EP0844890A1 - Verwendung von gallensäurederivaten - Google Patents
Verwendung von gallensäurederivatenInfo
- Publication number
- EP0844890A1 EP0844890A1 EP96928517A EP96928517A EP0844890A1 EP 0844890 A1 EP0844890 A1 EP 0844890A1 EP 96928517 A EP96928517 A EP 96928517A EP 96928517 A EP96928517 A EP 96928517A EP 0844890 A1 EP0844890 A1 EP 0844890A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- moiety
- compound
- fluorescent
- acid
- visualising
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical class C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 title description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 18
- 210000000013 bile duct Anatomy 0.000 claims abstract description 13
- 230000008685 targeting Effects 0.000 claims abstract description 8
- 239000000203 mixture Substances 0.000 claims abstract description 4
- 238000004519 manufacturing process Methods 0.000 claims abstract description 3
- 125000002345 steroid group Chemical group 0.000 claims abstract 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 9
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 claims description 6
- 239000007850 fluorescent dye Substances 0.000 claims description 6
- VCKPUUFAIGNJHC-UHFFFAOYSA-N 3-hydroxykynurenine Chemical compound OC(=O)C(N)CC(=O)C1=CC=CC(O)=C1N VCKPUUFAIGNJHC-UHFFFAOYSA-N 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 4
- VHRGRCVQAFMJIZ-UHFFFAOYSA-N cadaverine Chemical compound NCCCCCN VHRGRCVQAFMJIZ-UHFFFAOYSA-N 0.000 claims description 4
- YGPSJZOEDVAXAB-UHFFFAOYSA-N kynurenine Chemical compound OC(=O)C(N)CC(=O)C1=CC=CC=C1N YGPSJZOEDVAXAB-UHFFFAOYSA-N 0.000 claims description 4
- 125000005647 linker group Chemical group 0.000 claims description 4
- 210000004185 liver Anatomy 0.000 claims description 4
- KIDHWZJUCRJVML-UHFFFAOYSA-N putrescine Chemical compound NCCCCN KIDHWZJUCRJVML-UHFFFAOYSA-N 0.000 claims description 4
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 claims description 3
- GMKMEZVLHJARHF-UHFFFAOYSA-N (2R,6R)-form-2.6-Diaminoheptanedioic acid Natural products OC(=O)C(N)CCCC(N)C(O)=O GMKMEZVLHJARHF-UHFFFAOYSA-N 0.000 claims description 2
- OGNSCSPNOLGXSM-UHFFFAOYSA-N 2,4-diaminobutyric acid Chemical compound NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 claims description 2
- IKHFJPZQZVMLRH-RNFRBKRXSA-N 2-[[[(3r,5r)-3,6-diamino-5-hydroxyhexanoyl]amino]-methylamino]acetic acid Chemical compound OC(=O)CN(C)NC(=O)C[C@H](N)C[C@@H](O)CN IKHFJPZQZVMLRH-RNFRBKRXSA-N 0.000 claims description 2
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 claims description 2
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 claims description 2
- RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline Chemical compound NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 claims description 2
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 claims description 2
- RHGKLRLOHDJJDR-UHFFFAOYSA-N Ndelta-carbamoyl-DL-ornithine Natural products OC(=O)C(N)CCCNC(N)=O RHGKLRLOHDJJDR-UHFFFAOYSA-N 0.000 claims description 2
- 239000005700 Putrescine Substances 0.000 claims description 2
- ZJUKTBDSGOFHSH-WFMPWKQPSA-N S-Adenosylhomocysteine Chemical compound O[C@@H]1[C@H](O)[C@@H](CSCC[C@H](N)C(O)=O)O[C@H]1N1C2=NC=NC(N)=C2N=C1 ZJUKTBDSGOFHSH-WFMPWKQPSA-N 0.000 claims description 2
- MEFKEPWMEQBLKI-AIRLBKTGSA-N S-adenosyl-L-methioninate Chemical compound O[C@@H]1[C@H](O)[C@@H](C[S+](CC[C@H](N)C([O-])=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 MEFKEPWMEQBLKI-AIRLBKTGSA-N 0.000 claims description 2
- 229960001570 ademetionine Drugs 0.000 claims description 2
- 229960001230 asparagine Drugs 0.000 claims description 2
- 235000009582 asparagine Nutrition 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 229960002173 citrulline Drugs 0.000 claims description 2
- 235000013477 citrulline Nutrition 0.000 claims description 2
- OOTFVKOQINZBBF-UHFFFAOYSA-N cystamine Chemical compound CCSSCCN OOTFVKOQINZBBF-UHFFFAOYSA-N 0.000 claims description 2
