CN114478493B - Traceable 5-aminosalicylic acid derivative and preparation and application thereof - Google Patents
Traceable 5-aminosalicylic acid derivative and preparation and application thereof Download PDFInfo
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- CN114478493B CN114478493B CN202210099761.1A CN202210099761A CN114478493B CN 114478493 B CN114478493 B CN 114478493B CN 202210099761 A CN202210099761 A CN 202210099761A CN 114478493 B CN114478493 B CN 114478493B
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- aminosalicylic acid
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- KBOPZPXVLCULAV-UHFFFAOYSA-N mesalamine Chemical class NC1=CC=C(O)C(C(O)=O)=C1 KBOPZPXVLCULAV-UHFFFAOYSA-N 0.000 title claims abstract description 53
- 238000002360 preparation method Methods 0.000 title claims description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- 239000003814 drug Substances 0.000 claims abstract description 19
- 102100022365 NAD(P)H dehydrogenase [quinone] 1 Human genes 0.000 claims abstract description 12
- 108010066657 azoreductase Proteins 0.000 claims abstract description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 20
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 18
- 239000000523 sample Substances 0.000 claims description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 10
- 235000010288 sodium nitrite Nutrition 0.000 claims description 10
- 229940079593 drug Drugs 0.000 claims description 9
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 9
- 229960004889 salicylic acid Drugs 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 206010009887 colitis Diseases 0.000 claims description 5
- 238000004440 column chromatography Methods 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 239000012044 organic layer Substances 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 229910002651 NO3 Inorganic materials 0.000 claims description 4
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 4
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical group 0.000 claims description 4
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- -1 sulfonic group Chemical group 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- ALRHLSYJTWAHJZ-UHFFFAOYSA-N 3-hydroxypropionic acid Chemical compound OCCC(O)=O ALRHLSYJTWAHJZ-UHFFFAOYSA-N 0.000 claims description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 2
- 238000007865 diluting Methods 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 2
- BRGRTVOPAYSOKK-UHFFFAOYSA-N 4-aminobenzenesulfonohydrazide Chemical compound NNS(=O)(=O)C1=CC=C(N)C=C1 BRGRTVOPAYSOKK-UHFFFAOYSA-N 0.000 claims 1
- 208000004232 Enteritis Diseases 0.000 claims 1
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical compound NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 claims 1
- 229960004963 mesalazine Drugs 0.000 abstract description 25
- 230000009471 action Effects 0.000 abstract description 6
- 239000007850 fluorescent dye Substances 0.000 abstract description 4
- 238000012544 monitoring process Methods 0.000 abstract description 4
- 230000000112 colonic effect Effects 0.000 abstract description 3
- 238000001514 detection method Methods 0.000 abstract description 3
- 238000002474 experimental method Methods 0.000 abstract description 3
- 230000010354 integration Effects 0.000 abstract description 2
- 230000001737 promoting effect Effects 0.000 abstract description 2
- 230000000007 visual effect Effects 0.000 abstract description 2
- 210000004953 colonic tissue Anatomy 0.000 abstract 1
- 229940125890 compound Ia Drugs 0.000 description 19
- 206010009900 Colitis ulcerative Diseases 0.000 description 17
- 201000006704 Ulcerative Colitis Diseases 0.000 description 17
- 230000000694 effects Effects 0.000 description 13
- 210000001072 colon Anatomy 0.000 description 10
- 238000000799 fluorescence microscopy Methods 0.000 description 9
- 238000001727 in vivo Methods 0.000 description 9
- 241000699670 Mus sp. Species 0.000 description 8
- 230000000767 anti-ulcer Effects 0.000 description 8
- 210000001519 tissue Anatomy 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- 229940002612 prodrug Drugs 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000012632 fluorescent imaging Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 229940124530 sulfonamide Drugs 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000012954 diazonium Substances 0.000 description 3
- 150000001989 diazonium salts Chemical class 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 3
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 238000012449 Kunming mouse Methods 0.000 description 2
- 210000001015 abdomen Anatomy 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000003304 gavage Methods 0.000 description 2
- 150000002431 hydrogen Chemical group 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 210000004876 tela submucosa Anatomy 0.000 description 2
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- UETNIIAIRMUTSM-UHFFFAOYSA-N Jacareubin Natural products CC1(C)OC2=CC3Oc4c(O)c(O)ccc4C(=O)C3C(=C2C=C1)O UETNIIAIRMUTSM-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 208000027503 bloody stool Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229920003045 dextran sodium sulfate Polymers 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 238000001917 fluorescence detection Methods 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 208000035861 hematochezia Diseases 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 239000012216 imaging agent Substances 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 230000005865 ionizing radiation Effects 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- QQBDLJCYGRGAKP-FOCLMDBBSA-N olsalazine Chemical compound C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=C(C(O)=CC=2)C(O)=O)=C1 QQBDLJCYGRGAKP-FOCLMDBBSA-N 0.000 description 1
