NZ620487B2 - Alkylamidothiazoles, cosmetic or dermatological preparations containing said alkylamidothiazoles, and use thereof to combat or prevent undesired pigmentation of the skin - Google Patents
Alkylamidothiazoles, cosmetic or dermatological preparations containing said alkylamidothiazoles, and use thereof to combat or prevent undesired pigmentation of the skin Download PDFInfo
- Publication number
- NZ620487B2 NZ620487B2 NZ620487A NZ62048712A NZ620487B2 NZ 620487 B2 NZ620487 B2 NZ 620487B2 NZ 620487 A NZ620487 A NZ 620487A NZ 62048712 A NZ62048712 A NZ 62048712A NZ 620487 B2 NZ620487 B2 NZ 620487B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- thiazol
- dihydroxyphenyl
- alkylamidothiazoles
- cosmetic
- skin
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 206010062080 Pigmentation disease Diseases 0.000 title claims abstract description 23
- 239000002537 cosmetic Substances 0.000 title claims abstract description 15
- 210000003491 Skin Anatomy 0.000 title description 18
- 230000019612 pigmentation Effects 0.000 title description 13
- -1 N-(4-(2,4-Dihydroxyphenyl)thiazol-2-yl)isobutyramide N-(4-(2,4-dihydroxyphenyl)thiazol-2-yl)-4-(hydroxyl-methyl)cyclohexanecarboxamide N-(4-(2,4-dihydroxyphenyl)thiazol-2-yl)cyclohexane carboxamide Chemical compound 0.000 claims abstract description 17
- 230000000069 prophylaxis Effects 0.000 claims abstract description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
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- WFKAJVHLWXSISD-UHFFFAOYSA-N Isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 claims description 6
- 229940047889 isobutyramide Drugs 0.000 claims description 6
- AEDIXYWIVPYNBI-UHFFFAOYSA-N Heptanamide Chemical compound CCCCCCC(N)=O AEDIXYWIVPYNBI-UHFFFAOYSA-N 0.000 claims description 5
- XIPFMBOWZXULIA-UHFFFAOYSA-N Pivalamide Chemical compound CC(C)(C)C(N)=O XIPFMBOWZXULIA-UHFFFAOYSA-N 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- DNSISZSEWVHGLH-UHFFFAOYSA-N Butyramide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 claims description 4
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- 238000004519 manufacturing process Methods 0.000 claims description 2
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- IJIKGGBUMWIDCG-UHFFFAOYSA-N N-[4-(2,4-dihydroxyphenyl)-1,3-thiazol-2-yl]-2-[4-(hydroxymethyl)phenyl]acetamide Chemical compound C1=CC(CO)=CC=C1CC(=O)NC1=NC(C=2C(=CC(O)=CC=2)O)=CS1 IJIKGGBUMWIDCG-UHFFFAOYSA-N 0.000 abstract 2
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- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
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- PNZXMIKHJXIPEK-UHFFFAOYSA-N cyclohexanecarboxamide Chemical compound NC(=O)C1CCCCC1 PNZXMIKHJXIPEK-UHFFFAOYSA-N 0.000 description 3
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- IPCRBOOJBPETMF-UHFFFAOYSA-N N-carbamothioylacetamide Chemical compound CC(=O)NC(N)=S IPCRBOOJBPETMF-UHFFFAOYSA-N 0.000 description 1
- JHPAWUKVLIURBU-UHFFFAOYSA-N N-carbamothioylbutanamide Chemical compound CCCC(=O)NC(N)=S JHPAWUKVLIURBU-UHFFFAOYSA-N 0.000 description 1
- QBXDTNRTUPZXCO-UHFFFAOYSA-N N-carbamothioylcyclohexanecarboxamide Chemical compound NC(=S)NC(=O)C1CCCCC1 QBXDTNRTUPZXCO-UHFFFAOYSA-N 0.000 description 1
- IVFFBAJIIJDPJY-UHFFFAOYSA-N NCCC(Nc1nc(-c(c(O)c2)ccc2O)c[s]1)=O Chemical compound NCCC(Nc1nc(-c(c(O)c2)ccc2O)c[s]1)=O IVFFBAJIIJDPJY-UHFFFAOYSA-N 0.000 description 1
- IQSBHUULUCUDJH-UHFFFAOYSA-N OCCC(Nc1nc(-c(c(O)c2)ccc2O)c[s]1)=O Chemical compound OCCC(Nc1nc(-c(c(O)c2)ccc2O)c[s]1)=O IQSBHUULUCUDJH-UHFFFAOYSA-N 0.000 description 1
- 229940120511 OLEYL ERUCATE Drugs 0.000 description 1
- 210000003463 Organelles Anatomy 0.000 description 1
- 102000032738 PAR-2 Receptor Human genes 0.000 description 1
- 108010070503 PAR-2 Receptor Proteins 0.000 description 1
- 208000001818 Pseudofolliculitis Barbae Diseases 0.000 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N Retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- 206010040829 Skin discolouration Diseases 0.000 description 1
- 206010040844 Skin exfoliation Diseases 0.000 description 1
- 206010042496 Sunburn Diseases 0.000 description 1
- 229940035295 Ting Drugs 0.000 description 1
- 229960001727 Tretinoin Drugs 0.000 description 1
- 102000031061 Tyrosine 3-monooxygenases Human genes 0.000 description 1
- 108091000118 Tyrosine 3-monooxygenases Proteins 0.000 description 1
- BZUVPTAFNJMPEZ-XPWSMXQVSA-N [(E)-docos-13-enyl] (E)-docos-13-enoate Chemical compound CCCCCCCC\C=C\CCCCCCCCCCCCOC(=O)CCCCCCCCCCC\C=C\CCCCCCCC BZUVPTAFNJMPEZ-XPWSMXQVSA-N 0.000 description 1
- SZAMSYKZCSDVBH-CLFAGFIQSA-N [(Z)-octadec-9-enyl] (Z)-docos-13-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCCCCCC(=O)OCCCCCCCC\C=C/CCCCCCCC SZAMSYKZCSDVBH-CLFAGFIQSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 125000005213 alkyl heteroaryl group Chemical group 0.000 description 1
- 125000005189 alkyl hydroxy group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000000149 argon plasma sintering Methods 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 125000004429 atoms Chemical group 0.000 description 1
- 210000000270 basal cell Anatomy 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- 239000001273 butane Substances 0.000 description 1
- ULBTUVJTXULMLP-UHFFFAOYSA-N butyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCCC ULBTUVJTXULMLP-UHFFFAOYSA-N 0.000 description 1
- PUPZLCDOIYMWBV-UHFFFAOYSA-N butylene glycol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000001684 chronic Effects 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 229960005188 collagen Drugs 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 210000000736 corneocyte Anatomy 0.000 description 1
- 230000000875 corresponding Effects 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- RVOJTCZRIKWHDX-UHFFFAOYSA-N cyclohexanecarbonyl chloride Chemical compound ClC(=O)C1CCCCC1 RVOJTCZRIKWHDX-UHFFFAOYSA-N 0.000 description 1
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 1
- 235000004132 ellagic acid Nutrition 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 230000002255 enzymatic Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 239000010696 ester oil Substances 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 150000002215 flavonoids Chemical class 0.000 description 1
- 229930003935 flavonoids Natural products 0.000 description 1
- 235000017173 flavonoids Nutrition 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000002068 genetic Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 230000036074 healthy skin Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000001245 hexylamino group Chemical group [H]N([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 230000003425 hypopigmentation Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 230000002427 irreversible Effects 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- VQTUBCCKSQIDNK-UHFFFAOYSA-N isobutene Chemical compound CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 description 1
- 229940119170 jojoba wax Drugs 0.000 description 1