- 229940099500 cystamine Drugs 0.000 claims description 2
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical compound NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 claims description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 claims description 2
- 229960003151 mercaptamine Drugs 0.000 claims description 2
- GMKMEZVLHJARHF-SYDPRGILSA-N meso-2,6-diaminopimelic acid Chemical compound [O-]C(=O)[C@@H]([NH3+])CCC[C@@H]([NH3+])C([O-])=O GMKMEZVLHJARHF-SYDPRGILSA-N 0.000 claims description 2
- IKHFJPZQZVMLRH-UHFFFAOYSA-N negamycin Natural products OC(=O)CN(C)NC(=O)CC(N)CC(O)CN IKHFJPZQZVMLRH-UHFFFAOYSA-N 0.000 claims description 2
- 210000000232 gallbladder Anatomy 0.000 abstract description 6
- 239000000243 solution Substances 0.000 description 9
- 239000003613 bile acid Substances 0.000 description 7
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 6
- ZUJFMZPBQQCXQR-UHFFFAOYSA-N 5-[[5-carboxy-5-[4-(3,7,12-trihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl)pentanoylamino]pentyl]carbamothioylamino]-2-(3-hydroxy-6-oxoxanthen-9-yl)benzoic acid Chemical compound OC1CC2CC(O)CCC2(C)C(CC(O)C23C)C1C3CCC2C(C)CCC(=O)NC(C(O)=O)CCCCNC(=S)NC1=CC=C(C2=C3C=CC(=O)C=C3OC3=CC(O)=CC=C32)C(C(O)=O)=C1 ZUJFMZPBQQCXQR-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 125000003277 amino group Chemical group 0.000 description 6
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 6
- 208000014674 injury Diseases 0.000 description 6
- 150000003431 steroids Chemical class 0.000 description 6
- 208000027418 Wounds and injury Diseases 0.000 description 5
- 210000003445 biliary tract Anatomy 0.000 description 5
- 238000002192 cholecystectomy Methods 0.000 description 5
- 230000006378 damage Effects 0.000 description 5
- 229940043267 rhodamine b Drugs 0.000 description 5
- RUDATBOHQWOJDD-UHFFFAOYSA-N (3beta,5beta,7alpha)-3,7-Dihydroxycholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 RUDATBOHQWOJDD-UHFFFAOYSA-N 0.000 description 4
- 239000004380 Cholic acid Substances 0.000 description 4
- 229960002471 cholic acid Drugs 0.000 description 4
- 235000019416 cholic acid Nutrition 0.000 description 4
- 238000012800 visualization Methods 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 210000000941 bile Anatomy 0.000 description 3
- 239000003833 bile salt Substances 0.000 description 3
- 238000010253 intravenous injection Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- DKPMWHFRUGMUKF-UHFFFAOYSA-N (3alpha,5alpha,6alpha,7alpha)-3,6,7-Trihydroxycholan-24-oic acid Natural products OC1C(O)C2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 DKPMWHFRUGMUKF-UHFFFAOYSA-N 0.000 description 2
- HULQGYPWEGNXPA-PBDHEXIJSA-N (4r)-4-[(8r,9s,10s,13r,14s,17r)-3-hydroxy-10,13-dimethyl-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoic acid Chemical compound C1CC2CC(O)=CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@@H](CCC(O)=O)C)[C@@]1(C)CC2 HULQGYPWEGNXPA-PBDHEXIJSA-N 0.000 description 2
- JOYGXTIHTHBSOA-UHFFFAOYSA-N 1-(4-chlorophenyl)-3-thiophen-2-ylprop-2-en-1-one Chemical compound C1=CC(Cl)=CC=C1C(=O)C=CC1=CC=CS1 JOYGXTIHTHBSOA-UHFFFAOYSA-N 0.000 description 2
- GKQLYSROISKDLL-UHFFFAOYSA-N EEDQ Chemical compound C1=CC=C2N(C(=O)OCC)C(OCC)C=CC2=C1 GKQLYSROISKDLL-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 108010007979 Glycocholic Acid Proteins 0.000 description 2
- DGABKXLVXPYZII-UHFFFAOYSA-N Hyodeoxycholic acid Natural products C1C(O)C2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 DGABKXLVXPYZII-UHFFFAOYSA-N 0.000 description 2
- SMEROWZSTRWXGI-UHFFFAOYSA-N Lithocholsaeure Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 SMEROWZSTRWXGI-UHFFFAOYSA-N 0.000 description 2
- FTOTVNJFGHCOCZ-UHFFFAOYSA-N Lysine conjugated cholic acid Chemical compound OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NC(CCCCN)C(O)=O)C)C1(C)C(O)C2 FTOTVNJFGHCOCZ-UHFFFAOYSA-N 0.000 description 2
- BHQCQFFYRZLCQQ-PGHAKIONSA-N allocholic acid Chemical compound C([C@@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-PGHAKIONSA-N 0.000 description 2
