CN107496419A - A kind of pentamethylene with anti-inflammatory activity simultaneously [b] azoles - Google Patents
A kind of pentamethylene with anti-inflammatory activity simultaneously [b] azoles Download PDFInfo
- Publication number
- CN107496419A CN107496419A CN201610421383.9A CN201610421383A CN107496419A CN 107496419 A CN107496419 A CN 107496419A CN 201610421383 A CN201610421383 A CN 201610421383A CN 107496419 A CN107496419 A CN 107496419A
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- CN
- China
- Prior art keywords
- phenyl
- azoles
- methoxyphenyls
- bromophenyls
- acceptable salt
- 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
- 150000003851 azoles Chemical class 0.000 title claims abstract description 14
- 230000003110 anti-inflammatory effect Effects 0.000 title abstract description 17
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 title abstract description 7
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 title abstract description 7
- -1 cyclopentyl alkane Chemical class 0.000 claims abstract description 33
- 239000002260 anti-inflammatory agent Substances 0.000 claims abstract description 10
- 229940124599 anti-inflammatory drug Drugs 0.000 claims abstract description 6
- 238000006467 substitution reaction Methods 0.000 claims abstract description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims abstract description 3
- 150000003839 salts Chemical class 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 7
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- UJHSIDUUJPTLDY-UHFFFAOYSA-N (2-nitrophenyl)-phenylmethanone Chemical compound [O-][N+](=O)C1=CC=CC=C1C(=O)C1=CC=CC=C1 UJHSIDUUJPTLDY-UHFFFAOYSA-N 0.000 claims description 4
- MFYLRNKOXORIPK-UHFFFAOYSA-N (3-nitrophenyl)-phenylmethanone Chemical class [O-][N+](=O)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 MFYLRNKOXORIPK-UHFFFAOYSA-N 0.000 claims description 4
- ZYMCBJWUWHHVRX-UHFFFAOYSA-N (4-nitrophenyl)-phenylmethanone Chemical class C1=CC([N+](=O)[O-])=CC=C1C(=O)C1=CC=CC=C1 ZYMCBJWUWHHVRX-UHFFFAOYSA-N 0.000 claims description 4
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 4
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 4
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 4
- 125000006305 3-iodophenyl group Chemical group [H]C1=C([H])C(I)=C([H])C(*)=C1[H] 0.000 claims description 4
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 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 4
- 125000006306 4-iodophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1I 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000006304 2-iodophenyl group Chemical group [H]C1=C([H])C(I)=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
- 229940077388 benzenesulfonate Drugs 0.000 claims description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims description 3
- 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 claims description 2
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 2
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 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
- 235000002710 Ilex cornuta Nutrition 0.000 claims description 2
- 241001310146 Ilex cornuta Species 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- 235000010326 Osmanthus heterophyllus Nutrition 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 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
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([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
- VFNGKCDDZUSWLR-UHFFFAOYSA-L disulfate(2-) Chemical compound [O-]S(=O)(=O)OS([O-])(=O)=O VFNGKCDDZUSWLR-UHFFFAOYSA-L 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001188 haloalkyl group Chemical group 0.000 claims description 2
- 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 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 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
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 150000003891 oxalate salts Chemical class 0.000 claims description 2
- 125000004344 phenylpropyl group Chemical group 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
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- BWLBGMIXKSTLSX-UHFFFAOYSA-N 2-hydroxyisobutyric acid Chemical compound CC(C)(O)C(O)=O BWLBGMIXKSTLSX-UHFFFAOYSA-N 0.000 claims 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical class O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical class CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 1
- 229940022663 acetate Drugs 0.000 claims 1
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical class ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims 1
- 229910052731 fluorine Inorganic materials 0.000 claims 1
- 239000011737 fluorine Substances 0.000 claims 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims 1
- 239000004575 stone Substances 0.000 claims 1
- 229950004288 tosilate Drugs 0.000 claims 1
- 240000001307 Myosotis scorpioides Species 0.000 abstract description 7
- 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
- 229940121363 anti-inflammatory agent Drugs 0.000 abstract description 4
- 206010030113 Oedema Diseases 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract 1
- 229910052760 oxygen Inorganic materials 0.000 abstract 1
- 239000001301 oxygen Substances 0.000 abstract 1
- 238000010189 synthetic method Methods 0.000 abstract 1
- 150000003233 pyrroles Chemical class 0.000 description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- 206010061218 Inflammation Diseases 0.000 description 8
- 230000004054 inflammatory process Effects 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 230000006378 damage Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004889 Interleukin-6 Human genes 0.000 description 2
- 108090001005 Interleukin-6 Proteins 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 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
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 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
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000001066 destructive effect Effects 0.000 description 2
- 229940100601 interleukin-6 Drugs 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000000770 proinflammatory effect Effects 0.000 description 2
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 1
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 102000003777 Interleukin-1 beta Human genes 0.000 description 1
- 108090000193 Interleukin-1 beta Proteins 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 206010028851 Necrosis Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical class CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000003632 chemoprophylactic effect Effects 0.000 description 1
- 229940111134 coxibs Drugs 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 210000002570 interstitial cell Anatomy 0.000 description 1
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical class IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229940095064 tartrate Drugs 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
- 238000011282 treatment 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The anti-inflammatory activity of 1,2,5 3 1,4,5,6 tetrahydro cyclopentyl alkane of substitution simultaneously [b] azoles of synthetic method synthesis disclosed in the Chinese patent that Patent Application Publication number of the present invention is 201510253806.6.By the pentamethylene, simultaneously [b] azoles prove that it has good anti-inflammatory activity with commercially available anti-inflammatory agent celecoxib to the mouse ear edema model anti-inflammatory Experimental comparison that the acetate of 12 oxygen Tetradecanoylphorbol 13 (TPA) mediates.Therefore, the present invention can provide new source to prepare new anti-inflammatory drug.
Description
Technical field
The present invention relates to 1,2,5- tri- to substitute 1,4,5,6- tetrahydro cyclopentyls alkane simultaneously [b] azoles and its medicinal to connect
The anti-inflammatory activity for the salt received, belongs to pharmaceutical technology field.
Background technology
Inflammation is a kind of defense reaction of the body tissue to destructive stimulus (such as destructive stimulus, germ or physical damnification).
In inflammatory process, one side damage factor is caused directly or indirectly the destruction of tissue and cell, is on the other hand filled by inflammation
Blood and reaction is oozed out, to dilute, kill and surround damage factor.Make to be damaged by the regeneration function of essence and interstitial cell simultaneously
Tissue be able to repair and heal.Wherein, pro-inflammatory cytokine can cause inflammation local organization that denaturation and necrosis occurs, and leucocyte is situated between
- 1 β of element (IL-1 β), interleukin-6 (IL-6), tumor necrosis factor α (TNF-α) are common to the scorching factor, and it increases extremely
The generation of inflammation can be caused more.Therefore, excessive pro-inflammatory cytokine is reduced by medicine, is to realize the chemoprophylactic conjunction of inflammation
The strategy of reason.In addition, cyclooxygenase (COX) is the rate-limiting enzyme of arachidonic acid metabolic, wherein COX-2 is a kind of induced enzyme,
Enhancing is expressed when tissue damage, inflammation.Reduce the Critical policies of COX-2 expression and current prevention of inflammation.
Containing pentamethylene simultaneously [b] pyrrole structure compound 1- (4- aminomethyl phenyls) -2- (4- methanesulfonylphenYls)-two substitution 1,
Simultaneously [b] pyrroles as a kind of COX-2 inhibitors, has been developed as a kind of anti-inflammatory agent, simultaneously to 4,5,6- tetrahydro cyclopentyl alkane
Its use can reduce the gastrointestinal side effect being often accompanied by traditional anti-inflammatory agent, therefore, before it will have market very much as one kind
The anti-inflammatory drug (P.R.China Pat., CN1955163A, 2007) of scape.The Application No. that we declare before：
201510253806.6 Chinese patent reports a kind of synthesis 1,2,5- tri- and substitutes 1,4,5,6- tetrahydro cyclopentyls alkane simultaneously [b] pyrroles
The new method of class compound.A series of 1,2,5- tri- based on this method synthesis substitute 1,4,5,6- tetrahydro cyclopentyls alkane simultaneously [b] pyrrole
Cough up class compound.By such compound and commercially available anti-inflammatory agent celecoxib to 12- oxygen-Tetradecanoylphorbol -13- acetates
(TPA) the mouse ear edema model anti-inflammatory Experimental comparison of mediation proves that these molecules have good anti-inflammatory activity.Therefore, this hair
It is bright to provide new source to prepare new anti-inflammatory drug.
The content of the invention
Present invention aims at provide a kind of 1,2,5- tri- having to substitute 1,4,5,6- tetrahydro cyclopentyls alkane simultaneously [b] pyroles
The anti-inflammatory activity of compound and its medicinal acceptable salt.
The compound of formula I and its it is medicinal in application of the acceptable salt in anti-inflammatory drug is prepared.
Wherein R1For the tert-butyl group, substituted or unsubstituted phenyl, substituent can be halogen, alkyl, alkoxy, nitro；R2For
Hydrogen, propargyl, substituted or unsubstituted aromatic rings and aralkyl, C1-C8Substitution or unsubstituted straight or branched alkyl；R3For hydrogen,
Substituted or unsubstituted phenyl, substituent can be halogen, alkyl, alkoxy, nitro, haloalkyl, halogenated alkoxy.
The compound of formula I and its it is medicinal in acceptable salt, R1The tert-butyl group, phenyl, and substituted-phenyl are represented, such as 2- methyl
Phenyl, 3- aminomethyl phenyls, 4- aminomethyl phenyls, 2- methoxyphenyls, 3- methoxyphenyls, 4- methoxyphenyls, 2- fluorophenyls, 3-
Fluorophenyl, 4- fluorophenyls, 2- chlorphenyls, 3- chlorphenyls, 4- chlorphenyls, 2- bromophenyls, 3- bromophenyls, 4- bromophenyls, 2- iodobenzenes
Base, 3- iodophenyls, 4- iodophenyls, 2- nitrobenzophenones, 3- nitrobenzophenones, 4- nitrobenzophenones, 2- trifluoromethyls, 3- fluoroforms
Base phenyl, 4- trifluoromethyls.
The compound of formula I and its it is medicinal in acceptable salt, R2Represent hydrogen, methyl, ethyl, propyl group, cyclopropyl, isopropyl
Base, butyl, cyclobutyl, isobutyl group, the tert-butyl group, amyl group, cyclopenta, isopentyl, neopentyl, hexyl, cyclohexyl, phenyl, and take
For phenyl, such as 2- aminomethyl phenyls, 3- aminomethyl phenyls, 4- aminomethyl phenyls, 2- methoxyphenyls, 3- methoxyphenyls, 4- methoxyl groups
Phenyl, 2- fluorophenyls, 3- fluorophenyls, 4- fluorophenyls, 2- chlorphenyls, 3- chlorphenyls, 4- chlorphenyls, 2- bromophenyls, 3- bromophenyls,
4- bromophenyls, 2- iodophenyls, 3- iodophenyls, 4- iodophenyls, 2- nitrobenzophenones, 3- nitrobenzophenones, 4- nitrobenzophenones, 2- fluoroforms
Base phenyl, 3- trifluoromethyls, 4- trifluoromethyls, benzyl, 4- methoxy-benzyls, phenethyl, phenylpropyl
The compound of formula I and its it is medicinal in acceptable salt, R3Represent hydrogen, phenyl.
The compound of formula I and its it is medicinal in acceptable salt, it is preferable that generalformulaⅰcompound includes 2- phenyl-Isosorbide-5-Nitrae, 5,6-
Tetrahydro cyclopentyl alkane and pyrroles, 1- ethyls -2- phenyl-Isosorbide-5-Nitrae, 5,6- tetrahydro cyclopentyl alkane and pyrroles, 1- propyl group -2- phenyl-Isosorbide-5-Nitrae, 5,
6- tetrahydro cyclopentyls alkane and pyrroles, 1- propyl group -2- (4 methoxyphenyl)-Isosorbide-5-Nitrae, 5,6- tetrahydro cyclopentyl alkane and pyrroles, 1- cyclopropyl -
2- phenyl-Isosorbide-5-Nitrae, 5,6- tetrahydro cyclopentyl alkane and pyrroles, 1- butyl -2- phenyl-Isosorbide-5-Nitrae, 5,6- tetrahydro cyclopentyl alkane and pyrroles, 1- hexamethylenes
Base -2- phenyl-Isosorbide-5-Nitrae, 5,6- tetrahydro cyclopentyl alkane and pyrroles, 1- benzyls -2- phenyl-Isosorbide-5-Nitrae, 5,6- tetrahydro cyclopentyl alkane and pyrroles, 1-
(4- chlorphenyls) -2- phenyl-Isosorbide-5-Nitrae, 5,6- tetrahydro cyclopentyl alkane and pyrroles, 1- (4- chlorphenyls) -2- phenyl-Isosorbide-5-Nitrae, 5,6- tetrahydrochysene rings
Pentane and pyrroles, 2- (4- methoxyphenyls)-Isosorbide-5-Nitrae, 5,6- tetrahydro cyclopentyl alkane and pyrroles, 1- propyl group -2- (4- methoxyphenyls) -
Isosorbide-5-Nitrae, 5,6- tetrahydro cyclopentyl alkane and pyrroles, 1,2,5- triphenyls-Isosorbide-5-Nitrae, 5,6- tetrahydro cyclopentyl alkane and pyrroles, 1- propyl group -2,5- bis-
Phenyl-Isosorbide-5-Nitrae, 5,6- tetrahydro cyclopentyl alkane and pyrroles, 1- propyl group -2- (4- trifluoromethyls)-Isosorbide-5-Nitrae, 5,6- tetrahydro cyclopentyl alkane are simultaneously
Pyrroles.
The compound of formula I and its it is medicinal in acceptable salt, its pharmaceutically acceptable salt refers to inorganic acid salt and organic
Hydrochlorate, wherein inorganic salts have disulfate, sulfate, hydrochloride, hydrobromate, nitrate；Acylate has acetate, to first
Benzene sulfonate, benzene sulfonate, mesylate, oxalates, Chinese holly edge hydrochlorate, fumarate, malate, tartrate, pyruvic acid
Salt.
The anti-inflammatory activity of compound shown in main open formula I of the invention.
Specific embodiment
1,2,5- tri- substitutes the preparation of 1,4,5,6- tetrahydro cyclopentyls alkane simultaneously [b] azoles.
Pentamethylene and azoles can refer to Application No. 201510253806.6 before us in the present invention
It is prepared by the method for Chinese patent and journal of writings Chem.Commun.2015,51,12064 reports.
Present anti-inflammatory activity experiment
1,4,5,6- tetrahydro cyclopentyls alkane simultaneously [b] azoles a-j (formula 1) and commercially available anti-inflammatory are substituted using 1,2,5- tri-
Medicine celecoxib is tested to the mouse ear edema model anti-inflammatory of 12- oxygen-Tetradecanoylphorbol -13- acetates (TPA) mediation
Contrast to prove its anti-inflammatory activity.
1. the preparation of medicine：
1) TPA is prepared to 0.08uM solution with acetone solution.
2) respectively by celecoxib and compound a-j solvent (dichloromethane:Dimethyl sulfoxide (DMSO)=4:1) dissolving is prepared
0.75 μM of solution.
2 mouse select
Choose the female BAl BIc/c mouse (being bought from Guangdong Medical Lab Animal Center) of 5-6 weeks
3 test methods
0.75 μM (15ul) is taken uniformly to be applied to each group mouse ear dissolved with celecoxib and compound a-j solution respectively
Tow sides, blank control group and TPA groups 15ul mixed solvent (dichloromethane:Dimethyl sulfoxide (DMSO)=4:1) same processing.6
After minute, TPA groups, celecoxib positive controls and and compound a-j experimental groups respectively with 0.08uM (15ul) TPA
Manage (being uniformly applied to mouse ear tow sides), blank control group 15ul acetone treatments.After 6h, the disconnected cone of mouse is put to death,
Mouse ear is cut, auricle is taken with 6mm card punch, weighs.
Anti-inflammatory inhibiting rate：IE (%)=[(TPA group auricles weight)-(compound group auricle weight]/[(TPA group auricle weights
Amount)-(blank group auricle weight)] × 100.
The mouse ear anti-inflammation models detection pentamethylene and azole compounds antiinflammatory action of the TPA- of table 1 inductions
From table 1, simultaneously [b] azoles a-j has significant anti-inflammatory activity to pentamethylene, therefore, available for making
Standby anti-inflammatory drug.
Claims (5)
1. the application of type I compound and its medicinal acceptable salt in anti-inflammatory drug is prepared.
Wherein R1For the tert-butyl group, substituted or unsubstituted phenyl, substituent can be halogen, alkyl, alkoxy, nitro；R2For
Hydrogen, propargyl, substituted or unsubstituted aromatic rings and aralkyl, C1-C8Substitution or unsubstituted straight or branched alkyl；R3For hydrogen,
Substituted or unsubstituted phenyl, substituent can be halogen, alkyl, alkoxy, nitro, haloalkyl, halogenated alkoxy.
2. the 1,2,5- tri- described in claims 1 substitutes 1,4,5,6- tetrahydro cyclopentyls alkane simultaneously [b] azoles and its medicine
Acceptable salt, R in1The tert-butyl group, phenyl, and substituted-phenyl are represented, such as 2- aminomethyl phenyls, 3- aminomethyl phenyls, 4- methylbenzenes
Base, 2- methoxyphenyls, 3- methoxyphenyls, 4- methoxyphenyls, 2- fluorophenyls, 3- fluorophenyls, 4- fluorophenyls, 2- chlorobenzenes
Base, 3- chlorphenyls, 4- chlorphenyls, 2- bromophenyls, 3- bromophenyls, 4- bromophenyls, 2- iodophenyls, 3- iodophenyls, 4- iodophenyls, 2-
Nitrobenzophenone, 3- nitrobenzophenones, 4- nitrobenzophenones, 2- trifluoromethyls, 3- trifluoromethyls, 4- trifluoromethyls.
3. the 1,2,5- tri- described in claims 1 substitutes 1,4,5,6- tetrahydro cyclopentyls alkane simultaneously [b] azoles and its medicine
Acceptable salt, R in2Represent hydrogen, methyl, ethyl, propyl group, cyclopropyl, isopropyl, butyl, cyclobutyl, isobutyl group, tertiary fourth
Base, amyl group, cyclopenta, isopentyl, neopentyl, hexyl, cyclohexyl, phenyl, and substituted-phenyl, such as 2- aminomethyl phenyls, 3- methyl
Phenyl, 4- aminomethyl phenyls, 2- methoxyphenyls, 3- methoxyphenyls, 4- methoxyphenyls, 2- fluorophenyls, 3- fluorophenyls, 4- fluorine
Phenyl, 2- chlorphenyls, 3- chlorphenyls, 4- chlorphenyls, 2- bromophenyls, 3- bromophenyls, 4- bromophenyls, 2- iodophenyls, 3- iodophenyls,
4- iodophenyls, 2- nitrobenzophenones, 3- nitrobenzophenones, 4- nitrobenzophenones, 2- trifluoromethyls, 3- trifluoromethyls, 4- tri-
Trifluoromethylphenyl, benzyl, 4- methoxy-benzyls, phenethyl, phenylpropyl.
4. the 1,2,5- tri- described in claims 1 substitutes 1,4,5,6- tetrahydro cyclopentyls alkane simultaneously [b] azoles and its medicine
Acceptable salt, R in3Represent hydrogen, phenyl.
5. the 1,2,5- tri- described in claims 1 substitutes 1,4,5,6- tetrahydro cyclopentyls alkane simultaneously [b] azoles and its medicine
The acceptable salt in, its medicinal acceptable salt is to include disulfate, sulfate, hydrochloride, hydrobromate, nitric acid
Salt, acetate, tosilate, benzene sulfonate, mesylate, oxalates, Chinese holly edge hydrochlorate, fumarate, malate, wine
Stone hydrochlorate, acetonate.
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| CN109674790A (en) * | 2019-02-12 | 2019-04-26 | 兰州大学 | Thiazole and the application in preparing anti-inflammatory drugs of pyranone analog |
| CN109674790B (en) * | 2019-02-12 | 2021-06-29 | 兰州大学 | Application of thiazolopyrone analogue in preparation of anti-inflammatory drugs |
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