
- 125000004474 heteroalkylene group Chemical group 0.000 description 5
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 125000004430 oxygen atom Chemical group O* 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 4
- GDMJXXLVTYSBBE-UHFFFAOYSA-N 1,2-benzoxaborole Chemical class C1=CC=C2OB=CC2=C1 GDMJXXLVTYSBBE-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- SCRQAWQJSSKCFN-UHFFFAOYSA-N 2-bromo-5-hydroxybenzaldehyde Chemical compound OC1=CC=C(Br)C(C=O)=C1 SCRQAWQJSSKCFN-UHFFFAOYSA-N 0.000 description 4
- 241000283690 Bos taurus Species 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 description 4
- UNXISIRQWPTTSN-UHFFFAOYSA-N boron;2,3-dimethylbutane-2,3-diol Chemical compound [B].[B].CC(C)(O)C(C)(C)O UNXISIRQWPTTSN-UHFFFAOYSA-N 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000002953 preparative HPLC Methods 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 4
- 235000019260 propionic acid Nutrition 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 3
- 239000004475 Arginine Substances 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- ODKSFYDXXFIFQN-SCSAIBSYSA-N D-arginine Chemical compound OC(=O)[C@H](N)CCCNC(N)=N ODKSFYDXXFIFQN-SCSAIBSYSA-N 0.000 description 3
- KDXKERNSBIXSRK-RXMQYKEDSA-N D-lysine Chemical compound NCCCC[C@@H](N)C(O)=O KDXKERNSBIXSRK-RXMQYKEDSA-N 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- 241000282414 Homo sapiens Species 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 239000004472 Lysine Substances 0.000 description 3
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Substances IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 125000003710 aryl alkyl group Chemical group 0.000 description 3
- UENWRTRMUIOCKN-UHFFFAOYSA-N benzyl thiol Chemical compound SCC1=CC=CC=C1 UENWRTRMUIOCKN-UHFFFAOYSA-N 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 3
- 229960001231 choline Drugs 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 3
- 125000005647 linker group Chemical group 0.000 description 3
- 150000004702 methyl esters Chemical class 0.000 description 3
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000004434 sulfur atom Chemical group 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Substances C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 3
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 3
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 241000283707 Capra Species 0.000 description 2
- 241000700199 Cavia porcellus Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 241000283073 Equus caballus Species 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 241000287828 Gallus gallus Species 0.000 description 2
- 241000699694 Gerbillinae Species 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 238000006751 Mitsunobu reaction Methods 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 241001494479 Pecora Species 0.000 description 2
- 241000009328 Perro Species 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 241000282898 Sus scrofa Species 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 125000000129 anionic group Chemical group 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 125000005621 boronate group Chemical group 0.000 description 2
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 244000309464 bull Species 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
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- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 description 1
- ANSUDRATXSJBLY-VKHMYHEASA-N methyl (2s)-2-amino-3-hydroxypropanoate Chemical compound COC(=O)[C@@H](N)CO ANSUDRATXSJBLY-VKHMYHEASA-N 0.000 description 1
- ANSUDRATXSJBLY-UHFFFAOYSA-N methyl 2-amino-3-hydroxypropanoate Chemical compound COC(=O)C(N)CO ANSUDRATXSJBLY-UHFFFAOYSA-N 0.000 description 1
- PHOMRHZEYCDHOI-UHFFFAOYSA-N methyl 3-(4-bromo-3-formylphenoxy)-2-(tritylamino)propanoate Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)NC(C(=O)OC)COC1=CC=C(Br)C(C=O)=C1 PHOMRHZEYCDHOI-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000006682 monohaloalkyl group Chemical group 0.000 description 1
- 125000004572 morpholin-3-yl group Chemical group N1C(COCC1)* 0.000 description 1
- BXGTVNLGPMZLAZ-UHFFFAOYSA-N n'-ethylmethanediimine;hydrochloride Chemical compound Cl.CCN=C=N BXGTVNLGPMZLAZ-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
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 230000035515 penetration 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
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical class OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 210000004694 pigment cell Anatomy 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 125000006684 polyhaloalkyl group Polymers 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 1
- 150000008648 triflates Chemical class 0.000 description 1
- 239000013638 trimer Substances 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 235000013311 vegetables Nutrition 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
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Definitions
- This invention provides, among other things, novel compounds useful in boron neutron capture therapy.
- an active agent includes a single active agent as well as two or more different active agents in combination. It is to be understood that present teaching is not limited to the specific dosage forms, carriers, or the like, disclosed herein and as such may vary.
- Bn is aqueous; Ar is aryl; B 2 pin 2 is bis(pinacolato)diboron; Bn is, in general, benzyl [see Cbz for one example of an exception]; (BnS) 2 is benzyl disulfide; BnSH is benzyl thiol or benzyl mercaptan; BnBr is benzyl bromide; Boc is tert-butoxy carbonyl; Boc 2 0 is di-terf-butyl dicarbonate; Bz is, in general, benzoyl; BzOOH is benzoyl peroxide; Cbz or Z is benzyloxycarbonyl or carboxybenzyl;
- CS2CO3 cesium carbonate: CSA is camphor sulfonic acid; CTAB is
- Ra Ni or Raney Ni is Raney nickel
- Ph is phenyl
- PMB is /?-methoxybenzyl
- PrOH is 1-propanol
- iPrOH is 2-propanol
- POCl 3 is phosphorus chloride oxide
- PTSA is /?ara-toluene sulfonic acid
- Pyr. or Pyr or Py as used herein means pyridine; RT or rt or r.t. is room temperature; sat.
- (EtO) 2 POCH 2 COOEt is a triethylester of phosphonoacetic acid known as triethyl phosphonoacetate.
- Compound of the invention refers to the compounds discussed herein, salts (e.g. pharmaceutically acceptable salts), prodrugs, solvates and hydrates of these compounds.
- poly as used herein means at least 2.
- a polyvalent metal ion is a metal ion having a valency of at least 2.
- Moiety refers to a radical of a molecule that is attached to the remainder of the molecule.
- alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e. Ci-Cio means one to ten carbons).
- the term “alkyl” means a straight or branched chain, or combinations thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals.
- saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl,
- cyclohexyl (cyclohexyl)methyl, cyclopropylmethyl, homo logs and isomers of, for example, n- pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
- An unsaturated alkyl group is one having one or more double bonds or triple bonds.
- unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3- butynyl, and the higher homo logs and isomers.
- alkylene by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified, but not limited, by
- an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the invention.
- a “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
- alkenylene by itself or as part of another substituent means a divalent radical derived from an alkene.
- cycloalkylene by itself or as part of another substituent means a divalent radical derived from a cycloalkyl.
- heteroalkylene by itself or as part of another substituent means a divalent radical derived from an heteroalkane.
- heterocycloalkylene by itself or as part of another substituent means a divalent radical derived from an heterocycloalkane.
- arylene by itself or as part of another substituent means a divalent radical derived from an aryl.
- heteroarylene by itself or as part of another substituent means a divalent radical derived from heteroaryl.
- alkoxy alkylamino and “alkylthio” (or thioalkoxy) are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively.
- heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the stated number of carbon atoms and at least one heteroatom.
- the term “heteroalkyl,” by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the stated number of carbon atoms and at least one heteroatom.
- heteroalkyl by itself or in combination with another term, means a stable straight or branched chain, or combinations thereof, consisting of the stated number of carbon atoms and at least one heteroatom.
- the heteroatoms can be selected from the group consisting of B, O, N and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
- the heteroatom(s) B, O, N and S may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule.
- heteroalkylene by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-.
- heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like).
- no orientation of the linking group is implied by the direction in which the formula of the linking group is written.
- the formula -C(0) 2 R'- represents both -C(0) 2 R'- and - R'C(0) 2 -.
- cycloalkyl and “heterocycloalkyl”, by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl”, respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
- heterocycloalkyl examples include, but are not limited to, 1 -(1,2,5,6- tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3- morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1 -piperazinyl, 2-piperazinyl, and the like.
- halo or halogen
- haloalkyl by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
- terms such as “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl.
- halo(Ci-C4)alkyl is mean to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
- aryl means, unless otherwise stated, a polyunsaturated, aromatic, substituent that can be a single ring or multiple rings (preferably from 1 or 2 or 3 rings), which are fused together or linked covalently.
- heteroaryl refers to aryl groups (or rings) that contain from one to four heteroatoms.
- the heteroatom is selected from B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
- a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
- Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3- pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4- oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1- is
- aryl when used in combination with other terms (e.g. , aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined herein.
- arylalkyl is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g. , benzyl, phenethyl, pyridiylethyl and the like) including those alkyl groups in which a carbon atom (e.g. a methylene group) has been replaced by, for example, an oxygen atom (e.g. , phenoxymethyl, 2- pyridyloxymethyl, 3-(l-naphthyloxy)propyl, and the like).
- heteroaryl when used in combination with other terms (e.g., hetero aryloxy, heteroarylthioxy, heteroarylalkyl) includes those radicals in which a heteroaryl group is attached through the next moiety to the rest of the molecule.
- heteroarylalkyl is meant to include those radicals in which a heteroaryl group is attached to an alkyl group (e.g., pyridylmethyl and the like).
- heteroaryloxy is meant to include those radicals in which a heteroaryl group is attached to an oxygen atom.
- heteroaryloxyalkyl is meant to include those radicals in which an aryl group is attached to an oxygen atom which is then attached to an alkyl group, (e.g., 2-pyridyloxymethyl and the like). [0024] Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl” and
- heteroaryl are meant to include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.
- R', R", R'", R"" and R'" each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, e.g. , aryl substituted with 1 or 2 or 3 halogens, substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups.
- each of the R groups is independently selected as are each R', R", R'", R"" and R'"" groups when more than one of these groups is present.
- R' and R" When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring.
- -NR'R is meant to include, but not be limited to, 1-pyrrolidinyl and 4-morpholinyl.
- alkyl is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl ⁇ e.g., -CF 3 and -CH 2 CF 3 ) and acyl ⁇ e.g., -C(0)CH 3 , -C(0)CF 3 , -C(0)CH 2 OCH 3 , and the like).
- substituents for the aryl and heteroaryl groups are generically referred to as "aryl group substituents.”
- each of the R groups is independently selected as are each R', R", R'", R"" and R'"" groups when more than one of these groups is present.
- Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(0)-(CRR') q -U-, wherein T and U are independently -NR-, -0-, -CRR'- or a single bond, and q is an integer from 0 or 1 or 2 or 3.
- two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH 2 ) r -B-, wherein A and B are independently -CRR'-, -0-, -NR-, -S-, - S(O)-, -S(0) 2 -, -S(0) 2 NR'- or a single bond, and r is an integer from 1 or 2 or 3 or 4.
