CN115477656A - Dioxane-tetrahydro carboline-3-formylamino acid with P-selectin as target and preparation and application thereof - Google Patents
Dioxane-tetrahydro carboline-3-formylamino acid with P-selectin as target and preparation and application thereof Download PDFInfo
- Publication number
- CN115477656A CN115477656A CN202110665598.6A CN202110665598A CN115477656A CN 115477656 A CN115477656 A CN 115477656A CN 202110665598 A CN202110665598 A CN 202110665598A CN 115477656 A CN115477656 A CN 115477656A
- Authority
- CN
- China
- Prior art keywords
- residue
- carboline
- tetrahydro
- beta
- formyl
- 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.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims description 24
- 108010035766 P-Selectin Proteins 0.000 title abstract description 13
- 102000008212 P-Selectin Human genes 0.000 title abstract description 13
- 239000002253 acid Substances 0.000 title description 2
- 206010003178 Arterial thrombosis Diseases 0.000 claims abstract description 9
- 125000003412 L-alanyl group Chemical group [H]N([H])[C@@](C([H])([H])[H])(C(=O)[*])[H] 0.000 claims abstract description 8
- 239000003814 drug Substances 0.000 claims abstract description 8
- 125000002061 L-isoleucyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])[C@](C([H])([H])[H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims abstract description 7
- 125000003440 L-leucyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C(C([H])([H])[H])([H])C([H])([H])[H] 0.000 claims abstract description 7
- 125000003580 L-valyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(C([H])([H])[H])(C([H])([H])[H])[H] 0.000 claims abstract description 7
- 125000000393 L-methionino group Chemical group [H]OC(=O)[C@@]([H])(N([H])[*])C([H])([H])C(SC([H])([H])[H])([H])[H] 0.000 claims abstract description 6
- 125000002435 L-phenylalanyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims abstract description 6
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 0.000 claims abstract description 6
- 125000002707 L-tryptophyl group Chemical group [H]C1=C([H])C([H])=C2C(C([C@](N([H])[H])(C(=O)[*])[H])([H])[H])=C([H])N([H])C2=C1[H] 0.000 claims abstract description 6
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 239000007791 liquid phase Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000002260 anti-inflammatory agent Substances 0.000 claims 1
- 229940121363 anti-inflammatory agent Drugs 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 34
- 230000000694 effects Effects 0.000 abstract description 8
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 7
- 150000003862 amino acid derivatives Chemical class 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 20
- 239000000243 solution Substances 0.000 description 20
- 239000000843 powder Substances 0.000 description 19
- 238000002474 experimental method Methods 0.000 description 16
- 229920006395 saturated elastomer Polymers 0.000 description 14
- 229940126214 compound 3 Drugs 0.000 description 13
- 239000011780 sodium chloride Substances 0.000 description 12
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 11
- 241000699670 Mus sp. Species 0.000 description 10
- 241000700159 Rattus Species 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 208000007536 Thrombosis Diseases 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 238000004252 FT/ICR mass spectrometry Methods 0.000 description 8
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 6
- CRNAHTYRYIFFAZ-UHFFFAOYSA-N OC(C(C1=C(C2)C3=CC=CC=C3N1)NC2C(OCC1=CC=CC=C1)=O)O Chemical compound OC(C(C1=C(C2)C3=CC=CC=C3N1)NC2C(OCC1=CC=CC=C1)=O)O CRNAHTYRYIFFAZ-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000003032 molecular docking Methods 0.000 description 6
- 208000024172 Cardiovascular disease Diseases 0.000 description 5
- 206010014025 Ear swelling Diseases 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 230000008034 disappearance Effects 0.000 description 5
- 210000005069 ears Anatomy 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 230000004054 inflammatory process Effects 0.000 description 5
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical group CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 4
- 102000003886 Glycoproteins Human genes 0.000 description 4
- 108090000288 Glycoproteins Proteins 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 4
- 102000004889 Interleukin-6 Human genes 0.000 description 4
- 108090001005 Interleukin-6 Proteins 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 4
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 4
- 210000001367 artery Anatomy 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 229940100601 interleukin-6 Drugs 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229960001138 acetylsalicylic acid Drugs 0.000 description 3
- 210000004204 blood vessel Anatomy 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229960002897 heparin Drugs 0.000 description 3
- 229920000669 heparin Polymers 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 230000001732 thrombotic effect Effects 0.000 description 3
- 208000036490 Arterial inflammations Diseases 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical group CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 2
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical group CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 238000010936 aqueous wash Methods 0.000 description 2
- TYQYRKDGHAPZRF-INIZCTEOSA-N benzyl (2s)-2-amino-3-(1h-indol-3-yl)propanoate Chemical compound O=C([C@H](CC=1C2=CC=CC=C2NC=1)N)OCC1=CC=CC=C1 TYQYRKDGHAPZRF-INIZCTEOSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- RXKJFZQQPQGTFL-UHFFFAOYSA-N dihydroxyacetone Chemical compound OCC(=O)CO RXKJFZQQPQGTFL-UHFFFAOYSA-N 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 229960000310 isoleucine Drugs 0.000 description 2
- 210000004731 jugular vein Anatomy 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- CRSOQBOWXPBRES-UHFFFAOYSA-N neopentane Chemical compound CC(C)(C)C CRSOQBOWXPBRES-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- -1 polyethylene Polymers 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 238000002627 tracheal intubation Methods 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- QOLHWXNSCZGWHK-BWBORTOCSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecylcarbamoyloxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OC(=O)NCCCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 QOLHWXNSCZGWHK-BWBORTOCSA-N 0.000 description 1
- 229940126559 Compound 4e Drugs 0.000 description 1
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 229920002449 FKM Polymers 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- QNAYBMKLOCPYGJ-UWTATZPHSA-N L-Alanine Natural products C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 description 1
- JTTHKOPSMAVJFE-VIFPVBQESA-N L-homophenylalanine Chemical compound OC(=O)[C@@H](N)CCC1=CC=CC=C1 JTTHKOPSMAVJFE-VIFPVBQESA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical group CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- 229930182844 L-isoleucine Chemical group 0.000 description 1
