CA2825700A1

CA2825700A1 - Alpha-ketoheterocycles and methods of making and using

Alpha-ketoheterocycles and methods of making and using Download PDF

Info

Publication number: CA2825700A1
Authority: CA; Canada
Prior art keywords: compound; heteroaryl; mhz; aryl; cdc13
Prior art date: 2011-02-04
Legal status : Abandoned

Application number

CA2825700A

Other languages

English (en)

French (fr)

Inventor

Dale L. Boger

Current Assignee

Scripps Research Institute

Original Assignee

Scripps Research Institute

Priority date

2011-02-04

Filing date

2012-02-03

Publication date

2012-08-09

2012-02-03 Application filed by Scripps Research Institute filed Critical Scripps Research Institute

2012-08-09 Publication of CA2825700A1 publication Critical patent/CA2825700A1/en

Status Abandoned legal-status Critical Current

Links

238000000034 method Methods 0.000 title claims abstract description 130
150000001875 compounds Chemical class 0.000 claims abstract description 408
108010046094 fatty-acid amide hydrolase Proteins 0.000 claims abstract description 70
102100029111 Fatty-acid amide hydrolase 1 Human genes 0.000 claims abstract description 50
230000000202 analgesic effect Effects 0.000 claims abstract description 23
-1 -Z-aryl Chemical group 0.000 claims description 223
239000000203 mixture Substances 0.000 claims description 106
125000003118 aryl group Chemical group 0.000 claims description 76
125000001072 heteroaryl group Chemical group 0.000 claims description 63
125000000623 heterocyclic group Chemical group 0.000 claims description 56
125000002252 acyl group Chemical group 0.000 claims description 45
229910052799 carbon Inorganic materials 0.000 claims description 45
125000000217 alkyl group Chemical group 0.000 claims description 43
150000003839 salts Chemical class 0.000 claims description 40
125000001424 substituent group Chemical group 0.000 claims description 38
125000004432 carbon atom Chemical group C* 0.000 claims description 37
125000000753 cycloalkyl group Chemical group 0.000 claims description 35
229910052739 hydrogen Inorganic materials 0.000 claims description 30
208000002193 Pain Diseases 0.000 claims description 29
230000036407 pain Effects 0.000 claims description 28
229910052757 nitrogen Inorganic materials 0.000 claims description 26
125000004433 nitrogen atom Chemical group N* 0.000 claims description 26
238000011282 treatment Methods 0.000 claims description 26
239000001257 hydrogen Substances 0.000 claims description 24
125000004429 atom Chemical group 0.000 claims description 23
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
125000005843 halogen group Chemical group 0.000 claims description 17
125000003710 aryl alkyl group Chemical group 0.000 claims description 16
239000003814 drug Substances 0.000 claims description 16
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 16
238000001727 in vivo Methods 0.000 claims description 16
229910052794 bromium Inorganic materials 0.000 claims description 13
125000004446 heteroarylalkyl group Chemical group 0.000 claims description 12
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
229910052801 chlorine Inorganic materials 0.000 claims description 11
229910052760 oxygen Inorganic materials 0.000 claims description 10
125000002947 alkylene group Chemical group 0.000 claims description 9
229910052731 fluorine Inorganic materials 0.000 claims description 9
229910052736 halogen Inorganic materials 0.000 claims description 9
229910052740 iodine Inorganic materials 0.000 claims description 9
125000004076 pyridyl group Chemical group 0.000 claims description 9
229910052717 sulfur Inorganic materials 0.000 claims description 8
125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 7
230000003110 anti-inflammatory effect Effects 0.000 claims description 7
230000009286 beneficial effect Effects 0.000 claims description 7
208000019116 sleep disease Diseases 0.000 claims description 7
125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 6
229930003827 cannabinoid Natural products 0.000 claims description 6
239000003557 cannabinoid Substances 0.000 claims description 6
150000002367 halogens Chemical class 0.000 claims description 6
150000002825 nitriles Chemical group 0.000 claims description 6
125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 6
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 5
125000004093 cyano group Chemical group *C#N 0.000 claims description 5
125000001188 haloalkyl group Chemical group 0.000 claims description 5