- One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
- two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula - (CRR')s-X-(CR"R'")d-, where s and d are independently integers from 0 or 1 or 2 or 3, and X is -0-, -NR'-, -S-, -S(O)-, -S(0) 2 -, or -S(0) 2 NR'-.
- the substituents R, R', R" and R'" are preferably independently selected from hydrogen or substituted or unsubstituted (Ci or C 2 or C 3 or C 4 or C 5 or C 6 )alkyl.
- Ring means a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
- a ring includes fused ring moieties. The number of atoms in a ring is typically defined by the number of members in the ring. For example, a "5- to 7-membered ring" means there are 5 or 6 or 7 atoms in the encircling arrangement. Unless otherwise specified, the ring optionally includes a heteroatom.
- the term “5- to 7-membered ring” includes, for example phenyl, pyridinyl and piperidinyl.
- the term “ring” further includes a ring system comprising more than one "ring”, wherein each "ring” is independently defined as above.
- heteroatom includes atoms other than carbon (C) and hydrogen (H). Examples include oxygen (O), nitrogen (N) sulfur (S), silicon (Si), and boron (B).
- leaving group means a functional group or atom which can be displaced by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction.
- representative leaving groups include triflate, chloro, bromo and iodo groups; sulfonic ester groups, such as mesylate, tosylate, brosylate, nosylate and the like; and acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.
- R is a general abbreviation that represents a substituent group that is selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocycloalkyl groups.
- an effective amount of a drug, formulation, or permeant is meant a sufficient amount of an active agent to provide the desired local or systemic effect.
- a “Topically effective,” “pharmaceutically effective,” or “therapeutically effective” amount refers to the amount of drug needed to effect the desired therapeutic result.
- pharmaceutically acceptable salt is meant to include a salt of a compound of the invention which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
- base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
- Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino (such as choline or diethylamine or amino acids such as d-arginine, 1-arginine, d- lysine, or 1-lysine), or magnesium salt, or a similar salt.
- organic amino such as choline or diethylamine or amino acids such as d-arginine, 1-arginine, d- lysine, or 1-lysine
- magnesium salt or a similar salt.
- acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
- suitable inert solvent examples include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric,
- salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)).
- Certain specific compounds of the invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
- the neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compounds in the conventional manner.
- the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.
- the invention provides compounds which are in a prodrug form.
- Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to provide the compounds of the invention. Additionally, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an ex vivo environment.
- Certain compounds of the invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the invention. Certain compounds of the invention may exist in multiple crystalline or amorphous forms.
- Certain compounds of the invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and individual isomers are encompassed within the scope of the invention.
- the graphic representations of racemic, ambiscalemic and scalemic or enantiomerically pure compounds used herein are taken from Maehr, J. Chem. Ed. 1985, 62: 114-120. Solid and broken wedges are used to denote the absolute configuration of a stereocenter unless otherwise noted.
- the compounds described herein contain olefmic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are included.
- Compounds of the invention can exist in particular geometric or stereoisomeric forms.
- the invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, as falling within the scope of the invention.
- Additional asymmetric carbon atoms can be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
- Optically active (R)- and (5)-isomers and d and / isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If, for instance, a particular enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis, or by derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
- diastereomeric salts can be formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means known in the art, and subsequent recovery of the pure enantiomers.
- separation of enantiomers and diastereomers is frequently accomplished using chromatography employing chiral, stationary phases, optionally in combination with chemical derivatization (e.g., formation of carbamates from amines).
- the compounds of the invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
- the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). All isotopic variations of the compounds of the invention, whether radioactive or not, are intended to be encompassed within the scope of the invention.
- radioactive isotopes such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). All isotopic variations of the compounds of the invention, whether radioactive or not, are intended to be encompassed within the scope of the invention.
- pharmaceutically acceptable carrier or “pharmaceutically acceptable vehicle” refers to any formulation or carrier medium that provides the appropriate delivery of an effective amount of an active agent as defined herein, does not interfere with the effectiveness of the biological activity of the active agent, and that is sufficiently non-toxic to the host or patient.
- Representative carriers include water, oils, both vegetable and mineral, cream bases, lotion bases, ointment bases and the like. These bases include suspending agents, thickeners, penetration enhancers, and the like. Their formulation is well known to those in the art of cosmetics and topical pharmaceuticals. Additional information concerning carriers can be found in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005) which is incorporated herein by reference.
- excipients is conventionally known to mean carriers, diluents and/or vehicles used in formulating drug compositions effective for the desired use.
- Bio medium refers to both in vitro and in vivo biological milieus.
- exemplary in vitro “biological media” include, but are not limited to, cell culture, tissue culture, homogenates, plasma and blood. In vivo applications are generally performed in mammals, preferably humans.
- Embodiments of the invention also encompass compounds that are poly- or multi-valent species, including, for example, species such as dimers, trimers, tetramers and higher homologs of the compounds of use in the invention or reactive analogues thereof.
- Salt counterion refers to positively charged ions that associate with a compound of the invention when the boron is fully negatively or partially negatively charged.
- salt counterions include H + , H 3 0 + , ammonium, potassium, calcium, magnesium, organic amino (such as choline or diethylamine or amino acids such as d-arginine, 1-arginine, d-lysine, or 1-lysine) and sodium.
- the compounds comprising a boron bonded to a carbon and three heteroatoms can optionally contain a fully negatively charged boron or partially negatively charged boron. Due to the negative charge, a positively charged counterion may associate with this compound, thus forming a salt.
- positively charged counterions include H + , H 3 0 + , ammonium, potassium, calcium, magnesium, organic amino (such as choline or diethylamine or amino acids such as d-arginine, 1-arginine, d-lysine, 1-lysine), and sodium.
- the invention provides novel boron compounds, method of making such compounds, methods of using such compounds to treat diseases, and pharmaceutical formulations including such compounds.
- the compounds of the invention can be used in combination with boron neutron capture therapy to treat a disease, such as, for example, cancer.
- BPA /?-Boronophenylalanine
- BPA Boron Neutron Capture Therapy
- BPA with fructose or mannitol has been proposed to produce a water soluble form of BPA for BNCT. Mori, Y. et al, Pigment Cell Res. 1989, 2, 273-277. Also, the continued development of new boron delivery agents, including boron-containing amino acids or BPA analogues with water-solubilizing groups, is the subject of extensive research.
- Benzoxaboroles are boron-containing heterocycles that have emerged as a new class of potential therapeutics.
- the benzoxaborole core has been shown to have a lower pK» value (pK» 7.2) (Dowlut, M. et al, J. Am. Chem. Soc. 2006, 128, 4226- 4227) compared to that of phenylboronc acid (pK a 8.9), (Westmark, P. R. et al., J. Am. Chem. Soc. 1996, 118, 11093-11100) suggesting that it exists about 50% in anionic tetrahedral form at physiological pH and thus has an enhanced water solubility.
- the invention provides a compound of the invention.
- the invention provides a compound described herein.
- the invention provides a compound having a structure according to the formula which is:
- R is H or substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl or substituted or unsubstituted cycloalkyl or substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
- R 2 and R 3 are independently selected from H or substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl or substituted or unsubstituted cycloalkyl or substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or a salt thereof.
- R 1 is H and
- R 2 and R 3 are as defined herein.
- R 2 is H and R 1 and R 3 are as defined herein.
- R 1 is H
- R 3 is H
- R 2 is as defined herein.
- the invention provides a compound which is:
- the invention provides a compound which is:
- the invention provides a compound described herein, or a salt, hydrate or solvate thereof, or a combination thereof.
- the invention provides a compound described herein, or a salt, hydrate or solvate thereof.
- the invention provides a compound described herein, or a salt thereof.
- the salt is a pharmaceutically acceptable salt.
- the invention provides a compound described herein, or a hydrate thereof.
- the invention provides a compound described herein, or a solvate thereof.
- the invention provides a compound described herein, or a prodrug thereof.
- the invention provides a salt of a compound described herein. In an exemplary embodiment, the invention provides a pharmaceutically acceptable salt of a compound described herein. In an exemplary embodiment, the invention provides a hydrate of a compound described herein. In an exemplary embodiment, the invention provides a solvate of a compound described herein. In an exemplary embodiment, the invention provides a prodrug of a compound described herein.
- alkyl is linear alkyl. In another exemplary embodiment, alkyl is branched alkyl.
- heteroalkyl is linear heteroalkyl. In another exemplary embodiment, heteroalkyl is branched heteroalkyl. IILb) Compositions involving stereoisomers
- diastereomerically enriched refers to a composition having an enantiomeric excess (ee) or a diastereomeric excess (de) of greater than about 50%, preferably greater than about 70% and more preferably greater than about 90%. In general, higher than about 90%) enantiomeric or diastereomeric excess is particularly preferred, e.g., those compositions with greater than about 95%, greater than about 97% and greater than about 99%) ee or de.
- enantiomeric excess is related to the older term “optical purity” in that both are measures of the same phenomenon.
- the value of ee will be a number from 0 to 100, zero being racemic and 100 being enantiomerically pure.
- a composition which in the past might have been called 98% optically pure is now more precisely characterized by 96% ee.
- a 90%> ee reflects the presence of 95% of one enantiomer and 5% of the other(s) in the material in question.
- first compound and at least one additional compound are present in a composition, and the first compound and each of the additional compounds are stereoisomers, but not mirror images, of one another, and the first compound is present in the composition in a greater amount than each of the additional compounds, then the first compound is referred to herein as being present in
- the value of de will likewise be a number from 0 to 100, zero being an equal mixture of a first diastereomer and the remaining diastereomer(s), and 100 being 100% of a single diastereomer and zero% of the other(s) - i.e.
- the invention provides a composition including a first compound of the invention, wherein the first compound of the invention has at least one stereocenter, and at least one stereoisomer of the first compound of the invention.
- the invention provides a composition including a first compound of the invention, wherein the first compound of the invention has at least one stereocenter, and a second compound of the invention, wherein the first compound of the invention is a stereoisomer of the second compound of the invention.
- the invention provides a composition including a first compound of the invention, wherein the first compound of the invention has at least one stereocenter, and only one stereoisomer of the first compound of the invention.
- the invention provides a composition including a first compound of the invention, wherein the first compound of the invention has only one stereocenter, and an enantiomer of the first compound of the invention.
- the invention provides a composition including a first compound of the invention, wherein the first compound of the invention has two stereocenters, and an enantiomer of the first compound of the invention.
- the invention provides a composition including a first compound of the invention, wherein the first compound of the invention has two stereocenters, and at least one diasteromer of the first compound of the invention.
