UA129205C2 - Похідні альфа-d-галактопіранозиду - Google Patents

Info

Publication number

UA129205C2

UA129205C2 UAA202201022A UAA202201022A UA129205C2 UA 129205 C2 UA129205 C2 UA 129205C2 UA A202201022 A UAA202201022 A UA A202201022A UA A202201022 A UAA202201022 A UA A202201022A UA 129205 C2 UA129205 C2 UA 129205C2

Authority

UA

Ukraine

Prior art keywords

triazol

pyran

methyl

hydroxymethyl

tetrahydro

Prior art date

2019-08-29

Links

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• Global Dossier
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• -1 4,5-dihydroisoxazole-3,5-diyl Chemical group 0.000 claims abstract description 350
• 150000001875 compounds Chemical class 0.000 claims abstract description 224
• 150000003839 salts Chemical class 0.000 claims abstract description 31
• 238000002360 preparation method Methods 0.000 claims abstract description 11
• 239000003814 drug Substances 0.000 claims abstract description 9
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 450
• BHDLTOUYJMTTTM-UHFFFAOYSA-N oxan-3-ol Chemical compound OC1CCCOC1 BHDLTOUYJMTTTM-UHFFFAOYSA-N 0.000 claims description 277
• 125000004499 isoxazol-5-yl group Chemical group O1N=CC=C1* 0.000 claims description 218
• DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 claims description 194
• 125000001424 substituent group Chemical group 0.000 claims description 110
• 125000001607 1,2,3-triazol-1-yl group Chemical group [*]N1N=NC([H])=C1[H] 0.000 claims description 87
• 125000004284 isoxazol-3-yl group Chemical group [H]C1=C([H])C(*)=NO1 0.000 claims description 86
• RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical group C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 claims description 84
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 83
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 76
• 229910052757 nitrogen Inorganic materials 0.000 claims description 75
• IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 73
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 71
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 65
• 125000006588 heterocycloalkylene group Chemical group 0.000 claims description 51
• IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 claims description 44
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 39
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 37
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 35
• 229910052736 halogen Inorganic materials 0.000 claims description 34
• 150000002367 halogens Chemical class 0.000 claims description 34
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 33
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 32
• WXLPKTIAUMCNDX-UHFFFAOYSA-N 2h-pyran-3-ol Chemical compound OC1=CC=COC1 WXLPKTIAUMCNDX-UHFFFAOYSA-N 0.000 claims description 31
• 229910052739 hydrogen Inorganic materials 0.000 claims description 28
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 27
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 27
• 206010016654 Fibrosis Diseases 0.000 claims description 25
• 239000001257 hydrogen Substances 0.000 claims description 25
• 229910052717 sulfur Inorganic materials 0.000 claims description 25
• 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 24
• 125000001153 fluoro group Chemical group F* 0.000 claims description 23
• 125000004432 carbon atom Chemical group C* 0.000 claims description 22
• 229910052731 fluorine Inorganic materials 0.000 claims description 22
• 239000011737 fluorine Substances 0.000 claims description 22
• 125000004434 sulfur atom Chemical group 0.000 claims description 21
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 20
• 201000010099 disease Diseases 0.000 claims description 20
• 125000000217 alkyl group Chemical group 0.000 claims description 19
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 18
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 18
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 18
• 230000004761 fibrosis Effects 0.000 claims description 18
• 125000005842 heteroatom Chemical group 0.000 claims description 18
• 125000003118 aryl group Chemical group 0.000 claims description 17
• 125000005605 benzo group Chemical group 0.000 claims description 17
• 125000001072 heteroaryl group Chemical group 0.000 claims description 17
• JSPCTNUQYWIIOT-UHFFFAOYSA-N piperidine-1-carboxamide Chemical compound NC(=O)N1CCCCC1 JSPCTNUQYWIIOT-UHFFFAOYSA-N 0.000 claims description 17
• 125000006582 (C5-C6) heterocycloalkyl group Chemical group 0.000 claims description 16
• 206010028980 Neoplasm Diseases 0.000 claims description 16
• 208000020832 chronic kidney disease Diseases 0.000 claims description 16
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
• GVONPBONFIJAHJ-UHFFFAOYSA-N imidazolidin-4-one Chemical compound O=C1CNCN1 GVONPBONFIJAHJ-UHFFFAOYSA-N 0.000 claims description 16
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
• 125000006568 (C4-C7) heterocycloalkyl group Chemical group 0.000 claims description 15
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 15
• 208000037765 diseases and disorders Diseases 0.000 claims description 14
• 230000002757 inflammatory effect Effects 0.000 claims description 14
• 208000027866 inflammatory disease Diseases 0.000 claims description 13
• 229910052760 oxygen Chemical group 0.000 claims description 13
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 12