- 229960004705 kojic acid Drugs 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000003061 melanogenesis Effects 0.000 description 1
- UAVOCTDYPKOULU-UHFFFAOYSA-N methylchloranuidyl formate Chemical compound C[Cl-]OC=O UAVOCTDYPKOULU-UHFFFAOYSA-N 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 239000012184 mineral wax Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- TUNFSRHWOTWDNC-UHFFFAOYSA-M myristate Chemical compound CCCCCCCCCCCCCC([O-])=O TUNFSRHWOTWDNC-UHFFFAOYSA-M 0.000 description 1
- 150000002825 nitriles Chemical group 0.000 description 1
- YDPSQMGOAILWPE-UHFFFAOYSA-N octadec-2-enedioic acid Chemical compound OC(=O)CCCCCCCCCCCCCCC=CC(O)=O YDPSQMGOAILWPE-UHFFFAOYSA-N 0.000 description 1
- 229960002446 octanoic acid Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-M oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC([O-])=O ZQPPMHVWECSIRJ-KTKRTIGZSA-M 0.000 description 1
- BARWIPMJPCRCTP-CLFAGFIQSA-N oleyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCCOC(=O)CCCCCCC\C=C/CCCCCCCC BARWIPMJPCRCTP-CLFAGFIQSA-N 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M palmitate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 1
- PZQSQRCNMZGWFT-QXMHVHEDSA-N propan-2-yl (Z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC(C)C PZQSQRCNMZGWFT-QXMHVHEDSA-N 0.000 description 1
- ZPWFUIUNWDIYCJ-UHFFFAOYSA-N propan-2-yl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC(C)C ZPWFUIUNWDIYCJ-UHFFFAOYSA-N 0.000 description 1
- VZCGEDTVPJTYHY-UHFFFAOYSA-N propanamide Chemical compound CCC(N)=O.CCC(N)=O VZCGEDTVPJTYHY-UHFFFAOYSA-N 0.000 description 1
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 201000004681 psoriasis Diseases 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-M stearate Chemical compound CCCCCCCCCCCCCCCCCC([O-])=O QIQXTHQIDYTFRH-UHFFFAOYSA-M 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 210000000438 stratum basale Anatomy 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 150000007979 thiazole derivatives Chemical class 0.000 description 1
- 230000002110 toxicologic Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 229960000401 tranexamic acid Drugs 0.000 description 1
- 102000003995 transcription factors Human genes 0.000 description 1
- 108090000464 transcription factors Proteins 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 230000029663 wound healing Effects 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
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
-
- 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
- A61P17/16—Emollients or protectives, e.g. against radiation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
- C07D277/38—Nitrogen atoms
- C07D277/44—Acylated amino or imino radicals
- C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
- C07D277/38—Nitrogen atoms
- C07D277/44—Acylated amino or imino radicals
- C07D277/48—Acylated amino or imino radicals by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines
Abstract
The disclosure relates to alkylamidothiazoles of the formula (I), wherein X, Y, R1 and R2 are as defined in the specification. The disclose also relates to cosmetic or dermatological preparations having an effective content of one or more alkylamidothiazoles, as well as the use thereof for the cosmetic or dermatological treatment and/or prophylaxis of undesired skin pigmentation. Example compounds include: N-(4-(2,4-Dihydroxyphenyl)thiazol-2-yl)isobutyramide N-(4-(2,4-dihydroxyphenyl)thiazol-2-yl)-4-(hydroxyl-methyl)cyclohexanecarboxamide N-(4-(2,4-dihydroxyphenyl)thiazol-2-yl)cyclohexane carboxamide N-(4-(2,4-dihydroxyphenyl)thiazol-2-yl)-2-(4-(hydroxymethyl)phenyl)acetamide 4-(2-isopropylamino)thiazol-4-yl)benzene-1,3-diol tic or dermatological treatment and/or prophylaxis of undesired skin pigmentation. Example compounds include: N-(4-(2,4-Dihydroxyphenyl)thiazol-2-yl)isobutyramide N-(4-(2,4-dihydroxyphenyl)thiazol-2-yl)-4-(hydroxyl-methyl)cyclohexanecarboxamide N-(4-(2,4-dihydroxyphenyl)thiazol-2-yl)cyclohexane carboxamide N-(4-(2,4-dihydroxyphenyl)thiazol-2-yl)-2-(4-(hydroxymethyl)phenyl)acetamide 4-(2-isopropylamino)thiazol-4-yl)benzene-1,3-diol
Description
/068362
Description
ALKYLAMIDOTHIAZOLES, COSMETIC OR DERMATOLOGICAL
PREPARATIONS CONTAINING SAID ALKYLAMIDOTHIAZOLES, AND
USE F TO COMBAT OR PREVENT UNDESIRED PIGMENTATION
OF THE SKIN
The present invention relates to new
alkylamidothiazoles, to cosmetic or dermatological
preparations with a content of one or more such
alkylamidothiazoles and to the use of such
alkylamidothiazoles or preparations comprising such
alkylamidothiazoles for combating or ting
undesired pigmentation of the skin.
Melanocytes are responsible for the pigmenting of the
skin; these are found in the lowest layer of the
epidermis, the Stratum basale, alongside the basal
cells as pigment—forming cells which, depending on the
skin type, occur either individually or in rs of
varying size.
Melanocytes contain, as characteristic cell organelles,
somes, in which the melanin is formed.
Inter alia, upon stimulation by UV radiation, melanin
is formed to a greater extent. This is transported via
the living layers of the epidermis (keratinocytes)
ultimately into the horny layer (corneocytes) and
brings about a more or less pronounced brownish to
brown-black skin color.
Melanin is formed as the end stage of an ive
process in which tyrosine is converted, under the
co~action of the enzyme tyrosinase, via several
intermediates, to the brown to brown—black eumelanins
(DHICA and DHI n), or, with the participation of
sulfur—containing compounds, to the reddish
pheomelanin. DHICA and DHI melanin are formed via the
_ 2 _
common intermediates dopaquinone and dopachrome. The
latter, sometimes with the participation of further
enzymes, is converted either to indol—5,6—
ecarboxylic acid or into 5,6—quinone, from
which the two specified eumelanins are formed.
The formation of pheomelanin proceeds inter alia via
the ediates dopaquinone and cysteinyldopa. The
expression of the melanin—synthesizing enzymes is
controlled by a specific transcription factor
(microphthalmia—associated transcription factor, MITF).
Besides the described enzymatic processes of the
melanin synthesis, further proteins are also of
ance for the melanogenesis in the melanosomes. An
important role here appears to be attributed to the
so~called p—protein, although the exact function is
still unclear.
As well as the above—described s of the melanin
synthesis in the cytes, the transfer of the
melanosomes, their stay in the mis and also their
degradation and the degradation of the melanin are also
of decisive importance for the pigmenting of the skin.
It was shown that the PAR-2 receptor is important for
the transport of the melanosomes from the melanocytes
into the keratinocytes (M. Seiberg et al., 2000, J.
Cell. Sci., ll3:3093~101).
In addition, size and shape of the somes have an
influence on their light—scattering properties and thus
the color appearance of the skin. For example, in black
Africans there are more large spheroidal individual
melanosomes, whereas in Caucasians, smaller melanosomes
occurring in groups are to be found.