229940127240 opiate Drugs 0.000 claims description 5
125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 5
125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 4
125000004104 aryloxy group Chemical group 0.000 claims description 4
125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 4
229940111134 coxibs Drugs 0.000 claims description 4
239000003255 cyclooxygenase 2 inhibitor Substances 0.000 claims description 4
230000002401 inhibitory effect Effects 0.000 claims description 4
230000005923 long-lasting effect Effects 0.000 claims description 4
230000000631 nonopiate Effects 0.000 claims description 4
239000000546 pharmaceutical excipient Substances 0.000 claims description 4
125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
229910004679 ONO2 Inorganic materials 0.000 claims description 3
125000005518 carboxamido group Chemical group 0.000 claims description 3
125000001893 nitrooxy group Chemical group [O-][N+](=O)O* 0.000 claims description 3
239000008194 pharmaceutical composition Substances 0.000 claims description 3
125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
150000001735 carboxylic acids Chemical group 0.000 claims description 2
238000000338 in vitro Methods 0.000 claims description 2
125000003003 spiro group Chemical group 0.000 claims description 2
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 2
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims 1
208000020685 sleep-wake disease Diseases 0.000 claims 1
230000002557 soporific effect Effects 0.000 claims 1
230000000694 effects Effects 0.000 abstract description 40
LGEQQWMQCRIYKG-DOFZRALJSA-N anandamide Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(=O)NCCO LGEQQWMQCRIYKG-DOFZRALJSA-N 0.000 abstract description 33
LGEQQWMQCRIYKG-UHFFFAOYSA-N arachidonic acid ethanolamide Natural products CCCCCC=CCC=CCC=CCC=CCCCC(=O)NCCO LGEQQWMQCRIYKG-UHFFFAOYSA-N 0.000 abstract description 30
230000005764 inhibitory process Effects 0.000 abstract description 16
238000002360 preparation method Methods 0.000 abstract description 14
102000004190 Enzymes Human genes 0.000 abstract description 13
108090000790 Enzymes Proteins 0.000 abstract description 13
230000001939 inductive effect Effects 0.000 abstract description 6
230000015556 catabolic process Effects 0.000 abstract description 2
YZAZOMTZCPDGBK-UHFFFAOYSA-N bis(1,3-oxazol-2-yl)methanone Chemical class N=1C=COC=1C(=O)C1=NC=CO1 YZAZOMTZCPDGBK-UHFFFAOYSA-N 0.000 abstract 1
239000002621 endocannabinoid Substances 0.000 abstract 1
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 252
101150041968 CDC13 gene Proteins 0.000 description 250
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 216
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 162
238000003818 flash chromatography Methods 0.000 description 156
229910052681 coesite Inorganic materials 0.000 description 150
229910052906 cristobalite Inorganic materials 0.000 description 150
229910052682 stishovite Inorganic materials 0.000 description 150
229910052905 tridymite Inorganic materials 0.000 description 150
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 134
VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 116
239000000243 solution Substances 0.000 description 104
238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 102
238000005481 NMR spectroscopy Methods 0.000 description 97
229920006395 saturated elastomer Polymers 0.000 description 83
239000012230 colorless oil Substances 0.000 description 72
239000003112 inhibitor Substances 0.000 description 72
239000011541 reaction mixture Substances 0.000 description 71
239000007787 solid Substances 0.000 description 64
239000002904 solvent Substances 0.000 description 63
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 62
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 62
230000002829 reductive effect Effects 0.000 description 55
QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 50
239000012044 organic layer Substances 0.000 description 50
ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 47
238000005160 1H NMR spectroscopy Methods 0.000 description 43
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 43
229910001868 water Inorganic materials 0.000 description 43
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 41
239000012071 phase Substances 0.000 description 37
239000007832 Na2SO4 Substances 0.000 description 32
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 32
229910052938 sodium sulfate Inorganic materials 0.000 description 32
235000011152 sodium sulphate Nutrition 0.000 description 32
229910052943 magnesium sulfate Inorganic materials 0.000 description 31
235000019341 magnesium sulphate Nutrition 0.000 description 31
239000003921 oil Substances 0.000 description 29
235000019198 oils Nutrition 0.000 description 29
238000001704 evaporation Methods 0.000 description 28
230000008020 evaporation Effects 0.000 description 28
108091006629 SLC13A2 Proteins 0.000 description 27
238000004128 high performance liquid chromatography Methods 0.000 description 27
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 25
125000005842 heteroatom Chemical group 0.000 description 25
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 24
210000004556 brain Anatomy 0.000 description 21
239000011780 sodium chloride Substances 0.000 description 21
DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 20
MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 20
JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 19
241000699670 Mus sp. Species 0.000 description 18
SIOXPEMLGUPBBT-UHFFFAOYSA-M picolinate Chemical compound [O-]C(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-M 0.000 description 18
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
RCRCTBLIHCHWDZ-UHFFFAOYSA-N 2-Arachidonoyl Glycerol Chemical compound CCCCCC=CCC=CCC=CCC=CCCCC(=O)OC(CO)CO RCRCTBLIHCHWDZ-UHFFFAOYSA-N 0.000 description 16
208000004454 Hyperalgesia Diseases 0.000 description 16
RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
239000002253 acid Substances 0.000 description 15
150000001721 carbon Chemical group 0.000 description 15
HXYVTAGFYLMHSO-UHFFFAOYSA-N palmitoyl ethanolamide Chemical compound CCCCCCCCCCCCCCCC(=O)NCCO HXYVTAGFYLMHSO-UHFFFAOYSA-N 0.000 description 15
CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 15
YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 14
230000015572 biosynthetic process Effects 0.000 description 14
239000012043 crude product Substances 0.000 description 14
235000014113 dietary fatty acids Nutrition 0.000 description 14
239000000194 fatty acid Substances 0.000 description 14
229930195729 fatty acid Natural products 0.000 description 14
238000007912 intraperitoneal administration Methods 0.000 description 14
CKJNUZNMWOVDFN-UHFFFAOYSA-N methanone Chemical compound O=[CH-] CKJNUZNMWOVDFN-UHFFFAOYSA-N 0.000 description 14
BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 14
241001465754 Metazoa Species 0.000 description 13
239000003940 fatty acid amidase inhibitor Substances 0.000 description 13
239000000543 intermediate Substances 0.000 description 13
150000002576 ketones Chemical class 0.000 description 13
150000004702 methyl esters Chemical class 0.000 description 13
230000003389 potentiating effect Effects 0.000 description 13
238000003786 synthesis reaction Methods 0.000 description 13
238000012360 testing method Methods 0.000 description 13
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 12
238000010992 reflux Methods 0.000 description 12
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IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 11
230000003502 anti-nociceptive effect Effects 0.000 description 11
239000013078 crystal Substances 0.000 description 11
NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 11
150000004665 fatty acids Chemical class 0.000 description 11
229950007031 palmidrol Drugs 0.000 description 11
125000003545 alkoxy group Chemical group 0.000 description 10
206010053552 allodynia Diseases 0.000 description 10
238000004458 analytical method Methods 0.000 description 10
238000003556 assay Methods 0.000 description 10
150000001732 carboxylic acid derivatives Chemical class 0.000 description 10
239000000460 chlorine Substances 0.000 description 10
PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 description 10
150000002632 lipids Chemical class 0.000 description 10
IMRWILPUOVGIMU-UHFFFAOYSA-N 2-bromopyridine Chemical compound BrC1=CC=CC=N1 IMRWILPUOVGIMU-UHFFFAOYSA-N 0.000 description 9
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 9
208000027418 Wounds and injury Diseases 0.000 description 9
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 9
125000000392 cycloalkenyl group Chemical group 0.000 description 9
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
150000002431 hydrogen Chemical class 0.000 description 9
125000004304 oxazol-5-yl group Chemical group O1C=NC=C1* 0.000 description 9
