NO311005B1 - Use of benzaldehyde derivatives for the preparation of a therapeutic agent for the treatment of autoimmune diseases - Google Patents
Use of benzaldehyde derivatives for the preparation of a therapeutic agent for the treatment of autoimmune diseases Download PDFInfo
- Publication number
- NO311005B1 NO311005B1 NO20001450A NO20001450A NO311005B1 NO 311005 B1 NO311005 B1 NO 311005B1 NO 20001450 A NO20001450 A NO 20001450A NO 20001450 A NO20001450 A NO 20001450A NO 311005 B1 NO311005 B1 NO 311005B1
- Authority
- NO
- Norway
- Prior art keywords
- glucopyranose
- deoxy
- benzylidene
- methanol
- hydroxybenzylidene
- Prior art date
Links
- 239000003814 drug Substances 0.000 title claims description 18
- 150000003935 benzaldehydes Chemical class 0.000 title claims description 13
- 208000023275 Autoimmune disease Diseases 0.000 title claims description 12
- 238000011282 treatment Methods 0.000 title claims description 10
- 229940124597 therapeutic agent Drugs 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- -1 di-substituted phenyl Chemical group 0.000 claims description 9
- 201000004681 Psoriasis Diseases 0.000 claims description 6
- 201000003066 Diffuse Scleroderma Diseases 0.000 claims description 5
- 201000009594 Systemic Scleroderma Diseases 0.000 claims description 5
- 206010042953 Systemic sclerosis Diseases 0.000 claims description 5
- 229910052805 deuterium Inorganic materials 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 3
- 208000011231 Crohn disease Diseases 0.000 claims description 3
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 208000002874 Acne Vulgaris Diseases 0.000 claims description 2
- 206010002556 Ankylosing Spondylitis Diseases 0.000 claims description 2
- 201000001263 Psoriatic Arthritis Diseases 0.000 claims description 2
- 208000036824 Psoriatic arthropathy Diseases 0.000 claims description 2
- 206010039792 Seborrhoea Diseases 0.000 claims description 2
- 206010000496 acne Diseases 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 206010025135 lupus erythematosus Diseases 0.000 claims description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 2
- 208000008742 seborrheic dermatitis Diseases 0.000 claims description 2
- FOLRUCXBTYDAQK-SFZUHQLGSA-N (4ar,7r,8r,8as)-2-phenyl-4,4a,6,7,8,8a-hexahydropyrano[3,2-d][1,3]dioxine-6,7,8-triol Chemical group C([C@H]1OC([C@@H]([C@@H](O)[C@@H]1O1)O)O)OC1C1=CC=CC=C1 FOLRUCXBTYDAQK-SFZUHQLGSA-N 0.000 claims 1
- WQZGKKKJIJFFOK-UHFFFAOYSA-N alpha-D-glucopyranose Natural products OCC1OC(O)C(O)C(O)C1O WQZGKKKJIJFFOK-UHFFFAOYSA-N 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 163
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 84
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 49
- 239000000047 product Substances 0.000 description 43
- 150000001875 compounds Chemical class 0.000 description 34
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical compound OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 description 31
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 30
- 238000005481 NMR spectroscopy Methods 0.000 description 30
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 27
- 210000004027 cell Anatomy 0.000 description 26
- 238000006243 chemical reaction Methods 0.000 description 26
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 25
- 150000001299 aldehydes Chemical class 0.000 description 21
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 20
- 238000004821 distillation Methods 0.000 description 19
- 239000000243 solution Substances 0.000 description 19
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 16
- 239000002262 Schiff base Substances 0.000 description 15
- 239000000203 mixture Substances 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- 150000004753 Schiff bases Chemical class 0.000 description 14
- 239000003480 eluent Substances 0.000 description 14
- 229940079593 drug Drugs 0.000 description 13
- 238000000526 short-path distillation Methods 0.000 description 13
- HEVMDQBCAHEHDY-UHFFFAOYSA-N (Dimethoxymethyl)benzene Chemical class COC(OC)C1=CC=CC=C1 HEVMDQBCAHEHDY-UHFFFAOYSA-N 0.000 description 11
- 238000001704 evaporation Methods 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- 150000001241 acetals Chemical class 0.000 description 10
- 230000008020 evaporation Effects 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- XEDONBRPTABQFB-UHFFFAOYSA-N 4-[(2-formyl-3-hydroxyphenoxy)methyl]benzoic acid Chemical group C1=CC(C(=O)O)=CC=C1COC1=CC=CC(O)=C1C=O XEDONBRPTABQFB-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 239000007789 gas Substances 0.000 description 9
- 239000005457 ice water Substances 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- 238000004587 chromatography analysis Methods 0.000 description 8
- 229940125782 compound 2 Drugs 0.000 description 8
- 201000010099 disease Diseases 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 210000000987 immune system Anatomy 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- 230000001105 regulatory effect Effects 0.000 description 8
- 210000001744 T-lymphocyte Anatomy 0.000 description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 230000002441 reversible effect Effects 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 229950009795 tucaresol Drugs 0.000 description 7
- WQZGKKKJIJFFOK-SVZMEOIVSA-N (+)-Galactose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-SVZMEOIVSA-N 0.000 description 6
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 6
- 125000003277 amino group Chemical group 0.000 description 6
- 210000000612 antigen-presenting cell Anatomy 0.000 description 6
- 229940126543 compound 14 Drugs 0.000 description 6
- 230000001965 increasing effect Effects 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 239000002002 slurry Substances 0.000 description 6
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
- 238000004817 gas chromatography Methods 0.000 description 5
- 150000002466 imines Chemical class 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 5
- 238000001243 protein synthesis Methods 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- 235000000346 sugar Nutrition 0.000 description 5
- 239000006188 syrup Substances 0.000 description 5
- 235000020357 syrup Nutrition 0.000 description 5
- 230000014616 translation Effects 0.000 description 5
- ALXDDWGEZDTXOE-UHFFFAOYSA-N 1-(dimethoxymethyl)-3-nitrobenzene Chemical compound COC(OC)C1=CC=CC([N+]([O-])=O)=C1 ALXDDWGEZDTXOE-UHFFFAOYSA-N 0.000 description 4
- 101000686985 Mouse mammary tumor virus (strain C3H) Protein PR73 Proteins 0.000 description 4
- GZCGUPFRVQAUEE-SLPGGIOYSA-N aldehydo-D-glucose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O GZCGUPFRVQAUEE-SLPGGIOYSA-N 0.000 description 4
- 238000006482 condensation reaction Methods 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 229960001031 glucose Drugs 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 235000018102 proteins Nutrition 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 230000009257 reactivity Effects 0.000 description 4
- 231100000617 superantigen Toxicity 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 4
- SWTGJCNCBUCXSS-ISUZDFFFSA-N (2r)-3,4-dihydroxy-2-[(4s)-2-phenyl-1,3-dioxolan-4-yl]-2h-furan-5-one Chemical compound OC1=C(O)C(=O)O[C@@H]1[C@H]1OC(C=2C=CC=CC=2)OC1 SWTGJCNCBUCXSS-ISUZDFFFSA-N 0.000 description 3
- XILIYVSXLSWUAI-UHFFFAOYSA-N 2-(diethylamino)ethyl n'-phenylcarbamimidothioate;dihydrobromide Chemical compound Br.Br.CCN(CC)CCSC(N)=NC1=CC=CC=C1 XILIYVSXLSWUAI-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 3
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 239000012670 alkaline solution Substances 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 150000003934 aromatic aldehydes Chemical class 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000005100 correlation spectroscopy Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 210000002443 helper t lymphocyte Anatomy 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 229950006780 n-acetylglucosamine Drugs 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 230000000269 nucleophilic effect Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 210000003491 skin Anatomy 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 125000003396 thiol group Chemical group [H]S* 0.000 description 3
- VRYALKFFQXWPIH-PBXRRBTRSA-N (3r,4s,5r)-3,4,5,6-tetrahydroxyhexanal Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)CC=O VRYALKFFQXWPIH-PBXRRBTRSA-N 0.000 description 2
- KTWDTPBHCWJWGJ-UHFFFAOYSA-N 5-pyridin-4-yl-1,3,4-thiadiazol-2-amine Chemical compound S1C(N)=NN=C1C1=CC=NC=C1 KTWDTPBHCWJWGJ-UHFFFAOYSA-N 0.000 description 2
- 208000035143 Bacterial infection Diseases 0.000 description 2
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 102000015696 Interleukins Human genes 0.000 description 2
- 108010063738 Interleukins Proteins 0.000 description 2
- OVRNDRQMDRJTHS-CBQIKETKSA-N N-Acetyl-D-Galactosamine Chemical compound CC(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@H](O)[C@@H]1O OVRNDRQMDRJTHS-CBQIKETKSA-N 0.000 description 2
- MBLBDJOUHNCFQT-UHFFFAOYSA-N N-acetyl-D-galactosamine Natural products CC(=O)NC(C=O)C(O)C(O)C(O)CO MBLBDJOUHNCFQT-UHFFFAOYSA-N 0.000 description 2
- 241000920340 Pion Species 0.000 description 2
- 208000010362 Protozoan Infections Diseases 0.000 description 2
- 208000025747 Rheumatic disease Diseases 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 208000036142 Viral infection Diseases 0.000 description 2
- 238000006359 acetalization reaction Methods 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- PMMURAAUARKVCB-UHFFFAOYSA-N alpha-D-ara-dHexp Natural products OCC1OC(O)CC(O)C1O PMMURAAUARKVCB-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-PQMKYFCFSA-N alpha-D-mannose Chemical compound OC[C@H]1O[C@H](O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-PQMKYFCFSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 208000022362 bacterial infectious disease Diseases 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-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 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229940077731 carbohydrate nutrients Drugs 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000032823 cell division Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 238000007385 chemical modification Methods 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 229930182830 galactose Natural products 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 208000027866 inflammatory disease Diseases 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 230000037311 normal skin Effects 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 230000004962 physiological condition Effects 0.000 description 2
- 230000009145 protein modification Effects 0.000 description 2
- 230000001185 psoriatic effect Effects 0.000 description 2
- NGVDGCNFYWLIFO-UHFFFAOYSA-N pyridoxal 5'-phosphate Chemical compound CC1=NC=C(COP(O)(O)=O)C(C=O)=C1O NGVDGCNFYWLIFO-UHFFFAOYSA-N 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 238000004611 spectroscopical analysis Methods 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 238000009121 systemic therapy Methods 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- IQFYYKKMVGJFEH-OFKYTIFKSA-N 1-[(2r,4s,5r)-4-hydroxy-5-(tritiooxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound C1[C@H](O)[C@@H](CO[3H])O[C@H]1N1C(=O)NC(=O)C(C)=C1 IQFYYKKMVGJFEH-OFKYTIFKSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- YZUPZGFPHUVJKC-UHFFFAOYSA-N 1-bromo-2-methoxyethane Chemical compound COCCBr YZUPZGFPHUVJKC-UHFFFAOYSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- NCYCYZXNIZJOKI-IOUUIBBYSA-N 11-cis-retinal Chemical compound O=C/C=C(\C)/C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-IOUUIBBYSA-N 0.000 description 1
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 1
- VRYALKFFQXWPIH-HSUXUTPPSA-N 2-deoxy-D-galactose Chemical compound OC[C@@H](O)[C@H](O)[C@H](O)CC=O VRYALKFFQXWPIH-HSUXUTPPSA-N 0.000 description 1
- HUMNYLRZRPPJDN-QYKNYGDISA-N 2-deuteriobenzaldehyde Chemical compound [2H]C1=CC=CC=C1C=O HUMNYLRZRPPJDN-QYKNYGDISA-N 0.000 description 1
- ZETIVVHRRQLWFW-UHFFFAOYSA-N 3-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC(C=O)=C1 ZETIVVHRRQLWFW-UHFFFAOYSA-N 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Natural products OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 1
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 1
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
- OJRUSAPKCPIVBY-KQYNXXCUSA-N C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N Chemical compound C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N OJRUSAPKCPIVBY-KQYNXXCUSA-N 0.000 description 1
- 208000000419 Chronic Hepatitis B Diseases 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 108010036941 Cyclosporins Proteins 0.000 description 1
- 206010012434 Dermatitis allergic Diseases 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- 102000001390 Fructose-Bisphosphate Aldolase Human genes 0.000 description 1
- 108010068561 Fructose-Bisphosphate Aldolase Proteins 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 102100029966 HLA class II histocompatibility antigen, DP alpha 1 chain Human genes 0.000 description 1
- 101000864089 Homo sapiens HLA class II histocompatibility antigen, DP alpha 1 chain Proteins 0.000 description 1
- 101000930802 Homo sapiens HLA class II histocompatibility antigen, DQ alpha 1 chain Proteins 0.000 description 1
- 101000968032 Homo sapiens HLA class II histocompatibility antigen, DR beta 3 chain Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 229920000557 Nafion® Polymers 0.000 description 1
- 230000010799 Receptor Interactions Effects 0.000 description 1
- 102000004330 Rhodopsin Human genes 0.000 description 1
- 108090000820 Rhodopsin Proteins 0.000 description 1
- 238000006828 Rosenmund reduction reaction Methods 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 108091008874 T cell receptors Proteins 0.000 description 1
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-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 description 1
- 150000007854 aminals Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000003851 biochemical process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
- 229940043253 butylated hydroxyanisole Drugs 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 210000003040 circulating cell Anatomy 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 208000030499 combat disease Diseases 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 150000008266 deoxy sugars Chemical class 0.000 description 1
- 239000011903 deuterated solvents Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- GUJOJGAPFQRJSV-UHFFFAOYSA-N dialuminum;dioxosilane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[O-2].[Al+3].[Al+3].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O GUJOJGAPFQRJSV-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000002222 downregulating effect Effects 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000002900 effect on cell Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 150000002243 furanoses Chemical class 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 230000034659 glycolysis Effects 0.000 description 1
- 150000002337 glycosamines Chemical class 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 230000009422 growth inhibiting effect Effects 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 108010036302 hemoglobin AS Proteins 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 150000002401 hexose derivatives Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000008105 immune reaction Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 229940125721 immunosuppressive agent Drugs 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 230000000622 irritating effect Effects 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- TYQCGQRIZGCHNB-JLAZNSOCSA-N l-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 210000003810 lymphokine-activated killer cell Anatomy 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- XMYQHJDBLRZMLW-UHFFFAOYSA-N methanolamine Chemical compound NCO XMYQHJDBLRZMLW-UHFFFAOYSA-N 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- FEIOASZZURHTHB-UHFFFAOYSA-N methyl 4-formylbenzoate Chemical compound COC(=O)C1=CC=C(C=O)C=C1 FEIOASZZURHTHB-UHFFFAOYSA-N 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- SEVSMVUOKAMPDO-UHFFFAOYSA-N para-Acetoxybenzaldehyde Natural products CC(=O)OC1=CC=C(C=O)C=C1 SEVSMVUOKAMPDO-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 235000021395 porridge Nutrition 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 150000003215 pyranoses Chemical class 0.000 description 1
- 235000007682 pyridoxal 5'-phosphate Nutrition 0.000 description 1
- 239000011589 pyridoxal 5'-phosphate Substances 0.000 description 1
- 229960001327 pyridoxal phosphate Drugs 0.000 description 1
- 238000000197 pyrolysis Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
- 238000007157 ring contraction reaction Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 208000007056 sickle cell anemia Diseases 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000003930 superacid Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- ULSZVNJBVJWEJE-UHFFFAOYSA-N thiazolidine-2-carboxylic acid Chemical compound OC(=O)C1NCCS1 ULSZVNJBVJWEJE-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 229940098465 tincture Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000005891 transamination reaction Methods 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
- WFHFGDIKIXDWNX-ZQOBQRRWSA-N β-cyclodextrin-benzaldehyde Chemical compound O=CC1=CC=CC=C1.OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WFHFGDIKIXDWNX-ZQOBQRRWSA-N 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Denne oppfinnelsen vedrører anvendelse av benzaldehydderivater for fremstilling av terapeutiske midler til forebygging og/eller behandling av autoimmune sykdommer. This invention relates to the use of benzaldehyde derivatives for the production of therapeutic agents for the prevention and/or treatment of autoimmune diseases.
Aldehyder reagerer med en rekke O-, S- eller N-holdige nukleofile grupper som hydroksylgrupper, sulfhydrylgrupper og aminogrupper under dannelse av karbonylholdige kondensasjonsprodukter som acetaler, merkaptaler, aminaler etc. Med primære aminer vil reaksjonen imidlertid normalt føre til en addisjonsforbindelse i form av en Schiff-base (et imin). Det er velkjent at in vivo Schiff-basedannelse er involvert i biokjemiske nøkkelprosesser som transaminering, dekarboksylering og andre aminosyremodifiserende reaksjoner som katalyseres ved hjelp av pyridoksalfosfat, virkningen av aldolase på fruktosedifosfat i glykolysen og kondensasjonen av retinal med rodopsin i synsprosessen. Det er også kjent at signalisering gjennom membraner innebærer karbonylkondensasjonsreaksjoner, f.eks. når det skal settes i gang en respons fra immunsystemet. Aldehydes react with a number of O-, S- or N-containing nucleophilic groups such as hydroxyl groups, sulfhydryl groups and amino groups to form carbonyl-containing condensation products such as acetals, mercaptals, aminals etc. With primary amines, however, the reaction will normally lead to an addition compound in the form of a Schiff base (an imine). It is well known that in vivo Schiff base formation is involved in key biochemical processes such as transamination, decarboxylation, and other amino acid modifying reactions catalyzed by pyridoxal phosphate, the action of aldolase on fructose diphosphate in glycolysis, and the condensation of retinal with rhodopsin in the vision process. It is also known that signaling through membranes involves carbonyl condensation reactions, e.g. when a response from the immune system is to be initiated.
Dannelsen av iminer skjer ved en totrinnsmekanisme. Ved å tilsette en amino-nukleofil til karbonylgruppen dannes mellomproduktet karbinolamin (aminohydrin), deretter følger et dehydreringstrinn ved dannelsen av dobbeltbindingen C=N. Begge trinnene er reversible, men begunstiges ved forskjellige pH-verdier. Derfor går reaksjonen etter en karakteristisk klokkeformet pH-/hastighetsprofil hvor den høyeste totale reaksjonshastigheten opptrer ved moderat pH. The formation of imines occurs by a two-step mechanism. By adding an amino nucleophile to the carbonyl group, the intermediate carbinolamine (aminohydrin) is formed, then a dehydration step follows in the formation of the double bond C=N. Both steps are reversible, but are favored at different pH values. Therefore, the reaction follows a characteristic bell-shaped pH/rate profile where the highest overall reaction rate occurs at moderate pH.
Imidlertid vet man at Schiff-baser lett dannes også ved fysiologiske betingelser, og mange karbonylkondensasjonsreaksjoner er vel kjent in vivo (E.Schauenstein et. al., Aldehydes in Biological Systems, London, Pion Ltd., 1977). However, it is known that Schiff bases are easily formed also under physiological conditions, and many carbonyl condensation reactions are well known in vivo (E.Schauenstein et. al., Aldehydes in Biological Systems, London, Pion Ltd., 1977).
Schiff-basen er gjerne selv et reaktivt molekyl, og deltar ofte i ytterligere reaksjoner som fører til addisjon av nukleofile enheter til dobbeltbindingen. For visse svovelholdige aminer, spesielt aminosyrene cystein og metionin og for glutation, vil Schiff-basen som dannes først kunne gjennomgå reversibel intern ringdannelse hvor sulfhydrylgruppen adderes til iminet under dannelse av tiazolidinkarboksylat (M.Friedman, The Chemistry and Biochemistry of the Sulfhydryl Group in Amino Acids, Peptides and Proteins, Oxford, Pergamon Press, 1973). The Schiff base is often itself a reactive molecule, and often participates in further reactions that lead to the addition of nucleophilic units to the double bond. For certain sulphur-containing amines, especially the amino acids cysteine and methionine and for glutathione, the Schiff base that is first formed will be able to undergo reversible internal ring formation where the sulfhydryl group is added to the imine to form thiazolidine carboxylate (M.Friedman, The Chemistry and Biochemistry of the Sulfhydryl Group in Amino Acids, Peptides and Proteins, Oxford, Pergamon Press, 1973).
Indikasjoner på reaksjoner mellom karbonylforbindelser og frie aminogrupper i proteiner under dannelse av reversible Schiff-baser ble rapportert av G.E.Means og R.E.Feeney (Chemical Modification of Proteins, s. 125 - 138, San Francisco, Holden-Day, 1971). Aromatiske aldehyder er generelt mer reaktive enn mettede alifatiske aldehyder, og kan danne Schiff-baser selv uten at man fjerner vann under reaksjonen. (R.W.Layer, Chem. Rev. 63 (1963), 489-510). Dette er viktig når man tar i betraktning dannelse av Schiff-baser under fysiologiske betingelser. Med hemoglobin som kilde for aminogrupper har Zaugg et. al. (J. Biol. Chem. 252 Indications of reactions between carbonyl compounds and free amino groups in proteins to form reversible Schiff bases were reported by G.E.Means and R.E.Feeney (Chemical Modification of Proteins, pp. 125 - 138, San Francisco, Holden-Day, 1971). Aromatic aldehydes are generally more reactive than saturated aliphatic aldehydes, and can form Schiff bases even without removing water during the reaction. (R.W.Layer, Chem. Rev. 63 (1963), 489-510). This is important when considering the formation of Schiff bases under physiological conditions. With hemoglobin as a source of amino groups, Zaugg et. eel. (J. Biol. Chem. 252
(1977), 8542 - 8548) vist at aromatiske aldehyder er to til tre ganger så reaktive som alifatiske aldehyder for dannelse av Schiff-baser. En forklaring på den begrensede reaktiviteten til alkanalene kunne være at det i vannløsning ved nøytral pH kreves et meget stort overskudd av fritt aldehyd for å forskyve likevekten i retning av Schiff-basedannelse (E.Schauenstein et. al., Aldehydes in Biological Systems, London, Pion Ltd., 1977). (1977), 8542 - 8548) showed that aromatic aldehydes are two to three times as reactive as aliphatic aldehydes for the formation of Schiff bases. An explanation for the limited reactivity of the alkanal channels could be that in water solution at neutral pH a very large excess of free aldehyde is required to shift the equilibrium in the direction of Schiff base formation (E.Schauenstein et. al., Aldehydes in Biological Systems, London , Pion Ltd., 1977).
Benzaldehyd og salicylaldehyd danner lett Schiff-baseiminer med membran-aminogrupper, og det er målt høye likevektskonstanter for reaksjonen av benzaldehyd med aminer (J.J. Pesek og J.H.Frost, Org. Magnet. Res. 8 (1976), 173 -176, J.N.Williams Jr. og R.M.Jacobs, Biochim. Biophys. Acta., 154 (1968), 323 - 331). Med salicylaldehyd kan iminet stabiliseres ytterligere ved hydrogenbinding mellom det enslige elektronparet i iminnitrogenet og orto-hydroksylgruppen (G.E.Means og R.E.Feeney, Chemical Modification of Proteins, s. 125 -138, San Francisco, Holden-Day, 1971, J.M.Dornish og E.O.Pettersen, Biochem. Pharmac. 39 (1990), 309-318). Benzaldehyde and salicylaldehyde readily form Schiff base imines with membrane amino groups, and high equilibrium constants have been measured for the reaction of benzaldehyde with amines (J.J. Pesek and J.H.Frost, Org. Magnet. Res. 8 (1976), 173 -176, J.N.Williams Jr . and R. M. Jacobs, Biochim. Biophys. Acta., 154 (1968), 323-331). With salicylaldehyde, the imine can be further stabilized by hydrogen bonding between the lone pair of electrons in the imine nitrogen and the ortho-hydroxyl group (G.E.Means and R.E.Feeney, Chemical Modification of Proteins, pp. 125 -138, San Francisco, Holden-Day, 1971, J.M. Dornish and E.O.Pettersen , Biochem. Pharmac. 39 (1990), 309-318).
Det er kjent fra den britiske patentsøknaden 9026080.3 (WO 9209276) at benzaldehyd-forbindelser som fra før er kjent som midler mot kreft kan brukes til å bekjempe sykdommer som skyldes en abnormt øket celleformering. Slike forbindelser utøver også en effekt på celler som har en abnormt hevet celledelingshastighet, derfor kan forbindelsene brukes til behandling av slike sykdommer som psoriasis, betennelsessykdommer, revmatiske sykdommer og andre autoimmune sykdommer som ulcerøs kolitt og Crohns sykdom, samt allergiske hudreaksjoner. It is known from the British patent application 9026080.3 (WO 9209276) that benzaldehyde compounds previously known as anticancer agents can be used to combat diseases caused by an abnormally increased cell proliferation. Such compounds also exert an effect on cells that have an abnormally high rate of cell division, therefore the compounds can be used to treat such diseases as psoriasis, inflammatory diseases, rheumatic diseases and other autoimmune diseases such as ulcerative colitis and Crohn's disease, as well as allergic skin reactions.
Dermatologiske abnormiteter som psoriasis karakteriseres ofte ved rask omsetning av epidermis. Normal hud produserer omtrent 1250-nye celler/dag/cm<2>hud som består av omtrent 27.000 celler, men psoriatisk hud produserer 35.000 nye celler/dag/cm<2>utfra 52.000 celler. Cellene som er involvert i disse sykdommene er imidlertid "normale" celler som formerer seg hurtig og gjentatte ganger ved celledeling. Normal hudfornyelse tar omtrent 311 timer, mens psoriatisk hud fornyer seg på 10 til 36 timer. Dermatological abnormalities such as psoriasis are often characterized by rapid turnover of the epidermis. Normal skin produces approximately 1,250 new cells/day/cm<2>of skin consisting of approximately 27,000 cells, but psoriatic skin produces 35,000 new cells/day/cm<2>from 52,000 cells. However, the cells involved in these diseases are "normal" cells that multiply rapidly and repeatedly by cell division. Normal skin renewal takes approximately 311 hours, while psoriatic skin renews itself in 10 to 36 hours.
I dag behandles psoriasis, betennelsessykdommer, revmatiske sykdommer og andre autoimmune sykdommer med kortikosteroider, NSAID-medikamenter og i alvorlige tilfeller med immunsuppressive midler som cytostatika og cyklosporiner. Alle disse medikamentene kan gi alvorlige bivirkninger, og det er derfor behov for medikamenter med færre bivirkninger. Today, psoriasis, inflammatory diseases, rheumatic diseases and other autoimmune diseases are treated with corticosteroids, NSAID drugs and in severe cases with immunosuppressive agents such as cytostatics and cyclosporins. All these drugs can cause serious side effects, and there is therefore a need for drugs with fewer side effects.
Det er kjent at aromatiske aldehyder og visse acetalderivater av disse har en reversibel veksthemmende effekt på menneskelige celler. Denne veskthemmingen skyldes først og fremst en reduksjon i cellenes proteinsyntese. (Pettersen et al., Eur. J. Clin. Oncol., 19. bind, d. 935-940, 1983 og Cancer Res., bind 45, s. 2085-2091, 1985). Hemmingen av proteinsyntesen er bare effektiv så lenge disse midlene finnes i det cellulære mikromiljøet. Celleproteinsyntesen går for eksempel raskt tilbake til det normale nivået etter at midlet er borte fra cellene (f.eks. innen en time i de fleste tilfeller). It is known that aromatic aldehydes and certain acetal derivatives thereof have a reversible growth-inhibiting effect on human cells. This fluid inhibition is primarily due to a reduction in the cells' protein synthesis. (Pettersen et al., Eur. J. Clin. Oncol., vol. 19, d. 935-940, 1983 and Cancer Res., vol. 45, pp. 2085-2091, 1985). The inhibition of protein synthesis is only effective as long as these agents are present in the cellular microenvironment. For example, cellular protein synthesis quickly returns to normal levels after the agent is removed from the cells (eg, within an hour in most cases).
Dette har den virkningen at de normale cellene ikke skades etter behandling med de ovennevnte forbindelsene. This has the effect that the normal cells are not damaged after treatment with the above compounds.
Cellenes evne til å overføre signaler via mekanismer som er avhengige av cellekontakt ( binding ) har vært studert i mange år. Disse mekanismene er spesielt viktige for reaktiviteten av sirkulerende celler som lymfocytter, makrofager etc, og også for eksempel for metastatiske celler som forankrer seg i vev for å etablere nye tumorer. Muligheten til å endre bindingsegenskapene for celler som overvåker immun- eller betennelsesreaksjonene kan være av stor terapeutisk verdi for behandling av mange sykdommer som revmatoid artritt, psoriasis, psoriatisk artritt, lupus erythematosus, akne, Bechterews sykdom, progressiv systemisk sklerose (PSS), seborré og andre autoimmune sykdommer som ulcerøs kolitt og Crohns sykdom. The ability of cells to transmit signals via mechanisms that depend on cell contact (binding) has been studied for many years. These mechanisms are particularly important for the reactivity of circulating cells such as lymphocytes, macrophages, etc., and also, for example, for metastatic cells that anchor themselves in tissues to establish new tumors. The ability to change the binding properties of cells that monitor the immune or inflammatory reactions may be of great therapeutic value for the treatment of many diseases such as rheumatoid arthritis, psoriasis, psoriatic arthritis, lupus erythematosus, acne, Bechterew's disease, progressive systemic sclerosis (PSS), seborrhea and other autoimmune diseases such as ulcerative colitis and Crohn's disease.
Immunsystemet er nøye konstruert for å identifisere og eliminere alle substanser som kjennes som fremmede, enten det stammer fra en bakterie-, virus- eller protozoinfeksjon eller fra abnorme celler som kreftceller. For å kunne gi en spesifikk respons overfor det store utvalget av biologisk variasjon som de invaderende substansene representerer, må immunsystemet være svært allsidig. Imidlertid kan overstimulering av dette finstemte systemet føre til forskjellige allergi- og betennelsesreaksjoner og til autoimmune sykdommer. Å modulere immunsystemet, enten ved å opp- eller nedregulere en spesifikk respons, er derfor en stor terapeutisk utfordring. The immune system is carefully designed to identify and eliminate all substances that are perceived as foreign, whether they originate from a bacterial, viral or protozoan infection or from abnormal cells such as cancer cells. In order to be able to provide a specific response to the large range of biological variation that the invading substances represent, the immune system must be very versatile. However, overstimulation of this fine-tuned system can lead to various allergic and inflammatory reactions and to autoimmune diseases. Modulating the immune system, either by up- or down-regulating a specific response, is therefore a major therapeutic challenge.
Ved en immunologisk gjenkjennelsesprosess sperres et fragment av et fremmed protein inne i kløften i et MHC-klasse ll-protein på overflaten av en antigenpresenterende celle (APC). Til dette MHC-antistoffkomplekset bindes også reseptoren for en T-hjelpercelle. For å aktivere en T-hjelpercelle trengs minst to signaler. Det primære signalet gis av antigenet selv, via MHC-klasse Jl-komplekset og forsterkes av CD4-koreseptorene. Det andre signalet kan fås fra et spesifikt signaliseringsmolekyl som er bundet i plasmamembranen på overflaten av APC-cellen. Et tilsvarende koreseptorprotein befinner seg på overflaten av T-hjelpercellen. Begge signalene er nødvendige for å aktivisere T-cellene. Når de aktiviseres vil de stimulere sin egen formering ved å skille ut interleukinbaserte vekstfaktorer og syntetisere tilsvarende reseptorer på overflaten. Bindingen av interleukinet til disse reseptorene stimulerer så T-cellene direkte til å formere seg. In an immunological recognition process, a fragment of a foreign protein is trapped within the cleft of an MHC class II protein on the surface of an antigen-presenting cell (APC). The receptor for a T-helper cell is also bound to this MHC-antibody complex. To activate a T-helper cell, at least two signals are needed. The primary signal is given by the antigen itself, via the MHC class Jl complex and amplified by the CD4 co-receptors. The second signal can be obtained from a specific signaling molecule that is bound in the plasma membrane on the surface of the APC cell. A corresponding coreceptor protein is located on the surface of the T helper cell. Both signals are necessary to activate the T cells. When they are activated, they will stimulate their own reproduction by secreting interleukin-based growth factors and synthesizing corresponding receptors on the surface. The binding of the interleukin to these receptors then directly stimulates the T cells to multiply.
På 1980-tallet ble det kjent at et syklodekstrin-benzaldehydbasert inklusjonskompleks kunne stimulere immunsystemet ved å styrke de lymfokinaktiverte drepercellene i en musemodell (Y. Kuroki et al., J. Cancer Res. Clin. Oncol. 117, (1991), 109-114). In wfro-studier har senere avslørt naturen til de kjemiske reaksjonene ved APC-donor-/T-cellereseptor-interaksjonsstedene som er ansvarlige for det andre stimulerende signalet, og at disse reaksjonene har form av karbonyl-aminokondensasjoner (Schiff-basedannelse). Videre kan disse interaksjonene imiteres av syntetiske kjemiske enheter. Disse oppdagelsene åpner for nye terapeutiske muligheter for kunstig modulering av immunsystemet. I WO 94/07479 kreves patent for bruk av visse aldehyder og ketoner som danner Schiff-baser og hydrazoner med aminogrupper på T-celleoverflaten. I EP 0609606 A2 er den foretrukne immunstimulerende substansen 4-(2-formyl-3-hydroksyfenoksymetyl)benzosyre (Tucaresol), en forbindelse som opprinnelig var konstruert for å kurere sigdcelleanemi. Denne substansen gis oralt og er systemisk biotilgjengelig. Potensialet til Tucaresol for å kurere et antall sykdommer som f.eks. bakterie-, virus- og protozoinfeksjoner, autoimmune sykdommer og kreft undersøkes nå (H.Chen og J.Rhodes, J. Mol. Med. (1996) 74:497-504) og kombinasjonsstrategier hvor Tucaresol gis sammen med en vaksine for å kurere kronisk hepatitt B, HIV og malignt melanom er under utvikling. In the 1980s, it was known that a cyclodextrin-benzaldehyde-based inclusion complex could stimulate the immune system by enhancing the lymphokine-activated killer cells in a mouse model (Y. Kuroki et al., J. Cancer Res. Clin. Oncol. 117, (1991), 109- 114). In wfro studies have subsequently revealed the nature of the chemical reactions at the APC donor/T cell receptor interaction sites responsible for the second stimulatory signal, and that these reactions take the form of carbonyl-amino condensations (Schiff base formation). Furthermore, these interactions can be imitated by synthetic chemical entities. These discoveries open up new therapeutic possibilities for artificial modulation of the immune system. WO 94/07479 claims a patent for the use of certain aldehydes and ketones which form Schiff bases and hydrazones with amino groups on the T-cell surface. In EP 0609606 A2, the preferred immunostimulatory substance is 4-(2-formyl-3-hydroxyphenoxymethyl)benzoic acid (Tucaresol), a compound originally designed to cure sickle cell anemia. This substance is given orally and is systemically bioavailable. The potential of Tucaresol to cure a number of diseases such as bacterial, viral and protozoan infections, autoimmune diseases and cancer are now being investigated (H.Chen and J.Rhodes, J. Mol. Med. (1996) 74:497-504) and combination strategies where Tucaresol is given together with a vaccine to cure chronic hepatitis B, HIV and malignant melanoma are under development.
Måling av immunparametre in vitro og undersøkelser av virkningene in vivo resulterte i en klokkeformet dose-/responsprofil (H.Chen og J.Rhodes, J. Mol. Med. (1996) 74:497-504). Dette dose-/responsforholdet, som ellers er noe uvanlig, kan begrunnes ved å anta at en høy konsentrasjon av aldehydmedikamentet fører til at de ko-stimulerende ligandene som trengs for effektiv binding av APC til T-cellen mettes med medikamentmolekyler slik at virkningen svekkes. En dose som er nok til å danne en dynamisk likevekt som bidrar til stimulering uten å blokkere bindingen mellom cellene ser ut til å være optimal. Measurement of immune parameters in vitro and studies of effects in vivo resulted in a bell-shaped dose/response profile (H.Chen and J.Rhodes, J. Mol. Med. (1996) 74:497-504). This dose/response relationship, which is otherwise somewhat unusual, can be justified by assuming that a high concentration of the aldehyde drug leads to the co-stimulatory ligands needed for effective binding of the APC to the T cell being saturated with drug molecules so that the effect is weakened. A dose sufficient to form a dynamic equilibrium conducive to stimulation without blocking the binding between cells appears to be optimal.
Generelt er aldehyder i seg selv ustabile overfor oksidasjon. 4-(2-formyl-3-hydroksyfenoksymetyl)benzosyre (Tucaresol) som presenteres i EP-0609606 er betydelig mer aktiv in vivo enn in vitro. Årsaken til dette kan være at medikamentet oksideres i vannløsning in vitro (H.Chen og J.Rhodes, J. Mol. Med. (1996) 74:497-504). Mange aldehyder er for reaktive til å gis som aldehyder, og selv om benzaldehyd har vist seg å være et aktivt anticancer medikament in vitro, er det svært irriterende og uegnet for direkte bruk in vivo. I et biologisk system vil karbonylgruppen i aldehydet reagere raskt med nukleofile grupper som finnes i store mengder i alle kroppsvæsker. Disse uønskede sidereaksjonene kan føre til rask metabolisering av medikamentet og vanskeligheter med å kontrollere konsentrasjonen i serum av det aktive medikamentet. Å kontrollere medikamentet på cellenivået innen et smalt konsentrasjonsvindu er avgjørende for å oppnå en effektiv immunmodulering. Tucaresol gis oralt som et ubeskyttet aldehyd, og det kan være grunn til å mistenke at medikamentet kan være utsatt for oksidasjon og at farmakokinetikken kan være vanskelig å kontrollere. In general, aldehydes themselves are unstable to oxidation. 4-(2-formyl-3-hydroxyphenoxymethyl)benzoic acid (Tucaresol) presented in EP-0609606 is significantly more active in vivo than in vitro. The reason for this may be that the drug is oxidized in aqueous solution in vitro (H.Chen and J.Rhodes, J. Mol. Med. (1996) 74:497-504). Many aldehydes are too reactive to be given as aldehydes, and although benzaldehyde has been shown to be an active anticancer drug in vitro, it is highly irritating and unsuitable for direct use in vivo. In a biological system, the carbonyl group in the aldehyde will react rapidly with nucleophilic groups that are present in large quantities in all body fluids. These unwanted side reactions can lead to rapid metabolism of the drug and difficulties in controlling the serum concentration of the active drug. Controlling the drug at the cellular level within a narrow concentration window is essential to achieve effective immunomodulation. Tucaresol is given orally as an unprotected aldehyde, and there may be reason to suspect that the drug may be subject to oxidation and that the pharmacokinetics may be difficult to control.
Benzaldehydderivatene 4,6-benzyliden-D-glukose og den deutererte analogen (forbindelse 1 og 2) har vist seg å ha høy biotilgjengelighet enten de gis intravenøst eller peroralt. Biotilgjengeligheten for BALB-mus målt som konsentrasjon i serum etter oral tilførsel av forbindelse 2 var 93-99% (C.B. Dunsaed, J.M. Dornish og E.O. Pettersen, Cancer Chemother. Pharmacol. (1995) 35: 464-470). Dessuten kan glukosegruppen ha affinitet til reseptorer på celleoverflaten slik at medikamentet blir mer tilgjengelig på cellenivået. Det frie aldehydet kan lett frigjøres ved hydrolyse av acetalet slik at karbonylgruppen blir tilgjengelig for Schiff-basedannelse med målligandene. The benzaldehyde derivatives 4,6-benzylidene-D-glucose and the deuterated analogue (compounds 1 and 2) have been shown to have high bioavailability whether given intravenously or orally. The bioavailability for BALB mice measured as concentration in serum after oral administration of compound 2 was 93-99% (C.B. Dunsaed, J.M. Dornish and E.O. Pettersen, Cancer Chemother. Pharmacol. (1995) 35: 464-470). In addition, the glucose group can have an affinity for receptors on the cell surface so that the drug becomes more available at the cell level. The free aldehyde can be easily released by hydrolysis of the acetal so that the carbonyl group becomes available for Schiff base formation with the target ligands.
I den foreliggende patentsøknaden er aldehydene derivatiserte med biologisk akseptable karbohydrater som glukose, galaktose og andre og danner acetaler med dem. Sukkergruppen vil dermed gi bidrag til å øke stabiliteten og forbedre biotilgjengeligheten av aldehydfunksjonen for målcellene. Dette fører overraskende nok til, at karbonylkondensasjonsreaksjonene blir mer effektive og farmakokinetikken lettere kontrollerbar ved bruk av forbindelsene våre sammenliknet med tidligere kjente forbindelser. In the present patent application, the aldehydes are derivatized with biologically acceptable carbohydrates such as glucose, galactose and others and form acetals with them. The sugar group will thus contribute to increasing the stability and improving the bioavailability of the aldehyde function for the target cells. Surprisingly enough, this leads to the carbonyl condensation reactions becoming more efficient and the pharmacokinetics easier to control when using our compounds compared to previously known compounds.
For å sammenlikne forbindelse 2 med Tucaresol ble proteinsyntese og inaktivering av celler målt ved like store konsentrasjoner av de to medikamentene. Det påvist at forbindelse 2 var mer effektiv enn Tucaresol med hensyn til begge de målte parametrene. To compare compound 2 with Tucaresol, protein synthesis and inactivation of cells were measured at equal concentrations of the two drugs. It was demonstrated that compound 2 was more effective than Tucaresol with respect to both measured parameters.
Det er et hovedformål med oppfinnelsen å tilveiebringe forbindelser for forebygging og/eller behandling av sykdommer som er relatert til immunsystemet. It is a main purpose of the invention to provide compounds for the prevention and/or treatment of diseases related to the immune system.
Et annet formål med oppfinnelsen er å tilveiebringe forbindelser for forebygging eller behandling av autoimmune sykdommer, uten at forbindelsene har giftige bivirkninger. Another object of the invention is to provide compounds for the prevention or treatment of autoimmune diseases, without the compounds having toxic side effects.
Et tredje formål med oppfinnelsen er å tilveiebringe forbindelser for behandling av sykdommer som er relatert til immunsystemet, som psoriasis, tarmbetennelser, leddbetenneise, SLE, PSS etc. A third purpose of the invention is to provide compounds for the treatment of diseases related to the immune system, such as psoriasis, intestinal inflammation, arthritis, SLE, PSS etc.
Disse og andre mål med oppfinnelsen oppnås ved de vedlagte patentkravene. These and other aims of the invention are achieved by the attached patent claims.
Forbindelsene i henhold til den foreliggende oppfinnelsen har en generell formel The compounds according to the present invention have a general formula
(I): (IN):
hvor L er H eller D; where L is H or D;
Ar er fenyl eller mono- eller di- substituert fenyl, hvor substituenten (e) er valgt fra gruppen bestående av alkyl med 1-6 karbonatomer, CF3, fluor, klor, nitro, cyano, OR<1>, SR<1>, N(R<1>)2eller COOR<1>hvor R<1>er H, CF3eller alkyl med 1-6 karbonatomer, eller OC(0)R<2>, CA(OR<2>)2, CA[OC(0)R<2>]2, NHC(0)R<2>eller N[C(0)R<2>]2der A er H eller D og R<2>er CF3eller alkyl med 1-6 karbonatomer, eller C(0)R<3>der R<3>er H, D, CF3eller alkyl med 1-6 karbonatomer; Ar is phenyl or mono- or di-substituted phenyl, where the substituent (e) is selected from the group consisting of alkyl with 1-6 carbon atoms, CF3, fluorine, chlorine, nitro, cyano, OR<1>, SR<1>, N(R<1>)2or COOR<1>where R<1>is H, CF3or alkyl with 1-6 carbon atoms, or OC(0)R<2>, CA(OR<2>)2, CA[OC (0)R<2>]2, NHC(0)R<2>or N[C(0)R<2>]2where A is H or D and R<2>is CF3or alkyl with 1-6 carbon atoms, or C(0)R<3> where R<3> is H, D, CF3 or alkyl of 1-6 carbon atoms;
Y er valgt fra atomene eller gruppen bestående av H, D, fluor, klor, nitro, OR<1>, OC(0)R<2>, N(R<1>)2, NHC(0)R<2>eller N[C(0)R<2>]2hvorR1 og R2 er som angitt ovenfor; Y is selected from the atoms or group consisting of H, D, fluorine, chlorine, nitro, OR<1>, OC(0)R<2>, N(R<1>)2, NHC(0)R<2> or N[C(0)R<2>]2 wherein R1 and R2 are as defined above;
R er H, CF3eller alkyl med 1-6 karbonatomer; R is H, CF3 or alkyl of 1-6 carbon atoms;
eller et farmasøytisk akseptabelt salt derav. or a pharmaceutically acceptable salt thereof.
Det er underforstått at enhver stereoisomer i henhold til formel (I) omfattes av den foreliggende oppfinnelsen. It is understood that any stereoisomer according to formula (I) is encompassed by the present invention.
Detaljert beskrivelse av oppfinnelsen Detailed description of the invention
Oppfinnelsen beskrives videre nedenfor med eksempler og vedlagte figurer. Beskrivelse av figurene The invention is further described below with examples and attached figures. Description of the figures
Fig. 1: Perifere mononukleære blodceller og superantjgen i Ex Vivo 10-medium ble utsatt for enten benzaldehyd, deuterert benzaldehyd, forbindelse 2 eller zilascorb(<2>H). Formeringen av perifere mononukleære blodceller ble målt som inkorporering av tritiert tymidin ved de forskjellige medikamentkonsentrasjonene. Fig. 1: Peripheral blood mononuclear cells and superantigen in Ex Vivo 10 medium were exposed to either benzaldehyde, deuterated benzaldehyde, compound 2 or zilascorb(<2>H). The proliferation of peripheral blood mononuclear cells was measured as incorporation of tritiated thymidine at the different drug concentrations.
Fremstilling Manufacturing
5Som kjent gjennomgår aldehyder syrekatalyserte kondensasjonsreaksjoner med alkoholer under dannelse av acetaler. Samtidig fås vann som et biprodukt. Reaksjonen er reversibel, og i løsning dannes en likevektsblanding av aldehyd/alkohol og acetal/vann. Likevektsposisjonen bestemmes hovedsakelig av reaktiviteten og konsentrasjonen av hvert molekylslag. For å gjøre reaksjonen fullstendig fjerner man gjerne et av produktene (acetal eller vann) fra reaksjonsblandingen. 5As is known, aldehydes undergo acid-catalyzed condensation reactions with alcohols to form acetals. At the same time, water is obtained as a by-product. The reaction is reversible, and in solution an equilibrium mixture of aldehyde/alcohol and acetal/water is formed. The equilibrium position is mainly determined by the reactivity and concentration of each molecular species. To complete the reaction, one of the products (acetal or water) is removed from the reaction mixture.
I den foreliggende patentsøknaden kondenseres forskjellige sukkere, deoksysukkere og aminosukkere med aldehyder eller aldehydekvivalenter til sukkeracetaler. Spesielt foretrukket er en reacetaliseringsstrategi hvor aldehydet innføres beskyttet som dimetylacetalet i stedet for aldehydet selv. Dermed dannes metanol som biprodukt. Reaksjonsblandingen oppvarmes moderat ved redusert trykk for å fjerne metanolen så snart den dannes. I de fleste tilfellene vil disse reaksjonsbetingelsene lett forskyve likevekten til fordel for acetalet. In the present patent application, various sugars, deoxysugars and aminosugars are condensed with aldehydes or aldehyde equivalents to sugar acetals. Particularly preferred is a reacetalization strategy where the aldehyde is introduced protected as the dimethyl acetal instead of the aldehyde itself. Methanol is thus formed as a by-product. The reaction mixture is moderately heated under reduced pressure to remove the methanol as soon as it is formed. In most cases, these reaction conditions will easily shift the equilibrium in favor of the acetal.
Acetalisering av sukkere vil normalt føre til at det dannes blandinger av regio- og stereoisomerer. Det kan også opptre ringkontraksjoner som fører til blandinger av pyranoser og furanoser og i noen tilfeller dannes di-acetaliseringsprodukter. Hvis man ikke bruker beskyttelsesstrategier vil man derfor ofte få ytterst komplekse reaksjonsblandinger. Imidlertid ble det fremstilt overraskende rene produktfraksjoner etter passende opparbeiding, spesielt ved væskekromatografi. Identifikasjonen av produktene ble gjort ved GC-MS-spektroskopi og forskjellige NMR-teknikker. Acetalization of sugars will normally lead to the formation of mixtures of regio- and stereoisomers. Ring contractions can also occur which lead to mixtures of pyranoses and furanoses and in some cases di-acetalisation products are formed. If you do not use protection strategies, you will therefore often get extremely complex reaction mixtures. However, surprisingly pure product fractions were produced after suitable work-up, especially by liquid chromatography. The identification of the products was done by GC-MS spectroscopy and various NMR techniques.
De spesifikke reaksjonsbetingelsene og hvilke løsningsmidler og katalysatorer som brukes vil i hvert enkelt individuelt tilfelle avhenge av løseligheten og reaktiviteten av reaktantene og av egenskapene til produktet. Katalysatoren kan være en mineralsyre, f.eks. svovelsyre, en organisk syre, f.eks. paratoluensulfonsyre, et surt ionebyttemiddel, f.eks. Amberlyst 15, en elektrofil mineralleire, f.eks. montmorillonitt K-10 eller en resinstøttet supersyre, f.eks. Nafion NR 50. Reaksjonen kan gjerne utføres i et dipolart, aprotisk løsningsmiddel som dimetylformamid, dimetylacetamid, dimetylsulfoksid, N-metylpyrrolidon, dimetoksyetan eller liknende. Paratoluensulfonsyre i dimetylformamid var det foretrukne og mest brukte reaksjonsmediet. The specific reaction conditions and which solvents and catalysts are used will depend in each individual case on the solubility and reactivity of the reactants and on the properties of the product. The catalyst can be a mineral acid, e.g. sulfuric acid, an organic acid, e.g. paratoluenesulfonic acid, an acidic ion exchange agent, e.g. Amberlyst 15, an electrophilic mineral clay, e.g. montmorillonite K-10 or a resin-supported superacid, e.g. Nafion NR 50. The reaction can preferably be carried out in a dipolar, aprotic solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, dimethoxyethane or the like. Paratoluenesulfonic acid in dimethylformamide was the preferred and most widely used reaction medium.
Forbindelsene av formel (I) hvor L er deuterium kan fremstilles som bekrevet ovenfor, men med utgangspunkt i dimetylacetalet av et aldehyd som deutereres i formylposisjonen. Fremstilling av deutero-benzaldehyd kan utføres med en The compounds of formula (I) where L is deuterium can be prepared as described above, but starting from the dimethyl acetal of an aldehyde which is deuterated in the formyl position. Preparation of deutero-benzaldehyde can be carried out with a
modifisert Rosenmund-reduksjon med D2-gass i et deuterert løsningsmiddel, som beskrevet i EP 0 283 139 B1. Deutererte benzaldehydderivater med substituenter i fenylringen kan fremstilles i henhold til eksemplene som gis i EP 0 493 883 A1 og EP 0 552 880 A1. modified Rosenmund reduction with D2 gas in a deuterated solvent, as described in EP 0 283 139 B1. Deuterated benzaldehyde derivatives with substituents in the phenyl ring can be prepared according to the examples given in EP 0 493 883 A1 and EP 0 552 880 A1.
De følgende eksemplene illustrerer hvordan forbindelsene til den foreliggende oppfinnelsen kan fremstilles. The following examples illustrate how the compounds of the present invention can be prepared.
Forbindelse 1:4, 6- 0- benzvliden- D- qlukopyranose Compound 1:4, 6- O- benzvlidene- D- qlucopyranose
Denne kjente forbindelsen ble fremstilt som beskrevet for forbindelse 2, med utgangspunkt i udeuterert benzaldehyddimetylacetal. Identiteten ble bekreftet ved<1>H NMR-spektroskopi i DMSO-d6: 5 rel. til TMS: 7,58-7,29 (5H, m, Ar-H), 6,83 (0,4H, d, OH-1-B), 6,60 (0,6H, d, OH-1-a), 5,61 (1H, s+s, acetal-H), 5,25 (0.4H, d, OH-3-p), 5,21 (0,4H, d, OH-2-p), 5,62 (0,6H, d, OH-3-a), 5,00 (0,6H, H-1-a), 4,82 (0,6H, d, OH-2-a), 4,49 (0,4H, t, H-1-P), 4,18-4,02 (1H, m, H-6'-a+p), 3,89-3,77 (0,6H, m, H-5-a), 3,75-3,57 (1,6H, m, H-6"-a+p og H-3-a), 3,45-3,27 (2,5H, m, JH-3-p, H-4-a+p, H-5-p og IH-2-a) og 3,11-3,00 (0,4H, m, H-2-p). This known compound was prepared as described for compound 2, starting from undeuterated benzaldehyde dimethyl acetal. The identity was confirmed by <1>H NMR spectroscopy in DMSO-d6: 5 rel. to TMS: 7.58-7.29 (5H, m, Ar-H), 6.83 (0.4H, d, OH-1-B), 6.60 (0.6H, d, OH-1 -a), 5.61 (1H, s+s, acetal-H), 5.25 (0.4H, d, OH-3-p), 5.21 (0.4H, d, OH-2-p ), 5.62 (0.6H, d, OH-3-a), 5.00 (0.6H, H-1-a), 4.82 (0.6H, d, OH-2-a) , 4.49 (0.4H, t, H-1-P), 4.18-4.02 (1H, m, H-6'-a+p), 3.89-3.77 (0, 6H, m, H-5-a), 3.75-3.57 (1.6H, m, H-6"-a+p and H-3-a), 3.45-3.27 (2 .5H, m, JH-3-p, H-4-a+p, H-5-p and IH-2-a) and 3.11-3.00 (0.4H, m, H-2- p).
Forbindelse 2: 4. 6- Q-( benzyliden- di)- D- glukopvranose Compound 2: 4. 6-Q-(benzylidene-di)-D- glucopvranose
Benzaldehyd-di ble fremstilt og konvertert til benzaldehyddimetylacetal-di som beskrevet i EP 0 283 139 B1. Fremstillingen av 4,6-0-(benzyliden-di)-D-glukopyranose er også beskrevet i EP 0 283 139 B1, men denne gangen ble forbindelsen fremstilt etter en alternativ fremgangsmåte hvor høy renhet var prioritert: D(+)-glukose (706 g, 3,92 mol), benzaldehyddimetylacetal-d! (571 g, 3,73 mol), tørr DMF (1,68 kg) og paratoluensulfonsyre (4,5 g, 24 mmol) ble blandet i et tørrdestillasjonsapparat koblet til en vakuumpumpe gjennom en kaldreflukskondensator. Den mekanisk rørte blandingen ble oppvarmet til maks. Benzaldehyde di was prepared and converted to benzaldehyde dimethyl acetal di as described in EP 0 283 139 B1. The preparation of 4,6-0-(benzylidene-di)-D-glucopyranose is also described in EP 0 283 139 B1, but this time the compound was prepared according to an alternative method where high purity was prioritized: D(+)-glucose ( 706 g, 3.92 mol), benzaldehyde dimethyl acetal-d! (571 g, 3.73 mol), dry DMF (1.68 kg) and paratoluenesulfonic acid (4.5 g, 24 mmol) were mixed in a dry distillation apparatus connected to a vacuum pump through a cold flux condenser. The mechanically stirred mixture was heated to max.
69°C ved 30 torr for å destillere av metanol og etter 2 timer var det samlet opp 235 g. Reflukskondensatoren ble så stengt av og temperaturen økt til maks. 73°C for å destillere av DMF. Etter ytterligere 2 timer var det samlet opp ytterligere 1385 g og destillasjonen ble avbrutt. Destillasjonsresten ble avkjølt til 40°C og tilsatt isvann (2,9 I) før det var gått 5 min. Temperaturen falt under 0°C og det dannet seg et bunnfall, delvis som store klumper. Blandingen ble overført til et begerglass og tilsatt ytterligere 8-9 I isvann for å få klumpene til å falle fra hverandre og gå i suspensjon. Suspensjonen ble filtrert på to nutch-filtre og man lot de to filterkakene stå over natten på filtrene tilkoblet vannstrålepumpe og begge filterkakene ble tilført N2 gjennom en omvendt trakt. Filterkakene ble spredd ut på to plater og tørket ved 32°C i 20 timer i en vakuumovn. Vakuumet ble først satt til 13 millibar og så regulert ned til 1 millibar. 69°C at 30 torr to distill off methanol and after 2 hours 235 g had been collected. The reflux condenser was then shut off and the temperature increased to max. 73°C to distil off DMF. After a further 2 hours a further 1385 g had been collected and the distillation was stopped. The distillation residue was cooled to 40°C and ice water (2.9 L) was added before 5 min had elapsed. The temperature fell below 0°C and a precipitate formed, partly as large lumps. The mixture was transferred to a beaker and an additional 8-9 L of ice water was added to cause the lumps to fall apart and go into suspension. The suspension was filtered on two nutch filters and the two filter cakes were left overnight on the filters connected to a water jet pump and both filter cakes were supplied with N2 through an inverted funnel. The filter cakes were spread out on two plates and dried at 32°C for 20 hours in a vacuum oven. The vacuum was first set to 13 millibars and then regulated down to 1 millibar.
Råproduktet ble omkrystallisert (for å fjerne dibenzylidenacetaler) og vasket med vann (for å fjerne DMF og glukose) inntil disse forurensningene var eliminert. Følgelig ble råproduktet (500 g) løst i varm dioksan (800 ml) og løsningen overført til kokende kloroform (9 I) gjennom et foldefilter. Løsningen ble avkjølt, først til romtemperatur, så i et isbad over natten. Bunnfallet ble filtrert fra, tørket i 2 timer på filteret (under tilførsel av N2 som beskrevet over) og tørket videre over natten ved 31 °C i vakuum på en rotavapor. Produktet (142 g) ble suspendert i isvann (1 I), filtrert på en nutch (vasking med 200 ml isvann) og tørket på filteret over natten som beskrevet over. Deretter ble det oppmalt, siktet (0,5 mm gitter) og tørket i vakuum i 5 timer ved 31 °C på en rotavapor. Produktet (96 g) ble igjen suspendert i isvann (500 ml), filtrert (vasking med 150 ml isvann) og tørket (7 timer under N2-strøm). Det ble til slutt oppmalt i en morter, siktet (0,5 mm) og tørket i en vakuumovn. The crude product was recrystallized (to remove dibenzylidene acetals) and washed with water (to remove DMF and glucose) until these impurities were eliminated. Accordingly, the crude product (500 g) was dissolved in hot dioxane (800 mL) and the solution transferred to boiling chloroform (9 L) through a pleated filter. The solution was cooled, first to room temperature, then in an ice bath overnight. The precipitate was filtered off, dried for 2 hours on the filter (while supplying N2 as described above) and further dried overnight at 31 °C in vacuum on a rotavapor. The product (142 g) was suspended in ice water (1 L), filtered on a nutch (washing with 200 ml ice water) and dried on the filter overnight as described above. It was then ground, sieved (0.5 mm grid) and dried in vacuum for 5 hours at 31 °C on a rotavapor. The product (96 g) was resuspended in ice water (500 ml), filtered (washing with 150 ml ice water) and dried (7 hours under N 2 flow). It was finally ground in a mortar, sieved (0.5 mm) and dried in a vacuum oven.
Produktet var et hvitt, finfordelt pulver av høy renhet ifølge HPLC-analysen. Utbyttet var 95 g, 10% av teoretisk utbytte. NMR i DMSO-d6 indikerte et a:B anomerforhold på omtrent 7:3. The product was a white, finely divided powder of high purity according to the HPLC analysis. The yield was 95 g, 10% of theoretical yield. NMR in DMSO-d6 indicated an a:B anomer ratio of approximately 7:3.
<1>H og<13>C NMR (DMSO-d6), 6 rel. til TMS: 7,55-7,28 (5.00H, m, Ar-H), 6,85 (0.27H, d, OjH-1-6), 6,58 (0,71 H, d, OjH-1-a), 5,24 (0.27H, d, OH-3-B), 5,19 (0.28H, <1>H and<13>C NMR (DMSO-d6), 6 rel. to TMS: 7.55-7.28 (5.00H, m, Ar-H), 6.85 (0.27H, d, OjH-1-6), 6.58 (0.71H, d, OjH- 1-a), 5.24 (0.27H, d, OH-3-B), 5.19 (0.28H,
d, OH-2-<p>), 5,61 (0,71 H, d, OH-3-a), 4,99 (0.72H, H-1-a), 4,82 (0,71 H, d, 0H-2-a), 4,48 (0.29H, t, H-1-p), 4,20-4,04 (1.04H, m, H-6'-a+P), 3,88-3,73 (0.78H, m, H-5-a), 3,73-3,56 (1.72H, m, H-6"-a+p og H-3-a), 3,46-3,21 (2,61 H, m, H-3-p, H-4-a+p, H-5-p og H-2-a) og 3,09-2,99 (0.28H, m, H-2-p); 137,881, 128,854, 128,042, d, OH-2-<p>), 5.61 (0.71 H, d, OH-3-a), 4.99 (0.72H, H-1-a), 4.82 (0.71 H, d, 0H-2-a), 4.48 (0.29H, t, H-1-p), 4.20-4.04 (1.04H, m, H-6'-a+P), 3.88-3.73 (0.78H, m, H-5-a), 3.73-3.56 (1.72H, m, H-6"-a+p and H-3-a), 3 .46-3.21 (2.61 H, m, H-3-p, H-4-a+p, H-5-p and H-2-a) and 3.09-2.99 (0.28 H, m, H-2-p); 137.881, 128.854, 128.042,
126,435 (Ar-C), 100,462 (acetal-C), 97,642 (C-1-p), 93,211 (C-1-ct), 81,729 (C-4-a), 80,897 (C-4-p), 75,796 (C-2-p), 72,906 (C-2-a og C-3-p), 69,701 (C-3-a), 68,431 (C-6-a), 68,055 (C-6-p), 65,810 (C-5-p) og 62,032 (C-5-a). 126.435 (Ar-C), 100.462 (acetal-C), 97.642 (C-1-p), 93.211 (C-1-ct), 81.729 (C-4-a), 80.897 (C-4-p), 75.796 (C-2-p), 72.906 (C-2-a and C-3-p), 69.701 (C-3-a), 68.431 (C-6-a), 68.055 (C-6-p) , 65.810 (C-5-p) and 62.032 (C-5-a).
Forbindelse 3: 4, 6- O- benzvliden- D- qalaktopvranose Compound 3: 4, 6- O- benzvlidene- D- qalactopvranose
D(+)-galaktose (15,0 g, 0,083 mol) og tørr DMF (80 ml) ble blandet under omrøring ved 50°C i et destillasjonsapparat. Suspensjonen som dannet seg ble tilsatt benzaldehyddimetylacetal (12,2 g, 0,083 mmol) og paratoluensulfonsyre (0,14 g) og metanol/DMF ble sakte destillert av ved hjelp av en vannstrålepumpe. Etter 3 timer var det meste av galaktosen brukt opp og det resterende DMF fjernet på en rotavapor koblet til en vakuumpumpe. Destillasjonsresten, en nokså seig sirupsaktig masse, ble renset på en Lobar C RP-8-kolonne med metanol/vann (1:1) som eluent. Produktfraksjonene ble frysetørket. D(+)-galactose (15.0 g, 0.083 mol) and dry DMF (80 mL) were mixed with stirring at 50°C in a still. To the resulting suspension was added benzaldehyde dimethyl acetal (12.2 g, 0.083 mmol) and paratoluenesulfonic acid (0.14 g) and methanol/DMF was slowly distilled off using a water jet pump. After 3 hours, most of the galactose was used up and the remaining DMF was removed on a rotavapor connected to a vacuum pump. The distillation residue, a rather tough syrupy mass, was purified on a Lobar C RP-8 column with methanol/water (1:1) as eluent. The product fractions were freeze-dried.
Gasskromatografi for TMS-derivatene viste at produktet hovedsakelig besto av to isomerer. På basis av<1>H-,<13>C-, COSY-, DEPT- og C-H-korrelasjons-NMR-spektra ble produktet identifisert som a- og p-anomerene av tittelforbindelsen. Gas chromatography for the TMS derivatives showed that the product consisted mainly of two isomers. On the basis of<1>H,<13>C, COSY, DEPT and C-H correlation NMR spectra, the product was identified as the α and β anomers of the title compound.
<1>H og<13>C NMR (DMSO-d6), 5 rel. til TMS: 7,49-7,27 (5H, m, Ar-H), 5,57 (1H, s, acetal-H), 5,22 (0,5H, d, H-1-a), 4,56 (0,5H, d, H-1-p), 4,23+4,18 (0,5H+0,5H, d+d, H-4-a+p), 4,14-3,98 (2H, m, IH-6-a+p), 3,94-3,79 (1,5H, m, H-2-a, H-3-ct og H-5-a), 3,69-3,49 (1.5H, m, H-2-p, H-3-p og H-5-p); 137,422, 129,981 128,902 126,639 og 126,590 (Ar-C), 101,325 (acetal-C), 96,540 (C-1-p), 93,161 (C-1-a), 76,581 (C-4-a), 76,093 (C-4-p), 71,889 + 71,802 (C-2-p+C-3-p), 69,404 (C-6-a), 69,182 (C-6-p), 68,566 + 68.057 (C-2-a + C-3-p), 66,579 (C-5-p) og 62,886 (C-5-a). <1>H and<13>C NMR (DMSO-d6), 5 rel. to TMS: 7.49-7.27 (5H, m, Ar-H), 5.57 (1H, s, acetal-H), 5.22 (0.5H, d, H-1-a), 4.56 (0.5H, d, H-1-p), 4.23+4.18 (0.5H+0.5H, d+d, H-4-a+p), 4.14- 3.98 (2H, m, IH-6-a+p), 3.94-3.79 (1.5H, m, H-2-a, H-3-ct and H-5-a), 3.69-3.49 (1.5H, m, H-2-p, H-3-p and H-5-p); 137.422, 129.981 128.902 126.639 and 126.590 (Ar-C), 101.325 (acetal-C), 96.540 (C-1-p), 93.161 (C-1-a), 76.581 (C-4-a), 76.093 (C -4-p), 71.889 + 71.802 (C-2-p+C-3-p), 69.404 (C-6-a), 69.182 (C-6-p), 68.566 + 68.057 (C-2-a + C-3-p), 66.579 (C-5-p) and 62.886 (C-5-a).
Forbindelse 4: metvl- 4, 6- 0- benzvliden- a- D- mannopyranosid Compound 4: metvl- 4, 6- 0- benzvlidene- a- D- mannopyranoside
Metyl-a-mannopyranosid (18,1 g, 0,093 mol), benzaldehyddimetylacetal (21,0 g, 0,138 mol) og tørr DMF ble blandet under omrøring ved 50-55°C i et destillasjonsapparat. Det ble tilsatt paratoluensulfonsyre (ca. 0,1 g) og 10 min. senere ble det koblet til en vannstrålepumpe for å destillere av metanol. Etter 4 timer ble reaksjonsblandingen inndampet til et hvitt fast stoff. Inndampingsresten ble vasket med dibutyleter, filtrert og filterkaken ble løst i acetonitril. Det begynte å danne seg et bunnfall og blandingen ble satt i kjøleskap i 5 dager. Deretter ble bunnfallet filtrert fra og filtratet inndampet. Inndampingsresten ble renset på en Lobar C RP-8-kolonne med 30% acetonitril i vann som eluent. Produktfraksjoner fra 4 separate synteser ble frysetørket og kombinert. Methyl α-mannopyranoside (18.1 g, 0.093 mol), benzaldehyde dimethyl acetal (21.0 g, 0.138 mol) and dry DMF were mixed with stirring at 50-55°C in a still. Paratoluenesulfonic acid (approx. 0.1 g) was added and 10 min. later it was connected to a water jet pump to distill off methanol. After 4 hours, the reaction mixture was evaporated to a white solid. The evaporation residue was washed with dibutyl ether, filtered and the filter cake was dissolved in acetonitrile. A precipitate began to form and the mixture was refrigerated for 5 days. The precipitate was then filtered off and the filtrate evaporated. The evaporation residue was purified on a Lobar C RP-8 column with 30% acetonitrile in water as eluent. Product fractions from 4 separate syntheses were freeze-dried and combined.
Gasskromatografisk analyse av TMS-derivatene indikerte at produktet besto av 95 arealprosent monoacetaler. Monoacetalene besto for sin del av 4 topper som kunne integreres til henholdsvis 0,4, 3,2, 94,1 og 2,4 areal-%. På basis av<1>H-,<13>C-, COSY-, DEPT- og C-H-korrelasjons NMR-spektra sammen med gasskromatografi og MS-spektroskopi ble det dominerende molekylslaget identifisert som tittelforbindelsen. Gas chromatographic analysis of the TMS derivatives indicated that the product consisted of 95 area percent monoacetals. The monoacetals for their part consisted of 4 peaks which could be integrated to 0.4, 3.2, 94.1 and 2.4 area-% respectively. On the basis of<1>H,<13>C, COSY, DEPT and C-H correlation NMR spectra together with gas chromatography and MS spectroscopy, the dominant molecular species was identified as the title compound.
<1>H og<13>C NMR (aceton-d6), 8 rel. til TMS: 7,54-7,30 (5H, m, Ar-H), 5,60 (1H, s, acetal-H), 4,71 (1H, s, H-1), 4,34 (1H, bred s, OH), 4,22-4,02 (2H, m+bred s, H-6'+OH), 3,94-3,82 (3H, m, H-2, H-3 og H-4), 3,80-3,60 (2H, m, H-5+H-6") og 3,39 (3H, s, CH3); 139,264, 129,396, 128,662 og 127,211 (Ar-C), 102,825 (C-1), 102,468 (acetal-C), 79,888 (C-4), 72,090 (C-3), 69,308 (C-6), 69,127 (C-2), 64,363 (C-5) og 54,921 (CH3). <1>H and<13>C NMR (acetone-d6), 8 rel. to TMS: 7.54-7.30 (5H, m, Ar-H), 5.60 (1H, s, acetal-H), 4.71 (1H, s, H-1), 4.34 ( 1H, broad s, OH), 4.22-4.02 (2H, m+broad s, H-6'+OH), 3.94-3.82 (3H, m, H-2, H-3 and H-4), 3.80-3.60 (2H, m, H-5+H-6") and 3.39 (3H, s, CH3); 139.264, 129.396, 128.662 and 127.211 (Ar-C ), 102.825 (C-1), 102.468 (acetal-C), 79.888 (C-4), 72.090 (C-3), 69.308 (C-6), 69.127 (C-2), 64.363 (C-5) and 54.921 (CH 3 ).
Forbindelse 5: 4, 6-( benzvliden- di)- 2- deoksv- D- qlukopvranose Compound 5: 4, 6-( benzvlidene-di)- 2- deoxy- D- qlucupvranose
Benzaldehyd-di ble fremstilt og konvertert til benzaldehyddimetylacetal-di som beskrevet i EP 0 283 139 B1. Benzaldehyde di was prepared and converted to benzaldehyde dimethyl acetal di as described in EP 0 283 139 B1.
2-deoksy-D-glukose (10 g, 60,9 mmol), tørr DMF (35 ml), 2-deoxy-D-glucose (10 g, 60.9 mmol), dry DMF (35 mL),
benzaldehyddimetylacetal-di (11,7 g, 76,4 mmol) og paratoluensulfonsyre (70 mg, benzaldehyde dimethyl acetal-di (11.7 g, 76.4 mmol) and paratoluenesulfonic acid (70 mg,
0,37 mmol) ble blandet under N2til en hvit grøt. Ved oppvarming til 45-50°C ble det dannet en fargeløs løsning i løpet av en halv time. En vakuumpumpe ble tilkoblet for å fjerne metanol gjennom en avkjølt kolonne (for å hindre tap av benzaldehyddimetylacetal-di). Trykket ble regulert trinnvis ned fra 70 millibar til 20-30 millibar i løpet av 4,5 timer og temperaturen ble opprettholdt på 40-45°C. Deretter ble destillasjonen avbrutt, apparatet ombygd uten kolonnen og DMF ble fjernet ved kortbanedestillasjon ved 50-55°C, maks. vakuum. Resten var en svakt gul sirupsaktig masse. 0.37 mmol) was mixed under N2 to a white slurry. On heating to 45-50°C, a colorless solution was formed within half an hour. A vacuum pump was connected to remove methanol through a cooled column (to prevent loss of benzaldehyde dimethyl acetal-di). The pressure was regulated stepwise down from 70 millibars to 20-30 millibars during 4.5 hours and the temperature was maintained at 40-45°C. The distillation was then interrupted, the apparatus rebuilt without the column and the DMF was removed by short path distillation at 50-55°C, max. vacuum. The rest was a pale yellow syrupy mass.
1/4 av sirupsmassen ble løst i svakt alkalisk (NaHC03) metanol/vann 60/40 og renset på en Merck LiChroprep RP-8 omvendt fase-kolonne med metanol/vann 60/40 som eluent. Produktfraksjoner ble konsentrert for å fjerne metanol og frysetørket til et hvitt, ullent fast stoff. Produkter fra fire separate synteser ble kombinert til et utbytte på 3,5 g, 23% av det teoretiske. 1/4 of the syrup mass was dissolved in weakly alkaline (NaHCO 3 ) methanol/water 60/40 and purified on a Merck LiChroprep RP-8 reverse phase column with methanol/water 60/40 as eluent. Product fractions were concentrated to remove methanol and freeze-dried to a white, woolly solid. Products from four separate syntheses were combined in a yield of 3.5 g, 23% of theory.
Gasskromatografisk analyse av TMS-derivatene og NMR-spektroskopi viste at produktet besto av en 1:1 blanding av a- og B-anomerene. Gas chromatographic analysis of the TMS derivatives and NMR spectroscopy showed that the product consisted of a 1:1 mixture of the a and B anomers.
<1>H og<13>C NMR (DMSO-d6), 5 (ppm) rel. til TMS: 7,52-7,28 (m, 5H, Ar-H I + II), 6,9-6,65 (bred s, 1/2 H, OH-1 II), 6,55-6,32 (bred s, 1/2 H, OH-1 I), 5,25-5,12 (m, 1 H, OH-3 II og H-1 I), 5,12-5,0 (d, 1/2 H, OH-3 II), 4,84-4,73 (dd, 1/2 H, H-1 II), 4,20-4,02 (m, 1H, H-6 l+ll), 3,98-3,73 (m, 1H, H-3 I og H-5 I), 3,73-3,58 (m, 1,5H, H-6' l+ll og H-3 II), 3,42-3,18 (2,5 H, H-4 l+ll og H-5 II og H2O), 2,10-1,86 (m, 1H, H-2 l+ll) og 1,62-1,34 (m, 1H, H-2' l+ll); 137,979, 137,926, 128,841, 128,036 og 126,432 (Ar-C l+ll), 101,5-100,0 (acetal-C l+ll), 94,057 og 91,424 (C-1 l+ll), 83,916 og 83,093 (C-4 l+ll), 68,374 og 68,119 (C-6 l+ll), 66,889, 66,092, 64,174 og 62,604 (C-3 l+ll og C-5 l+ll) og 41,932 og 40,051 (C-2 l+ll). <1>H and<13>C NMR (DMSO-d6), δ (ppm) rel. to TMS: 7.52-7.28 (m, 5H, Ar-H I + II), 6.9-6.65 (broad s, 1/2 H, OH-1 II), 6.55-6 .32 (broad s, 1/2 H, OH-1 I), 5.25-5.12 (m, 1 H, OH-3 II and H-1 I), 5.12-5.0 (d , 1/2 H, OH-3 II), 4.84-4.73 (dd, 1/2 H, H-1 II), 4.20-4.02 (m, 1H, H-6 l+ ll), 3.98-3.73 (m, 1H, H-3 I and H-5 I), 3.73-3.58 (m, 1.5H, H-6' 1+ll and H- 3 II), 3.42-3.18 (2.5 H, H-4 l+ll and H-5 II and H2O), 2.10-1.86 (m, 1H, H-2 l+ll ) and 1.62-1.34 (m, 1H, H-2' 1+11); 137.979, 137.926, 128.841, 128.036 and 126.432 (Ar-C l+ll), 101.5-100.0 (acetal-C l+ll), 94.057 and 91.424 (C-1 l+ll), 83.916 and 83.093 ( C-4 l+ll), 68.374 and 68.119 (C-6 l+ll), 66.889, 66.092, 64.174 and 62.604 (C-3 l+ll and C-5 l+ll) and 41.932 and 40.051 (C-2 l+ll).
Forbindelse 6: 4, 6- Q-( 4- karbometoksvbenzvliden)- D- glukopvranose Compound 6: 4, 6- Q-( 4- carbomethoxybenzvlidene)- D- glucopvranose
Metyl-4-formylbenzoat (100 g, 0,609 mol), metanol (91,5 g, 2,86 mol), trimetylortoformiat (71 g, 0,67 mol) og konsentrert saltsyre (165 (il) ble blandet til en grøt i en 500 ml trehalset flaske. Grøten ble omdannet til en svakt gul løsning på få minutter og temperaturen økte spontant fra 15°C til 30°C. Etter 15 minutters omrøring ble reaksjonsblandingen refluksert ved 58°C i 25 minutter til og så nedkjølt til 10°C (isvann). Det ble laget en alkalisk løsning ved å løse KOH (8,3 g) i metanol (53 ml) og 7 ml av løsningen ble tilsatt til reaksjonsblandingen. Etter 25 minutters omrøring ved 10°C ble reaktoren ombygd for kortbanedestillasjon og alle flyktige stoffer fjernet i vakuum (vannstrålepumpe). Destillasjonen fortsatte deretter med en vakuumpumpe til det var igjen en fargeløs olje ved 112-114°C/0,5 millibar. Oljen omdannet seg til et fargeløst fast stoff med smeltepunkt 32-33°C, og ble identifisert ved NMR som metyl-4-formylbenzoatdimetylacetal. Utbyttet var 108,75 g, 85% av det teoretiske. Methyl-4-formylbenzoate (100 g, 0.609 mol), methanol (91.5 g, 2.86 mol), trimethyl orthoformate (71 g, 0.67 mol) and concentrated hydrochloric acid (165 µl) were mixed to a slurry in a 500 mL three-necked flask. The slurry was converted to a pale yellow solution in a few minutes and the temperature rose spontaneously from 15°C to 30°C. After 15 minutes of stirring, the reaction mixture was refluxed at 58°C for another 25 minutes and then cooled to 10 °C (ice water). An alkaline solution was made by dissolving KOH (8.3 g) in methanol (53 mL) and 7 mL of the solution was added to the reaction mixture. After 25 minutes of stirring at 10 °C, the reactor was rebuilt for short path distillation and all volatiles removed in vacuo (water jet pump). Distillation then continued with a vacuum pump until a colorless oil was left at 112-114°C/0.5 millibar. The oil converted to a colorless solid, m.p. 32-33 °C, and was identified by NMR as methyl-4-formylbenzoate dimethyl acetal.The yield was 108.75 g, 85% of the theoretical tic.
D(+)-glukose (8,0 g, 44,4 mmol), tørr DMF (25 ml), metyl-4-formylbenzoatdimetylacetal (10,4 g, 49,5 mmol) og paratoluensulfonsyre ble blandet ved 50°C under N2til en hvit suspensjon. Apparatet var koblet til en vakuumpumpe gjennom en vertikal kondensator og fordampningen av metanol startet ved 80-100 millibar, 55°C. Vakuumet ble gradvis økt til 40 millibar mens temperaturen ble holdt på 55-60°C. Reaksjonsblandingen ble gradvis klar og apparaturen ble ombygd for kortbanedestillasjon av DMF. Destillasjonsresten var en svakt gul sirupsmasse. D(+)-glucose (8.0 g, 44.4 mmol), dry DMF (25 mL), methyl 4-formylbenzoate dimethyl acetal (10.4 g, 49.5 mmol) and paratoluenesulfonic acid were mixed at 50°C under N2 to a white suspension. The apparatus was connected to a vacuum pump through a vertical condenser and the evaporation of methanol started at 80-100 millibar, 55°C. The vacuum was gradually increased to 40 millibars while the temperature was maintained at 55-60°C. The reaction mixture gradually became clear and the apparatus was rebuilt for short path distillation of DMF. The distillation residue was a pale yellow syrupy mass.
Sirupsmassen ble løst i en varm løsning av 100 mg NaHC03i 20 ml metanol og 8 ml vann og felt ved tilsetning av 100 ml etylacetat. Bunnfallet ble isolert fra modervæsken ved filtrering, vasket med kaldt vann (4 x 15-20 ml) og overført til en rotavaporflaske. Fuktigheten ble fjernet ved å tilsette etylacetat og inndampe to ganger. Produktet ble endelig tørket under høyt vakuum. Det ble filtrert av mer bunnfall fra modervæsken og vasket og tørket til nok en produktporsjon. De to porsjonene ble slått sammen til 1,94 g rent produkt, 13% av det teoretiske utbyttet. Gasskromatografisk analyse av TMS-derivatene viste to isomerer i forholdet 2:1. The syrup mass was dissolved in a warm solution of 100 mg of NaHCO 3 in 20 ml of methanol and 8 ml of water and filtered by adding 100 ml of ethyl acetate. The precipitate was isolated from the mother liquor by filtration, washed with cold water (4 x 15-20 ml) and transferred to a rotavapor bottle. The moisture was removed by adding ethyl acetate and evaporating twice. The product was finally dried under high vacuum. It was filtered off more sediment from the mother liquor and washed and dried for another product portion. The two portions were combined to give 1.94 g of pure product, 13% of the theoretical yield. Gas chromatographic analysis of the TMS derivatives showed two isomers in the ratio 2:1.
<1>H- og<13>C NMR (DMSO-d6), 8 (ppm) rel. til TMS: 7,99 og 7,61 (dd, 2+2H, furfuryl-H), 6,87 (d, 0.67H OH-1 II), 6,59 (d, 0.28H, OH-1 I), 5,68 (s+s, 1H, acetal-H l+ll), 5,29 (d, 0.68H, OH-3 II), 5,21 (d, 0.67H, OH-2 II), 5,16 (d, 0,31 H, OH-3 I), 5,00 (t, 0.30H, H-1 I), 4,85 (d, 0.28H, OH-2 I), 4,48 (t, 0,73H, H-1 II), 4,25-4,08 (m, 1.14H, H-6), 3,95-3,77 (m, 3.43H, OCH3 og H-5 I), 3,78-3,59 (m, 1.40H, H-3 I og H-6'), 3,49-3,23 (m, 3,59H, H-4 I og II, H-5 II, H-2 I og H-3 II), 3,10-2,98 (m, 0.72H, H-2 II); 165,978, 142,553, 142,553, 129,959, 129,067, 126,763, 99,982, 99,812, 97,661, 93,238, 81,794, 81,794, 80,963, 75,808, 72,902, 69,658, 68,487, 68,110, 65,714, 61,952 og 52,253. <1>H- and<13>C NMR (DMSO-d6), 8 (ppm) rel. to TMS: 7.99 and 7.61 (dd, 2+2H, furfuryl-H), 6.87 (d, 0.67H OH-1 II), 6.59 (d, 0.28H, OH-1 I) , 5.68 (s+s, 1H, acetal-H l+ll), 5.29 (d, 0.68H, OH-3 II), 5.21 (d, 0.67H, OH-2 II), 5 .16 (d, 0.31 H, OH-3 I), 5.00 (t, 0.30H, H-1 I), 4.85 (d, 0.28H, OH-2 I), 4.48 ( t, 0.73H, H-1 II), 4.25-4.08 (m, 1.14H, H-6), 3.95-3.77 (m, 3.43H, OCH3 and H-5 I) , 3.78-3.59 (m, 1.40H, H-3 I and H-6'), 3.49-3.23 (m, 3.59H, H-4 I and II, H-5 II , H-2 I and H-3 II), 3.10-2.98 (m, 0.72H, H-2 II); 165,978, 142,553, 142,553, 129,959, 129,067, 126,763, 99,982, 99,812, 97,661, 93,238, 81,794, 81,794, 80,963, 75,808, 72,902, 69,658, 68,487, 68,110, 65,714, 61,952 og 52,253.
Forbindelse 7: 4. 6- Q- benzvliden- 2- deoksv- D- qlukopvranose Compound 7: 4. 6- Q- benzvlidene- 2- deoxv- D- qlukopvranose
12-deoksy-D-glukose (10,0 g, 60,9 mmol), tørr DMF (34 ml), benzaldehyddimetylacetal (11,6 g, 76,2 mmol) og paratoluensulfonsyre (70 mg, 0,37 mmol) ble blandet under N2til en hvit grøt. Reaksjonsblandingen ble omrørt ved romtemperatur i 30 minutter og ved oppvarming til 45-50°C ble den faste substansen gradvis løst. Det ble koblet til en vakuumpumpe for å fjerne metanol gjennom en avkjølt kolonne (for å forhindre tap av benzaldehyddimetylacetal) og reaksjonen fortsatte i 4,5 timer. Deretter ble destillasjonen avbrutt, kolonnen fjernet og DMF destillert fra ved kortbanedestillasjon ved 50-55°C, maksimalt vakuum. Destillasjonsresten var en svakt gul sirupsmasse. 12-deoxy-D-glucose (10.0 g, 60.9 mmol), dry DMF (34 mL), benzaldehyde dimethyl acetal (11.6 g, 76.2 mmol) and paratoluenesulfonic acid (70 mg, 0.37 mmol) were mixed under N2 to a white porridge. The reaction mixture was stirred at room temperature for 30 minutes and by heating to 45-50°C the solid substance was gradually dissolved. A vacuum pump was connected to remove methanol through a cooled column (to prevent loss of benzaldehyde dimethyl acetal) and the reaction continued for 4.5 hours. The distillation was then interrupted, the column removed and DMF distilled from by short path distillation at 50-55°C, maximum vacuum. The distillation residue was a pale yellow syrupy mass.
Sirupsmassen ble løst i svakt alkalisk (NaHCOa) metanol/vann 60/40 og renset på en Merck LiChroprep RP-8 omvendt fase-kolonne med metanol/vann 60/40 som eluent. Produktfraksjonene ble konsentrert for å fjerne metanol og frysetørket til et hvitt, ullent fast stoff. Produktene fra fire separate synteser ble kombinert til 3,18 g, 21% av det teoretiske utbyttet. The syrup mass was dissolved in weakly alkaline (NaHCOa) methanol/water 60/40 and purified on a Merck LiChroprep RP-8 reverse phase column with methanol/water 60/40 as eluent. The product fractions were concentrated to remove methanol and freeze-dried to a white, woolly solid. The products from four separate syntheses were combined to give 3.18 g, 21% of the theoretical yield.
Gasskromatografisk analyse av TMS-derivatene og NMR-spektroskopi viste at produktet besto av en 1:1 blanding av a- og B-anomerene. Gas chromatographic analysis of the TMS derivatives and NMR spectroscopy showed that the product consisted of a 1:1 mixture of the a and B anomers.
<1>H og<13>C NMR (DMSO-d6), 8 (ppm) rel. til TMS: 7,52-7,30 (m, 5H, Ar-H I + II), 6,85-6,68 (bred s, 1/2 H, OH-1 II), 6,50-6,35 (bred s, 1/2 H, OH-1 I), 5,61 (s+s, 1H, <1>H and<13>C NMR (DMSO-d6), 8 (ppm) rel. to TMS: 7.52-7.30 (m, 5H, Ar-H I + II), 6.85-6.68 (broad s, 1/2 H, OH-1 II), 6.50-6 .35 (broad s, 1/2 H, OH-1 I), 5.61 (s+s, 1H,
acetal-H l+ll), 5,23-5,12 (m, 1 H, OH-3 II og H-1 I), 5,12-5,02 (d, 1/2 H, OH-3 II), 4,84-4,74 (dd, 1/2 H, H-1 II), 4,20-4,04 (m, 1H, H-6 l+ll), 3,98-3,74 (m, 1H, H-3 I og H-5 I), 3,74-3,57 (m, 1.5H, H-6' l+ll og H-3 II), 3,42-3,18 (2,5 H, H-4 l+ll og H-5 II og j±>0), 2,08-1,88 (m, 1H, H-2 l+ll) og 1,62-1,32 (m, 1H, H-2' l+ll). acetal-H l+ll), 5.23-5.12 (m, 1 H, OH-3 II and H-1 I), 5.12-5.02 (d, 1/2 H, OH-3 II), 4.84-4.74 (dd, 1/2 H, H-1 II), 4.20-4.04 (m, 1H, H-6 l+ll), 3.98-3, 74 (m, 1H, H-3 I and H-5 I), 3.74-3.57 (m, 1.5H, H-6' 1+11 and H-3 II), 3.42-3, 18 (2.5 H, H-4 l+ll and H-5 II and j±>0), 2.08-1.88 (m, 1H, H-2 l+ll) and 1.62-1 .32 (m, 1H, H-2' 1+11).
Forbindelse 8: 2- acetamido- 4, 6- 0- benzvliden- di- 2- deoksv- D- qlukopyranose Compound 8: 2- acetamido- 4, 6- 0- benzvlidene- di- 2- deoxv- D- qlucopyranose
Benzaldehyd-di ble fremstilt og konvertert til benzaldehyddimetylacetal-di som beskrevet i EP 0 283 139 B1. Benzaldehyde di was prepared and converted to benzaldehyde dimethyl acetal di as described in EP 0 283 139 B1.
Benzaldehyddimetylacetal-di (8,7 g, 56,8 mmol), N-acetyl-D-glukosamin (10,0 g, 45,2 mmol), tørr DMF (30 ml) og paratoluensulfonsyre (88 mg, 0,46 mmol) ble blandet under N2til en hvit suspensjon. Reaksjonsblandingen ble omrørt ved 50°C i 45 minutter, så ble det tilkoblet en vakuumpumpe gjennom en vertikal kondensator og reaksjonen fortsatte i 2 timer ved 55°C/60-70 mbar. Apparaturen ble ombygd for å fjerne DMF ved kortbanedestillasjon og destillasjonen fortsatte ved 55-60°C, maks. vakuum i 1 time til. Destillasjonsresten var en gulhvit, myk fast substans. Benzaldehyde dimethyl acetal-di (8.7 g, 56.8 mmol), N-acetyl-D-glucosamine (10.0 g, 45.2 mmol), dry DMF (30 mL) and paratoluenesulfonic acid (88 mg, 0.46 mmol ) was mixed under N2 to a white suspension. The reaction mixture was stirred at 50°C for 45 minutes, then a vacuum pump was connected through a vertical condenser and the reaction continued for 2 hours at 55°C/60-70 mbar. The apparatus was rebuilt to remove DMF by short path distillation and the distillation continued at 55-60°C, max. vacuum for 1 more hour. The distillation residue was a yellow-white, soft solid.
Det ble laget en løsning ved å blande NaHC03(150 mg) i 30 ml metanol/vann (3:2) og destillasjonsresten ble nøytralisert ved å tilsette løsningen. Dette resulterte i en kremaktig grøt som ble filtrert, vasket 2-3 ganger med en 1% NaHC03-løsning og flere ganger med eter. Produktet ble funnet å være tilstrekkelig rent ved analyse (GC) og tørket i vakuum. Utbyttet jvar 8,8 g, 63% av det teoretiske. A solution was made by mixing NaHCO 3 (150 mg) in 30 ml methanol/water (3:2) and the distillation residue was neutralized by adding the solution. This resulted in a creamy slurry which was filtered, washed 2-3 times with a 1% NaHCO 3 solution and several times with ether. The product was found to be sufficiently pure by analysis (GC) and dried in vacuo. The yield was 8.8 g, 63% of the theoretical.
Gasskromatografisk analyse av TMS-derivatene indikerte en 1:1 isomerblanding. NMR-spektroskopi i DMSO-d6-løsning identifiserte produktet som en 3:1 anomerblanding. Gas chromatographic analysis of the TMS derivatives indicated a 1:1 isomeric mixture. NMR spectroscopy in DMSO-d6 solution identified the product as a 3:1 anomeric mixture.
<1>H og<13>C NMR (DMSO-d6), 5 rel. til TMS: 7,83 (s+s, 1H, NH), 7,51-7,28 (m, 6H, Ar-H), 7,0-6,2 (bred s, 1H, OH-1), 5,65-5,05 (bred s, 1 H, OH-3), 4,99 (d, 1H, H-1 I), 4,61 (d, 0.3H, H-1 II), 4,21-4,03, 3,92-3,67 og 3,51-3,22 (m, 6H, H-2, H-3, H-4, <1>H and<13>C NMR (DMSO-d6), 5 rel. to TMS: 7.83 (s+s, 1H, NH), 7.51-7.28 (m, 6H, Ar-H), 7.0-6.2 (broad s, 1H, OH-1) , 5.65-5.05 (broad s, 1 H, OH-3), 4.99 (d, 1H, H-1 I), 4.61 (d, 0.3H, H-1 II), 4 ,21-4.03, 3.92-3.67 and 3.51-3.22 (m, 6H, H-2, H-3, H-4,
H-5 og H-6), og 1,85 (s+s, 3H, CH3); 169,452 (C=0), 137,818, 128,869, 128,035 og 126,438 (Ar-C), 100,505 (Acetal-C), 96,056, 91,500, 82,471, 81,505, 70,549, 68,300, 67,961, 67,218, 65,906, 62,123, 58,038, 54,790 (sukker-C) og 23,123 og 22,674 (CH3). H-5 and H-6), and 1.85 (s+s, 3H, CH3); 169,452 (C = 0), 137,818, 128,869, 128,035 and 126,438 (AR-C), 100,505 (Acetal-c), 96,056, 91,500, 82,471, 81,505, 70,549, 68,15, 67,15, 67,1,1,1. (sugar-C) and 23.123 and 22.674 (CH3).
Forbindelse 9: 2- acetamido- 2- deoksv- 4. 6- 0-( 3- nitrobenzvliden)- D- qlukopvranose Compound 9: 2- acetamido- 2- deoxy- 4. 6- O-( 3- nitrobenzvlidene)- D- qulcopvranose
3-nitrobenzaldehyd (100 g, 0,66 mol), metanol (99 g, 3,1 mol), trimetylotroformiat (77,3 g, 0,73 mol) og konsentrert saltsyre (165 ju.l) ble blandet i en 500 ml trehalset flaske til en gul grøt som forvandlet seg til en løsning i etter 5 minutter. Reaksjonsblandingen ble refluksert av~50°C i 15 minutter og avkjølt til 10°C med isvann. Reaksjonen ble stanset ved å tilsette 6,6 ml av en løsning som var laget ved å løse 2,5 g KOH i 16 ml metanol. Omrøringen fortsatte i 15 minutter og reaktoren ble ombygd for kortbane-vakuumdestillasjon. Flyktige substanser (CH3OH + HCOOCH3) ble destillert fra med vannstrålepumpe, destillasjonen ble avbrutt og en vakuumpumpe tilkoblet. Deretter fortsatte destillasjonen og en gul olje ble destillert fra ved 93 - 97,5°C/20 mbar. Ved NMR ble oljen funnet å være 3-nitrobenzaldehyddimetylacetal av høy renhet. Utbyttet var 127 g, 97,6% av det teoretiske. 3-Nitrobenzaldehyde (100 g, 0.66 mol), methanol (99 g, 3.1 mol), trimethyl otroformate (77.3 g, 0.73 mol) and concentrated hydrochloric acid (165 µl) were mixed in a 500 ml three-necked bottle to a yellow slurry which turned into a solution after 5 minutes. The reaction mixture was refluxed at ~50°C for 15 min and cooled to 10°C with ice water. The reaction was quenched by adding 6.6 ml of a solution made by dissolving 2.5 g of KOH in 16 ml of methanol. Stirring was continued for 15 minutes and the reactor was converted for short path vacuum distillation. Volatile substances (CH3OH + HCOOCH3) were distilled off with a water jet pump, the distillation was interrupted and a vacuum pump connected. Distillation then continued and a yellow oil was distilled from at 93 - 97.5°C/20 mbar. By NMR, the oil was found to be 3-nitrobenzaldehyde dimethyl acetal of high purity. The yield was 127 g, 97.6% of the theoretical.
3-nitrobenzaldehyddimetylacetal (5,5 g, 0,028 mol), N-acetyl-D-glukosamin (5,0 g, 0,023 mol), paratoluensulfonsyre (50 mg, 0,263 mmol) og tørr DMF (15 ml) ble blandet under omrøring ved 50°C til en svakt gul suspensjon. Etter 1/2 time ble det tilkoblet en vakuumpumpe og reaksjonen fortsatte ved 56°C/50 mbar i 11 timer. Reaksjonsblandingen ble inndampet og inndampingsresten fordelt mellom et lite volum svakt alkalisk (NaHC03) vann og kloroform. Vannfasen (som dannet en osteaktig suspensjon) ble ekstrahert to ganger med kloroform og filtrert og vasket flere ganger med vann og eter. Produktet ble tørket i vakuum til et svakt brunlig pulver. Utbyttet var 570 mg, 7% av det teoretiske. 3-Nitrobenzaldehyde dimethyl acetal (5.5 g, 0.028 mol), N-acetyl-D-glucosamine (5.0 g, 0.023 mol), paratoluenesulfonic acid (50 mg, 0.263 mmol) and dry DMF (15 mL) were mixed with stirring at 50°C to a pale yellow suspension. After 1/2 hour a vacuum pump was connected and the reaction continued at 56°C/50 mbar for 11 hours. The reaction mixture was evaporated and the evaporation residue partitioned between a small volume of weakly alkaline (NaHCO 3 ) water and chloroform. The aqueous phase (which formed a cheesy suspension) was extracted twice with chloroform and filtered and washed several times with water and ether. The product was dried in vacuo to a slightly brownish powder. The yield was 570 mg, 7% of the theoretical.
Gasskromatografisk analyse av TMS-derivatene indikerte at produktet besto av to isomerer i et 2:1 forhold. NMR-spektroskopi identifiserte produktet som en blanding av a- og B-anomerer.<1>H og13C NMR (DMSO-d6), 5 rel. til TMS: 8,4-8,1 Gas chromatographic analysis of the TMS derivatives indicated that the product consisted of two isomers in a 2:1 ratio. NMR spectroscopy identified the product as a mixture of α and β anomers.<1>H and13C NMR (DMSO-d6), 5 rel. to TMS: 8.4-8.1
(m, 2H, Ar-H), 8,05-7,79 (m, 2H, Ar-H), 7,79-7,60 (t, 1H, NH), 6,80 (d, 1H, OH-1), 5,81 (s+s, 1H, acetal-H), 5,30 og 5,18 (s+s, 1/2 H + 1/2 H, H-1), 4,30-4,10, 3,93-3,3 (m, 6H, H-2 - H-6), og 1,85 (d, 3H, CH3); 169,331 (0=O), 147,490, 139,544, 133,018, 129,862, 123,732, 120,884 (Ar-C), 99,000, 98,806 (acetal-C), 95,924, 91,406, 82,433, 81,454, 70,320, 68,240, 67,907, 67,020, 65,574, 61,833, 57,875, 54,609 (sukker-C) 23,014 og 22,557 (CH3). (m, 2H, Ar-H), 8.05-7.79 (m, 2H, Ar-H), 7.79-7.60 (t, 1H, NH), 6.80 (d, 1H, OH-1), 5.81 (s+s, 1H, acetal-H), 5.30 and 5.18 (s+s, 1/2 H + 1/2 H, H-1), 4.30 -4.10, 3.93-3.3 (m, 6H, H-2 - H-6), and 1.85 (d, 3H, CH3); 169,331 (0=O), 147,490, 139,544, 133,018, 129,862, 123,732, 120,884 (Ar-C), 99,000, 98,806 (acetal-C), 95,924, 91,406, 82,433, 81,454, 70,320, 68,240, 67,907, 67,020, 65,574 , 61.833, 57.875, 54.609 (sugar-C) 23.014 and 22.557 (CH3).
Forbindelse 10: 4, 6- 0-( benzvliden- di)- D- qalaktopvranose Compound 10: 4, 6- O-( benzvlidene-di)- D- qalactopvranose
Benzaldehyd-di ble fremstilt og konvertert til benzaldehyddimetylacetal-di som beskrevet i EP 0 283 139 B1. Benzaldehyde di was prepared and converted to benzaldehyde dimethyl acetal di as described in EP 0 283 139 B1.
D(+)-galaktose (15,0 g, 0,0833 mol) og tørr DMF (80 ml) ble omrørt i et destillasjonsapparat ved 45°C. Det ble tilsatt benzaldehyddimetylacetal-di (12,8 g, 0,0836 mol) og paratoluensulfonsyre (0,14 g) og metanol og DMF sakte destillert av i vakuum (vannstråle). Etter 3 timer ble det montert en vakuumpumpe og det resterende DMF ble destillert fra. Porsjoner av destillasjonsresten ble løst i metanol/vann (1:1) som inneholdt NaHC03(11 mg/ml) og renset på en Lobar C RP-8-kolonne med metanol/vann (1:1) som eluent. Produktfraksjoner fra 7 individuelle synteser ble frysetørket og slått sammen til et hvitt, ullent produkt. Utbyttet var 6,62 g, 30% av det teoretiske. D(+)-galactose (15.0 g, 0.0833 mol) and dry DMF (80 mL) were stirred in a still at 45°C. Benzaldehyde dimethyl acetal-di (12.8 g, 0.0836 mol) and paratoluenesulfonic acid (0.14 g) were added and methanol and DMF slowly distilled off in vacuo (water jet). After 3 hours a vacuum pump was fitted and the remaining DMF was distilled off. Portions of the distillation residue were dissolved in methanol/water (1:1) containing NaHCO 3 (11 mg/ml) and purified on a Lobar C RP-8 column with methanol/water (1:1) as eluent. Product fractions from 7 individual syntheses were freeze-dried and pooled into a white, woolly product. The yield was 6.62 g, 30% of the theoretical.
Gasskromatografisk og NMR-analyse viste at produktet besto av en 1:1 anomerblanding.<1>H og<13>C NMR (DMSO-d6), 8 rel. til TMS: 7,52-7,30 (m, 5H, Ar-H), 6,62 (0.5H, d, OH-1-B), 6,32 (0,5H, d, OH-1-a), 5,05 (0,5H, t, H-1-a), 4,85+4,69+4,49 (1H+0,5H+0,5H, m+d+d, OH-2+OH-3), 4,35 (0,5H, t, H-1-B), 4,12-3,92+3,81-3,71+3,69-3,59+3,49-3,39+3,39-3,28 (3H+1H+0.5H+1H+2H, m+m+m+m+m, H-2-H-6+H20); 138,753, 138,690, 128,607, 128,319, 127,913 og 126,3 (Ar-C), 99,345 (acetal-C), 97,307 og 93,178 (C-1), 76,738 og 76,158 (C-4), 72,101, 71,605, 68,947, 68,862, 68,486 og 67,730 (C-2, C-3 og C-6) og 65,829 og 62,068 (C-5). Gas chromatographic and NMR analysis showed that the product consisted of a 1:1 anomer mixture.<1>H and<13>C NMR (DMSO-d6), 8 rel. to TMS: 7.52-7.30 (m, 5H, Ar-H), 6.62 (0.5H, d, OH-1-B), 6.32 (0.5H, d, OH-1- a), 5.05 (0.5H, t, H-1-a), 4.85+4.69+4.49 (1H+0.5H+0.5H, m+d+d, OH- 2+OH-3), 4.35 (0.5H, t, H-1-B), 4.12-3.92+3.81-3.71+3.69-3.59+3, 49-3.39+3.39-3.28 (3H+1H+0.5H+1H+2H, m+m+m+m+m, H-2-H-6+H 2 O); 138.753. 68.862, 68.486 and 67.730 (C-2, C-3 and C-6) and 65.829 and 62.068 (C-5).
Forbindelse 11: 4. 6- 0-( benzvliden- di)- D- mannopvranose Compound 11: 4.6-0-(benzvlidene-di)-D-mannopvranose
Benzaldehyd-di ble fremstilt og konvertert til benzaldehyddimetylacetal-di som beskrevet i EP 0 283 139 B1. Benzaldehyde di was prepared and converted to benzaldehyde dimethyl acetal di as described in EP 0 283 139 B1.
D(+)-mannose (15,0 g, 0,0833 mol) og tørr DMF (70 ml) ble omrørt i en destillasjonsapparatur ved 40°C. Benzylidendimetylacetal-di og paratoluensulfonsyre (0,14 g) ble tilsatt og det dannet seg en klar løsning. Det ble tilkoblet en vakuumpumpe og metanol og DMF ble sakte destillert fra ved 70-20 mbar, 45-50°C. Etter 3 timer ble det resterende DMF destillert av ved maks. vakuum, slik at det ble igjen en svakt gul sirupsmasse. D(+)-mannose (15.0 g, 0.0833 mol) and dry DMF (70 mL) were stirred in a still at 40°C. Benzylidenedimethylacetal-di and paratoluenesulfonic acid (0.14 g) were added and a clear solution formed. A vacuum pump was connected and methanol and DMF were slowly distilled from at 70-20 mbar, 45-50°C. After 3 hours, the remaining DMF was distilled off at max. vacuum, so that a faint yellow syrupy mass remained.
Resten ble vasket flere ganger med eter for å fjerne lipofile substanser. Noen porsjoner av råproduktet ble løst i svakt alkalisk (NaHCOa) metanol/vann (3:2) og renset på en Lobar C RP-8-kolonne med metanol/vann (3:2) som eluent. gasskromatografi av TMS-derivatene indikerte at produktet besto av 4 isomerer i forholdet 10:3:1:4. Det ble re-eluert med metanol/vann (1:4) til et hvitt, ullent produkt som besto av bare to isomerer i forholdet 70/30, ifølge gasskromatografisk analyse. Utbyttet var 1,42 g, 6,4% av det teoretiske. The residue was washed several times with ether to remove lipophilic substances. Some portions of the crude product were dissolved in weakly alkaline (NaHCO 3 ) methanol/water (3:2) and purified on a Lobar C RP-8 column with methanol/water (3:2) as eluent. gas chromatography of the TMS derivatives indicated that the product consisted of 4 isomers in the ratio 10:3:1:4. It was re-eluted with methanol/water (1:4) to give a white, woolly product consisting of only two isomers in the ratio 70/30, according to gas chromatographic analysis. The yield was 1.42 g, 6.4% of the theoretical.
På basis av<1>H-,<13>C-, COSY-, DEPT- og C-H-korrelasjons-NMR ble den kjemiske strukturen bekreftet og a- og B-anomerene funnet å nå en likevekt ved et 1:8-forhold. On the basis of<1>H,<13>C, COSY, DEPT and C-H correlation NMR, the chemical structure was confirmed and the a and B anomers were found to reach an equilibrium at a 1:8 ratio .
<1>H og<13>C NMR (DMSO-d6) av den dominerende isomeren, 8 rel. til TMS: 7,5-7,28 (m, 5H, Ar-H), 6,56 (d, 1H, OH-1), 5,0-4,85 (m, 3H, OH-2 og OH-3), 4,10-4,02 (m, 1H, H-6), 3,63-3,40 (m, 5H, H-2, H-3, H-4, H-5 og H-6'); 138,045, 128,825, 128,029, 126,438 (Ar-C), 100,802 (Acetal-C), 95,233 (C-1), 78,967 (C-4), 72,032 (C-3), 68,317 (C-6), 67,252 (C-2), 63,495 (C-5). <1>H and<13>C NMR (DMSO-d6) of the dominant isomer, 8 rel. to TMS: 7.5-7.28 (m, 5H, Ar-H), 6.56 (d, 1H, OH-1), 5.0-4.85 (m, 3H, OH-2 and OH -3), 4.10-4.02 (m, 1H, H-6), 3.63-3.40 (m, 5H, H-2, H-3, H-4, H-5 and H -6'); 138.045, 128.825, 128.029, 126.438 (Ar-C), 100.802 (Acetal-C), 95.233 (C-1), 78.967 (C-4), 72.032 (C-3), 68.317 (C-6), 67.252 ( C-2), 63.495 (C-5).
Forbindelse 12: 2- acetamido- 4. 6- 0- benzvliden- 2- deoksv- g- D- aalaktopvranose Compound 12: 2- acetamido- 4. 6- 0- benzvlidene- 2- deoxv- g- D- aalactopvranose
Benzaldehyddimetylacetal (2,0 ml, 14 mmol) og deretter paratoluensulfonsyre-monohydrat (15 mg) ble tilsatt til en omrørt suspensjon av N-acetyl- D-galaktosamin (1,50 g, 6,77 mmol) i acetonitril (37 ml). Reaksjonsblandingen ble så senket ned i et varmt (60°C) oljebad og omrørt under nitrogen i 3 timer, mens man observerte at det dannet seg et tykt hvitt bunnfall. Reaksjonsblandingen ble så filtrert og det faste stoffet vasket med kald diklormetan (omtrent 2 ml), deretter fortsatte man med sugefiltrering under nitrogenstrøm. Det hvite pulveret ble så plassert i et forhåndsveid glass og satt under vakuum (0,06 mbar) i 72 timer slik at man fikk det rene, ønskede produktet som bare a-isomeren (1,74 g, 83%). Benzaldehyde dimethyl acetal (2.0 mL, 14 mmol) followed by paratoluenesulfonic acid monohydrate (15 mg) was added to a stirred suspension of N-acetyl-D-galactosamine (1.50 g, 6.77 mmol) in acetonitrile (37 mL) . The reaction mixture was then immersed in a hot (60°C) oil bath and stirred under nitrogen for 3 hours, while a thick white precipitate was observed to form. The reaction mixture was then filtered and the solid washed with cold dichloromethane (about 2 mL), then continued with suction filtration under nitrogen flow. The white powder was then placed in a preweighed glass and placed under vacuum (0.06 mbar) for 72 hours to give the pure desired product as only the α-isomer (1.74 g, 83%).
<1>H NMR 8H (300 MHz, d6-DMSO) 1,83 (3H, s, CH3), 3,80-4,17 (6H, m, H-2, H-3, H-4, H-5 og H-6), 4,65 (1H, d, OH-3), 5,06 (1H, t, H-1), 5,59 (1H, s, ArCH), 6,52 (1H,d, OH-1), 7,33-7,55 (5H, m, ArH) og 7,69 (1H,d, NH);<13>C NMR8C{<1>H}(75 MHz, d6-DMSO) 23 (CH3), 50, 62, 65, 69 og 76 (C-2, C-3, C-4, C-5, C-6), 91 (C-1), 100 (ArCH), 126, 128, 128 og 138 (arom. C) og 170 (C=0). <1>H NMR 8H (300 MHz, d6-DMSO) 1.83 (3H, s, CH3), 3.80-4.17 (6H, m, H-2, H-3, H-4, H -5 and H-6), 4.65 (1H, d, OH-3), 5.06 (1H, t, H-1), 5.59 (1H, s, ArCH), 6.52 (1H ,d, OH-1), 7.33-7.55 (5H, m, ArH) and 7.69 (1H,d, NH);<13>C NMR8C{<1>H}(75 MHz, d6 -DMSO) 23 (CH3), 50, 62, 65, 69 and 76 (C-2, C-3, C-4, C-5, C-6), 91 (C-1), 100 (ArCH) , 126, 128, 128 and 138 (arom. C) and 170 (C=0).
Forbindelse 13: 4. 6- 0-( 3- nitrobenzen)- D- qlukopvranose Compound 13: 4. 6- O-( 3- nitrobenzene)- D- qlucopvranose
3-nitrobenzaldehyddimetylacetal ble fremstilt som beskrevet for forbindelse 9. 3-Nitrobenzaldehyde dimethyl acetal was prepared as described for compound 9.
3-nitrobenzaldehyddimetylacetal (21,9 g, 0,11 mol), D(+)-glukose (16,0 g, 0,09 mol), paratoluensulfonsyre (100 mg, 0,5 mmol) og tørr DMF (50 ml) ble blandet under N2og omrørt ved 58°C i 25 minutter. Det ble tilkoblet en vakuumpumpe og metanol og DMF ble sakte destillert av gjennom en avkjølt kolonne ved 55-60°C, 30-40 mbar i løpet av 4 timer og 15 minutter. Apparaturen ble ombygd for å fjerne det meste av DMF ved kortbanedestillasjon og destillasjonen fortsatte i 1,5 time til. Destillasjonsresten var en svakt gul sirupsmasse. 3-nitrobenzaldehyde dimethyl acetal (21.9 g, 0.11 mol), D(+)-glucose (16.0 g, 0.09 mol), paratoluenesulfonic acid (100 mg, 0.5 mmol) and dry DMF (50 mL) was mixed under N 2 and stirred at 58°C for 25 min. A vacuum pump was connected and methanol and DMF were slowly distilled off through a cooled column at 55-60°C, 30-40 mbar over 4 hours and 15 minutes. The apparatus was rebuilt to remove most of the DMF by short path distillation and the distillation continued for another 1.5 hours. The distillation residue was a pale yellow syrupy mass.
Sirupsmassen ble løst i svakt alkalisk (NaHCOa) metanol/vann 60:40 og renset på en Lobar C RP-8-kolonne med metanol/vann 60:40 som eluent. Produktfraksjonene ble inndampet (for å fjerne metanol), frysetørket og slått sammen til 5 g av et hvitt, ullent fast stoff. Produktet ble renset en gang til med metanol/vann 60:40 som eluent for å få tittelforbindelsen tilstrekkelig ren. Utbyttet var 3,3 g, 12% av det teoretiske. Gasskromatografi indikerte at produktet besto av to isomerer i et 70:30-forhold. The syrup mass was dissolved in weakly alkaline (NaHCOa) methanol/water 60:40 and purified on a Lobar C RP-8 column with methanol/water 60:40 as eluent. The product fractions were evaporated (to remove methanol), freeze-dried and combined to give 5 g of a white, woolly solid. The product was purified once more with methanol/water 60:40 as eluent to obtain the title compound sufficiently pure. The yield was 3.3 g, 12% of the theoretical. Gas chromatography indicated that the product consisted of two isomers in a 70:30 ratio.
<1>H NMR (DMS0-d6), 5 rel. til TMS: 8,33-7,63 (5H, m, Ar-H), 6,89+6,60 (1H, d+d, OH-1-I+II), 5,78 (1H, s+s, acetal-H-i+ii), 5,34 (0.65H, d, OH-3-II), 5,57+5,71 (1.12H, d+d, OH-2-II + OH-3-I), 4,99 (0.56H, m, H-1-1), 4,88 (0.32H, OH-2-1), 4,49 (0.74H, m, H-1-II), 4,28-4,12 (1H, m, H-6-I+II), 3,85-3,53 (2.27H, m, H-3-I, H-5-I og H-6"-l+ll), 3,49-3,32 (2.58H, m, H-2-I, H-3-II, H-4-I+II og H-5-II) og 3,12-2,98 (0.85H, m, H-2-II). <1>H NMR (DMS0-d6), 5 rel. to TMS: 8.33-7.63 (5H, m, Ar-H), 6.89+6.60 (1H, d+d, OH-1-I+II), 5.78 (1H, s +s, acetal-H-i+ii), 5.34 (0.65H, d, OH-3-II), 5.57+5.71 (1.12H, d+d, OH-2-II + OH -3-I), 4.99 (0.56H, m, H-1-1), 4.88 (0.32H, OH-2-1), 4.49 (0.74H, m, H-1-II ), 4.28-4.12 (1H, m, H-6-I+II), 3.85-3.53 (2.27H, m, H-3-I, H-5-I and H- 6"-l+ll), 3.49-3.32 (2.58H, m, H-2-I, H-3-II, H-4-I+II and H-5-II) and 3, 12-2.98 (0.85H, m, H-2-II).
Forbindelse 14: 4, 6- 0-( 2- hvdroksvbenzvliden)- D- qlukopyranose Compound 14: 4,6-O-(2-Hydroxybenzvlidene)-D-glucopyranose
Salicylaldehyd (74,4 g, 0,609 mol), metanol (91,5 g, 2,86 mol), trimetylortoformiat (71 g, 0,67 mol) og konsentrert saltsyre (165 jo.1) blandes i en 500 ml trehalset flaske. Reaksjonsblandingen omrøres ved romtemperatur i 15 minutter og reflukseres i ytterligere 25 minutter. Etter avkjøling (isvann) tilsettes en alkalisk løsning som lages ved å løse KOH (1,1 g) i metanol (7 ml) og omrøringen fortsetter i 25 minutter. Alle flyktige stoffer fjernes (vannstrålepumpe) og det dannede salicylaldehyddimetylacetalet destilleres i vakuum (vakuumpumpe). Salicylic aldehyde (74.4 g, 0.609 mol), methanol (91.5 g, 2.86 mol), trimethyl orthoformate (71 g, 0.67 mol) and concentrated hydrochloric acid (165 jo.l) are mixed in a 500 ml three-necked flask . The reaction mixture is stirred at room temperature for 15 minutes and refluxed for a further 25 minutes. After cooling (ice water), an alkaline solution prepared by dissolving KOH (1.1 g) in methanol (7 ml) is added and stirring is continued for 25 minutes. All volatile substances are removed (water jet pump) and the formed salicylaldehyde dimethyl acetal is distilled in a vacuum (vacuum pump).
D(+)-glukose (8,0 g, 44,4 mmol), tørr DMF (25 ml), salicylaldehyddimetylacetal (8,33 g, 49,5 mmol) og paratoluensulfonsyre blandes under N2ved 50°C. Apparaturen tilkobles til en vakuumpumpe og fordampingen av metanol starter. Temperaturen opprettholdes ved 55-60°C og vakuumet reguleres gradvis ned for å gjøre reaksjonen fullstendig. Apparaturen ombygges for kortbanedestillasjon for å fjerne DMF. Det dannes en sirupsaktig rest. D(+)-glucose (8.0 g, 44.4 mmol), dry DMF (25 mL), salicylaldehyde dimethyl acetal (8.33 g, 49.5 mmol) and paratoluenesulfonic acid are mixed under N 2 at 50°C. The apparatus is connected to a vacuum pump and the evaporation of methanol starts. The temperature is maintained at 55-60°C and the vacuum is gradually regulated down to make the reaction complete. The apparatus is converted for short path distillation to remove DMF. A syrupy residue is formed.
Resten løses i svakt alkalisk (NaHCCb) metanol/vann og renses på en Lobar RP-8-kolonne med metanol/vann som eluent. Produktfraksjonene frysetørkes og slås sammen. Identiteten bekreftes ved NMR-analyse. The residue is dissolved in weakly alkaline (NaHCCb) methanol/water and purified on a Lobar RP-8 column with methanol/water as eluent. The product fractions are freeze-dried and combined. The identity is confirmed by NMR analysis.
Forbindelse 15: 2- deoksv- 4. 6- 0-( 2- hvdroksvbenzvliden)- D- qlukopvranose Salicylaldehyddimetylacetal fremstilles som beskrevet for forbindelse 14. Compound 15: 2-deoxy-4.6-0-(2-hydroxybenzvlidene)-D-qlucopvranose Salicylaldehyde dimethyl acetal is prepared as described for compound 14.
2-deoksy-D-glukose (7,3 g, 44,5 mmol), tørr DMF (25 ml), 2-deoxy-D-glucose (7.3 g, 44.5 mmol), dry DMF (25 mL),
salicylaldehyddimetylacetal (8,33 g, 49,5 mmol) og paratoluensulfonsyre blandes under N2ved 50°C. Apparaturen kobles til en vakuumpumpe og fordampingen av metanol starter. Temperaturen holdes ved like på 55-60°C og vakuumet reguleres gradvis ned for å drive reaksjonen til ende. Apparaturen ombygges for kortbanedestillasjon for å fjerne DMF. Det dannes en sirupsaktig rest. salicylaldehyde dimethyl acetal (8.33 g, 49.5 mmol) and paratoluenesulfonic acid are mixed under N2 at 50°C. The apparatus is connected to a vacuum pump and the evaporation of methanol starts. The temperature is kept at 55-60°C and the vacuum is gradually regulated down to drive the reaction to completion. The apparatus is converted for short path distillation to remove DMF. A syrupy residue is formed.
Resten løses i svakt alkalisk (NaHCOa) metanol/vann og renses på en Lobar RP-8-kolonne med metanol/vann som eluent. Produktfraksjonene frysetørkes og slås sammen. Identiteten bekreftes ved NMR-analyse. The residue is dissolved in weakly alkaline (NaHCOa) methanol/water and purified on a Lobar RP-8 column with methanol/water as eluent. The product fractions are freeze-dried and combined. The identity is confirmed by NMR analysis.
Forbindelse 16: 2- acetamido- 2- deoksv- 4. 6- 0-( 2- hvdroksvbenzvliden)-D- qlukopyranose Compound 16: 2- acetamido- 2- deoxy- 4. 6- O-( 2- hydroxybenzvlidene)-D- chloropyranose
Salicylaldehyddimetylacetal fremstilles som beskrevet for forbindelse 14. Salicylaldehyde dimethyl acetal is prepared as described for compound 14.
Salicylaldehyddimetylacetal (9,5 g, 56,5 mmol), N-acetyl-D-glukosamin (10,0 g, 45,2 mmol), tørr DMF (30 ml) og paratoluensulfonsyre (88 mg, 0,46 mmol) blandes under N2. Reaksjonsblandingen omrøres ved 50°C ved redusert trykk for å drive reaksjonen til ende. Apparaturen ombygges for å fjerne DMF ved kortbanedestillasjon og destillasjonen fortsettes ved 55-60°C, maks. vakuum. Mix salicylaldehyde dimethyl acetal (9.5 g, 56.5 mmol), N-acetyl-D-glucosamine (10.0 g, 45.2 mmol), dry DMF (30 mL) and paratoluenesulfonic acid (88 mg, 0.46 mmol) under N2. The reaction mixture is stirred at 50°C under reduced pressure to drive the reaction to completion. The apparatus is rebuilt to remove DMF by short path distillation and the distillation is continued at 55-60°C, max. vacuum.
Resten nøytraliseres ved å tilsette metanol/vann som inneholder litt NaHC03og renses på en Lobar RP-8-kolonne med metanol/vann som eluent. Identiteten bekreftes ved NMR-spektroskopi. The residue is neutralized by adding methanol/water containing a little NaHCO 3 and purified on a Lobar RP-8 column with methanol/water as eluent. The identity is confirmed by NMR spectroscopy.
Forbindelse 17: 4, 6- 0-( 2- hvdroksvbenzvliden)- D- qalaktopvranose Compound 17: 4, 6- O-( 2- hydroxybenzvlidene)- D- qalactopvranose
D(+)-galaktose (8,0 g, 44,4 mmol), tørr DMF (25 ml), salicylaldehyddimetylacetal (8,33 g, 49,5 mmol) og paratoluensulfonsyre blandes under N2ved 50°C. Apparaturen kobles til en vakuumpumpe og fordampningen av metanol starter. Temperaturen holdes ved like ved 55-60°C og vakuumet reguleres gradvis ned for å drive reaksjonen til ende. Apparaturen ombygges for kortbanedestillasjon for å fjerne DMF. Det dannes en sirupsaktig rest. D(+)-galactose (8.0 g, 44.4 mmol), dry DMF (25 mL), salicylaldehyde dimethyl acetal (8.33 g, 49.5 mmol) and paratoluenesulfonic acid are mixed under N 2 at 50°C. The apparatus is connected to a vacuum pump and the evaporation of methanol starts. The temperature is kept at around 55-60°C and the vacuum is gradually regulated down to drive the reaction to completion. The apparatus is converted for short path distillation to remove DMF. A syrupy residue is formed.
Resten løses i svakt alkalisk (NaHCG*3) metanol/vann og renses på en Lobar RP-8-kolonne med metanol/vann som eluent. Produktfraksjonene frysetørkes og slås sammen. Identiteten bekreftes ved NMR-analyse. The residue is dissolved in weakly alkaline (NaHCG*3) methanol/water and purified on a Lobar RP-8 column with methanol/water as eluent. The product fractions are freeze-dried and combined. The identity is confirmed by NMR analysis.
Forbindelse 18: 2- deoksv- 4, 6- 0-( 2- hvdroksvbenzvliden)- D- qalaktopvranose Salicylaldehyddimetylacetal fremstilles som beskrevet for forbindelse 14. Compound 18: 2-deoxy-4,6-O-(2-hydroxybenzvlidene)-D-qalactopvranose Salicylaldehyde dimethyl acetal is prepared as described for compound 14.
2-deoksy-D-galaktose (7,3 g, 44,5 mmol), tørr DMF (25 ml), 2-deoxy-D-galactose (7.3 g, 44.5 mmol), dry DMF (25 mL),
salicylaldehyddimetylacetal (8,33 g, 49,5 mmol) og paratoluensulfonsyre blandes under N2ved 50°C. Apparaturen kobles til en vakuumpumpe og fordampningen av metanol starter. Temperaturen holdes ved like ved 55-60°C og vakuumet reguleres gradvis ned for å drive reaksjonen til ende. Apparaturen ombygges for kortbanedestillasjon for å fjerne DMF. Det dannes en sirupsaktig rest. salicylaldehyde dimethyl acetal (8.33 g, 49.5 mmol) and paratoluenesulfonic acid are mixed under N2 at 50°C. The apparatus is connected to a vacuum pump and the evaporation of methanol starts. The temperature is kept at around 55-60°C and the vacuum is gradually regulated down to drive the reaction to completion. The apparatus is converted for short path distillation to remove DMF. A syrupy residue is formed.
Resten løses i svakt alkalisk (NaHCOa) metanol/vann og renses på en Lobar RP-8-kolonne med metanol/vann som eluent. Produktfraksjonene frysetørkes og slås sammen. Identiteten bekreftes ved NMR-analyse. The residue is dissolved in weakly alkaline (NaHCOa) methanol/water and purified on a Lobar RP-8 column with methanol/water as eluent. The product fractions are freeze-dried and combined. The identity is confirmed by NMR analysis.
Forbindelse 19: 2- acetamido- 2- deoksv- 4. 6-( 2- hvdroksvbenzvliden)-D- qalaktopvranose Compound 19: 2- acetamido- 2- deoxy- 4. 6-( 2- hydroxybenzvlidene)-D- chalactopvranose
Salicylaldehyddimetylacetal fremstilles som beskrevet for forbindelse 14. Salicylaldehyde dimethyl acetal is prepared as described for compound 14.
N-acetyl-D-galaktosamin (10,0 g, 45,2 mmol), tørr DMF (25 ml), salicylaldehyddimetylacetal (8,33 g, 49,5 mmol) og paratoluensulfonsyre blandes under N2ved 50°C. Apparaturen kobles til en vakuumpumpe og fordampningen av metanol starter. Temperaturen holdes ved like ved 55-60°C og vakuumet reguleres gradvis ned for å drive reaksjonen til ende. Apparaturen ombygges for kortbanedestillasjon for å fjerne DMF. Det dannes en destillasjonsrest. N-acetyl-D-galactosamine (10.0 g, 45.2 mmol), dry DMF (25 mL), salicylaldehyde dimethyl acetal (8.33 g, 49.5 mmol) and paratoluenesulfonic acid are mixed under N 2 at 50°C. The apparatus is connected to a vacuum pump and the evaporation of methanol starts. The temperature is kept at around 55-60°C and the vacuum is gradually regulated down to drive the reaction to completion. The apparatus is converted for short path distillation to remove DMF. A distillation residue is formed.
Det lages en svakt alkalisk løsning ved å blande NaHC03i metanol/vann og destillasjonsresten nøytraliseres ved å tilsette denne løsningen. Grøten som dannes filtreres og vaskes med 1% NaHCCMøsning og vann. Produktet analyseres ved gasskromatografi og omkrystalliseres hvis nødvendig. Produktet tørkes i vakuum når det er tilstrekkelig rent. A weakly alkaline solution is made by mixing NaHCO3 in methanol/water and the distillation residue is neutralized by adding this solution. The slurry that forms is filtered and washed with 1% NaHCCM solution and water. The product is analyzed by gas chromatography and recrystallized if necessary. The product is dried in a vacuum when it is sufficiently clean.
Identiteten bekreftes ved NMR-analyse. The identity is confirmed by NMR analysis.
Forbindelse 20: 4. 6- 2( hvdroksvbenzvliden)- D- mannopyranose Salicylaldehyddimetylacetal fremstilles som beskrevet for forbindelse 14. Compound 20: 4. 6-2(hydroxybenzvlidene)-D-mannopyranose Salicylaldehyde dimethyl acetal is prepared as described for compound 14.
D(+)-mannose (8,0 g, 44,4 mmol), tørr DMF (25 ml), salicylaldehyddimetylacetal (8,33 g, 49,5 mmol) og paratoluensulfonsyre blandes under N2ved 50°C. Apparaturen kobles til en vakuumpumpe og fordampningen av metanol starter. Temperaturen holdes ved like ved 55-60°C og vakuumet reguleres gradvis ned for å drive reaksjonen til ende. Apparaturen ombygges for kortbanedestillasjon for å fjerne DMF. Det dannes en sirupsaktig rest. D(+)-mannose (8.0 g, 44.4 mmol), dry DMF (25 mL), salicylaldehyde dimethyl acetal (8.33 g, 49.5 mmol) and paratoluenesulfonic acid are mixed under N 2 at 50°C. The apparatus is connected to a vacuum pump and the evaporation of methanol starts. The temperature is kept at around 55-60°C and the vacuum is gradually regulated down to drive the reaction to completion. The apparatus is converted for short path distillation to remove DMF. A syrupy residue is formed.
Resten løses i svakt alkalisk (NaHCOa) metanol/vann og renses på en Lobar RP-8-kolonne med metanol/vann som eluent. Produktfraksjonene frysetørkes og slås sammen. Identiteten bekreftes ved NMR-analyse. The residue is dissolved in weakly alkaline (NaHCOa) methanol/water and purified on a Lobar RP-8 column with methanol/water as eluent. The product fractions are freeze-dried and combined. The identity is confirmed by NMR analysis.
Biologiske eksperimenter Biological experiments
Eksempel 1 Example 1
Formering av perifere mononukleære blodceller Proliferation of peripheral blood mononuclear cells
Oppfinnerne utførte et eksperiment hvor perifere mononukleære blodceller ble utsatt for superantigen sammen med benzaldehyd, deuterert benzaldehyd, forbindelse 2 eller zilascorb(<2>H). Superantigen brukes som en meget aktiv standard for formering av T-celler og presenteres til T-celler ved hjelp av antigenpresenterende celler. The inventors performed an experiment in which peripheral blood mononuclear cells were exposed to superantigen together with benzaldehyde, deuterated benzaldehyde, compound 2 or zilascorb(<2>H). Superantigen is used as a highly active standard for the propagation of T cells and is presented to T cells by means of antigen-presenting cells.
Eksperimentet viste (se figur 1) at ved å tilsette benzaldehyd, deuterert benzaldehyd eller forbindelse 2 økte formeringen av perifere mononukleære blodceller signifikant på en klokkeformet doseavhengig måte, mens det ble funnet en svært liten virkning med zilascorb(<2>H). Det at vi var i stand til å øke formeringssignalet fra superantigenet tyder på at forbindelsene fungerer ved at de medvirker til å stimulere T-cellene. The experiment showed (see Figure 1) that adding benzaldehyde, deuterated benzaldehyde or compound 2 significantly increased the proliferation of peripheral blood mononuclear cells in a bell-shaped dose-dependent manner, while very little effect was found with zilascorb(<2>H). The fact that we were able to increase the propagation signal from the superantigen suggests that the compounds work by helping to stimulate the T cells.
Konklusjoner Conclusions
Benzaldehydderivatene i henhold til denne oppfinnelsen reagerer til Schiff-baser med visse grupper på celleoverflaten, f.eks. frie aminogrupper..Siden mange celleprosesser, som proteinsyntese, cellesyklus, immunrespons etc, kontrolleres av signaler fra celleoverflaten vil disse bindingene endre oppførselen til cellen. Vi har også vist at benzalsehydkompleksene på celleoverflaten endrer adhesjonskarakteristikaene til cellen. Vi har vist at forbindelsene i henhold til denne oppfinnelsen kan være nyttige i nye behandlinger for å bekjempe autoimmune sykdommer. The benzaldehyde derivatives according to this invention react to Schiff bases with certain groups on the cell surface, e.g. free amino groups..Since many cell processes, such as protein synthesis, cell cycle, immune response etc, are controlled by signals from the cell surface, these bonds will change the behavior of the cell. We have also shown that the benzaldehyde complexes on the cell surface change the adhesion characteristics of the cell. We have shown that the compounds of this invention may be useful in new treatments to combat autoimmune diseases.
Vi har funnet at heksosederivatene av benzaldehyder er overraskende mer effektive enn derivatene av andre karbohydrater.Vi tror at dette fenomenet er forbundet med reseptoraffiniteten til disse organene for sukkergruppen i derivatene. We have found that the hexose derivatives of benzaldehydes are surprisingly more effective than the derivatives of other carbohydrates. We believe that this phenomenon is connected with the receptor affinity of these organs for the sugar group in the derivatives.
Administrering Administration
De terapeutiske midlene som fremstilles ved foreliggende oppfinnelse kan gis ved behandling av sykdommer som oppstår på grunn av abnormt økt celleformering The therapeutic agents produced by the present invention can be given in the treatment of diseases that occur due to abnormally increased cell proliferation
og/eller for å bekjempe autoimmune sykdommer. Disse terapeutiske midlene kan også gis som immunmodulatorer. Til dette formålet kan forbindelsene av formel (I) formuleres på en hvilken som helst egnet måte for å gis til en pasient, enten alene eller tilsatt egnede farmasøytiske bærere eller hjelpestoffer. and/or to combat autoimmune diseases. These therapeutic agents can also be given as immunomodulators. For this purpose, the compounds of formula (I) may be formulated in any suitable manner for administration to a patient, either alone or with the addition of suitable pharmaceutical carriers or excipients.
Det foretrekkes spesielt at formuleringene for systemisk terapi fremstilles enten som orale preparater eller parenterale formuleringer. It is particularly preferred that the formulations for systemic therapy are prepared either as oral preparations or parenteral formulations.
Egnede enterale preparater vil være tabletter, kapsler, f.eks. bløte eller harde gelatinkapsler, korn eller pulvere, geleer, suspensjoner, løsninger eller stikkpiller. Slike preparater vil fremstilles på kjent måte ved å blande en eller flere av forbindelsene av formel (I) med ikke-giftige, inerte faste eller flytende bærere. Suitable enteral preparations will be tablets, capsules, e.g. soft or hard gelatin capsules, granules or powders, gels, suspensions, solutions or suppositories. Such preparations will be prepared in a known manner by mixing one or more of the compounds of formula (I) with non-toxic, inert solid or liquid carriers.
Egnede parenterale preparater av forbindelsene av formel (I) er injeksjons- eller infusjonsløsninger. Suitable parenteral preparations of the compounds of formula (I) are injection or infusion solutions.
Når de gis utvortes kan forbindelsene av formel (I) formuleres som en oppløsning, salve, krem, sirup, tinktur, spray eller liknende som inneholder forbindelsene av formel (I) med tilsetning av ikke-giftige, inerte faste eller flytende bærere som er vanlige i lokale preparater. Det er spesielt godt egnet å bruke en formulering som beskytter den aktive ingrediensen mot luft, vann eller liknende. When administered externally, the compounds of formula (I) may be formulated as a solution, ointment, cream, syrup, tincture, spray or the like containing the compounds of formula (I) with the addition of non-toxic, inert solid or liquid carriers which are customary in local preparations. It is particularly well suited to use a formulation that protects the active ingredient from air, water or the like.
Preparatene kan inneholde inerte eller farmakodynamisk aktive tilsetninger. F.eks. kan tabletter eller granulater inneholde en serie bindemidler, fyllmaterialer, bærersubstanser og/eller fortynningsmidler. Flytende preparater kan for eksempel foreligge i form av en steril løsning. Kapsler kan inneholde et fyllmateriale eller et fortykningsmiddel i tillegg til den aktive ingrediensen. Preparatet kan dessuten også inneholde smaksforbedrende tilsetninger så vel som slike substanser som vanligvis brukes som holdbarhets-, stabilisator-, emulgeringsmidler eller fuktighetsbevarende midler, salter for å variere det osmotiske trykket, buffere og andre tilsetninger. The preparations may contain inert or pharmacodynamically active additives. E.g. tablets or granules may contain a series of binders, fillers, carrier substances and/or diluents. Liquid preparations can, for example, be available in the form of a sterile solution. Capsules may contain a filler or thickener in addition to the active ingredient. Furthermore, the preparation may also contain flavor-enhancing additives as well as such substances which are usually used as preservatives, stabilizers, emulsifiers or humectants, salts to vary the osmotic pressure, buffers and other additives.
Doseringen kan variere i samsvar med sykdommen, bruksmåten og innføringsveien, så vel som pasientens behov. Generelt vil en daglig dose i en systemisk terapi for en gjennomsnittlig voksen pasient være omtrent 0,01-500 mg/kg kroppsvekt en eller to ganger om dagen, fortrinnsvis 0,5-100 mg/kg kroppsvekt en eller to ganger om dagen og helst 1-20 mg/kg vekt en eller to ganger om dagen. The dosage may vary according to the disease, the method of use and the route of administration, as well as the needs of the patient. In general, a daily dose in a systemic therapy for an average adult patient will be about 0.01-500 mg/kg body weight once or twice a day, preferably 0.5-100 mg/kg body weight once or twice a day and preferably 1-20 mg/kg weight once or twice a day.
Hvis man ønsker det kan det farmasøytiske preparatet av forbindelsen av formel (I) inneholde en antioksidant, f.eks. tokoferol, N-metyl-tokoferamin, butylert hydroksyanisol, askorbinsyre eller butylert hydroksytoluen. If desired, the pharmaceutical preparation of the compound of formula (I) may contain an antioxidant, e.g. tocopherol, N-methyl-tocopheramine, butylated hydroxyanisole, ascorbic acid or butylated hydroxytoluene.
Claims (2)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NO20001450A NO311005B1 (en) | 2000-03-20 | 2000-03-20 | Use of benzaldehyde derivatives for the preparation of a therapeutic agent for the treatment of autoimmune diseases |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NO20001450A NO311005B1 (en) | 2000-03-20 | 2000-03-20 | Use of benzaldehyde derivatives for the preparation of a therapeutic agent for the treatment of autoimmune diseases |
Publications (3)
Publication Number | Publication Date |
---|---|
NO20001450D0 NO20001450D0 (en) | 2000-03-20 |
NO20001450L NO20001450L (en) | 2000-08-21 |
NO311005B1 true NO311005B1 (en) | 2001-10-01 |
Family
ID=19910906
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO20001450A NO311005B1 (en) | 2000-03-20 | 2000-03-20 | Use of benzaldehyde derivatives for the preparation of a therapeutic agent for the treatment of autoimmune diseases |
Country Status (1)
Country | Link |
---|---|
NO (1) | NO311005B1 (en) |
-
2000
- 2000-03-20 NO NO20001450A patent/NO311005B1/en not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
NO20001450L (en) | 2000-08-21 |
NO20001450D0 (en) | 2000-03-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP4533415B2 (en) | Cosmetic composition | |
US5185436A (en) | Esters of normal butyric acid and their use as pharmaceuticals | |
US20100069311A1 (en) | Medicament comprising a reducing alkyl-sugar monomer for the treatment of inflammatory disorders | |
HU198091B (en) | Process for producing ganglioside derivatives and pharmaceutical compositions comprising same as active ingedient | |
NO309305B1 (en) | Use of benzaldehyde derivatives in the manufacture of pharmaceutical preparations for the prevention and / or treatment of cancer, as well as certain new benzaldehyde derivatives | |
EP2310020B1 (en) | Novel acetates of 2-deoxy monosaccharides with anticancer activity | |
EP2583972B1 (en) | Therapeutic agent for inflammatory diseases containing adenosine n1-oxide as active ingredient | |
CN102146107B (en) | Synthesis and anti-tumor activity of (S)-2-hydroxyalkyl-1,4-dihydroxyl-9-10-anthraquinone and glycosyl conjugates | |
NO311005B1 (en) | Use of benzaldehyde derivatives for the preparation of a therapeutic agent for the treatment of autoimmune diseases | |
KR101839313B1 (en) | Antidiabetic composition comprising radiation-treated rutin derivative as effective component | |
NZ226274A (en) | Saccharide derivatives; pharmaceutical compositions and preparatory processes | |
NO311004B1 (en) | Use of benzaldehyde derivatives for the preparation of a therapeutic agent for the treatment of microbial infections | |
WO2008033543A9 (en) | Halogenated alkyl di- and trisaccharides, pharmaceutical formulations, diagnostic kits and methods of treatment | |
EP2081944B1 (en) | Novel morphine derivatives | |
DE19755367A1 (en) | Pharmaceutical composition containing D-galactose and its use | |
AU739033B2 (en) | 13-deoxyanthracycline derivatives and processes for preparing them | |
RU2239640C2 (en) | Derivatives of 5-imino-13-deoxyanthracycline and method for their preparing (variants), pharmaceutical composition, method for treatment of cancer, autoimmune diseases or immunodeficient disorders | |
PH26117A (en) | Therapeutic use of the isopropyl ester derivative of monosialoganglioside in nervous pathologies with an inflammatory component | |
JP2000178295A (en) | Antitumor composition | |
NO309815B1 (en) | Derivatives of 5-nitrofurfural | |
KR20010052814A (en) | Therapeutic agents | |
WO2000035932A1 (en) | Process for the preparation of ganglioside gm3 by acid hydrolysis of ganglioside inner esters and its use in the pharmaceutical field | |
WO1985003706A1 (en) | Punaglandins and pharmaceutical use thereof | |
KR19990084528A (en) | New anthracycline derivatives and preparation methods | |
JPH07103024B2 (en) | Anticancer drug containing diyne compound |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MM1K | Lapsed by not paying the annual fees |
Free format text: LAPSED IN AUGUST 2003 |