CN107496419B - 一种具有抗炎活性的环戊烷并[b]吡咯类化合物 - Google Patents
一种具有抗炎活性的环戊烷并[b]吡咯类化合物 Download PDFInfo
- Publication number
- CN107496419B CN107496419B CN201610421383.9A CN201610421383A CN107496419B CN 107496419 B CN107496419 B CN 107496419B CN 201610421383 A CN201610421383 A CN 201610421383A CN 107496419 B CN107496419 B CN 107496419B
- Authority
- CN
- China
- Prior art keywords
- inflammatory
- group
- pyrrole
- inflammatory activity
- compound
- 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.)
- Active
Links
- -1 Cyclopenta [ b ] pyrrole compound Chemical class 0.000 title claims abstract description 30
- 230000003110 anti-inflammatory effect Effects 0.000 title claims abstract description 20
- 150000001875 compounds Chemical class 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 6
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 4
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 3
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 2
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims description 2
- 229940049920 malate Drugs 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 claims 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 claims 1
- 229940124599 anti-inflammatory drug Drugs 0.000 abstract description 8
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 abstract description 6
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 abstract description 6
- 229960000590 celecoxib Drugs 0.000 abstract description 6
- 239000002260 anti-inflammatory agent Substances 0.000 abstract description 5
- 240000001307 Myosotis scorpioides Species 0.000 abstract description 4
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 abstract description 3
- 206010030113 Oedema Diseases 0.000 abstract description 3
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 abstract description 3
- 230000001404 mediated effect Effects 0.000 abstract description 3
- 238000002474 experimental method Methods 0.000 abstract description 2
- NUQJULCGNZMBEF-UHFFFAOYSA-N Prostratin Natural products COC(=O)C12CC(C)C3(O)C(C=C(CO)CC4(O)C3C=C(C)C4=O)C1C2(C)C NUQJULCGNZMBEF-UHFFFAOYSA-N 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 abstract 1
- 206010061218 Inflammation Diseases 0.000 description 7
- 230000004054 inflammatory process Effects 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 230000002757 inflammatory effect Effects 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 210000005069 ears Anatomy 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 description 2
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 2
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 2
- 125000006304 2-iodophenyl group Chemical group [H]C1=C([H])C(I)=C(*)C([H])=C1[H] 0.000 description 2