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 9
JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 8
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
150000001412 amines Chemical class 0.000 description 8
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 8
230000006378 damage Effects 0.000 description 8
125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 8
208000014674 injury Diseases 0.000 description 8
230000008447 perception Effects 0.000 description 8
238000000926 separation method Methods 0.000 description 8
239000000758 substrate Substances 0.000 description 8
238000003419 tautomerization reaction Methods 0.000 description 8
229910004373 HOAc Inorganic materials 0.000 description 7
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
230000003213 activating effect Effects 0.000 description 7
125000003342 alkenyl group Chemical group 0.000 description 7
229940114079 arachidonic acid Drugs 0.000 description 7
235000021342 arachidonic acid Nutrition 0.000 description 7
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 7
150000003857 carboxamides Chemical class 0.000 description 7
239000002552 dosage form Substances 0.000 description 7
238000009472 formulation Methods 0.000 description 7
210000004185 liver Anatomy 0.000 description 7
229960005181 morphine Drugs 0.000 description 7
BOWVQLFMWHZBEF-KTKRTIGZSA-N oleoyl ethanolamide Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)NCCO BOWVQLFMWHZBEF-KTKRTIGZSA-N 0.000 description 7
230000003287 optical effect Effects 0.000 description 7
239000001301 oxygen Substances 0.000 description 7
238000001356 surgical procedure Methods 0.000 description 7
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 7
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 7
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 6
YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 6
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 6
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
241000124008 Mammalia Species 0.000 description 6
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
230000009471 action Effects 0.000 description 6
150000001540 azides Chemical class 0.000 description 6
239000002585 base Substances 0.000 description 6
238000006243 chemical reaction Methods 0.000 description 6
238000004587 chromatography analysis Methods 0.000 description 6
125000004122 cyclic group Chemical group 0.000 description 6
201000010099 disease Diseases 0.000 description 6
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
230000001965 increasing effect Effects 0.000 description 6
239000007924 injection Substances 0.000 description 6
238000002347 injection Methods 0.000 description 6
150000002500 ions Chemical class 0.000 description 6
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
SGNCOKUHMXLGAH-UHFFFAOYSA-N methyl 6-bromopyridine-2-carboxylate Chemical compound COC(=O)C1=CC=CC(Br)=N1 SGNCOKUHMXLGAH-UHFFFAOYSA-N 0.000 description 6
FATBGEAMYMYZAF-KTKRTIGZSA-N oleamide Chemical compound CCCCCCCC\C=C/CCCCCCCC(N)=O FATBGEAMYMYZAF-KTKRTIGZSA-N 0.000 description 6
125000002971 oxazolyl group Chemical group 0.000 description 6
230000009467 reduction Effects 0.000 description 6
235000017557 sodium bicarbonate Nutrition 0.000 description 6
229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
239000000126 substance Substances 0.000 description 6
QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 6
BSNIXNVMYNRRMG-UHFFFAOYSA-N 1,3-oxazole-5-carbonitrile Chemical compound N#CC1=CN=CO1 BSNIXNVMYNRRMG-UHFFFAOYSA-N 0.000 description 5
125000000304 alkynyl group Chemical group 0.000 description 5
239000002775 capsule Substances 0.000 description 5
150000001768 cations Chemical class 0.000 description 5
230000008859 change Effects 0.000 description 5
238000012512 characterization method Methods 0.000 description 5
229940125782 compound 2 Drugs 0.000 description 5
238000010511 deprotection reaction Methods 0.000 description 5
FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 5
239000003085 diluting agent Substances 0.000 description 5
ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 5
FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 5
230000003993 interaction Effects 0.000 description 5
239000007788 liquid Substances 0.000 description 5
ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 5
230000003647 oxidation Effects 0.000 description 5
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