CN104582695A - 用于治疗秃发的药物或化妆品组合物 - Google Patents
用于治疗秃发的药物或化妆品组合物 Download PDFInfo
- Publication number
- CN104582695A CN104582695A CN201380039622.9A CN201380039622A CN104582695A CN 104582695 A CN104582695 A CN 104582695A CN 201380039622 A CN201380039622 A CN 201380039622A CN 104582695 A CN104582695 A CN 104582695A
- Authority
- CN
- China
- Prior art keywords
- group
- compound
- spermidine
- formula
- aminopropyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 201000004384 Alopecia Diseases 0.000 title claims abstract description 36
- 231100000360 alopecia Toxicity 0.000 title claims abstract description 17
- 239000002537 cosmetic Substances 0.000 title claims abstract description 8
- 239000000203 mixture Substances 0.000 title claims description 24
- 150000001875 compounds Chemical class 0.000 claims abstract description 55
- 229940063673 spermidine Drugs 0.000 claims abstract description 46
- 210000004761 scalp Anatomy 0.000 claims abstract description 11
- ATHGHQPFGPMSJY-UHFFFAOYSA-N spermidine Chemical compound NCCCCNCCCN ATHGHQPFGPMSJY-UHFFFAOYSA-N 0.000 claims description 80
- -1 ethylidene, vinyl Chemical group 0.000 claims description 37
- 210000004209 hair Anatomy 0.000 claims description 24
- 125000004432 carbon atom Chemical group C* 0.000 claims description 23
- 230000000694 effects Effects 0.000 claims description 18
- 210000004919 hair shaft Anatomy 0.000 claims description 15
- 230000012010 growth Effects 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 14
- 239000011737 fluorine Substances 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 12
- 229920006395 saturated elastomer Polymers 0.000 claims description 12
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 9
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 9
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 9
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- PZSFTBARUSGJTA-UHFFFAOYSA-N 1-n-(4-aminobutyl)butane-1,3-diamine Chemical compound CC(N)CCNCCCCN PZSFTBARUSGJTA-UHFFFAOYSA-N 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 150000003335 secondary amines Chemical group 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 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
- 230000004936 stimulating effect Effects 0.000 claims description 3
- 125000003944 tolyl group Chemical group 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims 8
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 4
- AYDQIZKZTQHYIY-UHFFFAOYSA-N OC(=O)C1(C)CC(C(O)=O)=CC=C1 Chemical compound OC(=O)C1(C)CC(C(O)=O)=CC=C1 AYDQIZKZTQHYIY-UHFFFAOYSA-N 0.000 claims 2
- 230000008485 antagonism Effects 0.000 claims 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims 1
- 239000011976 maleic acid Substances 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 230000001737 promoting effect Effects 0.000 claims 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims 1
- 230000003676 hair loss Effects 0.000 abstract description 17
- 208000024963 hair loss Diseases 0.000 abstract description 16
- KIDHWZJUCRJVML-UHFFFAOYSA-N putrescine Chemical compound NCCCCN KIDHWZJUCRJVML-UHFFFAOYSA-N 0.000 abstract description 16
- 230000003647 oxidation Effects 0.000 abstract description 10
- 238000007254 oxidation reaction Methods 0.000 abstract description 10
- 239000000126 substance Substances 0.000 abstract description 7
- 230000000699 topical effect Effects 0.000 abstract description 7
- 239000004480 active ingredient Substances 0.000 abstract description 4
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 2
- 210000004027 cell Anatomy 0.000 description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 239000000243 solution Substances 0.000 description 25
- QWMQENCFXCIUIC-UHFFFAOYSA-N n'-(3-aminopropyl)-n-methylbutane-1,4-diamine Chemical compound CNCCCCNCCCN QWMQENCFXCIUIC-UHFFFAOYSA-N 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
- 230000003698 anagen phase Effects 0.000 description 19
- 210000003780 hair follicle Anatomy 0.000 description 19
- 238000011282 treatment Methods 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 16
- 238000012360 testing method Methods 0.000 description 15
- 239000002609 medium Substances 0.000 description 13
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 12
- OSCJHTSDLYVCQC-UHFFFAOYSA-N 2-ethylhexyl 4-[[4-[4-(tert-butylcarbamoyl)anilino]-6-[4-(2-ethylhexoxycarbonyl)anilino]-1,3,5-triazin-2-yl]amino]benzoate Chemical compound C1=CC(C(=O)OCC(CC)CCCC)=CC=C1NC1=NC(NC=2C=CC(=CC=2)C(=O)NC(C)(C)C)=NC(NC=2C=CC(=CC=2)C(=O)OCC(CC)CCCC)=N1 OSCJHTSDLYVCQC-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 229920000768 polyamine Polymers 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 10
- 230000003778 catagen phase Effects 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 102000052812 Ornithine decarboxylases Human genes 0.000 description 9
- 108700005126 Ornithine decarboxylases Proteins 0.000 description 9
- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitrogen oxide Inorganic materials O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 9
- 230000003779 hair growth Effects 0.000 description 8
- 239000004310 lactic acid Substances 0.000 description 8
- 235000014655 lactic acid Nutrition 0.000 description 8
- 239000002304 perfume Substances 0.000 description 8
- DWGWCWDDNTVOGF-UHFFFAOYSA-N Cl.Cl.Cl.Cl.Cl.Cl Chemical compound Cl.Cl.Cl.Cl.Cl.Cl DWGWCWDDNTVOGF-UHFFFAOYSA-N 0.000 description 7
- 239000004359 castor oil Substances 0.000 description 7
- 235000019438 castor oil Nutrition 0.000 description 7
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 7
- 239000003642 reactive oxygen metabolite Substances 0.000 description 7
- 230000009467 reduction Effects 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000003570 air Substances 0.000 description 6
- 229960002685 biotin Drugs 0.000 description 6
- 235000020958 biotin Nutrition 0.000 description 6
- 239000011616 biotin Substances 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 235000010469 Glycine max Nutrition 0.000 description 5
- 231100000002 MTT assay Toxicity 0.000 description 5
- 238000000134 MTT assay Methods 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 230000003078 antioxidant effect Effects 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 230000031774 hair cycle Effects 0.000 description 5
- 230000001965 increasing effect Effects 0.000 description 5
- 210000003491 skin Anatomy 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- JKQXZKUSFCKOGQ-JLGXGRJMSA-N (3R,3'R)-beta,beta-carotene-3,3'-diol Chemical compound C([C@H](O)CC=1C)C(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1=C(C)C[C@@H](O)CC1(C)C JKQXZKUSFCKOGQ-JLGXGRJMSA-N 0.000 description 4
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 4
- XVIFKRWLOQOKMV-UHFFFAOYSA-N 2-(hydroxymethylamino)acetic acid;sodium Chemical compound [Na].OCNCC(O)=O XVIFKRWLOQOKMV-UHFFFAOYSA-N 0.000 description 4
- JMGZEFIQIZZSBH-UHFFFAOYSA-N Bioquercetin Natural products CC1OC(OCC(O)C2OC(OC3=C(Oc4cc(O)cc(O)c4C3=O)c5ccc(O)c(O)c5)C(O)C2O)C(O)C(O)C1O JMGZEFIQIZZSBH-UHFFFAOYSA-N 0.000 description 4
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 4
- 206010020112 Hirsutism Diseases 0.000 description 4
- JKQXZKUSFCKOGQ-LQFQNGICSA-N Z-zeaxanthin Natural products C([C@H](O)CC=1C)C(C)(C)C=1C=CC(C)=CC=CC(C)=CC=CC=C(C)C=CC=C(C)C=CC1=C(C)C[C@@H](O)CC1(C)C JKQXZKUSFCKOGQ-LQFQNGICSA-N 0.000 description 4
- QOPRSMDTRDMBNK-RNUUUQFGSA-N Zeaxanthin Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCC(O)C1(C)C)C=CC=C(/C)C=CC2=C(C)CC(O)CC2(C)C QOPRSMDTRDMBNK-RNUUUQFGSA-N 0.000 description 4
- 238000002835 absorbance Methods 0.000 description 4
- JKQXZKUSFCKOGQ-LOFNIBRQSA-N all-trans-Zeaxanthin Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2=C(C)CC(O)CC2(C)C JKQXZKUSFCKOGQ-LOFNIBRQSA-N 0.000 description 4
- 230000003833 cell viability Effects 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000011928 denatured alcohol Substances 0.000 description 4
- IVTMALDHFAHOGL-UHFFFAOYSA-N eriodictyol 7-O-rutinoside Natural products OC1C(O)C(O)C(C)OC1OCC1C(O)C(O)C(O)C(OC=2C=C3C(C(C(O)=C(O3)C=3C=C(O)C(O)=CC=3)=O)=C(O)C=2)O1 IVTMALDHFAHOGL-UHFFFAOYSA-N 0.000 description 4
- 239000000787 lecithin Substances 0.000 description 4
- 229940067606 lecithin Drugs 0.000 description 4