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 2
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 description 2
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 2
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 2
- 125000006305 3-iodophenyl group Chemical group [H]C1=C([H])C(I)=C([H])C(*)=C1[H] 0.000 description 2
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 2
- 125000006306 4-iodophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1I 0.000 description 2
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000003777 Interleukin-1 beta Human genes 0.000 description 2
- 108090000193 Interleukin-1 beta Proteins 0.000 description 2
- 102000004889 Interleukin-6 Human genes 0.000 description 2
- 108090001005 Interleukin-6 Proteins 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 2
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 2
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 2
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 2
- 238000005520 cutting process Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 229940100601 interleukin-6 Drugs 0.000 description 2
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 2
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 2
- PHEDXBVPIONUQT-RGYGYFBISA-N phorbol 13-acetate 12-myristate Chemical compound C([C@]1(O)C(=O)C(C)=C[C@H]1[C@@]1(O)[C@H](C)[C@H]2OC(=O)CCCCCCCCCCCCC)C(CO)=C[C@H]1[C@H]1[C@]2(OC(C)=O)C1(C)C PHEDXBVPIONUQT-RGYGYFBISA-N 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- LOGFVTREOLYCPF-KXNHARMFSA-N (2s,3r)-2-[[(2r)-1-[(2s)-2,6-diaminohexanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxybutanoic acid Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H]1CCCN1C(=O)[C@@H](N)CCCCN LOGFVTREOLYCPF-KXNHARMFSA-N 0.000 description 1
- PFABQBKYUHXGFO-UHFFFAOYSA-N 1,2,5-triphenyl-5,6-dihydro-4H-cyclopenta[b]pyrrole Chemical compound C1(=CC=CC=C1)N1C(=CC2=C1CC(C2)C1=CC=CC=C1)C1=CC=CC=C1 PFABQBKYUHXGFO-UHFFFAOYSA-N 0.000 description 1
- IEMHESZWPQUDRH-UHFFFAOYSA-N 1-(4-chlorophenyl)-2-phenyl-5,6-dihydro-4H-cyclopenta[b]pyrrole Chemical compound Clc1ccc(cc1)-n1c2CCCc2cc1-c1ccccc1 IEMHESZWPQUDRH-UHFFFAOYSA-N 0.000 description 1
- QNUMCSBSFNMQLQ-UHFFFAOYSA-N 1-benzyl-2-phenyl-5,6-dihydro-4H-cyclopenta[b]pyrrole Chemical compound C(c1ccccc1)n1c2CCCc2cc1-c1ccccc1 QNUMCSBSFNMQLQ-UHFFFAOYSA-N 0.000 description 1
- LGSAXSHAKOJQNT-UHFFFAOYSA-N 2-(4-methoxyphenyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole Chemical compound COC1=CC=C(C=C1)C=1NC2=C(C=1)CCC2 LGSAXSHAKOJQNT-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 238000011725 BALB/c mouse Methods 0.000 description 1