- the invention provides a composition including a first compound of the invention, wherein the first compound of the invention has two stereocenters, and only one diasteromer of the first compound of the invention.
- the first compound of the invention can be present in an enantiomeric excess of at least about 80%, or at least about 90%, or at least about 92% or at least about 95%.
- the first compound of the invention can be present in an enantiomeric excess of at least about 96%, at least about 97%, at least about 98%, at least about 99% or at least about 99.5%.
- the first compound of the invention has at least one stereocenter and is enantiomerically pure (enantiomeric excess is about 100%).
- the first compound of the invention can be present in a diastereomeric excess of at least about 80%, or at least about 90%, or at least about 92% or at least about 95%. In situations where the first compound of the invention and at least one diastereomer of the first compound of the invention are present in a composition, the first compound of the invention can be present in a diastereomeric excess of at least about 96%, at least about 97%, at least about 98%>, at least about 99% or at least about 99.5%. In another embodiment, the first compound of the invention has at least two
- Enantiomeric or diastereomeric excess can be determined relative to exactly one other stereoisomer, or can be determined relative to the sum of at least two other stereoisomers.
- enantiomeric or diastereomeric excess can be determined relative to exactly one other stereoisomer, or can be determined relative to the sum of at least two other stereoisomers.
- enantiomeric or diastereomeric excess can be determined relative to exactly one other stereoisomer, or can be determined relative to the sum of at least two other stereoisomers.
- enantiomeric or diastereomeric excess can be determined relative to exactly one other stereoisomer, or can be determined relative to the sum of at least two other stereoisomers.
- diastereomeric excess is determined relative to all other detectable stereoisomers, which are present in the mixture.
- Stereoisomers are detectable if a concentration of such stereoisomer in the analyzed mixture can be determined using common analytical methods, such as chiral HPLC.
- composition that is "substantially free" of a compound means that the composition contains less than about 20%) by weight, or less than about 15% by weight, or less than about 10%> by weight, or less than about 5% by weight, or less than about 3% by weight, or less than about 2%> by weight, or less than about 1% by weight of the compound.
- the term "substantially free of the (or its) enantiomer” means that a composition contains a significantly greater proportion of a first compound of the invention than a second compound of the invention, wherein the first compound is a non-superimposable mirror image of the second compound.
- the term “substantially free of the enantiomer” means that the composition is made up of at least about 90% by weight of a first compound of the invention, and about 10% by weight or less of a second compound of the invention, wherein the first compound is a non-superimposable mirror image of the second compound.
- the term "substantially free of the (R) enantiomer” means that the composition is made up of at least about 90% by weight of a first compound of the invention which has only one stereocenter and the stereocenter is in an (S) configuration, and about 10% by weight or less of a second compound of the invention, wherein the second compound is the enantiomer of the first compound.
- the term “substantially free of the enantiomer” means that the composition is made up of at least about 95% by weight of a first compound of the invention, and about 5% by weight or less of a second compound of the invention, wherein the first compound is a non- superimposable mirror image of the second compound.
- the term "substantially free of the (R) enantiomer” means that the composition is made up of at least about 95% by weight of a first compound of the invention which has only one stereocenter and the stereocenter is in an (S) configuration, and about 5% by weight or less of a second compound of the invention, wherein the second compound is the enantiomer of the first compound.
- the term “substantially free of the enantiomer” means that the composition is made up of at least about 98% by weight of a first compound of the invention, and about 2% by weight or less of a second compound of the invention, wherein the first compound is a non-superimposable mirror image of the second compound.
- the term "substantially free of the (R) enantiomer” means that the composition is made up of at least about 98% by weight of a first compound of the invention which has only one stereocenter and the stereocenter is in an (S) configuration, and about 2% by weight or less of a second compound of the invention, wherein the second compound is the enantiomer of the first compound.
- the term “substantially free of the enantiomer” means that the composition is made up of at least about 99% by weight of a first compound of the invention, and about 1% by weight or less of a second compound of the invention, wherein the first compound is a non- superimposable mirror image of the second compound.
- the term "substantially free of the (R) enantiomer” means that the composition is made up of at least about 99% by weight of a first compound of the invention which has only one stereocenter and the stereocenter is in an (S) configuration, and about 1% by weight or less of a second compound of the invention, wherein the second compound is the enantiomer of the first compound.
- the invention provides a composition comprising a) first compound described herein ; and b) the enantiomer of the first compound, wherein the first compound described herein is present in an enantiomeric excess of at least 80%. In an exemplary embodiment, the enantiomeric excess is at least 92%. III. c) Preparation of Compounds
- Compounds of use in the invention can be prepared using commercially available starting materials or known intermediates. Compounds of use in the invention can be prepared using synthetic methods known in the art or described herein. Preparation of compounds are as described herein.
- the compounds of the invention exhibit potency against tumors, especially in conjunction with boron neutron capture therapy.
- the invention provides a method of treating a tumor through the use of boron neutron capture therapy.
- the method includes administering to the animal a therapeutically effective amount of the compound of the invention, sufficient to treat and/or prevent the disease.
- the compound is described herein, or a salt, prodrug, hydrate or solvate thereof, or a combination thereof.
- the invention provides a compound described herein, or a prodrug thereof.
- the invention provides a compound described herein, or a salt, hydrate or solvate thereof.
- the invention provides a compound described herein, or a salt thereof.
- the compound of the invention is a compound described herein, or a pharmaceutically acceptable salt thereof.
- the compound is a compound described herein, or a pharmaceutically acceptable salt thereof.
- the compound is according to a formula described herein, or a pharmaceutically acceptable salt thereof.
- the compound is part of a pharmaceutical formulation described herein.
- the animal is selected from the group consisting of human, cattle, deer, reindeer, goat, honey bee, pig, sheep, horse, cow, bull, dog, guinea pig, gerbil, rabbit, cat, camel, yak, elephant, ostrich, otter, chicken, duck, goose, guinea fowl, pigeon, swan, and turkey.
- the animal is a human.
- the animal is selected from the group consisting of a human, cattle, goat, pig, sheep, horse, cow, bull, dog, guinea pig, gerbil, rabbit, cat, chicken and turkey.
- the invention is a pharmaceutical formulation which includes: (a) a pharmaceutically acceptable excipient; and (b) a compound of the invention.
- the pharmaceutical formulation includes: (a) a pharmaceutically acceptable excipient; and (b) a compound according to a formula described herein.
- the pharmaceutical formulation includes: (a) a pharmaceutically acceptable excipient; and (b) a compound described herein, or a salt, prodrug, hydrate or solvate thereof.
- the pharmaceutical formulation includes: (a) a pharmaceutically acceptable excipient; and (b) a compound described herein, or a salt, hydrate or solvate thereof.
- the pharmaceutical formulation includes: (a) a pharmaceutically acceptable excipient; and (b) a compound described herein, or a salt, hydrate or solvate thereof.
- the pharmaceutical formulation includes: (a) a pharmaceutically acceptable excipient; and (b) a salt of a compound described herein.
- the salt is a pharmaceutically acceptable salt.
- the pharmaceutical formulation includes: (a) a pharmaceutically acceptable excipient; and (b) a prodrug of a compound described herein.
- the pharmaceutical formulation includes: (a) a pharmaceutically acceptable excipient; and (b) a compound described herein.
- the pharmaceutical formulation is a unit dosage form. In an exemplary embodiment, the pharmaceutical formulation is a single unit dosage form.
- the invention is a compound having a structure which is:
- R 1 is H or substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl or substituted or unsubstituted cycloalkyl or substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
- R 2 and R 3 are independently selected from H or substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl or substituted or unsubstituted cycloalkyl or substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or a salt thereof.
- the invention provides a pharmaceutical formulation comprising a) the compound according to any of the above paragraphs, or a pharmaceutically acceptable salt thereof, and b) a pharmaceutically acceptable excipient.
- the invention provides a method of tumor therapy, comprising administering a
- Reagents and conditions (a) triflate chloride, DMAP, dichloromethane, 0 °C, 1 h, 80%; (b) pinacol diboron, Pd(dppf)Cl 2 , KOAc, dioxane, N 2 , 80 °C, 16 h, 55%; (c) NaBH 4 , MeOH, r.t., 2 h, then 6N HC1, 12 h, 32% for 7, 39% for 8; (d) Pd/C, EtOH, H 2 , 10 h, 89%; (e) LiOH, MeOH, H 2 0, 30 min, r.t., 64%.
- Hydroxybenzaldehyde 4 was prepared according to Kalesh, K. A. et. al, Chem. Commun., 2010, 46, 589-591. Hydroxybenzaldehyde 4 was converted to its triflate derivative 5 in 80% yield by reaction with triflate chloride in dichloromethane. Without further purification, crude 5 was allowed to react with pinacol diboron in the presence of Pd(dppf)Cl 2 , Nakamura, H. et. al, J. Org. Chem. 1998, 63, 7529-7530, to afford boronate 6 in 55 > yield.
- benzoxaborole ring formation was accomplished by using a one-pot procedure as previously described in Zhang, Y.-K., et. al, Bioorg. Med. Chem. Lett. 2010, 20, 2270-2274. This included the treatment of 6 with sodium borohydride in methanol to convert the aldehyde to a hydroxylmethyl group. The hydroxylmethyl group simultaneously cyclized to the adjacent boronate and subsequently hydrolyzed to form the corresponding benzoxaborole ring upon addition of aqueous hydrochloric acid. Boc protecting group was also removed in this step resulting in the desired benzyl ester 7 in 32%> yield.
- BPA 1 has a solubility of 1.7 mg/mL, which is in consistent with the reported value (1.6 mg/mL) (Mori, Y. et. ⁇ , Pigment Cell Res. 1989, 2, 273-277; Nemoto, H., et. al, J. Med. Chem. 1995, 38, 1673-1678).
- compounds 2 and 3 exhibit improved water solubility of 5.2 mg/mL and 3.6 mg/mL, respectively. Their better solubility could be attributable to the lower pK a since the benzoxaborole would exist in anionic tetrahedral form to a significant extent at physiological pH. Compound 2 is more soluble than 3.
- One potential explanation is that the presence of the electron-donating oxygen atom para to the benzoxaborole in 3 would increase its pK a value and thus decrease its water solubility.
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Abstract
This invention provides benzoxaborole-containing phenylalanine analogues useful in boron neutron capture therapy.
Description
[0001] This invention provides, among other things, novel compounds useful in boron neutron capture therapy.
[0002] As used herein, the singular forms "a," "an", and "the" include plural references unless the context clearly dictates otherwise. For example, reference to "an active agent" includes a single active agent as well as two or more different active agents in combination. It is to be understood that present teaching is not limited to the specific dosage forms, carriers, or the like, disclosed herein and as such may vary.