- DKPMWHFRUGMUKF-GDYCBZMLSA-N alpha-muricholic acid Chemical compound C([C@H]1[C@H](O)[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 DKPMWHFRUGMUKF-GDYCBZMLSA-N 0.000 description 2
- DKPMWHFRUGMUKF-CRKPLTDNSA-N beta-muricholic acid Chemical compound C([C@H]1[C@H](O)[C@@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 DKPMWHFRUGMUKF-CRKPLTDNSA-N 0.000 description 2
- 229940093761 bile salts Drugs 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- RUDATBOHQWOJDD-BSWAIDMHSA-N chenodeoxycholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-BSWAIDMHSA-N 0.000 description 2
- 229960001091 chenodeoxycholic acid Drugs 0.000 description 2
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 2
- 125000003716 cholic acid group Chemical group 0.000 description 2
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 2
- 229960003964 deoxycholic acid Drugs 0.000 description 2
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 2
- SVWLIIFHXFGESG-UHFFFAOYSA-N formic acid;methanol Chemical compound OC.OC=O SVWLIIFHXFGESG-UHFFFAOYSA-N 0.000 description 2
- RFDAIACWWDREDC-FRVQLJSFSA-N glycocholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 RFDAIACWWDREDC-FRVQLJSFSA-N 0.000 description 2
- DGABKXLVXPYZII-SIBKNCMHSA-N hyodeoxycholic acid Chemical compound C([C@H]1[C@@H](O)C2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 DGABKXLVXPYZII-SIBKNCMHSA-N 0.000 description 2
- 239000012948 isocyanate Substances 0.000 description 2
- 150000002513 isocyanates Chemical class 0.000 description 2
- 150000002540 isothiocyanates Chemical class 0.000 description 2
- SMEROWZSTRWXGI-HVATVPOCSA-N lithocholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 SMEROWZSTRWXGI-HVATVPOCSA-N 0.000 description 2
- DKPMWHFRUGMUKF-NTPBNISXSA-N omega-muricholic acid Chemical compound C([C@H]1[C@@H](O)[C@@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 DKPMWHFRUGMUKF-NTPBNISXSA-N 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 2
- RUDATBOHQWOJDD-UZVSRGJWSA-N ursodeoxycholic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-UZVSRGJWSA-N 0.000 description 2
- 229960001661 ursodiol Drugs 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- KHNJPPGHIWPDLG-DXNXUNFASA-N (2s)-6-[(3',6'-dihydroxy-3-oxospiro[2-benzofuran-1,9'-xanthene]-5-yl)carbamothioylamino]-2-[[(4r)-4-[(3r,5s,7r,8r,9s,10s,12s,13r,14s,17r)-3,7,12-trihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]p Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H](C[C@H](O)[C@]13C)[C@@H]2[C@@H]3CC[C@@H]1[C@H](C)CCC(=O)N[C@H](C(O)=O)CCCCNC(=S)NC1=CC=C2C3(C4=CC=C(O)C=C4OC4=CC(O)=CC=C43)OC(=O)C2=C1 KHNJPPGHIWPDLG-DXNXUNFASA-N 0.000 description 1
- CKGCFBNYQJDIGS-UHFFFAOYSA-N 2-azaniumyl-6-(phenylmethoxycarbonylamino)hexanoate Chemical compound OC(=O)C(N)CCCCNC(=O)OCC1=CC=CC=C1 CKGCFBNYQJDIGS-UHFFFAOYSA-N 0.000 description 1
- RPKLZQLYODPWTM-NIRKWIOJSA-N 5alpha-cholanic acid Chemical compound C([C@@H]1CC2)CCC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RPKLZQLYODPWTM-NIRKWIOJSA-N 0.000 description 1
- 208000012260 Accidental injury Diseases 0.000 description 1
- 241000229175 Calotes Species 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- RFDAIACWWDREDC-UHFFFAOYSA-N Na salt-Glycocholic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCC(O)=O)C)C1(C)C(O)C2 RFDAIACWWDREDC-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 208000031481 Pathologic Constriction Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 210000003484 anatomy Anatomy 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000004656 cell transport Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 208000003167 cholangitis Diseases 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 125000001295 dansyl group Chemical group [H]C1=C([H])C(N(C([H])([H])[H])C([H])([H])[H])=C2C([H])=C([H])C([H])=C(C2=C1[H])S(*)(=O)=O 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 229940099347 glycocholic acid Drugs 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- CSJXLKVNKAXFSI-UHFFFAOYSA-N n-(2-aminoethyl)-5-(dimethylamino)naphthalene-1-sulfonamide Chemical compound C1=CC=C2C(N(C)C)=CC=CC2=C1S(=O)(=O)NCCN CSJXLKVNKAXFSI-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 206010034674 peritonitis Diseases 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 238000009901 transfer hydrogenation reaction Methods 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0052—Small organic molecules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
- A61K49/0041—Xanthene dyes, used in vivo, e.g. administered to a mice, e.g. rhodamines, rose Bengal
- A61K49/0043—Fluorescein, used in vivo
Definitions
- This invention relates to the novel use of bile acid derivatives, particularly bile acid derivatives carrying a fluorescent or visibly coloured moiety.
- Fluorescent bile acid probes for use in studying the mechanism of intra ⁇ cellular transport of bile acids have been disclosed by a number of workers, see for example Sherman, I.A. and Fisher, M.M., (1986) Hepatology 6: p 444-449 which discloses the use of glycocholic acid- FITC where the FITC (fluorescein isothiocyanate) moiety is on the 3 ⁇ - hydroxyl group of the steroid nucleus; and Crawford et al, Biochim. Biophys. Acta.
- these fluorescent bile acid derivatives can be used to assist surgeons in visualising the gall bladder and in identifying the existence of biliary leaks during operations, notably cholecystectomy operations.
- Accidental injury to the bile ducts during open cholecystectomy is the most severe complication of this operation with an incidence of one lesion per 300-500 cholecystectomies.
- the present invention is considered to be particularly useful in laparoscopic operations where the real impact of this complication in laparoscopic procedures is still controversial. Some authors believe that the frequency is comparable with, while others believe that it exceeds by up to tenfold, that of an open cholecystectomy.
- Bile duct injury necessitates complex and repeated operations with mortality and morbidity much higher than those of the original procedure.
- a significant long-term morbidity recurrent stricture, cholangitis, cirrhosis, and premature death
- Injuries recognised intraoperatively have much better outcome compared with the extensive morbidity and mortality associates with biliary peritonitis caused by overlooked injuries.
- bile duct injury usually represents failure to identify the anatomic structures in the triangle of Calot. Inability to identify anatomic structures properly is also the cause for conversion to an open procedure from a laparoscopic one, in almost every case.
- the length of the operating time, both laparoscopic and traditional, also depends on quick recognition of subhepatic anatomy.
- a coloured or fluorescent hepatobiliary targeting compound in the manufacture of an administrable composition for visualising the bile duct and/or visualising biliary leakage during an operation in the region of the bile duct.
- a method of visualising the bile duct and/or visualising biliary leakage comprising administering to a patient an effective amount of a coloured or fluorescent hepatobiliary targeting compound
- the coloured or fluorescent hepatobiliary targeting compound is most preferably a fluorescent compound, most preferably a UV light fluorescent compound.
- the compound preferably comprises a steroid moiety having an unblocked 3-hydroxyl substituent and an unblocked carboxyl group attached by means of an amide linkage to the side chain of the steroid moiety, and an active moiety which is to be targeted to the liver, said active moiety being attached to the ⁇ -carbon atom relative to the unblocked carboxyl group.
- said compound has the general formula ( I ):-
- D is -H, - ⁇ OH or - ⁇ OH;
- E is -H, - ⁇ OH or ⁇ -OH;
- L is a linking moiety;
- J is said coloured or fluorescent moiety; and
- n is 0 or 1.
- J is or includes a fluorescein, rhodamine or other fluorescing moiety.
- the linking moiety is preferably N-terminated at its end attached to active moiety J, and L may be:-
- the moiety -NH-CH(COOH)-L- may be derived from S- adenosylhomocysteine, S-adenosyl methionine, S-amino-imadazole-4- carboxamide, asparagine, cadaverine, cystamine, citrulline, diaminopimelic acid, 2, 4-diaminobutyric acid, cysteamine, glutamine, 3-hydroxykynurenine, kynurenine, putrescine or negamycin.
- acidic amino acids can be used instead of the above where active moiety J has one amino group and/or is hydrophobic.
- the steroid moiety is preferably a bile acid moiety based on cholic acid, chenodeoxycholic acid, deoxycholic acid, hyodeoxycholic acid, hyocholic acid, ⁇ -, ⁇ - or w-muricholic acid, nor-bile acids, lithocholic acid, 3 ⁇ -hydroxycholenoic acid, ursodeoxycholic acid, allocholic acid (5 ⁇ -cholan-24-oic-acid), or the like, hereinafter simply referred to as "a bile acid moiety".
- the compounds preferably used in the present invention can be produced by the steps of (a) reacting a steroid moiety having an unblocked 3-hydroxyl group and a side chain carboxyl group, with the ⁇ - amino group of an amino acid having a blocked amino group in the side chain, preferably at the ⁇ or ⁇ position relative to the carboxyl group to form an amide, (b) unblocking said blocked amine group, and (c) reacting the unblocked amine group with the active moiety, preferably an isocyanate or isothiocyanate derivative thereof.
- the active moiety or preferably an isocyanate or isothiocyanate derivative thereof, is reacted with a side chain amino group of an amino acid having a blocked ⁇ -amino group, and the blocked ⁇ -amino group is unblocked and then reacted with the side chain carboxyl group of the steroid moiety.
- the active moiety has a carboxyl group and an amino group
- the latter is reacted directly with the side chain carboxyl group of the steriod moiety.
- the bile acid moiety is cholic acid
- the above described reaction produces a moiety based on glycocholic acid, which is another bile acid.
- the solution was heated on the steam bath for 15 minutes and then evaporated in vacuo to half its original volume. After diluting the solution with 20 ml of water, it was acidified with 0.5m HCl. The precipitate was collected and washed with water to obtain cholyl-N- ⁇ -CBZ-L-lysine.
- the cholyl-lysine- CBZ was subjected to catalytic transfer hydrogenation by dissolving about 200 mg of cholyl-lysine-CBZ in 10ml of 4.4% formic acid- methanol, adding to a 25ml flask containing 200 mg of palladium black and 10 ml of 4.4% formic acid-methanol, and then stirring the mixture under a nitrogen atmosphere ovemight.
- the solution was evaporated to dryness at 40 ⁇ C and then triturated with ethyl acetate to obtain cholyl- lysine formate.
- the sodium salt was obtained by dissolving the formate salt in 5ml of a 0.1 M NaOH solution in methanol and precipitating with diethyl ether. 50mg of the sodium salt of cholyl-lysine obtained was then dissolved in 5ml of bicarbonate buffer (pH 9). 28mg of fluorescein solution in bicarbonate buffer (5ml) were added and the reagents stirred at rom temperature for 18 hours. Free fluorescein was removed by percolating cholyl-lysyl-fluorescein through Sep-Pak C 18 cartridges. Further purification was by thin layer chromatography to obtain homogenous cholyl-lysl-fluorescein of the formula:-
- Rhodamine B can also be attached to a bile salt-lysine conjugate in an analogous manner.
- R cholic acid, chenodeoxycholic acid, deoxycholic acid, hyodeoxycholic acid, hyocholic acid, ⁇ -, ⁇ - or ⁇ -muricholic acid, nor-bile acids, lithocholic acid, 3 ⁇ -hydroxy-cholenoic acid, ursodeoxycholic acid, or allocholic acid.
- Intraoperative imaging of the biliary tree with cholyl-lysyl-fluorescein (CLF) in animals has been studied and found to be extremely easy and simple to perform, involving an ordinary intravenous injection and the exposure of the hepatic region to the light of a Wood lamp (or other source of UV light).
- the fluorescein intensity was maximal after about 3 minutes and enabled excellent visualization of the entire biliary tree including the gall bladder which shined for the whole time of observation (20 min) and persisted much longer than the experimental observation limit (up to 45 min).
- an intravenous injection of between about 0.5 and 2mg of CLF per kilogram body weight is sufficient for effective visualisation of the biliary tree including the gallbladder.
- the fluorescent compound has been transported to the liver and from thence to the bile duct in a sufficient quantity to enable it to be readily discerned under UV light through the wall of the bile duct and continues to be visible for at least 45 minutes thereafter.
- the surgeon illuminates the surgical site with UV light in addition to visible light at least over the critical operation phase when it is important to be able to discern the biliary duct from the surrounding tissue.
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9517043.7A GB9517043D0 (en) | 1995-08-19 | 1995-08-19 | The use of bile acid derivatives |
| GB9517043 | 1995-08-19 | ||
| PCT/GB1996/002027 WO1997006829A1 (en) | 1995-08-19 | 1996-08-19 | The use of bile acid derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0844890A1 true EP0844890A1 (de) | 1998-06-03 |
Family
ID=10779505
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP96928517A Withdrawn EP0844890A1 (de) | 1995-08-19 | 1996-08-19 | Verwendung von gallensäurederivaten |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0844890A1 (de) |
| JP (1) | JP2000506491A (de) |
| CA (1) | CA2229530A1 (de) |
| GB (1) | GB9517043D0 (de) |
| WO (1) | WO1997006829A1 (de) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5928625A (en) | 1997-03-13 | 1999-07-27 | Mallinckrodt Inc. | Method of measuring physiological function |
| US6228344B1 (en) | 1997-03-13 | 2001-05-08 | Mallinckrodt Inc. | Method of measuring physiological function |
| US6280703B1 (en) | 1997-03-13 | 2001-08-28 | Mallinckrodt Inc. | Simultaneous multimodal measurement of physiological function |
| GB9716962D0 (en) * | 1997-08-12 | 1997-10-15 | Univ Birmingham | Liver function test |
| GB0019593D0 (en) * | 2000-08-10 | 2000-09-27 | Norgine Europe Bv | Production of bile acid derivatives |
| FR2889700B1 (fr) * | 2005-08-11 | 2012-11-23 | Synthinnove Lab | Marqueurs, leur procede de fabrication et leurs applications |
| EP2099498A2 (de) * | 2006-11-21 | 2009-09-16 | Mallinckrodt Inc. | Verfahren zur verwendung von optischen mitteln |
| JP5229700B2 (ja) * | 2007-04-19 | 2013-07-03 | 国立大学法人群馬大学 | 新規蛍光化合物およびそれを用いた細胞内コレステロールの検出方法 |
| GB0808777D0 (en) | 2008-05-15 | 2008-06-18 | Norgine Bv | Prognostic method |
| GB2467902A (en) * | 2009-02-12 | 2010-08-18 | Norgine Bv | Preparation of Cholyl-L-lysine from N-E-CBZ-cholyl-L-lysine |
| CN106749473B (zh) * | 2017-01-13 | 2018-08-17 | 常德云港生物科技有限公司 | 一种从鸭胆汁中提取鹅去氧胆酸和别胆酸的方法 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4264514A (en) * | 1977-11-14 | 1981-04-28 | Abbott Laboratories | Method and reagents for measuring the level of conjugated bile acids |
| US4848349A (en) * | 1987-04-29 | 1989-07-18 | Sherman Igor A | Substance and method for measuring hepatic blood flow |
-
1995
- 1995-08-19 GB GBGB9517043.7A patent/GB9517043D0/en active Pending
-
1996
- 1996-08-19 WO PCT/GB1996/002027 patent/WO1997006829A1/en not_active Application Discontinuation
- 1996-08-19 CA CA 2229530 patent/CA2229530A1/en not_active Abandoned
- 1996-08-19 EP EP96928517A patent/EP0844890A1/de not_active Withdrawn
- 1996-08-19 JP JP9509075A patent/JP2000506491A/ja active Pending
Non-Patent Citations (1)
| Title |
|---|
| See references of WO9706829A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1997006829A1 (en) | 1997-02-27 |
| JP2000506491A (ja) | 2000-05-30 |
| CA2229530A1 (en) | 1997-02-27 |
| GB9517043D0 (en) | 1995-10-25 |
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