JP4996682B2 - 化合物、その製法及びその用途 - Google Patents
化合物、その製法及びその用途 Download PDFInfo
- Publication number
- JP4996682B2 JP4996682B2 JP2009515316A JP2009515316A JP4996682B2 JP 4996682 B2 JP4996682 B2 JP 4996682B2 JP 2009515316 A JP2009515316 A JP 2009515316A JP 2009515316 A JP2009515316 A JP 2009515316A JP 4996682 B2 JP4996682 B2 JP 4996682B2
- Authority
- JP
- Japan
- Prior art keywords
- ala
- present
- cis
- skin
- hydrochloride
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 150000001875 compounds Chemical class 0.000 title claims description 24
- 238000004519 manufacturing process Methods 0.000 title claims description 12
- -1 4-pentenyl group Chemical group 0.000 claims description 55
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 32
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 16
- 208000002874 Acne Vulgaris Diseases 0.000 claims description 14
- 206010000496 acne Diseases 0.000 claims description 14
- 208000017520 skin disease Diseases 0.000 claims description 14
- 239000000126 substance Substances 0.000 claims description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 10
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 9
- ZCHHRLHTBGRGOT-SNAWJCMRSA-N (E)-hex-2-en-1-ol Chemical compound CCC\C=C\CO ZCHHRLHTBGRGOT-SNAWJCMRSA-N 0.000 claims description 6
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 claims description 6
- UIZVMOZAXAMASY-UHFFFAOYSA-N hex-5-en-1-ol Chemical compound OCCCCC=C UIZVMOZAXAMASY-UHFFFAOYSA-N 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 4
- BTSIZIIPFNVMHF-ARJAWSKDSA-N (Z)-2-penten-1-ol Chemical compound CC\C=C/CO BTSIZIIPFNVMHF-ARJAWSKDSA-N 0.000 claims description 3
- UFLHIIWVXFIJGU-ARJAWSKDSA-N (Z)-hex-3-en-1-ol Chemical compound CC\C=C/CCO UFLHIIWVXFIJGU-ARJAWSKDSA-N 0.000 claims description 3
- VTIODUHBZHNXFP-IHWYPQMZSA-N (e)-4-hexen-1-ol Chemical compound C\C=C/CCCO VTIODUHBZHNXFP-IHWYPQMZSA-N 0.000 claims description 3
- ZSPTYLOMNJNZNG-UHFFFAOYSA-N 3-Buten-1-ol Chemical compound OCCC=C ZSPTYLOMNJNZNG-UHFFFAOYSA-N 0.000 claims description 3
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 claims description 3
- 125000006043 5-hexenyl group Chemical group 0.000 claims description 3
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 3
- UFLHIIWVXFIJGU-UHFFFAOYSA-N hex-3-en-1-ol Natural products CCC=CCCO UFLHIIWVXFIJGU-UHFFFAOYSA-N 0.000 claims description 3
- LQAVWYMTUMSFBE-UHFFFAOYSA-N pent-4-en-1-ol Chemical compound OCCCC=C LQAVWYMTUMSFBE-UHFFFAOYSA-N 0.000 claims description 3
- 201000000849 skin cancer Diseases 0.000 claims description 3
- VTIODUHBZHNXFP-UHFFFAOYSA-N trans-hex-4-en-1-ol Natural products CC=CCCCO VTIODUHBZHNXFP-UHFFFAOYSA-N 0.000 claims description 3
- ACIAHEMYLLBZOI-ZZXKWVIFSA-N Unsaturated alcohol Chemical compound CC\C(CO)=C/C ACIAHEMYLLBZOI-ZZXKWVIFSA-N 0.000 claims description 2
- 229960002749 aminolevulinic acid Drugs 0.000 description 111
- ZGXJTSGNIOSYLO-UHFFFAOYSA-N 88755TAZ87 Chemical compound NCC(=O)CCC(O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 description 68
- 210000004027 cell Anatomy 0.000 description 55
- 210000003491 skin Anatomy 0.000 description 36