[0003] The abbreviations used herein generally have their conventional meaning within the chemical and biological arts, [0004] The following abbreviations have been used: Ac is acetyl; AcOH is acetic acid; ACTBr is cetyltrimethy [ammonium bromide; AIBN is azobisisobut ronitriie or 2,2 azobisisobutvronitriie; aq. is aqueous; Ar is aryl; B2pin2 is bis(pinacolato)diboron; Bn is, in general, benzyl [see Cbz for one example of an exception]; (BnS)2 is benzyl disulfide; BnSH is benzyl thiol or benzyl mercaptan; BnBr is benzyl bromide; Boc is tert-butoxy carbonyl; Boc20 is di-terf-butyl dicarbonate; Bz is, in general, benzoyl; BzOOH is benzoyl peroxide; Cbz or Z is benzyloxycarbonyl or carboxybenzyl;
CS2CO3 is cesium carbonate: CSA is camphor sulfonic acid; CTAB is
cetyltrimethylammomuro bromide; Cy is cyc!ohexyl; DABCO is 1,4- diazabicyclo[2.2.2]octane; DCM is dichloromethane or methylene chloride; DHP is dihydropyran; DiAD is diisopropyl azodicarboxylate; DIEA or DIPEA is N,N~ diisopropylethylamine; DMAP is 4-(dimethylamino)pyrtdine; DME is 1 ,2- dimethoxyethane; DMF is ,N-dimethy[formamide; DM SO is dimethylsulfoxide; equiv or eq. is equivalent; EtOAc is ethyl acetate; EtOH is ethano!; Et20 is diethyl ether; EDCi is Ar-(3-dimethylaminopropyl)-.N'~ethylcarbodiimide hydrochloride; ELS is evaporative light scattering; equiv or eq is equivalent; h is hours; HATU is 0-(7- azabenzotriazo[-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; HOBt is
N-hydroxybenzotriazole; HC1 is hydrochloric acid; HPLC is high pressure liquid chromatography; ISCO Companion is automated flash chromatography equipment with fraction analysis by UV absorption available from Presearch; KOAc or AcOK is potassium acetate; K2CO3 is potassium carbonate; L1AIH4 or LAH is lithium aluminum hydride; LDA is lithium diisopropylamide; LHMDS is lithium
bis(trimethylsilyl) amide; KHMDS is potassium bis(trimethylsilyl) amide; LiOH is lithium hydroxide; m-CPBA is 3-chloroperoxybenzoic acid; MeCN or ACN is methyl cyanide or cyanomethane or ethanenitrile or acetonitrile which are all names for the same compound; MeOH is methanol; MgS04 is magnesium sulfate; mins or min is minutes; Mp or MP is melting point; NaCNBH3 is sodium cyanoborohydride; NaOH is sodium hydroxide; Na2S04 is sodium sulfate; NBS is N-bromosuccinimide; NH4C1 is ammonium chloride; NIS is N-iodosuccinimide; N2 is nitrogen; NMM is N- methylmorpholine; n-BuLi is n-butyllithium; overnight is O/N; PdCl2(pddf) is Ι,Γ- Bis(diphenylphosphino) ferrocene]dichloropalladium(II); Pd/C is the catalyst known as palladium on carbon; Pd2(dba)3 is an organometallic catalyst known as
tris(dibenzylideneacetone) dipalladium(O); Ra Ni or Raney Ni is Raney nickel; Ph is phenyl; PMB is /?-methoxybenzyl; PrOH is 1-propanol; iPrOH is 2-propanol; POCl3 is phosphorus chloride oxide; PTSA is /?ara-toluene sulfonic acid; Pyr. or Pyr or Py as used herein means pyridine; RT or rt or r.t. is room temperature; sat. is saturated; Si- amine or Si-NH2 is amino-functionalized silica, available from SiliCycle; Si-pyr is pyridyl-functionalized silica, available from SiliCycle; TEA or Et3N is triethylamine; TFA is trifluoroacetic acid; Tf20 is trifluoromethanesulfonic anhydride; THF is tetrahydrofuran; TFAA is trifluoroacetic anhydride; THP is tetrahydropyranyl; TMSI is trimethylsilyl iodide; H20 is water; diN02PhS02Cl is dinitrophenyl sulfonyl chloride; 3-F-4-N02-PhS02Cl is 3-f uoro-4-nitrophenylsulfonyl chloride; 2-MeO-4- N02-PhS02Cl is 2-methoxy-4-nitrophenylsulfonyl chloride; and
(EtO)2POCH2COOEt is a triethylester of phosphonoacetic acid known as triethyl phosphonoacetate.
[0005] "Compound of the invention," as used herein refers to the compounds discussed herein, salts (e.g. pharmaceutically acceptable salts), prodrugs, solvates and hydrates of these compounds.
[0006] The term "poly" as used herein means at least 2. For example, a polyvalent metal ion is a metal ion having a valency of at least 2.
[0007] "Moiety" refers to a radical of a molecule that is attached to the remainder of the molecule.
[0008] The symbol /VWP s whether utilized as a bond or displayed perpendicular to a bond, indicates the point at which the displayed moiety is attached to the remainder of the molecule.
[0009] The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e. Ci-Cio means one to ten carbons). In some embodiments, the term "alkyl" means a straight or branched chain, or combinations thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl,
(cyclohexyl)methyl, cyclopropylmethyl, homo logs and isomers of, for example, n- pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3- butynyl, and the higher homo logs and isomers.
[0010] The term "alkylene" by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified, but not limited, by
-CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the invention. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
[0011] The term "alkenylene" by itself or as part of another substituent means a divalent radical derived from an alkene.
[0012] The term "cycloalkylene" by itself or as part of another substituent means a divalent radical derived from a cycloalkyl.
[0013] The term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from an heteroalkane.
[0014] The term "heterocycloalkylene" by itself or as part of another substituent means a divalent radical derived from an heterocycloalkane. [0015] The term "arylene" by itself or as part of another substituent means a divalent radical derived from an aryl.
[0016] The term "heteroarylene" by itself or as part of another substituent means a divalent radical derived from heteroaryl.
[0017] The terms "alkoxy," "alkylamino" and "alkylthio" (or thioalkoxy) are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively.
[0018] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the stated number of carbon atoms and at least one heteroatom. In some embodiments, the term
"heteroalkyl," by itself or in combination with another term, means a stable straight or branched chain, or combinations thereof, consisting of the stated number of carbon atoms and at least one heteroatom. In an exemplary embodiment, the heteroatoms can be selected from the group consisting of B, O, N and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) B, O, N and S may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, -CH2- CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2- CH2,-S(0)-CH3, -CH2-CH2-S(0)2-CH3, -CH=CH-0-CH3, -CH2-CH=N-OCH3, and - CH=CH-N(CH3)-CH3. Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3. Similarly, the term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of
the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(0)2R'- represents both -C(0)2R'- and - R'C(0)2-.
[0019] The terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of "alkyl" and "heteroalkyl", respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1 -(1,2,5,6- tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3- morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1 -piperazinyl, 2-piperazinyl, and the like.
[0020] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl," are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(Ci-C4)alkyl" is mean to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. [0021] The term "aryl" means, unless otherwise stated, a polyunsaturated, aromatic, substituent that can be a single ring or multiple rings (preferably from 1 or 2 or 3 rings), which are fused together or linked covalently. The term "heteroaryl" refers to aryl groups (or rings) that contain from one to four heteroatoms. In an exemplary embodiment, the heteroatom is selected from B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3- pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4- oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-
isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.
[0022] For brevity, the term "aryl" when used in combination with other terms (e.g. , aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined herein. Thus, the term "arylalkyl" is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g. , benzyl, phenethyl, pyridiylethyl and the like) including those alkyl groups in which a carbon atom (e.g. a methylene group) has been replaced by, for example, an oxygen atom (e.g. , phenoxymethyl, 2- pyridyloxymethyl, 3-(l-naphthyloxy)propyl, and the like).
[0023] For brevity, the term "heteroaryl" when used in combination with other terms (e.g., hetero aryloxy, heteroarylthioxy, heteroarylalkyl) includes those radicals in which a heteroaryl group is attached through the next moiety to the rest of the molecule. Thus, the term "heteroarylalkyl" is meant to include those radicals in which a heteroaryl group is attached to an alkyl group (e.g., pyridylmethyl and the like). The term "heteroaryloxy" is meant to include those radicals in which a heteroaryl group is attached to an oxygen atom. The term "heteroaryloxyalkyl" is meant to include those radicals in which an aryl group is attached to an oxygen atom which is then attached to an alkyl group, (e.g., 2-pyridyloxymethyl and the like). [0024] Each of the above terms (e.g., "alkyl," "heteroalkyl," "aryl" and
"heteroaryl") are meant to include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.
[0025] Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) are generically referred to as "alkyl group substituents," and they can be one or more of a variety of groups selected from, but not limited to: -R', -OR', =0, =NR', =N-OR', -NR'R", - SR', -halogen, -SiR'R"R"', -OC(0)R', -C(0)R', -C02R', -CONR'R", -OC(0)NR'R", -NR"C(0)R', -NR'-C(0)NR"R"', -NR"C(0)2R', -NR,""-C(NR'R"R'")=NR"", -NR""-C(NR'R")=NR'", -S(0)R', -S(0)2R', -S(0)2NR'R", -NR"S02R', -CN, -N02, -N3, -CH(Ph)2, fluoro(Ci-C4)alkoxy, and fluoro(Ci-C4)alkyl, in a number ranging from zero to (2m'+l), where m' is the total number of carbon atoms in such radical.
R', R", R'", R"" and R'"" each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, e.g. , aryl substituted with 1 or 2 or 3 halogens, substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups. When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R', R", R'", R"" and R'"" groups when more than one of these groups is present. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring. For example, -NR'R" is meant to include, but not be limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term "alkyl" is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl {e.g., -CF3 and -CH2CF3) and acyl {e.g., -C(0)CH3, -C(0)CF3, -C(0)CH2OCH3, and the like).
[0026] Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are generically referred to as "aryl group substituents." The substituents are selected from, for example: -R', -OR', =0, =NR', =N-OR', - NR'R", -SR.', -halogen, -SiR'R"R"', -OC(0)R', -C(0)R\ -C02R', -CONR'R", - OC(0)NR'R", -NR"C(0)R', -NR'-C(0)NR"R"', -NR"C(0)2R', -NR'""- C(NR'R"R"')=NR"", -NR""-C(NR'R")=NR"', -S(0)R', -S(0)2R', -S(0)2NR'R", -NR"S02R', -CN, -N02, -N3, -CH(Ph)2, fluoro(Ci-C4)alkoxy, and fhioro(Ci-C4)alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R", R'", R"" and R'"" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted heteroalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R', R", R'", R"" and R'"" groups when more than one of these groups is present.