• 208000024172 Cardiovascular disease Diseases 0.000 claims description 12
• 208000035475 disorder Diseases 0.000 claims description 12
• UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims description 12
• 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 12
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 11
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 11
• 229910052799 carbon Inorganic materials 0.000 claims description 11
• 125000005549 heteroarylene group Chemical group 0.000 claims description 11
• 208000019423 liver disease Diseases 0.000 claims description 11
• 239000001301 oxygen Chemical group 0.000 claims description 11
• XYVMOLOUBJBNBF-UHFFFAOYSA-N 3h-1,3-oxazol-2-one Chemical compound OC1=NC=CO1 XYVMOLOUBJBNBF-UHFFFAOYSA-N 0.000 claims description 10
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 10
• 210000000056 organ Anatomy 0.000 claims description 10
• XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 claims description 10
• 208000023275 Autoimmune disease Diseases 0.000 claims description 9
• 208000029523 Interstitial Lung disease Diseases 0.000 claims description 9
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 8
• 208000014644 Brain disease Diseases 0.000 claims description 8
• 208000018522 Gastrointestinal disease Diseases 0.000 claims description 8
• 125000004287 oxazol-2-yl group Chemical group [H]C1=C([H])N=C(*)O1 0.000 claims description 8
• 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 7
• 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 7
• HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 7
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 7
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 7
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 7
• 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 7
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
• 208000009304 Acute Kidney Injury Diseases 0.000 claims description 6
• 208000019693 Lung disease Diseases 0.000 claims description 6
• 208000016222 Pancreatic disease Diseases 0.000 claims description 6
• 208000033626 Renal failure acute Diseases 0.000 claims description 6
• 206010052779 Transplant rejections Diseases 0.000 claims description 6
• 230000002159 abnormal effect Effects 0.000 claims description 6
• 201000011040 acute kidney failure Diseases 0.000 claims description 6
• 230000033115 angiogenesis Effects 0.000 claims description 6
• CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 6
• 230000036210 malignancy Effects 0.000 claims description 6
• 208000033808 peripheral neuropathy Diseases 0.000 claims description 6
• HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 6
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 6
• 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 5
• 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 5
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 5
• 208000004296 neuralgia Diseases 0.000 claims description 5
• 208000021722 neuropathic pain Diseases 0.000 claims description 5
• 230000002062 proliferating effect Effects 0.000 claims description 5
• 150000007942 carboxylates Chemical class 0.000 claims description 4
• 208000030533 eye disease Diseases 0.000 claims description 4
• 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 4
• JQTMGOLZSBTZMS-UHFFFAOYSA-N 4-methylpiperazine-1-carbaldehyde Chemical compound CN1CCN(C=O)CC1 JQTMGOLZSBTZMS-UHFFFAOYSA-N 0.000 claims description 3
• PCDHSSHKDZYLLI-UHFFFAOYSA-N butan-1-one Chemical compound CCC[C]=O PCDHSSHKDZYLLI-UHFFFAOYSA-N 0.000 claims description 3
• 150000002431 hydrogen Chemical class 0.000 claims description 3
• 125000004501 isothiazol-5-yl group Chemical group S1N=CC=C1* 0.000 claims description 3
• 208000024691 pancreas disease Diseases 0.000 claims description 3
• UFUASNAHBMBJIX-UHFFFAOYSA-N propan-1-one Chemical compound CC[C]=O UFUASNAHBMBJIX-UHFFFAOYSA-N 0.000 claims description 3
• 125000004566 azetidin-1-yl group Chemical group N1(CCC1)* 0.000 claims description 2
• 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 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
• HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 claims description 2
• BUGOPWGPQGYYGR-UHFFFAOYSA-N thiane 1,1-dioxide Chemical compound O=S1(=O)CCCCC1 BUGOPWGPQGYYGR-UHFFFAOYSA-N 0.000 claims description 2
• NNLBRYQGMOYARS-UHFFFAOYSA-N thiane 1-oxide Chemical compound O=S1CCCCC1 NNLBRYQGMOYARS-UHFFFAOYSA-N 0.000 claims description 2
• 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims 4
• JBKVHLHDHHXQEQ-UHFFFAOYSA-N epsilon-caprolactam Chemical compound O=C1CCCCCN1 JBKVHLHDHHXQEQ-UHFFFAOYSA-N 0.000 claims 2
• CKJNUZNMWOVDFN-UHFFFAOYSA-N methanone Chemical compound O=[CH-] CKJNUZNMWOVDFN-UHFFFAOYSA-N 0.000 claims 2
• VZEOIIGXIMZHJW-UHFFFAOYSA-N OCC1OCC(C(C1O)N1N=NC(=C1)C1=CC(=C(C(=C1)F)F)F)OC Chemical compound OCC1OCC(C(C1O)N1N=NC(=C1)C1=CC(=C(C(=C1)F)F)F)OC VZEOIIGXIMZHJW-UHFFFAOYSA-N 0.000 claims 1
• 239000003937 drug carrier Substances 0.000 claims 1
• 108010001517 Galectin 3 Proteins 0.000 abstract description 12
• 102000000802 Galectin 3 Human genes 0.000 abstract description 10
• 239000003112 inhibitor Substances 0.000 abstract description 9
• 239000000543 intermediate Substances 0.000 description 203
• 238000000034 method Methods 0.000 description 128
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 120
• 239000000203 mixture Substances 0.000 description 100
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 91
• 239000002904 solvent Substances 0.000 description 88
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 75
• 102100026933 Myelin-associated neurite-outgrowth inhibitor Human genes 0.000 description 75
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 57
• 239000000243 solution Substances 0.000 description 55
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• 239000000047 product Substances 0.000 description 52
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• 206010012812 Diffuse cutaneous mastocytosis Diseases 0.000 description 36
• 238000005481 NMR spectroscopy Methods 0.000 description 31
• 238000010511 deprotection reaction Methods 0.000 description 28
• 230000015572 biosynthetic process Effects 0.000 description 27
• 238000010626 work up procedure Methods 0.000 description 27
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 26
• 239000012043 crude product Substances 0.000 description 26
• 150000002009 diols Chemical class 0.000 description 25
• 238000004128 high performance liquid chromatography Methods 0.000 description 24
• 238000010828 elution Methods 0.000 description 23
• PBNNCGIBXFUKMM-UHFFFAOYSA-N C(C1OCC(CC1O)OC)O Chemical compound C(C1OCC(CC1O)OC)O PBNNCGIBXFUKMM-UHFFFAOYSA-N 0.000 description 22
• 239000003480 eluent Substances 0.000 description 22
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• 238000003786 synthesis reaction Methods 0.000 description 22
• 238000011282 treatment Methods 0.000 description 22
• 238000002953 preparative HPLC Methods 0.000 description 21
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 20
• 238000011321 prophylaxis Methods 0.000 description 19
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• 239000012071 phase Substances 0.000 description 15
• 239000011541 reaction mixture Substances 0.000 description 15
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
• 239000012267 brine Substances 0.000 description 14
• 239000006227 byproduct Substances 0.000 description 14
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 14
• WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
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• 235000011089 carbon dioxide Nutrition 0.000 description 13
• 102000007563 Galectins Human genes 0.000 description 12
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• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
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• 238000000746 purification Methods 0.000 description 12
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 11
• 150000001345 alkine derivatives Chemical class 0.000 description 11
• 150000001412 amines Chemical class 0.000 description 11
• 208000019425 cirrhosis of liver Diseases 0.000 description 11
• 229960003082 galactose Drugs 0.000 description 11
• 239000000725 suspension Substances 0.000 description 11
• OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 10
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• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 10
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• 238000005804 alkylation reaction Methods 0.000 description 9
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 9
• 208000017169 kidney disease Diseases 0.000 description 9
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• 230000029936 alkylation Effects 0.000 description 8
• 230000027455 binding Effects 0.000 description 8
• PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 8
• HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 8
• 125000000335 thiazolyl group Chemical group 0.000 description 8
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
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• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 7
• 206010018364 Glomerulonephritis Diseases 0.000 description 7
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• 239000000460 chlorine Substances 0.000 description 7
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• 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
• 235000019341 magnesium sulphate Nutrition 0.000 description 7
• 150000002923 oximes Chemical class 0.000 description 7
• 238000005160 1H NMR spectroscopy Methods 0.000 description 6
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• 206010019280 Heart failures Diseases 0.000 description 6
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• 125000000753 cycloalkyl group Chemical group 0.000 description 6
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• AMWRITDGCCNYAT-UHFFFAOYSA-L hydroxy(oxo)manganese;manganese Chemical compound [Mn].O[Mn]=O.O[Mn]=O AMWRITDGCCNYAT-UHFFFAOYSA-L 0.000 description 6
• 125000002883 imidazolyl group Chemical group 0.000 description 6
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• GCFUUGDHFHQIIO-UHFFFAOYSA-N OC1=CC(O)=COC1 Chemical compound OC1=CC(O)=COC1 GCFUUGDHFHQIIO-UHFFFAOYSA-N 0.000 description 5
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• 238000001514 detection method Methods 0.000 description 5
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• JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 5
• 239000000126 substance Substances 0.000 description 5
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