- 229960004110 olsalazine Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- NCEXYHBECQHGNR-QZQOTICOSA-N sulfasalazine Chemical compound C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-QZQOTICOSA-N 0.000 description 1
- 229960001940 sulfasalazine Drugs 0.000 description 1
- NCEXYHBECQHGNR-UHFFFAOYSA-N sulfasalazine Natural products C1=C(O)C(C(=O)O)=CC(N=NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-UHFFFAOYSA-N 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/655—Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
-
- 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
- A61K49/0032—Methine dyes, e.g. cyanine dyes
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Biomedical Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention discloses a traceable 5-aminosalicylic acid derivative, which is formed by connecting 5-aminosalicylic acid with a near infrared fluorescent probe through an azo bond. Experiments show that the compound breaks azo bonds under the action of azo reductase secreted by colonic flora, releases anti-colonitis medicaments 5-aminosalicylic acid and a semi-near infrared fluorescent probe, realizes the integration of targeted release and fluorescence monitoring of 5-aminosalicylic acid in colonic tissues, has important significance for promoting accurate and personalized treatment of colonitis, and has potential application value in the fields of targeted medicament delivery release and visual detection.
Description
Technical Field
The invention relates to a 5-aminosalicylic acid derivative, in particular to a traceable 5-aminosalicylic acid derivative and a preparation method thereof; the invention also realizes accurate and personalized treatment of the colitis through the anti-colitis activity and fluorescence imaging performance analysis of the 5-aminosalicylic acid derivative, and belongs to the fields of compound synthesis and biological medicine.
Technical Field
Ulcerative colitis (Ulcerative colitis, UC) is a chronic disease with high incidence and high recurrence rate, and the main clinical symptoms are abdominal pain, diarrhea, mucous bloody stool, etc. 5-Aminosalicylic acid (5-Amino salicylic acid, 5-ASA), commercially available under the name mesalamineIs a first-line medicine for treating ulcerative colitis clinically at present. The 5-ASA has been used for treating the light ulcerative colitis for more than 30 years, and has the characteristics of good curative effect, high tolerance and the like. The 5-ASA has poor oral targeting, only a small amount of medicine can reach colorectal, so that the treatment effect is reduced, and serious adverse reactions are caused. The azo reductase produced by colonic bacteria is utilized to design and prepare the 5-ASA prodrug containing azo bonds, thus realizing the targeted release of the 5-ASA drug in colon. There are a number of azo reductase-responsive 5-ASA prodrugs currently in clinical use. For example, sulfasalazine can activate and release active drugs 5-ASA and sulfanilamide under the action of colon azo reductase, so as to realize targeted treatment of ulcerative colitis; olsalazine can release 5-ASA for use in the treatment of colitis by the action of azo reductase. (Vermilion, etc., journal of clinical medicine treatment, 2014, 12, 9-14；Ryan A.,Brit.J. Pharmacol., 2017, 174, 2161-2173）
ulcerative colitis can cause unbalanced intestinal flora, so that the individual variability of azo reductase-responsive 5-ASA prodrugs in the processes of in vivo activation, release and the like is large, and the curative effect is seriously affected. Real-time and accurate tracking of 5-ASA targeted drug release processes and biodistribution is an azo reductase responsive 5-ASA prodrug which is urgent to solve the core problem. The fluorescent imaging technology has the advantages of high imaging speed, high sensitivity, no ionizing radiation and the like, can realize real-time and nondestructive detection of drug absorption, distribution and metabolism signals in living bodies, and has wide application prospect in the field of accurate monitoring of drugsWang Shaojing, etc., chinese journal of new drugs, 2014, 23, 1398-1401; Yuan L., et al.J. Am. Chem. Soc. 2012, 134, 13510-13523). The development of novel azo reductase responsive 5-ASA prodrugs, the real-time monitoring of the active drug 5-ASA in vivo by utilizing a fluorescence imaging technology, and the method has important significance for accurate and personalized treatment of ulcerative colitis.
Disclosure of Invention
The invention aims to design and synthesize a traceable 5-aminosalicylic acid derivative;
another object of the present invention is to provide a process for the preparation of the aforementioned traceable 5-aminosalicylic acid derivative;
it is a further object of the present invention to provide specific applications of the aforementioned traceable 5-aminosalicylic acid derivatives as fluorescence imaging agents and targeted release in colon tissue.