[0027] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(0)-(CRR')q-U-, wherein T and U are independently -NR-, -0-, -CRR'- or a single bond, and q is an integer from 0 or 1 or 2 or 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)r-B-, wherein A and B are independently -CRR'-, -0-, -NR-, -S-, -
S(O)-, -S(0)2-, -S(0)2NR'- or a single bond, and r is an integer from 1 or 2 or 3 or 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula - (CRR')s-X-(CR"R'")d-, where s and d are independently integers from 0 or 1 or 2 or 3, and X is -0-, -NR'-, -S-, -S(O)-, -S(0)2-, or -S(0)2NR'-. The substituents R, R', R" and R'" are preferably independently selected from hydrogen or substituted or unsubstituted (Ci or C2 or C3 or C4 or C5 or C6)alkyl.
[0028] "Ring" as used herein, means a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. A ring includes fused ring moieties. The number of atoms in a ring is typically defined by the number of members in the ring. For example, a "5- to 7-membered ring" means there are 5 or 6 or 7 atoms in the encircling arrangement. Unless otherwise specified, the ring optionally includes a heteroatom. Thus, the term "5- to 7-membered ring" includes, for example phenyl, pyridinyl and piperidinyl. The term "5- to 7-membered heterocycloalkyl ring", on the other hand, would include pyridinyl and piperidinyl, but not phenyl. The term "ring" further includes a ring system comprising more than one "ring", wherein each "ring" is independently defined as above. [0029] As used herein, the term "heteroatom" includes atoms other than carbon (C) and hydrogen (H). Examples include oxygen (O), nitrogen (N) sulfur (S), silicon (Si), and boron (B).
[0030] The term "leaving group" means a functional group or atom which can be displaced by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction. By way of example, representative leaving groups include triflate, chloro, bromo and iodo groups; sulfonic ester groups, such as mesylate, tosylate, brosylate, nosylate and the like; and acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.
[0031] The symbol "R" is a general abbreviation that represents a substituent group that is selected from substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocycloalkyl groups.
[0032] By "effective" amount of a drug, formulation, or permeant is meant a sufficient amount of an active agent to provide the desired local or systemic effect. A "Topically effective," "pharmaceutically effective," or "therapeutically effective" amount refers to the amount of drug needed to effect the desired therapeutic result.
[0033] The term "pharmaceutically acceptable salt" is meant to include a salt of a compound of the invention which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino (such as choline or diethylamine or amino acids such as d-arginine, 1-arginine, d- lysine, or 1-lysine), or magnesium salt, or a similar salt. When compounds of the invention contain relatively basic
functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric,
dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric,
methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
[0034] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compounds in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents. [0035] In addition to salt forms, the invention provides compounds which are in a prodrug form. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to provide the compounds of the invention. Additionally, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an ex vivo environment. [0036] Certain compounds of the invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the invention. Certain compounds of the invention may exist in multiple crystalline or amorphous forms. [0037] Certain compounds of the invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and individual isomers are encompassed within the scope of the invention. The graphic representations of racemic, ambiscalemic and scalemic or enantiomerically pure compounds used herein are taken from Maehr, J. Chem. Ed. 1985, 62: 114-120. Solid and broken wedges are used to denote the absolute configuration of a stereocenter unless otherwise noted. When the compounds described herein contain olefmic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are included. [0038] Compounds of the invention can exist in particular geometric or stereoisomeric forms. The invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, as falling within the scope of the invention. Additional asymmetric carbon atoms can be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
[0039] Optically active (R)- and (5)-isomers and d and / isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If, for instance, a particular enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis, or by derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as an amino group, or an acidic functional group, such as a carboxyl group, diastereomeric salts can be formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means known in the art, and subsequent recovery of the pure enantiomers. In addition, separation of enantiomers and diastereomers is frequently accomplished using chromatography employing chiral, stationary phases, optionally in combination with chemical derivatization (e.g., formation of carbamates from amines). [0040] The compounds of the invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I) or carbon-14 (14C). All isotopic variations of the compounds of the invention, whether radioactive or not, are intended to be encompassed within the scope of the invention.
[0041] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable vehicle" refers to any formulation or carrier medium that provides the appropriate delivery of an effective amount of an active agent as defined herein, does not interfere with the effectiveness of the biological activity of the active agent, and that is sufficiently non-toxic to the host or patient. Representative carriers include water, oils, both vegetable and mineral, cream bases, lotion bases, ointment bases and the like. These bases include suspending agents, thickeners, penetration enhancers, and the like. Their formulation is well known to those in the art of cosmetics and topical pharmaceuticals. Additional information concerning carriers can be found in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005) which is incorporated herein by reference.
[0042] The term "excipients" is conventionally known to mean carriers, diluents and/or vehicles used in formulating drug compositions effective for the desired use.
[0043] "Biological medium," as used herein refers to both in vitro and in vivo biological milieus. Exemplary in vitro "biological media" include, but are not limited to, cell culture, tissue culture, homogenates, plasma and blood. In vivo applications are generally performed in mammals, preferably humans.
[0044] Boron is able to form additional covalent or dative bonds with oxygen, sulfur or nitrogen under some circumstances in this invention.
[0045] Embodiments of the invention also encompass compounds that are poly- or multi-valent species, including, for example, species such as dimers, trimers, tetramers and higher homologs of the compounds of use in the invention or reactive analogues thereof.
[0046] "Salt counterion", as used herein, refers to positively charged ions that associate with a compound of the invention when the boron is fully negatively or partially negatively charged. Examples of salt counterions include H+, H30+, ammonium, potassium, calcium, magnesium, organic amino (such as choline or diethylamine or amino acids such as d-arginine, 1-arginine, d-lysine, or 1-lysine) and sodium.
[0047] The compounds comprising a boron bonded to a carbon and three heteroatoms (such as three oxygens described in this section) can optionally contain a fully negatively charged boron or partially negatively charged boron. Due to the negative charge, a positively charged counterion may associate with this compound, thus forming a salt. Examples of positively charged counterions include H+, H30+, ammonium, potassium, calcium, magnesium, organic amino (such as choline or diethylamine or amino acids such as d-arginine, 1-arginine, d-lysine, 1-lysine), and sodium. These salts of the compounds are implicitly contained in descriptions of these compounds.
77. Introduction
[0048] The invention provides novel boron compounds, method of making such compounds, methods of using such compounds to treat diseases, and pharmaceutical formulations including such compounds. The compounds of the invention can be
used in combination with boron neutron capture therapy to treat a disease, such as, for example, cancer.
[0049] /?-Boronophenylalanine (BPA, 1) is a boronated amino acid which exhibits a specific affinity for tumor cells.
Its B-enriched form has been employed in Boron Neutron Capture Therapy (BNCT) for treatments of patients affected by different types of cancer. Yang, W. et al., Biological and Medicinal Applications of Boronic Acids. In Boronic Acids; Hall, D. G. Ed; Wiley- VCH: Weinheim, Germany, 2005; pp 481-512. Upon irradiation with thermal neutrons, BPA absorbs neutrons and self-destructs to release lithium ion (7Li) and alpha-particles (4He) of high energy in tumor cells, leading to radiation-induced cell death. However, the clinical use of BPA is limited by its poor water solubility at physiological pH. There has been a lack of new boron delivery agents to achieve effective neutron capture therapy of cancer. Barth, R. F. Appl. Radiat. Isot. 2009, 67, S3-S6. To facilitate the delivery of BPA to tissue sites, the complex formation of
BPA with fructose or mannitol has been proposed to produce a water soluble form of BPA for BNCT. Mori, Y. et al, Pigment Cell Res. 1989, 2, 273-277. Also, the continued development of new boron delivery agents, including boron-containing amino acids or BPA analogues with water-solubilizing groups, is the subject of extensive research.
[0050] Benzoxaboroles are boron-containing heterocycles that have emerged as a new class of potential therapeutics. The benzoxaborole core has been shown to have a lower pK» value (pK» 7.2) (Dowlut, M. et al, J. Am. Chem. Soc. 2006, 128, 4226- 4227) compared to that of phenylboronc acid (pKa 8.9), (Westmark, P. R. et al., J. Am. Chem. Soc. 1996, 118, 11093-11100) suggesting that it exists about 50% in anionic tetrahedral form at physiological pH and thus has an enhanced water solubility. The incorporation of benzoxaborole in phenylalanine resulted in boron delivery agents with improved physicochemical properties including water solubility at physiological pH. These improved properties suggest that these compounds are useful as boron delivery agents for boron neutron capture therapy.
///. The Compounds
III. a) Cyclic Boronic Esters
[0051] In one aspect, the invention provides a compound of the invention. In an exemplary embodiment, the invention provides a compound described herein.
[0052] In another aspect, the invention provides a compound having a structure according to the formula which is:
collectively referred to herein as Formula I, wherein R is H or substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl or substituted or unsubstituted cycloalkyl or substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R2 and R3 are independently selected from H or substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl or substituted or unsubstituted cycloalkyl or substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or a salt thereof. In an exemplary embodiment, R1 is H and
R2 and R3 are as defined herein. In an exemplary embodiment, R2 is H and R1 and R3 are as defined herein. In an exemplary embodiment, R1 is H, R3 is H, and R2 is as defined herein.
[0053] In another aspect, the invention provides a compound which is:
[0054] In another aspect, the invention provides a compound which is:
[0055] In an exemplary embodiment, the invention provides a compound described herein, or a salt, hydrate or solvate thereof, or a combination thereof. In an exemplary embodiment, the invention provides a compound described herein, or a salt, hydrate or solvate thereof. In an exemplary embodiment, the invention provides a compound described herein, or a salt thereof. In an exemplary embodiment, the salt is a pharmaceutically acceptable salt. In an exemplary embodiment, the invention
provides a compound described herein, or a hydrate thereof. In an exemplary embodiment, the invention provides a compound described herein, or a solvate thereof. In an exemplary embodiment, the invention provides a compound described herein, or a prodrug thereof. In an exemplary embodiment, the invention provides a salt of a compound described herein. In an exemplary embodiment, the invention provides a pharmaceutically acceptable salt of a compound described herein. In an exemplary embodiment, the invention provides a hydrate of a compound described herein. In an exemplary embodiment, the invention provides a solvate of a compound described herein. In an exemplary embodiment, the invention provides a prodrug of a compound described herein.
[0056] In an exemplary embodiment, alkyl is linear alkyl. In another exemplary embodiment, alkyl is branched alkyl.