- 235000010445 lecithin Nutrition 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- NBQCAFSSDFAIKS-UHFFFAOYSA-N n'-(3-aminopropyl)-n-ethylbutane-1,4-diamine Chemical compound CCNCCCCNCCCN NBQCAFSSDFAIKS-UHFFFAOYSA-N 0.000 description 4
- XTALVIACDLORFR-UHFFFAOYSA-N n'-(3-aminopropyl)-n-propylbutane-1,4-diamine Chemical compound CCCNCCCCNCCCN XTALVIACDLORFR-UHFFFAOYSA-N 0.000 description 4
- VWSAHAONBMPCAF-UHFFFAOYSA-N n-(3-aminopropyl)-n'-(2-methylpropyl)butane-1,4-diamine Chemical compound CC(C)CNCCCCNCCCN VWSAHAONBMPCAF-UHFFFAOYSA-N 0.000 description 4
- SQLGQLUMPZIXEP-UHFFFAOYSA-N n-(3-aminopropyl)-n'-cyclohexylbutane-1,4-diamine Chemical compound NCCCNCCCCNC1CCCCC1 SQLGQLUMPZIXEP-UHFFFAOYSA-N 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- 210000000056 organ Anatomy 0.000 description 4
- FDRQPMVGJOQVTL-UHFFFAOYSA-N quercetin rutinoside Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC=2C(C3=C(O)C=C(O)C=C3OC=2C=2C=C(O)C(O)=CC=2)=O)O1 FDRQPMVGJOQVTL-UHFFFAOYSA-N 0.000 description 4
- IKGXIBQEEMLURG-BKUODXTLSA-N rutin Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@@H]1OC[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](OC=2C(C3=C(O)C=C(O)C=C3OC=2C=2C=C(O)C(O)=CC=2)=O)O1 IKGXIBQEEMLURG-BKUODXTLSA-N 0.000 description 4
- ALABRVAAKCSLSC-UHFFFAOYSA-N rutin Natural products CC1OC(OCC2OC(O)C(O)C(O)C2O)C(O)C(O)C1OC3=C(Oc4cc(O)cc(O)c4C3=O)c5ccc(O)c(O)c5 ALABRVAAKCSLSC-UHFFFAOYSA-N 0.000 description 4
- 235000005493 rutin Nutrition 0.000 description 4
- 229960004555 rutoside Drugs 0.000 description 4
- PFNFFQXMRSDOHW-UHFFFAOYSA-N spermine Chemical compound NCCCNCCCCNCCCN PFNFFQXMRSDOHW-UHFFFAOYSA-N 0.000 description 4
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- KBPHJBAIARWVSC-XQIHNALSSA-N trans-lutein Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2C(=CC(O)CC2(C)C)C KBPHJBAIARWVSC-XQIHNALSSA-N 0.000 description 4
- 235000010930 zeaxanthin Nutrition 0.000 description 4
- 239000001775 zeaxanthin Substances 0.000 description 4
- 229940043269 zeaxanthin Drugs 0.000 description 4
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 4
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 3
- VFKZECOCJCGZQK-UHFFFAOYSA-M 3-hydroxypropyl(trimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)(C)CCCO VFKZECOCJCGZQK-UHFFFAOYSA-M 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 description 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 3
- 239000005977 Ethylene Substances 0.000 description 3
- 244000068988 Glycine max Species 0.000 description 3
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 102000004142 Trypsin Human genes 0.000 description 3
- 108090000631 Trypsin Proteins 0.000 description 3
- 239000012080 ambient air Substances 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000003098 androgen Substances 0.000 description 3
- 229940030486 androgens Drugs 0.000 description 3
- 230000010261 cell growth Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 description 3
- 235000019439 ethyl acetate Nutrition 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- 229920002674 hyaluronan Polymers 0.000 description 3
- 229960003160 hyaluronic acid Drugs 0.000 description 3
- 229920013818 hydroxypropyl guar gum Polymers 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 230000016507 interphase Effects 0.000 description 3
- 210000002510 keratinocyte Anatomy 0.000 description 3
- 239000006210 lotion Substances 0.000 description 3
- 230000002438 mitochondrial effect Effects 0.000 description 3
- AJVLOCDDVDBRHR-UHFFFAOYSA-N n'-(3-aminopropyl)-n'-methylbutane-1,4-diamine Chemical compound NCCCN(C)CCCCN AJVLOCDDVDBRHR-UHFFFAOYSA-N 0.000 description 3
- GLELLGNUUADRBM-UHFFFAOYSA-N octadecyl 2-tert-butyl-2-[(4-hydroxyphenyl)methyl]-3,3-dimethylbutanoate Chemical compound CCCCCCCCCCCCCCCCCCOC(=O)C(C(C)(C)C)(C(C)(C)C)CC1=CC=C(O)C=C1 GLELLGNUUADRBM-UHFFFAOYSA-N 0.000 description 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000012588 trypsin Substances 0.000 description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 3
- 229920002554 vinyl polymer Polymers 0.000 description 3
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 2
- QCDWFXQBSFUVSP-UHFFFAOYSA-N 2-phenoxyethanol Chemical compound OCCOC1=CC=CC=C1 QCDWFXQBSFUVSP-UHFFFAOYSA-N 0.000 description 2
- SNPLKNRPJHDVJA-ZETCQYMHSA-N D-panthenol Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCCO SNPLKNRPJHDVJA-ZETCQYMHSA-N 0.000 description 2
- XMSXQFUHVRWGNA-UHFFFAOYSA-N Decamethylcyclopentasiloxane Chemical compound C[Si]1(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O1 XMSXQFUHVRWGNA-UHFFFAOYSA-N 0.000 description 2
- 239000006145 Eagle's minimal essential medium Substances 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- FPVVYTCTZKCSOJ-UHFFFAOYSA-N Ethylene glycol distearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCOC(=O)CCCCCCCCCCCCCCCCC FPVVYTCTZKCSOJ-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- AMIMRNSIRUDHCM-UHFFFAOYSA-N Isopropylaldehyde Chemical compound CC(C)C=O AMIMRNSIRUDHCM-UHFFFAOYSA-N 0.000 description 2
- 229930182816 L-glutamine Natural products 0.000 description 2
- 229920002884 Laureth 4 Polymers 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 239000000637 Melanocyte-Stimulating Hormone Substances 0.000 description 2
- 108010007013 Melanocyte-Stimulating Hormones Proteins 0.000 description 2
- 244000062730 Melissa officinalis Species 0.000 description 2
- 235000010654 Melissa officinalis Nutrition 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- BELBBZDIHDAJOR-UHFFFAOYSA-N Phenolsulfonephthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2S(=O)(=O)O1 BELBBZDIHDAJOR-UHFFFAOYSA-N 0.000 description 2
- 229920000604 Polyethylene Glycol 200 Polymers 0.000 description 2
- 102000003946 Prolactin Human genes 0.000 description 2
- 108010057464 Prolactin Proteins 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 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
- 241000209140 Triticum Species 0.000 description 2
- 235000021307 Triticum Nutrition 0.000 description 2
- 229940087168 alpha tocopherol Drugs 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 206010068168 androgenetic alopecia Diseases 0.000 description 2
- 201000002996 androgenic alopecia Diseases 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 229960000541 cetyl alcohol Drugs 0.000 description 2
- 229940125810 compound 20 Drugs 0.000 description 2
- 229940126086 compound 21 Drugs 0.000 description 2
- 229940126208 compound 22 Drugs 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 230000007850 degeneration Effects 0.000 description 2
- 150000004985 diamines Chemical class 0.000 description 2
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 description 2
- AMTWCFIAVKBGOD-UHFFFAOYSA-N dioxosilane;methoxy-dimethyl-trimethylsilyloxysilane Chemical compound O=[Si]=O.CO[Si](C)(C)O[Si](C)(C)C AMTWCFIAVKBGOD-UHFFFAOYSA-N 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 229940079868 disodium laureth sulfosuccinate Drugs 0.000 description 2
- YGAXLGGEEQLLKV-UHFFFAOYSA-L disodium;4-dodecoxy-4-oxo-2-sulfonatobutanoate Chemical compound [Na+].[Na+].CCCCCCCCCCCCOC(=O)CC(C([O-])=O)S([O-])(=O)=O YGAXLGGEEQLLKV-UHFFFAOYSA-L 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000002500 effect on skin Effects 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 229940011871 estrogen Drugs 0.000 description 2
- 239000000262 estrogen Substances 0.000 description 2
- SFNALCNOMXIBKG-UHFFFAOYSA-N ethylene glycol monododecyl ether Chemical compound CCCCCCCCCCCCOCCO SFNALCNOMXIBKG-UHFFFAOYSA-N 0.000 description 2
- 230000003721 exogen phase Effects 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 239000011888 foil Substances 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 229940061515 laureth-4 Drugs 0.000 description 2
- 239000000865 liniment Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- OAIQHKWDTQYGOK-UHFFFAOYSA-L magnesium;2-[2-(2-dodecoxyethoxy)ethoxy]ethyl sulfate Chemical compound [Mg+2].CCCCCCCCCCCCOCCOCCOCCOS([O-])(=O)=O.CCCCCCCCCCCCOCCOCCOCCOS([O-])(=O)=O OAIQHKWDTQYGOK-UHFFFAOYSA-L 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- YCNKGIQJQLHPKB-UHFFFAOYSA-N n'-(3-aminopropyl)-n'-(2-methylpropyl)butane-1,4-diamine Chemical compound NCCCN(CC(C)C)CCCCN YCNKGIQJQLHPKB-UHFFFAOYSA-N 0.000 description 2