- 229940093444 Cyclooxygenase 2 inhibitor Drugs 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010020565 Hyperaemia Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 206010028851 Necrosis Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000002113 chemopreventative effect Effects 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- YEDVUDDWJVRKIS-UHFFFAOYSA-N cyclopenta[b]pyrrole Chemical group C1=C[C]2[N]C=CC2=C1 YEDVUDDWJVRKIS-UHFFFAOYSA-N 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 230000004665 defense response Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 210000002570 interstitial cell Anatomy 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001473 noxious effect Effects 0.000 description 1
- 229940039748 oxalate Drugs 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 210000004738 parenchymal cell Anatomy 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229940076788 pyruvate Drugs 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
Abstract
本发明公开专利申请号为201510253806.6的中国专利公开的合成方法合成的1，2，5‑三取代1，4，5，6‑四氢环戊烷并[b]吡咯类化合物的抗炎活性。通过该环戊烷并[b]吡咯类化合物与市售抗炎药塞来昔布对12‑氧‑十四烷酰佛波醇‑13‑醋酸酯（TPA）介导的小鼠耳朵水肿模型抗炎实验对比证明其有很好的抗炎活性。
Description
技术领域
本发明涉及1,2,5-三取代1,4,5,6-四氢环戊烷并[b]吡咯类化合物及其药用可接受的盐的抗炎活性，属于医药技术领域。
背景技术
炎症是机体组织对损伤性刺激(如有害刺激、病菌或物理损伤)的一种防御反应。在炎症过程中，一方面损伤因子直接或间接造成组织和细胞的破坏，另一方面通过炎症充血和渗出反应，以稀释、杀伤和包围损伤因子。同时通过实质和***的再生功能使受损的组织得以修复和愈合。其中，致炎因子可引起炎症局部组织发生变性和坏死，白细胞介素-1β(IL-1β)、白细胞介素-6 (IL-6)、肿瘤坏死因子α(TNF-α)是常见的至炎因子，其异常增多会导致炎症的发生。因此，通过药物减少过量的致炎因子，是实现炎症化学预防的一个合理的策略。此外，环氧合酶(COX)是花生四烯酸代谢的限速酶，其中 COX-2是一种诱导酶，在组织损伤、炎症等情况下表达增强。降低COX-2表达也是当前预防炎症的重要策略。
含有环戊烷并[b]吡咯结构的化合物1-(4-甲基苯基)-2-(4-甲磺酰基苯基) -二取代1,4,5,6-四氢环戊烷并[b]吡咯作为一种环氧合酶-2抑制剂，已经发展成为一种抗炎药，同时它的使用能够减少传统抗炎药中常伴有的胃肠道副反应，因此，它将成为一种很有市场前景的抗炎药物(P.R.China Pat.,CN1955163A, 2007)。我们之前申报的申请号为：201510253806.6的中国专利报道了一种合成1,2,5-三取代1,4,5,6-四氢环戊烷并[b]吡咯类化合物的新方法。基于该方法合成的一系列1,2,5-三取代1,4,5,6-四氢环戊烷并[b]吡咯类化合物。通过该类化合物与市售抗炎药塞来昔布对12-氧-十四烷酰佛波醇-13-醋酸酯(TPA)介导的小鼠耳朵水肿模型抗炎实验对比证明这些分子有很好的抗炎活性。因此，本发明可为制备新的抗炎药物提供了新的来源。
发明内容
本发明目的在于提供一种具有的1,2,5-三取代1,4,5,6-四氢环戊烷并[b]吡咯类化合物及其药用可接受的盐的抗炎活性。
式Ⅰ的化合物及其药用中可接受的盐在制备抗炎药物中的应用。
其中R1为叔丁基、取代或未取代的苯基，取代基可以是卤素、烷基、烷氧基、硝基；R2为氢、炔丙基、取代或未取代的芳香环和芳烷基、C1-C8取代或未取代直链或支链烷基；R3为氢、取代或未取代的苯基，取代基可以是卤素、烷基、烷氧基、硝基、卤代烷基、卤代烷氧基。
式Ⅰ的化合物及其药用中可接受的盐，R1代表叔丁基、苯基，及取代苯基，如2-甲基苯基、3-甲基苯基、4-甲基苯基、2-甲氧基苯基、3-甲氧基苯基、4-甲氧基苯基、2-氟苯基、3-氟苯基、4-氟苯基、2-氯苯基、3-氯苯基、4-氯苯基、2-溴苯基、3-溴苯基、4-溴苯基、2-碘苯基、3-碘苯基、4-碘苯基、2-硝基苯基、3-硝基苯基、4-硝基苯基、2-三氟甲基苯基、3-三氟甲基苯基、4-三氟甲基苯基。
式Ⅰ的化合物及其药用中可接受的盐，R2代表氢、甲基、乙基、丙基、环丙基、异丙基、丁基、环丁基、异丁基、叔丁基、戊基、环戊基、异戊基、新戊基、己基、环己基、苯基，及取代苯基，如2-甲基苯基、3-甲基苯基、4- 甲基苯基、2-甲氧基苯基、3-甲氧基苯基、4-甲氧基苯基、2-氟苯基、3-氟苯基、4-氟苯基、2-氯苯基、3-氯苯基、4-氯苯基、2-溴苯基、3-溴苯基、4-溴苯基、2-碘苯基、3-碘苯基、4-碘苯基、2-硝基苯基、3-硝基苯基、4-硝基苯基、 2-三氟甲基苯基、3-三氟甲基苯基、4-三氟甲基苯基、苄基、4-甲氧基苄基、苯乙基、苯丙基.
式Ⅰ的化合物及其药用中可接受的盐，R3代表氢、苯基。
式Ⅰ的化合物及其药用中可接受的盐，优选地，通式Ⅰ化合物包括2-苯基-1，4,5,6-四氢环戊烷并吡咯、1-乙基-2-苯基-1，4,5,6-四氢环戊烷并吡咯、1- 丙基-2-苯基-1，4,5,6-四氢环戊烷并吡咯、1-丙基-2-(4甲氧基苯基)-1，4,5,6- 四氢环戊烷并吡咯、1-环丙基-2-苯基-1，4,5,6-四氢环戊烷并吡咯、1-丁基-2-苯基-1，4,5,6-四氢环戊烷并吡咯、1-环己基-2-苯基-1，4,5,6-四氢环戊烷并吡咯、 1-苄基-2-苯基-1，4,5,6-四氢环戊烷并吡咯、1-(4-氯苯基)-2-苯基-1，4,5,6-四氢环戊烷并吡咯、1-(4-氯苯基)-2-苯基-1，4，5，6-四氢环戊烷并吡咯、2- (4-甲氧基苯基)-1，4,5,6-四氢环戊烷并吡咯、1-丙基-2-(4-甲氧基苯基)- 1，4,5,6-四氢环戊烷并吡咯、1,2,5-三苯基-1，4,5,6-四氢环戊烷并吡咯、1-丙基-2,5-二苯基-1，4,5,6-四氢环戊烷并吡咯、1-丙基-2-(4-三氟甲基苯基)-1， 4,5,6-四氢环戊烷并吡咯。
式Ⅰ的化合物及其药用中可接受的盐，其药学上可接受的盐是指无机酸盐和有机酸盐，其中无机盐有硫酸氢盐、硫酸盐、盐酸盐、氢溴酸盐、硝酸盐；有机酸盐有乙酸盐、对甲苯磺酸盐、苯磺酸盐、甲磺酸盐、草酸盐、枸缘酸盐、富马酸盐、苹果酸盐、酒石酸盐、丙酮酸盐。
本发明主要公开通式Ⅰ所示的化合物的抗炎活性。
具体实施例
1,2,5-三取代1,4,5,6-四氢环戊烷并[b]吡咯类化合物的制备。
本发明中环戊烷并吡咯类化合物均可参照我们之前申请号为 201510253806.6的中国专利和期刊文章Chem.Commun.2015,51,12064报道的方法制备。
本发明抗炎活性实验
采用1,2,5-三取代1,4,5,6-四氢环戊烷并[b]吡咯类化合物a-j(式1)与市售抗炎药塞来昔布对12-氧-十四烷酰佛波醇-13-醋酸酯(TPA)介导的小鼠耳朵水肿模型抗炎实验对比来证明其的抗炎活性。
1.药物的配制：
1)将TPA用丙酮溶解配制0.08uM的溶液。
2)分别将塞来昔布和化合物a-j用溶剂(二氯甲烷:二甲基亚砜＝4:1)溶解配制0.75μM的溶液。
2小鼠选择
选取5-6周的雌性BALB/c小鼠(从广东省医学实验动物中心购买)
3试验方法
取0.75μM(15ul)分别溶有塞来昔布和化合物a-j的溶液均匀涂抹在各组小鼠耳朵正反两面，空白对照组和TPA组用15ul混合溶剂(二氯甲烷:二甲基亚砜＝4:1)同样处理。6分钟后，TPA组，塞来昔布阳性对照组和以及化合物a-j 实验组分别用0.08uM(15ul)的TPA处理(均匀涂抹在小鼠耳朵正反两面)，空白对照组用15ul丙酮处理。6h后，将小鼠断锥处死，剪下小鼠耳朵，用6mm的打孔器取耳片，称重。
抗炎抑制率：IE(％)＝[(TPA组耳片重量)-(化合物组耳片重量]/[(TPA组耳片重量)-(空白组耳片重量)]×100.
表1 TPA-诱导的小鼠耳朵抗炎模型检测环戊烷并吡咯化合物抗炎作用
由表1可见，环戊烷并[b]吡咯类化合物a-j具有显著的抗炎活性，因此，可用于制备抗炎药物。
Claims (2)
1.式Ⅰ化合物及其药用上可接受的盐在制备抗炎药物中的应用，
（Ⅰ）
其中R3为氢，R1为苯基，R2为氢、乙基、丙基、环丙基、环己基、苄基、4-氯苯基、4-溴苯基；或R3为氢，R2为氢，R1为4-甲氧基苯基；或R1、R2和R3均为苯基。
2.如权利要求1所述的式Ⅰ化合物及其药用上可接受的盐在制备抗炎药物中的应用，其特征在于，所述药用上可接受的盐为硫酸氢盐、硫酸盐、盐酸盐、氢溴酸盐、硝酸盐、乙酸盐、对甲苯磺酸盐、苯磺酸盐、甲磺酸盐、草酸盐、枸缘酸盐、富马酸盐、苹果酸盐、酒石酸盐、丙酮酸盐。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610421383.9A CN107496419B (zh) | 2016-06-14 | 2016-06-14 | 一种具有抗炎活性的环戊烷并[b]吡咯类化合物 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610421383.9A CN107496419B (zh) | 2016-06-14 | 2016-06-14 | 一种具有抗炎活性的环戊烷并[b]吡咯类化合物 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107496419A CN107496419A (zh) | 2017-12-22 |
| CN107496419B true CN107496419B (zh) | 2021-03-23 |
Family
ID=60679095
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610421383.9A Active CN107496419B (zh) | 2016-06-14 | 2016-06-14 | 一种具有抗炎活性的环戊烷并[b]吡咯类化合物 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107496419B (zh) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109674790B (zh) * | 2019-02-12 | 2021-06-29 | 兰州大学 | 噻唑并吡喃酮类似物在制备抗炎药物中的应用 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3997557A (en) * | 1974-04-23 | 1976-12-14 | American Hoechst Corporation | Substituted N-aminoalkylpyrroles |
| CN100543015C (zh) * | 2005-10-28 | 2009-09-23 | 中国人民解放军军事医学科学院毒物药物研究所 | 环氧合酶-2选择性抑制剂及其医药用途 |
| GB201105979D0 (en) * | 2011-04-07 | 2011-05-18 | Karobio Ab | Novel estrogen receptor ligands |
| CN106278993B (zh) * | 2015-05-15 | 2019-05-21 | 兰州大学 | 一种金催化的多取代吡咯的合成方法 |
-
2016
- 2016-06-14 CN CN201610421383.9A patent/CN107496419B/zh active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN107496419A (zh) | 2017-12-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU754734B2 (en) | Indazole bioisostere replacement of catechol in therapeutically active compounds | |
| MX2022001671A (es) | Sales de un inhibidor de pd-1/pd-l1. | |
| EP1731506A1 (en) | 5-hydroxyindole-3-carboxylates derivatives and their use | |
| JP2017526727A5 (zh) | ||
| NZ604598A (en) | Naphth-2-ylacetic acid derivatives to treat aids | |
| NO20060981L (no) | Pyridazinderivater og deres anvendelse som terapeutiske midler | |
| JP2017527561A5 (zh) | ||
| US20020058687A1 (en) | Therapeutically active compounds based on indazole bioisostere replacement of catechol in pde4 inhibitors | |
| NO327709B1 (no) | 2'-substituerte 1,1'-bifenyl-2-karbonamider, deres anvendelse for fremstilling av et medikament sa vel som farmasoytiske preparater inneholdende disse | |
| ES2437346T3 (es) | Procedimiento para la producción de derivado de diamina | |
| MX2009008546A (es) | Derivados de 3-amino-pirrolo[3,4-c]pirazol-5(1h,4h,6h)carbaldehido como inhibidores de la proteina quinasa c. | |
| MA30344B1 (fr) | Pyrazoles actifs sur la 11-beta-hsd-1 | |
| JP2012533546A5 (zh) | ||
| CN107496419B (zh) | 一种具有抗炎活性的环戊烷并[b]吡咯类化合物 | |
| NO330888B1 (no) | Benzensylfonamidderivater, fremgangsmate for fremstilling av slike, terapeutisk preparatinneholdende slike samt anvendelse av slike for fremstilling av preparat for behandling av sykdom | |
| JP5759000B2 (ja) | 肝疾患治療の薬物の製造におけるジインドリルメタン及びその前駆体並びにその誘導体の応用 | |
| JP2005502636A5 (zh) | ||
| WO2010004221A3 (fr) | Utilisation de derives d'indole comme activateurs de nurr-1, pour le traitement de la maladie de parkinson | |
| RU2008129623A (ru) | Ингибиторы ccr9 активности | |
| EP0888316A1 (en) | 2-(3h)-oxazolone derivatives and their use as cox-2 inhibitors | |
| JP2009509927A5 (zh) | ||
| RU2485102C2 (ru) | Циклические индол-3-карбоксамиды, их получение и их применение в качестве лекарственных препаратов | |
| US9567291B2 (en) | N-(4-(bis(4-(dimethylamino)phenyl)methylene)-8-(dimethylamino) | |
| JP7043784B2 (ja) | 発毛剤 | |
| RU2580551C2 (ru) | Ароматические соединения бутан-2-ола, получение и их применение |
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 | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20240409 Address after: 055550 North side of Jingwu Road, Salt Chemical Industry Park, Ningjin County, Xingtai City, Hebei Province Patentee after: Lanqimengda Pharmaceutical Technology (Ningjin) Co.,Ltd. Country or region after: China Address before: 730000 Lanzhou University, 222 Tianshui South Road, Chengguan District, Lanzhou City, Gansu Province Patentee before: LANZHOU University Country or region before: China |
|
| TR01 | Transfer of patent right |