[0057] In an exemplary embodiment, heteroalkyl is linear heteroalkyl. In another exemplary embodiment, heteroalkyl is branched heteroalkyl. IILb) Compositions involving stereoisomers
[0058] As used herein, the term "chiral", "enantiomerically enriched" or
"diastereomerically enriched" refers to a composition having an enantiomeric excess (ee) or a diastereomeric excess (de) of greater than about 50%, preferably greater than about 70% and more preferably greater than about 90%. In general, higher than about 90%) enantiomeric or diastereomeric excess is particularly preferred, e.g., those compositions with greater than about 95%, greater than about 97% and greater than about 99%) ee or de.
[0059] When a first compound and a second compound are present in a composition, and the first compound is a non-superimposable mirror image of the second compound, and the first compound is present in the composition in a greater amount than the second compound, then the first compound is referred to herein as being present in "enantiomeric excess".
[ cone, oj z + cone, oj yj
wherein z is a first compound in a composition, y is a second compound in the composition, and the first compound is a non-superimposable mirror image of the second compound.
[0061] The term "enantiomeric excess" is related to the older term "optical purity" in that both are measures of the same phenomenon. The value of ee will be a number from 0 to 100, zero being racemic and 100 being enantiomerically pure. A composition which in the past might have been called 98% optically pure is now more precisely characterized by 96% ee. A 90%> ee reflects the presence of 95% of one enantiomer and 5% of the other(s) in the material in question. [0062] When a first compound and at least one additional compound are present in a composition, and the first compound and each of the additional compounds are stereoisomers, but not mirror images, of one another, and the first compound is present in the composition in a greater amount than each of the additional compounds, then the first compound is referred to herein as being present in
"diastereomeric excess".
[0063] When dealing with mixtures of diastereomers, the term "diastereomeric excess" or "de" is defined analagously to enantiomeric excess. Thus:
_ cone, of major diastereomer - cone, of min or diastereomer is) ^
conc. of major diastereomer + cone, of min or diastereomer -(s) J wherein the major diastereomer is a first compound in a composition, and the minor diastereomer(s) is at least one additional compound in the composition, and the major diastereomer and minor diastereomer(s) are stereoisomers, but not mirror images, of one another.
[0064] The value of de will likewise be a number from 0 to 100, zero being an equal mixture of a first diastereomer and the remaining diastereomer(s), and 100 being 100% of a single diastereomer and zero% of the other(s) - i.e.
diastereomerically pure. Thus, 90% de reflects the presence of 95% of one diastereomer and 5% of the other diastereomer(s) in the material in question.
[0065] Hence, in one embodiment, the invention provides a composition including a first compound of the invention, wherein the first compound of the invention has at least one stereocenter, and at least one stereoisomer of the first compound of the invention. In another embodiment, the invention provides a
composition including a first compound of the invention, wherein the first compound of the invention has at least one stereocenter, and a second compound of the invention, wherein the first compound of the invention is a stereoisomer of the second compound of the invention. In another embodiment, the invention provides a composition including a first compound of the invention, wherein the first compound of the invention has at least one stereocenter, and only one stereoisomer of the first compound of the invention.
[0066] In another embodiment, the invention provides a composition including a first compound of the invention, wherein the first compound of the invention has only one stereocenter, and an enantiomer of the first compound of the invention. In another embodiment, the invention provides a composition including a first compound of the invention, wherein the first compound of the invention has two stereocenters, and an enantiomer of the first compound of the invention. In another embodiment, the invention provides a composition including a first compound of the invention, wherein the first compound of the invention has two stereocenters, and at least one diasteromer of the first compound of the invention. In another embodiment, the invention provides a composition including a first compound of the invention, wherein the first compound of the invention has two stereocenters, and only one diasteromer of the first compound of the invention. [0067] In situations where the first compound of the invention and its enantiomer are present in a composition, the first compound of the invention can be present in an enantiomeric excess of at least about 80%, or at least about 90%, or at least about 92% or at least about 95%. In another embodiment, where the first compound of the invention and its enantiomer are present in a composition, the first compound of the invention can be present in an enantiomeric excess of at least about 96%, at least about 97%, at least about 98%, at least about 99% or at least about 99.5%. In another embodiment, the first compound of the invention has at least one stereocenter and is enantiomerically pure (enantiomeric excess is about 100%).
[0068] In situations where the first compound of the invention and at least one diastereomer of the first compound of the invention are present in a composition, the first compound of the invention can be present in a diastereomeric excess of at least about 80%, or at least about 90%, or at least about 92% or at least about 95%. In situations where the first compound of the invention and at least one diastereomer of
the first compound of the invention are present in a composition, the first compound of the invention can be present in a diastereomeric excess of at least about 96%, at least about 97%, at least about 98%>, at least about 99% or at least about 99.5%. In another embodiment, the first compound of the invention has at least two
stereocenters and is diastereomerically pure (diastereomeric excess is about 100%).
[0069] Enantiomeric or diastereomeric excess can be determined relative to exactly one other stereoisomer, or can be determined relative to the sum of at least two other stereoisomers. In an exemplary embodiment, enantiomeric or
diastereomeric excess is determined relative to all other detectable stereoisomers, which are present in the mixture. Stereoisomers are detectable if a concentration of such stereoisomer in the analyzed mixture can be determined using common analytical methods, such as chiral HPLC.
[0070] As used herein, and unless otherwise indicated, a composition that is "substantially free" of a compound means that the composition contains less than about 20%) by weight, or less than about 15% by weight, or less than about 10%> by weight, or less than about 5% by weight, or less than about 3% by weight, or less than about 2%> by weight, or less than about 1% by weight of the compound.
[0071] As used herein, the term "substantially free of the (or its) enantiomer" means that a composition contains a significantly greater proportion of a first compound of the invention than a second compound of the invention, wherein the first compound is a non-superimposable mirror image of the second compound. In one embodiment of the invention, the term "substantially free of the enantiomer" means that the composition is made up of at least about 90% by weight of a first compound of the invention, and about 10% by weight or less of a second compound of the invention, wherein the first compound is a non-superimposable mirror image of the second compound. In one embodiment of the invention, the term "substantially free of the (R) enantiomer" means that the composition is made up of at least about 90% by weight of a first compound of the invention which has only one stereocenter and the stereocenter is in an (S) configuration, and about 10% by weight or less of a second compound of the invention, wherein the second compound is the enantiomer of the first compound. In one embodiment of the invention, the term "substantially free of the enantiomer" means that the composition is made up of at least about 95% by weight of a first compound of the invention, and about 5% by weight or less of a
second compound of the invention, wherein the first compound is a non- superimposable mirror image of the second compound. In one embodiment of the invention, the term "substantially free of the (R) enantiomer" means that the composition is made up of at least about 95% by weight of a first compound of the invention which has only one stereocenter and the stereocenter is in an (S) configuration, and about 5% by weight or less of a second compound of the invention, wherein the second compound is the enantiomer of the first compound. In one embodiment of the invention, the term "substantially free of the enantiomer" means that the composition is made up of at least about 98% by weight of a first compound of the invention, and about 2% by weight or less of a second compound of the invention, wherein the first compound is a non-superimposable mirror image of the second compound. In one embodiment of the invention, the term "substantially free of the (R) enantiomer" means that the composition is made up of at least about 98% by weight of a first compound of the invention which has only one stereocenter and the stereocenter is in an (S) configuration, and about 2% by weight or less of a second compound of the invention, wherein the second compound is the enantiomer of the first compound. In one embodiment of the invention, the term "substantially free of the enantiomer" means that the composition is made up of at least about 99% by weight of a first compound of the invention, and about 1% by weight or less of a second compound of the invention, wherein the first compound is a non- superimposable mirror image of the second compound. In one embodiment of the invention, the term "substantially free of the (R) enantiomer" means that the composition is made up of at least about 99% by weight of a first compound of the invention which has only one stereocenter and the stereocenter is in an (S) configuration, and about 1% by weight or less of a second compound of the invention, wherein the second compound is the enantiomer of the first compound.
[0072] In an exemplary embodiment, the invention provides a composition comprising a) first compound described herein ; and b) the enantiomer of the first compound, wherein the first compound described herein is present in an enantiomeric excess of at least 80%. In an exemplary embodiment, the enantiomeric excess is at least 92%.
III. c) Preparation of Compounds
[0073] Compounds of use in the invention can be prepared using commercially available starting materials or known intermediates. Compounds of use in the invention can be prepared using synthetic methods known in the art or described herein. Preparation of compounds are as described herein.
IV. Methods of Treating and/or Preventing Disease
[0074] The compounds of the invention exhibit potency against tumors, especially in conjunction with boron neutron capture therapy.
[0075] In another aspect, the invention provides a method of treating a tumor through the use of boron neutron capture therapy. The method includes administering to the animal a therapeutically effective amount of the compound of the invention, sufficient to treat and/or prevent the disease. In an exemplary embodiment, the compound is described herein, or a salt, prodrug, hydrate or solvate thereof, or a combination thereof. In an exemplary embodiment, the invention provides a compound described herein, or a prodrug thereof. In an exemplary embodiment, the invention provides a compound described herein, or a salt, hydrate or solvate thereof. In an exemplary embodiment, the invention provides a compound described herein, or a salt thereof. In another exemplary embodiment, the compound of the invention is a compound described herein, or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is a compound described herein, or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is according to a formula described herein, or a pharmaceutically acceptable salt thereof. In an exemplary embodiment, the compound is part of a pharmaceutical formulation described herein. In another exemplary embodiment, the animal is selected from the group consisting of human, cattle, deer, reindeer, goat, honey bee, pig, sheep, horse, cow, bull, dog, guinea pig, gerbil, rabbit, cat, camel, yak, elephant, ostrich, otter, chicken, duck, goose, guinea fowl, pigeon, swan, and turkey. In another exemplary embodiment, the animal is a human. In another exemplary embodiment, the animal is selected from the group consisting of a human, cattle, goat, pig, sheep, horse, cow, bull, dog, guinea pig, gerbil, rabbit, cat, chicken and turkey.
V. Pharmaceutical Formulations
[0076] In another aspect, the invention is a pharmaceutical formulation which includes: (a) a pharmaceutically acceptable excipient; and (b) a compound of the invention. In another aspect, the pharmaceutical formulation includes: (a) a pharmaceutically acceptable excipient; and (b) a compound according to a formula described herein. In another aspect, the pharmaceutical formulation includes: (a) a pharmaceutically acceptable excipient; and (b) a compound described herein, or a salt, prodrug, hydrate or solvate thereof. In another aspect, the pharmaceutical formulation includes: (a) a pharmaceutically acceptable excipient; and (b) a compound described herein, or a salt, hydrate or solvate thereof. In another aspect, the pharmaceutical formulation includes: (a) a pharmaceutically acceptable excipient; and (b) a compound described herein, or a salt, hydrate or solvate thereof. In another aspect, the pharmaceutical formulation includes: (a) a pharmaceutically acceptable excipient; and (b) a salt of a compound described herein. In an exemplary embodiment, the salt is a pharmaceutically acceptable salt. In another aspect, the pharmaceutical formulation includes: (a) a pharmaceutically acceptable excipient; and (b) a prodrug of a compound described herein. In another aspect, the pharmaceutical formulation includes: (a) a pharmaceutically acceptable excipient; and (b) a compound described herein. In an exemplary embodiment, the pharmaceutical formulation is a unit dosage form. In an exemplary embodiment, the pharmaceutical formulation is a single unit dosage form.
[0077] Information regarding excipients of use in the formulations of the invention can be found in Remington: The Science and Practice of Pharmacy, 21st Ed., Pharmaceutical Press (2011) which is incorporated herein by reference. [0078] Exemplary embodiments are summarized herein below.
wherein R1 is H or substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl or substituted or unsubstituted cycloalkyl or substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R2 and R3 are independently selected
from H or substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl or substituted or unsubstituted cycloalkyl or substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or a salt thereof.
[0080] In an exemplary embodiment, according to the above paragraph, wherein R1 is H.
[0081] In an exemplary embodiment, according to any of the above paragraphs, wherein R2 is H and R3 is H.
[0082] In an exemplary embodiment, according to any of the above paragraphs, wherein the compound has a structure which is:
[0083] In an exemplary embodiment, according to any of the above paragraphs, wherein the compound is for use in therapy.
[0084] In an exemplary embodiment, according to any of the above paragraphs, wherein the compound is for use in boron neutron capture therapy.
[0085] In an exemplary embodiment, according to any of the above paragraphs, the invention provides a pharmaceutical formulation comprising a) the compound according to any of the above paragraphs, or a pharmaceutically acceptable salt thereof, and b) a pharmaceutically acceptable excipient.
[0086] In an exemplary embodiment, according to any of the above paragraphs, the invention provides a method of tumor therapy, comprising administering a
pharmaceutically effective amount of the compound according to any of the above paragraphs or a pharmaceutically acceptable salt thereof to a subject in need thereof in conjunction with boron neutron capture therapy.
[0087] The invention is further illustrated by the Examples that follow. The Examples are not intended to define or limit the scope of the invention.
EXAMPLES
[0088] All solvents used were commercially available and were used without further purification. Reactions were typically run using anhydrous solvents under an inert atmosphere of N2. [0089] 1H, 13C, and 19F NMR spectra were recorded at 400 MHz for proton, 100 MHz for carbon- 13, and 376 MHz for fluorine- 19 on a Varian 300 MercuryPlus station with an Oxford AS400 Spectrometer equipped with a Varian 400 ATB PFG probe. All deuterated solvents typically contained 0.03% to 0.05% v/v
tetramethylsilane, which was used as the reference signal (set at δ 0.00 for both 1H and 13C).
[0090] Compounds are named using ChemDraw 7.0 or their catalogue name if commercially available.
[0091] Starting materials used were either available from commercial sources or prepared according to literature procedures and had experimental data in accordance with those reported. 6-aminobenzo[c][l,2]oxaborol-l(3H)-ol, for example, can be synthesized according to the methods described in U.S. Pat. App. 12/142,692, as well as U.S. Pat. Pubs. US20060234981 and US20070155699.
EXAMPLE 1
2-Amino-3-(l-hvdro -l,3-dihvdrobenzofcJfl,2Joxaborol-5-yl)propanoic acid
[0092] Reagents and conditions: (a) triflate chloride, DMAP, dichloromethane, 0 °C, 1 h, 80%; (b) pinacol diboron, Pd(dppf)Cl2, KOAc, dioxane, N2, 80 °C, 16 h,
55%; (c) NaBH4, MeOH, r.t., 2 h, then 6N HC1, 12 h, 32% for 7, 39% for 8; (d) Pd/C, EtOH, H2, 10 h, 89%; (e) LiOH, MeOH, H20, 30 min, r.t., 64%.
[0093] Hydroxybenzaldehyde 4 was prepared according to Kalesh, K. A. et. al, Chem. Commun., 2010, 46, 589-591. Hydroxybenzaldehyde 4 was converted to its triflate derivative 5 in 80% yield by reaction with triflate chloride in dichloromethane. Without further purification, crude 5 was allowed to react with pinacol diboron in the presence of Pd(dppf)Cl2, Nakamura, H. et. al, J. Org. Chem. 1998, 63, 7529-7530, to afford boronate 6 in 55 > yield. Subsequently, benzoxaborole ring formation was accomplished by using a one-pot procedure as previously described in Zhang, Y.-K., et. al, Bioorg. Med. Chem. Lett. 2010, 20, 2270-2274. This included the treatment of 6 with sodium borohydride in methanol to convert the aldehyde to a hydroxylmethyl group. The hydroxylmethyl group simultaneously cyclized to the adjacent boronate and subsequently hydrolyzed to form the corresponding benzoxaborole ring upon addition of aqueous hydrochloric acid. Boc protecting group was also removed in this step resulting in the desired benzyl ester 7 in 32%> yield. Also methyl ester 8 was isolated in 39% yield due to transterification in methanol under these reaction conditions. Combination of two compounds 7 and 8 was accounted for 71 > yield. Hydrogenation of benzyl ester 7 or basic hydrolysis of methyl ester 8 afforded the desired compound 2 as white solid. [0094] Benzyl 2-(tert-butoxycarbonylamino)-3-(3-formyl-4-
(trifluoromethylsulfonyloxy)phenyl)propanoate 5: To a solution of compound 4 (5 g, 12.5 mmol) and DMAP (3.83 g, 31.3 mmol) in dry DCM (50 mL) at 0 °C was added TfCl (4.65 g, 27.6 mmol). The reaction mixture was stirred for 1 h at 0 °C. After 50 mL water was added, the DCM phase was separated. The organic layer was washed with brine, dried with Na2S04, filtered and concentrated. The residue was used directly without further purification (5.3 g, 80%>).
[0095] Benzyl 2-(tert-butoxycarbonylamino)-3-(3-formyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenyl)propanoate 6: To a solution of compound 5 (5.3 g, 10 mmol) in dioxane (80 mL) was added B2Pin2 (4.3g, 17 mmol), KOAc (2.24 g, 22.9 mmol) and Pd(dppf)Cl2 (828 mg, 1.13 mmol) under N2 atmosphere. The solution was stirred at 80 °C under N2 overnight. The mixture was concentrated and purified by silica-gel column chromatography (petroleum ether/ethyl acetate 20: 1 to 8:1) to give
compound 6 (2.8 g, 55%). 1H NMR (400 MHz, CDC13) δ 10.41 (s, 1H), 7.67-7.69 (d, 1H), 7.60 (s, 1H), 7.02-7.29 (m, 6H), 5.05 (s, 2H), 4.89-4.91 (m, 1H), 4.56-4.57 (m, 1H), 3.03-3.13 (m, 2H), 1.33 (s, 12H), 1.19 (s, 9H).
[0096] Benzyl 2-amino-3-(l-hydroxy-l,3-dihydrobenzo[c][l,2]oxaborol-5- yl)propanoate 7 and methyl 2-amino-3-(l-hydroxy-l,3-dihydrobenzo[c][l,2]oxaborol- 5-yl)propanoate 8: To a stirring suspension of compound 6 (2.8 g, 5.5 mmol) in dry MeOH (50 mL) was added NaBH4 (627 mg, 16.5 mmol) in portions at 0 °C. The solution was stirred at r.t for 2 h. Then 6N HC1 (20 ml) was added to the mixture. The reaction mixture was stirred at room temperature for 12 h. The mixture was concentrated in vacuo and the residue was purified by prep-HPLC (column: Luna
300x50.0 mm, 10μ; liquid phase: [A- H20; B-MeOH + 0.1% TFA] B%: 0%-15%, 20 min) to give compound 7 as colorless oil (550 mg, 32%) and compound 8 as colorless oil (500 mg, 39%). Compound 7: 1H NMR (400 MHz, MeOD) δ 7.58-7.60 (d, 1H), 7.14-7.33 (m, 7H), 5.16-5.22 (ds, 2H), 4.94 (s, 2H), 4.37 (m, 1H), 3.23-3.34 (m, 2H). Compound 8: 1H NMR (400 MHz, MeOD) δ 7.62-7.68 (d, 1H), 7.21-7.38 (m, 2H), 5.10 (s, 2H), 4.32-4.40 (m, 1H), 3.70 (s, 3H), 3.24-3.40 (m, 2H).
[0097] 2-Amino-3-(l-hydroxy-l,3-dihydrobenzo[c][l,2] oxaborol-5-yl)propanoic acid 2: To a solution of compound 7 (550 mg, 1.77 mmol) in ethanol (20 ml) was added Pd/C (50 mg) portionwise. The solution was stirred at r.t under H2 atmosphere for 10 h. After the reaction was completed as indicated by HPLC, ethanol was evaporated in vacuo. The residue was purified by prep-HPLC (column: Luna
300x50.0 mm, 10μ; mobile phase: [A-H20; B-MeCN + 0.1% TFA] B%: 0%-10%, 20 min) to give compound 2 as white solid (350 mg, 89%). Alternatively, LiOH (252 mg, 6 mmol) in 5 mL water was added to a solution of compound 8 (500 mg, 2.12 mmol) in MeOH (20 mL) portionwise. The solution was stirred at r.t for 30 min. After the reaction was complete as indicated by HPLC, the mixture was acidified to pH 5 with 2N HC1, and MeOH was evaporated in vacuo. The residue was purified by prep-HPLC (column: Luna 300x50.0 mm, 10μ; mobile phase: [A-H20; B-MeCN + 0.1% TFA] B%: 0%-10%, 20 min) to give compound 2 as white solid (300 mg, 64%). 1H NMR (400 MHz, MeOD) δ 7.65-7.67 (d, 1H, J= 7.6 Hz), 7.32 (s, 1H), 7.27-7.29 (d, 1H, J= 7.6 Hz), 5.07 (s, 2H), 4.20-4.23 (m, 1H), 3.35-3.40 (m, 1H), 3.16-3.21 (m, 1H); 13C NMR (400 MHz, MeOD) δ 170.27 (C=0), 154.91 (C), 137.56 (C), 130.51 (C), 128.03 (C), 121.84 (C), 70.75 (CH2), 54.19 (CH2), 36.35 (CH), carbon adjacent
to boron was not observed; HRMS calcd for C10H13BNO4 (M+H)+, 222.0938; found, 222.0938; HPLC purity: 99.4% (MaxPlot 190 - 370 nm), 99.4% (220 nm)].