- ZVBQKUVIFJDEHB-UHFFFAOYSA-N n'-(3-aminopropyl)-n'-ethylbutane-1,4-diamine Chemical compound NCCCN(CC)CCCCN ZVBQKUVIFJDEHB-UHFFFAOYSA-N 0.000 description 2
- VROUNQCTUDTEKW-UHFFFAOYSA-N n'-(3-aminopropyl)-n'-propylbutane-1,4-diamine Chemical compound NCCCN(CCC)CCCCN VROUNQCTUDTEKW-UHFFFAOYSA-N 0.000 description 2
- 125000000018 nitroso group Chemical group N(=O)* 0.000 description 2
- 231100000065 noncytotoxic Toxicity 0.000 description 2
- 229940101267 panthenol Drugs 0.000 description 2
- 239000011619 pantothenol Substances 0.000 description 2
- 235000020957 pantothenol Nutrition 0.000 description 2
- 229940086539 peg-7 glyceryl cocoate Drugs 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 229960003531 phenolsulfonphthalein Drugs 0.000 description 2
- 229960005323 phenoxyethanol Drugs 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 229940097325 prolactin Drugs 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 108700004121 sarkosyl Proteins 0.000 description 2
- 239000002453 shampoo Substances 0.000 description 2
- 229940083037 simethicone Drugs 0.000 description 2
- KSAVQLQVUXSOCR-UHFFFAOYSA-M sodium lauroyl sarcosinate Chemical compound [Na+].CCCCCCCCCCCC(=O)N(C)CC([O-])=O KSAVQLQVUXSOCR-UHFFFAOYSA-M 0.000 description 2
- 229940045885 sodium lauroyl sarcosinate Drugs 0.000 description 2
- 229940063675 spermine Drugs 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 2
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 2
- 229960000984 tocofersolan Drugs 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000002076 α-tocopherol Substances 0.000 description 2
- 235000004835 α-tocopherol Nutrition 0.000 description 2
- WCDDVEOXEIYWFB-VXORFPGASA-N (2s,3s,4r,5r,6r)-3-[(2s,3r,5s,6r)-3-acetamido-5-hydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-4,5,6-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@@H]1C[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O)[C@H](O)[C@H]1O WCDDVEOXEIYWFB-VXORFPGASA-N 0.000 description 1
- VQVUBYASAICPFU-UHFFFAOYSA-N (6'-acetyloxy-2',7'-dichloro-3-oxospiro[2-benzofuran-1,9'-xanthene]-3'-yl) acetate Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC(Cl)=C(OC(C)=O)C=C1OC1=C2C=C(Cl)C(OC(=O)C)=C1 VQVUBYASAICPFU-UHFFFAOYSA-N 0.000 description 1
- HXKKHQJGJAFBHI-UHFFFAOYSA-N 1-aminopropan-2-ol Chemical compound CC(O)CN HXKKHQJGJAFBHI-UHFFFAOYSA-N 0.000 description 1
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- 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 1
- MXZROAOUCUVNHX-UHFFFAOYSA-N 2-Aminopropanol Chemical compound CCC(N)O MXZROAOUCUVNHX-UHFFFAOYSA-N 0.000 description 1
- DWHIUNMOTRUVPG-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-(2-dodecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCO DWHIUNMOTRUVPG-UHFFFAOYSA-N 0.000 description 1
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 108010066551 Cholestenone 5 alpha-Reductase Proteins 0.000 description 1
- 241000207199 Citrus Species 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- 108020005199 Dehydrogenases Proteins 0.000 description 1
- 239000012594 Earle’s Balanced Salt Solution Substances 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 206010020864 Hypertrichosis Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010022971 Iron Deficiencies Diseases 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- YJPIGAIKUZMOQA-UHFFFAOYSA-N Melatonin Natural products COC1=CC=C2N(C(C)=O)C=C(CCN)C2=C1 YJPIGAIKUZMOQA-UHFFFAOYSA-N 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 102100021079 Ornithine decarboxylase Human genes 0.000 description 1
- 108010055012 Orotidine-5'-phosphate decarboxylase Proteins 0.000 description 1
- 208000012868 Overgrowth Diseases 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 239000005700 Putrescine Substances 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000019552 anatomical structure morphogenesis Effects 0.000 description 1
- 230000003656 anti-hair-loss Effects 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical group 0.000 description 1
- BQMNFPBUAQPINY-UHFFFAOYSA-N azane;2-methyl-2-(prop-2-enoylamino)propane-1-sulfonic acid Chemical compound [NH4+].[O-]S(=O)(=O)CC(C)(C)NC(=O)C=C BQMNFPBUAQPINY-UHFFFAOYSA-N 0.000 description 1
- 239000007640 basal medium Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000007321 biological mechanism Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000001851 biosynthetic effect Effects 0.000 description 1
- 239000001273 butane Substances 0.000 description 1
- QVYARBLCAHCSFJ-UHFFFAOYSA-N butane-1,1-diamine Chemical compound CCCC(N)N QVYARBLCAHCSFJ-UHFFFAOYSA-N 0.000 description 1
- CDQSJQSWAWPGKG-UHFFFAOYSA-N butane-1,1-diol Chemical compound CCCC(O)O CDQSJQSWAWPGKG-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- FAPWYRCQGJNNSJ-UBKPKTQASA-L calcium D-pantothenic acid Chemical compound [Ca+2].OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O.OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O FAPWYRCQGJNNSJ-UBKPKTQASA-L 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 229960002788 cetrimonium chloride Drugs 0.000 description 1
- WOWHHFRSBJGXCM-UHFFFAOYSA-M cetyltrimethylammonium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+](C)(C)C WOWHHFRSBJGXCM-UHFFFAOYSA-M 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 235000020971 citrus fruits Nutrition 0.000 description 1
- 238000011281 clinical therapy Methods 0.000 description 1
- MRUAUOIMASANKQ-UHFFFAOYSA-N cocamidopropyl betaine Chemical compound CCCCCCCCCCCC(=O)NCCC[N+](C)(C)CC([O-])=O MRUAUOIMASANKQ-UHFFFAOYSA-N 0.000 description 1
- 229940073507 cocamidopropyl betaine Drugs 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- LBJNMUFDOHXDFG-UHFFFAOYSA-N copper;hydrate Chemical compound O.[Cu].[Cu] LBJNMUFDOHXDFG-UHFFFAOYSA-N 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000013480 data collection Methods 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 230000002951 depilatory effect Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000004205 dimethyl polysiloxane Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- GLSRFBDXBWZNLH-UHFFFAOYSA-L disodium;2-chloroacetate;2-(4,5-dihydroimidazol-1-yl)ethanol;hydroxide Chemical compound [OH-].[Na+].[Na+].[O-]C(=O)CCl.OCCN1CCN=C1 GLSRFBDXBWZNLH-UHFFFAOYSA-L 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- VLCYCQAOQCDTCN-UHFFFAOYSA-N eflornithine Chemical compound NCCCC(N)(C(F)F)C(O)=O VLCYCQAOQCDTCN-UHFFFAOYSA-N 0.000 description 1
- 229960002759 eflornithine Drugs 0.000 description 1
- 238000005868 electrolysis reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 208000002854 epidermolysis bullosa simplex superficialis Diseases 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 description 1
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 1
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 1
- 230000001815 facial effect Effects 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001506 fluorescence spectroscopy Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229940075529 glyceryl stearate Drugs 0.000 description 1
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000003646 hair health Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- XJNUECKWDBNFJV-UHFFFAOYSA-N hexadecyl 2-ethylhexanoate Chemical compound CCCCCCCCCCCCCCCCOC(=O)C(CC)CCCC XJNUECKWDBNFJV-UHFFFAOYSA-N 0.000 description 1
- 229940014041 hyaluronate Drugs 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- BZUIJMCJNWUGKQ-BDAKNGLRSA-N hypusine Chemical compound NCC[C@@H](O)CNCCCC[C@H](N)C(O)=O BZUIJMCJNWUGKQ-BDAKNGLRSA-N 0.000 description 1
- 230000002055 immunohistochemical effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 229940031674 laureth-7 Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229960003987 melatonin Drugs 0.000 description 1
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 238000001531 micro-dissection Methods 0.000 description 1
- 239000011785 micronutrient Substances 0.000 description 1
- 235000013369 micronutrients Nutrition 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 239000003226 mitogen Substances 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- NJSAFBISRFECQL-UHFFFAOYSA-N n'-(3-aminopropyl)-n'-cyclohexylbutane-1,4-diamine Chemical compound NCCCCN(CCCN)C1CCCCC1 NJSAFBISRFECQL-UHFFFAOYSA-N 0.000 description 1
