TW201335160A

TW201335160A - Ｉｐ受體激動劑之雜環化合物

Ｉｐ受體激動劑之雜環化合物 Download PDF

Info

Publication number: TW201335160A
Authority: TW; Taiwan
Prior art keywords: alkyl; group; alkoxy; optionally substituted; halogen
Prior art date: 2012-01-13

Application number

TW102101219A

Other languages

English (en)

Chinese (zh)

Inventor

Catherine Leblanc

Claire Adcock

Original Assignee

Novartis Ag

Priority date

2012-01-13

Filing date

2013-01-11

Publication date

2013-09-01

2013-01-11 Application filed by Novartis Ag filed Critical Novartis Ag

2013-09-01 Publication of TW201335160A publication Critical patent/TW201335160A/zh

Links

108091006335 Prostaglandin I receptors Proteins 0.000 title abstract description 118
229940044601 receptor agonist Drugs 0.000 title description 102
239000000018 receptor agonist Substances 0.000 title description 102
150000002391 heterocyclic compounds Chemical class 0.000 title 1
125000000623 heterocyclic group Chemical group 0.000 claims abstract description 83
230000003176 fibrotic effect Effects 0.000 claims abstract description 11
239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
150000001875 compounds Chemical class 0.000 claims description 209
150000003839 salts Chemical class 0.000 claims description 93
125000005843 halogen group Chemical group 0.000 claims description 77
229910052736 halogen Inorganic materials 0.000 claims description 76
150000002367 halogens Chemical class 0.000 claims description 70
-1 O-aryl Chemical group 0.000 claims description 68
125000000217 alkyl group Chemical group 0.000 claims description 63
229910052760 oxygen Inorganic materials 0.000 claims description 56
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 54
125000000753 cycloalkyl group Chemical group 0.000 claims description 48
229910052717 sulfur Inorganic materials 0.000 claims description 48
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 47
238000011282 treatment Methods 0.000 claims description 46
125000001424 substituent group Chemical group 0.000 claims description 45
125000003118 aryl group Chemical group 0.000 claims description 44
201000010099 disease Diseases 0.000 claims description 44
125000005842 heteroatom Chemical group 0.000 claims description 44
239000003814 drug Substances 0.000 claims description 33
229910052757 nitrogen Inorganic materials 0.000 claims description 29
125000001072 heteroaryl group Chemical group 0.000 claims description 27
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 27
208000006673 asthma Diseases 0.000 claims description 24
125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 22
239000003795 chemical substances by application Substances 0.000 claims description 21
201000001320 Atherosclerosis Diseases 0.000 claims description 20
125000000000 cycloalkoxy group Chemical group 0.000 claims description 20
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 19
238000004519 manufacturing process Methods 0.000 claims description 19
208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 16
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 16
229910052799 carbon Inorganic materials 0.000 claims description 16
229910052739 hydrogen Inorganic materials 0.000 claims description 14
125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 11
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 11
208000027866 inflammatory disease Diseases 0.000 claims description 11
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 9
238000013176 antiplatelet therapy Methods 0.000 claims description 9
125000003831 tetrazolyl group Chemical group 0.000 claims description 9
125000002947 alkylene group Chemical group 0.000 claims description 8
239000013543 active substance Substances 0.000 claims description 7
201000001421 hyperglycemia Diseases 0.000 claims description 7
125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 6
125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 5
125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 5
125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
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
238000006467 substitution reaction Methods 0.000 claims description 4
125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 3
UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 3
125000005915 C6-C14 aryl group Chemical group 0.000 claims description 2
239000003937 drug carrier Substances 0.000 claims description 2
239000000835 fiber Substances 0.000 claims 1
238000000034 method Methods 0.000 abstract description 57
230000009286 beneficial effect Effects 0.000 abstract description 23
208000005069 pulmonary fibrosis Diseases 0.000 abstract description 5
210000000056 organ Anatomy 0.000 abstract description 4
230000008569 process Effects 0.000 abstract description 3
238000010171 animal model Methods 0.000 abstract description 2
230000019491 signal transduction Effects 0.000 abstract description 2
230000003213 activating effect Effects 0.000 abstract 1
208000002815 pulmonary hypertension Diseases 0.000 description 122
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 120
206010057190 Respiratory tract infections Diseases 0.000 description 83
239000000203 mixture Substances 0.000 description 83
235000019439 ethyl acetate Nutrition 0.000 description 61
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 54
238000004895 liquid chromatography mass spectrometry Methods 0.000 description 46
230000002829 reductive effect Effects 0.000 description 41
MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 40
IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 37
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 29
238000005481 NMR spectroscopy Methods 0.000 description 26
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
239000002253 acid Substances 0.000 description 24
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 23
239000000543 intermediate Substances 0.000 description 22
239000000725 suspension Substances 0.000 description 22
229940079593 drug Drugs 0.000 description 21
239000000243 solution Substances 0.000 description 21
239000011541 reaction mixture Substances 0.000 description 19
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
239000000651 prodrug Substances 0.000 description 17
229940002612 prodrug Drugs 0.000 description 17
238000003756 stirring Methods 0.000 description 17
IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 16
239000000284 extract Substances 0.000 description 16
BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 16
238000002360 preparation method Methods 0.000 description 16
239000002904 solvent Substances 0.000 description 16
201000000596 systemic lupus erythematosus Diseases 0.000 description 16
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
208000007536 Thrombosis Diseases 0.000 description 15
239000012043 crude product Substances 0.000 description 15
206010012601 diabetes mellitus Diseases 0.000 description 15
230000000694 effects Effects 0.000 description 14
TVQGDYNRXLTQAP-UHFFFAOYSA-N ethyl heptanoate Chemical compound CCCCCCC(=O)OCC TVQGDYNRXLTQAP-UHFFFAOYSA-N 0.000 description 14
OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 14
230000015572 biosynthetic process Effects 0.000 description 13
239000000460 chlorine Substances 0.000 description 13
208000024891 symptom Diseases 0.000 description 13
CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 12
IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
238000006243 chemical reaction Methods 0.000 description 12
239000003112 inhibitor Substances 0.000 description 12
238000003786 synthesis reaction Methods 0.000 description 12
125000004432 carbon atom Chemical group C* 0.000 description 11
239000000463 material Substances 0.000 description 11
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 10
101150003085 Pdcl gene Proteins 0.000 description 10
238000004587 chromatography analysis Methods 0.000 description 10
210000002216 heart Anatomy 0.000 description 10
KAQKFAOMNZTLHT-OZUDYXHBSA-N prostaglandin I2 Chemical compound O1\C(=C/CCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-OZUDYXHBSA-N 0.000 description 10
150000003180 prostaglandins Chemical class 0.000 description 10
230000002685 pulmonary effect Effects 0.000 description 10
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
208000035478 Interatrial communication Diseases 0.000 description 9
206010063837 Reperfusion injury Diseases 0.000 description 9
206010044565 Tremor Diseases 0.000 description 9
208000001910 Ventricular Heart Septal Defects Diseases 0.000 description 9
230000029936 alkylation Effects 0.000 description 9
238000005804 alkylation reaction Methods 0.000 description 9
125000004429 atom Chemical group 0.000 description 9
208000013914 atrial heart septal defect Diseases 0.000 description 9
206010003664 atrial septal defect Diseases 0.000 description 9
239000002585 base Substances 0.000 description 9
238000001816 cooling Methods 0.000 description 9
150000002148 esters Chemical class 0.000 description 9
XNFIYDNLYYQTNO-UHFFFAOYSA-N ethyl 7-[6-cyclopropyl-2,3,7,7-tetrakis(4-methylphenyl)-6H-pyrrolo[2,3-b]pyrazin-5-yl]heptanoate Chemical compound C1(CC1)C1C(C=2C(=NC(=C(N=2)C2=CC=C(C=C2)C)C2=CC=C(C=C2)C)N1CCCCCCC(=O)OCC)(C1=CC=C(C=C1)C)C1=CC=C(C=C1)C XNFIYDNLYYQTNO-UHFFFAOYSA-N 0.000 description 9
239000001301 oxygen Substances 0.000 description 9
229940094443 oxytocics prostaglandins Drugs 0.000 description 9
239000000047 product Substances 0.000 description 9
238000000746 purification Methods 0.000 description 9
229920006395 saturated elastomer Polymers 0.000 description 9
239000011734 sodium Substances 0.000 description 9
201000003130 ventricular septal defect Diseases 0.000 description 9
AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 8
OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 8
206010061218 Inflammation Diseases 0.000 description 8
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 8
239000000556 agonist Substances 0.000 description 8
239000005557 antagonist Substances 0.000 description 8
229940127218 antiplatelet drug Drugs 0.000 description 8
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 8
230000001746 atrial effect Effects 0.000 description 8
230000004087 circulation Effects 0.000 description 8
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
235000019253 formic acid Nutrition 0.000 description 8
230000004054 inflammatory process Effects 0.000 description 8
208000012947 ischemia reperfusion injury Diseases 0.000 description 8
125000006239 protecting group Chemical group 0.000 description 8
206010039073 rheumatoid arthritis Diseases 0.000 description 8
239000007787 solid Substances 0.000 description 8
208000004998 Abdominal Pain Diseases 0.000 description 7
208000002881 Colic Diseases 0.000 description 7
206010016654 Fibrosis Diseases 0.000 description 7
208000012322 Raynaud phenomenon Diseases 0.000 description 7
206010039710 Scleroderma Diseases 0.000 description 7
208000006011 Stroke Diseases 0.000 description 7
201000009594 Systemic Scleroderma Diseases 0.000 description 7
206010042953 Systemic sclerosis Diseases 0.000 description 7
230000031709 bromination Effects 0.000 description 7
238000005893 bromination reaction Methods 0.000 description 7
210000004027 cell Anatomy 0.000 description 7
210000000038 chest Anatomy 0.000 description 7
FTPOIZAMXIPZPT-UHFFFAOYSA-N ethyl 7-[2,3-bis(4-methylphenyl)pyrrolo[2,3-b]pyrazin-5-yl]heptanoate Chemical compound C=1C=C(C)C=CC=1C=1N=C2N(CCCCCCC(=O)OCC)C=CC2=NC=1C1=CC=C(C)C=C1 FTPOIZAMXIPZPT-UHFFFAOYSA-N 0.000 description 7
238000009472 formulation Methods 0.000 description 7
238000001727 in vivo Methods 0.000 description 7
239000003960 organic solvent Substances 0.000 description 7
238000005191 phase separation Methods 0.000 description 7
239000000106 platelet aggregation inhibitor Substances 0.000 description 7
VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 7
QUFINRKAGDWDMR-UHFFFAOYSA-N 5-[2,3-bis(4-methylphenyl)-5h-pyrrolo[2,3-b]pyrazin-6-yl]pentanoic acid Chemical compound C1=CC(C)=CC=C1C(C(=N1)C=2C=CC(C)=CC=2)=NC2=C1NC(CCCCC(O)=O)=C2 QUFINRKAGDWDMR-UHFFFAOYSA-N 0.000 description 6
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 6
208000029147 Collagen-vascular disease Diseases 0.000 description 6
FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 6
208000007342 Diabetic Nephropathies Diseases 0.000 description 6
PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 6
RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
238000006069 Suzuki reaction reaction Methods 0.000 description 6
150000001412 amines Chemical class 0.000 description 6
239000011324 bead Substances 0.000 description 6
239000012267 brine Substances 0.000 description 6
239000003153 chemical reaction reagent Substances 0.000 description 6
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
239000013078 crystal Substances 0.000 description 6
208000033679 diabetic kidney disease Diseases 0.000 description 6
229960001123 epoprostenol Drugs 0.000 description 6
230000004761 fibrosis Effects 0.000 description 6
239000000706 filtrate Substances 0.000 description 6
239000001257 hydrogen Substances 0.000 description 6
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
210000004072 lung Anatomy 0.000 description 6
230000001404 mediated effect Effects 0.000 description 6
208000010125 myocardial infarction Diseases 0.000 description 6
102000005962 receptors Human genes 0.000 description 6
108020003175 receptors Proteins 0.000 description 6
229910052708 sodium Inorganic materials 0.000 description 6
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
208000010110 spontaneous platelet aggregation Diseases 0.000 description 6
239000007858 starting material Substances 0.000 description 6
239000003643 water by type Substances 0.000 description 6
125000003161 (C1-C6) alkylene group Chemical group 0.000 description 5
MVOWRMCKFKAFTH-UHFFFAOYSA-N 7-[2,3-bis(4-methylphenyl)pyrrolo[2,3-b]pyrazin-5-yl]heptanoic acid Chemical compound C1=CC(C)=CC=C1C(C(=N1)C=2C=CC(C)=CC=2)=NC2=C1N(CCCCCCC(O)=O)C=C2 MVOWRMCKFKAFTH-UHFFFAOYSA-N 0.000 description 5
MJRHDDJEDAGLDQ-UHFFFAOYSA-N 7-[6-methyl-2,3-bis(4-methylphenyl)pyrrolo[2,3-b]pyrazin-5-yl]heptanoic acid Chemical compound C=1C=C(C)C=CC=1C=1N=C2N(CCCCCCC(O)=O)C(C)=CC2=NC=1C1=CC=C(C)C=C1 MJRHDDJEDAGLDQ-UHFFFAOYSA-N 0.000 description 5
BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 5
201000002829 CREST Syndrome Diseases 0.000 description 5
206010012689 Diabetic retinopathy Diseases 0.000 description 5
208000031953 Hereditary hemorrhagic telangiectasia Diseases 0.000 description 5
208000020875 Idiopathic pulmonary arterial hypertension Diseases 0.000 description 5
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 5
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
238000003477 Sonogashira cross-coupling reaction Methods 0.000 description 5
239000003146 anticoagulant agent Substances 0.000 description 5
238000003556 assay Methods 0.000 description 5
210000004369 blood Anatomy 0.000 description 5
239000008280 blood Substances 0.000 description 5
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
150000001732 carboxylic acid derivatives Chemical class 0.000 description 5
238000002425 crystallisation Methods 0.000 description 5
230000008025 crystallization Effects 0.000 description 5
210000004443 dendritic cell Anatomy 0.000 description 5
238000010931 ester hydrolysis Methods 0.000 description 5
QPFFFBBCUNXNGB-UHFFFAOYSA-N ethyl 7-[6-cyclopropyl-2,3-bis(4-methylphenyl)pyrrolo[2,3-b]pyrazin-5-yl]heptanoate Chemical compound C=1C=C(C)C=CC=1C=1N=C2N(CCCCCCC(=O)OCC)C(C3CC3)=CC2=NC=1C1=CC=C(C)C=C1 QPFFFBBCUNXNGB-UHFFFAOYSA-N 0.000 description 5
OOBFNDGMAGSNKA-UHFFFAOYSA-N ethyl 7-bromoheptanoate Chemical compound CCOC(=O)CCCCCCBr OOBFNDGMAGSNKA-UHFFFAOYSA-N 0.000 description 5
238000004128 high performance liquid chromatography Methods 0.000 description 5
230000006872 improvement Effects 0.000 description 5
230000003907 kidney function Effects 0.000 description 5
150000002632 lipids Chemical class 0.000 description 5
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 5
201000011461 pre-eclampsia Diseases 0.000 description 5
238000010992 reflux Methods 0.000 description 5
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238000007363 ring formation reaction Methods 0.000 description 5
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238000010911 splenectomy Methods 0.000 description 5
239000000126 substance Substances 0.000 description 5
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239000003053 toxin Substances 0.000 description 5
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YAJVENHNCNDLGP-UHFFFAOYSA-N 2,3-bis(4-methylphenyl)-5h-pyrrolo[2,3-b]pyrazine Chemical compound C1=CC(C)=CC=C1C(C(=N1)C=2C=CC(C)=CC=2)=NC2=C1NC=C2 YAJVENHNCNDLGP-UHFFFAOYSA-N 0.000 description 4
JTPXVCKCLBROOJ-UHFFFAOYSA-N 2-amino-6-chloropyrazine Chemical compound NC1=CN=CC(Cl)=N1 JTPXVCKCLBROOJ-UHFFFAOYSA-N 0.000 description 4
125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 4
UJFZQXLHYRDFBV-UHFFFAOYSA-N 3-bromo-5,6-bis(4-methylphenyl)pyrazin-2-amine Chemical compound C1=CC(C)=CC=C1C1=NC(N)=C(Br)N=C1C1=CC=C(C)C=C1 UJFZQXLHYRDFBV-UHFFFAOYSA-N 0.000 description 4
125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 4
YEBDYUMXHLRMBW-UHFFFAOYSA-N 6-chloro-5-iodopyrazin-2-amine Chemical compound NC1=CN=C(I)C(Cl)=N1 YEBDYUMXHLRMBW-UHFFFAOYSA-N 0.000 description 4
JXJZLAGXBTVWIY-UHFFFAOYSA-N 7-[2,3-bis(4-methylphenyl)-6-(trifluoromethyl)pyrrolo[2,3-b]pyrazin-5-yl]heptanoic acid Chemical compound C1=CC(C)=CC=C1C(C(=N1)C=2C=CC(C)=CC=2)=NC2=C1N(CCCCCCC(O)=O)C(C(F)(F)F)=C2 JXJZLAGXBTVWIY-UHFFFAOYSA-N 0.000 description 4
NHWZOYUFXXOWEQ-UHFFFAOYSA-N 7-[6,7-diethyl-2,3-bis(4-methylphenyl)pyrrolo[2,3-b]pyrazin-5-yl]heptanoic acid Chemical compound C=1C=C(C)C=CC=1C=1N=C2N(CCCCCCC(O)=O)C(CC)=C(CC)C2=NC=1C1=CC=C(C)C=C1 NHWZOYUFXXOWEQ-UHFFFAOYSA-N 0.000 description 4
KJRUENZZHUVCSP-UHFFFAOYSA-N 7-[6-cyclopropyl-2,3-bis(4-methylphenyl)pyrrolo[2,3-b]pyrazin-5-yl]heptanoic acid Chemical compound C1=CC(C)=CC=C1C(C(=N1)C=2C=CC(C)=CC=2)=NC2=C1N(CCCCCCC(O)=O)C(C1CC1)=C2 KJRUENZZHUVCSP-UHFFFAOYSA-N 0.000 description 4
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