WO2016023510A1 - 一种小分子化合物及其合成方法和应用 - Google Patents
一种小分子化合物及其合成方法和应用 Download PDFInfo
- Publication number
- WO2016023510A1 WO2016023510A1 PCT/CN2015/086908 CN2015086908W WO2016023510A1 WO 2016023510 A1 WO2016023510 A1 WO 2016023510A1 CN 2015086908 W CN2015086908 W CN 2015086908W WO 2016023510 A1 WO2016023510 A1 WO 2016023510A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- dichloro
- group
- alkyl
- substituted
- phenyl
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 21
- 238000000034 method Methods 0.000 title claims description 15
- 238000003786 synthesis reaction Methods 0.000 title description 10
- 230000015572 biosynthetic process Effects 0.000 title description 9
- -1 small molecule compound Chemical class 0.000 claims description 51
- 238000006243 chemical reaction Methods 0.000 claims description 35
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 26
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 18
- NWVVVBRKAWDGAB-UHFFFAOYSA-N p-methoxyphenol Chemical compound COC1=CC=C(O)C=C1 NWVVVBRKAWDGAB-UHFFFAOYSA-N 0.000 claims description 18
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- 125000003118 aryl group Chemical group 0.000 claims description 17
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 14
- 150000002431 hydrogen Chemical class 0.000 claims description 14
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 12
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 12
- 125000003277 amino group Chemical group 0.000 claims description 11
- 239000002585 base Substances 0.000 claims description 11
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 11
- 229910052757 nitrogen Chemical group 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 10
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Substances ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 9
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 8
- 125000003107 substituted aryl group Chemical group 0.000 claims description 8
- NJNJOWGRMHFOQS-UHFFFAOYSA-N 1,3-dichloro-2-(4-methoxyphenoxy)-5-nitrobenzene Chemical compound C1=CC(OC)=CC=C1OC1=C(Cl)C=C([N+]([O-])=O)C=C1Cl NJNJOWGRMHFOQS-UHFFFAOYSA-N 0.000 claims description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
- 230000002194 synthesizing effect Effects 0.000 claims description 7
- HHLCSFGOTLUREE-UHFFFAOYSA-N 1,2,3-trichloro-5-nitrobenzene Chemical compound [O-][N+](=O)C1=CC(Cl)=C(Cl)C(Cl)=C1 HHLCSFGOTLUREE-UHFFFAOYSA-N 0.000 claims description 6
- IOHPVZBSOKLVMN-UHFFFAOYSA-N 2-(2-phenylethyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1CCC1=CC=CC=C1 IOHPVZBSOKLVMN-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- 239000003638 chemical reducing agent Substances 0.000 claims description 5
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 230000009467 reduction Effects 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 239000011593 sulfur Substances 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 4
- YAIRXIFLIJWZEI-UHFFFAOYSA-N N-[3,5-dichloro-4-[3-[(4-fluorophenyl)methyl]-4-hydroxyphenoxy]phenyl]-N'-hydroxyoxamide Chemical compound ONC(=O)C(=O)NC1=CC(Cl)=C(OC2=CC(CC3=CC=C(F)C=C3)=C(O)C=C2)C(Cl)=C1 YAIRXIFLIJWZEI-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- 229910002651 NO3 Inorganic materials 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- ZFFBIQMNKOJDJE-UHFFFAOYSA-N 2-bromo-1,2-diphenylethanone Chemical compound C=1C=CC=CC=1C(Br)C(=O)C1=CC=CC=C1 ZFFBIQMNKOJDJE-UHFFFAOYSA-N 0.000 claims description 2
- 239000007818 Grignard reagent Substances 0.000 claims description 2
- 208000008589 Obesity Diseases 0.000 claims description 2
- 208000001132 Osteoporosis Diseases 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- BWOVZCWSJFYBRM-UHFFFAOYSA-N carbononitridic isocyanate Chemical compound O=C=NC#N BWOVZCWSJFYBRM-UHFFFAOYSA-N 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 claims description 2
- 230000017858 demethylation Effects 0.000 claims description 2
- 238000010520 demethylation reaction Methods 0.000 claims description 2
- XHQZXHMRBXBPEL-UHFFFAOYSA-N eaton reagent Chemical compound CS(O)(=O)=O.O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 XHQZXHMRBXBPEL-UHFFFAOYSA-N 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- 150000004795 grignard reagents Chemical class 0.000 claims description 2
- YNXURHRFIMQACJ-UHFFFAOYSA-N lithium;methanidylbenzene Chemical compound [Li+].[CH2-]C1=CC=CC=C1 YNXURHRFIMQACJ-UHFFFAOYSA-N 0.000 claims description 2
- 235000020824 obesity Nutrition 0.000 claims description 2
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 claims description 2
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000001174 sulfone group Chemical group 0.000 claims description 2
- 125000003375 sulfoxide group Chemical group 0.000 claims description 2
- 125000004354 sulfur functional group Chemical group 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims 1
- 238000010494 dissociation reaction Methods 0.000 claims 1
- 230000005593 dissociations Effects 0.000 claims 1
- 230000003660 hair regeneration Effects 0.000 claims 1
- 229910052744 lithium Inorganic materials 0.000 claims 1
- 230000003779 hair growth Effects 0.000 abstract description 42
- 238000012360 testing method Methods 0.000 abstract description 39
- 210000004209 hair Anatomy 0.000 abstract description 12
- 230000012010 growth Effects 0.000 abstract description 11
- 230000000694 effects Effects 0.000 abstract description 9
- 241001465754 Metazoa Species 0.000 abstract description 7
- 230000001737 promoting effect Effects 0.000 abstract description 7
- 230000008859 change Effects 0.000 abstract description 5
- 230000004580 weight loss Effects 0.000 abstract description 3
- 230000001747 exhibiting effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 29
- 241000699670 Mus sp. Species 0.000 description 23
- 239000002904 solvent Substances 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 238000001228 spectrum Methods 0.000 description 15