- 239000004395 L-leucine Chemical group 0.000 description 1
- 235000019454 L-leucine Nutrition 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 240000001307 Myosotis scorpioides Species 0.000 description 1
- TZYWCYJVHRLUCT-VABKMULXSA-N N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal Chemical compound CC(C)C[C@@H](C=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCC1=CC=CC=C1 TZYWCYJVHRLUCT-VABKMULXSA-N 0.000 description 1
- PNXMGYRJQIEEHK-UHFFFAOYSA-N OC(C(C1=C(C2)C3=CC=CC=C3N1)NC2C(O)=O)O Chemical compound OC(C(C1=C(C2)C3=CC=CC=C3N1)NC2C(O)=O)O PNXMGYRJQIEEHK-UHFFFAOYSA-N 0.000 description 1
- 208000001431 Psychomotor Agitation Diseases 0.000 description 1
- 206010038743 Restlessness Diseases 0.000 description 1
- 229960003767 alanine Drugs 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- DOKDMGOWZOTZRA-NTISSMGPSA-N benzyl (2s)-2-amino-3-(1h-indol-3-yl)propanoate;hydrochloride Chemical compound Cl.O=C([C@H](CC=1C2=CC=CC=C2NC=1)N)OCC1=CC=CC=C1 DOKDMGOWZOTZRA-NTISSMGPSA-N 0.000 description 1
- ZIUNABFUHGBCMF-MERQFXBCSA-N benzyl (2s)-2-amino-3-methylbutanoate;hydrochloride Chemical compound Cl.CC(C)[C@H](N)C(=O)OCC1=CC=CC=C1 ZIUNABFUHGBCMF-MERQFXBCSA-N 0.000 description 1
- QTQGHKVYLQBJLO-YDALLXLXSA-N benzyl (2s)-2-amino-4-methylpentanoate;4-methylbenzenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1.CC(C)C[C@H](N)C(=O)OCC1=CC=CC=C1 QTQGHKVYLQBJLO-YDALLXLXSA-N 0.000 description 1
- NEDMOHHWRPHBAL-MERQFXBCSA-N benzyl (2s)-pyrrolidin-1-ium-2-carboxylate;chloride Chemical compound Cl.O=C([C@H]1NCCC1)OCC1=CC=CC=C1 NEDMOHHWRPHBAL-MERQFXBCSA-N 0.000 description 1
- XAWVXTVKSVYPNE-JGAZGGJJSA-N benzyl (2s,3s)-2-amino-3-methylpentanoate;4-methylbenzenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1.CC[C@H](C)[C@H](N)C(=O)OCC1=CC=CC=C1 XAWVXTVKSVYPNE-JGAZGGJJSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 210000001168 carotid artery common Anatomy 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000007667 floating Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 229960003136 leucine Drugs 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229960002429 proline Drugs 0.000 description 1
- 238000004080 punching Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 230000002966 stenotic effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 229960004799 tryptophan Drugs 0.000 description 1
- 229960004295 valine Drugs 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/20—Spiro-condensed systems
-
- 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]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses 3S-1- (1, 1-dimethyl-1, 3-dioxane spiroyl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-AA (AA is L-alanine residue, L-phenylalanine residue, L-isoleucine residue, L-leucine residue, L-methionine residue, L-proline residue, L-valine residue and L-tryptophan residue) with the following formula, discloses the characteristic of selectively entering a P-selectin active pocket, and discloses the anti-arterial thrombosis activity and the anti-inflammatory activity of the amino acid derivatives. Therefore, the invention discloses the application of the compounds in preparing anti-arterial thrombosis medicaments and anti-inflammatory medicaments.
Description
Technical Field
The invention relates to 3S-1- (1, 1-dimethyl-1, 3-dioxane spiroyl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-AA (AA is L-alanine residue, L-phenylalanine residue, L-isoleucine residue, L-leucine residue, L-methionine residue, L-proline residue, L-valine residue and L-tryptophan residue), relates to the characteristic of selectively entering a P-selectin active pocket, and relates to the anti-arterial thrombosis activity and the anti-inflammatory activity of the amino acid derivatives. The invention thus relates to their use in the preparation of anti-arterio-thrombotic and anti-inflammatory medicaments. The invention belongs to the field of biological medicine.
Background
Cardiovascular diseases belong to frequently encountered diseases and common diseases, and have the advantages of long disease course, rapid disease progression, high fatality rate and disability rate. Arterial thrombosis is a significant link to the development of cardiovascular disease. After thrombosis, the lumen of the blood vessel becomes stenotic, resulting in blockage of the blood vessel, which in turn leads to myocardial necrosis, hypoxia and ischemia, and atherosclerosis. Inflammation can cause damage to the body and lead to various systemic diseases. In cardiovascular diseases, inflammation is an important cause of atherosclerosis. As such, arterial thrombosis and inflammation are commonly involved in the pathogenesis of cardiovascular disease. That is, the invention of the drug with double functions of anti-arterial thrombosis and anti-inflammation is of great importance for treating cardiovascular diseases.
P-selectin, tumor necrosis factor-alpha, glycoprotein IIAlaIII beta and interleukin-6 are important receptors of double-action medicines for resisting arterial thrombosis and inflammation. Only those compounds that are able to enter their active pocket have the potential to reduce the plasma concentration of these receptors or to down-regulate their expression. After analyzing the forms of the active pockets of P-selectin, tumor necrosis factor-alpha, glycoprotein IIAlaIII beta and interleukin-6, the inventors designed 3S-1- (1, 1-dimethyl-1, 3-dioxane spiroyl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-AA, wherein AA represents the amino acid residue commonly found in human body. The inventor uses molecular docking technology to dock 3S-1- (1, 1-dimethyl-1, 3-dioxane spiroyl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-AA with P-selectin, tumor necrosis factor-alpha, glycoprotein IIalpha III beta and interleukin-6 respectively. The results showed that 3S-1- (1, 1-dimethyl-1, 3-dioxane spiroyl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-AA (AA is L-alanine residue, L-phenylalanine residue, L-isoleucine residue, L-leucine residue, L-methionine residue, L-proline residue, L-valine residue and L-tryptophan residue) selectively entered the active pocket of P-selectin. FIG. 2 is a graph showing docking conditions and docking scores for the eight compounds and the active pocket of P-selectin. From this figure, it can be seen that the active pocket of P-selectin is well suited for these eight compounds. Unlike P-selectin, these eight compounds do not readily enter the active pocket of glycoprotein ilalllbeta, tumor necrosis factor-alpha and interleukin-6. Based on these theoretical studies, the present inventors completed the following experimental studies.
Disclosure of Invention
The first aspect of the present invention is to confirm that 3S-1- (1, 1-dimethyl-1, 3-dioxane spiroyl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-AA having the following formula is a novel compound, wherein AA is an L-alanine residue, an L-phenylalanine residue, an L-isoleucine residue, an L-leucine residue, an L-methionine residue, an L-proline residue, an L-valine residue, and an L-tryptophan residue.