Problems with hyperpigmentation of the skin have a wide
variety of causes and/or are accompanied phenomena of
many ical processes, e.g. UV radiation (e.g.
PCT/E92012/068362
_ 3 _
freckles, Ephelides), Genetic disposition, incorrect
pigmentation of the skin during wound healing or
scarring (post—inflammatory hyperpigmentation) or skin
aging (e.g. Lentigines seniles).
After matory reactions, the pigmentation system
of the skin reacts with sometimes te reactions.
This can lead either to nflammatory
igmentations or hypopigmentations. Post—
inflammatory hypomelanoses often arise inter alia in
conjunction with atopy, Lupus erythematosus and
,w-mm psoriasis. The different reaction forms of the
pigmentation system of the human skin as a result of
inflammatory phenomena are understood only very
incompletely.
Problems with post—inflammatory hyperpigmentation often
occur in darker skin types. ularly in d
males, the problem of Pseudofollikulitis barbae is
known, which is associated with cosmetically undesired
incorrect pigmentation and/or leads to this. Forms of
melasma, which occur in particular in women of Asiatic
origin on the face and on the décolletage area, and
also various forms of irregular pigmentation of the
skin are also types of post—inflammatory
hyperpigmentations. In addition, dark s around
the eyes are also considered to be a form of post—
inflammatory igmentations, the underlying
inflammation in most cases proceeding without clinical
manifestations.
In many cases, post—inflammatory incorrect pigmentation
of this type is increased further by the action of
sunlight (UV light) without resulting in a UV—induced
inflammation (sunburn).
Active ingredients and preparations are known which
counteract skin pigmentation. In practical use these
_ 4 _
are essentially ations based on hydroquinone,
although, on the one hand, these only exhibit their
effect after application for several weeks, and, on the
other hand, their excessively long application is
unacceptable for toxicological reasons. Albert Kligman
et al. has developed a led “triformula” which
constitutes a combination of 0.1% tretinoin, 5.0%
hydroquinone, 0.1% dexamethasone (A. Kligman, 1975,
Arch. Dermatol., 111:40—48). r, this formulation
too is highly disputed on account of possible
irreversible changes in the pigmentation system of the
skin.
In addition, skin—peeling s (chemical and
mechanical “peels”) are used, although these often lead
to inflammatory reactions and, on account of post—
inflammatory hyperpigmentations which may subsequently
arise, can even lead to greater pigmentation d of
reduced pigmentation. All of these customary methods,
which are also used for treating post~inflammatory
hyperpigmentations, are characterized by distinct side
effects.
Furthermore, s other substances are known for
which a skin—lightening effectiveness is described.
Mention is to be made here inter alia of hexadecene—
1,16—dicarboxylic acid, kojic acid and derivatives,
arbutin, ascorbic acid and derivatives, flavonoids,
ellagic acid and derivatives, tranexamic acid and
various resorcinol derivatives, such as e.g. 4—n—
butylresorcinol, 4—n—hexylresorcinol and 4—(1—
ethyl)benzene—l,3—diol.
J.M. Ready describes in a publication (Bioorganic &
Medicinal try Letter 17 (2007) 6871-6875 the
effect of inter alia substituted thiazole derivatives
for the inhibition of mushroom tyrosinase.
The patent application from Shiseido () describes
substituted thiazolamines and hydrothiazolamines for lightening
skin.
The substances described in the aforementioned prior art show a
moderate effectiveness and/or a poor cal ity.
Rings around the eyes can se be formed as a result of a
pigmentation disorder, with them in addition also appearing as a
reaction to general , such as e.g. too little sleep or
simply as a result of overexerting the eyes. In younger people,
the symptoms disappear again after an adequate nighttime rest,
but, over prolonged periods, the condition can become chronic
and very esome for those affected. There is also a lack of
sufficiently ing active ingredients and treatment s
to combat such skin phenomena.
It is an object of the present invention to overcome or
ameliorate at least one of the disadvantages of the prior art,
or to provide a useful alternative.
It was therefore an aim of a preferred embodiment of the
invention. below to provide a remedy‘ for the disadvantageous
prior art.
Any discussion of the prior art throughout the specification
should in no way be considered as an admission that such prior
art is widely known or forms part of common general knowledge in
the field.
According to a first aspect, the present invention. provides
alkylamidothiazole having any one of the following structures:
HO OH
N—(4—(2,4—dihydroxyphenyl)thiazol—2~yl)pivalamide
HO OH
N—(4w(2,4—dihydroxyphenyl)thiazol—z—yl)isobutyramide
HO OH
\ \mf/O\/\
N—(4—(2,4—dihydroxyphenyl)thiazol—2—yl)butyramide
HO OH
._.—O
\ °\/\/\/
N;(4—(2,4—dihydroxyphenyl)thiazol—Z—yl)heptanamide
—5b-
HO 0H
N;(4—(2,4-dihydroxyphenyl)thiazol—Z—yl)hydroxyhexanamide
| \>¥~H
0 0H
N-(4—(2,4—dihydroxyphenyl)thiazol-Z-yl)hydroxypropanamide
g \>_NH
o o———
2,4-dihydroxyphenyl)thiazol—Z—yl)methoxyacetami§e
; \>_~H
0 MHz
N—(4-(2,4—dihydroxyphenyl)thiazol—Z—yl)propanimide
HO OH
\>’~<C’CHa
S /
N—(4—(2,4—dihydroxyphenyl)thiazol-2~yl)acetamide
N- (4 -(2, ydroxyphenyl)thiazol- 2-WylI:\>_:H4-m:
(hydroxymethyl)cyclohexanecarboxamide
HO OH
N~(4—(2,4—dihydroxyphenyl)thiazol—Z—
yl)cyclohexanecarboxamide
OH OH
-Sd-
N-(4—(2,4—dihydroxyphenyl)thiazol—Z—yl)—2—(4—
hydroxymethyl)phenyl)acetamide.
According to a second. aspect, the present invention. provides
cosmetic or dermatological preparations with a content of one or
more alkylamidothiazoles as defined in the first .
According to a third aspect, the present ion provides use
of one or more alkylamidothiazoles defined in the first aspect,
or preparations containing one or more such alkylamidothiazoles
in the manufacture of a ment for the cosmetic or
dermatological treatment and/or" laxis of undesired. skin
pigmentation.
Also described herein are alkylamidothiazoles of the general
formula
N 0
YflT/fl\w/
in which
_ 6 _
R1, R2, X and Y can be different, partly identical or
completely identical and, ndently of one another,
can mean:
R1 = ~C1~Cu—alkyl (linear and branched), ~C1~Cfl—alkenyl
(linear and branched), -cycloalkyl, —C1-C3-
cycloalkyl—alkylhydroxy, —C1—CM-alkylhydroxy (linear
and branched), —C1—CM alkylamine (linear and ed),
—alkylaryl (linear and branched), ~Cl—CN-
alkylaryl~alkyl~hydroxy (linear and branched), ~C1uCMm
alkylheteroaryl (linear and branched), ~C1—Cg—alkyle0~
alkyl (linear and branched), —C1—CM alky—
morpholino, —C1—CM alky—piperidino, -C1-CM alky—
piperazino, —C1—CM alky—piperazino—N—alkyl,
R2 = H, -C1—CM-alkyl r and branched), —C1—CM—
alkenyl r~ and. branched), —C1—C3—cycloalkyl, —C1~
Cu—hydroxyalkyl (linear and branched), —C1~Cu~alkylaryl
(linear and branched), —C1-CN-alkylheteroaryl (linear
and branched),
X = —H, —C1—CM—alkyl (linear and branched), —C1*Cu—
alkenyl (linear and, branched), —C1—C8-cycloalkyl, ~C1—
Cu—aryl (optionally mono— or bstituted with —OH,
-F, «Cl, ~Br, -1, ~OMe, —NH2, —CN), —C1—Cu—heteroaryl
(optionally monOe or polysubstituted with —OH, —F, —Cl,
-Br, —I, —OMe, —NHZ, —CN), —C1—CM—alkylaryl (linear and
branched), —C1—C“—alkylheteroaryl (linear and
branched), —aryl (optionally mono— or polysubstituted
3O with -OH, —F, -Cl, -Br, ~I, —0Me, -NH2, -CN), —phenyl,
—2,4—dihydroxyphenyl, —2,3—dihydroxyphenyl, —2,4~
dimethoxyphenyl, w~2,3~-dimethoxyphenyl,
Y = H, —C1—Cm~alkyl (linear and branched), —C1—Cm—
alkenyl (linear and, branched), —C1—C3—cycloalkyl, —C1—
Cu—aryl, heteroaryl, —alkylaryl (linear
and branched), ~C1—CM—alkylheteroaryl (linear and
branched), —aryl, -phenyl, —2,4—dihydroxyphenyl, -2,3-
dihydroxyphenyl, —2,4~dimethoxyphenyl, —2,3—dimethoxyphenyl,
~COO—alkyl, —COO—alkenyl, ~COO-cycloalkyl, —COO—aryl, —COO~
heteroaryl;
and X, Y can optionally also mean = condensed aromatic,
where X and Y can form with one another aromatic or aliphatic
homo- or heterocyclic ring systems with up to 11 ring—forming
atoms, and where the number n can assume values from 5 to 8, and
the respective ring s can in turn be substituted with up
to n—l alkyl groups, hydroxyl groups, carboxyl groups, amino
groups, nitrile functions, sulfur—containing substituents, ester
groups and/or ether groups.
Said thiazoles can either be in the form of the free base or the
salt: e.g. fluoride, chloride, bromide, iodide, sulfate,
carbonate, ascorbate, acetate or phosphate. In particular in the
form of halogen salts, such as e.g. chloride and bromide.
rmore, there is an ageous ation of the present
invention in a second aspect to provide cosmetic or
dermatological preparations with an effective content of one or
more entioned alkylamidothiazoles of the invention.
Also in a third aspect in accordance with the invention is the
use of the aforementioned midothiazoles of the invention
for the treatment and/or prophylaxis of undesired skin
pigmentation.
Here, treatment and/or prophylaxis of undesired skin
pigmentation can be both. in the cosmetic sphere and in the
pharmaceutical sphere.
In this connection, the pharmaceutical (or ological)
treatment is primarily understood for diseased skin conditions,
whereas the cosmetic treatment and/or laxis of undesired
skin pigmentation primarily relates to healthy skin.
Unless the context y requires ise, throughout the
description and the claims, the words “comprise”, “comprising”,
and the like are to be construed in an inclusive sense as
opposed to an exclusive or exhaustive sense; that is to say, in
the sense of “including, but not limited to”.
Advantageously, X is selected from the group of substituted
phenyls, in which case the substituents (Z) can be selected from
the group —H, —OH, —F, —Cl, -Br, —I, -OMe, —NH2, -CN, acetyl and
can be identical or different.
"Ni,
Particularly‘ advantageously; X is ed. from the group of
phenyl groups substituted with one or more hydroxyl groups, in
which case the substituent (Z) can be selected from the group -
H, —OH, —F, —Cl, —Br, —I, ~0Me, ~NH2, —CN, acetyl, and
preference is given to the following generic structure in which
Y, R} and R? can have the properties defined above.
HO 2
Particularly ageous compounds are those in which
‘vy.
_. 9 _
H0 2
Y = H
R1 = 4—alkyl (linear and branched), —C1—C24—alkenyl
(linear and ed), —C1—C3—cycloalkyl, —C1—C8—
cycloalkyl—alkylhydroxy, —C1—C24 alkylhydroxy (linear
and branched), -C1—C24 alkylamine (linear and branched),
-C1—C24-alkylaryl (linear and branched), ”Cl-‘Cgr‘
alkylaryl—alkyl—hydroxy (linear and branched), 4—
alkylheteroaryl (linear and branched), "C1-C24—alkyl—O—
C1—C24—alkyl (linear and branched) , —C1—~C24—alky-
morpholino, —Cl—C24 alky—piperidino, —C1——C24 alky—
zino, —C1—C24 al ky—piperazino—N—al kyl
R2 = H, —C1—C24—alkyl (linear and branched),
Z = —H, -O§-I, —F, —Cl, —Br, ~I, —OMe, ~NH2, -CN, acetyl.
Particular preference is given to those compounds in
which
HO OH
X n
Y = 8
R1 = —C1—C24—alkyl (linear and ed), —C1—C24—alkenyl
(linear and ed) , —C1—C3-cycloalkyl, ~C1—Cg—
cycloalkyl—alkylhydroxy, —C1—C24-alkylhydroxy (linear
_ 10 w
and branched), —C1~CM mine (linear and branched),
—alkylaryl (linear and branched), ~C1—Cu—alkyl—
aryl—alkyl—hydroxy (linear and branched), —C1-C“—
alkylheteroaryl (linear and branched), ~C1—CM-alkyl—O~
C1—Cu~alkyl (linear and branched), ~Cl-CM alkymorpholino
, —C1—CN alky-piperidino, wC1—C24 alky~
piperazino, —C1—CM alky-piperazino—N—alkyl,
R2=H.
The compounds
HO OH
N-(4-(2,4-dihydroxyphenyl)thiazol-2—y])pivalamide
HO OH
N~(4-(2,4-dihydroxyphenyl)thiazol—2—yl)isobutyramide
WO 41526
\ N\>\T/l!\/\
N—(4~(2,4-dihydroxypheny1)thiazoI-2—yl)butyramide
HO OH
N-(4-(2,4-dihydroxyphenyl)thiazoiyl)heptanamide
HO OH
/C\/\/\/OH
N-(4-(2,4-dihydroxyphenyl)thiazolyl)hydroxyhexauamide
WO 41526
_ 12 _
l \H
O OH
N~(4—(2,4-dihydroxypheny])thiazol-2—y1)«3—hydroxypropanamide
I >—
oh
N—(4—(2,4—di11yd1‘oxyphenyl)thiazol-2—yl)—2-methoxyacetamide
0 NH2
3-amino-N-(4-(2,4-dihydroxyphenyl)thiazol-Z-y1)propanamide
._ 13 _
HO OH
\ \>—-’NH\c/CH3
S 0//
N-(4~(2,4-dihydroxyphenyI)thiazol~2-yDacetamide
,:\>_NH 0H
2,4-dfi1ydroxypheny1)thiazolyI)(hydroxymethyi)cyc10hexanecarboxamide
HO OH
N-(4—(2,4—dihydroxyphenyl)thiazolyl)cyclohexanecarboxamide
_ 14 -
OH OH
l \>,NH
N-(4-(2,4-dihydroxyphenyl)111ia201—2-y1)(4-(hydroxymefl)yl)phenyl)acetamide
are red according to the invention.
Surprisingly, it was able to be shown that the
alkylamidothiazoles according to the invention have a
higher galenical stability and/or increased
effectiveness compared to the corresponding
alkylaminothiazoles.
See Table l and Table 2.
Method description of the stability investigations:
For the purposes of incorporation into the
ations, the amines and amides were dissolved in
butylene glycol ~ optionally with heating - and added
to the emulsion before the first homogenization at ca.
65°C. All of the active ingredients were incorporated
in a concentration of 0.1% in the experimental batches.
The emulsion was poured into 20 ml glass vials for the
storage tests and stored under various standard
conditions (room temperature, light and 40°C).
For the stability investigations, the stored s
were analyzed after 14 days.
_ 15 _
Analysis/recovery:
The samples to be measured were extracted in a
methanol/water mixture [70:30] and determined by means
of HPLC—DAD. The determination was carried out by means
of external standard calibration ence section].
The evaluation was carried out at 296 nm.
Instrument:
HPLC: Agilent 1100
Column: Phenomenex Synergi , 50 x 2 mm i.d.
[2.5 um]
Solvent: nt acetonitrile/water with 0.1%
phosphoric acid
Flow rate: 0.3 ml/min
Gradient: Time [min] H20 [%] MeCN {%]
0.1% H3904
0.0 90.0 10.0
.0 10.0 90.0
12.0 10.0 90.0
13.0 90.0 10.0
.0 90.0 10.0
Injection volume: 3 ul
The raw materials used in each case served as
reference.
WO 41526 2012/068362
i 16 i
Table 1:
Formula 1 — with
N—(4—(2,4—dihydroxyphenyl)thiazolw
2~yl)isobutyramide
Formula 2 — with
4—(2—isopropylamino)thiazol~4~
yl)benzene-l,3—diol
Formula 3 — with
4—(2—(tert—butylamino)thiazol
yl)benzene~1,3~diol
Formula 4 — with
N—(4—(2,4~dihydroxyphenyl)thiazol—
2—yl)pivalamide
Formula 5 — with
N—(4—(2,4—dihydroxyphenyl)thiazol-
2~yl)butyramide
Formula 6 — with
4—(2—propy1amino)thiazol—4-
yl)benzene—l,3—diol
Formula 7 — with
N—(4—(2,4—dihydroxyphenyl)thiazol—
2—yl)cyclohexanecarboxamide
Formula 8 — with
cyclohexylamino)thiazol—4-
yl)benzene—l,3—diol
Formula 9 — with
N—(4—(2,4—dihydroxyphenyl)thiazol—
2—yl)heptanamide
Formula 10 — with
4—(2—(hexylamino)thiazol—4—
yl)benzene—l,3~diol
_ 17 a
Method descriEtion of the effectiveness igations:
The iveness of the thiazoles was trated
using an enzyme test in which conversion of L—DOPA to
L—dopaquinone by a Inuman tyrosinase was measured. In
this literature—known method (Winder, A.J. and Harris,
H., New assays for the tyrosine hydroxylase and dopa
oxidase activities of nase. Eur. J. Biochem.
(1991), 198, 317—26), the reaction product
L—dopaquinone is reacted with MBTH (3—methyl—2—
benzothiazoline hydrazone) to give a pink—colored
substance, the increase of which is measured over the
time by absorption at 490 nm. Table 1 shows by way of
example the effectiveness data for some of the claimed
substances. It can be concluded from this that the
substances according to the invention are extremely
effective pigmentation—inhibiting substances.
_ 18 _
Table 2: Inhibition of the tyrosinase activity by
thiazoles
Substance Inhibition Concentra
(% of the —tion
control)
N—(4— (2 4Dihydroxyphenyl))thiazol—
2--yl)isobutyramide) "-
—~—-yl)()benzene-l,3~diol
——-2—
-—-Uyl heptanamide)
_~"—-yl)(benzene 1, 3—diolyl)()benzene—1,3—diol
—_g—-2—Vylpivalamide
:—yl)butyramide2—
):)benzene—l,3—~diol
2—4yl) cyclohexanecarboxamide
yl)(benzene— l, 3—diol
N— (4— 2, ydroxyphenyl))thiazol— 10 ug/ml
2—yl)—4 ~(hydroxymethyl)~
cyclohexanecarboxamide
(4—(Hydroxymethyl)phenyl)w 10 ug/ml
amino)thiazol—4—yl)benzene~1,3~
diol
N—(4—(2,4~Dihydroxyphenyl)thiazol— 10 ug/ml
2~yl)—2—(4—(hydroxymethyl)—
phenyl)acetamide
2012/068362
_ 19 i
S nthesis rocedures of alk lamidothiazoles selected b
way of example:
2~Bromo—2’,4’—bismethox carbon lox aceto henone:
Hour quam. Br2 PGO OPG
THF CHCI W
70 %
PG— COOCH3
Mitchell, David; Doecke, Christopher W.; Hay, Lynne A.;
Koenig, Thomas M.; Wirth, David D. Tetrahedron Letters,
1995
A solution of 60 g (369 mmol) of 2,4-dihydroxy—
acetophenone and 186 ml of triethylamine in 900 ml of
tetrahydrofuran was cooled to 0°C, and 93 ml of methyl
chloroformate in 400 ml of tetrahydrofuran was slowly
added drOpwise. 11 white precipitate is formed. After
stirring for 3 hours at room temperature, the reaction
is complete (TLC control). The precipitate was filtered
off with suction and washed with s amounts of
tetrahydrofuran. The te was evaporated to dryness
on a rotary evaporator, taken up in ethyl acetate,
washed with 1N HCl and NaCl solution (sat.) and dried
over ium sulfate, filtered from the magnesium
sulfate, and the ethyl acetate was concentrated on a
rotary evaporator. This gave 105 g of
2,4~bismethoxycarbonyloxyacetophenone. 1H NMR DQ:
8.05 (d, 1H), 7.38 (d, 18), 7.36 (s, 1H), 3.86 (d, 6H).
The product was used without further purification. 63 g
(392 mmol) of bromine in 450 ml of chloroform were
added dropwise to the solution of 105 g of
2,4—bismethoxycarbonyloxyacetophenone in chloroform
(1000 ml) over the course of 3 h. The reaction was then
stirred for a further 15 min at room temperature. The
solvent was evaporated on a rotary evaporator. The
WO 41526
_ 20 _
residue was stirred in ethyl acetate/n-hexane, and the
resulting precipitate was filtered off with suction.
Recrystallization from ethyl e/n—hexane produced
100 g of 2—bromo—2’,4’—bismethoxycarbonyloxy-
acetophenone. 1H NMR (DMSO—De): 8.11 (d, 1H), 7.42 (m,
2H), 4.87 (s, 2H), 3.87 (s, 3H), 3.85 (s, 3H) ppm; m.p.
N—(4—(2,4—Dih drox hen l)thiazol~2~ l) ide:
“(W—K‘ :>1,JL\M O 3
’fL\N tomene ’lL\
11112111232321; fi M3
R30 095 0
1 peace sea
+ i
m: 11
Br ,1 41511 iso {\N>__,
126 g (1.66 mmol) of thiourea were introduced into
toluene (1000 ml), and 100 g (829 mmol) of pivaloyl
chloride were added dropwise. The reaction solution was
boiled under reflux for 3 hours, during which two
phases formed. The upper phase was decanted off and
cooled. The precipitated colorless needles were
filtered off with suction and washed with cyclohexane
and dried in vacuo. Yield: 64 g. 1H NMR {DMSO~D6): 10.27
(s, 18), 9.74 (s, 18), 9.40 (s, 1H), 1.19 (s, 9H) ppm.
107.7 g (310 mmol) of 2-bromo"2',4’-bismethoxycarbonyl-
oxyacetophenone were boiled with 49.7 g (13.6 mmol) of
N—pivaloylthiourea and 39.2 g (466 mmol) of NaHC03 in
1.2 1 of ethanol under reflux for 0.5 h. The reaction
solution was cooled and admixed with 50.6 g (1.27 mol)
of NaOH in 250 m1 of water. After stirring for 30 min
at room temperature, the reaction solution was taken up
with 300 ml of water and neutralized with 2N HCl. The
_ 21 _
resulting precipitate was filtered off and
recrystallized from ethanol/water. 80 g of thiazole
were obtained. 1H NMR (DMSO—DG): 11.77 (bs, 1H), 11.02
(bs, 1H), 9.47 (bs, 2H), 7.65 (d, 18), 7.39 (s, 1H),
6.30 (s, 1H), 6.28 (d, 1H), 1.27 (s, 9H) ppm; m.p.
257—259°C.
N—(4—(2,4—Dih drox hen l)thiazol—2— l)isobut ramide:
0 S 0 S
+ k toluene i
C! H?! RIf: ‘nyc 5:11 NH:
{3°Cr GF‘G s Q 80 GM
)L 1. meet} 801'? O
+ KN H “""7’ N
* S <
a H amho
\ yflfiH
e a
114 g (1.5 mol) of thiourea were introduced into
e (800 ml), and 80 g (0.75 mol) of isobutyryl
chloride were added dropwise. The reaction solution was
boiled under reflux for 3 hours, during which two
phases formed. The upper phase was decanted off and
cooled. The precipitated white crystals were ed
off with suction and washed with toluene and dried in
vacuo. Yield: 62 g. 1H NMR (DMSO—Dd: 11.03 (bs, 1H),
9.66 (bs, 1H), 9.35 (bs, 1H), 2.72 (m, 1H), 1.03 (2,
6H) ppm.
89 g (260 mmol) of 2—bromo—2’,4’—bismethoxycarbonyl—
oxyacetophenone were boiled under reflux with 37.5 g
(260 mmol) of N—isobutyrylthiourea and 32 g (380 mmol)
of NaHC03 in 1000 ml of ethanol for 0.5 h. The reaction
solution was cooled and d with 41 g (0.93 mol) of
NaOH in 250 m1 of water. After stirring for 30 min at
room temperature, the reaction solution was taken up
with 300 ml of water and adjusted to pH=3 with 2N HCl.
_ 22 _
The resulting precipitate was filtered off and
recrystallized from ethanol/water. 56 g of le
were obtained. in NMR (DMSO—Ds): 12.16 (bs, 1H), 10.88
(bs, 1H), 9.47 (bs, 1H), 7.65 (m, 1H), 7.41 (s, 1H),
6.32 (m, 2H), 2.75 (m, 1H), 1.14 (d, 6H) ppm; m.p.
°C.
N~(4-(2,4—Dih drox hen l)thiazol—2— l)but ramide:
O S 0 .3
”/\\\’/JL\ 4' (Ji\ towene
" """"'" 111‘
c: we N34. N
iZfi'C NH:
see ope H0 0%
azmsco sea 0
.. mlAA tr
& 2NKT£maHo
‘ >PNH
G c
143 g (1.88 mol) of thiourea were introduced into
e (1000 ml), and 100 g (0.93 mol) of n—butyryl
chloride were added dropwise. The reaction solution was
boiled under reflux for 3 hours, during which two
phases formed. The upper' phase was decanted off and
cooled. The precipitated slightly yellowish crystals
were filtered off with suction and washed with toluene
and dried in vacuo. Yield: 88 g. 1H NMR (DMSO—De): 11.03
(bs, 1H), 9.65 (bs, 1H), 9.33 (bs, 1H), 2.33 (t, 2H),
1.53 (m, 2H), 0.86 (t, 3H) ppm; m.p. 115-188°C
92 g (265 mmol) of 2—bromo—2',4'—bismethoxycarbonyl—
oxyacetophenone were boiled under reflux with 38.75 g
(265 mmol) of N-butyrylthiourea and 34 g (397 mmol) of
NaHCO3 in 900 ml of ethanol for 0.5 h. The reaction
solution was cooled and admixed with 37 g (0.93 mol) of
NaOH in 300 ml of water. After stirring for 30 min at
room temperature, the reaction solution was taken up
with 300 ml of water and neutralized with 2N HCl. The
resulting precipitate was filtered off and
tallized from l/water. 67 g of thiazole
_ 23 _
were obtained. 1H NMR (Dmsowe): 12.18 (bs, 10), 10.89
(be, 1H), 9.48 (bs, 1H), 7.65 (1 aronn H), 7.40 (s,
1H), 6.31 (2 arom. H), 2.43 (t, 2H), 1.64 (m, 2H), 0.91
(t, 38) ppm; m.p. 227—229°C.
N~(4—(2,4—Dih drox hen l)thiazol~2~ l)acetamide:
PGO OPG s 0
JL HO OH
1. NaHCOa, EtOH 0
Br fl 2 N OHIEtOH/H o. a N j
2 \ N
o 1 Sh
4.71 g (13.6 mmol) of 2-bromo—2’,4’—bismethoxycarbonyl—
oxyacetophenone were boiled under reflux with 1.61 g
(13.6 mmol) of N—acetylthiourea and 1.72 g (20.4 mmol)
of NaHC03 in 45 ml of ethanol for 0.5 h. The reaction
solution was cooled and admixed with 2.0 g (50 mmol) of
NaOH in 20 ml of water. After ng for 20 min at
0°C, the reaction solution was taken up with 30 ml of
water and neutralized with oncentrated HCl. The
resulting precipitate was filtered off and
recrystallized from ethanol/water. 2.73 g of product
were obtained. in NMR (01480—06): 12.20 (b, 1H), 10.85
(s, 1H), 9.46 (s, 1H), 7.64 (m, 1H), 7.38 (s, 1H), 6.28
(m, 2H), 2.15 (s, 3H) ppm; m.p. 264—264°C.
N—(4—(2,4—Dih drox hen l)thiazol—2— l)—4—(h drox —
methzl)czclohexanecarboxamide:
O I. A2330. ne O
cect.&rc
05. OR ______;____4_
“‘3 2. e130, 3003 Y9
Procedure ous to the literature.
_ 24 _
BANYU Pharmaceutical Co. Ltd., EP2072519 A1, 2009
Yield: 96%. 1H NMR (DMSO-Ds): 12.03 (133, 1H), 3.85, 3.82
(2 X d, 2H), 2.50, 2.47 (2 x m, 1H), 2.00 (s, 3H),
0.95-1.90 (m, 9H) ppm
o s
S 1,somm7ec ,H\
OH + A N NH?
HzN NH2 H
\[ro 2. toluene, 120°C fir0
P60\I::]:n/A\WOPG Mu’JLW::1\J01Ks.Ncho aoH W‘I:::[;Elw2. NaoH/EIOH/H-0 \>FHN
95 g (0.47 mol) of 4~acetoxymethylcyclohexanecarboxylic
acid were heated under reflux in 350 ml of thionyl
chloride for 2 h. After removing the excess thionyl
chloride in vacuo, the residue was taken up in 1 l of
toluene, and 71 g (0.94 mol) of thiourea were added.
The reaction on was boiled under reflux for
3 hours and then filtered off while hot. After cooling
the mother liquor, the resulting white crystals were
filtered off with suction, washed with e and
dried in vacuo. Yield: 59 g. 1H NMR (DMSO—DG): 11.03,
.97 (2 x s, 1H), 9.64 (bs, 1H), 9.35 (bs, 18), 3.93,
3.82 (2 x d, 2H), 2.61, 2.42 (2 x m, 1H), 2.00 (s, 3H),
1.60 (m, 8H), 1.35, 0.94 (2 x m, 1H) ppm;
79 g (228 mmol) of o—2’,4’—bismethoxycarbonyl—
oxyacetophenone were boiled under reflux for 0.5 h with
59 g (228 mmol) of ~-(4—acetoxymethylcyclo—
hexylcarbonyl)thiourea and 29 g (340 mmol) of NaHC03 in
1000 ml of ethanol. The reaction solution was cooled
and d with 73 g (1.8 mol) of NaOH in 300 m1 of
water. After stirring for 30 min at room temperature,
the reaction solution was taken up with 300 ml of water
and adjusted to pH=3 with 2N HCl. The resulting
_ 25 i
itate was filtered off and recrystallized. from
ethanol/water. 47 g of thiazol were obtained. 1H NMR
(DMSO—Ds): 12.15, 12.10 (2 x s, 1H), 10.96 (2 x s, 1H),
9.47 (br, 2H), 7.64 (d, 1H), 7.39 (s, 1H), 6.29 (m,
2H), 4.40 (br, 1H), 3.32, 3.23 (2 x d, 2H), 2.65, 2.44
(2 X m, 1H), 1.90 (m, 1H), 1.78 (m, 2H), 1.50 (m, 58),
0.94 (m, 1H) ppm; m.p. 152—160°C.
N—(4—(2,4~Dih drox hen l)thiazol—2- l)c clohexane—
carboxamide:
o s 0 S
+ k toluene JL
Cl HzN NH2 120°C ” NH2
PGO OPG S 0 HO OH
+ JL 1. Ncho,. ElOH
HzN El —> N
& ZNxmemwmo 1 §~fi
52 g (0.68 mol) of thiourea were introduced into
toluene (500 ml), and 50 g (0.34 mol) of cyclohexanoyl
chloride were added dropwise. The reaction solution was
boiled under reflux for 3 hours, during which two
phases formed. The upper phase was decanted off and
cooled. The precipitated crystals were filtered off
with suction, washed with toluene and recrystallized
from methanol. Yield: 35 g. 1H NMR (DMSO—DG): 10.98 (bs,
1H), 9.65 (bs, 1H), 9.32 (bs, 1H), 2.49 (t, 1H), 1.75
(m, 4H), 1.61 (m, 1H), 1.18 (m, 5H) ppm.
92 g (265 mmol) of o—Z’,4’—bismethoxycarbonyl—
oxyacetophenone were boiled under reflux for 0.5 h with
49.4 g (265 mmol) of N—cyclohexanoylthiourea and 34 g
(397 mmol) of NaHCO3 in 900 ml of ethanol. The reaction
on was cooled and d with 37 g (930 mmol) of
NaOH in 300 ml of water. After stirring for 30 min at
roonl temperature, the reaction solution was taken up
with 300 ml of water and neutralized with 2N HCl. The
ethanol was largely removed on a rotary ator. The
precipitate formed was filtered off and recrystallized
from ethanol/water. 70 g of thiazol were obtained.
1H NMR (DMSO—De): 12.14 (bs, 1H), 11.00 (bs, 1H), 9.48
(bs, 1H), 7.64 (1 arom. H), 7.39 (s, 1H), 6.30 (2 arom.
H), 2.49 (m, 1H), 1.84 (m, 2H), 1.76 (m, 2H), 1.65 (m,
1H), 1.42 (m, 28), 1.25 (m, 3H), ppm; m.p.: 262—266°C.
N-(4—(2,4—Dih drox hen l)thiazol—2~ l) ~2~(4~
(hydroxymethyl)Qhenyl)acetamide:
1 A020 pyridine
”OmOH CHCIs, 60°C OY
2 H0 100°C omOH
Procedure analogous to the literature.
BANYU Pharmaceutical Co. Ltd., EP2072519 A1, 2009
Yield: 76%. 1H NMR (01150—06): 12.31 (bs, 1H), 7.26 (m,
4H), 5.05 (s, 2H), 3.57 (s, 2H), 2.05 (s, 3H) ppm
3 1. 300,, we
0§r’ OH 0
+ JL N NW
HZN NH2 ‘11!
O 0 2. loluene. 120”C O 0
01-!
P60 OPG
H 1. Ncho3 ElOHH o
+ HEN
a: \H/ 2 NaOHIE!OH/Ho
s o CY “3,,“H O
3.7 g (18 mmol) of 4-acetoxymethylphenylacetic acid
were heated under reflux in 40 ml of thionyl de
for 2 h. After removing the excess l chloride in
vacuo, the residue was taken up in 70 ml of toluene,
WO 41526
_ 27 _
and 2.7 g (36 mmol) of thiourea were added. The
reaction solution was boiled under reflux for 3 hours
and then the solvent was removed in vacuo. Purification
was by means of column chromatography with
cyclohexane/ethyl acetate 1/1 on silica gel. Yield:
2.7 g. 1H NMR DG): 11.29 (bs, 1H), 9.55 (bs, 1H),
9.40 (bs, 1H), 7.30 (m, 4H), 5.04 (s, 2H), 3.71 (s,
2H), 2.05 (s, 3H) ppm;
3.5 g (10 mmol} of 2—bromo—2',4’—bismethoxycarbonyl—
oxyacetophenone were boiled under reflux for 0.5 h with
2.7 g (10 mmol) of N—[2—(4—acetoxymethylphenyl)~
acetlethiourea and 1.3 g (15 mmol) of NaHC03 in 50 ml
of ethanol. The reaction solution was cooled and
admixed with 4.0 g (0.1 mol) of NaOH in 20 ml of water.
After stirring for 2 h at 60°C, the on solution
was taken up in 100 ml of water and adjusted to pH=3
with 2N HCl. The resulting precipitate was filtered off
and recrystallized from l/water. 1.3 g of thiazol
were obtained. 1H NMR (DMSO-De): 12.44 (s, 1H), 10.80
(s, 1H), 9.48 (s, 1H), 7.66 (d, 1H), 7.41 (s, 1H), 7.29
(m, 4H), 6.32 (m, 2H), 5.13 (t, 1H), 4.47 (d, 2H), 3.77
(s, 2H) ppm; m.p. 254—256°C.
Cosmetic or dermatological preparations with a content
of alkylamidothiazoles and their use for the treatment
and/or prophylaxis of undesired skin pigmentation are
likewise advantageous embodiments of the present
ion.
It is particularly advantageous if such preparations
comprise 0.000001 to 10% by weight, in particular
0.0001 to 3% by weight, very particularly 0.001 to 1%
by weight, of one or more of the alkylamidothiazoles
according to the invention, based on the total weight
of the preparation.
_ 28 _
Cosmetic and dermatological preparations according to
the invention can be in various forms. Thus, they can
be e.g. a solution, an anhydrous preparation, an
emulsion or microemulsion of the water—in—oil (W/O)
type or of the oil—in—water (O/W) type, a multiple
emulsions, for example of the water—in—oil—in—water
(W/O/W) type, a gel, a solid stick, a balm or else an
aerosol. It is also advantageous according to the
invention to administer the substances used according
to the ion and/or their derivatives in
encapsulated form, e.g. in collagen matrices and other
customary encapsulation materials, e.g. as ose
ulations, in gelatin or liposomally encapsulated.
It is also possible and advantageous within the context
of the present invention to add the substances used
according to the invention and/or their tives in
aqueous s or surfactant preparations for cleaning
the skin and the hair.
The lipid phase can advantageously be selected from the
ing substance group:
~ l oils, mineral waxes
— oils, such as triglycerides of capric acid or of
caprylic acid, also natural oils such as e.g.
castor oil;
— fats, waxes and other natural and synthetic fatty
bodies, preferably esters of fatty acids with
alcohols of low carbon number, e.g. with
3O isopropanol, propylene glycol or glycerol, or
esters of fatty alcohols with alkanoic acids of
low carbon number or with fatty acids;
~ alkyl benzoates;
* silicone oils such as dimethylpolysiloxanes,
diethylpolysiloxanes, ylpolysiloxanes and
mixtures thereof.
. 29 i
The oil phase of the emulsions, oleogels or
hydrodispersions or lipodispersions within the context
of the present invention is advantageously selected
from the group of esters of saturated and/or
unsaturated, branched and/or unbranched
alkanecarboxylic acids of chain length frown 3 to 30
carbon atoms and ted and/or unsaturated, ed
and/or unbranched alcohols of chain length from 3 to 30
carbon atoms, from the group of esters of aromatic
carboxylic acids and saturated and/or unsaturated,
branched and/or unbranched alcohols of chain length
frmn 3 to 30 carbon atoms. Such ester oils can then
advantageously be selected from the group pyl
myristate, pyl palmitate, isopropyl stearate,
isopropyl oleate, n~butyl stearate, l e,
n—decyl oleate, yl stearate, isononyl stearate,
yl isononanoate, 2-ethylhexyl palmitate,
2—ethylhexyl laurate, 2—hexyldecyl stearate,
2—octyldodecyl palmitate, oleyl oleate, oleyl erucate,
erucyl oleate, erucyl erucate, and synthetic,
semisynthetic and natural mixtures of such esters, e.g.
jojoba oil.
In particular, mixtures of the aforementioned ts
are used. In the case of alcohol ts, water may be
a further constituent.
Emulsions according to the invention are advantageous
and comprise e.g. said fats, oils, waxes and other
3O fatty bodies, and also water and an emulsifier, as is
usually used for such a type of formulation.
Suitable propellants for preparations according to the
invention which can be sprayed from aerosol containers
are the customary known readily volatile, liquefied
propellants, for example hydrocarbons (propane, butane,
isobutene), which can be used on their own or in a
_ 30 _
mixture with one another. Compressed air can also
advantageously be used.
The examples below are intended to illustrate the
present ion without ng it. Unless stated
otherwise, all of the quantities, fractions and
percentages given are percentages by weight, based on
the weight and the total amount or on the total weight
of the preparations.
Formulation examgles:
INCI/Substance
N—(4—(2,4—Dihydroxyphenyl)—
thiazol—Z-yl)isobutyramide
4—(2—Isopropylamino)thiazol—
4—yl)benzene—l,3-diol
4-(2-tert-
Butylamino)thiazol
yl)benzene—1,3~diol
N-(4-(2,4-Dihydroxyphenyl)-
l-Z—yl)pivalamide
N—(4~(2,4-Dihydroxyphenyl)-
thiazol—Z—yl)butyramide
4 - (2— Propyl amino) thiazol—4 - II...-
yl)benzene-l,3-diol
8.70
3.00
0.03
0.20
0.10
mmmmm
0.10
0.20
INCI/Substance Formula Formula Formula Formula
7 8 9 10
N—(4-(2,4—Dihydroxyphenyl)—
thiazolyl)cyclohexane—
carboxamide
4—(2—(Cyclohexylamino)—
thiazolyl)benzene—l,3—
diol
N—(4—(2,4—Dihydroxyphenyl)-
thiazol-Z-yl)heptanamide III-
4— (2— (Hexylamino) l ---
yl)benzene—l,3“diol
2 . 00
0.70
0.00
0.00
0.20
0.00
-m-m_
0.00
0.20
Claims (8)
1. midothiazole having any' one of the following structures : HO OH AF(4—(2,4—dihydroxyphenyl)thiazol—Z—yl)pivalamide HO OH N—(4—(2,4—dihydroxyphenyl)thiazol—Z—yl)isobutyramide HO OH \ ”\N/ \/\ N—(4~(2,4—dihydroxyphenyl)thiazol—Z-yl)butyramide HO OH \ NEW/QM N~(4~(2,4~dihydroxyphenyl)thiazol—Z—yl)heptanamide H0 OH N\ f \ N/"\/\/\/°H S .L 2,4—dihydroxyphenyl)thiazol—Z—yl)hydroxyhexanamide 01-! I \>_NH 0 0H N-(4—(2,4—dihydroxyphenyl)thiazol—Z—yl)hydroxypropanamide I "\>—~n ‘°‘ (he... N>(4-(2,4—dihydroxyphenyl)thiazol—Z—yl)methoxyacetamide \>—NH o NH2 N—(4w(2,4—dihydroxyphenyl)thiazol-Z-yl)propanimide HO OH \N\>,~H>/O// AF(4—(2,4—dihydr0xyphenyl)thiazol—Z—yl)acetamide N— (4— (2, ydroxyphenyl))thiazol2Wyl (hydroxymethyl)cyclohexanecarboxamide HO OH N~(4—(2,4—dihydroxyphenyl)thiazol—Z— lohexanecarboxamide OH OH I gen“\ N>(4—(2,4-dihydroxyphenyl)thiazol-z-yl)—2-(4- hydroxymethyl)phenyl)acetamide.
2. Alkylamidothiazole according to claim 1, wherein. in the form of halide, carbonate, ascorbate, sulfate, acetate or phosphate salt.
3. Cosmetic or dermatological preparations with a content of one or more alkylamidothiazoles as defined in claim 1 or claim ’5va 2.
4. Preparation according 133 claim 3, containing 0.000001 to 10% by weight of one or more of the midothiazoles defined in claim 1 or claim 2, based on the total weight of the preparation.
5. Preparation according to claim 3, ning in particular 0.0001 to 3% by weight of one or more of the alkylamidothiazoles defined in claim 1 or claim 2, based on the total weight of the preparation.
6. Preparation according to claim 3, containing 0.001 to 1% by weight of one or‘ more of the alkylamidothiazoles defined in claim 1 or claim 2, based on the total weight of the preparation.
7. Use of one or more alkylamidothiazoles defined in claim 1 or claim 2, or preparations containing one or more such alkylamidothiazoles in the manufacture of a medicament for the cosmetic or dermatological treatment and/or prophylaxis of undesired skin pigmentation.
8. Alkylamidothiazoles as defined in claim 1; cosmetic or dermatological ations as d in claim 3; or use of one or more alkylamidothiazoles as defined in claim 7, substantially as herein described with reference to any one of the embodiments of the invention illustrated in the anying examples.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE102011083259.9 | 2011-09-23 | ||
DE102011083259A DE102011083259A1 (en) | 2011-09-23 | 2011-09-23 | Alkylamidothiazoles, their cosmetic or dermatological use and cosmetic or dermatological preparations containing such Alkylamidothiazolen |
PCT/EP2012/068362 WO2013041526A1 (en) | 2011-09-23 | 2012-09-18 | Alkylamidothiazoles, cosmetic or dermatological preparations containing said alkylamidothiazoles, and use thereof to combat or prevent undesired pigmentation of the skin |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ620487A NZ620487A (en) | 2016-02-26 |
NZ620487B2 true NZ620487B2 (en) | 2016-05-27 |
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