- 241000699666 Mus <mouse, genus> Species 0.000 description 14
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 13
- 238000002474 experimental method Methods 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 10
- 235000019439 ethyl acetate Nutrition 0.000 description 10
- 210000003491 skin Anatomy 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 230000035484 reaction time Effects 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 239000002994 raw material Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000001819 mass spectrum Methods 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- 201000004384 Alopecia Diseases 0.000 description 5
- 206010015150 Erythema Diseases 0.000 description 5
- 230000003698 anagen phase Effects 0.000 description 5
- 231100000321 erythema Toxicity 0.000 description 5
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- 238000011735 C3H mouse Methods 0.000 description 4
- 208000001840 Dandruff Diseases 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- ZFMITUMMTDLWHR-UHFFFAOYSA-N Minoxidil Chemical compound NC1=[N+]([O-])C(N)=CC(N2CCCCC2)=N1 ZFMITUMMTDLWHR-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 230000031774 hair cycle Effects 0.000 description 4
- 229960003632 minoxidil Drugs 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 230000002093 peripheral effect Effects 0.000 description 4
- 239000013612 plasmid Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 3
- FLVGFHIYWGTIAZ-UHFFFAOYSA-N 1,3-dichloro-2-[3-[(4-fluorophenyl)methyl]-4-methoxyphenoxy]-5-nitrobenzene Chemical compound C1=C(CC=2C=CC(F)=CC=2)C(OC)=CC=C1OC1=C(Cl)C=C([N+]([O-])=O)C=C1Cl FLVGFHIYWGTIAZ-UHFFFAOYSA-N 0.000 description 3
- PCIMDOARAQBBIO-UHFFFAOYSA-N 3,5-dichloro-4-[3-[(4-fluorophenyl)methyl]-4-methoxyphenoxy]aniline Chemical compound C1=C(CC=2C=CC(F)=CC=2)C(OC)=CC=C1OC1=C(Cl)C=C(N)C=C1Cl PCIMDOARAQBBIO-UHFFFAOYSA-N 0.000 description 3
- 108020004414 DNA Proteins 0.000 description 3
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 3
- 231100000360 alopecia Toxicity 0.000 description 3
- 239000003098 androgen Substances 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 229950005499 carbon tetrachloride Drugs 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000001119 stannous chloride Substances 0.000 description 3
- 235000011150 stannous chloride Nutrition 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- NVKAWKQGWWIWPM-ABEVXSGRSA-N 17-β-hydroxy-5-α-Androstan-3-one Chemical compound C1C(=O)CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 NVKAWKQGWWIWPM-ABEVXSGRSA-N 0.000 description 2
- BBYDXOIZLAWGSL-UHFFFAOYSA-N 4-fluorobenzoic acid Chemical compound OC(=O)C1=CC=C(F)C=C1 BBYDXOIZLAWGSL-UHFFFAOYSA-N 0.000 description 2
- KDXKERNSBIXSRK-RXMQYKEDSA-N D-lysine Chemical compound NCCCC[C@@H](N)C(O)=O KDXKERNSBIXSRK-RXMQYKEDSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- 208000030695 Sparse hair Diseases 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000006143 cell culture medium Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 239000012894 fetal calf serum Substances 0.000 description 2
- DBEPLOCGEIEOCV-WSBQPABSSA-N finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 description 2
- 229960004039 finasteride Drugs 0.000 description 2
- 210000003780 hair follicle Anatomy 0.000 description 2
- 230000003781 hair follicle cycle Effects 0.000 description 2
- 208000024963 hair loss Diseases 0.000 description 2
- 230000003676 hair loss Effects 0.000 description 2
- 230000003659 hair regrowth Effects 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- 230000037311 normal skin Effects 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 238000007747 plating Methods 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000008470 skin growth Effects 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 238000004611 spectroscopical analysis Methods 0.000 description 2
- 230000003797 telogen phase Effects 0.000 description 2
- 238000001890 transfection Methods 0.000 description 2
- 239000012096 transfection reagent Substances 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 0 *N(C(C(*c1ccc(*c(cc2)ccc2O)cc1)=O)=O)O* Chemical compound *N(C(C(*c1ccc(*c(cc2)ccc2O)cc1)=O)=O)O* 0.000 description 1
- JSXLDGPAKGJPLU-UHFFFAOYSA-N 1-[2-[5-(2,6-dichloro-4-nitrophenoxy)-2-methoxyphenyl]-4-fluorophenyl]ethanone Chemical compound CC(=O)C1=C(C=C(C=C1)F)C1=C(C=CC(=C1)OC1=C(C=C(C=C1Cl)[N+](=O)[O-])Cl)OC JSXLDGPAKGJPLU-UHFFFAOYSA-N 0.000 description 1
- JHNLZOVBAQWGQU-UHFFFAOYSA-N 380814_sial Chemical compound CS(O)(=O)=O.O=P(=O)OP(=O)=O JHNLZOVBAQWGQU-UHFFFAOYSA-N 0.000 description 1
- 229940113178 5 Alpha reductase inhibitor Drugs 0.000 description 1
- 239000002677 5-alpha reductase inhibitor Substances 0.000 description 1
- 206010000117 Abnormal behaviour Diseases 0.000 description 1
- 210000003771 C cell Anatomy 0.000 description 1
- ZMOKGBALWNPFIS-UHFFFAOYSA-N CN1CCN(Cc2cc(OC(C(Cl)=CC(C3)NC(C(NO)=O)=O)=C3Cl)ccc2O)CC1 Chemical compound CN1CCN(Cc2cc(OC(C(Cl)=CC(C3)NC(C(NO)=O)=O)=C3Cl)ccc2O)CC1 ZMOKGBALWNPFIS-UHFFFAOYSA-N 0.000 description 1
- 108010066551 Cholestenone 5 alpha-Reductase Proteins 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 102000003967 Fibroblast growth factor 5 Human genes 0.000 description 1
- 108090000380 Fibroblast growth factor 5 Proteins 0.000 description 1
- 102000003972 Fibroblast growth factor 7 Human genes 0.000 description 1
- 108090000385 Fibroblast growth factor 7 Proteins 0.000 description 1
- 206010019044 Hair growth abnormal Diseases 0.000 description 1
- 108090000031 Hedgehog Proteins Proteins 0.000 description 1
- 102000003693 Hedgehog Proteins Human genes 0.000 description 1
- 206010020112 Hirsutism Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 108060001084 Luciferase Proteins 0.000 description 1
- 239000005089 Luciferase Substances 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 241000699667 Mus spretus Species 0.000 description 1
- 108010025020 Nerve Growth Factor Proteins 0.000 description 1
- 102000015336 Nerve Growth Factor Human genes 0.000 description 1
- JZWUVKRJCKKHRU-UHFFFAOYSA-N Oc(cc1)c(Cc(cc2Cl)ccc2Cl)cc1Oc(c(Cl)cc(NC(C(NO)=O)=O)c1)c1Cl Chemical compound Oc(cc1)c(Cc(cc2Cl)ccc2Cl)cc1Oc(c(Cl)cc(NC(C(NO)=O)=O)c1)c1Cl JZWUVKRJCKKHRU-UHFFFAOYSA-N 0.000 description 1
- 239000012124 Opti-MEM Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 108700008625 Reporter Genes Proteins 0.000 description 1
- 108091027981 Response element Proteins 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- AUYYCJSJGJYCDS-LBPRGKRZSA-N Thyrolar Chemical class IC1=CC(C[C@H](N)C(O)=O)=CC(I)=C1OC1=CC=C(O)C(I)=C1 AUYYCJSJGJYCDS-LBPRGKRZSA-N 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 1
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 229960003473 androstanolone Drugs 0.000 description 1
- 238000003975 animal breeding Methods 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 239000003181 biological factor Substances 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 208000016252 change in skin color Diseases 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 239000012649 demethylating agent Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- KJOZJSGOIJQCGA-UHFFFAOYSA-N dichloromethane;2,2,2-trifluoroacetic acid Chemical compound ClCCl.OC(=O)C(F)(F)F KJOZJSGOIJQCGA-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- XWBDWHCCBGMXKG-UHFFFAOYSA-N ethanamine;hydron;chloride Chemical compound Cl.CCN XWBDWHCCBGMXKG-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000013401 experimental design Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000003209 gene knockout Methods 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 230000003662 hair growth rate Effects 0.000 description 1
- 210000004919 hair shaft Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 210000002510 keratinocyte Anatomy 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229940053128 nerve growth factor Drugs 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 239000000820 nonprescription drug Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- SYXYWTXQFUUWLP-UHFFFAOYSA-N sodium;butan-1-olate Chemical compound [Na+].CCCC[O-] SYXYWTXQFUUWLP-UHFFFAOYSA-N 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 239000005495 thyroid hormone Substances 0.000 description 1
- 229940036555 thyroid hormone Drugs 0.000 description 1
- 102000004217 thyroid hormone receptors Human genes 0.000 description 1
- 108090000721 thyroid hormone receptors Proteins 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
- A61K8/42—Amides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q7/00—Preparations for affecting hair growth
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C239/00—Compounds containing nitrogen-to-halogen bonds; Hydroxylamino compounds or ethers or esters thereof
- C07C239/08—Hydroxylamino compounds or their ethers or esters
- C07C239/22—Hydroxylamino compounds or their ethers or esters having oxygen atoms of hydroxylamino groups esterified
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C317/22—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
- C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
Definitions
- the present invention relates to the field of chemical synthesis, and in particular to a small molecule compound and a synthesis method and application thereof.
- the hair follicle is a tiny organ that repeats three growth stages: the anagen (growth phase), the middle anagen phase (degeneration phase), and the telogen phase (dormant phase).
- growth phase the middle anagen phase
- telogen phase the telogen phase
- HBK hair keratinocytes
- Minoxidil was first used in the treatment of hypertension, and almost all patients who used minoxidil developed symptoms of hirsutism during treatment.
- 2% of minoxidil solution It is passed as an over-the-counter drug for alopecia caused by androgen.
- Finasteride is the only drug approved by the FDA for clinical treatment of alopecia and is a 5 ⁇ -reductase inhibitor. It inhibits the activity of 5 ⁇ -reductase (type II), thereby preventing the conversion of testosterone in the hair to dihydrotestosterone (DHT), reducing the amount of DHT in the hair loss zone (promoting hair growth).
- the present invention aims to study a new drug that can be applied to hair growth.
- R 1 is selected from hydrogen, halogen, C 0 -C 6 alkyl or it is optionally substituted with one to three substituents, cyano, isocyanate, amide, isosulfonyl, isosulfonamide, sulfonate Amido, sulfinamido, S-alkyl, S-aryl, S-aryl,
- substituent is selected from the group consisting of halogen, aryl, substituted aryl, heteroaryl, O-alkyl, O-aryl, O-aryl, N-alkyl, N-aryl, N- Heteroaryl
- R 2 is selected from the group consisting of hydrogen, halogen, C 0 -C 6 alkyl or substituted alkyl, alkoxy, aryl, substituted aryl, benzyl, substituted benzyl;
- R 3 is selected from the group consisting of hydrogen, halogen, C 0 -C 6 alkyl or substituted alkyl, alkoxy, aryl, substituted aryl, benzyl, substituted benzyl;
- R 4 is selected from hydrogen, C 1 -C 6 alkyl or substituted alkyl
- R 5 is selected from hydrogen, C 0 -C 6 alkyl or substituted alkyl
- X is selected from an alkyl or substituted alkyl group, an amine group or a substituted amine group;
- Y is selected from an alkyl group or a substituted alkyl group, an oxygen group, a sulfur group, an amino group, a carbonyl group, a sulfoxide group, and a sulfone group.
- the alkyl group involved may be a substituted or unsubstituted linear alkyl group, a branched alkyl group, a cycloalkyl group; when it is a cycloalkyl group, an alkyl group
- the carbon atom on the ring may be optionally substituted by oxygen, sulfur or nitrogen, and any one or several bonds of the cyclic structure may be an aromatic group or a heteroaryl group in parallel.
- the small molecule compound provided by the present invention may preferably be represented by the following structural formula:
- R is a mono- or poly-substituted halogen, an alkylsulfonyl group, an alkyl group, a methoxy group, a nitro group, an amino group, a carboxyl group, an ester group, a hydroxyl group, an aryl group, a benzyl group, or a hydrogen.
- the small molecule compound provided by the present invention may also preferably be represented by the following structural formula:
- R is a mono- or poly-substituted halogen, alkylsulfonyl, alkyl, methoxy, nitro, amino, carboxy, ester, hydroxy, aryl, benzyl, hydrogen, O-alkyl, O -aryl, O-arylhetero, N-alkyl, N-aryl, N-heteroaryl;
- X is carbon and nitrogen
- Z 1 , Z 2 , Z 3 , Z 4 and Z 5 are carbon, oxygen, sulfur, nitrogen, carbonyl (ie, forming an aromatic or non-aromatic lactam lactam).
- the small molecule compound provided by the present invention may also preferably be represented by the following structural formula:
- R is a mono- or poly-substituted halogen, alkylsulfonyl, alkyl, methoxy, nitro, amino, carboxy, ester, hydroxy, aryl, benzyl, hydrogen, O-alkyl, O -aryl, O-arylhetero, N-alkyl, N-aryl, N-heteroaryl;
- X is carbon and nitrogen
- Z 1 , Z 2 , Z 3 and Z 4 are carbon, oxygen, sulfur, nitrogen, carbonyl (ie, forming an aromatic or non-aromatic lactam lactam).
- the alkyl group involved may be a substituted or unsubstituted linear alkyl group, a branched alkyl group, a cycloalkyl group; when it is a polysubstituted group, a substituent bonded to Z 1 -Z 5 may also be aroma in parallel with any or any of Z 1 and Z 2 , Z 2 and Z 3 , Z 3 and Z 4 , Z 4 and Z 5 , heteroaryl or cycloalkyl group.
- the small molecule compound provided by the present invention is:
- the invention also provides a method for synthesizing the above small molecule compound, characterized in that: 4- Methoxyphenol and 1,2,3-trichloro-5-nitrobenzene are the starting materials.
- Step 1 The reaction of 4-methoxyphenol with 1,2,3-trichloro-5-nitrobenzene to form 1,3-dichloro-2-(4-methoxyphenoxy)-5-nitrate Base benzene
- Step 2 reacting 1,3-dichloro-2-(4-methoxyphenoxy)-5-nitrobenzene with a benzoic acid derivative to form (5-(2,6-dichloro-4-nitrogen) Phenoxy)-2-methoxyphenyl)(substituted phenyl)methyl ketone;
- Step 3 Reduction of the carbonyl group of (5-(2,6-dichloro-4-nitrophenoxy)-2-methoxyphenyl)(substituted phenyl)methyl ketone to methylene and nitro After reduction to amino group, 3,5-dichloro-4-(3-(substituted benzyl)-4-methoxyphenoxy)phenylamine is obtained;
- Step 4 Reaction of 3,5-dichloro-4-(3-(substituted benzyl)-4-methoxyphenoxy)phenylamine with oxalyl chloride monoethyl ester to give 2-((3,5-dichloro) 4-(3-(substituted benzyl)-4-methoxyphenoxy)phenyl)amino)-oxalyl ethyl ester;
- Step 5 Reaction of 2-((3,5-dichloro-4-(3-(substituted benzyl)-4-methoxyphenoxy)phenyl)amino)-oxalyl ethyl ester with hydroxylamine hydrochloride Producing N1-(3,5-dichloro-4-(3-(substituted benzyl)-4-methoxyphenoxy)phenyl)-N2-oxalyl hydroxylamine;
- Step 6 Demethoxymethylation of N1-(3,5-dichloro-4-(3-(substituted benzyl)-4-methoxyphenoxy)phenyl)-N2-oxalylhydroxylamine
- the target small molecule compound is obtained after the base.
- benzoic acid derivative can also be replaced with an acid of the following structure:
- R may be a C0-C6 alkyl group or optionally substituted with one to three substituents
- the substituent is selected from the group consisting of halogen, aryl, substituted aryl, heteroaryl, O-alkyl, O-aryl, O-aryl, N-alkyl, N-aryl, N-hetero Base, S-alkyl, S-aryl, S-arylhetero.
- the first step is carried out under a strong base condition, and the molar ratio of the strong base to the 4-methoxyphenol is from 1.5 to 2:1.
- the strong base may be selected from various organic/inorganic various types of strong base reagents which can be applied to the ether-forming reaction. Preferred from potassium amide, sodium amide, sodium cyanide, potassium cyanide, butyl lithium, lithium diisopropylamide, benzyl lithium, Grignard reagent, alkyl copper lithium, sodium methoxide, sodium ethoxide, potassium ethoxide, uncle Any one of sodium butoxide, sodium hydroxide, potassium hydroxide and the like, the reaction temperature is 120-160 ° C, and the reaction time is 1-6 hours.
- reaction is preferably carried out in a solvent similar to DMF and its physical/chemical properties, and the molar ratio of the reactant 4-methoxyphenol to 1,2,3-trichloro-5-nitrobenzene is 1:1. -2. 1,2,3-trichloro-5-nitrate
- the benzene is preferably added after the 4-methoxyphenol is mixed with the alkaline agent and stirred uniformly (generally 30-60 minutes).
- Step 2 is carried out in an Eaton reagent at a reaction temperature of 80-130 ° C and a reaction time of 2-8 hours.
- the molar ratio of 1,3-dichloro-2-(4-methoxyphenoxy)-5-nitrobenzene to the benzoic acid derivative is 1:1.25-2;
- the purpose of the third step is to reduce the carbonyl group to a methylene group.
- Dichloro-4-nitrophenoxy)-2-methoxyphenyl)(substituted phenyl)methyl ketone trifluoroacetic acid: triethyl silane in a molar ratio of 1:4-6:3-5
- the solvent is preferably dichloromethane, chloroform, tetrachloromethane or the like, and the reaction is carried out at room temperature, preferably for a period of from 1 to 6 hours.
- the purpose of the fourth step is to reduce the nitro group to an amine group.
- the reducing agent may be a preparation for reduction such as stannous chloride, iron, zinc, Pt or Ni.
- the molar ratio of 5-(2,6-dichloro-4-nitrophenoxy)-2-methoxyphenyl)(substituted phenyl)methyl ketone to the reducing agent is 1:10-20.
- the reaction was refluxed for 1-6 hours.
- the molar ratio of 3,5-dichloro-4-(3-(substituted benzyl)-4-methoxyphenoxy)phenylamine to oxalyl chloride monoethyl ester in step 5 is 1:1.5-3; oxalyl chloride single
- the molar ratio of ethyl ester to triethylamine is 1:1.3-2.3. The reaction is carried out for 0.5-3 hours.
- Step 6 2-((3,5-Dichloro-4-(3-(substituted)benzyl)-4-methoxyphenoxy)phenyl)amino)-oxalyl ethyl ester and hydroxylamine hydrochloride
- the ratio is 1:5-10, and the molar ratio of hydroxylamine hydrochloride to base (such as sodium hydroxide) is 1:1.
- the reaction is carried out for 8-14 hours.
- the demethylation in the step 7 can be carried out using aluminum trichloride, zinc chloride or boron tribromide.
- the demethylating agent used per 50 mg of the raw material is 1-5 drops (about 1-20 mg), and the reaction is carried out for 1-5 hours.
- the solvent used in the above steps may be chloroform, dichloromethane, tetrachloromethane, ethyl acetate, methyl acetate, toluene, benzene, chlorobenzene, DMF, dioxane, ethanol, acetone or the like.
- any conventional synthetic means can be used to synthesize the substance.
- the above specific synthetic route is only one of the means.
- the above-mentioned one kind of small molecule compound provided by the invention is characterized in that it can be applied to diseases such as hair growth, osteoporosis, obesity, etc., especially for hair regrowth, and can be used for targeted treatment of androgen type alopecia. problem.
- the present invention synthesizes a novel substance which can be used for hair regrowth.
- mice in each group changed in body weight slowly, indicating that the test compound did not cause weight loss in the animals.
- FIG. 1 TDM-001-1 photo of mouse hair growth
- Figure 17 a graph showing changes in body weight during administration
- Figure 18 is a graph of hair growth score during administration
- Figure 19 is a graph showing the dandruff score during administration
- Figure 20 is a graph of erythema score during administration.
- Step 2 Synthesis of (5-(2,6-dichloro-4-nitrophenoxy)-2-methoxyphenyl)(4-fluorophenyl)methyl ketone
- 1,3-Dichloro-2-(3-(4-fluorobenzyl)-4-methoxyphenoxy)-5-nitrobenzene (3.5 g, 8.3 mmol) was dissolved in ethyl acetate (50 mL) Among them, stannous chloride (18.7 g, 83 mmol) was added, followed by heating under reflux for three hours. The reaction solution was cooled to room temperature, adjusted to pH-8 with aqueous sodium bicarbonate, and then filtered. The extract was concentrated to give the product (2.6 g, 81%).
- Step 5 Synthesis of 2-((3,5-dichloro-4-(3-(4-fluorobenzyl)-4-methoxyphenoxy)phenyl)amino)-oxalyl ethyl ester
- reaction conditions different reaction conditions were chosen.
- Step 6 Synthesis of N1-(3,5-dichloro-4-(3-(4-fluorobenzyl)-4-methoxyphenoxy)phenyl)-N2-oxalylhydroxylamine
- Step 7 Synthesis of N1-(3,5-dichloro-4-(3-(4-fluorobenzyl)-4-hydroxyphenoxy)phenyl)-N2-oxalylhydroxylamine
- reaction conditions were chosen. Such as: boron tribromide (1mg, 5mg, 10mg, 15mg, 20mg, etc.), the solvent is (chlorobenzene, chloroform, tetrachloromethane, etc.), reaction time (1 hour, 2 hours, 5 hours, etc.), the obtained product Yields range from 4-30%.
- test compound (TMI-105795) was loaded from the pharmaceutical portion and stored in a refrigerator at -20 °C. All test compounds (including solvents) were labeled as TDM-001-1, TDM-001-2, TDM-001-3, TDM-001-4.
- mice Female C3H mice (35-39 days old) were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd. Healthy and clean mice were selected as experimental mice. Prior to grouping, 5 random mice were housed in a cage, and all mice were conditioned at least one week in the animal house, and the animals were labeled on the tail and on the cage.
- mice single per cage
- soft stuffing corn cob or sawdust
- test compound was TMI-105795 (the solvent was polyethylene glycol/ethanol (30/70)), and it was dispensed into a daily dose and stored in a refrigerator at -20 °C. It is administered twice daily with the solvent at 9:30 am and 4:00 pm.
- mice The abnormal behavior and hair growth of the mice were checked daily and carefully recorded.
- each mouse was weighed before daily administration.
- Hair growth levels, peripheral hair growth, dandruff, and erythema were scored on Monday, Wednesday, and Friday from the first day of the experiment to the end.
- Test object (TMI-105795)
- mice All mice were subjected to hair growth scores on Monday, Wednesday and Friday from the first day to the last day of the experiment according to the following criteria:
- Peripheral hair growth ( hair growth in the shaved area, not hair growth in the dosing area):
- the hair growth rate of the mice in different concentrations was significantly different. Among them, the growth rate of TDM-001-2 was much lower than that of TDM-001-3 and TDM-001-4.
- mice in TDM-001-2 were transdermally treated, and the skin color of the mice turned black on the 12th day. After 16 days, the hair began to grow and continued to grow.
- the growth rate and growth level of the mice at the low concentration are significantly lower than those of the high-concentration mice, and when the concentration reaches 0.01%, although the hair growth process exists. There is a certain difference, but when the hair growth reaches a certain level, the difference in hair growth and state is no longer obvious.
- mice in each group gained very slowly, indicating that the test compound did not cause weight loss in the animals.
- mice in each group showed no dandruff and erythema.
- test compound including the lowest dose showed positive hair growth promoting effects.
- mice b. No dandruff and erythema appeared in all mice.
- mice showed normal skin color and symptom manifestations.
- test substance TMI-105795 significantly promoted hair growth in C3H mice.
- the back hair of C3H mice is known to have a time-corresponding hair growth cycle, ie, 2.5 to 3.5 weeks old and 5 to 14 weeks old, the back hair is at the end of telogen (dormant), 0 to 2.0 weeks old and 4.0 to 4.5 Zhou Ling's back hair is in the early stage of hair growth.
- test object (TMI-105795) can significantly change the hair growth cycle and promote hair growth.
- TR ⁇ thyroid receptor
- TRE thyroid hormone response element
- test compound dilution The test compound is gradually subjected to semi-log dilution in DMEM medium (containing 0.1% dimethyl sulfoxide) containing 10% activated carbon for fetal bovine serum. The highest concentration of the test compound is 10 ⁇ M. .
- DMEM medium containing 0.1% dimethyl sulfoxide
- activated carbon for fetal calf serum was added.
- TMI-105905 399.5 TMI-105965 95.97 TMI-105966 61.13 TMI-105906 925.4 TMI-105956 6521 TMI-105957 8757 TMI-105958 9701 TMI-105959 617.2 TMI-105960 6.478E7 TMI-105961 9243 TMI-105962 3719 TMI-105963 9577
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Physical Education & Sports Medicine (AREA)
- Dermatology (AREA)
- Rheumatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Birds (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Child & Adolescent Psychology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Indole Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Cosmetics (AREA)
Abstract
Description
编号 | EC50(nM) |
105796 | 179.4 |
TMI-105902 | 250.3 |
TMI-105903 | 136.4 |
TMI-105905 | 399.5 |
TMI-105965 | 95.97 |
TMI-105966 | 61.13 |
TMI-105906 | 925.4 |
TMI-105956 | 6521 |
TMI-105957 | 8757 |
TMI-105958 | 9701 |
TMI-105959 | 617.2 |
TMI-105960 | 6.478E7 |
TMI-105961 | 9243 |
TMI-105962 | 3719 |
TMI-105963 | 9577 |
Claims (12)
- 一种小分子化合物,其特征在于,由如下结构式所示:R1选自氢、卤素、C0-C6的烷基或其任意地被一个到三个取代基取代、氰基、异氰酸酯基、酰胺基、异磺酰胺基、异亚磺酰胺基、磺酰胺基、亚磺酰胺基、S-烷基、S-芳基、S-芳杂基,其中,所述取代基选自于卤素、芳基、取代芳基、杂芳基、O-烷基、O-芳基、O-芳杂基、N-烷基、N-芳基、N-杂芳基;R2选自氢、卤素、C0-C6的烷基或取代烷基、烷氧基、芳基、取代芳基、苄基、取代苄基;R3选自氢、卤素、C0-C6的烷基或取代烷基、烷氧基、芳基、取代芳基、苄基、取代苄基;R4选自氢、C1-C6的烷基或取代烷基;R5选自氢、C0-C6的烷基或取代烷基;X选自烷基或取代烷基、胺基或取代胺基;Y选自烷基或取代烷基、氧、硫、氨基、羰基、亚砜基、砜基。
- 如权利要求1所述的一种小分子化合物,其特征在于:为N1-(3,5-二氯 -4-(3-(4-氟苄基)-4-羟基苯氧基)苯基)-N2-草酰羟胺;或N1-(3,5-二氯-4-(3-(4-甲磺酰基苄基)-4-羟基苯氧基)苯基)-N2-草酰羟胺;或N1-(3,5-二氯-4-(3-(4-甲基苄基)-4-羟基苯氧基)苯基)-N2-草酰羟胺;或N1-(3,5-二氯-4-(3-(3,4-二氯苄基)-4-羟基苯氧基)苯基)-N2-草酰羟胺;或N1-(3,5-二氯-4-(3-(3-氟苄基)-4-羟基苯氧基)苯基)-N2-草酰羟胺;或N1-(3,5-二氯-4-(3-(2-氟苄基)-4-羟基苯氧基)苯基)-N2-草酰羟胺;或N1-(3,5-二氯-4-4-羟基-3-(甲基吗啉)苯氧基)苯基)-N2-草酰羟胺;或N1-(3,5-二氯-4-(4-羟基-3-(4-羟基哌啶-1-基)苯氧基)苯基)-N2-草酰羟胺;或N1-(3,5-二氯-4-(4-羟基-3-(4-甲基哌嗪-1-甲基)苯氧基)苯基)-N2-草酰羟胺;或N1-(3,5-二氯-4-(4-羟基-3-(吡咯烷-1-甲基)苯氧基)苯基)-N2-草酰羟胺;或N1-(4-(3-((4-苄基哌啶-1-甲基)-4-羟基苯氧基)-3,5-二氯苯基)N2-草酰羟胺;或N1-(3,5-二氯-4-(4-羟基-3-((4-羟基-4-苯基哌啶-1-甲基)苯氧基)苯基)N2-草酰羟胺;或N1-(3,5-二氯-4-(4-羟基-3-(异吲哚啉-2-甲基)苯氧基)苯基)-N2-草酰羟胺;或N1-(3,5-二氯-4-(3-(3,4-二氢异喹啉-2(1H)-甲基)-4-羟基苯氧基)苯基)-N2-草酰羟胺;或N1-(3,5-二氯-4-(4-羟基-3-(3-哌嗪酮-1-甲基)苯氧基)苯基)-N2-草酰羟胺。
- 一种小分子化合物的合成方法,其特征在于:步骤一、通过4-甲氧基苯酚与1,2,3-三氯-5-硝基苯反应生成1,3-二氯-2-(4-甲氧基苯氧基)-5-硝基苯;步骤二、将1,3-二氯-2-(4-甲氧基苯氧基)-5-硝基苯与苯甲酸衍生物反应生成(5-(2,6-二氯-4-硝基苯氧基)-2-甲氧基苯基)(取代苯基)甲基酮;步骤三、将(5-(2,6-二氯-4-硝基苯氧基)-2-甲氧基苯基)(取代苯基)甲基酮的羰基还原为亚甲基得到1,3-二氯-2-(3-(取代苄基)-4-甲氧基苯氧基)-5-硝基苯;步骤四、将1,3-二氯-2-(3-(取代苄基)-4-甲氧基苯氧基)-5-硝基苯的硝基还原为氨基后得到3,5-二氯-4-(3-(取代苄基)-4-甲氧基苯氧基)苯胺;步骤五、将3,5-二氯-4-(3-(取代苄基)-4-甲氧基苯氧基)苯胺与草酰氯单乙酯反应生成2-((3,5-二氯-4-(3-(取代苄基)-4-甲氧基苯氧基)苯基)胺基)-草酰乙酯;步骤六、将2-((3,5-二氯-4-(3-(取代苄基)-4-甲氧基苯氧基)苯基)胺基)-草酰乙酯与盐酸羟胺反应生成N1-(3,5-二氯-4-(3-(取代苄基)-4-甲氧基苯氧基)苯基)-N2-草酰羟胺;步骤七、将N1-(3,5-二氯-4-(3-(取代苄基)-4-甲氧基苯氧基)苯基)-N2-草酰羟胺上的甲氧基脱甲基后获得目标小分子化合物。
- 如权利要求6所述的一种小分子化合物的合成方法,其特征在于:步骤一中4-甲氧基苯酚与1,2,3-三氯-5-硝基苯的摩尔比为1:1-2;步骤二中1,3-二氯-2-(4-甲氧基苯氧基)-5-硝基苯与苯甲酸衍生物的摩尔比为1:1.25-2;步骤四中1,3-二氯-2-(3-(取代苄基)-4-甲氧基苯氧基)-5-硝基苯与还原剂的摩尔比为1:10-20;步骤五中3,5-二氯-4-(3-(取代苄基)-4-甲氧基苯氧基)苯胺与草酰氯单乙酯的摩尔比为1:1.5-3;步骤六中2-((3,5-二氯-4-(3-(取代苄基)-4-甲氧基苯氧基)苯基)胺基)-草酰乙酯与盐酸羟胺的摩尔比为1:5-10。
- 如权利要求6所述的一种小分子化合物的合成方法,其特征在于:步骤一在强碱条件下进行,所述强碱可选自氨基钾、氨基钠、氰化钠、氰化钾、丁基锂、二异丙基氨锂、苄基锂、格氏试剂,烷基铜锂、甲醇钠、乙醇钠、乙醇钾、叔丁醇钠、氢氧化钠、氢氧化钾,反应温度为120-160℃;步骤二在伊顿试剂中进行,反应温度为80-130℃。
- 如权利要求6所述的一种小分子化合物的合成方法,其特征在于:步骤三中采用三氟乙酸和三乙基硅烷将羰基还原为亚甲基,其中,5-(2,6-二氯-4-硝基苯氧基)-2-甲氧基苯基)(取代苯基)甲基酮:三氟乙酸:三乙基硅烷的摩尔比为1:4-6:3-5。
- 如权利要求6所述的一种小分子化合物的合成方法,其特征在于:步骤七中的脱甲基可采用三氯化铝、氯化锌、三溴化硼进行。
- 如权利要求1所述的一种小分子化合物,其特征在于:可应用于毛发的再生、骨质疏松症、肥胖。
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP15831295.9A EP3181556B1 (en) | 2014-08-14 | 2015-08-13 | Micromolecule compound, method of synthesis and application thereof |
DK15831295.9T DK3181556T5 (da) | 2014-08-14 | 2015-08-13 | Mikromolekyleforbindelse, fremgangsmåde til syntese og anvendelse deraf |
JP2017502885A JP6444487B2 (ja) | 2014-08-14 | 2015-08-13 | 小分子化合物、その合成方法、及びその応用 |
US15/431,779 US9920022B2 (en) | 2014-08-14 | 2017-02-14 | Small molecule compound and synthesizing method and uses thereof |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410398184.1A CN104193699B (zh) | 2014-08-14 | 2014-08-14 | 一种小分子化合物及其合成方法和应用 |
CN201410398184.1 | 2014-08-14 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/431,779 Continuation US9920022B2 (en) | 2014-08-14 | 2017-02-14 | Small molecule compound and synthesizing method and uses thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2016023510A1 true WO2016023510A1 (zh) | 2016-02-18 |
Family
ID=52079108
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2015/086908 WO2016023510A1 (zh) | 2014-08-14 | 2015-08-13 | 一种小分子化合物及其合成方法和应用 |
Country Status (7)
Country | Link |
---|---|
US (1) | US9920022B2 (zh) |
EP (1) | EP3181556B1 (zh) |
JP (1) | JP6444487B2 (zh) |
CN (1) | CN104193699B (zh) |
DK (1) | DK3181556T5 (zh) |
HU (1) | HUE057149T2 (zh) |
WO (1) | WO2016023510A1 (zh) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104193699B (zh) | 2014-08-14 | 2016-05-25 | 嘉兴特科罗生物科技有限公司 | 一种小分子化合物及其合成方法和应用 |
CN104877136B (zh) * | 2015-04-30 | 2017-08-01 | 大连理工大学 | 一种长支链聚砜阴离子膜及其制备方法 |
CN105461588A (zh) * | 2015-12-17 | 2016-04-06 | 上海海洋大学 | 一种立达霉中代谢产物6的合成方法 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001070687A1 (de) * | 2000-03-23 | 2001-09-27 | Bayer Aktiengesellschaft | Indole zur behandlung von krankheiten die mit schilddrüsenhormonen behandeln werden können |
CN103479627A (zh) * | 2013-05-16 | 2014-01-01 | 武汉光谷百桥国际生物科技有限公司 | 一种血管紧张素ii的i型受体拮抗剂在促进毛发生长方面的应用 |
CN104193699A (zh) * | 2014-08-14 | 2014-12-10 | 嘉兴特科罗生物科技有限公司 | 一种小分子化合物及其合成方法和应用 |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE159515T1 (de) * | 1992-07-21 | 1997-11-15 | Ciba Geigy Ag | Oxamidsäure-derivate als hypocholesterämische mittel |
CZ20013117A3 (cs) * | 1999-03-01 | 2002-06-12 | Pfizer Products Inc. | Oxamové kyseliny a jejich deriváty jako ligandy thyreoidního receptoru |
CO5160290A1 (es) * | 1999-03-29 | 2002-05-30 | Novartis Ag | Derivados de acido fenoxifeniloxamico sustituido . |
AU3507700A (en) * | 1999-06-01 | 2000-12-18 | University Of Texas Southwestern Medical Center, The | Method of treating hair loss using diphenylether derivatives |
DE10024939A1 (de) * | 2000-05-19 | 2001-11-29 | Bayer Ag | Neue Diphenylmethanderivate für Arzneimittel |
GB2374009A (en) * | 2001-02-12 | 2002-10-09 | Novartis Ag | Method of treating hair loss |
-
2014
- 2014-08-14 CN CN201410398184.1A patent/CN104193699B/zh active Active
-
2015
- 2015-08-13 HU HUE15831295A patent/HUE057149T2/hu unknown
- 2015-08-13 JP JP2017502885A patent/JP6444487B2/ja active Active
- 2015-08-13 WO PCT/CN2015/086908 patent/WO2016023510A1/zh active Application Filing
- 2015-08-13 EP EP15831295.9A patent/EP3181556B1/en active Active
- 2015-08-13 DK DK15831295.9T patent/DK3181556T5/da active
-
2017
- 2017-02-14 US US15/431,779 patent/US9920022B2/en active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001070687A1 (de) * | 2000-03-23 | 2001-09-27 | Bayer Aktiengesellschaft | Indole zur behandlung von krankheiten die mit schilddrüsenhormonen behandeln werden können |
CN103479627A (zh) * | 2013-05-16 | 2014-01-01 | 武汉光谷百桥国际生物科技有限公司 | 一种血管紧张素ii的i型受体拮抗剂在促进毛发生长方面的应用 |
CN104193699A (zh) * | 2014-08-14 | 2014-12-10 | 嘉兴特科罗生物科技有限公司 | 一种小分子化合物及其合成方法和应用 |
Also Published As
Publication number | Publication date |
---|---|
CN104193699A (zh) | 2014-12-10 |
US20170158651A1 (en) | 2017-06-08 |
CN104193699B (zh) | 2016-05-25 |
EP3181556A4 (en) | 2018-01-10 |
JP2017522329A (ja) | 2017-08-10 |
EP3181556B1 (en) | 2021-09-29 |
DK3181556T3 (da) | 2022-01-03 |
HUE057149T2 (hu) | 2022-04-28 |
US9920022B2 (en) | 2018-03-20 |
EP3181556A1 (en) | 2017-06-21 |
JP6444487B2 (ja) | 2019-01-09 |
DK3181556T5 (da) | 2022-01-10 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2005285035B2 (en) | Novel imidazolidin-2-one derivatives as selective androgen receptor modulators (SARMS) | |
JP2021120420A (ja) | ガンの治療方法 | |
US10179781B2 (en) | Sodium channel modulators for the treatment of pain | |
JP3564680B2 (ja) | 甲状腺レセプターリガンドとしてのシアノ基含有オキサミド酸及び誘導体 | |
CA2769474C (fr) | Derives d'acyl-guanidines modulateurs de la voie de signalisation des proteines hedgehog | |
WO2016023510A1 (zh) | 一种小分子化合物及其合成方法和应用 | |
TW200821286A (en) | 2-phenyl-indoles as prostaglandin D2 receptor antagonists | |
JP6148400B2 (ja) | フェノキシエチルジヒドロ−1h−イソキノリン化合物 | |
WO2019218797A1 (zh) | 4-苯氧基-苯基-2h-[1,2,4]三嗪-3,5-二酮衍生物及其制备方法和促进毛发生长的用途 | |
BR112015032370B1 (pt) | Derivado de biarila, composição, e, método para preparar uma composição | |
EP2291352B1 (fr) | N-acylthiourees et n-acylurees inhibiteurs de la voie de signalisation des proteines hedgehog | |
JP2010536771A5 (zh) | ||
CA2696012A1 (en) | Derivatives of 5-amino-4,6-disubstituted indole and 5-amino-4,6-disubstituted indoline as potassium channel modulators | |
US20210220342A1 (en) | Pridopidine for the treatment of mitochondrial-associated diseases and disorders and endoplasmic reticulum (er) stress | |
JP2022519131A (ja) | グルコシルセラミドシンターゼ(gcs)阻害剤を使用した繊毛病の処置 | |
EP2300424B1 (fr) | Utilisation de derives d'indole comme activateurs de nurr-1, pour le traitement de la maladie de parkinson | |
EP2875026B1 (fr) | Derive d'imidazopyridine utiles dans le traitement du diabete | |
EP1836177B1 (en) | Vitamin d receptor modulators | |
US20110294800A1 (en) | Hypoglycemic dihydropyridones | |
US10870644B2 (en) | Crystalline forms of 4-(5-(4,7-dimethylbenzofuran-2-yl)-l,2,4-oxadiazol-3-yl)benzoic acid and processes for their preparation | |
EP1646610B1 (en) | Tetrahydrocarbazole derivatives and their pharmaceutical use | |
RU2468020C2 (ru) | Биарилкарбоксиариламиды как модуляторы ванилоидного рецептора типа 1 | |
US11925632B2 (en) | Isoquinoline derivatives for use in treating GLUT1 deficiency syndrome | |
CA2246482C (fr) | Nouvelles trans-3,4,4a,5,6,10b-hexahydro-2h-napht [1,2-b]-1,4-oxazines disubstitues, leur procede de preparation et les compositions pharmaceutiques qui les contiennent | |
JP6952350B2 (ja) | インスリン分泌促進剤又はインスリン抵抗性改善剤 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 15831295 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2017502885 Country of ref document: JP Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
REEP | Request for entry into the european phase |
Ref document number: 2015831295 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2015831295 Country of ref document: EP |