The second aspect of the present invention provides a process for preparing 3S-1- (1, 1-dimethyl-1, 3-dioxaspiroyl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-AA (AA is as defined above) of the above formula, which comprises the steps of:
1) Preparing 3S-1, 1-dihydroxymethyl-1, 2,3, 4-tetrahydro-beta-carboline-3-benzyl carboxylate;
2) Preparing 3S-1- (1, 1-dimethyl-1, 3-dioxane spiroyl) -1,2,3, 4-tetrahydro-beta-carboline-3-benzyl carboxylate;
3) Preparing 3S-1- (1, 1-dimethyl-1, 3-dioxane spiroyl) -1,2,3, 4-tetrahydro-beta-carboline-3-carboxylic acid;
4) Using dicyclohexylcarbodiimide as a condensing agent and 1-hydroxybenzotriazole as a catalyst to synthesize 3S-1- (1, 1-dimethyl-1, 3-dioxane spiroyl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-AA-benzyl ester in a liquid phase;
5) Preparing 3S-1- (1, 1-dimethyl-1, 3-dioxane spiroyl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-AA.
The third aspect of the present invention is to evaluate the anti-arterial thrombotic activity of 3S-1- (1, 1-dimethyl-1, 3-dioxane spiroyl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-AA.
A fourth aspect of the present invention is to evaluate the anti-inflammatory activity of 3S-1- (1, 1-dimethyl-1, 3-dioxaspiro-yl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-AA.
Drawings
FIG. 1, 3S-1- (1, 1-dimethyl-1, 3-dioxane spiroyl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-AA: i) Trifluoroacetic acid, 1, 3-dihydroxyacetone; ii) N, N-dimethylformamide, p-toluenesulfonic acid, 2-dimethylpropane; iii) Pd/C, H 2 (ii) a iv) dicyclohexylcarbodiimide, 1-hydroxybenzotriazole, N-methylmorpholine.
FIG. 2 and FIG. 2 show the docking state of 3S-1- (1, 1-dimethyl-1, 3-dioxane spiroyl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-AA in the P-selectin active pocket; in the figure, when AA is L-alanine residue, L-phenylalanine residue, L-isoleucine residue, L-leucine residue, L-methionine residue, L-proline residue, L-valine residue and L-tryptophan residue, the butt scores are respectively 104.54,121.05,111.62,115.60, 117.49,104.53,107.43 and 137.94.
Detailed Description
To further illustrate the invention, a series of examples are given below. These examples are purely illustrative and are intended to be a detailed description of the invention and should not be taken as limiting the invention.
EXAMPLE 1 preparation of benzyl 3S-1, 1-dihydroxymethyl-1, 2,3, 4-tetrahydro-beta-carboline-3-carboxylate (1)
3.0g (10.2 mmol) of L-tryptophan benzyl ester is dissolved in 30mL of dichloromethane, and 3mL of trifluoroacetic acid is slowly added dropwise to the resulting clear and transparent solution in ice bath, followed by addition of 1.08g (12 mmol) of 1, 3-dihydroxyacetone and reaction at room temperature for 14 hours. TLC showed disappearance of L-tryptophan benzyl ester (dichloromethane/methanol, 10/1). 100mL of a saturated aqueous sodium bicarbonate solution was added to the reaction solution and stirred, followed by standing for separation, a methylene chloride phase was separated, the solvent was removed by concentration under reduced pressure, the residue was dissolved in 30mL of ethyl acetate, and the resulting solution was sequentially dissolved in saturated NaHCO 3 Aqueous (10 mL. Times.3) and saturated aqueous NaCl (10 mL. Times.3). The obtained ethyl acetate layer was dried over anhydrous sodium sulfate for 12 hours, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Dichloromethane/methanol, 70/1) yield 2.82g (76%) of the title compound as a pale yellow powder. ESI-MS (m/e) 367[ 2 ], [ M ] +H] + 。
EXAMPLE 2 preparation of benzyl 3S-1- (1, 1-dimethyl-1, 3-dioxaspiroyl) -1,2,3, 4-tetrahydro-beta-carboline-3-carboxylate (2)
1.5g (4 mmol) of 3S-1, 1-dihydroxymethyl-1, 2,3, 4-tetrahydro-beta-carboline-3-carboxylic acid benzyl ester (1) is dissolved with 30mL of ethyl acetate and 23mL of dichloromethane, 4mL of ethyl acetate solution of hydrogen chloride is added under ice bath, and solid particles are separated out after stirring for 10 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 10mLN, N-dimethylformamide to give a light brown clear solution. Then, 1.35mL (10 mmol) of 2, 2-dimethylpropane and 90mg of p-toluenesulfonic acid were further added, and the mixture was stirred at room temperature for 17 hours. TLC monitoring showed disappearance of compound 1 (ethyl acetate/petroleum ether = 1/1). 80mL of ethyl acetate was added, followed by 80mL of saturated NaHCO 3 An aqueous solution. The resulting solution was sequentially saturated NaHCO 3 Aqueous solution (30 mL. Times.3) and saturated aqueous NaCl solution (30 mL. Times.3). The ethyl acetate layer was washed with anhydrous Na 2 SO 4 Drying for 12 hours, filtering, and concentrating the filtrate under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1) to give 1.05g (63%) of the title compound as a pale yellow powder. ESI-MS (m/e): 407[ m ] +H] + 。
Example 3 preparation of 3S-1- (1, 1-dimethyl-1, 3-dioxaspiroyl) -1,2,3, 4-tetrahydro-beta-carboline-3-carboxylic acid (3)
1.0g (2.4 mmol) of 3S-1- (1, 1-dimethyl-1, 3-dioxane spiro) -1,2,3, 4-tetrahydro-beta-carboline-3-carboxylic acid benzyl ester (2) is dissolved in 15mL of methanol, 150mg of Pd/C is added under stirring, air is pumped out by a water pump, and hydrogen is introduced to react for 5 hours at normal temperature. TLC monitoring showed the disappearance of compound 2 (dichloromethane/methanol, 10/1). Filtering, and concentrating the filtrate under reduced pressure. The residue was triturated with dry ether to give 760mg (98%) of the title compound as a colorless powder. ESI-MS (m/e): 315[ M-H ]] - ； 1 H NMR(300 MHz,DMSO-d 6 ):δ/ppm＝11.05(s,1H),7.44(d,J＝7.7Hz,1H),7.36(d,J＝8.0Hz,1H),7.08 (m,1H),6.98(m,1H),4.47(m,1H),3.94(m,2H),3.66(m,2H),2.82(m,2H),2.50(s,1H), 1.63(s,3H),1.40(s,3H)。
EXAMPLE 4 preparation of 3S-1- (1, 1-dimethyl-1, 3-dioxaspiro-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-L-alanine benzyl ester (4 a)
450mg (1.40 mmol) of 3S-1- (1, 1-dimethyl-1, 3-dioxane spiroyl) -1,2,3, 4-tetrahydro-beta-carboline-3-carboxylic acid (compound 3) was dissolved in 10mL of anhydrous tetrahydrofuran, 210mg (1.55 mmol) of 1-hydroxybenzotriazole and 350mg (1.62 mmol) of dicyclohexylcarbodiimide were added to the resulting solution under ice bath, 370mg (1.55 mmol) of L-benzyl alanine was added after stirring for 30 minutes, N-methylmorpholine was added to adjust the pH of the solution to 8, and the reaction was carried out at normal temperature for 12 hours, and TLC showed disappearance of compound 3 (dichloromethane/methanol, 20/1). Insoluble matter was removed by filtration and then concentrated under reduced pressure, the residue was dissolved in 30mL of ethyl acetate, and the resulting solution was successively treated with saturated NaHCO 3 Aqueous wash (10 mL. Times.3), saturated aqueous NaCl wash (10 mL. Times.3), 5% KHSO 4 Aqueous solution (10 mL. Times.3), saturated aqueous NaCl solution (10 mL. Times.3), saturated aqueous NaHCO solution 3 Aqueous wash (10 mL. Times.3) and saturated aqueous NaCl wash (10 mL. Times.3). The obtained ethyl acetate layer liquid was treated with anhydrous Na 2 SO 4 Dried for 12 hours, filtered and the filtrate concentrated under reduced pressure. The residue is separated by silica gel column chromatography (dichloromethane/methanol, 120/1) to yield 520mg (77%) of the title compound as a colorless powder, ESI-MS (m/e): 478[ M + H ])] + ； 1 H NMR(300MHz, DMSO-d 6 ):δ/ppm＝10.95(s,1H),8.35(s,1H),7.70(m,1H),7.40-6.97(m,9H),5.16(s,2H), 4.44(m,2H),4.15(m,2H),3.77(m,1H),3.61(m,1H),3.00(m,2H),2.55(m,1H),1.62(s,3H), 1.39(s,3H)。
EXAMPLE 5 preparation of 3S-1- (1, 1-dimethyl-1, 3-dioxaspiro-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-L-phenylalanine benzyl ester (4 b)
Using the experimental method of example 4, 800mg (2.50 mmol) of Compound 3 and 915mg (3.20 mmol) of L-benzyl phenylalanine hydrochloride give 1.05g (75%) of the title compound as a colorless powder, ESI-MS (m/e): 554 (, [ M ] +H ])] + ； 1 H NMR (300MHz,CDCl 3 ):δ/ppm＝8.71(s,1H),7.47(d,J＝6.3Hz,1H),7.4-7.0(14H),5.18(s,2H), 4.96(m,1H),4.00-3.80(m,3H),3.67(m,2H),3.48(s,2H),3.2-3.0(m,3H),2.88(m,1H),2.61 (m,1H),1.61(s,3H),1.55(s,3H)。
EXAMPLE 6 preparation of 3S-1- (1, 1-dimethyl-1, 3-dioxaspiro-yl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-L-isoleucine benzyl ester (4 c)
Using the experimental method of example 4 from 800mg (2.50 mmol) of Compound 3 and 1.03g (2.70 mmol) of L-isoleucine benzyl ester p-toluenesulfonate to give 1.07g (82%) of the title compound as a colorless powder, ESI-MS (m/e): 542[ m ] +Na] + ； 1 H NMR(300MHz,CDCl 3 )δ/ppm＝8.64(s,1H),7.50(d,J＝7.7Hz,1H), 7.43-7.28(m,6H),7.23-7.00(m,3H),5.20(s,2H),4.72(dd,J 1 ＝8.8Hz,J 2 ＝4.9Hz,1H),3.98 (m,3H),3.91-3.67(m,2H),3.25(s,1H),2.72(s,1H),2.17(m,1H),1.61(s,6H),1.35-1.07(m, 3H),0.97-0.85(m,3H)。
EXAMPLE 7 preparation of 3S-1- (1, 1-dimethyl-1, 3-dioxaspiro-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-L-leucine benzyl ester (4 d)
Using the experimental method of example 4 from 800mg (2.50 mmol) of compound 3 and 1.03g (2.70 mmol) of L-leucine benzyl ester p-toluenesulfonate, 730mg (82%) of the title compound are obtained as a colorless powder, ESI-MS (m/e): 520[ m ] +H ],] + ； 1 H NMR(300MHz,DMSO-d 6 ):δ/ppm＝10.95(s,1H),8.26(d,J＝7.7Hz,1H),7.54-7.26(m,7H), 7.2-6.87(m,2H),5.16(s,2H),4.40(m,2H),4.10(m,1H),3.72(m,2H),3.57(m,1H),3.00(m, 2H),2.56(m,1H),1.70(m,2H),1.61(s,3H),1.38(s,3H),1.18(t,J＝7.1Hz,1H),0.90(dd,J 1 ＝ 8.8Hz,J 2 ＝6.1Hz,6H)。
EXAMPLE 8 preparation of 3S-1- (1, 1-dimethyl-1, 3-dioxaspiro-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-L-methionine benzyl ester (4 e)
Using the experimental method of example 4, 230mg (0.73 mmol) of Compound 3 and 220mg (0.80 mmol) of L-benzyl methionine hydrochloride gave 230mg (59%) of the title compound as a colorless powder, ESI-MS (m/e): 538, [ M ] +H] + ； 1 H NMR(300MHz,DMSO-d 6 ):δ/ppm＝10.91(s,1H),8.30(d,J＝7.5Hz,1H),7.35(m,7H),7.02 (m,2H),5.16(s,2H),4.53(m,1H),4.18(m,2H),3.76(m,1H),3.60(m,2H),2.98(m,2H), 2.56(m,2H),2.05(m,2H),1.70(m,2H),1.60(s,3H),1.49(m,2H),1.37(s,3H)。
EXAMPLE 9 preparation of 3S-1- (1, 1-dimethyl-1, 3-dioxaspiroyl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-L-proline benzyl ester (4 f)
Using the experimental method of example 4, from 600mg (1.89 mmol) of compound 3 and 504mg (2.08 mmol) of L-proline benzyl ester hydrochloride, 500mg (53%) of the title compound as a colorless powder is obtained, ESI-MS (m/e): 504[ M ] +H ] +] + ； 1 H NMR(300 MHz,DMSO-d 6 ):δ/ppm＝10.90(s,1H),7.52-7.24(m,7H),7.20-6.89(m,2H),5.15(m,2H), 4.44(m,2H),4.08-3.82(m,4H),3.62(m,3H),2.86-2.54(m,3H),2.28(m,1H),1.91(m,3H), 1.61(s,3H),1.39(s,3H)。
EXAMPLE 10 preparation of 3S-1- (1, 1-dimethyl-1, 3-dioxaspiro-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-L-valine benzyl ester (4 g)
Using the experimental method of example 4, from 810mg (2.56 mmol) of Compound 3 and 750mg (3.08 mmol) of L-valine benzyl ester hydrochloride, 1.00g (80%) of the title compound is obtained as a colorless powder, ESI-MS (m/e): 506, [ M ] +H ]] + ； 1 H NMR(300 MHz,DMSO-d 6 ):δ/ppm＝10.93(s,1H),8.14(d,J＝7.9Hz,1H),7.40(m,7H),7.04(dd,J 1 ＝ 14.3Hz,J 2 ＝6.9Hz,2H),5.18(m,2H),4.35(m,2H),4.00(d,J＝11.4,1H),3.75(m,2H),3.59 (m,1H),2.95(m,2H),2.58(m,1H),2.15(dd,J 1 ＝13.4Hz,J 2 ＝6.6Hz,1H),1.62(s,3H),1.39 (s,3H),0.93(d,J＝6.3Hz,6H)。
EXAMPLE 11 preparation of 3S-1- (1, 1-dimethyl-1, 3-dioxaspiro-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-L-tryptophan benzyl ester (4 h)
Using the experimental procedure of example 4 from 450mg (1.42 mmol) of compound 3 and 517mg (1.52 mmol) of L-tryptophan benzyl ester hydrochloride, 710mg (84%) of the title compound are obtained as a colorless powder, ESI-MS (m/e): 593 2[ m + H ] +] + ； 1 H NMR(300 MHz,DMSO-d 6 ):δ/ppm＝10.92(s,2H),8.30(d,J＝7.4Hz,1H),7.55(d,J＝7.8Hz,1H), 7.45-7.30(m,6H),7.24(m,2H),7.03(m,4H),5.09(m,2H),4.70(q,J＝7.2Hz,1H),4.38(m, 1H),3.98(m,1H),3.78(m,1H),3.58(m,2H),3.26(m,2H),2.95(m,2H),2.50(m,2H),1.62(s, 3H),1.38(s,3H)。
EXAMPLE 12 preparation of 3S-1- (1, 1-dimethyl-1, 3-dioxaspiroyl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-L-alanine (5 a)
280mg of the test substance were prepared by the method of example 3(0.58 mmol) of 3S-1- (1, 1-dimethyl-1, 3-dioxaspiro-yl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-L-alanine benzyl ester (4 a) gave 200mg (88%) of the title compound as a colorless powder. Mp is 161.4-162.4 ℃;
(c =0.10, methanol); FT-MS (m/e) 388.1899[ m ] +H] + (theoretical value: 388.1794); 1 H NMR(300MHz,DMSO-d 6 ):δ/ppm＝10.95(s,1H),8.13(s,1H),7.42(d,J＝7.80Hz,1H), 7.37(d,J＝7.80Hz,1H),7.10(dd,J 1 ＝6.9Hz,J 2 ＝1.2Hz,1H),6.96(dd,J 1 ＝7.2Hz,J 2 ＝1.2 Hz,1H),4.40(m,1H),4.33(m,1H),3.99(m,1H),3.78(m,1H),3.60(m,2H),3.02(m,1H), 2.59(m,1H),1.61(s,3H),1.36(s,3H)。
EXAMPLE 13 preparation of 3S-1- (1, 1-dimethyl-1, 3-dioxaspiroyl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-L-phenylalanine (5 b)
Using the experimental procedure of example 3, from 100mg (0.18 mmol) of 3S-1- (1, 1-dimethyl-1, 3-dioxaspiro-yl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-L-phenylalanine benzyl ester (4 b) 76mg (92%) of the title compound are obtained as a colorless powder; mp is 126.5-128.4 ℃;
(c =0.10, methanol); FT-MS (m/e) 464.2214[ 2 ], [ M + H ]] + (theoretical value: 464.2107); 1 H NMR(300MHz,DMSO-d 6 ):δ/ppm＝10.94(s,1H),8.14(s,2H),8.08(d,J＝7.8Hz,1H), 7.4-7.0(m,9H),4.54(m,1H),4.39(d,J＝9.0Hz,1H),3.97(m,1H),3.76(m,1H),3.57(m, 2H),3.14(m,1H),3.05(m,1H),2.92(m,1H),1.61(s,3H),1.38(s,3H)。
EXAMPLE 14 preparation of 3S-1- (1, 1-dimethyl-1, 3-dioxaspiro-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-L-isoleucine (5 c)
From 190mg (0.37 mmol) of 3S-1- (1, 1-dimethyl-1, 3-dioxaspiro-nyl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-L-isoleucine benzyl ester (4 c) using the experimental method of example 3, 146mg (93%) of the title compound are obtained as colorless powder; mp is 120.8-122.5 ℃;
(c =0.10, methanol); FT-MS (m/e) 430.2387[ m ] +H] + (theoretical value: 430.2264); 1 H NMR(300MHz,DMSO-d 6 ):δ/ppm＝10.93(s,1H),7.93(d,J＝8.2Hz,1H),7.40 (m,2H),7.07m,1H),6.98(m,1H),4.38(m,1H),4.27(m,1H),3.90(m,2H),3.69(m,1H), 3.58(m,1H),3.01(m,1H),2.58(m,1H),1.86(m,1H),1.62(s,3H),1.50(m,1H)1.39(s,3H), 1.33-1.06(m,1H),0.90(m,6H)。
EXAMPLE 15 preparation of 3S-1- (1, 1-dimethyl-1, 3-dioxaspiro-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-L-leucine (5 d)
Using the experimental method of example 3, from 200mg (0.39 mmol) of 3S-1- (1, 1-dimethyl-1, 3-dioxaspiro-yl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-L-leucine benzyl ester (4 d) 160mg (97%) of the title compound are obtained as a colorless powder; mp is 130.8-132.6 ℃;
(c =0.10, methanol); FT-MS (m/e) 430.2379[ m ] +H] + (theoretical value: 430.2264); 1 H NMR(300MHz,DMSO-d 6 ):δ/ppm＝10.95(s,1H),8.05(d,J＝8.0Hz,1H),7.40 (dd,J 1 ＝15.3Hz,J 2 ＝7.8Hz,2H),7.03(m,2H),4.35(m,2H),3.95(m,2H),3.60(m,2H),3.17 (s,2H),3.03(m,1H),2.58(m,1H),1.80-1.49(m,3H),1.61(s,3H),1.39(s,3H),0.91(t,J＝6.9 Hz,6H)。
EXAMPLE 16 preparation of 3S-1- (1, 1-dimethyl-1, 3-dioxaspiro-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-L-methionine (5 e)
70mg (0.13 mmol) of 3S-1- (1, 1-dimethyl-1, 3-dioxane spiroyl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-L-methionine benzyl ester (4 e) is added into 20mL of methanol for dissolution, 30 mu L of 2 mol/L NaOH aqueous solution is slowly dripped into the obtained clear and transparent solution under ice bath to adjust the pH value of the reaction solution to 12, and the reaction is carried out for 6 hours at room temperature. TLC showed disappearance of Compound 4e (dichloromethane/methanol, 10/1). Saturated KHSO is added into the reaction liquid dropwise in ice bath 4 Adjusting pH of the reaction solution to 7 with water solution, concentrating under reduced pressure to remove solvent, adding small amount of distilled water into the residue, and adding saturated KHSO dropwise into the residual solution under ice bath 4 The reaction mixture was adjusted to pH 2 with an aqueous solution, and the resulting solution was washed with ethyl acetate (10 mL. Times.5), and the combined ethyl acetate layers were washed with saturated aqueous NaCl (20 mL. Times.3). The obtained ethyl acetate layer was dried over anhydrous sodium sulfate for 12 hours, filtered, and the filtrate was concentrated under reduced pressure. The residue was isolated by C-18 silica gel column chromatography (methanol/water, 70/30) to give 30mg (52%) of the title compound as a colorless solid powder. Mp is 108.3-110.0 ℃;
(c =0.10, methanol); FT-MS (M/e) 448.1940 [ M + H ]] + (theoretical value: 448.1828); 1 H NMR(300MHz,DMSO-d 6 ):δ/ppm＝11.09(s,1H),8.28(s, 1H),7.42(d,J＝7.6Hz,2H),7.28-6.93(m,2H),4.46(m,2H),4.04(m,1H),3.78(m,3H),3.35 (m,2H),3.10(m,1H),2.56(m,1H),2.105(s,3H),1.67(s,3H),1.42(s,3H)。
EXAMPLE 17 preparation of 3S-1- (1, 1-dimethyl-1, 3-dioxaspiroyl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-L-proline (5 f)
Using the experimental method of example 3, from 150mg (0.30 mmol) of 3S-1- (1, 1-dimethyl-1, 3-dioxaspiroyl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-L-proline benzyl ester (4 f) 120mg (94%) of the title compound are obtained as colorless powder; mp is 174.1-175.6 ℃;
(c =0.10, methanol); FT-MS (m/e) 414.2053[ 2 ], [ M + H ]] + (theoretical value: 414.1951); 1 H NMR(300MHz,DMSO-d 6 ):δ/ppm＝10.91(s,1H),7.43(dd,J 1 ＝8.1Hz,J 2 ＝3.6Hz,1H),7.37(d,J＝8.0,1H),7.03(m,1H),6.97(m,1H),4.39(m,1H),4.30(m,1H), 4.05-3.84(m,4H),3.79-3.53(m,3H),3.17(s,1H),2.74(m,2H),2.20(m,1H),2.03-1.74(m, 3H),1.61(s,3H),1.38(s,3H)。
EXAMPLE 18 preparation of 3S-1- (1, 1-dimethyl-1, 3-dioxaspiro-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-L-valine (5 g)
The experimental procedure used in example 3 was repeated, starting from 480mg (0.95 mmol) of 3S-1- (1, 1-dimethyl-1, 3-dioxaspiroyl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-L-valine benzyl ester (4 g)370mg (94%) of the title compound are obtained as a colorless solid powder; mp is 138-140 ℃;
(c =0.10, methanol); FT-MS (m/e) 416.2233[ 2 ], [ M + H ]] + (theoretical value: 416.2107); 1 H NMR(300MHz,DMSO-d 6 ):δ/ppm＝10.93(s,1H),7.92(d,J＝8.3Hz,1H),7.40(m,7.9,2H), 7.08(m,1H),6.98(m,1H),4.38(m,1H),4.22(dd,J 1 ＝8.2Hz,J 2 ＝5.9Hz,1H),4.00(m,1H), 3.80(m,1H),3.70(dd,J＝10.5,3.8,1H),3.59(m,1H),3.02(m,1H),2.58(m,10.7,1H),2.13 (dd,J 1 ＝13.3Hz,J 2 ＝6.7Hz,,1H),1.62(s,3H),1.39(s,3H),0.94(dd,J 1 ＝6.7Hz,J 2 ＝1.5Hz, 6H)。
EXAMPLE 19 preparation of 3S-1- (1, 1-dimethyl-1, 3-dioxaspiro-yl) -1,2,3, 4-tetrahydro-beta-carboline-3-formyl-L-tryptophan (5 h)
From 230mg (0.39 mmol) of 3S-1- (1, 1-dimethyl-1, 3-dioxaspiro-nyl) -1,2,3, 4-tetrahydro- β -carboline-3-formyl-L-tryptophane benzyl ester (4 h) 190mg (97%) of the title compound were obtained as a colorless solid powder using the experimental procedure of example 3; mp is 150-152 ℃;
(c =0.10, methanol); FT-MS (m/e) 503.2355[ 2 ], [ M + H ]] + (theoretical value: 503.2216); 1 H NMR(300MHz,DMSO-d 6 ):δ/ppm＝10.91(s,2H),8.04(d,J＝7.5Hz,1H),7.59(d,J＝7.6 Hz,1H),7.38(m,3H),7.20(m,1H),7.15-6.90(m,4H),4.60(dd,J 1 ＝12.9Hz,J 2 ＝7.1Hz,2H), 4.38(d,J＝11.2m,1H),3.98(m,1H),3.77(m,2H),3.58(m,2H),3.26(m,2H),2.97(m,1H), 2.51(m,1H),1.62(s,3H),1.39(s,3H)。
EXAMPLE 20 evaluation of the anti-arterial Thrombus Activity of Compounds 5a-h
1) Drawing a polyethylene tube into a thin tube with one end being an oblique opening, wherein the fixed length is 10.0cm, and the thin tube is respectively used for inserting a right jugular vein (with a thicker tube diameter) and a left carotid artery (with a thinner tube diameter); the length of the middle section polyethylene tube is 8.0cm, the thrombus line is pressed in the carotid intubation direction, and the tube needs to be filled with heparin before intubation.
2) Male rats weighing 200 ± 20g were acclimatized and fasted for one day prior to surgery. The groups were randomly divided into a saline group (0.3 mL/100g,11 rats), an aspirin group (167. Mu. Mol/kg,11 rats), and compound 5a-h groups (0.1. Mu. Mol/kg,11 rats). The drug was administered orally to rats in the prescribed dose. After 30 minutes of administration, rats were anesthetized by intraperitoneal injection of 20% urethane solution (7 mL/kg), and surgery was started 2 minutes later. The rat lies on the back on the fixed plate in the operation, cuts open neck skin, separates right common carotid artery and left jugular vein, line ball under the blood vessel, ligature telecentric end, near telecentric end department at the vein and cut a osculum, insert the intubate vein end, inject heparin, then take off the syringe of injection heparin, the tie line is fixed, reuse artery presss from both sides and presss from both sides the artery and nears the heart end, cuts a osculum near telecentric end direction, ligates the artery end, loosens the artery after the tie line is fixed and presss from both sides, establishes the extracorporeal circulation bypass. After circulating for 15 minutes, the venous end is firstly cut off to observe whether the blood circulation is normal, if the blood circulation is normal, a thrombus thread is taken out from the arterial end, dry floating blood is stained on paper, then the weighing is carried out, the thrombus weight represents the activity, and the data are listed in a table 1 through single-factor variance analysis. The thrombus weights in Table 1 show that aspirin effectively inhibits arterial thrombosis in rats at an oral dose of 167 μmol/kg. The thrombus weight of the compound 5b,5e,5f and 5 h-treated rats at the 0.1 μmol/kg oral dose was not significantly different from the thrombus weight of the saline-treated rats. This result demonstrates that the molecular docking and docking scores at 5b,5e,5f and 5h for the active pocket of P-selectin deviate in predicting the anti-arterial thrombotic activity of these 4 compounds. Nonetheless, compounds 5a,5c,5d and 5g showed excellent arterial thrombotic activity at an oral dose of 0.1. Mu. Mol/kg. Therefore, the invention has outstanding technical effects.
TABLE 1 anti-arterial Thrombus Activity of Compounds 5a-h
a) P <0.01 to saline; b) P <0.05 to saline, P >0.05 to compound 3; c) P <0.01 to saline, P >0.05 to aspirin; n =11
EXAMPLE 21 evaluation of anti-inflammatory Activity of Compounds 5a,5c,5d and 5g
Laboratory animal
ICR mice, male, 20 + -2 g, purchased from Experimental animals technology, inc., viton, beijing.
Dosage and mode of administration
The oral dose of compounds 5a,5f,5h and 5p was 0.14. Mu. Mol/kg, the oral dose of positive control aspirin was 1.11 mmol/kg, and the negative control was normal saline.
Experimental method
Xylene-induced ICR mouse ear swelling model
Experimental procedures
The newly arrived mice were allowed to rest for one day and then randomly grouped, 12 mice per group. The sequential method is adopted for intragastric administration of the mice, 6 mice are administered in each group at intervals of 5 minutes according to the specified dosage, the mice are sequentially fixed and grabbed in the intragastric administration sequence after half an hour, the right ears of the mice are exposed, and 30 mu L of dimethylbenzene is evenly smeared at the edge of the auricle of the right ear of each mouse by using a liquid transfer gun until the dimethylbenzene is naturally volatilized. After application of xylene, the mice had restlessness and red and swollen right ears. Two hours after molding the mice were anesthetized with ether and sacrificed by cervical dislocation. The ears on both sides of the mouse are cut off along the root, the edges of the mouse are stacked together, two round ear sheets with the same area and size of the two ears at the same position are punched by an electric ear swelling ear punching device (model: YLS 025A) with the diameter of 7mm, and the round ear sheets are respectively weighed, wherein the ear swelling degree is the difference value of the two ear weights.
Results of the experiment
Ear swelling = right ear weight-left ear weight; ear swelling degree is expressed as mean value + -SD mg, and statistical comparison among groups is carried out by single-factor variance analysis; the results are shown in Table 2. The results show that the swelling degree of the ears of the mice treated by the compounds 5a,5c and 5d and 5g at the oral dose of 0.1 mu mol/kg is obviously different from that of the normal saline, and has no obvious difference from the compound 3. As can be seen, compound 3, after being modified with L-alanine, L-isoleucine, L-leucine and L-valine, still has excellent anti-inflammatory activity when the oral dosage is as low as 1/10. That is, the present invention has a remarkable technical effect.
TABLE 2 Activity of Compounds 5a,5c,5d and 5g for inhibiting inflammation
a) P <0.01 to saline, P >0.05 to compound 3; n =12.
Claims (4)
1. 3S-1-dioxane spiro-1, 2,3, 4-tetrahydro-beta-carboline-3-formyl-AA with the structure as shown,
wherein AA is an L-alanine residue, an L-phenylalanine residue, an L-isoleucine residue, an L-leucine residue, an L-methionine residue, an L-proline residue, an L-valine residue or an L-tryptophan residue.
2. A process for preparing 3S-1-dioxane spiro-1, 2,3, 4-tetrahydro- β -carboline-3-formyl-AA having the structure of claim 1, comprising the steps of:
2.1. preparing 3S-1, 1-dihydroxymethyl-tetrahydro-beta-carboline-3-benzyl carboxylate;
2.2. preparing 3S-1-dioxane spiro-1, 2,3, 4-tetrahydro-beta-carboline-3-benzyl carboxylate;
2.3. preparing 3S-1-dioxane spiro-1, 2,3, 4-tetrahydro-beta-carboline-3-carboxylic acid;
2.4. adopting dicyclohexylcarbodiimide as a condensing agent and 1-hydroxybenzotriazole as a catalyst to synthesize 3S-1-dioxane spiroyl-1, 2,3, 4-tetrahydro-beta-carboline-3-formyl-AA-benzyl ester in a liquid phase;
2.5. preparing 3S-1-dioxane spiro-1, 2,3, 4-tetrahydro-beta-carboline-3-formyl-AA with the structure of claim 1.
3. The use of 3S-1-dioxane spiroyl-1, 2,3, 4-tetrahydro- β -carboline-3-formyl-AA having the structure of claim 1 in the preparation of an anti-arterial thrombosis medicament.
4. Use of 3S-1-dioxane spiro-1, 2,3, 4-tetrahydro- β -carboline-3-formyl-AA having the structure of claim 1, in the preparation of an anti-inflammatory agent, wherein the AA is selected from the group consisting of L-alanine residue, L-isoleucine residue, L-leucine residue and L-valine residue.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110665598.6A CN115477656B (en) | 2021-06-16 | 2021-06-16 | Dioxahexacyclic-tetrahydrocarboline-3-formylamino acid targeting P-selectin, preparation and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110665598.6A CN115477656B (en) | 2021-06-16 | 2021-06-16 | Dioxahexacyclic-tetrahydrocarboline-3-formylamino acid targeting P-selectin, preparation and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115477656A true CN115477656A (en) | 2022-12-16 |
| CN115477656B CN115477656B (en) | 2024-04-19 |
Family
ID=84419569
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110665598.6A Active CN115477656B (en) | 2021-06-16 | 2021-06-16 | Dioxahexacyclic-tetrahydrocarboline-3-formylamino acid targeting P-selectin, preparation and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115477656B (en) |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103159827A (en) * | 2011-12-13 | 2013-06-19 | 首都医科大学 | Synthesis, anti-thrombotic activity, and application of (1R, 3S) -1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline acyl amino acid |
| CN103450333A (en) * | 2012-05-29 | 2013-12-18 | 首都医科大学 | 1,1-dimethyl-beta-carboline carboxylic acid-modified RGD peptides and their synthesis, anti-thrombus effect and use |
| CN108969770A (en) * | 2017-05-31 | 2018-12-11 | 首都医科大学 | 1- methyl -3- methylol-tetrahydro-beta-carboline of dipeptides modification, synthesis and application |
| CN109134607A (en) * | 2017-06-16 | 2019-01-04 | 首都医科大学 | 1,1- dihydroxymethyl-tetrahydro-beta-carboline -3- formyl-GRGDS, synthesis, activity and application |
| CN112898377A (en) * | 2019-12-02 | 2021-06-04 | 首都医科大学 | Dioxane-modified tetrahydrocarboline-3-formyl-The-HGE, preparation thereof, anti-inflammatory activity thereof and application thereof |
| CN112898381A (en) * | 2019-12-02 | 2021-06-04 | 首都医科大学 | Dioxahexacyclic modified tetrahydrocarboline-3-formyl-The-EDG, preparation, anti-inflammatory and antithrombotic activity and application thereof |
| CN112898380A (en) * | 2019-12-02 | 2021-06-04 | 首都医科大学 | Dioxohexa-ring modified tetrahydrocarboline-3-formyl-The-HGK, preparation thereof, antithrombotic activity thereof and application thereof |
-
2021
- 2021-06-16 CN CN202110665598.6A patent/CN115477656B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103159827A (en) * | 2011-12-13 | 2013-06-19 | 首都医科大学 | Synthesis, anti-thrombotic activity, and application of (1R, 3S) -1-p-nitrophenyl-1,2,3,4-tetrahydro-beta-carboline acyl amino acid |
| CN103450333A (en) * | 2012-05-29 | 2013-12-18 | 首都医科大学 | 1,1-dimethyl-beta-carboline carboxylic acid-modified RGD peptides and their synthesis, anti-thrombus effect and use |
| CN108969770A (en) * | 2017-05-31 | 2018-12-11 | 首都医科大学 | 1- methyl -3- methylol-tetrahydro-beta-carboline of dipeptides modification, synthesis and application |
| CN109134607A (en) * | 2017-06-16 | 2019-01-04 | 首都医科大学 | 1,1- dihydroxymethyl-tetrahydro-beta-carboline -3- formyl-GRGDS, synthesis, activity and application |
| CN112898377A (en) * | 2019-12-02 | 2021-06-04 | 首都医科大学 | Dioxane-modified tetrahydrocarboline-3-formyl-The-HGE, preparation thereof, anti-inflammatory activity thereof and application thereof |
| CN112898381A (en) * | 2019-12-02 | 2021-06-04 | 首都医科大学 | Dioxahexacyclic modified tetrahydrocarboline-3-formyl-The-EDG, preparation, anti-inflammatory and antithrombotic activity and application thereof |
| CN112898380A (en) * | 2019-12-02 | 2021-06-04 | 首都医科大学 | Dioxohexa-ring modified tetrahydrocarboline-3-formyl-The-HGK, preparation thereof, antithrombotic activity thereof and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| KUN YAO 等: "A class of oral N-[(1S, 3S)-1-methyl-1, 2, 3, 4-tetrahydro-[3-carboline-3-carbonyl]-N\'-(amino-acid-acyl)hydrazine: Discovery, synthesis, in vitro anti-platelet aggregation/in vivo anti-thrombotic evaluation and 3D QSAR analysis", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 46, pages 3237 - 3249 * |
| 薛宝玉 等: "3S-1, 2, 3, 4-四氢-β-咔啉-3-羧酸的结构修饰和抗血栓活性研究", 首都医科大学学报, vol. 26, no. 1, pages 38 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115477656B (en) | 2024-04-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US7087645B2 (en) | Compounds and methods for treating transplant rejection | |
| JPH10279590A (en) | Water-soluble extract containing asiaticoside and madecassoside separated from centella asiatica and its separation | |
| TWI564291B (en) | Agent for regulating the formation of nitrogen monoxide | |
| CN116987014A (en) | Nitrite salts of 1, 1-metformin, pharmaceutical compositions and methods of use | |
| CN101250183A (en) | Optical isomer of rebeprazole as well as preparation method and medical use thereof | |
| CA3027118A1 (en) | Compositions and methods for the treatment of cancer | |
| CN112898381B (en) | Dioxahexacyclic modified tetrahydrocarboline-3-formyl-The-EDG, preparation, anti-inflammatory and antithrombotic activity and application thereof | |
| CN115477656A (en) | Dioxane-tetrahydro carboline-3-formylamino acid with P-selectin as target and preparation and application thereof | |
| CN108948146B (en) | 1R-methyl-beta-tetrahydrocarboline acyl-K (ARPAK) -RGDV, and synthesis, activity and application thereof | |
| CN108929372B (en) | 1R-methyl-beta-tetrahydrocarboline acyl-K (GRPAK) -RGDV, and synthesis, activity and application thereof | |
| WO2019233474A1 (en) | Antiviral compounds and methods of use thereof | |
| CN115477655B (en) | Preparation and application of dioxane-tetrahydrocarboline-3-formylamino acid in butt joint with tumor necrosis factor-alpha | |
| CN115466304A (en) | Dioxane-tetrahydrocarboline-3-formylamino acid with glycoprotein IIAlbeta as target and preparation and application thereof | |
| CN115477683A (en) | Dioxiexacyclo-tetrahydrocarboline-3-formylamino acid with interleukin-6 as target and preparation and application thereof | |
| CN108948155B (en) | 1R-methyl-beta-tetrahydrocarboline acyl-K (QRPAK) -RGDV, and synthesis, activity and application thereof | |
| CN108948145B (en) | 1R-methyl-beta-tetrahydrocarboline acyl-K (PAK) -RGDV, and synthesis, activity and application thereof | |
| CN111848727B (en) | Preparation, activity and application of theanyl tetrahydroimidazopyridine-6-formyl nonpolar amino acid | |
| CN110577572B (en) | Synthesis, activity and application of 1S-methyl-beta-tetrahydrocarboline acyl-K (PAK) | |
| CN106699844B (en) | The-RGDVGRPAK decapeptide, and preparation, activity and application thereof | |
| CN111848726B (en) | Preparation, activity and application of theanyl tetrahydroimidazopyridine-6-formyl aromatic amino acid | |
| CN110615828B (en) | 1S-methyl-beta-tetrahydrocarboline acyl-K and synthesis, activity and application thereof | |
| CN110577575B (en) | 1S-methyl-beta-tetrahydrocarboline acyl-K (ARPAK) -RGDV, and synthesis, activity and application thereof | |
| CN111848724B (en) | Preparation, activity and application of theanyl tetrahydroimidazopyridine-6-formyl acidic amino acid | |
| CN105732612B (en) | A kind of preparation of pril jamaicin conjugates and medical usage | |
| CN111848729B (en) | Preparation, activity and application of theanyl tetrahydroimidazopyridine-6-formyl asparagine and glutamine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |