MXPA99003663A - Bi-aromatic compounds bound by a heteroethynylene radical and pharmaceutical and cosmetic compositions containing same - Google Patents
Bi-aromatic compounds bound by a heteroethynylene radical and pharmaceutical and cosmetic compositions containing sameInfo
- Publication number
- MXPA99003663A MXPA99003663A MXPA/A/1999/003663A MX9903663A MXPA99003663A MX PA99003663 A MXPA99003663 A MX PA99003663A MX 9903663 A MX9903663 A MX 9903663A MX PA99003663 A MXPA99003663 A MX PA99003663A
- Authority
- MX
- Mexico
- Prior art keywords
- tetrahydro
- tetramethyl
- methyl
- naphthylslanilethynyl
- radical
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims description 54
- 239000002537 cosmetic Substances 0.000 title claims description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 130
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 92
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 28
- 201000010099 disease Diseases 0.000 claims abstract description 25
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 24
- 125000005843 halogen group Chemical group 0.000 claims abstract description 15
- 239000011780 sodium chloride Substances 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 13
- 210000003491 Skin Anatomy 0.000 claims abstract description 11
- 230000032683 aging Effects 0.000 claims abstract description 8
- 230000003780 keratinization Effects 0.000 claims abstract description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 62
- -1 2-ethylhexyl Chemical group 0.000 claims description 53
- 150000003254 radicals Chemical group 0.000 claims description 42
- 239000005711 Benzoic acid Substances 0.000 claims description 34
- 235000010233 benzoic acid Nutrition 0.000 claims description 29
- WPYMKLBDIGXBTP-UHFFFAOYSA-M benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-M 0.000 claims description 28
- QPJVMBTYPHYUOC-UHFFFAOYSA-N Methyl benzoate Natural products COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 claims description 24
- 239000002253 acid Substances 0.000 claims description 18
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 15
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 15
- 229940095102 methyl benzoate Drugs 0.000 claims description 15
- PVNIIMVLHYAWGP-UHFFFAOYSA-N nicotinic acid Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 15
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 13
- XBLVHTDFJBKJLG-UHFFFAOYSA-N Ethyl nicotinate Chemical compound CCOC(=O)C1=CC=CN=C1 XBLVHTDFJBKJLG-UHFFFAOYSA-N 0.000 claims description 12
- DFPAKSUCGFBDDF-UHFFFAOYSA-N nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 12
- 239000011664 nicotinic acid Substances 0.000 claims description 9
- 235000001968 nicotinic acid Nutrition 0.000 claims description 8
- 229960003512 nicotinic acid Drugs 0.000 claims description 7
- 230000003287 optical Effects 0.000 claims description 7
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 239000004721 Polyphenylene oxide Substances 0.000 claims description 6
- 229940064982 ethylnicotinate Drugs 0.000 claims description 6
- 230000002757 inflammatory Effects 0.000 claims description 6
- 229960003966 nicotinamide Drugs 0.000 claims description 6
- 235000005152 nicotinamide Nutrition 0.000 claims description 6
- 239000011570 nicotinamide Substances 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 229920000570 polyether Polymers 0.000 claims description 6
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N Ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 claims description 5
- 235000001014 amino acid Nutrition 0.000 claims description 5
- 150000001413 amino acids Chemical class 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000003107 substituted aryl group Chemical group 0.000 claims description 5
- OEQLIEOMTZSOOM-UHFFFAOYSA-N 4-[2-[(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)sulfanyl]ethynyl]benzoic acid Chemical compound C=1C=C2C(C)(C)CCC(C)(C)C2=CC=1SC#CC1=CC=C(C(O)=O)C=C1 OEQLIEOMTZSOOM-UHFFFAOYSA-N 0.000 claims description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 4
- 150000001732 carboxylic acid derivatives Chemical group 0.000 claims description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- WULIZEOAYMSIHS-UHFFFAOYSA-N 4-chloro-5-methylpyrrolo[3,2-d]pyrimidine-6-carbaldehyde Chemical compound C1=NC(Cl)=C2N(C)C(C=O)=CC2=N1 WULIZEOAYMSIHS-UHFFFAOYSA-N 0.000 claims description 3
- 229940097275 Indigo Drugs 0.000 claims description 3
- 235000000177 Indigofera tinctoria Nutrition 0.000 claims description 3
- 206010072736 Rheumatic disease Diseases 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 125000005842 heteroatoms Chemical group 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 claims description 2
- WXZMFSXDPGVJKK-UHFFFAOYSA-N 2,2-bis(hydroxymethyl)propane-1,3-diol Chemical group OCC(CO)(CO)CO WXZMFSXDPGVJKK-UHFFFAOYSA-N 0.000 claims description 2
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- PVTGNLGJIDTJII-UHFFFAOYSA-N 4-[2-[(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)sulfonyl]ethynyl]benzoic acid Chemical compound C=1C=C2C(C)(C)CCC(C)(C)C2=CC=1S(=O)(=O)C#CC1=CC=C(C(O)=O)C=C1 PVTGNLGJIDTJII-UHFFFAOYSA-N 0.000 claims description 2
- 229960005261 Aspartic Acid Drugs 0.000 claims description 2
- GZCGUPFRVQAUEE-KCDKBNATSA-N D-(+)-Galactose Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)C=O GZCGUPFRVQAUEE-KCDKBNATSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 claims description 2
- 239000004471 Glycine Substances 0.000 claims description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 2
- 229910052783 alkali metal Chemical class 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- 229910052784 alkaline earth metal Chemical class 0.000 claims description 2
- 125000000539 amino acid group Chemical group 0.000 claims description 2
- 235000003704 aspartic acid Nutrition 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 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 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- CKJNUZNMWOVDFN-UHFFFAOYSA-N methanone Chemical compound O=[CH-] CKJNUZNMWOVDFN-UHFFFAOYSA-N 0.000 claims description 2
- 125000002950 monocyclic group Chemical group 0.000 claims description 2
- 125000004433 nitrogen atoms Chemical group N* 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 2
- 230000000241 respiratory Effects 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- 239000011701 zinc Substances 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- WQZGKKKJIJFFOK-PHYPRBDBSA-N α-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- AEMOLEFTQBMNLQ-QIUUJYRFSA-N β-D-glucuronic acid Chemical group O[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-QIUUJYRFSA-N 0.000 claims description 2
- 208000008787 Cardiovascular Disease Diseases 0.000 claims 2
- 241001062009 Indigofera Species 0.000 claims 2
- 230000000552 rheumatic Effects 0.000 claims 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 1
- SIOXPEMLGUPBBT-UHFFFAOYSA-N Picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 claims 1
- 206010038683 Respiratory disease Diseases 0.000 claims 1
- 240000003670 Sesamum indicum Species 0.000 claims 1
- 150000001342 alkaline earth metals Chemical class 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 229910052731 fluorine Inorganic materials 0.000 claims 1
- 239000011737 fluorine Substances 0.000 claims 1
- 125000003367 polycyclic group Chemical group 0.000 claims 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 86
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 51
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 31
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 28
- 239000007787 solid Substances 0.000 description 28
- 239000000243 solution Substances 0.000 description 28
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 26
- 239000000377 silicon dioxide Substances 0.000 description 25
- 101700067048 CDC13 Proteins 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
- 239000000047 product Substances 0.000 description 16
- 239000003921 oil Substances 0.000 description 15
- 235000019198 oils Nutrition 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 15
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- 239000001301 oxygen Substances 0.000 description 14
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical group O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 13
- 238000000746 purification Methods 0.000 description 13
- 239000002904 solvent Substances 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 10
- 235000019341 magnesium sulphate Nutrition 0.000 description 10
- 238000004062 sedimentation Methods 0.000 description 10
- 206010000496 Acne Diseases 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Chemical compound [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 9
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 238000001665 trituration Methods 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 7
- 239000012429 reaction media Substances 0.000 description 7
- 125000003118 aryl group Chemical group 0.000 description 6
- 230000004069 differentiation Effects 0.000 description 6
- 150000002148 esters Chemical group 0.000 description 6
- 239000011669 selenium Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 5
- 239000012230 colorless oil Substances 0.000 description 5
- 150000003959 diselenides Chemical class 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- JPGRSTBIEYGVNO-UHFFFAOYSA-N methyl 4-ethynylbenzoate Chemical compound COC(=O)C1=CC=C(C#C)C=C1 JPGRSTBIEYGVNO-UHFFFAOYSA-N 0.000 description 5
- 239000002674 ointment Substances 0.000 description 5
- 238000005191 phase separation Methods 0.000 description 5
- 230000035755 proliferation Effects 0.000 description 5
- 229910052711 selenium Inorganic materials 0.000 description 5
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 4
- NHQDETIJWKXCTC-UHFFFAOYSA-N Meta-Chloroperoxybenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 4
- LXCFILQKKLGQFO-UHFFFAOYSA-N Methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 4
- JQWHASGSAFIOCM-UHFFFAOYSA-M Sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 210000004027 cells Anatomy 0.000 description 4
- 230000000875 corresponding Effects 0.000 description 4
- 239000006071 cream Substances 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000002609 media Substances 0.000 description 4
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 4
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 239000001184 potassium carbonate Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 230000000699 topical Effects 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- 229940064701 Corticosteroid nasal preparations for topical use Drugs 0.000 description 3
- 229960001334 Corticosteroids Drugs 0.000 description 3
- 206010013082 Discomfort Diseases 0.000 description 3
- 102000004310 Ion Channels Human genes 0.000 description 3
- 108090000862 Ion Channels Proteins 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 208000001608 Teratocarcinoma Diseases 0.000 description 3
- 150000000475 acetylene derivatives Chemical class 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 125000004432 carbon atoms Chemical group C* 0.000 description 3
- 239000003246 corticosteroid Substances 0.000 description 3
- 230000002500 effect on skin Effects 0.000 description 3
- OYFSSBJCRDCFPA-UHFFFAOYSA-N ethyl 6-ethynylpyridine-3-carboxylate Chemical compound CCOC(=O)C1=CC=C(C#C)N=C1 OYFSSBJCRDCFPA-UHFFFAOYSA-N 0.000 description 3
- 125000002534 ethynyl group Chemical class [H]C#C* 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 239000006210 lotion Substances 0.000 description 3
- VIFZPWTVYZSHIT-UHFFFAOYSA-N methyl 4-ethynyl-2-hydroxybenzoate Chemical compound COC(=O)C1=CC=C(C#C)C=C1O VIFZPWTVYZSHIT-UHFFFAOYSA-N 0.000 description 3
- PGYCVRHIHIYNBF-UHFFFAOYSA-N methyl 5-ethynylpyridine-2-carboxylate Chemical compound COC(=O)C1=CC=C(C#C)C=N1 PGYCVRHIHIYNBF-UHFFFAOYSA-N 0.000 description 3
- 239000004005 microsphere Substances 0.000 description 3
- 239000002077 nanosphere Substances 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- BUGBHKTXTAQXES-UHFFFAOYSA-N selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000002194 synthesizing Effects 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 229940083878 topical for treatment of hemorrhoids and anal fissures Corticosteroids Drugs 0.000 description 3
- 235000019166 vitamin D Nutrition 0.000 description 3
- 239000011710 vitamin D Substances 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-dichloroethane Chemical group ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- CXKRATPLFTXWTQ-UHFFFAOYSA-N 1-bromo-2-(3-methylbut-2-enylsulfanyl)benzene Chemical compound CC(C)=CCSC1=CC=CC=C1Br CXKRATPLFTXWTQ-UHFFFAOYSA-N 0.000 description 2
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- MVDIYGIRUWKTKY-UHFFFAOYSA-M [Br+].C(C1=CC=CC=C1)(=O)[O-] Chemical compound [Br+].C(C1=CC=CC=C1)(=O)[O-] MVDIYGIRUWKTKY-UHFFFAOYSA-M 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- 229940087168 alpha Tocopherol Drugs 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 230000003042 antagnostic Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000000111 anti-oxidant Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960002255 azelaic acid Drugs 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 235000019400 benzoyl peroxide Nutrition 0.000 description 1
- OENHQHLEOONYIE-VYAWBVGESA-N beta-Carotene Natural products CC=1CCCC(C)(C)C=1\C=C\C(\C)=C/C=C/C(/C)=C\C=C\C=C(\C)/C=C/C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-VYAWBVGESA-N 0.000 description 1
- 235000013734 beta-carotene Nutrition 0.000 description 1
- 239000011648 beta-carotene Substances 0.000 description 1
- 230000003115 biocidal Effects 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- AZWXAPCAJCYGIA-UHFFFAOYSA-N bis(2-methylpropyl)alumane Chemical compound CC(C)C[AlH]CC(C)C AZWXAPCAJCYGIA-UHFFFAOYSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229910010277 boron hydride Inorganic materials 0.000 description 1
- 235000014121 butter Nutrition 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- 229940074360 caffeic acid Drugs 0.000 description 1
- 235000004883 caffeic acid Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 150000001747 carotenoids Chemical class 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000001413 cellular Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 230000001684 chronic Effects 0.000 description 1
- 229960002227 clindamycin Drugs 0.000 description 1
- 229960004729 colecalciferol Drugs 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 230000001808 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000005712 crystallization Effects 0.000 description 1
- 239000007854 depigmenting agent Substances 0.000 description 1
- 201000004624 dermatitis Diseases 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 229960004042 diazoxide Drugs 0.000 description 1
- KLDBIFITUCWVCC-UHFFFAOYSA-N diborane(6) Chemical compound [H]B1([H])[H]B([H])([H])[H]1 KLDBIFITUCWVCC-UHFFFAOYSA-N 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- SOCTUWSJJQCPFX-UHFFFAOYSA-N dichromate(2-) Chemical compound [O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O SOCTUWSJJQCPFX-UHFFFAOYSA-N 0.000 description 1
- 150000002019 disulfides Chemical class 0.000 description 1
- 229960002311 dithranol Drugs 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 230000037336 dry skin Effects 0.000 description 1
- 231100001003 eczema Toxicity 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- HGAVGUOKLFNPCA-UHFFFAOYSA-N ethyl 4-(2-trimethylsilylethynyl)benzoate Chemical compound CCOC(=O)C1=CC=C(C#C[Si](C)(C)C)C=C1 HGAVGUOKLFNPCA-UHFFFAOYSA-N 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000001963 growth media Substances 0.000 description 1
- 230000003676 hair loss Effects 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 239000008079 hexane Substances 0.000 description 1
- KLGZELKXQMTEMM-UHFFFAOYSA-N hydride Chemical compound [H-] KLGZELKXQMTEMM-UHFFFAOYSA-N 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 230000002209 hydrophobic Effects 0.000 description 1
- 229960004337 hydroquinone Drugs 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229940079866 intestinal antibiotics Drugs 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
- 150000002496 iodine Chemical class 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000008274 jelly Substances 0.000 description 1
- 201000004607 keratosis follicularis Diseases 0.000 description 1
- 229960004705 kojic acid Drugs 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229910000468 manganese oxide Inorganic materials 0.000 description 1
- AMWRITDGCCNYAT-UHFFFAOYSA-L manganese(II,III) oxide Inorganic materials [Mn].O[Mn]=O.O[Mn]=O AMWRITDGCCNYAT-UHFFFAOYSA-L 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- WUFUURSWOJROKY-UHFFFAOYSA-N methyl 2-hydroxy-4-iodobenzoate Chemical compound COC(=O)C1=CC=C(I)C=C1O WUFUURSWOJROKY-UHFFFAOYSA-N 0.000 description 1
- BGEVNLARAQEEBS-UHFFFAOYSA-N methyl 4-[2-[(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)selanyl]ethynyl]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1C#C[Se]C1=CC=C2C(C)(C)CCC(C)(C)C2=C1 BGEVNLARAQEEBS-UHFFFAOYSA-N 0.000 description 1
- NXZLGYVMTGCRMZ-UHFFFAOYSA-N methyl 4-[2-[(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)sulfanyl]ethynyl]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1C#CSC1=CC=C2C(C)(C)CCC(C)(C)C2=C1 NXZLGYVMTGCRMZ-UHFFFAOYSA-N 0.000 description 1
- CZNGTXVOZOWWKM-UHFFFAOYSA-N methyl 4-bromobenzoate Chemical compound COC(=O)C1=CC=C(Br)C=C1 CZNGTXVOZOWWKM-UHFFFAOYSA-N 0.000 description 1
- AYLOVBNEYSUPQC-UHFFFAOYSA-N methyl 4-trimethylsilylbenzoate Chemical compound COC(=O)C1=CC=C([Si](C)(C)C)C=C1 AYLOVBNEYSUPQC-UHFFFAOYSA-N 0.000 description 1
- QETAXCDWNFMFCM-UHFFFAOYSA-N methyl 5-iodopyridine-2-carboxylate Chemical compound COC(=O)C1=CC=C(I)C=N1 QETAXCDWNFMFCM-UHFFFAOYSA-N 0.000 description 1
- CGFVEUUNDFAFHE-UHFFFAOYSA-N methyl 6-iodopyridine-3-carboxylate Chemical compound COC(=O)C1=CC=C(I)N=C1 CGFVEUUNDFAFHE-UHFFFAOYSA-N 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- QDHHCQZDFGDHMP-UHFFFAOYSA-N monochloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 1
- YNAVUWVOSKDBBP-UHFFFAOYSA-N morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 1
- 229940113083 morpholine Drugs 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 229940005935 ophthalmologic Antibiotics Drugs 0.000 description 1
- 125000002734 organomagnesium group Chemical group 0.000 description 1
- 230000003204 osmotic Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N oxygen atom Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000004430 oxygen atoms Chemical group O* 0.000 description 1
- 201000008743 palmoplantar keratosis Diseases 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-M phenylacetate Chemical compound [O-]C(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-M 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- SIOXPEMLGUPBBT-UHFFFAOYSA-M picolinate Chemical compound [O-]C(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-M 0.000 description 1
- 230000019612 pigmentation Effects 0.000 description 1
- 230000023603 positive regulation of transcription initiation, DNA-dependent Effects 0.000 description 1
- 230000002335 preservative Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000001185 psoriatic Effects 0.000 description 1
- VBICKXHEKHSIBG-UHFFFAOYSA-N rac-1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 201000004700 rosacea Diseases 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000002453 shampoo Substances 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- 230000036555 skin type Effects 0.000 description 1
- 239000000344 soap Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000001476 sodium potassium tartrate Substances 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- 239000001433 sodium tartrate Substances 0.000 description 1
- 235000011004 sodium tartrates Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-M stearate Chemical compound CCCCCCCCCCCCCCCCCC([O-])=O QIQXTHQIDYTFRH-UHFFFAOYSA-M 0.000 description 1
- 239000010902 straw Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 125000004434 sulfur atoms Chemical group 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 235000019529 tetraterpenoid Nutrition 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 230000035916 transactivation Effects 0.000 description 1
- 229940040064 ubiquinol Drugs 0.000 description 1
- QNTNKSLOFHEFPK-UPTCCGCDSA-N ubiquinol-10 Chemical compound COC1=C(O)C(C)=C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)C(O)=C1OC QNTNKSLOFHEFPK-UPTCCGCDSA-N 0.000 description 1
- 230000017260 vegetative to reproductive phase transition of meristem Effects 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- MECHNRXZTMCUDQ-RKHKHRCZSA-N vitamin D2 derivatives Chemical class [CH3:27][CH:25]([CH3:26])[C@@H:24](C)\[CH:23]=[CH:22]\[C@@H:20]([CH3:21])[C@@:17]1([H])[CH2:16][CH2:15][C@@:14]2([H])\[C:8]([CH2:9][CH2:11][CH2:12][C@:13]12[CH3:18])=[CH:7]\[CH:6]=[C:5]1\[CH2:4][C@@H:3](O)[CH2:2][CH2:1][C:10]1=[#6H2:19] MECHNRXZTMCUDQ-RKHKHRCZSA-N 0.000 description 1
- 235000005282 vitamin D3 Nutrition 0.000 description 1
- 239000011647 vitamin D3 Substances 0.000 description 1
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 1
- 229940021056 vitamin D3 Drugs 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
- OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 description 1
Abstract
The invention concerns compounds of formula (I) in which:Ar represents a radical selected among formulae (a) to (c). Z being O, S, or N-R6;R1 represents in particular a halogen atom, -CH3, or carboxyl;R2 and R3 represent in particular H, alkyl, cycloalkyl;or R2 and R3 together form a cycle with 5 or 6 chains;R4 and R5 represent in particular H or a halogen atom;R6 represents in particular H or alkyl;X represents a radical Y-C=C-;Y represents O,¿S(O)n? or Se(O)n', n being 0, 1 or 2, and the salts of the compounds of formula (I). Said compounds can be used in particular for treating dermatological diseases related to keratinization disorder, and to fight against skin ageing.
Description
BIAROMÁTIC COMPOUNDS UNITED BY A RADICAL HETEROETINYLENE, AND PHARMACEUTICAL AND COSMETIC COMPOSITIONS THAT CONTAIN THEM
DESCRIPTION
The invention relates, as novel and useful industrial products, to biaromatic compounds whose aromatic rings are linked via a divalent heteroetinylene radical. The invention also relates to the use of these novel compounds in pharmaceutical compositions designed for use in human or veterinary medicine, or alternatively in cosmetic compositions. The compounds according to the invention have pronounced activity in the fields of cell differentiation and proliferation and find applications more particularly in the topical and systemic treatment of dermatological diseases associated with keratinization disorders, dermatological (or other) discomforts with an inflammatory component and / or immunoallergenic, and dermal or hyperdermal proliferations, whether benign or malignant. These compounds have also been used in the treatment of connective tissue degenerative diseases, to combat skin aging, whether induced by light or chronological aging, and to treat disorders of the skin.
REF; 30008
cicratization. In addition, they find an application in the ophthalmological field, in particular in the treatment of corneopathy. The compounds according to the invention can also be used in cosmetic compositions for body and hair hygiene. Biaromatic compounds whose aromatic rings are linked via a divalent propynylene have already been described in EP-661,258, as active substances in pharmaceutical or cosmetic compositions. The compounds according to EP-661,258 correspond to the following general formula:
wherein: Ar is a divalent aromatic radical optionally substituted with a radical R5 or a heteroaromatic radical optionally substituted with a radical R6 when the heteroatom is nitrogen,
Ri represents H, -CH3, -CH2OR6, -OR6, -COR7 or -S (0) tR9, t is 0, 1 or 2. R2 and R3 represent H, CJ-CZQ alkyl, -0R6 or -SR6, or R2 and R3 taken together form a 5- or 6-membered ring optionally substituted with methyl group and / or optionally interrupted by an oxygen or sulfur atom,
R4 and R5 represent H, a halogen, lower alkyl or -0R6, R6 represents H, lower alkyl or -COR9,
R7 represents H, lower alkyl,
R 8 represents H, linear or branched C 1 -CJC alkyl, alkenyl, mono- or polyhydroxyalkyl, optionally substituted aryl or aralkyl, or a sugar or amino acid or a peptide residue, R 9 represents lower alkyl, R and R 'represent H, lower alkyl , mono- or polyhydroxyalkyl, optionally substituted aryl or a sugar or amino-acid or peptide residue, or R and R ', taken together, form a heterocycle, and
X represents a divalent radical which, from right to left or vice versa, has the formula:
in which: R10 represents H, lower alkyl or -OR6, R1 ± represents -0R6, or R10 and RX1, taken together, form an oxo radical
(= 0), and the salts of such compounds of the above formula when Rx represents a carboxylic acid function, and the optical and geometric isomers of such compounds. The compounds according to the present invention differ from those of EP-661,258 essentially in that the radical X or the divalent propynylene radical has been substituted with a divalent heteroethylenol radical. The reason for this is that it has been found, surprisingly and unexpectedly, that this structural change makes it possible to significantly increase the properties
pharmaceutical and cosmetic products and also decreases certain side effects thereof. Therefore, the object of the present invention are novel compounds which can be represented by the following general formula:
(I)
wherein: Ar represents a radical that is chosen from formulas (a) to (c) below:
(to)
(b)
(c)
Z is O or S, or N-R6, Rx represents a halogen atom, -CH3, -CH2-0R7, -OR7, -C0R8 or a polyether radical, R2 and R3, which may be identical or different, represent H , Ci-C ^ alkyl, linear or branched, C3-C12 cycloalkyl, -0R7 or -SR7, at least one of R2 and R3 is straight or branched Cj-Cg alkyl or cycloalkyl
3A R2 and R3 taken together form a 5 or 6 membered ring, optionally substituted with at least one methyl and / or optionally interrupted by a heteroatom which is chosen from O and S,
R4 and R5 represent H, a halogen atom, linear or branched CL-CJQ alkyl, -0R7 or a polyether radical, R6 represents H, straight or branched CL-C ^ alkyl or -OCOR9, R7 represents H, alkyl of CJ-CK, straight or branched or -C0R9, R8 represents H, straight or branched Cx-C10 alkyl, -OR10 or
R9 represents Ci-C ^ alkyl, linear or branched,
R10 represents H, straight or branched C1-C20 alkyl, mono- or polyhydroxyalkyl, allyl, aryl or optionally substituted aralkyl, a sugar residue, rt and r, t, which may be identical or different, represent H, Cx- alkyl C10, mono- or polyhydroxyalkyl, optionally substituted aryl, an amino acid or peptide residue or, taken together with the nitrogen atom form a heterocycle, X represents a divalent radical which, from right to left or vice versa, has the formula:
where: Y represents O, S (0) not Se (0) n, n and n "are 0, 1 or 2, with the proviso that when n = 2 and Ar is a radical of formula (a) above, in wherein Rx = CH3 and R5 = H, then at least one of the radicals R2 or R3 is different from -CH3, and the salts of the compounds of formula (I) when Rx represents a carboxylic acid function, as well as the Optical isomers of such compounds of formula (I) When the compounds according to the invention are in the form of a salt, it is preferably an alkali metal or alkaline earth metal salt, or alternatively zinc or an organic amine. the present invention, the term "alkyl of
preferably it refers to methyl, ethyl, isopropyl, butyl, tertbutyl, hexyl, 2-ethylhexyl and octyl radicals.
The term "linear or branched C C-CJO alquilo alkyl" refers in particular to the methyl, ethyl, propyl, 2-ethylhexyl, octyl, dodecyl, hexadecyl and octadecyl radicals. The term "C3-C12 cycloalkyl radical" refers to a mono- or polycyclic radical in particular the cyclopropyl, cyclopentyl, cyclohexyl, 1-methylcyclohexyl and 1-adamantyl radicals. The term "polyether radical" refers to a radical containing from 2 to 5 carbon atoms interrupted by at least 2 oxygen atoms such as the methoxy ethoxy, methoxyethoxy and methoxyethoxymethoxy radicals. The term "monohydroxyalkyl" refers to a radical that preferably contains 2 or 3 carbon atoms, in particular a 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl radical. The term "polyhydroxyalkyl" refers to a radical that preferably contains 3 to 6 carbon atoms and 2 to 5 hydroxyl groups, such as the 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl and 2,3,4-radicals , 5-tetrahydroxypentyl or the residue pentaerythritol. The term "aryl" preferably refers to a phenyl radical optionally substituted with at least 1 halogen atom, a hydroxyl or a nitro function. The term "aralkyl" preferably refers to a benzyl or phenethyl radical optionally substituted with
- at least one halogen atom, one hydroxyl or one nitro function. The term "sugar residue" refers to a residue derived in particular from glucose, from galactose or from mannose, or alternatively from glucuronic acid. The term "amino acid residue" refers in particular to a residue derived from licina, glycine or aspartic acid, and the term "peptide residue" refers more particularly to a dipeptide or tripeptide residue resulting from the combination of amino acids. The term "heterocycle" preferably refers to a piperidino radical, morpholino, pyrrolidino or piperazino, optionally substituted at the 4-position with a lower alkyl of C-L-Cg or a mono- or polyhydroxyalkyl as defined above. When R1, R4 and / or R5 represent a halogen atom, this is preferably a fluorine, chlorine or bromine atom. According to a first preferred embodiment, the compounds according to the invention correspond to the following general formula:
(II)
in which: Ar 'represents a radical of formula:
(to)
or 20
(b)
R17 R4, R5 and X are as defined above for formula (I), Rn Ri2- P-13 and Ri4 which may be identical or different represent H or -CH3, and n is 1 or 2. According to a second preferred embodiment, the compounds according to the invention correspond to the following formula:
(III)
wherein: W represents O or S, R4, Rn, R12, Ar 'and X are as defined above in formulas (I) and (II). Finally, according to a third modality
/ preferred, the compounds according to the invention correspond to the following formula:
(IV)
wherein: R4, Ar 'and X are as defined above in the formulas
(I) to (III), and at least one of the radicals R'2 and / or R'3 represent a cycloalkyl mono- or polycyclic radical of C5-C10, the others represent one of the meanings given for R2 or R3 . Among the compounds of formulas (I) to (IV) above, according to the present invention, mention may be made in particular of the following: 4- (5, 5, 8, 8-tetramethyl-5, 6,7, Methyl 8-tetrahydro-2-naphthylsilyanilinyl) benzoate, 4- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-2-naphthylsulfanylethynyl) benzoic acid, 4- (5, 5 Methyl, 8, 8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulfonylethynyl) benzoate,
4- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyloxyethynyl) methyl benzoate, 4- (5, 5, 8, 8-tetramethyl-5, 6,7 acid , 8-tetrahydro-2-naphthyloxyethynyl) benzoic acid, methyl 4- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulfanylethynyl) benzoate, 4- (5, 5) acid , 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-2-naphthylsulfilenylnyl) benzoic acid, 4- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2- methyl (naphthylsulfonylethynyl) benzoate, 4- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-2-naphthylsulfonylethynyl) benzoic acid, 4- (5, 5, 8, 8-tetramethyl-5) Methyl, 6, 7, 8-tetrahydro-2-naphthylsulfinylinyl) benzoate, 4- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-2-naphthylsulfinylethynyl) benzoic acid, 4- ( 5, 5, 8, 8 -tetramethi, 1-5, ß, 7,8-tetrahydro-2-naphthylslanilethynyl) methyl benzoate, 4- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8 -tetrahydro-2-naphthylslanilethynyl) benzoic acid, methyl 2-hydroxy-4- (5,5,8, 8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylslanilethynyl) benzoate, ac gone 2-hydroxy-4- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylslanilethynyl) benzoic acid,
6- (4-methoxymethoxyp eni let inil selanil) -1, 1, 4, 4-tetramethyl-1, 2,3,4-tetrahydronaphthalene, 6- (5, 5, 8, 8-tetramethyl-5, 6, 7 , 8-tetrahydro-2-naphthylselanilethynyl) ethyl nicotinate, 6- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-2-naphthylslanilethynyl) nicotinic acid, N- (4-hydroxyphenyl) -4- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylesphenylethynyl) benzamide, 5- (5, 5, 8, 8-tetramethyl-5,6 carboxylate) , 7, 8-tetrahydro-2-naphthylslanilethynyl) -2-pyridine methyl 2- (4-chlorofenilselaniletinyl) -5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene, 4- (3 , 5, 5, 8, 8 - ent ame tyl-5, 6, 7, 8-tetrahydro-2-naphyl-phenylethynyl) methyl benzoate, 4- (3, 5, 5, 8, 8-pentamethyl-5 , 6, 7, 8-tetrahydro-2-naphyl-phenylethynyl) benzoic acid, 2-hydroxy-4- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylslanilethynyl) benzoate of methyl, 2-hydroxy-4- (3, 5, 5, 8, 8-pentamethyl-5,6,7,8-tetrahydro-2-naphyl-phenylethynyl) -benzoic acid, 6- (3, 5, 5, 8, 8-pentamethyl-5, 6, 7, 8-tetra idro-2-naphyl-phenylethynyl) ethyl nicotinate, 6- (3,5,5,8,8-pentamethyl-5,6, 7, 8-tetrahydro-2-naphthylslanilethynyl) nicotinic,
N- (4-hydroxyphenyl) -6- (3, 5, 5, 8, 8-pentamethyl-5,6,7,8-tetrahydxo-2-naphthylasphenylethynyl) nicotinamide, N-butyl-6- (3, 5 , 5, 8, 8-pentamethyl-5, 6, 7, 8-tetrahydro-2-naphylselanilethynyl) nicotinamide, morpholin-4-yl- [6- (3,5,5,8, 8 -p ent ame ti 1-5, 6,7,8-tetrahydro-2-naphthylesphenylethynyl) -3-pyridyl] methoxy, 5- (3, 5, 5, 8, 8-pentamethyl-5, 6, 7, 8 -tetrahi dro-2-naphilselaniletinyl) yl pyridine-2-carboxylate, 5- (3,5,5,8,8-pentayl-5,6,7,8-tetrahydro-2-acid) -naf-tyl-phenylethynyl) -pyridine-2-carboxylic acid, [4- (5, 5, 8, 8-tetrayl-5, 6,7, 8-te-tr- ahydro-2-naphthyl, the indigo t -yl) phenyl] -anol, 4- (5, 5, 8, 8-tetrayl-5, 6, 7, 8-tetrahydro-2-naphoryltinsulfonyl) yl benzoate, 4- (5, 5, 8, 8-tetrayl-5, 6.7, yl 8-tetrahydro-2-naphthylethylsulfonyl) benzoate, 4- (5, 5, 8, 8-yl, yl, 1-5, 6, 7, 8-tetrahydro-2-naphthinylsulfonyl) benzoate, acid 4- (5,5,8,8-tetrayl-5,6,7,8-tetrahydro-2-naphthylethylsulfonyl) benzoic acid 4- (5, 5, 8, 8-tetrayl-5,6,7) 8-tetrahydro-2-naphthalethylsulfonyl) benzoic acid, 4- (5, 5, 8, 8-tetrayl-5, 6, 7, 8-tetrahydro-2-naphthalethylsulphyl) benzoic acid,
4- (3, 5, 5, 8, 8 -pentamethi-5, 6,7, 8-tetrahydro-2-naphthylslanilethynyl) phenol, 4- (4-hydroxy-5, 5, 8, 8-tetramethyl-5, Ethyl 6, 7, 8-tetrahydro-2-naphthylselanilethynyl) enzoate, 4- (4-methoxymethoxy-5,5,8,8-tetramethi-1-5,6,7,8-tetrahydro-2-naphthylslanilethynyl) enzoate ethyl, 4- (4-methoxymethoxy-5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylslanilethynyl) benzoic acid, 4- (4-pentyloxy-5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylslanilethynyl) benzoic acid 4- (3-methoxymethoxy-5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylslanilethynyl) ) ethyl benzoate, ethyl 4- (3-methoxyethoxymethoxy-5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanilethynyl) benzoate, 4- (3-methoxyethoxymethoxy-5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-2-naphthylslanilethynyl) benzoic acid, 4- (3-methoxymethoxy-5, 5, 8, 8-tetramethyl-5, 6, 7, 8- tetrahydro-2-naphthylslanilethynyl) benzoic acid, 4- (3-pentyloxy-5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-2-naphthylslanilethynyl) ethyl benzoate, 4- (3-pentyloxy-5, 5, 8, 8-tetramethyl-5, 6,7,8-tetrahydro-2-naphthylslanilethynyl) benzoic acid, [4 - (5, 5, 8, 8 - te tramet il - 5, 6, 7, 8 - tet rahi dro - 2 -naphthylslanilethynyl) phenyl] carbaldehyde,
4- (4,4-dimethylthiochroman-8-yl-silyl-t-methyl) -benzoate, methyl, 4- (4,4-dimethylthio-chroman-8-yl-phenylethynyl) -benzoic acid 4- (5, 5, 8, 8 methyl-tetramethyl-5, 6, 7, 8-tetrahydro-8-naphyl-t-phenylethynyl) -benzoate, 4- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-8-naphilsene-phenylethynyl) ) benzoic acid, 4- [3- (1-adamantyl) -4-methoxy-f-enyl) -1-ylserinyl-ethynyl] -benzoate, 4- [3- (1-adaman-t-yl) -4-methoxy-phenyl) -1 -ylselanilethynyl] enzoic, methyl 4- (4- (1-adamantyl) -3-? ethoxy-enyl) -1-ylsalkylaniline] benzoate, and 4- [4- (1-adamantyl) -3-methoxy-enyl) - 1-ilselaniletinyl] benzoic acid. An object of the present invention are also the processes for preparing the compounds of formula (I) above according to the reaction schemes provided in Tables A and B. With reference to Table A, the compounds of formula (I) in which X represents a divalent radical
V X
that is, the compounds of formula (la) can be obtained according to two different synthesis routes depending on whether Y = oxygen or Y? oxygen. When X = oxygen, the starting material is the compound of formula (JL), which, in the presence of a base such as potassium hydride or sodium hydride, is then coupled with trichlorethylene. The obtained dichloroethylene product of formula (2) is then subjected to the action of a lithiated phase such as butyllithium, in a solvent such as THF, to provide the acetylenic compound of formula (3_). This acetylene is then coupled with an aryl halide or a heteroaryl halide, preferably an iodine derivative, in the presence of a palladium catalyst to provide the compounds of formula (Ha) with Y = oxygen. When and ? Oxygen, is first prepared in lithium acetylide of formula (5_), from aromatic or heteroaromatic acetylenic compound (4), in the presence of a lite derivative such as butyllithium, in a solvent such as THF. Starting with the lithium acetylide (_5) which is not isolated, a coupling is carried out with the compound of the formula (_6) in a solvent such as THF, to provide the compounds of the formula (la) with Y? oxygen. Starting with these compounds of formula (la), in which Y = S or Se, it is possible to have access to derivatives
oxidized by oxidation using an oxidizing agent such as meta-chloroperbenzoic acid (mCPBA) or sodium periodate. Referring now to Table B, the compounds of formula (I), in which X represents a divalent radical
that is, the compounds of formula (le), can also be obtained according to two different synthesis routes based on whether Y = oxygen or Y? oxygen. When Y = oxygen, the starting material is an aromatic or heteroaromatic compound of formula (7_), which, in the presence of a base such as potassium hydride or sodium hydride, in a solvent such as THF, is then coupled with trichlorethylene . The obtained (8_) dichloroethylene product is then subjected to the action of a lithiated base such as butyllithium, in THF to provide the oxoacetylenic compound of the formula (S >);). This acetylene is then coupled with aryl halide (1_0) preferably an iodo derivative, in the presence of a palladium catalyst, to provide compounds of formula (le) with Y = oxygen.
When and ? Oxygen, the starting material is an aromatic acetylenic compound of formula (1_1) which is then converted to a lithiated derivative in the presence of butyllithium, for example in a solvent such as THF. The lithiated acetylene derivative (12), which is not isolated, is then coupled with an aromatic or heteroaromatic compound of formula (13) the coupling reaction is carried out in a solvent such as THF. The compounds of formula (le) with Y? Oxygen in this way are obtained by this synthesis route. Starting with these compounds of formula (le), in which Y = S or Se, it is also possible to obtain the oxidized derivatives by oxidation using an oxidizing agent such as meta-chloroperbenzoic acid (mCPBA) or sodium periodate. In the compounds according to the invention, when the radical R ± represents -COOH, these radicals are prepared by protecting the carboxylic acid function with a protecting group of the alkyl type. By saponification of the ester function in the presence of a base such as sodium hydroxide or lithium hydroxide in an alcohol solvent or in THF, in this manner the corresponding free acids are obtained. When Rx is -OH, the compounds can be obtained from the corresponding acid by reduction in the presence of hydride such as boron hydride.
When Rx is -CH = 0, the compounds can be obtained by oxidation of the corresponding alcohols using manganese oxide or pyridinium dichromate. When R ± is
the compounds can be obtained by conversion of the corresponding acid into the acid chloride, for example thionyl chloride, followed by reaction with aqueous ammonia or a suitable amine. An object of the present invention are also compounds of the formula (I) as defined above, as medical products. The compounds of the general formula (I) have agonist or antagonist activity with respect to the expression of one or more biological markers in the differentiation tests of mouse embryonic teratocarcinoma cells (F9) (Skin Pharmacol, 3, p. 267, 1990) and / or the in vitro differentiation of human keratonicites (Skin Pharmacol, 3, pp. 70-85, 1990). These tests mentioned above show the activities of the compounds in the fields of differentiation and proliferation. The activities are also
can measure in cellular transactivation tests using recombinant RAR receptors according to the method of B.A. Bernard et al., Bichemical and Biophysical Research Communication, vol. 186, 977-983, 1992. The compounds according to the invention are particularly suitable in the following fields of treatment: 1) for treating dermatological complaints associated with keratinization disorders which are based on differentiation and / or proliferation, in particular for treatment of common acne, comedones, polymorphonuclear leukocytes, rosacea, acne nodules and acne conglobata, senile acne and secondary acne such as solar acne, related to medication or occupational, 2) to treat other types of keratinization disorders, particularly ichthyosis, ichthyosiform states, Darier's disease, palmoplantar keratoderma, leukoplakia and leukoplasiform states and cutaneous or mucous lichen (buccal),
3) to treat other dermatological complaints associated with a disorder in keratinization with an inflammatory and / or immunoallergic component and, in particular, with all forms of psoriasis, whether cutaneous, mucosal, or psoriasis, and even psoriatic rheumatism or alternatively atopy cutaneous such as eczema or respiratory atopy or alternatively gingival hypertrophy; the
compounds can also be used in certain inflammatory discomforts which do not present keratinization disorders; 4) to treat all dermal or epidermal proliferations, whether benign or malignant and whether they are of viral origin or of some other origin, such as common warts, flat warts, and verriform epidermodisplasia, is also possible for oral or flowering papillomatous and proliferations that are induced by ultraviolet radiation, particularly in the case of vasocellular or spinocellular epithelium, 5) to treat other dermatological disorders such as bulosis and collagen diseases, 6) to treat certain ophthalmological disorders, in particular corneopathies, 7) to prepare or combat aging of the skin, whether it is induced by light or chronic aging, or to reduce actinic keratosis and pigmentations, or any pathology associated with chronological or actinic aging, 8) to prevent or cure the stigmata of epidermal and / or dermal atrophy induced by local or systemic corticosteroids, or any other form of cutaneous atrophy, 9) to prevent or treat scarring disorders or to prevent or repair stretch marks,
) to combat sebaceous functioning disorders such as hyperseborrhea or acne or simple seborrhea,
11) in the treatment or prevention of cancerous or precancerous conditions, 12) in the treatment of inflammatory discomforts such as arthritis, 13) in the treatment of any general or cutaneous disease of viral origin, 14) in the prevention or treatment of alopecia, 15) in the treatment of dermatological or general diseases that have an in unological component, and 16) in the treatment of diseases of the cardiovascular system such as arteriosclerosis. In the therapeutic fields mentioned above, the compounds according to the invention can be advantageously used in combination with other compounds of retinoid-like activity, with vitamins D or derivatives thereof, with corticosteroids, with agents that eliminate free radicals, a- hydroxy or -ceto acids or derivatives thereof, or alternatively with ion channel blockers. The expression "vitamin D or derivatives thereof" means, for example, derivatives of vitamin D2 or D3 and in particular 1,25-dihydroxyvitamin D3. The expression "agents against free radicals" means, for example, -tocopherol, superoxide dismutase or SOD, ubiquinol or certain chelating agents.
metallic The expression "α-hydroxy or α-keto acids or derivatives thereof" means, for example, lactic, malic, citric, glycolic, mandelic, tartaric, glyceric or ascorbic acids or the salts, amides or esters thereof. Finally, the term "ion channel blockers" means, for example, minoxidyl (2,4-diamino-6-piperidinopyrimidine-3-oxide) and derivatives thereof. An object of the present invention are also pharmaceutical compositions containing at least one compound of formula (I) as defined above, one of the optical or geometric isomers thereof or one of the salts thereof. The pharmaceutical compositions are designed in particular to treat the diseases mentioned above and are characterized in that they comprise a pharmaceutically acceptable carrier which is compatible with the selected mode of administration, at least one compound of formula (I), one of the optical isomers or geometries of the same or one of the salts thereof. The compounds according to the invention can be administered enterally, parenterally, topically or ocularly. Via the enteral route, the compositions may be in the form of tablets, gelatin capsules, sugar-coated tablets, syrups, suspensions, solutions, powders, granules, emulsions, microspheres or nanospheres or
polymeric or lipid vesicles which allow controlled release. Via the parenteral route, the compositions may be in the form of solutions or suspensions for infusion or injection. The compounds according to the invention are generally administered at a daily dose of about 0.01 mg / kg, up to 100 mg / kg of body weight, taken in 1 to 3 doses. By means of the topical route, pharmaceutical compositions based on the compounds according to the invention are designed more particularly for the treatment of the skin and mucous membranes and may be in the form of ointments, creams, milks, ceratos or thick ointments, powders , impregnated pads, solutions, gels, sprays, lotions or suspensions. They can also be in the form of microspheres or nanospheres or polymeric or lipid vesicles, or polymeric patches and hydrogels which allow the controlled release of the active principle. In addition, these topical compositions may be in anhydrous form or in aqueous form, based on the clinical indication. By means of the ocular route, these can be mainly in eye drops. These compositions for topical or ocular use contain at least one compound of formula (I) as defined above, or one of the optical or geometric isomers thereof or
alternatively one of the salts thereof, at a concentration preferably between 0.001% and 5% by weight relative to the total weight of the composition. The compounds of formula (I) according to the invention also find an application in the cosmetic field, in particular in the hygiene of the body and hair and especially to treat skin types with a tendency to acne to promote the growth of hair again , to combat hair loss, to combat the oily appearance of the skin or hair, in protection against the harmful effects of the sun or in the treatment of physiologically dry skin types, and to prevent and / or combat induced aging by the skin. light or chronological. In the cosmetic field, the compounds according to the invention can also be used advantageously in combination with other compounds of retinoid-like activity, with vitamins D or derivatives thereof, with corticosteroids, with agents against free radicals, α-hydroxy or α-keto acids or derivatives thereof, or alternatively with ion channel blockers, all of these latter compounds are as defined above. The present invention is therefore also directed towards a cosmetic composition which is characterized in that it comprises, on a cosmetically acceptable support, at least one compound of formula (I) as
defines before or one of the optical or geometric isomers thereof or one of the salts thereof, it being possible for the cosmetic composition to be, in particular, in the form of a cream, a milk, a lotion, a gel, microspheres or nanospheres of polymeric or lipid vesicles, a soap or a shampoo. The concentration of compounds of formula (I) in the cosmetic compositions according to the invention is advantageously between 0.001% and 3% by weight in relation to the total weight of the composition. The pharmaceutical and cosmetic compositions according to the invention also contain inert additives or even pharmacodynamically or cosmetically active additives or combinations of these additives and, in particular: wetting agents; depigmenting agents such as hydroquinone, azelaic acid, caffeic acid or kojic acid; emollients; wetting agents such as glycerol, PEG-400, thiamorpholinone, and derivatives thereof, or urea; anti-seborrhea or acne agents such as S-carboxymethylcysteine, S-benzylcysteamine, and the salts or derivatives thereof, or benzoyl peroxide; antibiotics such as erythromycin or esters thereof, neomycin, clindamycin and esters thereof, and tetracycline; antifungal agents such as ketaconazole, or 4,5-polymethylene-3-isothiazolidones; agents to promote the creation again
of hair, such as minoxidil (2,4-diamino-6-piperidinopyrimidine-3-oxide) and derivatives thereof, diazoxide (7-chloro-3-methyl-1,2,4-benzothiadizine 1,1-dioxide) and phenytoin (5,4-diphenylimidazolidin-2,4-dione); non-spheroidal anti-inflammatory agents; carotenoids and, in particular, β-carotene; anti-psoriasis agents such as anthralin and derivatives thereof and, finally, eicosa-5, 8, 11, 14-tetrainoic acid and eicosa-5, 8, 11-triinoic acid, the ethers and amides thereof. The compositions according to the invention may also contain flavor improving agents, preservatives such as para-hydroxybenzoic acid esters, stabilizing agents, moisture regulators, pH regulators, osmotic pressure modifiers, emulsifying agents, UV filter agents. -A and UV-B, and antioxidants such as α-tocopherol, butylated hydroxyanisole or butylated hydroxytoluene. Several examples for obtaining the active compounds of the formula (I) according to the invention, as well as the various cosmetic and pharmaceutical formulations based on such compounds will now be provided for illustrative purposes and without limiting nature.
Examples
Example 1 4- (5,5,8, 8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulfanylethynyl) -benzoic acid methyl ester
(a) Methyl 4-trimethylsilylbenzoate
To a three-necked flask are introduced 21.5 g (0.1 moles) of methyl 4-bromobenzoate, 300 ml of triethylamine and a mixture of 200 mg of palladium acetate and
400 mg of triphenylphosphine. Then 20 g are added
(0.204 moles) of trimethylsilylacetylene, after which the mixture is gradually heated to 90 ° C for 1 hour and left at this temperature for 5 hours. After the reaction medium is cooled, the salt is filtered off and the filtrate is evaporated. The residue is taken up in 200 ml of hydrochloric acid (5%) and 400 ml of ethyl ether. The ether phase is separated after sedimentation has taken place, washed with water, dried over magnesium sulfate and evaporated. The obtained residue is purified by chromatography on a silica column eluted with dichloromethane. After evaporation of the solvents, 23 g (100%) of the expected derivative are collected in the form of a colorless oil.
(b) methyl 4-ethynylbenzoate
Thirty-three grams (226 mmoles) of the product obtained above in 300 ml of methanol is introduced into a three-necked flask. Then 125 g of potassium carbonate are added and the medium is stirred for 48 hours at room temperature. The solvent is removed by evaporation and the residue obtained is purified by chromatography on a silica column using the dichloromethane. After evaporation of the solvents, the residue is taken up in heptane and, after filtration, 32 g (100%) of the expected derivative is collected in the form of a yellow or straw solid.
(c) 4 - (5 r 5, 8, 8 - t e t ram e t i l - 5, 6, 7, 8 - t e t rah i dro -2 naf tilsulfaniletinil) methyl benzoate
A 2.5 M solution of butyllithium in hexane is added
(20 min., 8.1 ml) was added to a solution of methyl 4-ethynylbenzoate (3 g, 18.7 mmol) in THF (300 ml) at -78 ° C. The temperature is maintained for 45 minutes and then increased to -40 ° C. A disulfide solution of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalene (J. Med. Chem. 1995, 38, 3171) (16.5 g) is then added at this temperature. , 37.4 mmoles) in THF (60 ml). The reaction medium is subsequently stirred for 1 hour at 0 ° C, after which the
Pour into a mixture of ethyl ether and a saturated solution of ammonium chloride. The organic phase is washed twice with water, dried over anhydrous magnesium sulfate and concentrated on a rotary evaporator under vacuum at 40 ° C. After chromatography on a silica column, using a mixture of heptane / methylene chloride (60/40), and after evaporation, 1.9 g of a white solid (27%) are obtained. H (CDC1, 1.28 (6H, s), 1.30 (6H, s), 1.69 (4H, s), 3.92 (3H, s), 7.25 to 7.31 (2H Ar, m), 7.42 (1H Ar, d, J = 2Hz), 7.50 (1H, Ar, d, J = 7.5Hz), 8.00 (1H, Ar, d, J = 7.5Hz) 13C (CDC13): 32.25 (CH3), 34.60 (C), 35.02 (C ), 35.36 (CH2), 52.68 (OCH3), 81.26 (C), 96.96 (C), 124.82 (CH Ar), 125.56 (CH Ar), 128.29 (C Ar), 128.37 (CH Ar), 128.85 (C Ar) ), 129.88 (C Ar), 130.04 (2 CH Ar), 131.29 (2 CH Ar), 144.66 (C, Ar), 146.88 (C Ar), 166.95 (COO).
Example 2: 4- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulfanylethynyl) benzoic acid
Refluxing for 24 hours a solution of
4- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-2-naphthylsulfanylethynyl) methyl benzoate (590 mg, 1.6 mmol) and lithium hydroxide (383 mg, 9.3 mmol) in THF The reaction mixture is poured into a mixture of Eto20 / water, acidified to pH 1 with a concentrated hydrochloric acid solution, and extracted once
with diethyl ether. After phase separation by sedimentation, the organic phase is washed twice with water, dried over magnesium sulfate and concentrated on a rotary evaporator under vacuum at 40 ° C. The solid obtained crystallizes from heptane and 440 mg (77%) of a white solid, m.p. (melting point) = 193.5 ° C.
NMR d ppm: XH (CDC13): 1.28 (6H, s), 1.30 (6H, s), 1.69 (4H, s), 7.29 to 7.32 (2H Ar, m), 7.42 (1H Ar, d, J = 2Hz ), 7.53 (1H Ar, d, J = 8, 5Hz), 8.08 (1H Ar, d, J = 8.5Hz). 13 C (CDCl 3): 31.44 (CH3), 33.80 (C), 34.22 (C), 34.54 (CH2), 81.30 (C), "100.01 (C), 124.06 (CH Ar), 124.81 (CH Ar), 127.59 ( CH Ar), 127.94 (C Ar), 128.46 (C Ar), 129.87 (2 CH Ar), 130.49 (2 CHAr), 143.93 (C Ar), 146.12 (C Ar), 171.06 (COO).
Example 3: Methyl 4- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulfonylethynyl) benzoate
A solution of metaperbenzoic acid (700 mg) in CHC13 (12 ml) is added dropwise at 0 ° C to a solution of the product of Example 1 (500 mg, 1.3 mmol) in 6 ml of CHC13. After stirring for 1 hour, the mixture is concentrated on a rotary evaporator under vacuum. After chromatography on
a column of silica with a mixture of heptane / methylene chloride (30/70), 280 mg of a white solid (52%) are obtained.
XH (CDC13): 1.32 (6H, s), 1.34 (6H, s), 1.73 (4H, s), 3.93 (3H, s), 7.51 (2H Ar, d, J = 8.3Hz), 7.60 (2H Ar , d, J = 8.5Hz), 7.78 R Ar, dd, Jl = 8.5Hz, J2 = 2Hz), 7.98 to 8.05 (3H Ar, m). 13 C (CDCl 3): 31.63 (CH 3), 31.73 (CH 3), 34.58 (CH 2), 34.64 (CH 2),
34. 85 (C), 34.98 (C), 52.52 (CH3), 87.77 (C), 90.99 (C), 122.61
(C Ar), 124.35 (CH Ar), 125.99 (CH Ar), 128.04 (CH Ar), 129.68
(CH Ar), 132.44 (C Ar), 132.69 (CH Ar), 138.37 (C Ar), 152.50
(C Ar), 165.83 (COO).
Example 4: Methyl 4- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylslanylethyl) benzoate
(a) Disselenide of 5, 6, 7, 8-tetrahydro-5, 5, 8, 8-tetramethyl-2-naphthalene
A solution of 1.7 M of tert-butyllithium in pentane (37.4 mmol, 22 ml) is added to a solution of 2-bromo-5,6,7,8-tetrahydro-5, 5, 8, 8-tetramethyl-naphthalene ( 4.22 g, 15.8 mmol) in THF (100 ml) at -78 ° C for 10 minutes. The mixture is stirred at 0 ° C for 30 minutes. Selenium (1.33 g, 16.8 mmol) is added in two portions. The mixture is stirred at 0 ° C for 15 minutes and then at room temperature for 30 minutes. A solution of 1N HCl (40 ml) and the mixture of
reaction is then treated with ethyl ether. The organic phase is washed twice with water, dried over anhydrous magnesium sulfate and concentrated on a rotary evaporator under vacuum at 40 ° C. 10 ml of ethanol and 50 mg of sodium hydroxide are added to the obtained oil. The mixture is vigorously stirred for a few minutes and then concentrated on a rotary evaporator under vacuum at 40 ° C. The solid obtained is filtered through silica (eluted with heptane) and then crystallized from a mixture of ethanol / ether. After filtration, 2.9 g (69%) of a orange-colored solid is obtained. t NMR (CDC13): 1.21 (6H, s), 1.25 (6H, s), 1.65 (4H, s), 7.20 (1H Ar, d, J = 8.25 Hz), 7.38 (1H Ar, dd, J = l .9 Hz, J = 8.25 Hz), 7.51 (1H Ar, d, J = 1.9 Hz).
(b) methyl 4- (5, 5, 8, 8-tetramethyl-5,6,1,8-tetrahydro-2-naphryl-phenylethynyl) benzoate
Bromine (0.15 ml, 2.9 mmol) is added to a diselenide solution of 5, 6, 7, 8-tetrahydro-5, 5, 8, 8-tetramethyl-2-naphthalene (1.5 g, 2.8 mmol) in THF (3 g. ml). The mixture is stirred at room temperature for 2 h and the solvent is subsequently removed. Copper iodide (2.15 g, 11.3 mmol), methyl 4-ethynylbenzoate (810 mg, 5 mmol) obtained according to Example 1 (b) and DMF (15 ml) are added. The
The reaction mixture is stirred at room temperature for 3 h and then treated with ethyl ether and an aqueous solution of ammonia. The organic phase is washed twice with water, dried over anhydrous magnesium sulfate and concentrated on a rotary evaporator under vacuum at 40 ° C. The residue is recrystallized from heptane and, after filtration, 1.8 g (75%) of a white powder, m.p. = 90-l ° C. XH NMR (CDC13): 1.28 (6H, s), 1.30 (6H, s), 1.69 (4H, s), 3.92 (3H, s), 7.29 (1H Ar, d, J = 8.3 Hz), 7.36 (1H Ar, dd, J = 1.9 Hz, J = 8.3 Hz), 7.48 to 7.53 (3H Ar, m), 7.98 (2H Ar, d, J = 8.5Hz).
Example 5: Acid '5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylslanylethyl) enzoic acid
Lithium hydroxide (440 mg) is added to a solution of methyl 4- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-2-naphthylselanyl-ethynyl) benzoate (740 mg, 1.74 mmoles), obtained in Example 4, in 15 ml of THF and 2 ml of a water / methanol mixture (1/1). The reaction medium is refluxed for 8 h. It is then poured into a mixture of ethyl ether / water, acidified to pH 1 with a concentrated hydrochloric acid solution and extracted with ethyl ether. After phase separation by sedimentation, the organic phase is washed twice with water, dried over anhydrous magnesium sulfate and concentrated in a rotary evaporator under vacuum
at 40 ° C. The residue recrystallizes from heptane. After filtration, 615 mg (86%) of a white powder, m.p. = 182 ° C. XH NMR (CDC13): 1.28 (6H, s), 1.30 (6H, s), 1.69 (4H, s), 7.29 (1H Ar, d, J = 8.3 Hz), 7.36 (1H Ar, dd, J = l .9 Hz, J = 8.3 Hz), 7.52 to 7.55 (3H Ar, m), 8.07 (2H Ar, d, J = 8.5Hz).
Example 6: Methyl 2-hydroxy-4- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylslanylethyl) benzoate
(a) Methyl 4-trimethylsilanylethynyl-2-hydroxybenzoate
In a manner similar to that of Example 1 (a), starting with 4.00 g (14.4 mmol) of methyl 4-iodo-2-hydroxybenzoate, 3.07 g (86%) of the expected compound are obtained in the form of a colored oil orange. ? NMR (CDC13): 0.06 (s, 9H), 3.75 (s, 3H), 6.76 (dd, 1H, J = 8.2 / 1.5 Hz), 6.87 (d, 1H, J = 1.4 Hz), 7.56 (d, 1H , J = 8.2 Hz), 10.53 (s, 1H).
(b) Methyl 4-ethynyl-2-hydroxybenzoate
3.07 g (12.4 mmol) of methyl 4-trimethylsilanylethynyl-2-hydroxybenzoate are mixed in a 500 ml three-necked flask with 50 ml of THF and added dropwise.
13. 7 ml of a solution of tetrabutyl onium fluoride (1 M / THF). The reaction medium is stirred for 1 h at room temperature and then poured into water and extracted with ethyl ether. After phase separation by sedimentation, the organic phase is dried over magnesium sulfate and concentrated. 2.48 g (100%) of a beige powder are obtained. p.f. = 62 ° C. XH NMR (CDC13): 3.21 (s, 1H), 3.96 (s, 3H), 6.98 (dd, 1H, J = 8.2 / 1.5 Hz), 7.10 (d, 1H, J = 1.3 Hz), 7.78 (d, 1H, J = 8.2 Hz), 10.76 (s, 1H).
(c) methyl 2-hydroxy-4- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl-ailethyl) benzoate
In a manner similar to that of Example 4 (b), after reaction of 1.5 g (2.8 mmol) of 5,6,7,8-tetrahydro-5, 5, 8, 8-tetramethyl-2-naphthalene diselenide, in 2 ml of THF, with bromine (0.15 ml, 2.9 mmol), add copper iodide (2.15 g, 11.3 mmol) and methyl 4-ethynyl-2-hydroxybenzoate (890 mg, 5 mmol) in 10 ml of DMF. . After purification on a silica column (dichloromethane 10 / heptane 90), 2.15 g (97%) of the expected ester derivative is obtained in the form of a yellow solid: m.p. = 70 ° C.
? NMR (CDCl 3): 1.28 (d, 12H); 1.69 (s, 4H) 3.95 (s, 3H); 6.94 (dd, 1H); 7.04 (d, 1H); 7.26 to 7.37 (m, 2H); 7.51 (d, 1H); 7.77 (d, 1H); 10.77 (s, 1H).
13 C NMR (CDCl 3): 31.8; 4 * CH3 / 34.2; Cq / 34.6 Cq / 34.9; 2 * CH2 / 52.4; CH3 / 75.1; Cq / 101.6 Cq / 111.9; Cq / 119.7; CH / 121.9; CH / 124.5 -Cq / 127.0; CH / 127.8; CH / 128.1; CH / 129.9; CH / 130.4; Cq / 144.7; C / 146.7; Cq / 161.2; Cq / 170.1; Cq.
Example 7: 2-Hydroxy-4- (5,5,8,8-tetramethyl) acid
,6,7, 8-tetrahydro-2-naphthylslanilethynyl) benzoic acid
A solution of methyl 2-hydraxy-4- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-2-naphthylselanyl-ethynyl) benzoate (1.2 g, 2.72 mmol) obtained in Example 6 (c) and sodium hydroxide (1.5 g, 37.5 mmol) in 20 ml of THF is refluxed for 24 h. The reaction medium is then poured into a mixture of ethyl acetate / water, acidified to pH 1 with a concentrated hydrochloric acid solution and extracted once with ethyl acetate. After phase separation by sedimentation, the organic phase is washed twice with water, dried over magnesium sulfate and concentrated on a rotary evaporator under vacuum at 40 ° C. 1 g (86%) of a yellow solid, m.p. = 170 ° C.
X H NMR (DMSO): 1.28 (, 12H); 1.68 (s, 4H); 6.95 (d, 1H); 7.03 (s, 1H); 7.25 to 7.37 (m, 2H); 7.51 (s, 1H); 7.83 (d, 1H). XC NMR (DMSO): 31.8; 4 * CH3 / 34.2; Cq / 34.6; Cq / 34.9; 2 * CH2 / 76.0; Cq / 101.5; Cq / 119.7 CH / 122.1; CH / 124.4; Cq / 127.1; Cq / 127.9 CH / 128.2; CH / 130.9; CH / 131.4; Cq / 144.7 Cq / 146.7; Cq / 161.6; Cq / 174.2; Cq.
Example 8: 6- (4-methoxymethoxy-phenylethylsenyl)
1,1,4,4-tetramethyl-1,2,4,4-tetrahydronaphthalene
(aj 2-iodine-4-mephroxy-Oethoxybenzene
g (22.7 mmol) of 4-iodophenol are added to a suspension of 75% sodium hydride (872 mg; 27.25 mmoles) in 20 ml of dimethylformamide. The mixture is stirred for 30 minutes at room temperature and then 2.5 ml (34.1 mmoles) of methoxymethyl chloride are added. The solution is stirred for 2 h and then the medium is poured into a mixture of ethyl acetate / water. After phase separation by sedimentation, the organic phase is washed twice with water, dried over magnesium sulfate and concentrated on a rotary evaporator under vacuum at 40 ° C. 5.74 g (96%) of a colorless oil are obtained. ? NMR (CDC13): 3.45 (s, 3H); 5.13 (s, 2H); 6.80 (d, 2H); 7.55 (d, 2H)
13 C NMR (CDCl 3): 56.0; CH3 / 84.3; Cq / 94.3; CH2 / 118.4; 2 * CH / 138.2; 2 * CH / 157.0; Cq (b) l-trimethylsilylethynyl-4-methoxymethoxybenzene
They are introduced in a three-necked flask 5.74 g
(21.7 mmoles) of l-iodo-4-methoxymethoxybenzene, 100 ml of triethylamine and a mixture of 1.53 g (2.18 mmoles) of dichloro-bis (triphenylphosphine) palladium and 831 mg (4.37 mmoles) of copper iodide. Then 6.14 ml (43.5 mmol) of trimethylsilylacetylene are added and the medium is stirred for 48 h at room temperature. It is then poured into a water / ethyl acetate mixture. The organic phase is washed twice with water, and after separation of the phases by sedimentation, washed with magnesium sulfate and concentrated.
(c) l-ethynyl-4-methoxymethoxybenzene
In a manner similar to that of Example 1 (b), by reaction of the product obtained according to Example 8 (b) with 50 ml of methanol and with potassium carbonate for 15 h at room temperature, and after purification on a column of silica (dichloromethane 20 / heptane 80), 840 mg (24%) of the expected product are obtained in the form of a yellow oil.
X H NMR (CDCl 3)): 3.00 (s, 1 H); 3.46 (s, 3H) 5.17 (s, 2H); 6.97 (d, 2H); 7.42 (d, 2H). 13 C NMR (CDC13): 56.1; CH3 / 76.1; Cq / 83.5; CH / 94.2; CH2 / 115.4; Cq / 116.1; CH / 133.6 CH / 157.6; Cq
(d) 6- (4-methoxymethoxyphenylethynylselanyl-1,4,4-tetramethyl-1,2,3,4-tetrahydronaf
In a manner similar to that of Example 4 (b), after reaction for 1.3 g (2.44 mmol) of diselenide of 5, 6,7, 8-tetrahydro-5, 5, 8, 8-tetramethyl-2-naphthalene in 2 ml of
THF, with bromine (0.13 ml, 2.5 mmol), copper iodide is added
(1.86 g, 9.8 mmol) and l-ethynyl-4-methoxymethoxybenzene (713 mg;
4.4 mmol) in 10 ml of DMF. After purification on a silica column (dichloromethane 20 / heptane 80), 1.7 g (90%) of the expected derivative is obtained in the form of a yellow oil. EMI NMR (CDCl3): 1.27 (m, 12H); 1.67 (s, 4H) 3.47 (s, 3H); 5.18
(s, 2H); 6.98 (dd, 2H); 7.01 to 7.51 (, 5H). 13 C NMR (CDCl 3): 31.8; 4 CH3 / 34.1; Cq / 34.5; Cq 34.9; 2 CH2 / 56.1; CH3 / 68.3; Cq / 77.5; Cq / 102.0; Cq / 116.1; 2 * Ch / 116.7;
Cq / 125.3; Cq / 133.3; 2 * CH / 144.2; Cq / 146.5; Cq / 157.4; Cq
Example 9: 6- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanilethynyl) nicotinic acid
(a) ethyl 6-trimethylsilylethynyl -3-pyridinecarboxylate
In a manner similar to that of Example 1 (a), starting with 4 g (14.4 mmoles) of methyl 6-iodo-3-pyridinecarboxylate, 3.29 g (92%) of the expected compound are obtained, in the form of a beige. p.f. = 55 ° C. tE NMR (CDC13) 6 0.10 (s, 9H), 1.22 (t, 2H, J = 7.1 Hz), 4.23 (q, 3H, J = 7.1 Hz), 7.33 (d, 1H, J = 8.2 Hz), 8.06 (dd, 1H, J = 8.1 / 2.1 Hz), 8.97 (d, 1H, J = 2.1 HZ).
(b) Ethyl 6-ethynylnicotinate
In a manner similar to that of Example 6 (b), starting with 3.29 g (13.3 mmol) of ethyl 6-trimethylsilylethynylnicotinate, 1.00 g are obtained
(43%) of the expected compound in the form of beige flakes. p.f. = 35 ° C. * H NMR (CDCl 3) d 1.42 (t, 3H, J = 7.1 Hz), 3.33 (s, 1H), 4.42 (q, 2H, J = 7.2 Hz), 7.56 (d, 1H, J = 8.1 Hz), 8.28 (dd, 1H, J = 8.1 / 2.1 Hz), 9.18 (d, 1H, J = 2.0 Hz)
(c) 6- (5,5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-2-naphylethyl ethynyl) ethyl nicotinate
In a manner similar to that of Example 4 (b), after reaction of 1.84 g (3.4 mmol) of 5,6,7,8-tetrahydro-5, 5, 8, 8-tetramethyl-2-naphthalene diselenide, in 2 ml of THF, with bromine (0.18 ml, 3.49 mmol), copper iodide (2.64 g, 13.9 mmol) and ethyl 6-ethynylnicotinate (1 g, 5.7 mmol) are added in 10 ml of DMF. 1.95 g (78%) of the expected derivative is obtained in the form of a brown oil. XH NMR (CDC13): 1.28 to 1.30 (m, 12H); 1.40 (t, 3H); 1.69 (s, 4H); 4.41 (q, 2H); 7.12 to 7.59 (m, 4H); 8.24 (dd, 1H); 9.16 (d, 1H).
(d) 6- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-2-naphthylslanylethyl) nicotinic acid
In a manner similar to that of Example 7, by reaction of 600 mg (1.36 mmol) of 6- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-2-naphthylslanilethynyl) ethyl nicotinate in 30 ml of THF and 1 g of sodium hydroxide, and after trituration from heptane, 200 mg (36%) of the expected compound are obtained in the form of a yellow solid, mp. = 128 ° C.
X H NMR (CDCl 3): 1.27 to 1.30 (m, 12H); 1.68 (s, 4H); 7.26 to 7.52
(m, 5H); 8.32 (d, 1H); 9.26 (s, 1H) 13 C NMR (CDC13): 31.8; 4*
CH3 / 34.2; Cq / 34.6; Cq / 34.8; CH2 / 34.9; CH2 / 78.6; Cq / 101.4;
Cq / 123.6; Cq / 123.8; Cq / 125.8; CH / 127.8; CH / 128.4; CH /
128. 5; 137.9; CH / 145.1; Cq / 146.8; Cq / 147.0; Cq / 151.5; CH / 169.0; Cq.
Example 10: N- (4-hydroxyphenyl) -4- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-2-naphthylslanilethynyl) benzamide
To a solution of 250 mg (0.63 mmol) of acid 4- (5,5,8, 8-tetramethi-1-5, 6,7, 8-tetrahydro-2-naphthylslanilethynyl) benzoic obtained in Example 5, 169 mg (1.25 mmoles) of 1-hydroxybenzotriazole, 240 mg (1.25 mmoles) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDC) and 82 mg (0.75 mmoles) of 4-aminophenol in 20 ml of THF are stirred at room temperature. environment for 15 h. Then water and ethyl acetate are added. After stirring and separation of the phases by sedimentation, the aqueous phase is extracted with ethyl acetate. The organic phases are then combined and washed with water, dried over magnesium sulfate and concentrated on a rotary evaporator under vacuum at 40 ° C. The product is purified on a silica column (ethyl acetate 20 / heptane 80). 200 mg (65%) of a white solid, m.p. = 202 ° C.
X H NMR (DMSO): 1.23 (s, 6H); 1.25 (s, 6H); 1.64 (s, 4H); 6.72 to 6.76 (d, 2H); 7.39 (c, 1H); 7.51 to 7.55 (d, 2H); 7.59 to 7.61 (d, 2H); 7.64 to 7.67 (d, 2H); 7.95 to 7.98 (d, 2H); 9.28 (s, 1H); 10.10 (s, 1H).
Example 11: 5- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-2-naphyl-phenylethynyl) -2-pyridinecarboxylate
(a) methyl 5-trimethylsilylethynyl-2-pyridinecarboxylate
In a manner similar to that of Example 1 (a) starting with 7 g (26.6 mmol) of methyl 5-iodo-2-pyridinecarboxylate, 4.25 g (68%) of the expected compound are obtained in the form of an orange powder , pf = 45 ° C. XH NMR (CDC13) d 0.28 (s, 9H), 4.01 (s, 3H), 7.87 (dd, 1H, J = 8.1 / 2.0 Hz), 8.08 (d, 1H, J = 8.1 Hz), 8.77 (d, 1H, J = 1.3 Hz).
(b) Methyl 5-ethynyl-2-pyridinecarboxylate
In a manner similar to that of Example 6 (b), starting with 2.25 g (9.6 mmol) of methyl 5-trimethylsilylethynyl-2-pyridinecarboxylate, 380 mg (24%) of the expected compound are obtained in the form of a yellow powder, pf = 40-5 ° C.
? NMR (CDCl 3) d 3.40 (s, 1H), 4.02 (s, 3H), 7.93 (dd, 1H, = 8.1 / 2.0 Hz), 8.12 (d, 1H, J = 8.1 Hz), 8.83 (d, 1H, = 1.9 Hz).
(c) methyl 5- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-2-nafyl-diphenylethynyl) -2-pyridinecarboxylate
In a manner similar to that of Example 4 (b), after the reaction of 918 mg (1.73 mmol) of 5, 6, 7, 8-tetrahydro-5, 5, 8, 8-tetramethyl-naphthalene-2-diselenide in 2 ml of THF, with bromine. (0.092 mL, 1.78 mmol), copper iodide (1.62 g, 8.5 mmol) and methyl 5-ethynyl-2-pyridinecarboxylate (500 g, 3.1 mmol) are added in 10 mL of DMF. After trituration from heptane, 420 mg (32%) of the expected derivative is obtained in the form of a yellow solid, m.p. = 75 ° C. XR NMR (CDCl 3): 1.28 to 1.29 (d, 12H); 1.69 (s, 4H); 4.02 (s, 3H); 1 .21 to 1. 31 (m, 2H); 7.54 (d, 1H); 7.84 (dd, 1H); 8.11 (d, 1H); 8.77 (s, 1H). 13 C NMR (CDCl 3): 31.7; 4 * CH3 / 34.2; Cq / 34.6; Cq / 34.8; 2 * CH2 / 53.0; CH3 / 79.2; Cq / 98.3; Cq / 123.9; 2 * Cq / 124.5; CH / 127.4; CH / 128.2; CH / 128.3; CH / 138.7; CH / 145.1; CH / 145.8; Cq / 146.9; Cq / 151.6; CH / 165.2; Cq.
Example 12: 2- (4-chlorophenyl-p-lanylethynyl-5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydronaphthalene
In a manner similar to that of Example 4 (b), after reaction of 2 g (5.25 mmol) of bis (4-chlorophenyl) diselenide in 5 ml of THF with bromine (0.266 ml, 5.15 mmol), iodide of copper (4.11 g: 21.6 mmoles) and 6-ethynyl-l, 1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (2.15 g, 10 mmoles)
(described in patent application EP 0,661,258 Al) in 20 ml of DMF, and after purification on a silica column
(heptane), 1.85 g (45%) of the expected derivative is obtained in the form of a colorless oil. * H NMR (CDC13): 1.28 '(s, 12H); 1.68 (s, 4H); 7.26 to 7.30 (, 4H); 7.46 to 7.52 (m, 3H).
Example 13: methyl 4- (3, 5, 5, 8, 8-pentamethyl-5,6,7,8-tetrahydro-2-naphryl-phenylethynyl) benzoate
(a) Dislelenide of 5, 6, 1, 8-tetrahydro-3, 5, 5, 8, 8-pentamethyl-2-naphthal ene
In a manner similar to that of Example 4 (a), by reaction of 4.4 g (15.8 mmol) of 2-bromo- (5, 6, 7, 8-tetrahydro-3, 5, 5, 8, 8-pentamethylnaphthalene) With 22 ml of ter-butyl lithium and selenium (1.33 g, 16.8 mmol) in 100 ml of THF,
3. 26 g (74%) of the expected selected derivative, in the form of a yellow solid, (mp 126 ° C). XH NMR (CDC13): 1.14 (6H, s), 1.23 (6H, s), 1.61 (4H, s), 2.35 (3H, s), 7.05 (1H Ar, s), 7.55 (1H Ar, s).
(b) methyl 4- (3, 5, 5, 8, 8 -pentamethyl-5, 6, 7, 8-tetrahydro-2-naphryl-phenylethynyl) benzoate
In a manner similar to that of Example 4 (b), after reaction of 1.5 g (2.75 mmol) of 5,6,7,8-tetrahydro-3, 5, 5, 8, 8-pentamethyl-2-diselenide Naphthalene (in 5 ml of THF, with bromine (0.15 ml, 2.9 mmol), copper iodide (2.1 g, 11.05 mmol) and methyl 4-ethynylbenzoate (790 mg, 4.94 mmol) in 20 ml of DMF are added, and after trituration from heptane, 1.57 g (70%) of the expected derivative is obtained in the form of a white solid, mp = 104 ° C. NMR (CDCl 3): 1.27 to 1.29 (m, 12H); s, 4H), 2.36 (s, 3H), 3.91 (s, 3H), 7.12 (s, 1H), 7.50 (d, 2H) 7.73 (s, 1H), 8.00 (d, 2H), 13C NMR (CDCI3 ): 21.4; CH3 / 32.3; 2 * CH3 / 32.4; 2 * CH3 / 34.5; Cq / 34.8; Cq / 35.5; 2 * CH2 / 52.7; CH3 / 75.0; Cq / 102.2; Cq / 125.9; Cq / 128.5; Cq / 129.1; 2 * CH / 129.8; Cq / 130.1; 2 * CH / * 131.5; 2 * CH / 134.9; Cq / 144.7; Cq / 145.3; Cq / 167.0 Cq.
Example 14: 4- (3, 5,5,8,8-pentamethyl-5,6,7,7-tetrahydro-2-naphthylsphenylethynyl) benzoic acid
In a manner similar to that of Example 7, by reaction of 1.35 g (3.07 mmol) of 4- (3, 5, 5, 8, 8-pentamethyl-5, 6, 7, 8-tetrahydro-2-naphthylslanilethynyl) benzoate of methyl in 20 ml of THF and 3 g of sodium hydroxide, and after trituration from heptane, 1.05 g (80%) of the expected compound are obtained in the form of a white solid, mp = 240 ° C.
XH NMR (CDC13): 1.27 to 1.30 (m, 12H); 1.68 (s, 4H); 2.35 (s, 3H); 7.13 (s, 1H); 7.50 (d, 2H); 7.71 (s, 1H); 8.00 (d, 2H). 13 C NMR (CDCl 3): 20.5; CH3 / 31.5; 4 * CH3 / 33.6; Cq / 33.9; Cq / 34.6; 2 * CH2 / 73.6; Cq / 101.6; Cq / 125.0; Cq / 127.1; Cq / 127.9; CH / 128.3; CH / 129.4; 2 * CH / 130.5; 2 * CH / 133.8; Cq / 143.9; 2 * Cq / 144.5; Cq / 167.5; Cq.
Example 15: Methyl 2-hydroxy-4- (3, 5,5,8, 8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylslanilethynyl) benzoate
In a manner similar to that of Example 4 (b), after reaction of 1 g (1.78 mmol) of 5,6,7,8-tetrahydro-3, 5, 5, 8, 8-pentamethyl-2-diselenide Naphthalene in 5 ml of THF with bromine (0.092 ml, 1.78 mmol), copper iodide is added
(1.36 g, 7.15 mmol) and methyl 4-ethynyl-2-hydroxybenzoate
(566 mg, 3.2 mmol) obtained according to Example 6 (b) in 10 ml of DMF, and after trituration from heptane, 715 mg (49%) of the expected derivative is obtained in the form of a brown solid. p.f. = 102 ° C. X H NMR (CDC13): 1.20 (s, 6H); 1.23 (s, 6H) 1.60 (s, 4H); 2.28 (s, 3H); 3.87 (s, 3H) 6.87 (dd, 1H); 6.97 (d, 1H); 7.04 (s, 1H) 7.64 (s, 1H); 7.71 (d, 1H); 10.70 (s, 1H). 13 C NMR (CDCl 3): 20.7; CH3 / 31.7; 4 * CH3 / 33.8; Cq / 34.1; Cq / 34.8; 2 * CH2 / 74.9; Cq / 101.4; Cq / 111.7; Cq / 119.4; Cq / 121.6; CH / 125.1; Cq / 128.4; 2 * CH / 129.7; CH / 130.3; Cq / 134.2; Cq / 144.1; Cq / 144.7; Cq / 161.1; Cq / 169.9; Cq.
Example 16: 2-Hydroxy-4- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylsphenylethynyl) benzoic acid
In a manner similar to that of Example 7, by reaction of 500 mg (1.1 mmol) of 2-hydroxy-4- (3, 5, 5, 8, 8-pentamethyl-5,6,7,8-tetrahydro-2) methyl-naphthylslanilethynyl benzoate in 20 ml of THF with 500 mg of sodium hydroxide yields 464 mg (99%) of the expected compound in the form of a brown solid. p.f. = 248 ° C. JH NMR (CDCl 3 + DMSO): 0.89 (s, 6H); 0.92 (s, 6H); 1.30 (s, 4H); 1.96 (s, 3H); 6.55 (dd, 1H) 6.60 (s, 1H); 7.31 (s, 1H); 7.43 (d, 1H); 10.96 (sb, lH).
13 C NMR (CDCl 3 + DMSO): 20.6; CH3 / 31.6; 4 * CH3 / 34.0; Cq / 34.6; Cq / 34.7; 2 * CH2 / 74.1; Cq / 101.6; Cq / 112.5; Cq / 118.9; CH / 121.3; CH / 125.0; Cq / 128.0; CH / 128.3; CH / 129.6; Cq / 130.4; CH / 133.9; Cq / 144.0; Cq / 144.0; Cq / 144.5; Cq / 161.4; Cq / 171.9; Cq.
Example 17: 6- (3, 5, 5, 8, 8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylslanilethynyl) -nicnicinate
In a manner similar to that of Example 4 (b), after reaction of 1 g (1.78 mmol) of 5,6,7,8-tetrahydro-3, 5, 5, 8, 8-pentamethyl-2-diselenide Naphthalene, in 5 ml of THF, with bromine (0.092 ml, 1.78 mmol), copper iodide (1.36 g, 7.15 mmol) and ethyl 6-ethynylnicotinate (463 mg, 2.64 mmol) in 10 ml of DMF are added, and 1.06 g (88%) of the expected derivative is obtained in the form of a brown solid. p.f. = 95 ° C. X H NMR (CDCl 3): 1.20 (s, 6 H); 1.24 (s, 6H) 1.34 (t, 3H); 1.61 (s, 3H); 4.33 (q, 2H); 7.07 (s, 1H); 7.38 (d, 1H); 7.67 (s, 1H); 8.17 (dd, 1H) 9.08 (d, 1H). 13 C NMR (CDCl 3): 13.9; CH3 / 20.9; CH3 / 31.5; 4 * CH3 / 33.7; Cq / 34.0; Cq / 34.6; 2 * CH2 / 61.2; CH2 / 77.2; Cq / 101.2; Cq / 124.2; Cq / 124.3; Cq / 125.2; Cq / 128.4; CH / 129.4; CH / 134.8; Cq / 136.8; Cq / 144.0; Cq / 145.1; Cq / 146.3; Cq / 150.8; Cq / 164.5; Cq.
Example 18: 6- (3,5,5,8,8-pentamethyl-5,6,7, tetrahydro-2-naphthylsphenylethynyl) -nicotinic acid
In a manner similar to that of Example 7, by reaction of 8Q0 mg (1.73 mmoles) of 6- (3, 5, 5, 8, 8-pentamethyl-5, 6, 7, 8-tetrahydro-2-naphthylselanilethynyl) nicotinate of ethyl, in 20 ml of THF, with 800 mg of sodium hydroxide and after purification on a silica column (ethyl acetate), 135 mg (19%) of the expected compound are obtained in the form of a yellow solid, mp = 185 ° C. 2 H NMR (CDC13): 1.27 (s, 6H); 1.31 (s, 6H); 1.68 (s, 4H); 2.40 (s, 3H); 7.15 (s, 1H); 7.26 (s, 1H); 7.49 (d, 1H); 7.74 (s, 1H); 8.32 (d, 1H); 9.25 (s, 1H). 13 C NMR (CDCl 3): 21.7; CH3 / 32.2; 4 * CH3 / 34.5; Cq / 34.7; Cq / 35.3; 2 * CH2 / 78.9; Cq / 101.7; Cq / 124.0; Cq / 124.9; Cq / 126.1; CH / 129.1; CH / 130.2; CH / 135.6; Cq / 1382; CH / 144.8; Cq / 145.9; Cq / 147.6; Cq / 152.0; CH / 169.5; Cq.
Example 19: N- (4-hydroxyphenyl) -6- (3, 5, 5, 8, 8-pentamethyl-5, 6, 7, 8-tetrahydro-2-naphylselanilethynyl) nicotinamide
In a manner similar to that of Example 10, by reaction of 300 mg (0.72 mmol) of the acid 6- (3, 5, 5, 8, 8-pentamethyl-5, 6, 7, 8-tetrahydro-2-naphthylslanilethynyl) nicotinic acid with 194 mg (1.45 mmol) of 1-hydroxybenzotriazole, 300 mg
(1.45 mmol) of 1,3-dicyclohexylcarbodimide and 95 mg
(0.87 mmol) of 4-aminophenol in 20 ml of THF, and after purification on a silica column (ethyl acetate
/ heptane 80), 20 mg (6%) of a yellow solid are obtained. p.f. = 172 ° C. X H NMR (DMSO): 1.17 to 1.19 (m, 12H); 1.56 (s, 4H); 2.27 (s, 3H); 6.68 (d, 2H); 7.21 (s, 1H); 7.46 (d, 2H); 7.58 (d, 1H); 7.64 (s, 1H); 8.22 (dd, 1H); 8.99 (s, 1H) 9.30 (s, 1H); 10.2 (s, 1H). 13 C NMR (DMSO): 31.6; 4 * CH3 / 33.5; CH2 / 33.8; CH2 / 34.0; Cq / 34.5, Cq / 47.6; CH3 / 74.9; Cq / 102.0; Cq / 115.2; 2 * CH / 122.3; 2 * CH / 124.4; Cq / 125.9; CH / 128.7; CH / 128.9; CH / 130.4; Cq / 134.8; Cq / 136.1; CH / 144.0; Cq / 144.1 Cq / 145.1; Cq / 149.3; Cq / 154.1; Cq / 156.8; Cq.
Example 20: N-butyl-6- (3, 5, 5, 6, 8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylslanilethynyl) nicotinamide
In a manner similar to that of Example 10, 300 mg (0.72 mol) of 6- (3, 5, 5, 8, 8-pentamethyl-5, 6, 7, 8-tetrahydro-2-naphthylasphenylethynyl) are reacted nicotinic acid with 194 mg (1.45 mmol) of 1-hydroxybenzotriazole, 300 mg
(1.45 mmoles) of 1,3-dicyclohexylcarbodiiraide and 63.5 mg
(0.87 mmol) of butylamine in 20 ml of THF. After purification on a silica column (ethyl acetate
/ heptane 80), 60 mg (17%) of a yellow solid, m.p. = 172 ° C. X H NMR (CDC13): 0.97 (t, 3H); 1.27 to 1.37 (, 12H) 1.37 to 1.46
(m, 4H); 1.68 (s, 4H); 2.39 (s, 3H) 3.47 (q, 2H); 6.13 (m, 1H); 7.14 (s, 1H) 7.46 (d, 1H); 7.74 (s, 1H); 8.07 (dd, 1H); 8.87
(s, 1H). 13 C NMR (CDCl 3): 31.8; CH3 / 20.2; CH2 / 21.2; CH3 / 31.7; 4 * CH3 / 34.0; Cq / 34.3; Cq / 35.0; 2 * CH2 / 40.0; CH2 / 76.2; Cq / 101.2; Cq / 124.7; Cq / 126.0; CH / 128.7; CH / 129.7; CH /; CH / 35.1; Cq / 135.3; CH / 144.3; Cq / 145.4; Cq / 145.5; Cq /; Cq.
Example 21: Morpholin-4-yl- [6- (3, 5, 5, 8, 8-pentamethyl-5, 6, 7, 8-tetrahydro-2-naphthylasphenylethynyl) -3-pyridyl] methanone
In a manner similar to that of Example 10, 300 mg (0.72 mmol) of 6- (3, 5, 5, 8, 8-pentamethyl-5, 6, 7, 8-tetrahydro-2-naphthylslanilethynyl) are reacted nicotinic acid with 194 mg (1.45 mmol) of 1-hydroxybenzotriazole, 300 mg
(1.45 mmoles) of 1,3-dicyclohexylcarbodiimide and 75.7 mg (0.87 mmoles) of morpholine in 20 ml of THF. After purification on a silica column (ethyl acetate / heptane 80), 60 mg (17%) of a colorless oil are obtained. X H NMR (CDCl 3): 1.27 to 1.32 (m, 12H); 1.68 (s, 4H); 2.39 (s, 3H); 3.81 (broad s, 8H); 7.13 (s, 1H) 7.45 (d, 1H); 7.71 to 7.75 (m, 2H); 8.61 (d, 1H).
13 C NMR (CDCl 3): 21.2; CH3 / 31.8; 4 * CH3 / 34.1; Cq / 34.3; Cq / 35.0; 2 * CH2 / 66.8; 4 * CH2 / 75.5; Cq / 101.1; Cq / 124.7; Cq / 126.0; CH / 128.7; CH / 129.4; Cq / 129.7; CH / 135.1; Cq / 135.5; CH / 144.3; Cq / 144.5; Cq / 145.4; Cq / 148.3; CH / 167.4; Cq.
Example 22: 5- (3, 5, 5, 8, 8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylslanilethynyl) -2-pyridinecarboxylate methyl
In a manner similar to that of Example 4 (b), after reaction of 945 mg (1.68 mmol) of 5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-diselenide Naphthalene, in 5 ml of THF with bromine (0.092 ml, 1.78 mmol), add copper iodide (1.32 g, 6.95 mmol) and methyl 5-ethynyl-2-pyridinecarboxylate (500 mg, 3.1 mmol) in 10 ml of DMF, and after trituration from heptane, 1 g (73%) of the expected derivative is obtained in the form of a yellow solid, mp = 52 ° C. E MMR (CDCI3): 1-27 to 1.29 (m, 12H); 1.68 (s, 4H); 2.37 (s, 3H) and 4.02 (s, 3H); 7.14 (s, 1H) 7.71 (s, 7.85 (dd, 1H); 8.02 (s, 1H) 8.11 (d, 1H) .13C NMR (CDCI3): 20.7; CH3 / 31.5; 2 * CH3 / 31.6; 2 * CH3 / 33.7; Cq / 34.0; Cq / 34.6; 2 CH2 / 52.7; CH3 / 78.9; Cq / 98.1; Cq / 123.7; Cq / 124.2; CH / 124.5; Cq / 128.4; CH / 128.5; CH / 134.3; Cq / 138.3; CH / 144.0; Cq / 144.9; Cq / 145.5; Cq / 151.2; CH / 162.2; Cq.
Example 23: 5- (3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthylslanilethynyl) -2-pyridinecarboxylic acid
In a manner similar to that of Example 7, by reaction of 800 mg (1.73 mmol) of 5- (3, 5, 5, 8, 8-pentamethyl-5, 6, 7, 8-tetrahydro-2-naphthylslanilethynyl) - Methyl 2-pyridinecarboxylate in 20 ml of THF, with 2 g of sodium hydroxide and after trituration from heptane, 580 mg are obtained
(65%) of the expected compound in the form of a white solid, m.p. = 164 ° C. X H NMR (CDC13): 1.28 (s, 6H); 1.30 (s, 6H); 7.69 (s, 1H); 7.93
(d, 1H); 8.17 (broad d, 1H); 8.66 (broad s, 1H). 13 C NMR (CDCl 3): 21.2; CH3 / 31.8; * 2 CH3 / 3.9; 2 * CH3 / 34.1; Cq / 34.3; Cq / 34.9; 2 CH2 / 124.6; Cq / 128.8; CH / 129.3; CH / 134.9; Cq / 139.8; CH / 144.4; 2 Cq / 145.5; 2 * Cq.
Example 24: [4- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-2-naphthylslanilethynyl) phenyl] methanol
A 1M solution of diisobutylaluminum hydride in toluene (4 ml, 4 mmol) is added dropwise at 0 ° C to a solution of 4- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8 methyl-tetrahydro-2-naphthylslanilethynyl) -benzoate obtained according to Example 4 (750 mg, 1.8 mmol) in toluene (20 ml). The solution is stirred for 4 h at 0 ° C and then treated with a
Sodium potassium and sodium tartrate solution is filtered and taken up in a mixture of ethyl ether and water. The organic phase is washed with water, dried over magnesium sulfate and concentrated on a rotary evaporator under vacuum at 40 ° C. 418 mg (60%) of a colorless oil are obtained. XH NMR (CDC13): 1.26 (s, 6H), 1.28 (s, 6H), 1.76 (s, 4H), 4.67 (s, 2H), 7.24 to 7.37 (, 4H), 7.46 (d, 2H, J = 8.2 Hz), 7.52 (d, 1H, J = 1.9 Hz).
Example 25: 4- (5, 5, 8, 8-tetramethyl-5, 6,7, 8-tetrahydro-2-naphthylethylsulfane) methyl benzoate
In a manner similar to that of Example 1 (c), by reaction of 234 mg (1.1 mmol) of 6-ethynyl-1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene in 5 ml of THF, with butyl lithium
2. 5 M (0.4 ml, 1 mmol) and 2, 2 '-dithiobis (methyl benzoate)
(267 mg, 0.8 mmol), and after purification on a silica column (dichloromethane 30 / heptane 70), the expected derivative is obtained in the form of a white solid. * H NMR (CDCl 3): 1.28 (6H, s), 1.29 (6H, s), 1.69 (4H, s), 3.91 (3H, s), 7.30 (2H Ar, s), 7.49 to 7.54 (3H Ar, m), 8.0 (2H Ar, d, J = 6.9Hz).
Example 26: 4- (3, 5, 5, 8, 8-pentamethyl-5, 6, 7, 8-tetrahydro-2-naphthylselanilethynyl) phenol
(a) 4-Trimethylsilylethynylphenyl Acetate
In a manner similar to that of Example 1 (a), starting with 4.63 g (17.7 mmol) of 4-iodophenyl acetate, 3.72 g (90%) of the expected compound are obtained in the form of a yellow powder, m.p. = 45 ° C. XR NMR / CDCl 3: O.05 (5; 9H); 2.10 (s, 3H) 6.84 (dt, 2H); 7.28 (dt, 2H). 13 C NMR / CDCl 3: O.00; 2 * CH3 / 21.2; CH3 / 94.4; Cq / 104.3; Cq / 120.9; Cq / 121.2; 2 * CH / 133.2; 2 * CH / 150.7; Cq / 169.1; Cq.
(b) Acetate of 4- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphilselanilethynyl) phenyl
In a manner similar to that of Example 4 (b), after reaction of 1.39 g (2.4 mmol) of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalene diselenide, in THF, with bromine (0.22 ml, 4.3 mmol), copper iodide (1.82 g, 9.6 mmol) and 4-trimethylsilylethynylphenyl acetate (1 g, 4.3 mmol) are added in DMF at 80 ° C for 15 h, and then of purification on a silica column (dichloromethane 20 / heptane
80), 220 mg (16%) of the expected derivative is obtained in the form of a yellow oil. X H NMR / CDCl 3: 1.19 (d, 12 H); 1.59 (s, 4H) 2.22 (s, 3H); 2.26 (s, 3H); 6.97 to 7.02 (, 3H); 7.39 to 7.42 (dd, 2H); 7.65 (s, 1H). 13 C NMR / CDCl 3: 19.2; CH3 / 19.5; CH3 / 30.3 4 * CH3 / 32.4; Cq / 32.7; Cq / 33.4; CH2 / 33.5; CH2 / 68.7; Cq / 99.9; Cq / 119.5; Cq / 120.1; 2 CH / 124.2; Cq / 126.7; CH / 126.9; CH / 131.0 2 CH / 133.0; Cq / 142.5; Cq / 143.5; Cq / 138.0 Cq / 167.5; Cq.
(c) 4- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphilselanilethynyl) phenol
A mixture of 4- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-2-naphthylslanilethynyl) phenyl acetate (500 mg,
1. 1 mmol) and potassium carbonate (160 mg, 1.1 mmol) in methanol (20 ml) is stirred for 24 h at room temperature and then treated with ethyl ether and water. The organic phase is washed twice with water, dried over anhydrous magnesium sulfate and concentrated on a rotary evaporator under vacuum at 40 ° C. The product is purified on a silica column
(ethyl acetate 20 / heptane 80). 300 mg (66%) of a clear oil are obtained. X H NMR / CDCl 3: 1.25 to 11.27 (m, 12H); 1.66 (s, 4H) 2.35 (s, 3H) i 6.77 (d, 2H); 7.09 (s, 1H) 7.38 (dd, 2H); 7.73 (s, 1H).
13 C NMR / CDCl 3: 20.3; CH3 / 31.4; 4 * CH3 / 33.6 2 * Cq / 34.6; 2 * CH2 / 67.2; Cq / 103.7; Cq / 115.3; Cq / 115.6; 2 CH / 127.7; Cq / 128.5; 2 CH / 133.0; 2 CH / 133.6; Cq / 143.6; Cq / 143.9; Cq / 156.0; Cq.
Example 27: Ethyl 4- (4-hydroxy-5, 5, 8, 8-tetramethyl-5, 6,7, tetrahydro-2-naphthylslanilethynyl) benzoate
In a manner similar to that of Example 4 (b), after reaction of 1 g (1.5 mmole) of diselenide of 4-ratoxymethoxy-5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro- 2-naphthalene, in THF with bromine (0.092 ml, 1.78 mmol), copper iodide and ethyl 4-triraethylsilylethylbenzoate (644 mg, 2.8 mmol) in DMF were added at 80 ° C for 15 h. After purification on a silica column (dichloromethane 20 / heptane 80), 220 mg (16%) of the expected derivative is obtained in the form of a yellow oil. X H NMR / CDCl 3: 1.29 (s, 6H); 1.37 to 1.43 (, 9H) 1.65 (q, 4H); 4.39 (q, 2H); 5.72 (s, 1H) 7.26 (s, 1H); 7.43 (s, 1H); 7.55 (d, 2H); 8.03 (d, 2H).
Example 28: Ethyl 4- (4-methoxymethoxy-5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl-selanilinyl) ethyl benzoate
In a manner similar to that of Example 4 (b), after reaction of 1 g (1.5 mmol) of diselenide 4-
methoxymethoxy-5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-2-naphthalene, in THF with bromine (0.092 ml, 1.78 mmol), copper iodide and ethyl 4-trimethylsilylethynylbenzoate ( 644 mg, 2.8 immoles) in DMF at 80 ° C for 15 h. After purification on a silica column (dichloromethane 20 / heptane 80), 420 mg (31%) of the expected derivative is obtained in the form of a yellow oil. ? NMR / CDCl 3: 1.17 (q, 6H); 1.31 (m, 9H); 1.49 to 1.57 (m, 4H); 3.38 (s, 3H); 4.25 (q, 2H) 5.10 (s, 2H); 7.08 (d, 1H); 7.14 (d, 1H) 7.41 (d, 2H); 7.88 (d, 2H).Example 29: 4- (4-Methoxymethoxy-5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanyl-ethynyl) benzoic acid
In a manner similar to that of Example 7, by reaction of 300 mg of ester of 4- (4-methoxymethoxy-5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-2-naphthylslanilethynyl) benzoate of ethyl in 30 ml of THF with 500 mg of sodium hydroxide, and after trituration from heptane, the expected compound is obtained in the form of a white solid. TH NMR / CDCl 3: 1.28 (s, 6H); 1.39 (s, 6H); 1.66 (m, 2H); 3.51 (s, 3H); 5.23 (s, 2H); 7.19 (d, 1H, J = 1.8 Hz); 7.25 (d, 1H, J = 1.8 Hz); 7.56 (d, 2H, J = 8.5 Hz); 8.06 (d, 2H, J = 8.5 Hz).
Example 30: [4- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-2-naphthylslanilethynyl) -phenyl] carbaldehyde
A mixture of [4- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-2-naphthylslanilethynyl) -phenyl] methanol obtained in Example 24 (280 mg, 0.7 mmol) and dichromate pyridinium
(526 mg, 1.4 mmol) in dichloromethane (10 ml) is stirred at room temperature for 4 h. After filtration through silica and concentration in a rotary evaporator under vacuum at 40 ° C, 173 mg (63%) of the expected product are obtained in the form of a yellow oil. XH NMR / CDC13: 1.28 (s, 6H), 1.30 (s, 6H), 1.70 (s, 4H), 4.67
(s, 2H), 7.23 (1H Ar, d, J = 8.3 Hz), 7.29 (1H Ar, dd, J = 1.9 Hz, J = 8.3 Hz), 7.52 to 7.59 (3H Ar, m), 7.84 (1H Ar, d, J = 6.7 Hz); 9.99 (.H, s).
Example 31: (4-d irae t i l t i o c r oman methyl ilselaniletinylbenzoate
(a) 2-bromo-l- (3-methylbut-2-enylthio) benzene
A 19.30 g (102.0 mmol) of 2-bromothiophenol, 160 ml of DMF and 15.50 g (112.0 mmol) of potassium carbonate are introduced into a three-necked flask. 13 ml (112.0 mmoles) of l-bromo-3-methyl-2-butene are added dropwise and the mixture is stirred
at room temperature for 2 hours. The reaction medium is poured into water and extracted with ethyl acetate, and the organic phase is separated after the sedimentation has taken place, washed with water, dried over magnesium sulfate and evaporated. 26.00 g (99%) of the expected compound are collected in the form of an orange oil. X H NMR / CDCl 3 d 1.65 (s, 3 H), 1.73 (s, 3 H), 3.56 (d, 2 H, J = 7.7 Hz), 5.32 (td, 1 H, J = 7.7 / 1.4 Hz), 6.96 to 7.06 mt, 1H), 7.22 to 7.26 (, 2H), 7.52 (d, 1H, J = 7.7 Hz).
(b) 4, 4-dimethyl-8-bromothiochroman
To a three-necked flask are introduced 26.00 (102.0 mmol) of 2-bromo-l- (3-methylbut-2-enylthio) benzene, 180 of toluene and 23.20 g (122.0 mmol) of paratoluenesulfonic acid. The reaction medium is refluxed for 4 hours and evaporated to dryness. The residue is taken up in an aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate, and the organic phase is separated after the sedimentation has been carried out, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column eluted with heptane. 20.00 g (76%) of the expected compound are collected in the form of an orange oil.
X H NMR (CDCl 3) d 1.33 (5, 6H), 1.94 (t, 2H, J = 6.0 Hz), 3.04 (t, 2H, J = 6.1 Hz), 6.89 (t, 1H, J = 7.9 Hz), 7.34 (d, 2H, J = 7.9 Hz).
(c) 4,4-dimethyl-8-thiochroman
A crystal of iodine, magnesium (208 mg, 8.56 mmol) and a few drops of a solution of 4,4-dimethyl-8-bromothiochroman (2 g, 7.78 mmol) in ethyl ether (15 ml) are heated until it is started the organomagnesium reagent. The rest of the solution is added dropwise. The medium is heated for 2 h and then selenium is added
(615 mg, 7.78 mmol) at room temperature. Stirring is continued for 30 min and then a 1N HCl solution is added. The reaction mixture is treated with ethyl ether. The organic phase is washed twice with water, dried over anhydrous magnesium sulfate and concentrated on a rotary evaporator under vacuum at 40 ° C. Ethanol and sodium hydroxide are added to the oil obtained. The mixture is vigorously stirred for a few minutes and then concentrated on a rotary evaporator under vacuum at 40 ° C. The product is purified on a silica column (dichloromethane 20 / heptane 80). 300 mg (15%) of a white solid are obtained.
XH NMR (CDC13): 1.33 (6H, s), 1.96 (2H,), 3.09 (2H,), 6.93 (1H Ar, t, J = 7.8 Hz), 7.26 (1H Ar, dd, J = 7.8 Hz, J = 1. 3 Hz), 7.47 (1 H Ar, dd, J = 7.8 Hz, J = 1.3 Hz).
(c) Methyl 4 - (4, 4 -dimethylthiochroman-8-ylelenylethynyl) benzoate _
In a manner similar to that of Example 4 (b), after reaction of 300 mg (1.9 mmol) of 4,4-dimethyl-8-trichroman diselenide, in 2 ml of THF, with bromine (0.117 ml, 2.2 min. ), copper iodide (780 mg) and methyl 4-ethynylbenzoate (562 mg, 3.5 mmol) were added in 20 ml of DMF, and after purification on a silica column (dichloromethane 20 / heptane 80), the expected derivative in the form of a yellow solid. ? E NMR (CDCI3): 1.35 (6H, s), 1.97 (2H, m), 3.10 (2H,), 3.93 (3H, s), 7.07 (1H Ar, t, J = 7.8 Hz), 7.31 (1H Ar, dd, J = 7.8 Hz, J = 1.3 Hz), 7.55 (2H Ar, d, J = 8.5 Hz) 7.59 (1H Ar, dd, J = 7.8 Hz, J = 1.3 Hz), 8.00 (2H Ar, d, J = 8.5 Hz).
Example 32: 4- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylethylsulfa) benzoic acid
In a manner similar to that of Example 2, by reaction of 4- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-2-)
Naphthylethylsulphane) methyl benzoate in THF, and after crystallization from heptane, the expected derivative is obtained in the form of a white solid. X H NMR (CDCl 3): 1.28 (6H, s), 1.29 (6H, s), 1.70 (4H, s), 7.30 (2H Ar, s), 7.43 to 7.50 (3H Ar, t), 7.99 (2H Ar, d, J = 7.5 Hz).
FORMULATION EXAMPLES
Example 1:
Various pharmaceutical and cosmetic formulations based on the compounds according to the invention are described below.
ORALLY
(a) tablet of 0. 2 g Compound of Example 1 10,001 g - Almidium 0.114 g Dicalcium phosphate 0.020 g Silica 0.020 g Lactose 0.030 g Talc 0.010 g Magnesium stearate 0.005 g
In this Example, the compound of Example 1 can be substituted with the same amount of one of the compounds of Examples 4, 6, 11, 13 or 15.
(b) Ingestible suspension in 5 ml bottles
Compound of Example 3 20,001 g Glycerol 0.500 g Sorbitol 70% 0.500 g Sodium saccharinate 0.010 g methyl p-hydroxybenzoate 0.040 g flavoring, q.s. Purified water q.s. 5 ml
(c) Tablet of 0. 8 g Compound of Example 2 0.500 g Pregelatinized starch 0.100 g Microcrystalline cellulose 0.115 g Lactose 0.075 g Magnesium stearate 0.010 g
In this example, the compound according to Example 2 can be substituted with the same amount of one of the compounds of Examples 6, 11, 14 or 28.
(d) Ingestible suspension in 10 ml vials Compound of Example 3 0.200 g Glycerol 1,000 g Sorbitol 70% 1,000 g Sodium saccharinate 0.010 g methyl p-hydroxybenzoate 0.080 g Saborizante, c.s. Purified water, c.s. 10 ml
B. VIA TÓPICA
(a) Compound Ointment of Example 2 20,020 g Isopropyl myristate 81,700 g
Fluid liquid petroleum jelly 9,100 g Silica ("Aerosil 200" sold by Degussa) 9,180 g
(b) Compound Ointment of example 1 0.300 g - Codex white oil jelly 100 g
(c) Non-ionic water cream in oil
Compound of Example 1 0.100 g Mixture of lanolin alls emulsifiers, waxes and oils ("anhydrous eucerin" sold by BDF) 39,900 g methyl p-hydroxybenzoate 0.075 g propyl p-hydroxybenzoate 0.075 g Sterile demineralized water q.s. 100 g
In this example, the compound according to Example 1 can be substituted with the same amount of one of the compounds of Examples 4, 16, 22, 27 or 32.
(d) Compound Lotion of the po 3 axis 0.100 g Polyethylene glycol (PEG-400) 69,900 g 95% Ethanol 30,000 g
(e) Hydrophobic ointment Compound of Example 1 0.300 g - Isopropyl myristate 36,400 g Silicone oil ("Rhodorsil 47V300" sold by Rhóne-Poulene) 36,400 g
Beeswax 13,600 g Silicone oil ("Abil 300,000 cst" sold by Goldschmidt) 100 g
(f) Oil non-ionic cream in water Compound of Example 2 1,000 g Cetyl all 4,000 g Glyceryl monostearate 2,500 g PEG 502,500 g stearate Faceted butter 9,200 g Propylene glycol 12,000 g methyl p-hydroxybenzoate 0.075 g propyl p-hydroxybenzoate 0.075 g g Sterile demineralized water 100 g
In this example, the compound according to Example 2 can be substituted with the same amount of one of the compounds of Examples 5, 9, 12, 19 and 32.
PROOF OF ACTIVITY
The results of differentiation tests in mouse embryonic teratocarcinoma cells (F9) for
identify molecules, RAR agonites as described in Skin Pharmacol. 3, pp. 256-267, 1990. After treatment with the compounds of the Examples mentioned in the following table, the F9 mouse embryonic teratocarcinoma cells differentiated into endothermic cells. This differentiation is characterized by the secretion of the plasminogen activator in the culture medium. The activity of the product is expressed by the AC50 value representing the concentration of the test product which produces half the maximum amount of secreted plasminogen activity.
These results indicate that the compounds of Examples 1, 2, 4, 5, 16 and 18 are RAR agonist compounds.
TABLE A
(Ib)
n = 0 if Y is oxygen
TABLE B
^ CuCl, Et2 NH ed (ii)
n = 0 if Y is oxygen
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.
Claims (26)
1. Biatro-atomic compounds joined via a heteroethynylene linkage, characterized in that they correspond to the general formula (I) below: (i) wherein: Ar represents a radical that is chosen from formulas (a) to (c) below: (to) (b) (c) Z is O or S, or N-Rg, Rx represents a halogen atom, -CH3, -CH2-OR7, -OR7, -COR8 or a polyether radical, R2 and R3, which may be identical or different, represent H linear or branched C1-C20 alkyl, C3-C12 cycloalkyl, -OR7 or -SR7, at least one of R2 and R3 is linear or branched C ^ C ^ alkyl or C3-C10 cycloalkyl, or R2 and R3 taken together, form a 5 or 6 membered ring, optionally substituted with at least one methyl and / or optionally interrupted by a heteroatom which is chosen from O and S, R4 and R5 represent H, a halogen atom, alkyl of linear or branched CL-CJO, -OR7 or a polyether radical, R6 represents H, alkyl of linear or branched or -OCOR9, R7 represents H, straight or branched Cx-C10 alkyl or -COR9, R8 represents H, straight or branched C1-C10 alkyl, -OR10 or R9 represents linear or branched Cx-C10 alkyl, R10 represents H, linear or branched Cj-Cgo alkyl, mono- or polyhydroxyalkyl, allyl, optionally substituted aryl or aralkyl, or a sugar residue, r "and r'1, which may be identical or different, represent H, C 1 -C 4 alkyl, mono- or polyhydroxyalkyl, optionally substituted aryl, an amino acid or peptide residue or, taken together with the nitrogen atom form a heterocycle, X represents a divalent radical which, from right to left or vice versa, has the formula: where: Y represents O, S (0) not Se (0) n, n and n 'are 0, 1 or 2, with the proviso that when Ar is a radical of formula (a) above, in which Rx = CH3; a halogen atom or a radical -OR7 and R5 = H, then at least one of the radicals R2 or R3 is different from -CH3, and the salts of the compounds of formula (I) when R2 represents a carboxylic acid function , as well as the optical isomers of such compounds of formula (I).
2. The compounds according to claim 1, characterized in that they are in the form of a salt or an alkali metal or alkaline earth metal, or alternatively zinc or an organic amine.
The compounds according to any of claims 1 and 2, characterized in that the Ct-C10 alkyl radical is selected from the group consisting of methyl, ethyl, isopropyl, butyl, tertbutyl, hexyl, 2-ethylhexyl and octyl.
4. The compounds according to any of the preceding claims, characterized in that the alkyl radical of Linear or branched is selected from the group consisting of the methyl, ethyl, propyl, 2-ethylhexyl, octyl, dodecyl, hexadecyl and octadecyl radicals.
5. The compounds according to any of the preceding claims, characterized in that the C3-C12 cycloalkyl radical is selected from the group consisting of the cyclopropyl, cyclopentyl, cyclohexyl, 1-methylcyclohexyl and 1-adamantyl radicals.
6. The compounds according to any of the preceding claims, characterized in that the polyether radical is selected from the group consisting of the methoxymethoxy, methoxyethoxy, and methoxyethoxymethoxy radicals.
The compounds according to any of the preceding claims, characterized in that the monohydroxyalkyl radical is selected from the group consisting of the 2-hydroxyethyl, 2-hydroxypropyl and 3-hydroxypropyl radicals.
The compounds according to any of the preceding claims, characterized in that the polyhydroxyalkyl radical is selected from the group consisting of 2, 3-dihydroxypropyl, 2, 3, 4-trihydroxybutyl, 2, 3, 4, 5-tetrahydropentyl radicals and the pentaerythritol residue.
9. The compounds according to any of the preceding claims, characterized in that the aryl radical is a phenyl radical optionally substituted with at least one halogen atom, a hydroxyl or a nitro function.
10. The compounds according to any of the preceding claims, characterized in that the aralkyl radical is selected from the group consisting of the benzyl and phenethyl radicals optionally substituted with at least one halogen atom, a hydroxyl function or a nitro function.
11. The compounds according to any of the preceding claims, characterized in that the sugar residue is selected from the group consisting of glucose, galactose, mannose and glucuronic acid residues.
12. The compounds according to any of the preceding claims, characterized in that the amino acid residue is selected from the group consisting of the residues derived from usina, glycine or aspartic acid.
The compounds according to any of the preceding claims, characterized in that the heterocyclic radical is selected from the group consisting of the piperidino, morpholino, pyrrolidino and peperazino radicals, optionally substituted in the 4-position with an Ci-Cg alkyl or a mono- or polyhydroxyalkyl.
The compounds according to any of the preceding claims, characterized in that the halogen atom is selected from the group consisting of fluorine, chlorine and bromine.
15. The compounds according to any of the preceding claims, characterized in that they correspond to the following general formula: (II) in which: Ar 'represents a radical of formula; (to) (b) Rl r R4, R5 and X are as defined above for formula (I), R? I / - Ri2 Ri3 and Ri l ° s which may be identical or different represent H or -CH3, and n is 1 or 2.
16 The compounds according to any of claims 1 to 14, characterized in that it corresponds to the following general formula (III) wherein: W represents O or S, R4, Rn, R12, Ar 'and X are as defined in accordance with claim 15.
17. The compounds according to any of claims 1 to 14, characterized in that they correspond to the following general formula: (IV) wherein: R4, Ar 'and X are as defined in accordance with claim 15, and at least one of the radicals R'2 and / or R'3 represents a cycloalkyl radical of C5-C10 mono- or polycyclic , the others represent one of the meanings indicated for R2 and R3 as defined in accordance with claim 1.
18. The compounds according to any of the preceding claims, characterized in that they are taken from the group consisting of: 4- (Methyl 5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulfanylethynyl) benzoate, 4- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8 -tetrahydro-2-naphthylsulfanylethynyl) benzoic acid, methyl 4- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylsulfonylethynyl) benzoate, 4- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyloxy-ethynyl) methyl benzoate, 4- (5, 5, 8, 8-tetramethyl-5, 6,7 acid) , 8-tetrahydro-2-naphinatedloxyethynyl) benzoic acid, 4- (5, 5, 8, 8-tetramet-il-5,6,7,8-tetrahydro-2-naphthylsulfanylethynyl) methyl benzoate, 4- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-2-naphthylsulfanylethynyl) benzoic acid, 4- (5, 5, 8, 8-tetramet-il-5,6,8,8-tetrahydro-2-) methyl naphthylsulfonylethynyl) benzoate, 4- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-2-naphthylsulfonylethynyl) benzoic acid, 4- (5, 5, 8, 8-tetr methyl-5, 6, 7, 8-tetrahydro-2-naphthylsulfinylethynyl) methyl benzoate, 4- (5, 5, 8, 8-tetramethyl-5, 6,7,8-tetrahydro-2-naphylethyldinylenenyl) ) benzoic, 4- (5, 5, 8, 8-tetr amethyl-5, 6, 7, 8-tetrahydro-2-naphyl-t-phenylethynyl) methyl benzoate, 4- (5, 5, 8, 8-tetramethyl) -5, 6, 7, 8-tetrahydro-2-naphyl-t-phenylethynyl) -benzoic acid, 2-hydroxy-4- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl) elaniletinyl) methyl benzoate, 2-hydroxy-4- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-2-naphilselanilethynyl) benzoic acid, 6- (4-methoxymethoxy-methylethylanilyl) -1,4,4-tetramethyl-1,2,3,4-tetrahydronafatural, 6- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8 -tetrahydro-2-naphthylslanilethynyl) ethyl nicotinate, 6- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-2-naphthylselanilethynyl) nicotinic acid, N- (4-hydroxyphenyl) -4 - (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphyl-phenylethynyl) -benzamide, 5- (5, 5, 8, 8-tetramethyl-5,6,7) carboxylate Methyl 8-tetrahydro-2-naphthylslanilethynyl) -2-pyridine 2- (4-chlorofenyl-slanilethynyl) -5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene, 4- (3, 5, Methyl 5, 8, 8-pentamethyl-5, 6,7, 8-tetrahydro-2-naphilselanilethynyl) benzoate, 4- (3, 5, 5, 8, 8-pentamethyl-5, 6, 7, 8 -tetrahydro-2-naphinyl-phenylethynyl) -benzoic acid, methyl 2-hydroxy-4- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylslanilethynyl) benzoate 2- hydroxy-4- (3, 5, 5, 8, 8-pentamethyl-5, 6, 7, 8-tetrahydro-2-naphilselanilethynyl) benzoic, 6- (3, 5, 5, 8, 8 -p ent ame ti 1-5, 6, 7, 8-tetrahydro-2-naphthylselaniletinyl) ethyl nicotinate, 6- (3, 5,5,8, 8-pentamethyl-5, 6, 7, 8-tetrahydro) -2-naphthylslanilethynyl) nicotinic, N- (4-hydroxyphenyl) -6- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylslanilethynyl) nicotinamide, N-butyl-6- (3, 5, 5, 8, 8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylslanilethynyl) nicotinamide, morpholin-4-yl- [6- (3,5,5,8,8-pentamethi-5,6, 7,8-tetrahydro-2-naphthylslanilethynyl) -3-pyridyl] methanone, 5- (3, 5, 5, 8, 8-pentamethyl-5, 6, 7, 8-tetrahydro-2-naphthylslanilethynyl) pyridin-2- methyl carboxylate, 5- (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylslanilethynyl) pyridine-2-carboxylic acid, [4- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-2-naphyl-phenylethynyl) phenyl] -methanol, 4- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-2-naph tiletinylsulf indigo) methyl benzoate, 4- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-2-naphthylethylsulfonyl) methyl benzoate, 4- (5, 5, 8, 8-tetramet methyl 1- 1,5-, 6,7,7,8-tetrahydro-2-naphthylethylsulfinyl) benzoate, 4- (5, 5, 8, 8-tetramethyl-5,6,7,8-tetrahydro-2-naphylethylsulfur) indigo) benzoic, á 4- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-2-naphylethylsulf onyl) benzoic acid, 4- (5, 5, 8, 8-tetramethyl-5,6, 7,8-tetrahydro-2-naphethyltinylsulphyl) benzoic acid, 4- (3, 5, 5, 8, 8-pentamethyl-5, 6, 7, 8-tetrahydro-2-naphthylslanilethynyl) phenol, 4- (4-hydroxy-5, 5, 8, 8-tetramethyl-5, Ethyl 6, 7, 8-tetrahydro-2-naphthylslanilethynyl) benzoate, ethyl 4- (4-methoxymethoxy-5, 5,8, 8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylslanilethynyl) enzoate , 4- (4-methoxymethoxy-5, 5,8, 8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylslanilethynyl) benzoic acid, 4- (4-pentyloxy-5, 5, 8, 8 -tetramethyl-5, 6, 7, 8-tetrahydro-2-naphthylslanilethynyl) benzoic acid, 4- (3-methoxymethoxy-5, 5,8, 8-tetramethi-5, 6,7,8-tetrahydro-2-naphthylslanilethynyl) ) ethyl benzoate, ethyl 4- (3-ethoxyethoxymethoxy-5, 5,8, 8-tetramethyl-5,6,1,8-tetrahydro-2-naphthylslanilethynyl) benzoate, 4- (3-methoxyethoxymethoxy-5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-2-naphthylslanilethynyl) benzoic acid, 4- (3-methoxymethoxy-5, 5, 8, 8-tetramethyl-5, 6,7, 8- tetrahydro-2-naphthylslanilethynyl) benzoic acid, 4- (3-pentyloxy-5, 5,8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-2-naphthyselanile tinyl) ethyl benzoate, 4- (3-pentyloxy-5, 5,8, 8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylslanilethynyl) benzoic acid, [4 - (5, 5, 8, 8 - te trame til - 5, 6, 7, 8 - te trahi dro -2-naphthylsphenylethynyl) phenyl] carbaldehyde, 4- (4,4-Dimethylthiochroman-8-yl-phenylethynyl) methyl benzoate, 4- (4,4-dimethylthiochroman-8-yl-phenylethynyl) enzoic acid, 4- (5, 5, 8, 8-tetramet-il-5, 6 , 7, 8-tetrahydro-8-naphthylesphenylethynyl) methyl benzoate, 4- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-8-naphthylslanilethynyl) benzoic acid, 4- [3 Methyl 4- (3- (1-adamantyl) -4-methoxy-phenyl) -1-yl-phenylethynyl] -benzoic acid (1-adamantyl) -4-methoxyphenyl) -1-yl-phenylethynyl] -benzoateMethyl 4- [4- (1-adamantyl) -3-methoxyphenyl) -1-ylslanilethynyl] benzoate and 4- [4- (1-adamantyl) -3-methoxyphenyl) -1-yl-phenylethynyl] -benzoic acid.
19. The compounds according to any of the preceding claims, characterized in that they are used as a medicinal product.
The compounds according to claim 19, characterized in that they are used as a medicinal product designed for the treatment of dermatological diseases, dermatological diseases with an inflammatory and / or immunoallergic component of the rheumatic type or respiratory disease, cardiovascular diseases and ophthalmological disorders.
21. The use of at least one of the compounds according to any of claims 1 to 18, characterized in that it is used for the preparation of a medicinal product designed for the treatment of dermatological diseases, dermatological diseases with an inflammatory component and / or immunoallergic of the rheumatic or respiratory type, cardiovascular diseases and ophthalmological disorders.
22. A pharmaceutical composition, characterized in that it comprises, in a pharmaceutically acceptable carrier, at least one compound according to any of claims 1 to 18.
23. The composition according to claim 22, characterized in that the concentration of less a compound according to one of claims 1 to 18 is between 0.001% and 5% by weight relative to the total weight of the composition.
24. A cosmetic composition, characterized in that it contains, in a cosmetically acceptable support, at least one compound according to any of claims 1 to 18.
25. The composition according to claim 24, characterized in that the concentration of at least one compound according to any of claims 1 to 18 is between 0.001% and 3% by weight relative to the total weight of the composition.
26. The use of a cosmetic composition, according to any of claims 23 and 25, characterized in that it is used for the hygiene of the body or the hair. SUMMARY OF THE INVENTION Compounds of formula (I) are provided (I) in which: Ar represents a radical that is chosen from the formulas (a) to (c) below: (to) (b) (c) Rx represents, in particular, a halogen atom, -CH3, or carboxyl, R2 and R3, represent, in particular, H, alkyl or cycloalkyl, or R2 and R3 taken together, form a ring of 5 or 6 members, R4 and R5 represent in particular, H, or a halogen atom, R6 represents, in particular, H, or alkyl, X represents a radical -YC = C-, Y represents O, S (0) not Se (0) n, n is 0, 1 or 2, and the salts of the compounds of formula (I). These compounds can be used in particular in the treatment of dermatological diseases associated with a keratinization disorder and to combat the aging of the skin.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR97/10554 | 1997-08-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA99003663A true MXPA99003663A (en) | 2000-05-01 |
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