SG193404A1 - C4-monomethyl triterpenoid derivatives and methods of use thereof - Google Patents

Info

Publication number

SG193404A1

SG193404A1 SG2013068291A SG2013068291A SG193404A1 SG 193404 A1 SG193404 A1 SG 193404A1 SG 2013068291 A SG2013068291 A SG 2013068291A SG 2013068291 A SG2013068291 A SG 2013068291A SG 193404 A1 SG193404 A1 SG 193404A1

Authority

SG

Singapore

Prior art keywords

compound

mmol

hydrogen

compound according

groups

Prior art date

2011-03-11

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• 238000000034 method Methods 0.000 title claims abstract description 35
• 150000001875 compounds Chemical class 0.000 claims abstract description 423
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
• 229910052739 hydrogen Inorganic materials 0.000 claims description 98
• 239000001257 hydrogen Substances 0.000 claims description 86
• -1 hydroxy, amino Chemical group 0.000 claims description 77
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 57
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 44
• 150000002431 hydrogen Chemical class 0.000 claims description 42
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 37
• 125000003118 aryl group Chemical group 0.000 claims description 37
• 201000010099 disease Diseases 0.000 claims description 34
• 125000004429 atom Chemical group 0.000 claims description 33
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 33
• 125000003545 alkoxy group Chemical group 0.000 claims description 30
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 30
• 125000005843 halogen group Chemical group 0.000 claims description 30
• 125000001072 heteroaryl group Chemical group 0.000 claims description 30
• 125000004432 carbon atom Chemical group C* 0.000 claims description 29
• 125000000217 alkyl group Chemical group 0.000 claims description 27
• 125000003282 alkyl amino group Chemical group 0.000 claims description 26
• 150000003839 salts Chemical class 0.000 claims description 25
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 23
• 125000001769 aryl amino group Chemical group 0.000 claims description 21
• 125000005553 heteroaryloxy group Chemical group 0.000 claims description 21
• 125000004423 acyloxy group Chemical group 0.000 claims description 20
• 125000004663 dialkyl amino group Chemical group 0.000 claims description 20
• 125000003368 amide group Chemical group 0.000 claims description 17
• 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 17
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 17
• 229910052757 nitrogen Inorganic materials 0.000 claims description 16
• 125000003342 alkenyl group Chemical group 0.000 claims description 14
• 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 14
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 14
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 12
• 125000000304 alkynyl group Chemical group 0.000 claims description 11
• 125000006323 alkenyl amino group Chemical group 0.000 claims description 9
• 125000005241 heteroarylamino group Chemical group 0.000 claims description 9
• 208000035475 disorder Diseases 0.000 claims description 8
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 8
• 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 8
• 125000003302 alkenyloxy group Chemical group 0.000 claims description 7
• 125000001691 aryl alkyl amino group Chemical group 0.000 claims description 7
• 125000004104 aryloxy group Chemical group 0.000 claims description 5
• 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims description 5
• 125000000547 substituted alkyl group Chemical group 0.000 claims description 5
• 125000005035 acylthio group Chemical group 0.000 claims description 4
• 125000002883 imidazolyl group Chemical group 0.000 claims description 4
• XTEOJPUYZWEXFI-UHFFFAOYSA-N butyl n-[3-[4-(imidazol-1-ylmethyl)phenyl]-5-(2-methylpropyl)thiophen-2-yl]sulfonylcarbamate Chemical compound S1C(CC(C)C)=CC(C=2C=CC(CN3C=NC=C3)=CC=2)=C1S(=O)(=O)NC(=O)OCCCC XTEOJPUYZWEXFI-UHFFFAOYSA-N 0.000 claims description 3
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
• 125000001153 fluoro group Chemical group F* 0.000 claims description 3
• 239000012948 isocyanate Substances 0.000 claims description 3
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
• 125000006002 1,1-difluoroethyl group Chemical group 0.000 claims description 2
• 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 2
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical group OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 2
• 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 2
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
• 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 claims description 2
• 125000002346 iodo group Chemical group I* 0.000 claims description 2
• 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 2
• 125000001715 oxadiazolyl group Chemical group 0.000 claims description 2
• 125000004043 oxo group Chemical group O=* 0.000 claims description 2
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims 13
• 101100145173 Drosophila melanogaster Non3 gene Proteins 0.000 claims 1
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• 102100021015 Ubiquitin carboxyl-terminal hydrolase 6 Human genes 0.000 claims 1
• IQPQWNKOIGAROB-UHFFFAOYSA-N isocyanate group Chemical group [N-]=C=O IQPQWNKOIGAROB-UHFFFAOYSA-N 0.000 claims 1
• 125000005415 substituted alkoxy group Chemical group 0.000 claims 1
• 239000000203 mixture Substances 0.000 abstract description 208
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• 239000003963 antioxidant agent Substances 0.000 abstract description 8
• 239000000543 intermediate Substances 0.000 abstract description 2
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 546
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 309
• 235000019439 ethyl acetate Nutrition 0.000 description 273
• 239000000243 solution Substances 0.000 description 199
• 239000007787 solid Substances 0.000 description 187
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 172
• 239000000741 silica gel Substances 0.000 description 169
• 229910002027 silica gel Inorganic materials 0.000 description 169
• 238000004440 column chromatography Methods 0.000 description 146
• 238000006243 chemical reaction Methods 0.000 description 132
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 132
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 123
• 239000000284 extract Substances 0.000 description 104
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 98
• XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 89
• 239000011734 sodium Substances 0.000 description 66
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 60
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 52
• 239000006260 foam Substances 0.000 description 49
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 48
• WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 46
• 229910052799 carbon Inorganic materials 0.000 description 43
• 239000003607 modifier Substances 0.000 description 37
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 36
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 35
• 239000012267 brine Substances 0.000 description 34
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 34
• 238000003756 stirring Methods 0.000 description 34
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 31
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 27
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 26
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 23
• 230000037396 body weight Effects 0.000 description 22
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 21
• 230000036542 oxidative stress Effects 0.000 description 21
• 239000011541 reaction mixture Substances 0.000 description 21
• 230000001225 therapeutic effect Effects 0.000 description 21
• MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 20
• 229960000549 4-dimethylaminophenol Drugs 0.000 description 18
• CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 18
• 238000000746 purification Methods 0.000 description 18
• 239000003795 chemical substances by application Substances 0.000 description 17
• VRLDVERQJMEPIF-UHFFFAOYSA-N dbdmh Chemical compound CC1(C)N(Br)C(=O)N(Br)C1=O VRLDVERQJMEPIF-UHFFFAOYSA-N 0.000 description 17
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 17
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• 230000000670 limiting effect Effects 0.000 description 16
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• UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 13
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