- LCNBIHVSOPXFMR-UHFFFAOYSA-N n'-(3-aminopropyl)butane-1,4-diamine;hydron;trichloride Chemical compound Cl.Cl.Cl.NCCCCNCCCN LCNBIHVSOPXFMR-UHFFFAOYSA-N 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 150000002832 nitroso derivatives Chemical class 0.000 description 1
- 230000002020 noncytotoxic effect Effects 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- AEIJTFQOBWATKX-UHFFFAOYSA-N octane-1,2-diol Chemical compound CCCCCCC(O)CO AEIJTFQOBWATKX-UHFFFAOYSA-N 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229940100460 peg-100 stearate Drugs 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 238000007626 photothermal therapy Methods 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- TWAMIPJUDRVMJD-DFASFAQMSA-M potassium;(2e,4e,6e)-octa-2,4,6-trienoate Chemical compound [K+].C\C=C\C=C\C=C\C([O-])=O TWAMIPJUDRVMJD-DFASFAQMSA-M 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical group CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 229940096792 quaternium-15 Drugs 0.000 description 1
- UKHVLWKBNNSRRR-TYYBGVCCSA-M quaternium-15 Chemical compound [Cl-].C1N(C2)CN3CN2C[N+]1(C/C=C/Cl)C3 UKHVLWKBNNSRRR-TYYBGVCCSA-M 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229940096501 sodium cocoamphoacetate Drugs 0.000 description 1
- 229940057950 sodium laureth sulfate Drugs 0.000 description 1
- SXHLENDCVBIJFO-UHFFFAOYSA-M sodium;2-[2-(2-dodecoxyethoxy)ethoxy]ethyl sulfate Chemical compound [Na+].CCCCCCCCCCCCOCCOCCOCCOS([O-])(=O)=O SXHLENDCVBIJFO-UHFFFAOYSA-M 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- CXVGEDCSTKKODG-UHFFFAOYSA-N sulisobenzone Chemical compound C1=C(S(O)(=O)=O)C(OC)=CC(O)=C1C(=O)C1=CC=CC=C1 CXVGEDCSTKKODG-UHFFFAOYSA-N 0.000 description 1
- 229960000368 sulisobenzone Drugs 0.000 description 1
- 235000020238 sunflower seed Nutrition 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- 230000003797 telogen phase Effects 0.000 description 1
- 230000003664 tensile strength of the hair Effects 0.000 description 1
- 238000009864 tensile test Methods 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 150000003536 tetrazoles Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940036555 thyroid hormone Drugs 0.000 description 1
- 239000005495 thyroid hormone Substances 0.000 description 1
- 229940035289 tobi Drugs 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 229940085654 trideceth-5 Drugs 0.000 description 1
- 231100000164 trypan blue assay Toxicity 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Classifications
-
- 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
- A61K8/41—Amines
-
- 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
- A61K31/13—Amines
- A61K31/132—Amines having two or more amino groups, e.g. spermidine, putrescine
-
- 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
-
- 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
- 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
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/02—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C211/14—Amines containing amino groups bound to at least two aminoalkyl groups, e.g. diethylenetriamines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2121/00—Preparations for use in therapy
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Organic Chemistry (AREA)
- Dermatology (AREA)
- Birds (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Cosmetics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明涉及用于治疗秃发并通常用于对抗过量脱发的化妆品或药物组合物，其包括作为活性成分的式(I)的化合物R-N1-亚精胺、或1,4-丁二胺,N-(3-氨丙基)-N1-R。按照本发明的目标，通式(I)的化合物是有活性的，并还足够地稳定以允许有效地应用于头皮上局部使用，没有由于氧化作用潜在地被转化成为不再具有活性的不同物质。
Description
发明领域
本发明涉及用于治疗秃发且通常用于对抗过量脱发的药物或化妆品组合物。
现有技术
毛囊(HF)是具有再生能力的人体中最复杂的小型器官之一。在出生后生命中毛发的生长周期描述了随时间的过去的毛干(shaft)和毛囊(follicle)的形态组织学变化。周期活动开始于毛发的产生，随后是毛干的快速生长和伸长(生长阶段(anagen phase))。毛囊和毛发随后经受了由细胞凋亡驱动的退化(退行阶段(catagen phase))，随后是休止期(静息阶段(telogen))和最后的脱发阶段(脱落阶段(exogen))。
这些转化涉及基于在被识别为毛发周期的关键介体的细胞因子、激素、酶、神经递质和其同源受体、以及转录因子的表达和/或活性中的变化的上皮和真皮组分的快速重塑。
尽管毛干的延长、阶段的持续时间和长度在身体的不同区域之间和取决于其遗传规划、年龄和健康状况的个体之间变化，但身体的所有的毛发经受了类似的生命周期。此外，毛发的生物学涉及许多调节因子，影响形态发生并调节生长阶段的开始和持续时间。
存在多种激素参与调节毛发生长周期，包括褪黑激素、催乳激素、黑素细胞刺激激素(MSH)、甲状腺激素和雌激素。例如，已发现催乳激素在小鼠和人两者中都参与毛发生长的调节。
这些调节因子中的许多可以是临床治疗的靶。例如，不包括阴部毛囊和腋下毛囊，雄激素需要酶5α-还原酶，其能够使得睾酮代谢为更为有力的代谢物5α-二氢睾酮(DHT)。事实上，这是用于临床和化妆品领域两者中对抗在雄激素性脱发的情况下的脱发的机制。
与脱发相反，毛发的过度生长可成为问题，特别是对于女性。与雄激素性脱发相对照，伴随毛囊的异常增大而延长的生长阶段产生了多毛症和毛发过多。
对抗该状态的通常治疗是使用脱毛膏和蜡，这仅暂时地减轻了问题，因为刺激或撕裂快速地诱导了毛囊的生长阶段和再生长。其他所用的系统是电解法和选择性光热疗法，通过使用激光来破坏毛干和毛囊的真皮乳突。可获得的最新的治疗是非常侵略性的。
为了解决这些问题，需要新的和更有效的方法。在近几十年来，对毛发周期中鸟氨酸脱羧酶(ODC)和多胺的作用存在特别的科学兴趣。该兴趣主要是由于毛囊是最高度地增殖性器官之一的事实。在多胺生物合成中的限速酶ODC是抑制剂药物(诸如依氟鸟氨酸)的靶，其导致了面部毛发在体内(in vivo)生长的速度的减少和在器官培养中人毛发的生长的抑制。
为了临床用于控制毛发产生的量的目的，一个策略是改变生长的持续时间，在多毛症的情况下缩短其，或增加其以对抗秃发。通常，人毛囊的紊乱，诸如多毛症、白头发和秃发对受影响的个体的心理和自尊具有显著的消极作用。
相同申请人的专利EP 1469843公开了用于对抗脱发的药物、化妆品或饮食用途的组合物，其中活性成分是用于口服使用和用于在头皮上局部使用(topical use)两者的已知为亚精胺或N’-(3-氨丙基)-1,4-二氨基丁烷的多胺。亚精胺的分子式是H2N–(CH2)3–NH–(CH2)4–NH2。
该专利报道了包含照原样的和与其他微量营养素添加剂结合的亚精胺的组合物可延缓并阻止过量脱发，并同时提高毛发的抗性和毛发健康的一般状态的试验性证据。拉伸测试显示了亚精胺增加了毛发的抗拉强度，同时毛发图(trichogram)和洗涤测试显示了在毛球(hair bulb)中发生的改善。除在洗涤之后在脱落的毛发数量上的大量减少之外，相对于在脱落阶段中脱落的毛发的数量(自然置换的脱落)，在静息阶段中脱落的毛发的数量(病理脱落)也减少了。因此，用亚精胺的治疗大大提高了被静息阶段中脱发的疾病改变的毛发循环，将其带回正常的生理水平。因此，亚精胺是用于对抗秃发的有效的活性成分。
然而如同其他多胺，亚精胺容易受到氧化作用，特别是在头皮上的局部应用的情况下，在这种情况下，在被皮肤吸收并进行其作用之前化合物与空气保持了延长的一段时间的接触。在吸收之前的这段时间内亚精胺的任何氧化作用将导致不再具有活性的(如果不是潜在地有害的)氧化产物。
本发明的主要目的是找到该问题的解决方法。在理论上的解决方法中，易受氧化作用的氨基官能团的潜在化学保护似乎通常不适合于实践，特别是从以下专利总结的现有技术的观点上看。
WO9937277描述了用于减少哺乳动物的毛发生长的取代的多胺，所述减少是通过选择将产生该作用的皮肤的区域且将包含取代的多胺作为生物合成羟腐胺赖氨酸(hypusine)途径的抑制剂的皮肤病学上可接受的组合物以有效地减少毛发生长的量应用到皮肤的该区域。因此，可在正常生长的情况下，或同样地在异常或紊乱(例如多毛症)引起的增长的情况下，减少在哺乳动物中包括人类中的不希望的毛发生长，特别是受雄激素刺激的毛发生长。
WO02062341涉及包含有效量的取代的多胺或其盐的药物组合物，所述药物组合物适于在人类或非人类哺乳动物中局部应用以控制应用其的区域中的毛发的生长。在该案例中描述了来自多胺的ODC(鸟氨酸脱羧酶)抑制机制，所述多胺与细胞中出现的ODC不可逆地结合以便阻止ODC催化鸟氨酸到腐胺的脱羧反应。根据该专利，通过向人类和非人类哺乳动物应用特定的取代的多胺可调节毛发的生长，所述取代的多胺主要地阻止了在吸收其的细胞中ODC的形成。通过该方式，认为讨论中的取代的多胺通过阻止ODC的合成来起作用，而不是充当真正的ODC抑制剂。在该文献中试验性的实例显示了在该情况下为二乙基-高亚精胺的被施用的多胺停止了小鼠中被剃的毛发的再生长。
发明概述
在任何情况下，无论防止毛发生长的最终取得的作用背后的生物学机制如何，该已知的现有技术明显地并不支持用官能团取代亚精胺以便获得应用于头皮的皮肤上的区域中刺激生长的相反作用的解决方案作为假设的可行解决方案，而该解决方案是本发明的目标。
同时，本发明的又一个目标在于提供至少在某些性质上可在对抗脱发中比亚精胺更具活性的化合物。
发明详述
与从以上所概述的现有技术可得出的相反，根据本发明，现已令人惊奇地发现式(I)的化合物R-N1-亚精胺、或1,4-丁二胺,N-(3-氨丙基)-N1-R，
(I) H2N–(CH2)3–N1(R)–(CH2)4–NH2
其中R是结合到亚精胺的仲胺官能团(secondary amine function)的取代基，选自：
-由1到6个碳原子组成的饱和的或不饱和的、直链或支链的烃基基团，其中任选地一个或更多个碳原子被氟取代，例如甲基、乙基、三氟甲基、三氟乙基、丙基、异丙基、丁基、异丁基、戊基、己基、亚乙基、乙烯基、亚丙基、亚丁基；
-芳基或芳烃基例如苯基、萘基、苄基、甲苯基，其中任选地一个或更多个碳原子被氟取代，且其中所述芳烃基包含由1到6个碳原子组成的饱和的或不饱和的、直链或支链的烃基基团，其中任选地一个或更多个碳原子被氟取代，例如甲基、乙基、三氟甲基、三氟乙基、丙基、异丙基、丁基、异丁基、戊基、己基、亚乙基、乙烯基、亚丙基、亚丁基；
-由3到8个碳原子组成的饱和的或不饱和的环烃基基团，所述环烃基基团任选地被由1到6个碳原子组成的饱和的或不饱和的、直链或支链的烃基基团取代，其中任选地一个或更多个碳原子被氟取代，例如甲基、乙基、三氟甲基、三氟乙基、丙基、异丙基、丁基、异丁基、戊基、己基、亚乙基、乙烯基、亚丙基、亚丁基；
-或其药学上可接受的盐，
具有基本上比得上亚精胺的抗脱发活性，但在局部应用到头皮时在环境空气存在的情况下不会经受氧化作用的问题。事实上，按照本发明的目标，它们对于空气是如此稳定以至于它们使在头皮上用于局部使用的有效应用成为可能，而没有被转化为惰性的或没有活性的氧化的副产品。
特别地，还令人惊奇地，至少关于如下所述的特定性质而言，根据本发明的这些化合物被证明是在对抗秃发中比亚精胺更具活性。
因此，本发明涉及这些R-N1-亚精胺化合物(I)对抗脱发的用途且涉及包含它们作为有效成分的用于药物或化妆品用途的组合物。
根据本发明优选的式(I)的化合物是下式的N1-甲基亚精胺或N-(3-氨丙基)-N1-甲基-1,4-丁二胺(CAS登录号51460-23-2)：
(II) H2N–(CH2)3–N1(CH3)–(CH2)4–NH2
其照原样或作为药学上可接受的盐例如三盐酸盐(3HCl)或三马来酸盐用于根据本发明的组合物。根据本发明更优选的式(I)的化合物是下式的N1-环己基亚精胺或N-(3-氨丙基)-N1-环己基-1,4-丁二胺(CAS登录号183070-28-2)：
(III) H2N–(CH2)3–N1(C6H11)–(CH2)4–NH2。
其照原样或作为药学上可接受的盐例如三盐酸盐(3HCl)或三马来酸盐用于根据本发明的组合物。根据本发明更优选的式(I)的化合物是下式的N1-乙基亚精胺或N-(3-氨丙基)-N1-乙基-1,4-丁二胺(CAS登录号97141-36-1)：
(IV) H2N–(CH2)3–N1(C2H5)–(CH2)4–NH2。
其照原样或作为药学上可接受的盐例如三盐酸盐(3HCl)或三马来酸盐用于根据本发明的组合物。根据本发明更优选的式(I)的化合物是下式的N1-丙基亚精胺或N-(3-氨丙基)-N1-丙基-1,4-丁二胺(CAS登录号62659-14-7)：
(V) H2N–(CH2)3–N1(C3H7)–(CH2)4–NH2。
其照原样或作为药学上可接受的盐例如三盐酸盐(3HCl)或三马来酸盐用于根据本发明的组合物。根据本发明更优选的式(I)的化合物是式N1-异丁基亚精胺或N-(3-氨丙基)-N1-异丁基-1,4-丁二胺的式：
(VI) H2N–(CH2)3–N1(C4H9)–(CH2)4–NH2。
其照原样或作为药学上可接受的盐例如三盐酸盐(3HCl)或三马来酸盐用于根据本发明的组合物。该化合物(VI)在文献中是未知的。因此，在以下参考以下反应示意图描述了用于合成其的方法，所述反应示意图中化合物(VI)被分离作为化合物4。
化合物19的合成：将丁二胺(1g，0.0113mol，5当量)溶解于CH2Cl2(15ml)中。向该溶液中加入溶解于CH2Cl2(15ml)的Boc2O(0.619g，0.00283mol，1当量)。将反应混合物放置于RT中搅拌16小时。通过TLC(8份CH2Cl2/2份MeOH/0.2份33％NH4OHaq)评价产物的结构。过滤所形成的悬浮液并通过旋转蒸发仪干燥滤液。用EtOAc(15ml)洗脱油性残留物并用饱和的NaCl溶液(3×10ml)洗涤以移除过量未反应的二胺。有机提取物通过硫酸钠脱水并蒸发。获得了0.520g的黄色油。收率97.65％。1HNMR(400MHz,CDCl3)δ1.38(s,9H),1.52-1.59(m,4H),2.34(brs,2H,D2O exch.),2.72-2.79(m,2H),3.19-3.24(m,2H),5.95(brs,1H,D2O exch.)。
