KR20240055039A

KR20240055039A - Ampk 활성화제로서 유용한 티아디아졸론 유도체

Ampk 활성화제로서 유용한 티아디아졸론 유도체 Download PDF

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Publication number: KR20240055039A
Authority: KR; South Korea
Prior art keywords: compound; methyl; oxo; chlorophenyl; hydrogen
Prior art date: 2021-09-02
Legal status : Pending

Application number

KR1020247010453A

Other languages

English (en)

Korean (ko)

Inventor

토마스 에들룬드

야카브 베스트만

Original Assignee

베타게논 에이비

Priority date

2021-09-02

Filing date

2022-09-01

Publication date

2024-04-26

2022-09-01 Application filed by 베타게논 에이비 filed Critical 베타게논 에이비

2024-04-26 Publication of KR20240055039A publication Critical patent/KR20240055039A/ko

Status Pending legal-status Critical Current

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102100036009 5'-AMP-activated protein kinase catalytic subunit alpha-2 Human genes 0.000 title claims 6
101000783681 Homo sapiens 5'-AMP-activated protein kinase catalytic subunit alpha-2 Proteins 0.000 title claims 6
239000012190 activator Substances 0.000 title description 8
XWMXMWHHTIEXRE-UHFFFAOYSA-N thiadiazole 1-oxide Chemical class O=S1C=CN=N1 XWMXMWHHTIEXRE-UHFFFAOYSA-N 0.000 title 1
150000001875 compounds Chemical class 0.000 claims abstract description 382
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 39
230000004913 activation Effects 0.000 claims abstract description 25
208000035475 disorder Diseases 0.000 claims abstract description 23
230000001668 ameliorated effect Effects 0.000 claims abstract description 17
-1 Dimethylamino-acetic acid 5-[(Z)-4-chloro-benzoylimino]-2-(4-chloro-benzyl)-3-oxo-[1,2,4]thiadiazolidin-4-ylmethyl ester Chemical compound 0.000 claims description 145
229910052739 hydrogen Inorganic materials 0.000 claims description 91
239000001257 hydrogen Substances 0.000 claims description 91
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 73
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 47
238000006243 chemical reaction Methods 0.000 claims description 46
150000002431 hydrogen Chemical class 0.000 claims description 43
238000000034 method Methods 0.000 claims description 43
150000003839 salts Chemical class 0.000 claims description 32
CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 28
208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 27
125000000217 alkyl group Chemical group 0.000 claims description 25
239000012453 solvate Substances 0.000 claims description 25
206010028980 Neoplasm Diseases 0.000 claims description 22
229910052799 carbon Inorganic materials 0.000 claims description 21
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
229930182852 proteinogenic amino acid Natural products 0.000 claims description 20
150000001413 amino acids Chemical class 0.000 claims description 19
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 18
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235000001014 amino acid Nutrition 0.000 claims description 16
201000011510 cancer Diseases 0.000 claims description 16
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RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 12
235000003704 aspartic acid Nutrition 0.000 claims description 12
OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 12
239000000825 pharmaceutical preparation Substances 0.000 claims description 12
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206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 11
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235000020824 obesity Nutrition 0.000 claims description 10
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125000006239 protecting group Chemical group 0.000 claims description 10
125000001424 substituent group Chemical group 0.000 claims description 10
208000024172 Cardiovascular disease Diseases 0.000 claims description 9
QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 8
208000007342 Diabetic Nephropathies Diseases 0.000 claims description 8
208000033679 diabetic kidney disease Diseases 0.000 claims description 8
206010019280 Heart failures Diseases 0.000 claims description 6
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208000026251 Opioid-Related disease Diseases 0.000 claims description 6
230000004054 inflammatory process Effects 0.000 claims description 6
125000006620 amino-(C1-C6) alkyl group Chemical group 0.000 claims description 5
208000023275 Autoimmune disease Diseases 0.000 claims description 4
206010022489 Insulin Resistance Diseases 0.000 claims description 4
208000001132 Osteoporosis Diseases 0.000 claims description 4
125000000592 heterocycloalkyl group Chemical group 0.000 claims description 4
208000028774 intestinal disease Diseases 0.000 claims description 4
208000037976 chronic inflammation Diseases 0.000 claims description 3
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238000004519 manufacturing process Methods 0.000 claims description 3
235000018102 proteins Nutrition 0.000 claims description 3
102000004169 proteins and genes Human genes 0.000 claims description 3
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239000000651 prodrug Substances 0.000 abstract description 6
229940002612 prodrug Drugs 0.000 abstract description 6
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 117
239000011541 reaction mixture Substances 0.000 description 108
239000000243 solution Substances 0.000 description 88
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 74
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 73
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 64
238000002360 preparation method Methods 0.000 description 59
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 56
239000007787 solid Substances 0.000 description 56
102000014156 AMP-Activated Protein Kinases Human genes 0.000 description 52
108010011376 AMP-Activated Protein Kinases Proteins 0.000 description 52
QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 48
239000000203 mixture Substances 0.000 description 42
125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 42
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 33
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 30
238000009472 formulation Methods 0.000 description 28
229960000549 4-dimethylaminophenol Drugs 0.000 description 26
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 25
125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 24
229940125904 compound 1 Drugs 0.000 description 23
238000004128 high performance liquid chromatography Methods 0.000 description 23
238000004895 liquid chromatography mass spectrometry Methods 0.000 description 23
WEDWLYRQKUTOAX-UHFFFAOYSA-N 4-chloro-n-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide Chemical compound C1=CC(Cl)=CC=C1CN1C(=O)N=C(NC(=O)C=2C=CC(Cl)=CC=2)S1 WEDWLYRQKUTOAX-UHFFFAOYSA-N 0.000 description 22
238000004440 column chromatography Methods 0.000 description 22
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 21
KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 21
239000000706 filtrate Substances 0.000 description 21
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 21
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 20
229940125782 compound 2 Drugs 0.000 description 20
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
229940126214 compound 3 Drugs 0.000 description 19
238000005481 NMR spectroscopy Methods 0.000 description 18
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 15
ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 15
210000004027 cell Anatomy 0.000 description 15
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 15
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
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239000002904 solvent Substances 0.000 description 14
KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical group NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 13
239000003795 chemical substances by application Substances 0.000 description 13
AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 12
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WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 12
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MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 10
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KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
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MPLLLQUZNJSVTK-UHFFFAOYSA-N 5-[3-[4-[2-(4-fluorophenyl)ethoxy]phenyl]propyl]furan-2-carboxylic acid Chemical compound O1C(C(=O)O)=CC=C1CCCC(C=C1)=CC=C1OCCC1=CC=C(F)C=C1 MPLLLQUZNJSVTK-UHFFFAOYSA-N 0.000 description 9
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MJRWXIQFTMLYFG-LBPRGKRZSA-N 2-[[(2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoyl]amino]acetic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(=O)NCC(O)=O)CC1=CC=CC=C1 MJRWXIQFTMLYFG-LBPRGKRZSA-N 0.000 description 7
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