1. Traceable 5-aminosalicylic acid derivatives
The structural formula of the traceable 5-aminosalicylic acid derivative is shown as the following formula:
wherein: n is independently selected from integers of 1 to 10; the substituent R is selected from hydrogen, methyl, carboxyl, sulfonic group, hydroxyl, halogen and amino. X is X - Selected from iodide, bromide, chloride, nitrate, sulfate, carbonate, sulfite.
The preparation of the traceable 5-aminosalicylic acid derivative comprises the steps of dissolving a near infrared probe compound into an organic solution, adding acid and sodium nitrite, stirring and reacting for 20-30 min, adding sulfanilamide, stirring for 15-20 min, adding salicylic acid, and reacting for 0.5-15 h at 0-60 ℃; diluting with water after the reaction, extracting with dichloromethane, collecting an organic layer, drying, concentrating under reduced pressure, and separating by column chromatography to obtain the target compound.
The synthesis of the near infrared probe compound is described in the literatureZhaoX. B., et al. Anal. Chem. 2021, 93, 45, 15080; Ha W., et al. ACS Appl. Mater. Interfaces 2018, 10, 21149). Compared with the conventional fluorescence detection, the near infrared probe compound has deeper tissue penetration depth and smaller damage to biological tissues, so that the application prospect is wider. The structural formula of the near infrared probe compound is shown as the following formula:
wherein:n is independently selected from integers of 1 to 10; the substituent R is selected from hydrogen, methyl, carboxyl, sulfonic group, hydroxyl, halogen and amino. X is X - Selected from iodide, bromide, chloride, nitrate, sulfate, carbonate, sulfite.
The organic solvent is at least one of tetrahydrofuran, acetonitrile, dimethyl sulfoxide, N-dimethylformamide, methanol, dichloromethane, benzene, toluene, xylene, chlorobenzene, chloroform, petroleum ether, ethanol, dioxane, ethylamine, hydroxypropionic acid, ethylenediamine, glycerol, diglyme, pyridine, acetone and hexamethylphosphoramide.
The acid is at least one of trifluoroacetic acid, hydrochloric acid and nitric acid. The purpose of adding the acid environment is to provide an acid environment for the reaction, and the molar ratio of the near infrared probe compound to the acid is 1:1-1:5.
Sodium nitrite is an important reaction raw material for synthesizing target compounds; the molar ratio of the near infrared probe compound to the sodium nitrite is 1:0.5-1:5. And diazotizing sodium nitrite and the near infrared probe compound in an acidic environment to generate a corresponding near infrared probe diazonium salt intermediate. The structural formula of the near infrared probe diazonium salt intermediate is shown as the following formula:
。
the sulfonamide is added to consume sodium nitrite which is not completely reacted; the molar ratio of the near infrared probe compound to the sulfanilamide is 1:1-1:5.
Salicylic acid is also an important reaction raw material for synthesizing target compounds; the molar ratio of the near infrared probe compound to salicylic acid is 1:0.5-1:5. And (3) performing a coupling reaction on salicylic acid and the near infrared probe diazonium salt intermediate to generate a traceable 5-aminosalicylic acid derivative.
The synthesis formula of the traceable 5-aminosalicylic acid derivative is as follows:
the traceable 5-aminosalicylic acid derivative is prepared by connecting a therapeutic drug 5-aminosalicylic acid with a near infrared fluorescent probe reagent through an azo bond. The azo bond of the compound with the structure is broken under the action of azo reductase secreted by colonic flora, 5-aminosalicylic acid serving as an anti-colonitis drug is released, and meanwhile, the released hemicyanine near infrared fluorescent reagent has strong absorption and emission performance in a near infrared region, and the in vivo fluorescent imaging is facilitated to be realized by utilizing the strong penetrability of near infrared.
2. Traceable 5-aminosalicylic acid derivatives against ulcerative colitis activity
Taking the compound Ia prepared in the example 1 of the invention as an example, the anti-ulcerative colitis activity of the 5-aminosalicylic acid derivative synthesized by the invention is illustrated by an in vivo anti-ulcerative colitis experiment and analyzed.
Standard body weight Kunming mice were fed with drinking water containing 3.5% dextran sodium sulfate (w/v, MW 36-50 kDa) for 7 days, and then respectively gavaged with physiological saline (indicated as blank) and compound Ia solution (indicated as dosing group) 1 time daily for 10 consecutive days. After 14 days of gavage, the mice were sacrificed and the colon was dissected. Dissected colon tissue was fixed with 4% formalin solution and paraffin embedded. Cut to a thickness of 5 microns, stained with H & E kit and observed with an optical microscope.
Fig. 3 is a graph of the anti-ulcerative colitis activity of compound Ia. Fig. 3 shows that colon tissue mucosal layer intestinal glands and mucosal epithelial cells of the mice in the blank group disappear, a large amount of connective tissue hyperplasia is visible, the injury invades and submucosa is visible, more inflammatory cell infiltration is visible in the mucosal layer and submucosa, lymphocytes, granulocytes and the like, and the ulcerative colitis model mice are successfully established. The colon tissue of the mice of the administration group only has local ulcers, and has certain protection effect on colon tissue inflammation and the integrity of the crypt structure of the mice, thus showing good anti-ulcerative colitis activity. Therefore, the method can be used for preparing the anti-ulcerative colitis medicine.
3. Traceable fluorescent imaging properties of 5-aminosalicylic acid derivatives
Taking the compound Ia prepared in the example 1 of the invention as an example, the fluorescent imaging of the synthesized 5-aminosalicylic acid derivative of the invention was analyzed.
Standard body weight Kunming mice were gavaged with 0.2 ml of compound Ia solution and fluorescence imaged using a small animal in vivo fluorescence imager, and imaging results were recorded before (labeled Pro) and after 12 hours of gavage.
FIG. 4 is a diagram of in vivo fluorescence imaging of compound Ia in mice. Fig. 4 shows that there is no apparent fluorescent signal on the abdomen of the mice prior to lavage, indicating that the background fluorescence interference of the mice is less. In contrast, after 12 hours of intragastric administration, a significant fluorescent signal appears in the abdomen, since compound Ia breaks down the azo bond by the action of the azo reductase in vivo, releasing the fluorescent reagent, and thus generating a fluorescent signal. Thus, compound Ia can be used for fluorescence imaging analysis of 5-ASA drug release in colon.
Experiments show that other 5-aminosalicylic acid derivatives provided by the application can break azo bonds under the action of in vivo azo reductase, release anti-colonitis medicaments 5-aminosalicylic acid and semi-near infrared fluorescent probes, realize the integration of targeted release and fluorescence monitoring of 5-aminosalicylic acid in colon tissues, have important significance for promoting accurate and personalized treatment of colonitis, and have potential application value in the fields of targeted medicament delivery release and visual detection.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of compound Ia.
FIG. 2 is a nuclear magnetic resonance carbon spectrum of the compound Ia.
Fig. 3 is a graph of the anti-ulcerative colitis activity of compound Ia.
FIG. 4 is a diagram of in vivo fluorescence imaging of compound Ia in mice.
Detailed Description
The preparation of 5-aminosalicylic acid derivatives, anti-colitis activity and fluorescence imaging properties according to the invention are further illustrated by the following examples.
Example 1: preparation of Compound Ia
Compound 3 (1 mmol) was dissolved in 5 ml acetonitrile/dichloromethane (1/4 volume ratio) containing 1% trifluoroacetic acid, sodium nitrite (1.2 mmol) was added at 0 ℃ and stirred for 0.5 hours, sulfamic acid (1.2 mmol) was added and stirred for 15 minutes, and finally salicylic acid (3 mmol) was added; the resulting mixture was then stirred at 5 ℃ for 5 hours, diluted with water and extracted with dichloromethane; the organic layer was collected, dried, concentrated under reduced pressure and separated by column chromatography to give compound Ia. Of compound Ia 1 H NMR 13 The C NMR data are shown in FIGS. 1 and 2. 1 H NMR （400 MHz, CDCl 3 -CD 3 OD）: δ 8.78 （d, J=14.4 Hz, 1H）, 8.59 （s, 1H）, 8.08 （d, J=8.8 Hz, 1H）, 7.86 （d, J=8.0 Hz, 1H）, 7.74 （s, 1H）, 7.50-7.62 （m, 5H）. 7.31 （s, 1H）, 7.08 （d, J=8.8 Hz, 1H）, 6.49 （d, J=15.6 Hz, 1H）, 5.35 （s, 1H）, 3.93 （s, 3H）, 2.73-7.85 （m, 4H）, 2.01 （s, 2H）, 1.90 （s, 3H）. 13 C NMR （100 MHz, CDCl 3 -CD 3 OD）: δ178.7, 160.9, 154.2, 153.2, 146.5, 145.2, 141.8, 132.4, 131.2, 129.4, 128.2, 123.5, 122.5, 121.0, 115.4, 112.8, 108.7, 104.9, 32.6, 29.4, 27.9, 24.0, 20.1。
The synthetic formula of compound Ia is as follows:
the anti-ulcerative colitis activity and fluorescence imaging properties of compound Ia are shown in figures 3, 4.
Example 2: preparation of Compound Ia
Compound 3 (1 mmol) was dissolved in 5 mL of tetrahydrofuran containing 1% trifluoroacetic acid, sodium nitrite (1.2 mmol) was added at 0deg.C and stirred for 0.5 hours, followed by sulfamic acid (1.2 mmol) and stirred for 15 minutes. Finally salicylic acid (15 mmol) was added; the resulting mixture was stirred at 25 ℃ for 15 hours, diluted with water and extracted with dichloromethane; the organic layer was collected, dried, concentrated under reduced pressure and separated by column chromatography to give compound Ia.
Example 3: preparation of Compound Ib
Compound 4 (1 mmol) was dissolved in 5 mL acetonitrile/chloroform (2/3, volume ratio) containing 1% trifluoroacetic acid, sodium nitrite (1.2 mmol) was added at 0deg.C and stirred for 0.5 hours; sulfamic acid (1.2 mmol) was then added and stirred for 15 minutes; finally salicylic acid (0.5 mmol) was added and the resulting mixture stirred at 50 ℃ for 1 hour, diluted with water and extracted with dichloromethane; the organic layer was collected, dried, concentrated under reduced pressure and separated by column chromatography to give compound Ib. The synthesis formula is as follows:
the anti-ulcerative colitis activity and fluorescence imaging properties of compound Ib are similar to those of figures 3 and 4.
Claims (9)
1. A traceable 5-aminosalicylic acid derivative having the structural formula:
wherein: n is independently selected from integers of 1 to 10; the substituent R is independently selected from hydrogen, methyl, carboxyl, sulfonic group, hydroxyl, halogen and amino; x is X - Selected from iodide, bromide, chloride, nitrate, sulfate, carbonate, sulfite.
2. The method for preparing the traceable 5-aminosalicylic acid derivative according to claim 1, wherein a near infrared probe compound is dissolved in an organic solvent, acid and sodium nitrite are added, stirring reaction is carried out for 20-30 min, sulfamide is added, stirring is carried out for 15-20 min, salicylic acid is added, and reaction is carried out for 0.5-15 h at 0-60 ℃; diluting with water after the reaction, extracting with dichloromethane, collecting an organic layer, drying, concentrating under reduced pressure, and separating by column chromatography to obtain a target compound; the structural formula of the near infrared probe compound is shown as follows:
wherein: n is independently selected from integers of 1 to 10; the substituent R is selected from hydrogen, methyl, carboxyl, sulfonic group, hydroxyl, halogen and amino; x is X - Selected from iodide, bromide, chloride, nitrate, sulfate, carbonate, sulfite.
3. A process for the preparation of a traceable 5-aminosalicylic acid derivative according to claim 2 wherein: the organic solvent is at least one of tetrahydrofuran, acetonitrile, dimethyl sulfoxide, N-dimethylformamide, methanol, dichloromethane, benzene, toluene, xylene, chlorobenzene, chloroform, petroleum ether, ethanol, dioxane, ethylamine, hydroxypropionic acid, ethylenediamine, glycerol, diglyme, pyridine, acetone and hexamethylphosphoramide.
4. A process for the preparation of a traceable 5-aminosalicylic acid derivative according to claim 2 wherein: the acid is at least one of trifluoroacetic acid, hydrochloric acid and nitric acid; the molar ratio of the near infrared probe compound to the acid is 1:1-1:5.
5. A process for the preparation of a traceable 5-aminosalicylic acid derivative according to claim 2 wherein: the molar ratio of the near infrared probe compound to the sodium nitrite is 1:0.5-1:5.
6. A process for the preparation of a traceable 5-aminosalicylic acid derivative according to claim 2 wherein: the molar ratio of the near infrared probe compound to the amino sulfanilamide is 1:1-1:5.
7. A process for the preparation of a traceable 5-aminosalicylic acid derivative according to claim 2 wherein: the molar ratio of the near infrared probe compound to salicylic acid is 1:0.5-1:5.
8. Use of a traceable 5-aminosalicylic acid derivative according to claim 1 for visually detecting or tracking the release of enteritis drugs by azo reductase.
9. Use of a traceable 5-aminosalicylic acid derivative according to claim 1 for the preparation of an anti-colitis drug.
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