化合物20的合成：将如前述的化合物19(0.358g，0.00190mol，1当量)溶解于EtOH(5ml)。将3A分子筛和异丁醛(0.137g，0.00190mol，0.17ml，1当量)加入溶液。将反应混合物于RT中搅拌18小时。加入NaBH4(0.144g,0.0038mol,2当量)且将混合物于RT中搅拌16小时。通过TLC(9份CH2Cl2/1份MeOH/0.1份33％NH4OHaq)评价产物的结构。蒸发溶剂，然后油性残留物用CH2Cl2(10ml)洗脱并用饱和的NaCl溶液(5ml)洗涤。有机提取物通过硫酸钠脱水并蒸发，且通过使用9份CH2Cl2/1份MeOH/0.1份33％NH4OHaq的混合物作为洗脱液相的快速色谱纯化所获得的残留物。获得了0.215mg的无色油。收率46.33％。1H NMR(400MHz,CDCl3)δ0.88(d,6H,J＝6.8Hz),1.41(s,9H),1.49-1.52(m,4H),1.72-1.75(m,1H),2.38(d,2H,J＝7.2Hz),2.59(t,2H,J＝6.6Hz),3.07-3.09(m,2H),4.95(brs,1H,D2O exch.)。
化合物21的合成：将氨基丙醇(0.49g，0.51ml，0.00652mol，1当量)溶解于甲苯(5ml)。在冰浴下将SOCl2(3.10g，1.90ml，0.00261mol，4当量)加入溶液中。在回流下搅拌反应混合物2小时。通过TLC(9份CH2Cl2/1份MeOH/0.1份33％NH4OHaq)评价产物的结构。蒸发溶剂，且用H2O(10ml)洗脱油性残留物并用CH2Cl2(5ml)洗涤。水相不进一步纯化地用于以下步骤中，将Net3(0.659mg,0.9ml,0.00652mol,1当量)加入溶液，然后混合物在RT中搅拌30分钟。加入Boc2O(1.42g，0.00652mol，1当量)在THF(10ml)中的溶液。反应混合物在RT中搅拌18小时。通过TLC(8份石油醚/2份EtOAc)评价起始物的消失。蒸发溶剂，且用EtOAc洗脱残留物并用H2O洗涤。有机提取物通过硫酸钠脱水并蒸发。获得了1.23g的棕色油。收率97.70％。1H NMR(400MHz,CDCl3)δ1.43(s,9H),1.94-1.97(m,2H),3.26(t,2H,J＝6.4Hz),3.58(t,2H,J＝6.4),4.75(brs,1H,D2Oexch.)。
化合物22的合成：将前述的化合物20(0.120g，0.00049mol，1当量)溶解于DMF(3ml)。向该溶液中加入溶解于DMF(2ml)的前述的化合物21(0.104g，0.00054mol，1.1当量)。在回流下搅拌反应混合物6小时。通过TLC(9份CH2Cl2/1份MeOH/0.03份33％NH4OHaq)评价产物的结构。蒸发溶剂，并通过使用9份CH2Cl2/1份MeOH/0.03份33％NH4OHaq的混合物作为洗脱液相的快速色谱纯化油性残留物。获得了0.084mg的黄色油。收率42.71％。1H NMR(400MHz,CDCl3)δ0.87(d,6H,J＝6.8Hz),1.43(s,18H),1.57-1.61(m,7H),1.98-2.01(m,2H),2.31-2.35(m,2H),2.38-2.42(m,2H),3.10-3.12(m,2H),3.16-3.18(m,2H),4.72(brs,1H,exch D2O),5.69(brs,1H,D2O exch.)。
化合物4的合成：将HCl 3N(10ml)滴在溶解于MeOH(2ml)并保持在冰浴中的所述化合物22上(0.084g,0.00021mol,1当量)。在室温下搅拌反应混合物18小时。通过TLC(9份CH2Cl2/1份MeOH/0.03份NH4OHaq)评价起始物的消失。蒸发MeOH，并用二乙醚(2×8ml)洗涤残留物溶液并干燥。获得了作为三盐酸盐的0.065g的化合物4。收率100％。1H NMR(400MHz,D2O)δ1.02(d,6H,J＝6.8Hz),1.76-1.78(m,2H),1.79-1.84(m,2H),2.14-2.17(m,3H),3.06-3.25(m,6H),3.26-3.33(m,4H)；13C NMR(100MHz,D2O)δ19.27,20.15,21.26,23.83,28.92,36.52,38.77,50.18,52.66,58.88,60.59.MS(ESI+)m/z＝202(M+H)+。
附图中的图7、图8和图9分别显示了化合物4的即如以上定义的式(VI)的1H-NMR、13C-NMR和质谱。
实施例组合物
以下通过非限定性的实例描述了用于在头皮上局部使用的根据本发明的组合物的一些实例。在以下实例中，通过在用于化妆品产品所需的相应的INCI名称提及N1-甲基亚精胺，即：N-甲基亚精胺。这也应用于所给出作为实例的其他发明的化合物。
实施例1
用于减少脱发的香波治疗
组分(INCI名称)........................................................量％p/p
月桂醇聚醚磺基琥珀酸酯二钠................................1.00-5.00
月桂醇聚醚硫酸酯镁................................................5.00-9.00
PEG-7椰油酸甘油酯................................................0.50-1.00
椰油酸单异丙醇酰胺(Cocamide MIPA)...................0.50-2.00
PEG-200氢化棕榈油酸甘油酯................................0.50-2.00
聚季铵盐-10..............................................................0.10-0.50
月桂酰肌氨酸钠.......................................................1.00-4.00
EDTA四钠................................................................0.05-0.20
N-甲基亚精胺...........................................................0.001-0.30
生物素.......................................................................0.01-0.10
泛酸钙.......................................................................0.01-3.0
十一碳烯酰基小麦蛋白钾........................................0.50-1.00
月桂醇聚醚-4............................................................0.01-0.80
香水...........................................................................0.10-0.80
乙二醇二硬脂酸酯....................................................0.50-1.00
月桂醇聚醚-7............................................................0.50-0.80
椰油酰两性基乙酸钠................................................0.05-3.00
椰油酰胺丙基甜菜碱................................................0.01-2.00
月桂醇聚醚硫酸酯钠................................................0.01-3.00
羟甲基甘氨酸钠.......................................................0.20-0.45
氢氧化钠...................................................................适量
柠檬酸.......................................................................适量
水...............................................................................适量至100.00
实施例2
用于减少脱发的洗液治疗
组分(INCI名称)........................................................量％p/v
水...............................................................................适量至100ml
羟丙基三甲基氯化铵透明质酸(Hydroxypropyltrimonium Hyaluronate)..........................................................................................0.005-0.50
聚氨酯-26..................................................................0.004-4.0
卵磷脂(大豆).............................................................0.005-5.0
变性乙醇...................................................................15.0-20.0
N-甲基亚精胺...........................................................0.005-0.30
生物素.......................................................................0.01-0.10
泛酸钙.......................................................................0.1-3.0
芦丁...........................................................................0.001-0.05
PEG-40氢化蓖麻油..................................................0.5-2.0
十八烷醇二-t-丁基-4-羟基氢化肉桂酸酯................0.05
香水...........................................................................0.20
玉米黄素...................................................................0.002-0.01
葵花籽油...................................................................0.001-0.01
乳酸...........................................................................适量至pH 5.0
实施例3
协助减少脱发的香脂护发素
组分(INCI名称)........................................................量％p/v
水...............................................................................适量至100ml
棕榈醇.......................................................................0.50-7.00
PEG-40氢化蓖麻油..................................................0.50-2.00
司拉氯铵...................................................................0.10-2.00
N-甲基亚精胺...........................................................0.010-0.30
EDTA二钠................................................................0.025-0.05
香水...........................................................................0.20
羟甲基甘氨酸钠.......................................................0.20-0.45
乳酸...........................................................................适量至pH 5.0
实施例4
用于减少脱发的香脂治疗
组分(INCI名称)........................................................量p/v(％)
水...............................................................................适量至100ml
EDTA二钠................................................................0.025-0.05
木糖醇.......................................................................0.50-1.50
泛醇...........................................................................0.50-1.50
羟乙基纤维素...........................................................0.10-0.90
西曲氯铵...................................................................0.50-5.00
双-异丁基PEG/PPG-20/35/聚二甲基硅氧烷共聚物…0.05-0.75
鲸蜡醇乙基己酸酯....................................................0.05-1.00
聚山梨酯80..............................................................0.05-4.00
丁二醇.......................................................................0.05-3.00
环戊硅氧烷...............................................................0.10-3.00
C12-13烃基乳酸酯...................................................0.50-5.00
甘油硬脂酸酯...........................................................1.00-5.00
PEG-100硬脂酸酯....................................................0.50-4.00
二甲硅油...................................................................1.00-4.00
聚二甲基硅氧烷醇....................................................0.10-0.80
棕榈醇.......................................................................1.00-5.00
苯氧乙醇...................................................................0.30-0.90
辛甘醇.......................................................................0.30-0.90
玉米黄质...................................................................0.00005-0.00030
芦丁...........................................................................0.0005-0.003
N-甲基亚精胺...........................................................0.00010-0.15
香水...........................................................................0.10-0.30
实施例5
强化精华液(intensive serum)毛发治疗
组分(INCI名称)........................................................量％p/v
水...............................................................................适量至100ml
变性乙醇类型C........................................................10.00-20.00
泛酸钙.......................................................................0.05-2.00
N-甲基亚精胺...........................................................0.05-0.210
辛三烯酸钾(Potassium octatrienoate)........................0.001-0.18
生物素.......................................................................0.005-0.020
匍匐筋骨草提取物...................................................0.001-0.10
乳酸菌大豆发酵产物................................................0.01-0.15
泛醇...........................................................................0.10-1.00
羟丙基三甲基氯化铵透明质酸................................0.002-0.50
聚氨酯-26..................................................................0.004-4.0
卵磷脂(大豆(Glycine max L.))..................................0.005-5.0
PEG-40氢化蓖麻油..................................................0.50-2.00
香水...........................................................................0.10-0.30
羟丙基瓜尔胶...........................................................0.10-0.40
乙氧基二甘醇...........................................................0.10-0.70
乳酸...........................................................................0.05-0.50
实施例6
强化精华液抗脱治疗
组分(INCI名称)........................................................量％p/v
水...............................................................................适量至100ml
甘油...........................................................................di1.00-8.00
丙烯酰二甲基牛磺酸铵/VP共聚物.........................0.50-5.00
环戊硅氧烷...............................................................1.00-8.00
苯氧乙醇...................................................................0.30-0.90
香水...........................................................................0.10-0.70
聚硅氧烷季铵盐-15..................................................0.20-1.90
二甲硅油...................................................................0.10-6.00
甘草酸铵...................................................................0.05-0.75
C11-15链烷醇聚醚-5...............................................0.05-1.00
C11-15链烷醇聚醚-9...............................................0.05-1.00
EDTA二钠................................................................0.025-0.05
N-甲基亚精胺...........................................................0.025-0.210
泛酸钙.......................................................................0.010-0.50
羟苯乙酯...................................................................0.010-0.030
羟苯甲酯...................................................................0.05-0.120
十三烷醇聚醚-5........................................................0.010-0.40
十三烷醇聚醚-10......................................................0.010-0.40
乳酸...........................................................................适量至pH 4.5
实施例7
用于减少脱发的香波治疗
组分(INCI名称)........................................................量％p/p
月桂醇聚醚磺基琥珀酸酯二钠................................1.00-5.00
月桂醇聚醚硫酸酯镁................................................5.00-9.00
PEG-7椰油酸甘油酯................................................0.50-1.00
椰油酸单异丙醇酰胺................................................0.50-2.00
PEG-200氢化棕榈油酸甘油酯................................0.50-2.00
聚季铵盐-10..............................................................0.10-0.50
月桂酰肌氨酸钠.......................................................1.00-4.00
EDTA四钠................................................................0.05-0.20
N-甲基亚精胺三马来酸盐........................................0.002-0.60
生物素.......................................................................0.01-0.10
泛酸钙.......................................................................0.01-3.0
十一碳烯酰基小麦蛋白钾........................................0.50-1.00
月桂醇聚醚-4............................................................0.01-0.80
乙二醇二硬脂酸酯....................................................0.50-1.00
羟甲基甘氨酸钠.......................................................0.20-0.45
水...............................................................................适量至100.00
实施例8
用于减少脱发的洗液治疗
组分(INCI名称)........................................................量％p/v
水...............................................................................70-90
乙醇...........................................................................10-20
聚氧乙烯化的氢化蓖麻油........................................0.5-2.5
乳酸溶液80％...........................................................0.2-0.4
N-甲基亚精胺三马来酸盐........................................0.05-0.3
柑橘类香水2807/03(Parfum Agrumes 2807/03)......0.05-0.3
羟丙基三甲基氯化铵透明质酸................................0.01-0.1
卵磷脂NAT 8539.....................................................0.01-0.1
十八烷醇二-t-丁基-4-羟基氢化肉桂酸酯................0.01-0.1
Fluorolink 5032.........................................................0.01-0.1
实施例9
加强定型凝胶
组分(INCI名称)........................................................量％p/v
水...............................................................................85-95
Fixate PLUS聚合物..................................................1.5-3.5
PEG-40氢化蓖麻油..................................................1-3
香水...........................................................................0.5-2
山梨醇.......................................................................0.5-2
羟甲基甘氨酸钠.......................................................0.5-2
羟丙基瓜尔胶...........................................................0.2-1.2
二苯酮-4....................................................................0.05-1
Gafquat 755N.............................................................0.05-1
EDTA二钠二水合物................................................0.05-1
牛磺酸.......................................................................0.025-0.1
D-泛酸钙...................................................................0.01-0.05
芦丁...........................................................................0.005-0.02
玉米黄质...................................................................0.005-0.02
匍匐筋骨草提取物...................................................0.005-0.02
N-甲基亚精胺三马来酸盐........................................0.0015-0.006
生物素.......................................................................0.0001-0.0004
实施例10
用于减少脱发的洗液治疗
组分(INCI名称)........................................................量％p/v
变性酒精...................................................................15.0-20.0
N-(3-氨丙基)-N1-异丁基-1,4-丁二胺......................0.005-0.30
生物素.......................................................................0.01-0.10
泛酸钙.......................................................................0.1-3.0
芦丁...........................................................................0.001-0.05
PEG-40氢化蓖麻油..................................................0.5-2.0
十八烷醇二-t-丁基-4-羟基氢化肉桂酸酯................0.05
玉米黄素...................................................................0.002-0.01
乳酸...........................................................................适量至pH 5.0
水...............................................................................适量至100ml
实施例11
强化精华液毛发治疗
组分(INCI名称)........................................................量％p/v
变性乙醇类型C........................................................10-20
N-(3-氨丙基)-N1-乙基-1,4-丁二胺..........................0.05-0.2.0
羟丙基三甲基氯化铵透明质酸................................0.002-0.5
聚氨酯-26..................................................................0.004-4.0
卵磷脂(大豆)...........................................................0.005-5.0
PEG-40氢化蓖麻油..................................................0.50-2.0
羟丙基瓜尔胶...........................................................0.10-0.4
乙氧基二甘醇...........................................................0.10-0.7
乳酸...........................................................................0.05-0.5
水...............................................................................适量至100ml
试验部分和附图
与通过作为对照的亚精胺(3HCl)相比，对无论是作为游离碱或作为盐，三盐酸盐(3HCl)或三马来酸盐的根据本发明的式(II)的化合物，N1-甲基亚精胺或N-(3-氨丙基)-N1-甲基-1,4-丁二胺的活性，进行了以下测试。
在图1和图2中，还将相关的测试扩展到以三盐酸盐(3HCl)的形式的N1-环己基亚精胺、N1-乙基亚精胺、N1-丙基亚精胺和N1-异丁基亚精胺，即根据本发明的式(III)、式(IV)、式(V)、式(VI)的化合物。
在这方面，将按照以下附图的附图附到本说明书中。
图1和图2是MTT实验(MTT Assay)测试的结果的图。
图3是抗氧化测试的结果的图。
图4是毛发伸长测试的结果的图。
图5和图6是在图4的测试中对于生长阶段和退行阶段的结果图
最后，如上所述，图7、图8和图9分别显示了化合物4的1H-NMR、13C-NMR和质谱，化合物4即如以上所定义的式(VI)。
还研究了在将其溶液暴露到周围环境空气之后式(I)的化合物的稳定性和反应性。
1.MTT实验
介绍
MTT实验是用于分析细胞活力的测试(Mosmann,1983)。它是基于使用四唑盐MTT的比色测试，其测量了随后可通过微孔板分光光度计定量的细胞活力。在细胞线粒体中黄色化合物MTT(3-(4,5-二甲基-2-噻唑基)-2,5-二苯基四氮唑溴盐)被还原为紫色物质甲臜(formazan)。可通过使用分光光度仪在给定波长(570nm)下测量其来定量该有色的溶液的吸光度。最大吸光度将取决于所用的溶剂。该还原仅发生在线粒体还原酶有活性时，并因此可将向甲臜的转化直接地与活细胞的数目相关。当将用物质处理的细胞产生的甲臜的数量与未处理的对照细胞产生的数量相比时，通过产生剂量-反应曲线推断被测试的物质在引起细胞死亡的功效是可能的。不含酚红的溶解于PBS或细胞培养基中的MTT溶液具有淡黄的颜色。在活细胞中，线粒体脱氢酶切断四唑环，产生了在水溶液中不溶的紫色甲臜晶体。该晶体可溶解于酸化的异丙醇或DMSO。通过分光光度法分析产生的紫色溶液。细胞数目的增加将导致获得的甲臜的增加和吸光度的增加。MTT测试的使用具有受以下影响的限制：1)细胞的生理状态和2)在不同细胞类型中线粒体脱氢酶的活性的变化。尽管这样，用于细胞确定的MTT实验在测量细胞生长对于分裂素、抗原刺激、生长因子和促进细胞生长的其他试剂的反应，细胞毒性研究，和细胞生长曲线的创建中是有用的。
当在多孔板中制备培养物时，用于细胞确定的MTT实验是特别地有用的。为了更好的结果，应在指数生长期确定细胞的数目。
材料
生物模型
从在意大利的热那亚的国家癌症研究所(National Institute for CancerResearch)获得了NCTC2544人角质细胞的细胞系(Perry V.P.等,1957)。
培养参数
细胞系在添加了10％FBS、2mM L-谷酰胺、1％NEAA 1X溶液和1％青霉素(10,000U/ml)/链霉素(10,000μg/ml)混合物的EMEM培养基(EBSS)中生长，并在25cm2培养瓶中在37℃、5％CO2下保持。每隔一天，在用PBS 1X(不含Ca2+和Mg2+)洗涤后使用胰蛋白酶/EDTA将铺满培养物以1:3到1:6分开并在37℃、5％CO2下以2-5×104细胞/cm2接种。
用于冷冻的培养基：添加了20％FBS、2mM L-谷酰胺、1％青霉素/链霉素混合物和10％DMSO的培养基。
细胞定量：台盼蓝实验
试剂和仪器
方法
第1天：接种细胞
当NCTC 2544人角质细胞已达到约80％的铺满时，将其分离并用胰蛋白酶/EDTA收集，以5×104细胞/ml的密度接种在96孔板，并然后在37℃、5％CO2孵育(24h)。
第2-3天：暴露试剂24-48小时
当细胞已达到约80％的铺满时，将其暴露到递增浓度的前述的根据本发明的活性化合物：作为游离碱和作为三盐酸(3HCl)盐和三马来酸盐两者的N1-甲基亚精胺；且还有作为三盐酸(3HCl)盐的N1-环己基亚精胺(N1-cycloesilspermidine)、N1-乙基亚精胺、N1-丙基亚精胺、N1-异丁基亚精胺，以及作为参考的亚精胺三盐酸盐用于比较。以一式两份测试了每种化合物。测试了所有化合物的以下浓度：1nM、500nM、1μM、500μM(在培养基中的终浓度)。使用SDS作为内标。
制备了每种化合物的期望的稀释物后，从板中移除培养基且用每种浓度的100μl接种孔。在每个板中包括了仅包含培养基的对照。
细胞在37℃、5％CO2孵育不同的处理时间(24-48小时)。
第4天：MTT实验
在96孔板中用所关心的化合物处理(24-48小时)结束后，培养基被移除并用100μl/孔的MTT溶液置换，且在37℃、5％CO2孵育板3小时。将MTT盐溶解于PBS(5mg/ml)并在用10％FCS、2mM谷酰胺、1％NEAA100X溶液(液体)和1％抗生素混合物补充的不含酚红的EMEM培养基中以1:10稀释地加入细胞。
用铝箔覆盖板。随后，将培养基小心移除。将100μl的DMSO加入每个孔以溶解紫色甲臜产物。用铝箔覆盖板并在室温下搅拌15分钟。
使用预先设定方案和正确设定板的布局之后，在Biotek ELX808酶标仪用630nm的参比过滤片在570nm读取溶液的吸光度。
数据收集和统计分析
直接从Biotek ELX808酶标仪的软件中记录光密度数据。该软件自动进行任何转换。
-转换1：计算Delta OD 570-630nm(在自动白色减除(white subtraction)之后)
-转换2：计算活力％(相对于对照)
随后将获得的数据输出到Excel中并进行统计分析和图形分析，以便确定在该浓度可测试化合物的无细胞毒性的浓度。
所用的试剂和仪器
结果
图1和图2分别概括了从在24小时(图1)和48小时(图2)的图中获得的结果。如在其中所指明的，在那对相同浓度的每组给出的8个柱从左到右分别归属于：全部以三盐酸盐(3HCl)形式的亚精胺、N1-甲基亚精胺、N1-环己基亚精胺、N1-乙基亚精胺、N1-丙基亚精胺、N1-异丁基亚精胺；N1-甲基亚精胺三马来酸盐；N1-甲基亚精胺游离碱。
以相对于对照的百分比表示细胞活力，所述对照即细胞群在不加入亚精胺或根据本发明的化合物的标准条件下生长。在测试的浓度下(1nM、500nM、1mM、500mM)，在暴露人角质细胞(NCTC2544)的细胞系24小时或48小时之后亚精胺不具有细胞毒性作用。类似地，用根据本发明的化合物处理24小时或48小时后细胞活力基本上没有减少，且在一些情况下甚至提高了，证明化合物没有细胞毒性。从根据本发明的化合物获得的结果与从亚精胺获得那些没有统计学上的不同。
总之，可以得出结论MTT实验证明根据本发明的化合物没有细胞毒性。
2.抗氧化测试——活性氧物质(ROS)的产生
通过使用如Tobi等(Tobi SE,Paul N,T McMillan J.J Photochem.Photobiol,B 2000:57:102-112)所描述的2’,7’-二氯荧光素二乙酸酯(DCFH-DA)的荧光光谱测定法监测活性氧物质(ROS)的产生。
使用胰蛋白酶/EDTA分离前述的NCTC2544细胞(约80％铺满)并以5x104细胞/孔的密度接种于96-孔板。随后，用根据本发明的N-甲基亚精胺和亚精胺处理细胞。测试了N-甲基亚精胺和亚精胺的以下浓度：1nM、500nM、1μM、500μM、1mM(在培养基中的终浓度)。
使用α-生育酚(250μg/ml)作为对比。在37℃、5％CO2中孵育板1.5小时。使用含10％FBS基础培养基上生长的细胞作为对照。
图3的图概括了获得的结果。从确定活性氧物质的细胞内浓度获得的结果证实了如文献中报道的亚精胺的抗氧化活性。与用H2O2处理的对照细胞相比，用250μg/ml的α-生育酚、亚精胺和N-甲基亚精胺处理的细胞显示了ROS产物的浓度的减少。当亚精胺的抗氧化活性与N-甲基亚精胺的抗氧化活性相比时，不能证明具有显著性不同。
3.毛干伸长测试
在使得测量在毛干的伸长中的作用成为可能的离体模型中测试了N-甲基亚精胺的活性。
材料和方法
按照赫尔辛基宣言(Helsinki Declaration)和在Lübeck大学伦理委员会(Ethics Committee of the University of Lübeck)的批准下，在来自进行手术(整容)的受试者的知情同意后，在第VI生长阶段的毛囊(HF)的器官培养涉及人头皮(颞-额部区域)的皮肤中HF的显微解剖。在该模型中，HF的生长期(生长阶段)持续了几天以与在体内的生长阶段相类似的速度产生着色的毛干，在体外另外表现出周期性生长活性，自发地进入了毛发循环的退化阶段(退行阶段)。
培养分离的毛囊连续6天以用于免疫组织化学研究。
对每次培养基的更换(每48小时)以0.5μM的浓度施用亚精胺、N-甲基亚精胺和介质(蒸馏水)一次。
将冷冻切片储藏在-80℃直至其被使用。
毛发生长测量
用介质、亚精胺和N-甲基亚精胺处理之后，使用配有一个含标线(reticle)的目镜的Zeiss倒置双目显微镜(Carl Zeiss,Oberkochen,德国)在第0天、第1天、第4天和第6天进行了毛干伸长的测量。
结果
在图4的图中显示了毛干伸长的结果，其显示了在第6天的结果。相对于介质，根据本发明的亚精胺和N-甲基亚精胺两者都显著地提高了毛干的伸长。在亚精胺和N-甲基亚精胺之间观察到的不同不具有统计学上的显著性，且因此应当认为在所比较的两个例子中的伸长作用是差不多的。
4.生长阶段和退行阶段的结果
在图5和图6的图中概括的生长阶段和退行阶段的以下结果，也获得自对毛干伸长的之前测试所描述的相同的毛囊(HF)离体模型。
图5的图显示了在生长周期的不同阶段中用N-甲基亚精胺处理的毛囊的百分数。
由此可看出，在N-甲基亚精胺处理6天后带来了毛囊的百分数在生长阶段中的显著的增加和在退行阶段中的减少。在N-甲基亚精胺的存在下，仅30％(大约)的毛囊自发地进入了退行阶段，然而在介质的存在下多于60％的毛囊进入了退行阶段。
图6的图显示了对于亚精胺(0.5μM)和N-甲基-亚精胺(0.5μM)所获得的毛囊的阶段相对于对照的相应百分数的值。
两种化合物之间的比较令人惊奇地证明了在N-甲基亚精胺的情况下比用亚精胺对延长生长阶段具有更大的影响。因此，用N-甲基亚精胺处理之后，进入退行阶段的毛发的数目(分为阶段：初始、中间和最后)比用亚精胺显著地更低。
5.反应性的结果
通过与相应的非取代的衍生物的比较，研究了暴露到空气的1,4-丁二胺,N-(3-氨丙基)-N1-甲基(II)和1,4-丁二胺,N-(3-氨丙基)-N1-环己基(III)的性质，在所述衍生物中，没有R取代基的N1胺基团成为仲胺基团，即1,4-丁二胺,N-(3-氨丙基)。由于仲氨基基团(secondary amino group)的氧化作用的通常产物之一是以通过与存在于空气中氮氧化物的反应形成的N-亚硝基衍生物的形式，因此在使测试化合物的溶液接触空气后形成的亚硝基化的衍生物被确定为反应性的参数。
材料和方法
所用的仪器操作由在其中进行了亚硝酸盐离子的分析和N-亚硝胺类的分析的阶段组成，后者处于强脱亚硝基条件下。通过化学发光检测仪评价了按照亚硝酸盐离子的量形成的氮氧化物和按照亚硝基基团的数量形成的氮氧化物。
在0-4℃的温度下使用醋酸/碘化钾(5ml/1ml的5％水溶液)的还原性混合物分析了NO2-离子。在70℃的温度下使用醋酸/氢溴酸(5ml/1ml)的脱亚硝基混合物分析了亚硝基基团。
试剂是市售的例如来自Sigma-Aldrich。使用高纯度气体(He2和NO)。
确定化合物的空气氧化作用的方法如下。
a)将测试物质在纯化的水中的2mM溶液以等于500μl的量双倍地接种在惰性塑料材料(聚苯乙烯)的6-孔板的合适的孔中；
b)用500μl的纯化的水和无污染的乙醇(85/15)的混合物稀释在每个孔中溶液。这提高了在孔表面上的液体膜的分散度；
c)将以该方式制备的板暴露于环境空气持续72小时；
d)在暴露时间结束后，用1ml的纯化的水洗脱在孔中的残留物并然后用于化学发光分析。
结果
| 化合物 | 72小时暴露之后的亚硝基衍生物 |
| 1,4-丁二胺,N-(3-氨丙基) | 2.3ppm |
| 1,4-丁二胺,N-(3-氨丙基)-N1-甲基 | 不存在 |
| 1,4-丁二胺,N-(3-氨丙基)-N1-环己基 | 不存在 |
6.结论
在没有细胞毒性、对ROS的抗氧化活性和毛干的伸长方面，以上试验证明了根据本发明的化合物提供了与从用亚精胺可获得的那些结果基本上没有不同的结果。
而且，令人惊奇地，在延长毛发的生长阶段上N-甲基亚精胺看起来具有比亚精胺更高的活性。
尽管刺激毛干的伸长和延长生长阶段两者都有助于毛发的生理性生长，然而从临床观点可认为，在使毛干伸长的作用方面，对生长阶段的延长的结果更显著并更相关，因为拖长的生长阶段对脱发的减少有直接积极影响，其是本发明的主要目标。
如上对N-甲基亚精胺所指出的，延长生长阶段和相对抑制退行阶段的活性在对抗以由于生长阶段的非生理性减少引起的过量脱发为特征的许多不同形式的脱发或秃发中是有用的，例如由雄激素、毛囊周炎症、缺铁和雌激素引起的或由导致非生理性脱发作为副作用的药物的施用引起的过量脱发。
因此，从作为整体的以上的描述中，可以看出按照本发明的目标通式(I)的化合物是有活性的，并还足够地稳定以允许有效地应用于头皮上局部使用，没有由于氧化作用潜在地被转化成为不再具有活性的不同物质。
Claims (18)
1.式(I)的化合物R-N1-亚精胺或1,4-丁二胺,N-(3-氨丙基)-N1-R或其药学上可接受的盐的用途，
(I) H2N–(CH2)3–N1(R)–(CH2)4–NH2
其中R是结合到亚精胺的仲胺官能团的取代基，所述R选自：
-由1到6个碳原子组成的饱和的或不饱和的、直链或支链的烃基基团，其中任选地一个或更多个碳原子被氟取代，例如甲基、乙基、三氟甲基、三氟乙基、丙基、异丙基、丁基、异丁基、戊基、己基、亚乙基、乙烯基、亚丙基、亚丁基；
-芳基或芳烃基例如苯基、萘基、苄基、甲苯基，其中任选地一个或更多个碳原子被氟取代，且其中所述芳烃基包含由1到6个碳原子组成的饱和的或不饱和的、直链或支链的烃基基团，其中任选地一个或更多个碳原子被氟取代，例如甲基、乙基、三氟甲基、三氟乙基、丙基、异丙基、丁基、异丁基、戊基、己基、亚乙基、乙烯基、亚丙基、亚丁基；
-由3到8个碳原子组成的饱和的或不饱和的环烃基基团，所述环烃基基团任选地被由1到6个碳原子组成的饱和的或不饱和的、直链或支链的烃基基团取代，其中任选地一个或更多个碳原子被氟取代，例如甲基、乙基、三氟甲基、三氟乙基、丙基、异丙基、丁基、异丁基、戊基、己基、亚乙基、乙烯基、亚丙基、亚丁基；
所述用途是对抗脱发。
2.根据权利要求1所述的用途，其中所述式(I)的化合物局部地应用于头皮。
3.根据权利要求1所述的用途，其中所述式(I)的化合物是下式的N1-甲基亚精胺或N-(3-氨丙基)-N1-甲基-1,4-丁二胺：
(II) H2N–(CH2)3–N1(CH3)–(CH2)4–NH2。
4.根据权利要求1所述的用途，其中所述式(I)的化合物是下式的N1-环己基亚精胺或N-(3-氨丙基)-N1-环己基-1,4-丁二胺：
(III) H2N–(CH2)3–N1(C6H11)–(CH2)4–NH2。
5.根据权利要求1所述的用途，其中所述式(I)的化合物为下式的N1-乙基亚精胺或N-(3-氨丙基)-N1-乙基-1,4-丁二胺：
(IV) H2N–(CH2)3–N1(C2H5)–(CH2)4–NH2。
6.根据权利要求1所述的用途，其中所述式(I)的化合物是下式的N1-丙基亚精胺或N-(3-氨丙基)-N1-丙基-1,4-丁二胺：
(V) H2N–(CH2)3–N1(C3H7)–(CH2)4–NH2。
7.根据权利要求1所述的用途，其中所述式(I)的化合物是下式的N1-异丁基亚精胺或N-(3-氨丙基)-N1-异丁基-1,4-丁二胺：
(VI) H2N–(CH2)3–N1(C4H9)–(CH2)4–NH2。
8.根据权利要求1所述的用途，其中所述式(I)的化合物是以三盐酸盐的形式。
9.根据权利要求1所述的用途，其中所述式(I)的化合物是以与马来酸的盐的形式。
10.根据权利要求1所述的用途，所述用途是同时地通过刺激毛干的伸长的作用和延长生长阶段的作用来促进毛发的生理生长。
11.对抗脱发的药物或化妆品组合物，其中式(I)的化合物R-N1-亚精胺或1,4-丁二胺,N-(3-氨丙基)-N1-R
(I) H2N–(CH2)3–N1(R)–(CH2)4–NH2
其中R是结合到亚精胺的仲胺官能团的取代基，所述R选自：
-由1到6个碳原子组成的饱和的或不饱和的、直链或支链的烃基基团，其中任选地一个或更多个碳原子被氟取代，例如甲基、乙基、三氟甲基、三氟乙基、丙基、异丙基、丁基、异丁基、戊基、己基、亚乙基、乙烯基、亚丙基、亚丁基；
-芳基或芳烃基例如苯基、萘基、苄基、甲苯基，其中任选地一个或更多个碳原子被氟取代，且其中所述芳烃基包含由1到6个碳原子组成的饱和的或不饱和的、直链或支链的烃基基团，其中任选地一个或更多个碳原子被氟取代，例如甲基、乙基、三氟甲基、三氟乙基、丙基、异丙基、丁基、异丁基、戊基、己基、亚乙基、乙烯基、亚丙基、亚丁基；
-由3到8个碳原子组成的饱和的或不饱和的环烃基基团，所述环烃基基团任选地被由1到6个碳原子组成的饱和的或不饱和的、直链或支链的烃基基团取代，其中任选地一个或更多个碳原子被氟取代，例如甲基、乙基、三氟甲基、三氟乙基、丙基、异丙基、丁基、异丁基、戊基、己基、亚乙基、乙烯基、亚丙基、亚丁基；
或其药学上可接受的盐，
与适于在头皮上局部施用的赋形剂一起配制。
12.根据权利要求11所述的组合物，其中所述式(I)的化合物是下式的N1-甲基亚精胺或N-(3-氨丙基)-N1-甲基-1,4-丁二胺：
(II) H2N–(CH2)3–N1(CH3)–(CH2)4–NH2。
13.根据权利要求11所述的组合物，其中所述式(I)的化合物是下式的N1-环己基亚精胺或N-(3-氨丙基)-N1-环己基-1,4-丁二胺：
(III) H2N–(CH2)3–N1(C6H11)–(CH2)4–NH2。
14.根据权利要求11所述的组合物，其中所述式(I)的化合物是下式的乙基亚精胺或N-(3-氨丙基)-N1-乙基-1,4-丁二胺：
(IV) H2N–(CH2)3–N1(C2H5)–(CH2)4–NH2。
15.根据权利要求11所述的组合物，其中所述式(I)的化合物是下式的N1-丙基亚精胺或N-(3-氨丙基)-N1-丙基-1,4-丁二胺：
(V) H2N–(CH2)3–N1(C3H7)–(CH2)4–NH2。
16.根据权利要求11所述的组合物，其中所述式(I)的化合物是下式的N1-异丁基亚精胺或N-(3-氨丙基)-N1-异丁基-1,4-丁二胺：
(VI) H2N–(CH2)3–N1(C4H9)–(CH2)4–NH2。
17.根据权利要求11所述的组合物，其中所述式(I)的化合物以按重量计0.001％到0.30％之间的量存在。
18.下式的N1-异丁基亚精胺化合物，或N-(3-氨丙基)-N1-异丁基-1,4-丁二胺化合物：
(VI) H2N–(CH2)3–N1(C4H9)–(CH2)4–NH2。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI2012A001323 | 2012-07-27 | ||
| IT001323A ITMI20121323A1 (it) | 2012-07-27 | 2012-07-27 | Composizione farmaceutica o cosmeticaper il trattamento dell' alopecia |
| PCT/EP2013/065793 WO2014016407A1 (en) | 2012-07-27 | 2013-07-26 | Pharmaceutical or cosmetic composition for treating alopecia |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104582695A true CN104582695A (zh) | 2015-04-29 |
| CN104582695B CN104582695B (zh) | 2018-01-09 |
Family
ID=46982687
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201380039622.9A Active CN104582695B (zh) | 2012-07-27 | 2013-07-26 | 用于治疗秃发的药物或化妆品组合物 |
Country Status (22)
| Country | Link |
|---|---|
| US (1) | US9241888B2 (zh) |
| EP (1) | EP2877168B1 (zh) |
| JP (1) | JP2015522647A (zh) |
| CN (1) | CN104582695B (zh) |
| AU (1) | AU2013294973B2 (zh) |
| CA (1) | CA2880275C (zh) |
| CY (1) | CY1121551T1 (zh) |
| DK (1) | DK2877168T3 (zh) |
| ES (1) | ES2711133T3 (zh) |
| HR (1) | HRP20190318T1 (zh) |
| HU (1) | HUE041609T2 (zh) |
| IT (1) | ITMI20121323A1 (zh) |
| LT (1) | LT2877168T (zh) |
| MX (1) | MX349593B (zh) |
| PL (1) | PL2877168T3 (zh) |
| PT (1) | PT2877168T (zh) |
| RS (1) | RS58372B1 (zh) |
| RU (1) | RU2635627C2 (zh) |
| SI (1) | SI2877168T1 (zh) |
| SM (1) | SMT201900130T1 (zh) |
| TR (1) | TR201902440T4 (zh) |
| WO (1) | WO2014016407A1 (zh) |
Families Citing this family (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ITMI20130218A1 (it) * | 2013-02-18 | 2014-08-19 | Giuliani Spa | Composizione per uso cosmetico atta a produrre un effetto di pigmentazione dei capelli |
| GB2541137B (en) * | 2013-08-01 | 2017-11-29 | Liqwd Inc | Method and kits for treating hair |
| UA116148C2 (uk) * | 2013-08-01 | 2018-02-12 | Ліквд, Інк. | Способи відновлення волосся і шкіри |
| US9095518B2 (en) | 2013-08-01 | 2015-08-04 | Liqwd, Inc. | Methods for fixing hair and skin |
| US12233289B2 (en) | 2013-08-01 | 2025-02-25 | Olaplex, Inc. | Methods for fixing hair and skin |
| GB2533883B (en) * | 2013-08-01 | 2017-02-22 | Liqwd Inc | Methods and kits for coloring hair |
| DE202015104742U1 (de) | 2014-05-16 | 2015-10-08 | Liqwd, Inc. | Keratinbehandlungsformulierungen und Verwendungen derselben |
| KR102661331B1 (ko) | 2015-04-24 | 2024-04-30 | 올라플렉스, 인코포레이티드 | 릴렉싱된 헤어의 처리 방법 |
| KR20210082277A (ko) | 2015-05-01 | 2021-07-02 | 로레알 | 화학적 처리 중 활성제의 용도 |
| CN108139386A (zh) * | 2015-10-02 | 2018-06-08 | 株式会社特美解决方案 | 肿瘤的检测方法 |
| RU2771234C2 (ru) | 2015-11-24 | 2022-04-28 | Л'Ореаль | Композиции для обработки волос |
| US11213470B2 (en) | 2015-11-24 | 2022-01-04 | L'oreal | Compositions for treating the hair |
| WO2017091796A1 (en) | 2015-11-24 | 2017-06-01 | L'oreal | Compositions for treating the hair |
| US9872821B1 (en) | 2016-07-12 | 2018-01-23 | Liqwd, Inc. | Methods and formulations for curling hair |
| US9713583B1 (en) | 2016-07-12 | 2017-07-25 | Liqwd, Inc. | Methods and formulations for curling hair |
| US11135150B2 (en) | 2016-11-21 | 2021-10-05 | L'oreal | Compositions and methods for improving the quality of chemically treated hair |
| US9974725B1 (en) | 2017-05-24 | 2018-05-22 | L'oreal | Methods for treating chemically relaxed hair |
| IT201700089680A1 (it) | 2017-08-03 | 2019-02-03 | Giuliani Spa | Composizione sinergica come promoter di autofagia/a synergistic composition as a promoter of autophagy |
| ES2914404T3 (es) | 2017-12-29 | 2022-06-10 | Oreal | Composiciones para alterar el color del cabello |
| US11090249B2 (en) | 2018-10-31 | 2021-08-17 | L'oreal | Hair treatment compositions, methods, and kits for treating hair |
| US11419809B2 (en) | 2019-06-27 | 2022-08-23 | L'oreal | Hair treatment compositions and methods for treating hair |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999037277A1 (en) * | 1998-01-21 | 1999-07-29 | The Gillette Company | Reduction of hair growth |
| CN1620287A (zh) * | 2002-02-01 | 2005-05-25 | 朱利亚尼股份公司 | 防止脱发用药物或食疗用途组合物 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002062341A1 (en) * | 2001-02-07 | 2002-08-15 | University Of Florida | Method and composition for the control of hair growth |
| US20030036561A1 (en) * | 2001-08-10 | 2003-02-20 | Peter Styczynski | Reduction of hair growth |
| JP2004323480A (ja) * | 2003-04-28 | 2004-11-18 | Lion Corp | 育毛養毛剤 |
| JPWO2007148739A1 (ja) * | 2006-06-22 | 2009-11-19 | 東洋紡績株式会社 | 植物由来の細胞賦活化剤、抗老化剤及び細胞外マトリックス産生促進剤 |
-
2012
- 2012-07-27 IT IT001323A patent/ITMI20121323A1/it unknown
-
2013
- 2013-07-26 MX MX2015000900A patent/MX349593B/es active IP Right Grant
- 2013-07-26 EP EP13753286.7A patent/EP2877168B1/en active Active
- 2013-07-26 RU RU2015106730A patent/RU2635627C2/ru active
- 2013-07-26 RS RS20190211A patent/RS58372B1/sr unknown
- 2013-07-26 WO PCT/EP2013/065793 patent/WO2014016407A1/en active Application Filing
- 2013-07-26 TR TR2019/02440T patent/TR201902440T4/tr unknown
- 2013-07-26 HU HUE13753286A patent/HUE041609T2/hu unknown
- 2013-07-26 US US14/417,598 patent/US9241888B2/en active Active
- 2013-07-26 PT PT13753286T patent/PT2877168T/pt unknown
- 2013-07-26 HR HRP20190318TT patent/HRP20190318T1/hr unknown
- 2013-07-26 PL PL13753286T patent/PL2877168T3/pl unknown
- 2013-07-26 JP JP2015523565A patent/JP2015522647A/ja active Pending
- 2013-07-26 AU AU2013294973A patent/AU2013294973B2/en active Active
- 2013-07-26 DK DK13753286.7T patent/DK2877168T3/en active
- 2013-07-26 SM SM20190130T patent/SMT201900130T1/it unknown
- 2013-07-26 ES ES13753286T patent/ES2711133T3/es active Active
- 2013-07-26 LT LTEP13753286.7T patent/LT2877168T/lt unknown
- 2013-07-26 SI SI201331351T patent/SI2877168T1/sl unknown
- 2013-07-26 CA CA2880275A patent/CA2880275C/en active Active
- 2013-07-26 CN CN201380039622.9A patent/CN104582695B/zh active Active
-
2019
- 2019-02-21 CY CY20191100226T patent/CY1121551T1/el unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999037277A1 (en) * | 1998-01-21 | 1999-07-29 | The Gillette Company | Reduction of hair growth |
| CN1620287A (zh) * | 2002-02-01 | 2005-05-25 | 朱利亚尼股份公司 | 防止脱发用药物或食疗用途组合物 |
Non-Patent Citations (1)
| Title |
|---|
| CARL W. PORTER等: "BiologicalPropertiesof N4-and N1,N8-SpermidinDeerivativesin Cultured L1210 Leukemia Cells", 《CANCER RESEARCH》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| PT2877168T (pt) | 2019-02-25 |
| SI2877168T1 (sl) | 2019-03-29 |
| RU2635627C2 (ru) | 2017-11-14 |
| US20150202132A1 (en) | 2015-07-23 |
| PL2877168T3 (pl) | 2019-05-31 |
| RU2015106730A (ru) | 2016-09-20 |
| LT2877168T (lt) | 2019-02-11 |
| EP2877168B1 (en) | 2018-11-21 |
| MX349593B (es) | 2017-08-04 |
| CN104582695B (zh) | 2018-01-09 |
| CA2880275A1 (en) | 2014-01-30 |
| AU2013294973B2 (en) | 2017-08-03 |
| HUE041609T2 (hu) | 2019-05-28 |
| WO2014016407A1 (en) | 2014-01-30 |
| CA2880275C (en) | 2020-10-06 |
| MX2015000900A (es) | 2015-07-17 |
| TR201902440T4 (tr) | 2019-03-21 |
| RS58372B1 (sr) | 2019-03-29 |
| ITMI20121323A1 (it) | 2014-01-28 |
| HRP20190318T1 (hr) | 2019-04-19 |
| DK2877168T3 (en) | 2019-02-18 |
| ES2711133T3 (es) | 2019-04-30 |
| US9241888B2 (en) | 2016-01-26 |
| SMT201900130T1 (it) | 2019-05-10 |
| EP2877168A1 (en) | 2015-06-03 |
| AU2013294973A1 (en) | 2015-03-05 |
| JP2015522647A (ja) | 2015-08-06 |
| CY1121551T1 (el) | 2020-05-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104582695B (zh) | 用于治疗秃发的药物或化妆品组合物 | |
| CN108473432B (zh) | 使用硫代吡啶酮化合物脱色角蛋白材料的方法 | |
| CZ301910B6 (cs) | 2-Hydroxy-2-methyl-N-(4-substituovaný-3-(trifluormethyl)fenyl)-3-(perfluoracylamino)propionamid a jeho použití pro lécení androgenního vypadávání vlasu a/nebo holohlavosti a kosmetický nebo farmaceutický prípravek s jeho obsahem | |
| US6448285B1 (en) | Indolecarboxylic compounds and their use as pharmaceutical compounds | |
| JP6138251B2 (ja) | 新規なレソルシノール系化合物を使用してケラチン物質を脱色素する方法 | |
| JP3222846B2 (ja) | Ｎ−アリール−２−ヒドロキシアルキルアミドから誘導された新規化合物 | |
| JP2024532812A (ja) | 毛髪処置のための組成物、製剤および方法 | |
| CN101744740B (zh) | 使用二硫戊环化合物将角蛋白材料脱色素的化妆方法 | |
| US20070258921A1 (en) | Process for depigmenting the skin | |
| CN108368026B (zh) | 针对其化妆用途的间苯二酚衍生物 | |
| CN105408306B (zh) | 间苯二酚衍生物及其化妆应用 | |
| FR3067027B1 (fr) | Derives de resorcinol pour leur utilisation cosmetique | |
| CN111527086A (zh) | 用于其美容用途的二硫杂氮杂环辛烷化合物 | |
| WO2023151292A1 (zh) | 作为透明质酸酶抑制剂的3α-齐墩果酸衍生物及其在美容产品中的应用 | |
| TWI465272B (zh) | 用於美白皮膚的組合物、植物萃取美白組合物與具有美白功能之組合物 | |
| JP2004331664A (ja) | ピリミジン−ｎ−オキシド誘導体を含有する毛髪用組成物、ケラチン繊維の成長を刺激し及び／又は抜毛を減少させるためのその使用 | |
| US20040162328A1 (en) | Compounds of the family of 3-alkyl-(4,5-diphenyl-imidazol-1-yl) and their use as soothing agents | |
| WO2019063710A1 (en) | COSMETIC USE OF RESORCINOL DERIVATIVES | |
| US7326717B2 (en) | Pyrimidine n-oxide compounds for stimulating the growth of keratin fibers and/or reducing loss thereof | |
| WO1995027474A1 (fr) | Preparation dermatologique | |
| KR100643511B1 (ko) | 히드록삼산 유도체 및 이의 제조방법 | |
| US20040192928A1 (en) | Novel compounds of the family of 3-alkyl-(4,5-diphenyl-imidazol-1-yl) and their use as soothing agents | |
| WO2024123668A1 (en) | Compositions, formulations, and methods for hair treatment |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |