CA2679310A1

CA2679310A1 - Tetrasubstituted glucopyranosylated benzene derivatives, medicaments containing such compounds, their use and process for their manufacture

Tetrasubstituted glucopyranosylated benzene derivatives, medicaments containing such compounds, their use and process for their manufacture Download PDF

Info

Publication number: CA2679310A1
Authority: CA; Canada
Prior art keywords: alkyl; groups; compound; group; aryl
Prior art date: 2007-02-21
Legal status : Withdrawn

Application number

CA002679310A

Other languages

English (en)

French (fr)

Inventor

Frank Himmelsbach

Matthias Eckhardt

Peter Eickelmann

Leo Thomas

Current Assignee

Boehringer Ingelheim International GmbH

Original Assignee

Individual

Priority date

2007-02-21

Filing date

2008-02-20

Publication date

2008-08-28

2008-02-20 Application filed by Individual filed Critical Individual

2008-08-28 Publication of CA2679310A1 publication Critical patent/CA2679310A1/en

Status Withdrawn legal-status Critical Current

Links

150000001875 compounds Chemical class 0.000 title claims abstract description 120
125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 title claims abstract description 31
238000004519 manufacturing process Methods 0.000 title claims description 8
238000000034 method Methods 0.000 title description 23
230000008569 process Effects 0.000 title description 9
239000003814 drug Substances 0.000 title description 4
239000000203 mixture Substances 0.000 claims abstract description 45
150000003839 salts Chemical class 0.000 claims abstract description 42
208000030159 metabolic disease Diseases 0.000 claims abstract description 8
-1 C1-4-alkylcarbonyl Chemical group 0.000 claims description 104
229910052739 hydrogen Inorganic materials 0.000 claims description 49
239000001257 hydrogen Substances 0.000 claims description 46
238000006243 chemical reaction Methods 0.000 claims description 38
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 36
125000003118 aryl group Chemical group 0.000 claims description 31
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 30
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 30
239000000460 chlorine Substances 0.000 claims description 30
229910052801 chlorine Inorganic materials 0.000 claims description 30
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 29
229910052794 bromium Inorganic materials 0.000 claims description 23
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 22
229910052731 fluorine Inorganic materials 0.000 claims description 22
239000011737 fluorine Substances 0.000 claims description 21
239000008194 pharmaceutical composition Substances 0.000 claims description 21
125000001424 substituent group Chemical group 0.000 claims description 21
125000000217 alkyl group Chemical group 0.000 claims description 20
229910052751 metal Inorganic materials 0.000 claims description 19
239000002184 metal Substances 0.000 claims description 19
125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 claims description 18
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 17
229910052736 halogen Inorganic materials 0.000 claims description 17
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 16
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 15
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 15
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
239000002253 acid Substances 0.000 claims description 14
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 13
125000000753 cycloalkyl group Chemical group 0.000 claims description 13
150000002367 halogens Chemical group 0.000 claims description 13
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
125000006239 protecting group Chemical group 0.000 claims description 13
125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 12
102000000070 Sodium-Glucose Transport Proteins Human genes 0.000 claims description 11
108010080361 Sodium-Glucose Transport Proteins Proteins 0.000 claims description 11
102100037202 Sodium/myo-inositol cotransporter 2 Human genes 0.000 claims description 11
101710090560 Sodium/myo-inositol cotransporter 2 Proteins 0.000 claims description 11
201000010099 disease Diseases 0.000 claims description 11
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 11
230000002401 inhibitory effect Effects 0.000 claims description 11
229910052740 iodine Inorganic materials 0.000 claims description 11
230000002265 prevention Effects 0.000 claims description 11
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 10
125000004036 acetal group Chemical group 0.000 claims description 10
125000005129 aryl carbonyl group Chemical group 0.000 claims description 10
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
125000006702 (C1-C18) alkyl group Chemical group 0.000 claims description 9
125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 9
125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 9
108091006269 SLC5A2 Proteins 0.000 claims description 8
125000004432 carbon atom Chemical group C* 0.000 claims description 8
206010012601 diabetes mellitus Diseases 0.000 claims description 8
125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 7
PHOQVHQSTUBQQK-SQOUGZDYSA-N D-glucono-1,5-lactone Chemical compound OC[C@H]1OC(=O)[C@H](O)[C@@H](O)[C@@H]1O PHOQVHQSTUBQQK-SQOUGZDYSA-N 0.000 claims description 7
239000002841 Lewis acid Substances 0.000 claims description 7
125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 7
239000003638 chemical reducing agent Substances 0.000 claims description 7
229960003681 gluconolactone Drugs 0.000 claims description 7
ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical group O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 claims description 7
125000001624 naphthyl group Chemical group 0.000 claims description 7
150000003214 pyranose derivatives Chemical group 0.000 claims description 7
210000002237 B-cell of pancreatic islet Anatomy 0.000 claims description 6
239000007848 Bronsted acid Substances 0.000 claims description 6
208000008589 Obesity Diseases 0.000 claims description 6
239000003085 diluting agent Substances 0.000 claims description 6
125000001153 fluoro group Chemical group F* 0.000 claims description 6
235000012209 glucono delta-lactone Nutrition 0.000 claims description 6
210000004185 liver Anatomy 0.000 claims description 6
235000020824 obesity Nutrition 0.000 claims description 6
125000004430 oxygen atom Chemical group O* 0.000 claims description 6
125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 5
125000006704 (C5-C6) cycloalkyl group Chemical group 0.000 claims description 5
230000002159 abnormal effect Effects 0.000 claims description 5
238000009825 accumulation Methods 0.000 claims description 5
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 5
239000000969 carrier Substances 0.000 claims description 5
125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 5
150000002902 organometallic compounds Chemical class 0.000 claims description 5
229910052760 oxygen Inorganic materials 0.000 claims description 5
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 5
239000005977 Ethylene Substances 0.000 claims description 4
206010020772 Hypertension Diseases 0.000 claims description 4
229910002091 carbon monoxide Inorganic materials 0.000 claims description 4
125000004093 cyano group Chemical group *C#N 0.000 claims description 4
239000002934 diuretic Substances 0.000 claims description 4
125000001072 heteroaryl group Chemical group 0.000 claims description 4
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
238000006478 transmetalation reaction Methods 0.000 claims description 4
201000001320 Atherosclerosis Diseases 0.000 claims description 3
206010007558 Cardiac failure chronic Diseases 0.000 claims description 3
206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 3
125000000304 alkynyl group Chemical group 0.000 claims description 3
239000003795 chemical substances by application Substances 0.000 claims description 3
230000007850 degeneration Effects 0.000 claims description 3
150000002012 dioxanes Chemical group 0.000 claims description 3
230000006806 disease prevention Effects 0.000 claims description 3
150000007522 mineralic acids Chemical class 0.000 claims description 3
150000007524 organic acids Chemical class 0.000 claims description 3
235000005985 organic acids Nutrition 0.000 claims description 3
125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 3
125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 3
125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
208000010444 Acidosis Diseases 0.000 claims description 2
125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 2
208000032928 Dyslipidaemia Diseases 0.000 claims description 2
206010060378 Hyperinsulinaemia Diseases 0.000 claims description 2
201000001431 Hyperuricemia Diseases 0.000 claims description 2
208000013016 Hypoglycemia Diseases 0.000 claims description 2
206010022489 Insulin Resistance Diseases 0.000 claims description 2
208000007976 Ketosis Diseases 0.000 claims description 2
208000001145 Metabolic Syndrome Diseases 0.000 claims description 2
206010027417 Metabolic acidosis Diseases 0.000 claims description 2
206010030113 Oedema Diseases 0.000 claims description 2
201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 2
150000003855 acyl compounds Chemical class 0.000 claims description 2
230000010933 acylation Effects 0.000 claims description 2
238000005917 acylation reaction Methods 0.000 claims description 2
125000003342 alkenyl group Chemical group 0.000 claims description 2
125000001118 alkylidene group Chemical group 0.000 claims description 2
125000004658 aryl carbonyl amino group Chemical group 0.000 claims description 2
125000005163 aryl sulfanyl group Chemical group 0.000 claims description 2
125000005135 aryl sulfinyl group Chemical group 0.000 claims description 2
125000004657 aryl sulfonyl amino group Chemical group 0.000 claims description 2
125000004391 aryl sulfonyl group Chemical group 0.000 claims description 2
125000004104 aryloxy group Chemical group 0.000 claims description 2
230000001882 diuretic effect Effects 0.000 claims description 2
208000018914 glucose metabolism disease Diseases 0.000 claims description 2
125000005223 heteroarylcarbonyl group Chemical group 0.000 claims description 2
125000005224 heteroarylcarbonylamino group Chemical group 0.000 claims description 2
125000005553 heteroaryloxy group Chemical group 0.000 claims description 2
125000005150 heteroarylsulfinyl group Chemical group 0.000 claims description 2
125000005143 heteroarylsulfonyl group Chemical group 0.000 claims description 2
230000035879 hyperinsulinaemia Effects 0.000 claims description 2
239000011630 iodine Substances 0.000 claims description 2
230000004140 ketosis Effects 0.000 claims description 2
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
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 claims description 2
229910052717 sulfur Inorganic materials 0.000 claims description 2
125000006698 (C1-C3) dialkylamino group Chemical group 0.000 claims 5
150000002431 hydrogen Chemical class 0.000 claims 4
125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 3
125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims 2
125000003830 C1- C4 alkylcarbonylamino group Chemical group 0.000 claims 2
125000004768 (C1-C4) alkylsulfinyl group Chemical group 0.000 claims 1
125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims 1
125000004760 (C1-C4) alkylsulfonylamino group Chemical group 0.000 claims 1
125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 1
102000058081 Sodium-Glucose Transporter 2 Human genes 0.000 claims 1
230000003276 anti-hypertensive effect Effects 0.000 claims 1
125000006576 di-(C1-C3-alkyl)-aminocarbonyl group Chemical group 0.000 claims 1
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 51
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 36
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 35
239000000243 solution Substances 0.000 description 35
239000013543 active substance Substances 0.000 description 33
235000002639 sodium chloride Nutrition 0.000 description 33
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
239000002904 solvent Substances 0.000 description 25
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 23
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 18
238000003786 synthesis reaction Methods 0.000 description 17
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 15
230000015572 biosynthetic process Effects 0.000 description 15
238000001819 mass spectrum Methods 0.000 description 15
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
210000004027 cell Anatomy 0.000 description 14
229960000583 acetic acid Drugs 0.000 description 12
230000000875 corresponding effect Effects 0.000 description 12
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
238000002360 preparation method Methods 0.000 description 12
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 11
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 10
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
239000003112 inhibitor Substances 0.000 description 10
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
230000009467 reduction Effects 0.000 description 10
238000006722 reduction reaction Methods 0.000 description 10
239000003826 tablet Substances 0.000 description 10
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
229910052723 transition metal Inorganic materials 0.000 description 10
150000003624 transition metals Chemical class 0.000 description 10
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
239000012267 brine Substances 0.000 description 9
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 9
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 8
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 8
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
239000005557 antagonist Substances 0.000 description 8
239000002775 capsule Substances 0.000 description 8
125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 8
239000000126 substance Substances 0.000 description 8
WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 7
102100020888 Sodium/glucose cotransporter 2 Human genes 0.000 description 7
239000003054 catalyst Substances 0.000 description 7
229910052744 lithium Inorganic materials 0.000 description 7
125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 7
125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 description 7
229910052938 sodium sulfate Inorganic materials 0.000 description 7
235000011152 sodium sulphate Nutrition 0.000 description 7
XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 6
GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 6
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 6
229910052799 carbon Inorganic materials 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
229960004132 diethyl ether Drugs 0.000 description 6
PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 6
239000008101 lactose Substances 0.000 description 6
239000011777 magnesium Substances 0.000 description 6
229910052749 magnesium Inorganic materials 0.000 description 6
239000012044 organic layer Substances 0.000 description 6
AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 6
CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 6
CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 5
229920002261 Corn starch Polymers 0.000 description 5
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 5
239000000556 agonist Substances 0.000 description 5
238000004587 chromatography analysis Methods 0.000 description 5
239000008120 corn starch Substances 0.000 description 5
CZZYITDELCSZES-UHFFFAOYSA-N diphenylmethane Chemical compound C=1C=CC=CC=1CC1=CC=CC=C1 CZZYITDELCSZES-UHFFFAOYSA-N 0.000 description 5
230000000694 effects Effects 0.000 description 5
125000004672 ethylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C(*)=O 0.000 description 5
PSCMQHVBLHHWTO-UHFFFAOYSA-K indium(iii) chloride Chemical compound Cl[In](Cl)Cl PSCMQHVBLHHWTO-UHFFFAOYSA-K 0.000 description 5
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
235000019359 magnesium stearate Nutrition 0.000 description 5
229910052943 magnesium sulfate Inorganic materials 0.000 description 5
239000012074 organic phase Substances 0.000 description 5
239000001267 polyvinylpyrrolidone Substances 0.000 description 5
229920000036 polyvinylpyrrolidone Polymers 0.000 description 5
235000013855 polyvinylpyrrolidone Nutrition 0.000 description 5
239000002243 precursor Substances 0.000 description 5
239000000741 silica gel Substances 0.000 description 5
229910002027 silica gel Inorganic materials 0.000 description 5
235000017557 sodium bicarbonate Nutrition 0.000 description 5
229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
239000007787 solid Substances 0.000 description 5
239000007858 starting material Substances 0.000 description 5
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 4
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 4
208000004930 Fatty Liver Diseases 0.000 description 4
206010019708 Hepatic steatosis Diseases 0.000 description 4
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
150000007513 acids Chemical class 0.000 description 4
PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 4
229910052796 boron Inorganic materials 0.000 description 4
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
238000001816 cooling Methods 0.000 description 4
239000012043 crude product Substances 0.000 description 4
125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 4
NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 4
125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 4
125000004705 ethylthio group Chemical group C(C)S* 0.000 description 4
208000010706 fatty liver disease Diseases 0.000 description 4
239000013067 intermediate product Substances 0.000 description 4
235000019341 magnesium sulphate Nutrition 0.000 description 4
229940098779 methanesulfonic acid Drugs 0.000 description 4
229910052757 nitrogen Inorganic materials 0.000 description 4
208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 4
229910052763 palladium Inorganic materials 0.000 description 4
239000012279 sodium borohydride Substances 0.000 description 4
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