2-Amino-3-((l-hvdroxy-l,3-dihvdrobenzofc}fl,2}oxaborol-5-yl)oxy)propanoic acid
[0098] Reagents and conditions: (a) TrtCl, Et3N, dichloromethane, addition over 1.5 h, then r.t. 16 h, 100%; (b) 2-bromo-5-hydroxybenzaldehyde, dry toluene, PPh3, DIAD, N2, 0 °C, 30 min, then 60 °C, 16 h, 24%; (c) pinacol diboron, Pd(dppf)Cl2, KOAc, dioxane, N2, 80 °C, 16 h, 56%; (d) NaBH4, MeOH, r.t., 2 h, then 6N HCl, 2 h, 79%; (e) LiOH, MeOH, H20, r.t. 10 min, 27%. [0099] The synthesis of compound 3 was carried out using DL-serine methyl ester 9. A key step in the synthesis was to convert the hydroxyl group of serine methyl ester to phenyl ether by Mitsunobu reaction. During our initial attempts, we found that the reaction of Boc or Cbz-protected serine ester with 2-bromo-5- hydroxybenzaldehyde in the presence of DIAD and PPh3 failed to give any desired ether product. The β-elimination product was isolated instead, which is attributed to the fact that the relative acidity of the a proton of the carbamate-protected serine ester causes its facile elimination under Mitsunobu conditions, Panda, G. et. ah, Synlett. 2004, 4, 714-716. Subsequently, compound 9 was protected with trityl group, a non- carbamate type protecting group, by reacting with trityl chloride in the presence of triethylamine to convert to ester 10 in quantitative yield. Mitsunobu reaction of 10 and 2-bromo-5-hydroxybenzaldehyde in the presence of DIAD and PPh3 afforded phenyl ether compound 11. Full conversion of 10 to 11 was observed, and low isolated yield (24%) was due to compound loss during column purification and was not optimized. Compound 11 was reacted with pinacol diboron in the presence of Pd(dppf)Cl2 to afford boronate 12 in 56%> yield. Reduction of 12 with sodium
borohydride in methanol converted the aldehyde to its hydroxylmethyl group which simultaneously cyclized to the adjacent boronate and hydro lyzed to give
benzoxaborole, upon addition of 6N HC1. Under these conditions, trityl protecting group was also removed resulting in benzoxaborole 13 in 79% yield. Hydrolysis of methyl ester 13 gave the desired compound 3 as off white solid.
[0100] Methyl 3-hydroxy-2-(tritylamino)propanoate 10: To a solution of methyl 2- amino-3-hydroxypropanoate hydrochloride (39 g, 251 mmol) in CH2CI2 (460 ml) was added Et3N (52.1 g, 516 mmol) over 30 min at r.t. Then a solution of TrtCl (71.3 g, 256 mmol) in 390 mL CH2CI2 was added to the reaction mixture over 1.5 h at 25-30 °C. The reaction mixture was stirred for overnight at r.t. Subsequently, 300 mL of water was added to the mixture and the mixture was stirred for 1 h. After separation, the aqueous layer was washed with CH2CI2. The organic layers were washed with brine, dried with Na2S04, and filtered. After concentrated in vacuo, compound 10 was obtained as white solid (90 g, quant.). 1H NMR (400 MHz, CDC13) δ 7.46-7.54 (m, 6H), 7.25-7.35 (m, 6H), 7.15-7.24 (m, 3H), 3.70-3.76 (m, 1H), 3.53-3.62 (m, 2H), 3.31 (s, 3H), 3.00 (d, 1H), 2.37 (t, 1H).
[0101] Methyl 3-(4-bromo-3-formylphenoxy)-2-(tritylamino)propanoate 11: To a solution of methyl 3-hydroxy-2-(tritylamino)propanoate 10 (41.8 g, 0.115 mol) and 2- bromo-5-hydroxybenzaldehyde (21.2 g, 0.105 mol) in dry toluene (350 ml) at 0 °C was added PPh3 (33 g, 0.126 mol). Subsequently, DIAD (25.5 g, 0.126 mol) was added to the cold solution over 10 min under N2 atmosphere. After stirred at 0 °C for 0.5 h, the mixture was heated to 60 °C and stirred for overnight. After the solvent was removed in vacuo, the residue was purified by column chromatography (petroleum ether/ethyl acetate 100: 1) to give compound 11 as yellow solid (13.6 g, 24%). 1H NMR (400 MHz, CDC13) δ 10.31 (s, 1H), 7.50-7.53 (m, 7H), 7.25-7.28 (m, 7H), 7.17- 7.21 (m, 3H), 6.98-7.01 (m, 1H), 4.24-4.27 (m, 1H), 4.00-4.04 (m, 1H), 3.65-3.75 (m, 1H), 3.24 (s, 3H), 2.9 (m, 1H).
[0102] Methyl 3-(3-formyl-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)phenoxy)-2-(tritylamino)propanoate 12: To a solution of compound 11 (13.6 g, 0.025 mol) in dioxane (200 ml) was added B2Pin2 (7.62 g, 0.03 mol), KOAc (7.36 g, 0.075 mol) and Pd(dppf)Cl2 (1.8 g, 2.5 mmol) under N2. The solution was stirred at 80 °C under N2 for overnight. After aqueous work-up, the crude residue was purified by
silica-gel column chromatography (petroleum ether/ethyl acetate = 50: 1) to give compound 12 as yellow solid (8.3 g, 56%). 1H NMR (400 MHz, CDC13) δ 10.67 (s, 1H), 7.05-7.85 (m, 18H), 4.30-4.35 (m, 1H), 4.05-4.10 (m, 1H), 3.68-3.73 (m, 1H), 3.24 (s, 3H), 2.90 (m, 1H), 1.37 (s, 12H). [0103] Methyl 2-amino-3 -(1 -hydroxy- 1,3 -dihydrobenzo[c][ l,2]oxaborol-5- yloxy)propanoate 13: To a stirring suspension of compound 12 (8.3 g, 14 mmol) in dry MeOH (100 ml) was added NaBH4 (1.6 g, 42 mmol) in portions at 0 °C. The solution was stirred at r.t. for 4 h. After 6N HCl (20 ml) was added, the reaction mixture was stirred at room temperature for overnight. The mixture was concentrated in vacuo and the residue was purified by prep-HPLC to give compound 13 as white solid (2.8 g, 79%). 1H NMR (400 MHz, DMSO-D6) δ 8.65-8.85 (b, 3H), 7.57-7.64 (m, 1H), 7.00-7.14 (ds, 1H), 6.79-6.94 (m, 1H), 4.63-4.66 (m, 1H), 4.40-4.46 (m, 1H), 4.30-4.35 (m, 1H), 4.69-4.92 (ds, 2H), 3.77 (s, 3H).
[0104] (2-Amino-3-(l-hydroxy-l,3-dihydrobenzo[c][l,2] oxaborol-5- yloxy)propanoic acid 3: To a solution of compound 13 (2 g, 8 mmol) in MeOH (60 ml) was added LiOH (1.3 g, 32 mmol) in 5 mL water portionwise. The solution was stirred at r.t. for 40 min. After the reaction was completed as indicated by HPLC, the mixture was acidified to pH 6-6.5 with 2N HCl, to precipitate the product. The solid collected by filtration and washed with methanol to give compound 3 as off white solid (515 mg, 27%). 1H NMR: (400 MHz, MeOD): δ 7.59-7.61 (d, 1H, J= 8.0 Hz), 7.02 (s, 1H), 6.99-7.01 (d, 1H, J= 8.0 Hz), 5.03 (s, 2H), 4.43-4.53 (m, 2H), 4.36-4.38 (m, 1H); 13C NMR (400 MHz, MeOD) 169.50 (C=0), 161.91 (C), 157.98 (C), 132.79 (C), 116.08 (C), 107.69 (C), 72.10 (CH2), 67.09 (CH2), 54.07 (CH), carbon adjacent to boron was not observed; HRMS calcd for Ci0Hi3BNO5 (M+H)+, 238.0887; found, 238.0889; HPLC purity: 98.3% (MaxPlot 190 - 370 nm), 98.5% (220 nm).
EXAMPLE 2
Water solubility of the compounds of the invention
[0105] Various amounts of compounds 1-3 were added to 0.1 M, pH 7.4 phosphate buffer. After vortex-mixing, the mixture was sonicated and incubated at room temperature for 24 h. If material is precipitated after incubation then the solubility is lower than the concentration assayed. If the solution becomes transparent, then solubility is equal to or higher than the concentration assayed. The solubility was
calculated by dividing the amount of material by total volume of buffer in final transparent solution. Multiple replications of each experiment were carried out and the results were averaged). BPA 1 has a solubility of 1.7 mg/mL, which is in consistent with the reported value (1.6 mg/mL) (Mori, Y. et. αί, Pigment Cell Res. 1989, 2, 273-277; Nemoto, H., et. al, J. Med. Chem. 1995, 38, 1673-1678).
Compared to 1, compounds 2 and 3 exhibit improved water solubility of 5.2 mg/mL and 3.6 mg/mL, respectively. Their better solubility could be attributable to the lower pKa since the benzoxaborole would exist in anionic tetrahedral form to a significant extent at physiological pH. Compound 2 is more soluble than 3. One potential explanation is that the presence of the electron-donating oxygen atom para to the benzoxaborole in 3 would increase its pKa value and thus decrease its water solubility.
[0106] It is to be understood that the invention covers all combinations of aspects with all other suitable aspects and/or exemplary embodiments described herein. It is to be understood that the invention also covers all combinations of exemplary embodiments with all other suitable aspects and/or exemplary embodiments described herein.
[0107] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.
Claims
wherein
R1 is H or substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl or substituted or unsubstituted cycloalkyl or substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
R2 and R3 are independently selected from H or substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl or substituted or unsubstituted cycloalkyl or substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl,
or a salt thereof.
2. The compound of claim 1, wherein R1 is H.
3. The compound of claim 1, wherein R2 is H and R3 is H.
5. The compound of claim 1, for use in therapy.
6. The compound of claim 1, for use in boron neutron capture therapy.
7. The compound of claim 1, for use in diagnostics.
8. A pharmaceutical formulation comprising: a) the compound of claim 1, or a pharmaceutically acceptable salt thereof, and b) a pharmaceutically acceptable excipient.
9. A method of tumor therapy, comprising administering a pharmaceutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof, to a subject in need thereof in conjunction with boron neutron capture therapy.
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