- KSFOVUSSGSKXFI-GAQDCDSVSA-N CC1=C/2NC(\C=C3/N=C(/C=C4\N\C(=C/C5=N/C(=C\2)/C(C=C)=C5C)C(C=C)=C4C)C(C)=C3CCC(O)=O)=C1CCC(O)=O Chemical compound CC1=C/2NC(\C=C3/N=C(/C=C4\N\C(=C/C5=N/C(=C\2)/C(C=C)=C5C)C(C=C)=C4C)C(C)=C3CCC(O)=O)=C1CCC(O)=O KSFOVUSSGSKXFI-GAQDCDSVSA-N 0.000 description 31
- 229950003776 protoporphyrin Drugs 0.000 description 31
- 239000002674 ointment Substances 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 17
- 238000000034 method Methods 0.000 description 13
- 241000699670 Mus sp. Species 0.000 description 12
- 150000002148 esters Chemical class 0.000 description 12
- 210000001519 tissue Anatomy 0.000 description 11
- 241000024188 Andala Species 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 206010028980 Neoplasm Diseases 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 230000008520 organization Effects 0.000 description 7
- 238000002428 photodynamic therapy Methods 0.000 description 7
- 230000035945 sensitivity Effects 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- 206010004146 Basal cell carcinoma Diseases 0.000 description 5
- 206010020649 Hyperkeratosis Diseases 0.000 description 5
- 208000001126 Keratosis Diseases 0.000 description 5
- 208000009621 actinic keratosis Diseases 0.000 description 5
- 229910052785 arsenic Inorganic materials 0.000 description 5
- RQNWIZPPADIBDY-UHFFFAOYSA-N arsenic atom Chemical compound [As] RQNWIZPPADIBDY-UHFFFAOYSA-N 0.000 description 5
- 230000030833 cell death Effects 0.000 description 5
- 239000003504 photosensitizing agent Substances 0.000 description 5
- 206010041823 squamous cell carcinoma Diseases 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000002500 effect on skin Effects 0.000 description 4
- 239000000835 fiber Substances 0.000 description 4
- 238000001506 fluorescence spectroscopy Methods 0.000 description 4
- 210000002510 keratinocyte Anatomy 0.000 description 4
- 230000003902 lesion Effects 0.000 description 4
- 201000001441 melanoma Diseases 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 210000001732 sebaceous gland Anatomy 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- 108090000672 Annexin A5 Proteins 0.000 description 3
- 102000004121 Annexin A5 Human genes 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 3
- 210000000805 cytoplasm Anatomy 0.000 description 3
- 231100000263 cytotoxicity test Toxicity 0.000 description 3
- 210000005175 epidermal keratinocyte Anatomy 0.000 description 3
- 210000002615 epidermis Anatomy 0.000 description 3
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 3
- 230000017074 necrotic cell death Effects 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- ZTHFREFSSRAGEH-UHFFFAOYSA-N pent-4-enyl 5-amino-4-oxopentanoate;hydrochloride Chemical compound Cl.NCC(=O)CCC(=O)OCCCC=C ZTHFREFSSRAGEH-UHFFFAOYSA-N 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- JPYXNXYJLSVTLO-UHFFFAOYSA-N prop-2-enyl 5-amino-4-oxopentanoate;hydrochloride Chemical compound Cl.NCC(=O)CCC(=O)OCC=C JPYXNXYJLSVTLO-UHFFFAOYSA-N 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 3
- WKEVRZCQFQDCIR-UHFFFAOYSA-N 4-chlorobut-1-ene Chemical compound ClCCC=C WKEVRZCQFQDCIR-UHFFFAOYSA-N 0.000 description 2
- 229950010481 5-aminolevulinic acid hydrochloride Drugs 0.000 description 2
- 108010040476 FITC-annexin A5 Proteins 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- UIMYUTFWSKEOKR-FXRZFVDSSA-N [(e)-hex-2-enyl] 5-amino-4-oxopentanoate;hydrochloride Chemical compound Cl.CCC\C=C\COC(=O)CCC(=O)CN UIMYUTFWSKEOKR-FXRZFVDSSA-N 0.000 description 2
- 230000000172 allergic effect Effects 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 208000010668 atopic eczema Diseases 0.000 description 2
- OQWLVHTUXXRULZ-UHFFFAOYSA-N but-3-enyl 5-amino-4-oxopentanoate;hydrochloride Chemical compound Cl.NCC(=O)CCC(=O)OCCC=C OQWLVHTUXXRULZ-UHFFFAOYSA-N 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- 210000002421 cell wall Anatomy 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 238000000684 flow cytometry Methods 0.000 description 2
- 210000004209 hair Anatomy 0.000 description 2
- KVVHYPUYVWTITK-UHFFFAOYSA-N hex-5-enyl 5-amino-4-oxopentanoate;hydrochloride Chemical compound Cl.NCC(=O)CCC(=O)OCCCCC=C KVVHYPUYVWTITK-UHFFFAOYSA-N 0.000 description 2
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 210000000434 stratum corneum Anatomy 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- YTXXOKPWZPVIFH-SNAWJCMRSA-N (e)-1-chlorohex-2-ene Chemical compound CCC\C=C\CCl YTXXOKPWZPVIFH-SNAWJCMRSA-N 0.000 description 1
- 125000006040 2-hexenyl group Chemical group 0.000 description 1
- UUKLWKRZKHHFEE-UHFFFAOYSA-N 3-amino-4-oxopentanoic acid hydrochloride Chemical compound Cl.CC(=O)C(N)CC(O)=O UUKLWKRZKHHFEE-UHFFFAOYSA-N 0.000 description 1
- UPOBJNRMUDPATE-UHFFFAOYSA-N 5-chloropent-1-ene Chemical compound ClCCCC=C UPOBJNRMUDPATE-UHFFFAOYSA-N 0.000 description 1
- BLMIXWDJHNJWDT-UHFFFAOYSA-N 6-chlorohex-1-ene Chemical compound ClCCCCC=C BLMIXWDJHNJWDT-UHFFFAOYSA-N 0.000 description 1
- OSDWBNJEKMUWAV-UHFFFAOYSA-N Allyl chloride Chemical compound ClCC=C OSDWBNJEKMUWAV-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 208000010368 Extramammary Paget Disease Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000011782 Keratins Human genes 0.000 description 1
- 108010076876 Keratins Proteins 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 231100000002 MTT assay Toxicity 0.000 description 1
- 238000000134 MTT assay Methods 0.000 description 1
- 206010034972 Photosensitivity reaction Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000002744 anti-aggregatory effect Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 210000000270 basal cell Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- 238000013043 cell viability test Methods 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 208000017563 cutaneous Paget disease Diseases 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 210000004207 dermis Anatomy 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 210000003780 hair follicle Anatomy 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000037311 normal skin Effects 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- 231100000760 phototoxic Toxicity 0.000 description 1
- 208000007578 phototoxic dermatitis Diseases 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 150000004032 porphyrins Chemical class 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 230000000405 serological effect Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000000475 sunscreen effect Effects 0.000 description 1
- 239000000516 sunscreening agent Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229940100615 topical ointment Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/22—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/10—Anti-acne agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Epidemiology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
本発明は、化合物とその製法及び光線力学療法に前記化合物を含有した治療用の薬学的組成物に関する発明であって、本発明の実施によって経皮吸収が容易で細胞毒性の少ない化合物を提供し、アミノ基の保護過程を経ないことによって、収率を高めた製法を提供することを特徴とする。
本発明の薬学的組成物は、患者の病変皮膚に均等に塗布するか貼布するが、投与して4時間を超過しないようにする。
5−アミノレブリン酸 2−プロペニル塩酸塩[5−アミノレブリン酸アリル塩酸塩)2−propenyl 5−aminolevulinate hydrochloride、(ALA allyl ester hydrochloride)]の製造
5−アミノレブリン酸 3−ブテニル塩酸塩(3−butenyl 5−aminolevulinate hydrochloride )の製造
5−アミノレブリン酸 4−ペンテニル塩酸塩(4−pentenyl 5−aminolevulinate hydrochloride)の製造
5−アミノレブリン酸 5−ヘキセニル塩酸塩(5−hexenyl 5−aminolevulinate hydro chloride)の製造
1H NMR(300MHz、DMSO−d6):δ8.33(s、3H)、5.85〜5.71(m、1H)、5.04〜4.92(m、2H)、3.99(t、J=6.5Hz、2H)、3.93(s、2H)、2.78(t、J=6.6Hz、2H)、2.53(t、J=6.6Hz、2H)、2.02(q、J=7Hz、2H)、1.56(quintet、J=6.7Hz、2H)、1.38(quintet、J=5.1Hz、2H);13C NMR(75MHz、DMSO−d6):δ202.66、172.05、138.41、115.02、63.92、46.52、34.26、32.69、27.56、27.08、24.55。
5−アミノレブリン酸 cis−2−ペンテニル塩酸塩(cis−2−pentenyl 5−aminolevulinate hydrochloride)の製造
5−アミノレブリン酸 cis−3−ヘキセニル塩酸塩(cis−3−hexenyl 5−aminolevulinate hydrochloride)の製造
5−アミノレブリン酸 cis−4−ヘキセニル塩酸塩(cis−4−hexenyl 5−aminolevulinate hydrochloride)の製造
5−アミノレブリン酸 trans−2−ヘキセニル塩酸塩(trans−2−hexenyl 5−aminolevulin−ate hydrochloride)の製造
1.公示材料
ア.細胞株
人体表皮角質形成細胞株(human epidermal keratinocyte、HEK)、
人体真皮線維細胞株(human dermal fibroblast、hF)
扁平細胞癌細胞株:A431(KCLB No.80005)
悪性黒色腫細胞株:TXM13(KCLB No.80029)
イ.動物
ICRマウス(大韓バイオリンク、韓國生命工學研究院、韓国)7〜8株の雌(female;♀)
ウ.光源照射器
光源照射器は、LED(Light Emitting Diode)光源器を利用し、最大波長410nm(波長帯;400〜430nm)であるblue light(青色)及び635nm(波長帯;615〜645nm)である赤色LED(Luxeon、Lumileds Light)を用いて5−30J/cm2の光源量を照射した。
本実験は、前記実施例で製造された本発明のALAエステル(粉末)の溶媒別の溶解度検査を実行した。
本実験は、細胞毒性検査であるMTT assay(Chemicon、serologicals corporation、USA)を通じて次のような細胞毒性検査を実行した。
約24時間経過後、細胞が培養容器の底を60〜70%程度覆った時、ALA及びALA−esterを濃度別に含有した無血清培養液100ulずつ交換して24時間さらに培養した。
ALA及び本発明のALAエステルを処理した人体角質形成細胞(human epidermal keratinocyte)で細胞生存率の結果を対照区(ALA)と比べて、下記表1及び表2に表わした。この際、表1と表2は、相異なる時期に実験して異なる数値方法で表わしたものである。
蛍光分光法を通じてALA及び不飽和アルキル基を有したALAエステルによるPpIXの合成量を細胞及び皮膚組職で定量化した。
2×105個の各細胞株は、10cm2のdishes(Falcon)に分周させて、70〜80%の融合された状態(confluent state)になった時、ALA及びALAエステルを濃度別(0.001〜1mM)に含有した無血清培養液を添加して4時間培養した。
(1)軟膏剤の製造
ALA及び本発明のALAエステルを含有した軟膏剤は、ALA及び本発明のALAエステル粉末とオクタデシルアルコール、ポリエチレングリコール、精製水などで組成されている水溶性ベース(water soluble base)である水溶性軟膏基剤(SAMABASE、韓国)を混合して製造した。この際、ALA及び本発明のALAエステルの混合比率は、それぞれ5%、10%及び15%(w/w)にした。
前記製造した濃度別の軟膏剤は、毛が除去されたICRマウスの背中(back)に一定量(0.25g)を塗布させた。
前記本発明のALAエステルを含んだ軟膏剤は、前記同一の方法で各細胞株及びICRマウスの皮膚組職に処理し、該処理した細胞株と皮膚組職で合成されたPpIXの発現部位とを蛍光顕微鏡で観察した。
本実験は、本発明のALAエステル及びALAを正常細胞株である人体角質形成細胞(HEK)と人体真皮線維細胞株(hK)及び癌細胞である扁平細胞癌細胞株であるA431(C)と悪性黒色腫細胞株であるTXM13(D)の培養液に**mMで処理した後、各細胞の細胞質で合成されるPpIXの蛍光を蛍光顕微鏡で観察した。
本実験は、本発明のALAエステル及びALAを含んだ軟膏剤をIPCマウス皮膚に塗布した後、1時間、2時間及び3時間後に発現されるPpIXを蛍光顕微鏡で測定した。
ア.細胞株
流体細胞測定法(Flow cytometry、FACS:FACSCalibur、BD、USA)を用いて6well plateに培養した各細胞株は、ALA及び本発明のALAエステルで処理し、LED可視光線を照射した後、Annexin V−FITCとPI(Annexin V−FITC Apoptosis detectionKit、BD)とで染色して、細胞枯死(apoptosis)を測定した。
濃度別(5〜15%)にALA及び本発明のALAエステルを含有した軟膏剤は、毛が除去されたICRマウスの背中に一定量(0.25g)を塗布させた。
本実験例は、前記4−(イ)−(1)で製造した軟膏剤がアレルギー性及び原発性接触皮膚炎(allergic and primary contact dermatitis)を起こすかどうかを調べるのために、50名の正常人を対象で貼布検査を施行した。
したがって、本発明のALAエステルを含んだ軟膏剤は、如何なるアレルギー性または一次的接触(光毒性)皮膚炎も引き起こさないことが分かった。
本実験は、15%(w/w)のALA−6(ALA hexenyl ester)を含有した軟膏剤をにきび、光線角化症、砒素角化症及び基底細胞癌の患者に光線力学療法で治療して、治療効果があるか否かを確認しようとした。
Claims (5)
- 薬学的に許容される塩は、塩酸塩であることを特徴とする請求項1に記載の化学式(I)で表示される化合物または薬学的に許容されるその塩。
- (a)下記化学式(II)化合物を塩化チオニル及びN,N−ジメチルホルムアミドと反応させる段階と、
(b)前記(a)段階で得られた物質をアリルアルコール、3−ブテノール(3−butenol)、4−ペンテノール(4−pentenol)、5−ヘキセノール(5−hexenol)、シス−2−ペンテノール(cis−2−pentenol)、シス−3−ヘキセノール(cis−3−hexenol)、シス−4−ヘキセノール(cis−4−hexenol)及びトランス−2−ヘキセノール(trans−2−hexenol)からなる群から選択された不飽和アルコールと反応させる段階と、を含むことを特徴とする請求項1または2に記載の化学式(I)で表示される化合物または薬学的に許容されるその塩の製法:
- 請求項1または2に記載の化学式(I)で表示される化合物または薬学的に許容されるその塩を有効成分として含むことを特徴とする皮膚疾患治療用の薬学的組成物。
- 前記皮膚疾患は、
にきびまたは皮膚癌であることを特徴とする請求項4に記載の皮膚疾患治療用の薬学的組成物。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR20060059124 | 2006-06-29 | ||
KR10-2006-0059124 | 2006-06-29 | ||
KR10-2007-0040869 | 2007-04-26 | ||
KR1020070040869A KR100796450B1 (ko) | 2006-06-29 | 2007-04-26 | 5-아미노레불린산의 불포화 알킬 에스터 및 약학적으로허용되는 그의 염, 이의 제조방법 및 이의 용도 |
PCT/KR2007/003145 WO2008002087A1 (en) | 2006-06-29 | 2007-06-28 | Unsaturated alkyl esters of 5-aminolevulinic acid, their preparation and their use |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2009539971A JP2009539971A (ja) | 2009-11-19 |
JP4996682B2 true JP4996682B2 (ja) | 2012-08-08 |
Family
ID=39213587
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2009515316A Expired - Fee Related JP4996682B2 (ja) | 2006-06-29 | 2007-06-28 | 化合物、その製法及びその用途 |
Country Status (5)
Country | Link |
---|---|
US (1) | US8198325B2 (ja) |
EP (1) | EP2032526B1 (ja) |
JP (1) | JP4996682B2 (ja) |
KR (1) | KR100796450B1 (ja) |
WO (1) | WO2008002087A1 (ja) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103635205A (zh) * | 2011-07-01 | 2014-03-12 | 思佰益药业股份有限公司 | 使用光增敏剂或5-氨基乙酰丙酸类的光动力学治疗 |
KR101505446B1 (ko) * | 2013-05-16 | 2015-03-25 | (주) 위디어 | 5-아미노레불린산의 제조방법 및 그 용도 |
CN105770894B (zh) * | 2016-03-28 | 2019-10-01 | 中国人民解放军南京军区福州总医院 | 盐酸氨酮戊酸温度敏感型原位凝胶制剂及其制备方法 |
EP4349401A1 (en) | 2019-02-13 | 2024-04-10 | Alpheus Medical, Inc. | Non-invasive sonodynamic therapy |
CN111635464B (zh) * | 2020-05-12 | 2022-03-25 | 上海易全化学有限公司 | 一种5-氨基酮戊酸葡聚糖酯的制备方法 |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
HU225148B1 (en) * | 1995-03-10 | 2006-07-28 | Photocure Asa | Esters of 5-aminolevulinic acid as photosensitizing agents in photochemotherapy or diagnosis, products and kits comprising thereof and method of in vitro diagnosis by their using |
JP4619558B2 (ja) * | 2001-03-23 | 2011-01-26 | 株式会社コスモ総合研究所 | 5−アミノ−4−ヒドロキシペンタン酸誘導体とその製造方法 |
EP1312353A1 (en) * | 2001-11-16 | 2003-05-21 | Ecole Polytechnique Federale De Lausanne (Epfl) | Method for hair removal |
GB0406917D0 (en) * | 2004-03-26 | 2004-04-28 | Photocure Asa | Compounds |
GB0424833D0 (en) * | 2004-11-10 | 2004-12-15 | Photocure Asa | Method |
CA2604388A1 (en) * | 2005-04-11 | 2006-10-19 | Lupin Limited | Preparation of [2-methyl-5-phenyl-3-(piperazin-1-ylmethyl)] pyrrole derivatives |
-
2007
- 2007-04-26 KR KR1020070040869A patent/KR100796450B1/ko active IP Right Grant
- 2007-06-28 JP JP2009515316A patent/JP4996682B2/ja not_active Expired - Fee Related
- 2007-06-28 EP EP07768517A patent/EP2032526B1/en not_active Expired - Fee Related
- 2007-06-28 WO PCT/KR2007/003145 patent/WO2008002087A1/en active Application Filing
- 2007-06-28 US US12/227,085 patent/US8198325B2/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
KR20080001603A (ko) | 2008-01-03 |
US8198325B2 (en) | 2012-06-12 |
US20090176881A1 (en) | 2009-07-09 |
JP2009539971A (ja) | 2009-11-19 |
KR100796450B1 (ko) | 2008-01-22 |
EP2032526A4 (en) | 2011-10-05 |
EP2032526B1 (en) | 2012-10-10 |
EP2032526A1 (en) | 2009-03-11 |
WO2008002087A1 (en) | 2008-01-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8492578B2 (en) | Compounds useful in therapeutic and cosmetic methods | |
CN1137087C (zh) | 用作光化学疗法中的光致敏剂的5-氨基酮戊酸的酯 | |
EP1313695B1 (en) | Esters of 5-aminolevulinic acid as photosensitizing agents in photochemotherapy | |
DE60211918T2 (de) | Sulfonierte chlorine als photosensitizer | |
CA2820233C (en) | Perylenequinone derivatives and uses thereof | |
TWI537278B (zh) | 甲矽烷基聚合苯甲酸酯化合物、其用途及組成物 | |
CN103282348B (zh) | 使用雷琐辛衍生物使角蛋白材料脱色的方法 | |
JP4996682B2 (ja) | 化合物、その製法及びその用途 | |
EP3663286A1 (en) | Photosensitizer and derivatives and application thereof | |
JP6280117B2 (ja) | 化合物 | |
JP2002522366A (ja) | エクトインまたはエクトイン誘導体の化粧品製剤における使用 | |
JP2019533635A (ja) | 新規なジヒドロポルフィンe6誘導体及びその薬学的に許容される塩、その調製方法並びに使用 | |
US20120258063A1 (en) | Preventing or ameliorating agent for pigmentation | |
JP7073384B2 (ja) | 化合物及び使用方法 | |
KR101505446B1 (ko) | 5-아미노레불린산의 제조방법 및 그 용도 | |
JP3318930B2 (ja) | アミノ酸誘導体及び抗活性酸素剤 | |
CN110121491A (zh) | 3,4,5-三甲氧基肉桂酸酯衍生物、其制备方法以及含有该衍生物的皮肤美白组合物 | |
EP2007711A1 (en) | 5-aminolevulinic acid salts and their use | |
Godal et al. | New derivatives of 5-aminolevulinic acid for photodynamic therapy: chemical synthesis and porphyrin production in in vitro and in vivo biological systems | |
Vena et al. | 5-Aminolevulinic acid ester–induced protoporphyrin IX in a murine melanoma cell line | |
JP2005505556A (ja) | カルボキシレート−ゲート−ニトロキシド(cgn)化合物および組成物ならびにその使用方法 | |
KR20140106814A (ko) | 광역학 진단 또는 치료용 광감작제 및 그 제조방법 | |
RomiszewskA et al. | The use of 5-aminolevulinic acid and its derivatives in photodynamic therapy and diagnosis | |
JP3736405B2 (ja) | アミノ酸誘導体及び抗活性酸素剤 | |
KR20110045790A (ko) | 메틸 5-아미노레불리네이트 염산염의 제조방법과 이를 이용한 여드름 및 피부 개선을 위한 피부 외용 화장료 조성물 및 이의 제조방법 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20111004 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20111005 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20111207 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20120417 |
|
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20120511 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20150518 Year of fee payment: 3 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 4996682 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
LAPS | Cancellation because of no payment of annual fees |