CN115819326B - Amide compound, preparation method and application thereof - Google Patents
Amide compound, preparation method and application thereof Download PDFInfo
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- CN115819326B CN115819326B CN202211134819.8A CN202211134819A CN115819326B CN 115819326 B CN115819326 B CN 115819326B CN 202211134819 A CN202211134819 A CN 202211134819A CN 115819326 B CN115819326 B CN 115819326B
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- China
- Prior art keywords
- alkyl
- compound
- substituted
- butyl
- mmol
- Prior art date
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- -1 Amide compound Chemical class 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 95
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 claims abstract description 11
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 claims abstract description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 54
- 150000002367 halogens Chemical class 0.000 claims description 54
- 125000000217 alkyl group Chemical group 0.000 claims description 31
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 29
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 20
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 17
- 125000005842 heteroatom Chemical group 0.000 claims description 15
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 14
- 239000000126 substance Substances 0.000 claims description 14
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 13
- 208000002193 Pain Diseases 0.000 claims description 12
- 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 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 12
- 239000011737 fluorine Substances 0.000 claims description 12
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 12
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 11
- JXASPPWQHFOWPL-UHFFFAOYSA-N Tamarixin Natural products C1=C(O)C(OC)=CC=C1C1=C(OC2C(C(O)C(O)C(CO)O2)O)C(=O)C2=C(O)C=C(O)C=C2O1 JXASPPWQHFOWPL-UHFFFAOYSA-N 0.000 claims description 10
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- 206010020772 Hypertension Diseases 0.000 claims description 6
- 238000011282 treatment Methods 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 206010061218 Inflammation Diseases 0.000 claims description 4
- 230000004054 inflammatory process Effects 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 208000017169 kidney disease Diseases 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 2
- 208000031229 Cardiomyopathies Diseases 0.000 claims description 2
- 229940122204 Cyclooxygenase inhibitor Drugs 0.000 claims description 2
- 208000002249 Diabetes Complications Diseases 0.000 claims description 2
- 206010012655 Diabetic complications Diseases 0.000 claims description 2
- 206010065390 Inflammatory pain Diseases 0.000 claims description 2
- 206010035664 Pneumonia Diseases 0.000 claims description 2
- 208000003782 Raynaud disease Diseases 0.000 claims description 2
- 208000012322 Raynaud phenomenon Diseases 0.000 claims description 2
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- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 claims description 2
- 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
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- 238000006482 condensation reaction Methods 0.000 claims description 2
- 208000028208 end stage renal disease Diseases 0.000 claims description 2
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- 239000011630 iodine Substances 0.000 claims description 2
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- 239000002599 prostaglandin synthase inhibitor Substances 0.000 claims description 2
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- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims 1
- 239000002671 adjuvant Substances 0.000 claims 1
- 208000033679 diabetic kidney disease Diseases 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 66
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 51
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- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 28
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 241000700159 Rattus Species 0.000 description 24
- 238000000034 method Methods 0.000 description 22
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 20
- 238000012360 testing method Methods 0.000 description 20
- 238000005160 1H NMR spectroscopy Methods 0.000 description 17
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 17
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 14
- 235000019253 formic acid Nutrition 0.000 description 14
- 239000000843 powder Substances 0.000 description 14
- 125000004093 cyano group Chemical group *C#N 0.000 description 13
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 12
- 125000003545 alkoxy group Chemical group 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- 229910052739 hydrogen Inorganic materials 0.000 description 12
- 239000001257 hydrogen Substances 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
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- 239000012074 organic phase Substances 0.000 description 10
- 238000000926 separation method Methods 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 108020002908 Epoxide hydrolase Proteins 0.000 description 8
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 8
- 206010012601 diabetes mellitus Diseases 0.000 description 8
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- 238000002347 injection Methods 0.000 description 8
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 7
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 6
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
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- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 5
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- BPFZRKQDXVZTFD-UHFFFAOYSA-N disulfur decafluoride Chemical compound FS(F)(F)(F)(F)S(F)(F)(F)(F)F BPFZRKQDXVZTFD-UHFFFAOYSA-N 0.000 description 4
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- UPSFMJHZUCSEHU-JYGUBCOQSA-N n-[(2s,3r,4r,5s,6r)-2-[(2r,3s,4r,5r,6s)-5-acetamido-4-hydroxy-2-(hydroxymethyl)-6-(4-methyl-2-oxochromen-7-yl)oxyoxan-3-yl]oxy-4,5-dihydroxy-6-(hydroxymethyl)oxan-3-yl]acetamide Chemical compound CC(=O)N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@H]1[C@H](O)[C@@H](NC(C)=O)[C@H](OC=2C=C3OC(=O)C=C(C)C3=CC=2)O[C@@H]1CO UPSFMJHZUCSEHU-JYGUBCOQSA-N 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000002732 pharmacokinetic assay Methods 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000012716 precipitator Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- UAXOELSVPTZZQG-UHFFFAOYSA-N tiglic acid Natural products CC(C)=C(C)C(O)=O UAXOELSVPTZZQG-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种酰胺类化合物、其制备方法及其应用。本发明的酰胺类化合物的结构如式I‑1或I‑2所示。本发明的化合物对可溶性环氧酶具有较好的抑制效果。 The present invention discloses an amide compound, a preparation method thereof and an application thereof. The structure of the amide compound of the present invention is shown in Formula I-1 or I-2. The compound of the present invention has a good inhibitory effect on soluble cyclooxygenase.
Description
Technical Field
The invention relates to an amide compound, a preparation method and application thereof.
Background
Epoxide hydrolases (EH, EC 3.3.2.3) catalyze the hydrolysis of epoxides or aromatic oxides to their corresponding diols (see Oesch, F. Et al, xenobiological, 1973,3,305-340). Some EHs play a vital role in the metabolism of a variety of compounds, including hormones, chemotherapeutics, carcinogens, environmental pollutants, mycotoxins and other harmful foreign compounds.
Microsomal epoxide hydrolase (mEH) and soluble epoxide hydrolase (sEH) are two well-studied EHs. In recent years, 1, 3-disubstituted ureas, carbamates and amides have been reported to be effective and stable novel inhibitors of sEH. Chinese patent CN101084216a reports urea containing a trifluoromethylphenyl substitution. There is still a need to develop more compounds with similar or improved activity.
Disclosure of Invention
The invention aims to solve the technical problem that the structure of the existing medicine for inhibiting the soluble cyclooxygenase is single, and therefore, the invention provides an amide compound, a preparation method and application thereof. The compound has a good inhibition effect on soluble cyclooxygenase.
The invention provides a compound shown as a formula I-1 or I-2 or pharmaceutically acceptable salt thereof,
Wherein R 1 is a 5-to 8-membered heterocycloalkyl group, "cyclohexyl group substituted by 1 or more R 1-2" or "5-to 8-membered heterocycloalkyl group substituted by 1 or more R 1-1";
Each R 1-1 is independently C 1-C6 alkyl, Phenyl, "C 1-C6 alkyl substituted with 1 or more halo" or "phenyl substituted with 1 or more R 1-1-2";
R 1-1-1 is hydrogen, C 3-C6 cycloalkyl or C 1-C6 alkyl;
R 1-1-2 is carboxyl or cyano;
R 1-1-1-1 is hydrogen, C 3-C6 cycloalkyl or C 1-C6 alkyl;
Each R 1-1-1-2 is independently hydrogen, C 3-C6 cycloalkyl or C 1-C6 alkyl;
Each R 1-2 is independently
R 1-2-1 is phenyl or "phenyl substituted with 1 or more R 1-2-1-1";
Each R 1-2-1-1 is independently carboxyl or cyano;
n is 0, 1, 2 or 3;
Each R 2 is independently C 1-C6 alkyl, "C 1-C6 alkyl substituted with 1 or more halogens", "C 1-C6 alkoxy substituted with 1 or more halogens", halogen or sulfur pentafluoride;
R 1' is 'cyclohexyl substituted by 1 or more R 1'-2' or '5-to 8-membered heterocycloalkyl substituted by 1 or more R 1'-1', wherein in the 5-to 8-membered heterocycloalkyl, the heteroatom is nitrogen, and the number of the heteroatoms is 1 or 2;
each R 1'-1 is independently "C 1-C6 alkyl substituted with 1 or more halogens";
each R 1'-2 is independently
R 1'-2-1 is phenyl or "phenyl substituted with 1 or more R 1'-2-1-1";
Each R 1'-2-1-1 is independently carboxyl or cyano.
In one embodiment, in the compound shown as I-1 or I-2 or the pharmaceutically acceptable salt thereof, certain groups can be defined as follows, other groups can be defined as described in any one of the embodiments (hereinafter referred to as "in one embodiment"),
Wherein R 1 is a 5-to 8-membered heterocycloalkyl group, "cyclohexyl group substituted by 1 or more R 1-2" or "5-to 8-membered heterocycloalkyl group substituted by 1 or more R 1-1";
Each R 1-1 is independently C 1-C6 alkyl, Phenyl, "C 1-C6 alkyl substituted with 1 or more halo" or "phenyl substituted with 1 or more R 1-1-2";
R 1-1-1 is hydrogen, C 3-C6 cycloalkyl or C 1-C6 alkyl;
R 1-1-2 is carboxyl or cyano;
R 1-1-1-1 is hydrogen, C 3-C6 cycloalkyl or C 1-C6 alkyl;
Each R 1-1-1-2 is independently hydrogen, C 3-C6 cycloalkyl or C 1-C6 alkyl;
Each R 1-2 is independently
R 1-2-1 is phenyl or "phenyl substituted with 1 or more R 1-2-1-1";
Each R 1-2-1-1 is independently carboxyl or cyano.
In one scheme, R 1 is 6-membered heterocycloalkyl, cyclohexyl substituted by 1R 1-2 or 6-membered nitrogen-containing heterocycloalkyl substituted by 1R 1-1, wherein in the 6-membered heterocycloalkyl, a heteroatom is nitrogen, and the number of heteroatoms is 1 or 2;
r 1-1 is C 1-C6 alkyl, "C 1-C6 alkyl substituted with 2 halogens", "C 1-C6 alkyl substituted with 3 halogens", or
R 1-1-1 isOr C 1-C6 alkyl;
r 1-1-1-1 is C 3-C6 cycloalkyl or C 1-C6 alkyl;
Each R 1-1-1-2 is independently hydrogen or C 1-C6 alkyl, and two R 1-1-1-2 are not simultaneously hydrogen;
R 1-2 is
R 1-2-1 is phenyl or "phenyl substituted with 1R 1-2-1-1";
R 1-2-1-1 is carboxyl or cyano;
n is 1 or 2, each R 2 is independently "C 1-C6 alkyl substituted with 3 halogens", "C 1-C6 alkoxy substituted with 3 halogens", halogen or sulfur pentafluoride;
R 1' is "cyclohexyl substituted with 1R 1'-2" or "6 membered nitrogen containing heterocycloalkyl substituted with 1R 1'-1";
Each R 1'-1 is independently "C 1-C6 alkyl substituted with 3 halogens";
each R 1'-2 is independently
R 1'-2-1 is phenyl or "phenyl substituted with 1R 1'-2-1-1";
Each R 1'-2-1-1 is independently carboxyl or cyano.
In one scheme, R 1 is 6-membered heterocycloalkyl, cyclohexyl substituted by 1R 1-2 or 6-membered nitrogen-containing heterocycloalkyl substituted by 1R 1-1, wherein in the 6-membered heterocycloalkyl, a heteroatom is nitrogen, and the number of heteroatoms is 1 or 2;
R 1-1 is C 1-C6 alkyl, "C 1-C6 alkyl substituted by 3 halogens" or
R 1-1-1 isOr C 1-C6 alkyl;
r 1-1-1-1 is C 3-C6 cycloalkyl or C 1-C6 alkyl;
Each R 1-1-1-2 is independently hydrogen or C 1-C6 alkyl, and two R 1-1-1-2 are not simultaneously hydrogen;
R 1-2 is
R 1-2-1 is phenyl or "phenyl substituted with 1R 1-2-1-1";
R 1-2-1-1 is carboxyl or cyano.
In one embodiment, R 1 is "cyclohexyl substituted with 1R 1-2" or "6 membered nitrogen containing heterocycloalkyl substituted with 1R 1-1";
R 1-1 is "C 1-C6 alkyl substituted by 3 halogens" or
R 1-1-1 isOr C 1-C6 alkyl;
R 1-1-1-1 is C 1-C6 alkyl;
R 1-2 is
R 1-2-1 is phenyl or "phenyl substituted with 1R 1-2-1-1";
R 1-2-1-1 is carboxyl or cyano;
n is 1 or 2, each R 2 is independently "C 1-C6 alkyl substituted with 3 halogens", "C 1-C6 alkoxy substituted with 3 halogens", halogen or sulfur pentafluoride;
R 1' is "6 membered nitrogen containing heterocycloalkyl substituted with 1R 1'-1";
R 1'-1 is "C 1-C6 alkyl substituted with 3 halogens".
In one embodiment, R 1 is "6 membered nitrogen containing heterocycloalkyl substituted with 1R 1-1";
R 1-1 is "C 1-C4 alkyl substituted by 3 fluorine" or
R 1-1-1 isOr c 1-C4 alkyl;
R 1-1-1-1 is C 1-C4 alkyl;
When n is 1, R 2 is "C 1-C6 alkoxy substituted with 3 halogens", R 1' is "6 membered nitrogen containing heterocycloalkyl substituted with 1R 1'-1", R 1'-1 is "C 1-C4 alkyl substituted with 3 halogens";
When n is 2, R 2 is "C 1-C6 alkoxy substituted with 3 halogens" and halogen, R 1' is "6 membered nitrogen containing heterocycloalkyl substituted with 1R 1'-1", R 1'-1 is "C 1-C4 alkyl substituted with 3 halogens".
In one embodiment, R 1 is 6 membered heterocycloalkyl, "cyclohexyl substituted with 1R 1-2" or "6 membered nitrogen containing heterocycloalkyl substituted with 1R 1-1", wherein the heteroatom is nitrogen and the number of heteroatoms is 1 or 2, preferably R 1 is "cyclohexyl substituted with 1R 1-2" or "6 membered nitrogen containing heterocycloalkyl substituted with 1R 1-1", and more preferably R 1 is "6 membered nitrogen containing heterocycloalkyl substituted with 1R 1-1".
In one embodiment, R 1-1 is C 1-C6 alkyl, "C 1-C6 alkyl substituted with 2 halogens", "C 1-C6 alkyl substituted with 3 halogens", orPreferably, R 1-1 is "C 1-C6 alkyl substituted by 3 halogens" orMore preferably, R 1-1 is "C 1-C4 alkyl substituted with 3 fluoro" or
In one embodiment, R 1-1-1 isOr C 1-C6 alkyl, preferably R 1-1-1 isOr C 1-C6 alkyl, more preferably R 1-1-1 isOr C 1-C4 alkyl.
In one embodiment, R 1-1-1-1 is C 3-C6 cycloalkyl or C 1-C6 alkyl, preferably R 1-1-1-1 is C 1-C6 alkyl, more preferably R 1-1-1-1 is C 1-C4 alkyl.
In one embodiment, each R 1-1-1-2 is independently hydrogen or C 1-C6 alkyl, and two R 1-1-1-2 are not both hydrogen.
In one embodiment, R 1-2 is
In one embodiment, R 1-2-1 is phenyl or "phenyl substituted with 1R 1-2-1-1".
In one embodiment, R 1-2-1-1 is carboxyl or cyano.
In one embodiment, n is 1 or 2.
In one embodiment, R 2 is independently "C 1-C6 alkyl substituted with 3 halogens", "C 1-C6 alkoxy substituted with 3 halogens", halogen or sulfur pentafluoride.
In one embodiment, R 1' is "cyclohexyl substituted with 1R 1'-2" or "6 membered nitrogen containing heterocycloalkyl substituted with 1R 1'-1", preferably R 1' is "6 membered nitrogen containing heterocycloalkyl substituted with 1R 1'-1".
In one embodiment, each R 1'-1 is independently "C 1-C6 alkyl substituted with 3 halogens".
In one embodiment, each R 1'-2 is independently
In one embodiment, R 1'-2-1 is phenyl or "phenyl substituted with 1R 1'-2-1-1".
In one embodiment, each R 1'-2-1-1 is independently carboxyl or cyano.
In one embodiment, when n is 1, R 2 is "C 1-C6 alkoxy substituted with 3 halogens".
In one embodiment, when n is 2, R 2 is "C 1-C6 alkoxy substituted with 3 halogens" and halogen.
In one scheme, R 1 is 'cyclohexyl substituted by 1R 1-2' or '5-to 8-membered heterocycloalkyl substituted by 1 or more R 1-1', wherein in the 5-to 8-membered heterocycloalkyl, a heteroatom is nitrogen, and the number of heteroatoms is 1 or 2;
R 1-1 is C 1-C6 alkyl, Or "C 1-C6 alkyl substituted with 1 or more halogens";
R 1-1-1 is Or C 1-C6 alkyl, R 1-1-1-1 is C 1-C6 alkyl;
R 1-2 is
R 1-2-1 is phenyl or "phenyl substituted by 1R 1-2-1-1", R 1-2-1-1 is carboxyl or cyano.
In one embodiment, R 1 is a 5-or 6-membered heterocycloalkyl, optionally piperidinyl, e.g.
In one embodiment, R 1, the "5-to 8-membered heterocycloalkyl substituted with 1 or more R 1-1" may be "5-or 6-membered heterocycloalkyl substituted with 1 or more R 1-1"; e.gWherein nitrogen is attached to R 1-1 connected with .
In one embodiment, R 1-1 is C 1-C6 alkyl which may be C 1-C4 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, ethyl or isopropyl.
In one embodiment, in R 1-1, the C 1-C6 alkyl in the "C 1-C6 alkyl substituted by 1 or more halogens" may be C 1-C4 alkyl, the C 1-C4 alkyl may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, and may also be methyl, ethyl, n-propyl or isopropyl.
In one embodiment, R 1-1 wherein halogen in the "C 1-C6 alkyl substituted with 1 or more halogen" is fluorine, chlorine, bromine or iodine, further preferably the "C 1-C6 alkyl substituted with 1 or more halogen" is C 1-C6 alkyl substituted with 1 or more fluorine ", for example trifluoromethyl,
In one embodiment, R 1-1, the "phenyl substituted with 1 or more R 1-1-2" may be phenyl substituted with carboxyl or phenyl substituted with cyano, e.g
In one embodiment, R 1-1-1 is C 1-C6 alkyl which may be C 1-C4 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, or isobutylOr isopropyl.
In one embodiment, R 1-1-1 is a C 3-C6 cycloalkyl group which may be cyclopropane, cyclobutane, cyclopentane or cyclohexane, or may be cyclopropane.
In one embodiment, R 1-1-1-1 is C 1-C6 alkyl which may be C 1-C4 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, or methyl, ethyl or isopropyl.
In one embodiment, R 1-1-1-1 is a C 3-C6 cycloalkyl group which may be cyclopropane, cyclobutane, cyclopentane or cyclohexane, or may be cyclopropane.
In one embodiment, R 1-1-1-2 is C 1-C6 alkyl which may be C 1-C4 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, or methyl or isopropyl.
In one embodiment, R 1-1-1-2 is a C 3-C6 cycloalkyl group which may be cyclopropane, cyclobutane, cyclopentane or cyclohexane, or may be cyclopropane.
In one embodiment, in R 2, the C 1-C6 alkyl in the "C 1-C6 alkyl" may be C 1-C4 alkyl, the C 1-C4 alkyl may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, and may be ethyl.
In one embodiment, in R 2, the C 1-C6 alkyl in the "C 1-C6 alkyl substituted by 1 or more halogens" may be C 1-C4 alkyl, and the C 1-C4 alkyl may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, and may also be ethyl.
In one embodiment, R 2, the "C 1-C6 alkyl substituted with 1 or more halogen" halogen may be fluoro, chloro, bromo or iodo, and more preferably, the "C 1-C6 alkyl substituted with 1 or more halogen" may be "C 1-C6 alkyl substituted with 1 or more fluoro", such as trifluoromethyl.
In one embodiment, in R 2, the C 1-C6 alkoxy group in the "C 1-C6 alkoxy group substituted with 1 or more halogens" may be a C 1-C4 alkoxy group, the C 1-C4 alkoxy group is preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy, the C 1-C4 alkoxy group is also preferably methyloxy, and further preferably the "C 1-C6 alkoxy group substituted with 1 or more halogens" is a trifluoro-substituted C 1-C4 alkoxy group, such as trifluoromethoxy.
In a certain scheme, in R 2, the halogen can be fluorine, chlorine, bromine or iodine, and also can be fluorine.
In one embodiment, R 1', the "5-to 8-membered heterocycloalkyl substituted with 1 or more R 1'-1" may be "5-or 6-membered heterocycloalkyl substituted with 1 or more R 1'-1"; e.gWherein nitrogen is attached to R 1'-1.
In one embodiment, in R 1'-1, the C 1-C6 alkyl in the "C 1-C6 alkyl substituted by 1 or more halogens" is C 1-C4 alkyl, and the C 1-C4 alkyl may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, and may also be methyl, ethyl or isopropyl.
In one embodiment, R 1'-1 wherein the halogen in the "C 1-C6 alkyl substituted with 1 or more halogens" may be fluorine, chlorine, bromine or iodine, and further preferably the "C 1-C6 alkyl substituted with 1 or more halogens" is "C 1-C6 alkyl substituted with 1 or more fluorine", such as trifluoromethyl or trifluoroethyl.
In one aspect of the present invention,Can be
In one embodiment, R 1 may bePreferably isR 1-1 and R 1-2 are as described above.
In one embodiment, R 1-1 may be
The present invention also provides a compound of formula (i),
In one embodiment, the compound shown as the formula I-1 is
The invention also provides a preparation method of the compound shown in the formula I-1, which comprises the following steps of carrying out condensation reaction of the compound shown in the formula II and an amine compound in the presence of alkali in a solvent, wherein R 1 is defined as above;
In one embodiment, the solvent may be a solvent conventional in the art, and the solvent may be an anhydrous solvent. The solvent may be selected from one or more of an ether solvent, a chlorinated alkane and an aromatic solvent. The ether solvent is preferably diethyl ether, tetrahydrofuran or tert-butyl methyl ether. The chlorinated alkane is preferably dichloromethane. The aromatic solvent is preferably toluene or benzene.
In one embodiment, the solvent is used in an amount conventional in the art, for example, the solvent to compound of formula II may be used in a volume molar ratio of 1-10mL/mmol, for example, 2mL/mmol or 8mL/mmol.
In one embodiment, the molar ratio of the compound of formula II to the amine compound may be 1:1-3, e.g., 1.5 or 1.7.
In one embodiment, the base may be an organic base conventional in the art, for example, the base may be a nitrogen-containing organic base, such as triethylamine.
In one embodiment, the base may be used in amounts conventional in the art, for example, the molar ratio of the compound of formula II to base may be 1:1-3, for example 1.5 or 1.7.
The invention also provides application of the substance Z in preparing a medicament for treating and/or preventing diseases related to soluble cyclooxygenase, wherein the substance Z is a compound shown as the formula I-1 or the formula I-2 or pharmaceutically acceptable salt thereof.
Preferably, the disease is hypertension, pain, cardiomyopathy, inflammation, adult respiratory distress syndrome, diabetic complications, kidney disease, raynaud's syndrome or arthritis.
The pain is preferably neuropathic pain and/or inflammatory pain.
The kidney disease is preferably end stage kidney disease.
The hypertension is preferably renal hypertension, liver hypertension or pulmonary hypertension.
The inflammation is preferably kidney inflammation, vascular inflammation or lung inflammation.
The invention also provides application of the substance Z in preparing the soluble cyclooxygenase inhibitor, wherein the substance Z is a compound shown as the formula I-1 or the formula I-2 or pharmaceutically acceptable salt thereof.
The invention also provides a pharmaceutical composition which comprises a substance Z and pharmaceutical excipients, wherein the substance Z is a compound shown as the formula I-1 or the formula I-2 or pharmaceutically acceptable salt thereof.
In the pharmaceutical composition, the substance Z may be a therapeutically effective amount of substance Z.
Definition of terms
Certain chemical groups defined herein are preceded by a simplified symbol to indicate the total number of carbon atoms present in the group. For example, C 1-C6 alkyl refers to an alkyl group as defined below having a total of 1,2,3, 4, 5 or 6 carbon atoms. The total number of carbon atoms in the reduced notation does not include carbon that may be present in a substituent of the group.
The term "plurality" refers to 2, 3, 4, or 5.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "heterocycloalkyl" refers to a cyclic group of a specified number of ring atoms (e.g., 5-10 membered), of a specified number of heteroatoms (e.g., 1,2, or 3), of a specified heteroatom species (one or more of N, O and S), which is a single ring, bridged ring, or spiro ring, and each ring is saturated. Heterocycloalkyl groups include, but are not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, piperidinyl, and the like.
The term "nitrogen-containing heterocycloalkyl" refers to a cyclic group having a specified number of ring atoms (e.g., 5-10 membered, such as 6 membered) and a specified number of heteroatoms (e.g., 1,2, or 3), the heteroatoms being nitrogen, and each ring being saturated.
The term "pharmaceutically acceptable salt" refers to salts formed from suitable non-toxic organic acids, inorganic acids, organic bases or inorganic bases with compounds of formula I-1 which retain the biological activity of the compounds of formula I-1.
The term "pharmaceutical excipients" refers to excipients and additives used in the manufacture of medicaments and formulation of prescriptions, and is all matter contained in the pharmaceutical formulation except for the active ingredient. See the pharmacopoeia of the people's republic of China (2015 Edition), or Handbook of Pharmaceutical Excipients (Raymond C Rowe,2009 sibth Edition).
The term "treatment" refers to therapeutic therapy. Treatment, where a particular disorder is involved, refers to (1) alleviation of a disease or one or more biological manifestations of a disorder, (2) interference with (a) one or more points in a biological cascade leading to or causing a disorder or (b) one or more biological manifestations of a disorder, (3) amelioration of one or more symptoms, effects or side effects associated with a disorder, or one or more symptoms, effects or side effects associated with a disorder or treatment thereof, or (4) alleviation of progression of a disorder or one or more biological manifestations of a disorder.
The term "preventing" refers to a reduced risk of acquiring or developing a disease or disorder.
The term "therapeutically effective amount" refers to an amount of a compound that is sufficient to effectively treat a disease or disorder described herein when administered to a patient. The "therapeutically effective amount" will vary depending on the compound, the condition and severity thereof, and the age of the patient to be treated, but can be adjusted as desired by one of ordinary skill in the art.
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.
The reagents and materials used in the present invention are commercially available.
The positive progress of the invention is that the compound has one or more of better inhibition effect on soluble cyclooxygenase, good metabolic property (such as half-life, exposure dose AUC, maximum blood concentration Cmax) and higher pain inhibition effect.
Drawings
Fig. 1 is the effect of compounds on the mechanical pain threshold of diabetic neuropathic pain rats, each group compared to pre-dose (0 h), "x" indicated P <0.05; "×" indicated P <0.01.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
Preparation of chromatographic conditions for isolation (purification):
Separation conditions:
Mobile phase A water (0.225% formic acid) mobile phase B acetonitrile
Chromatographic column Phenomenexluna C, 150 x 40mm x 15 μm
Gradient elution of 37-67% mobile phase B
Gradient elution time 10min
Detection wavelength of 254nm
The flow rate (mL/min) was 60mL/min.
EXAMPLE 1 Synthesis of BX20-6-I05
The synthetic route is shown in the following formula:
Triphosgene (0.91 g,3.07 mmol) was dissolved in anhydrous DCM (15 mL), ethanol/liquid nitrogen bath was cooled to-78 ℃, XR020007-S1 (1.50 g,6.84 mmol), TEA (triethylamine) (1.04 g,10.3 mmol) was dissolved in anhydrous DCM (15 mL), and then added dropwise to the reaction solution, after reaction for 1h at 0℃and then cooled again to-78 ℃, XR020007-S2 (2.05 g,10.3 mmol), TEA (1.04 g,10.3 mmol) was dissolved in anhydrous DCM (15 mL), and then added dropwise to the reaction solution, after the dropwise addition was completed and then reaction was carried out for 0.5h at room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (PE/EA=10/1 to 1/1, V/V) to give a white solid BX20-6-I05 (2.60 g, 86.6%).
1H NMR(400MHz,DMSO-d6)δ＝8.87(s,1H),7.71(d,J＝7.6Hz,2H),7.53(d,J＝7.6Hz,2H),6.36(d,J＝8.0Hz,1H),3.81-3.79(m,2H),3.65-3.60(m,1H),2.92-2.85(m,2H),1.79-1.75(m,2H),1.38(s,9H),1.29-1.21(m,2H);MS(ESI,m/z)390.1[M-t-Bu+H]+.
Example 2 Synthesis of BX20-6-007
First step Synthesis of BX20-6-I05
By proceeding as in example 1, white solid BX20-6-I05 was obtained.
Second step XR020007-I03 Synthesis
The synthetic route is shown in the following formula:
Compound BX20-5-I05 (0.80 g,1.35 mmol) was added to HCl/MeOH (2M, 10 mL) and the reaction mixture was hydrogenated at room temperature for 12h. After the reaction, the reaction mixture was concentrated directly to give compound XR020007-I03 (0.62 g, hydrochloride, crude) which was used directly in the next reaction, MS (ESI, m/z) 346.3[ M+H ] +.
Third step, synthesis of BX20-6-007
The synthetic route is shown in the following formula:
Crude compound XR020007-I03 (0.62 g,1.80 mmol), isobutyric acid (0.19 g,2.16 mmol), T3P (3.44 g,50% ethyl acetate solution, 5.40 mmol), TEA (0.55 g,5.40 mmol) were added sequentially to anhydrous DCM (10 mL) and the reaction mixture reacted at 15℃for 18h. After the reaction, the reaction mixture was concentrated directly at 40℃under reduced pressure to give a residue, which was purified by preparative separation (formic acid system) and lyophilized to give Compound BX20-6-007 (72 mg, yield 9.6%) as a white powder.
1H NMR(400MHz,DMSO-d6)δ＝8.91(s,1H),7.71(d,J＝7.6Hz,2H),7.54(d,J＝7.6Hz,2H),6.40(d,J＝8.0Hz,1H),4.19-4.16(m,1H),3.85-3.82(m,1H),3.72-3.69(m,1H),3.17-3.11(m,1H),2.89-2.73(m,2H),1.87-1.77(m,2H),1.31-1.17(m,2H),0.99-0.96(m,6H);MS(ESI,m/z)416.4[M+H]+.
EXAMPLE 3 Synthesis of BX20-6-010
Synthesis of S4-010 in the first step
Triphosgene (0.49 g,1.64 mmol) was dissolved in anhydrous DCM (30 ml) under N2 protection, ethanol/liquid nitrogen bath was cooled to-78 ℃, XR020007-S1 (0.80 g,3.65 mmol), TEA (triethylamine) (0.55 g,5.50 mmol) was dissolved in anhydrous DCM (15 ml), added dropwise to the above reaction solution, after reaction for 1h at 0℃and cooling again to-78 ℃, S3-010 (1.18 g,5.47 mmol), TEA (0.55 g,5.50 mmol) were dissolved in anhydrous DCM (15 ml), added dropwise to the above reaction solution, after the addition was completed and naturally warmed to room temperature for 0.5h, the reaction was concentrated directly at 40℃under reduced pressure, the residue was purified by column chromatography (PE/EA=2/1~0/1, V/V) to give white solid S4-010 (0.90 g, yield 53%).
Second step Synthesis of BX20-6-010
The synthetic route is shown in the following formula:
Crude S4-010 (0.65 g,1.41 mmol) was added to absolute ethanol (20 mL) and a further 6N NaOH solution (10 mL) and the reaction mixture was reacted at 75℃for 12h. After the reaction, the reaction solution was adjusted to pH 2 with concentrated HCl to precipitate a solid, and the reaction solution was filtered to obtain a cake, which was purified by preparative separation (formic acid system) and lyophilized to give BX20-6-010 (310 mg, yield 45.8%) as a white powder.
1H NMR(400MHz,DMSO-d6)δ＝8.84(s,1H),7.86(d,J＝7.6Hz,2H),7.73(d,J＝7.6Hz,2H),7.55(d,J＝8.0Hz,2H),7.03(d,J＝8.0Hz,2H),6.34(d,J＝7.6Hz,1H),4.48-4.43(m,1H),3.57-3.54(m,1H),2.07-1.93(m,4H),1.54-1.35(m,4H).
EXAMPLE 4 Synthesis of BX20-6-023
First step XR020007-I03 Synthesis
According to the second step of example 2, compound XR020007-I03 was obtained.
Second step Synthesis of BX20-6-023
The synthetic route is shown in the following formula:
(S) - (+) -2-methylbutanoic acid (0.19 g,2.16 mmol), HATU (912 mg,2.20 mmol) were added to anhydrous DMF (5 mL), stirred at 25℃for 10min, the reaction mixture was cooled to 0℃and XR020007-I03 (0.76 g,2.00 mmol), DIPEA (1.03 g,8.00 mmol) was added and the reaction mixture reacted at 25℃for 12h. After the reaction, water (50 mL) was added to the reaction solution, extracted with EA (20 ml×3), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 40 ℃, the residue was purified by column chromatography (PE/ea=2/1~0/1), purified by preparative separation (formic acid system), and lyophilized to give a white powdery compound BX20-6-023 (305 mg, yield 35.5％).1H NMR(400MHz,DMSO-d6)δ＝8.87(d,J＝11.6Hz,1H),7.73(d,J＝7.6Hz,2H),7.56(d,J＝7.6Hz,2H),6.43-6.39(m,1H),4.25-4.19(m,1H),3.90-3.87(m,1H),3.76-3.69(m,1H),3.20-3.14(m,1H),2.82-2.68(m,2H),1.87-1.77(m,2H),1.58-1.52(m,1H),1.33-1.23(m,3H),0.97(t,J＝6.0Hz,3H),0.83-0.78(m,3H);MS(ESI,m/z)430.1[M+H]+.
Example 5 Synthesis of BX20-6-024
First step XR020007-I03 Synthesis
According to the second step of example 2, compound XR020007-I03 was obtained.
Second step Synthesis of BX20-6-024
The synthetic route is shown in the following formula:
XR020007-I03 (0.60 g,1.57 mmol) was added to anhydrous DCM (15 mL), triethylamine (0.47 g,4.71 mmol) was added and the reaction mixture stirred for 5min at 25℃then isopropyl chloroformate (0.23 g,1.90 mmol) was added dropwise and the reaction mixture reacted at 25℃for 12h. After completion of the reaction, water (1 mL) was added to the reaction mixture, which was concentrated under reduced pressure at 40℃to give a residue, which was purified by column chromatography (PE/ea=2/1~0/1) to give compound BX20-6-024 (416 mg, yield 61%) as a white powder.
1H NMR(400MHz,DMSO-d6)δ＝8.88(s,1H),7.73(d,J＝7.6Hz,2H),7.52(d,J＝7.6Hz,2H),6.36(d,J＝7.6Hz,1H),4.79-4.73(m,1H),3.87-3.83(m,2H),3.70-3.64(m,1H),3.00-2.94(m,2H),1.82-1.77(m,2H),1.29-1.23(m,2H),1.18(d,J＝8.0Hz,6H);MS(ESI,m/z)432.1[M+H]+.
Example 6 Synthesis of BX20-6-025
First step XR020007-I03 Synthesis
According to the second step of example 2, compound XR020007-I03 was obtained.
Second step Synthesis of BX20-6-025
The synthetic route is shown in the following formula:
Compound XR020007-I03 (0.60 g,1.57 mmol) was dissolved in anhydrous DCM (10 mL), TEA (0.48 g,4.72 mmol) was added dropwise, stirred at 0deg.C for 5min, dimethyl dicarbonate (0.21 g,1.57 mmol) was added dropwise and the reaction mixture stirred at 25deg.C for 12h. After the reaction, the reaction mixture was concentrated directly at 40℃under reduced pressure to give a residue which was purified by silica gel column chromatography (PE: EA=1: 1~0:1) to give compound BX20-6-025 (480 mg, yield 75.8%) as a pale yellow solid. m/z=404.1 [ m+h ] +.
1H NMR(400MHz,DMSO-d6)＝8.88(s,1H),7.73(d,J＝8.0Hz,2H),7.55(d,J＝8.0Hz,2H),6.36(d,J＝8.0Hz,1H),3.86-3.83(m,2H),3.68-3.65(m,1H),3.59(s,3H),2.99-2.95(m,2H),1.83-1.79(m,2H),1.35-1.23(m,2H).
Example 7 Synthesis of BX20-6-026
First step XR020007-I03 Synthesis
According to the second step of example 2, compound XR020007-I03 was obtained.
Second step Synthesis of BX20-6-026
The synthetic route is shown in the following formula:
Compound XR020007-I03 (0.50 g,1.31 mmol), BX20-6-026-S2 (0.37 g,1.59 mmol), TEA (0.7 mL,5.20 mmol) were added sequentially to DMF (10 mL) and the reaction mixture heated to 75deg.C overnight with stirring for 12h. After the reaction, the reaction mixture was concentrated directly at 40℃under reduced pressure to give a residue, which was purified by column chromatography on silica gel (PE: EA=2:1 to 1:1), and lyophilized to give Compound BX20-6-026 (230 mg, yield 41%) as a white powder. MS (ESI, m/z) 428.0[ M+H ] +.
1H NMR(400MHz,DMSO-d6)＝8.86(s,1H),7.71-7.69(m,2H),7.54-7.52(m,2H),6.28(d,J＝8.0Hz,1H),3.54-3.41(m,1H),3.16-3.09(m,2H),2.84-2.81(m,2H),2.41(t,J＝12.0Hz,2H),1.78-1.76(m,2H),1.45-1.35(m,2H).
Example 8 Synthesis of BX20-6-027
First step XR020007-I03 Synthesis
According to the second step of example 2, compound XR020007-I03 was obtained.
Second step Synthesis of BX20-6-027
The synthetic route is shown in the following formula:
XR020007-I03 (320 mg,0.84 mmol) was dissolved in MeCN (10 mL) and K 2CO3 (350 mg,2.52 mmol) and 3-fluoro-1-iodopropane (377 mg,1.68 mmol) were added and the reaction stirred at 60℃for 16 h. After water quenching, ethyl acetate (25 ml x 3) extraction and drying, concentration under reduced pressure at 40 ℃ and purification of the residue by column chromatography (PE/ea=10/1 to 5/1, V/V) gave a crude product, which was purified by preparative separation (formic acid system) and lyophilized to give compound BX20-6-027 (190 mg, yield 22.0%) as a white powder. m/z=442.1 [ m+h ] +.
1H NMR(400MHz,DMSO-d6)δ＝8.92(d,J＝3.6Hz,1H),7.72(d,J＝9.2Hz,2H),7.55(d,J＝8.8Hz,2H),6.37-6.35(m,1H),3.48-3.44(m,3H),2.76(d,J＝12.0Hz,2H),2.52-2.37(m,2H),2.09(t,J＝11.2Hz,2H),1.80-1.77(m,2H),1.43-1.33(m,2H).
EXAMPLE 9 Synthesis of BX20-6-032
First step, S1 synthesis
The synthetic route is shown in the following formula:
The procedure was as for S0 (50 mg,0.44 mmol) in anhydrous DCM (2 mL) and pyridine (51 mg,0.66 mmol) was added. Tf 2 O (123 mg,0.66 mmol) was added dropwise at 0deg.C and the reaction stirred at room temperature for half an hour. The reaction solution was filtered to give a DCM solution (about 0.2mmol/mL,2 mL) containing S1, which was used directly in the next step.
Second step, synthesis of BX20-6-032
The synthetic route is shown in the following formula:
XR020007-103 (150 mg,0.4 mmol) was dissolved in ACN (10 mL) and then K 2CO3 (81 mg,0.6 mmol) and a solution of S1 in DCM (about 0.2mmol/mL,2 mL) were added and the reaction stirred at 50℃for 16 h. After the reaction, the mixture was filtered, and the filtrate was purified by preparative purification (formic acid system) and lyophilized to give Compound BX20-6-032 (16 mg, yield 9.0%) as pale yellow powder. m/z=442.2 [ m+h ] +.
1H NMR(400MHz,CD3OD)δ＝8.86(s,1H),7.70(d,J＝8.0Hz,2H),7.52(d,J＝8.0Hz,2H),3.37-3.49(m,2H),2.77-2.89(m,2H),2.50-2.53(m,1H),2.40-2.43(m,1H),1.76-1.79(m,2H),1.30-1.43(m,2H),1.13(d,J＝4.0Hz,2H).
Example 10 Synthesis of BX20-6-033
The synthetic route is shown in the following formula:
In ice bath, compound S0' (200 mg,1.75 mmol), pyridine (150 mg,1.9 mmol) was dissolved in anhydrous DCM (4 mL), tf 2 O (535 mg,1.9 mmol) was slowly added dropwise and the reaction mixture was stirred in ice bath for 30 min. After the reaction, the reaction mixture was filtered to give a DCM solution of S1'. The above solution was added to ACN (10 mL), followed by K 2CO3 (323 mg,2.34 mmol), stirred at 60℃for 1 hour, the reaction was completed, the reaction solution was filtered, purified by preparative separation (formic acid system), and lyophilized to give pale yellow solid powder BX20-6-033 (22 mg, yield 6.4%).
1H NMR(400MHz,METHANOL-d4)＝7.57(d,J＝9.2Hz,2H),7.40(d,J＝8.8Hz,2H),3.52-3.45(m,1H),3.27-3.15(m,1H),2.86-2.79(m,2H),2.56(t,J＝11.2Hz,1H),2.46(t,J＝11.2Hz,1H),1.84-1.79(m,2H),1.42-1.32(m,2H),1.13(d,J＝6.8Hz,3H).
EXAMPLE 11 Synthesis of BX20-6-034
The synthetic route is shown in the following formula:
The compound XR020007-I03 (0.30 g,0.79 mmol), K 2CO3 (0.33 g,2.36 mmol) was dissolved in DMF (6 mL) and a solution of iodoethane (0.11 g,0.71 mmol) in DMF (3 mL) was slowly added dropwise and the reaction mixture stirred at room temperature for 12h. After the reaction, the reaction mixture was concentrated directly at 40℃under reduced pressure to give a residue, which was purified by preparative separation (formic acid system) and lyophilized to give compound BX20-6-034 (90 mg, yield 31%) as a white powder. MS (ESI, m/z) 374.12[ M+H ] +.
1H NMR(400MHz,METHANOL-d4)＝8.50(s,1H),7.69-7.66(m,2H),7.55-7.53(m,2H),3.88-3.83(m,1H),3.50-3.47(m,2H),3.12(q,J＝8.0Hz,2H),3.07-3.01(m,2H),2.20-2.16(m,2H),1.83-1.77(m,2H),1.33(t,J＝8.0Hz,3H).
EXAMPLE 12 Synthesis of BX20-6-035
The synthetic route is shown in the following formula:
the method was carried out by dissolving compound XR020007-I03 (0.30 g,0.79 mmol), K 2CO3 (0.33 g,2.36 mmol) in DMF (6 mL), slowly dropwise adding a solution of bromoisopropyl (0.12 g,0.94 mmol) in DMF (3 mL) and heating the reaction mixture to 60℃and stirring for 12h. After the reaction, the reaction mixture was concentrated directly at 40℃under reduced pressure to give a residue, which was purified by preparative separation (formic acid system) and lyophilized to give Compound BX20-6-035 (110 mg, yield 36%) as a white powder. MS (ESI, m/z) 388.14[ M+H ] +.
1H NMR(400MHz,METHANOL-d4)δ8.54(s,1H),7.69-7.67(m,2H),7.55-7.53(m,2H),3.87-3.82(m,1H),3.46-3.38(m,3H),3.13-3.07(m,2H),2.21-2.18(m,2H),1.81-1.78(m,2H),1.34-1.33(m,6H).
EXAMPLE 13 Synthesis of BX20-6-036
The synthetic route is shown in the following formula:
The procedure was to dissolve XR020007-I03 (300 mg,0.78 mmol) in DMF (10 mL) and then to add TEA (162 mg,1.6 mmol) and S0 (377 mg,1.68 mmol) and stir the reaction at room temperature for 16 hours. After quenching with water, extraction with ethyl acetate (25 ml x 3) and drying, concentration under reduced pressure at 40 ℃ and purification of the residue (formic acid system) followed by lyophilization, the compound BX20-6-036 (220 mg, yield 68.9%) was obtained as a white powder. m/z=410.2 [ m+h ] +.
1H NMR(400MHz,CD3OD)δ＝7.60-7.56(m,2H),7.42(d,J＝8.8Hz,2H),6.04(tt,J＝55.2Hz,J＝4.0Hz,1H),3.64-3.57(m,1H),3.13-2.99(m,4H),2.66(t,J＝11.2Hz,2H),1.97-1.93(m,2H),1.61-1.51(m,2H).
EXAMPLE 14 Synthesis of BX20-6-037
First step, synthesis of intermediate XR020003-I01
The synthetic route is shown in the following formula:
To a solution of compound XR02-S1 (2.00 g,9.85 mmol) in DCM (40 mL) at 0deg.C was added TEA (1.91 g,14.8 mmol). XR02-S2 (2.37 g,11.8 mmol) was added to the solution. The reaction is carried out for 1 hour at 20 ℃, and crude products are obtained after spin drying. The crude product was purified by column chromatography on silica gel to give XR020003-I01 (2.70 g, 68.0% yield) as a white solid. MS (ESI, m/z) 404.2[ M+H ] +.
Second step, synthesis of intermediate XR020003-I02
The synthetic route is shown in the following formula:
method to a solution of XR020003-I01 (1.00 g,2.48 mmol) in MeOH (5 mL) was added MeOH (3 mL,12 mmol) at room temperature. After the completion of the reaction, the crude product was dried by spin-drying to give a pale yellow product (1.08 g, crude product) which was directly used as the next step. MS (ESI, m/z) 304.2[ M+H ] +.
Third step, synthesis of BX20-6-037
The synthetic route is shown in the following formula:
Method to a solution of XR020003-I02 (200 mg,0.59 mmol) and XR02-S3 (204 mg,0.88 mmol) in DMF (5 mL) was added Et 3 N (178 mg,1.77 mmol) and the reaction was stirred at 75℃for 16 h. The reaction solution was concentrated under reduced pressure, and purified by preparative (formic acid system) to give BX20-6-037 (110 mg, yield 45.0%) as a white solid. MS (ESI, m/z) 386.1[ M+H ] +.
1H NMR(400MHz,CD3OD)δ＝7.41(d,J＝8.0Hz,2H),7.14(d,J＝8.0Hz,2H),3.57-3.59(m,1H),3.07(q,J＝10.1Hz,2H),2.93-2.96(m,2H),2.49-2.52(m,2H),1.89-1.92(m,2H),1.50-1.54(m,2H).
EXAMPLE 15 Synthesis of BX20-6-038
Synthesis of BX20-6-038
The synthetic route is shown in the following formula:
The procedure was followed by dissolving compound XR020007-I03 (0.30 g,0.79 mmol), SM2 (0.13 g,0.79 mmol), TEA (0.24 g,2.36 mmol) in DCM (6 mL) and stirring the reaction mixture at room temperature for 12h. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography to give Compound BX20-6-038 (220 mg, yield 67%) as a white powder. MS (ESI, m/z) 418.11[ M+H ] +.
1H NMR(400MHz,METHANOL-d4)δ7.69-7.67(m,2H),7.53-7.51(m,2H),4.12(q,J＝8.0Hz,2H),4.05-4.02(m,2H),3.80-3.75(m,1H),3.01-2.99(m,2H),1.96-1.92(m,2H),1.43-1.33(m,2H),1.26(t,J＝8.0Hz,3H).
EXAMPLE 16 Synthesis of BX20-6-041
First step, synthesis of intermediate XR02001-S2
The synthetic route is shown in the following formula:
The procedure was followed by dissolving triphosgene (0.3 g,1.1 mmol) in DCM (20 mL) as solution A and displacing N 2. XR02001-S1 (0.5 g,2.1 mmol), TEA (0.6 g,6.3 mmol) was dissolved in DCM (5 mL) as solution B. And cooling the solution A to-78 ℃ by using a liquid nitrogen ethanol bath, slowly dropwise adding the solution B, and naturally heating to-10 ℃ for reaction for 1h. XR02001-S2 was obtained. XR02001-S2 is directly put into the next step without treatment.
Second step, intermediate XR02001-S3 synthesis
The synthetic route is shown in the following formula:
The procedure was followed taking A1 (0.5 g,2.5 mmol), TEA (0.6 g,6.3 mmol) in DCM (5 mL) as solution C. The reaction solution of XR02001-S2 was cooled to-78℃and solution C was slowly added dropwise followed by reaction at 25℃for 1h. After the reaction, excess triphosgene was quenched by addition of H 2 O (10 mL), the organic phase was collected and dried, concentrated under reduced pressure and purified by column chromatography to give compound XR02001-S3 (0.9 g, 92.5%) as a white solid. MS (ESI, m/z) =464.1 [ m+h ] +.
Third step, XR02001-S4 synthesis
The synthetic route is shown in the following formula:
The procedure is to dissolve compound XR02001-S3 (0.5 g,1.1 mmol) in MeOH (10 mL) and add HCl/1,4-dioxane (2.7 mL,10.8 mmol) at 25℃and the reaction mixture is stirred at room temperature for 12h. After the reaction, it was concentrated directly under reduced pressure to give compound XR02001-S4 (0.43 g, trude) as a pale yellow oil. MS (ESI, m/z) =364.1 [ m+h ] +.
Fourth step, synthesizing BX20-6-041
The synthetic route is shown in the following formula:
the procedure is to dissolve compound XR02001-S4 (0.43 g, crude) in DMF (10 mL), add A2 (0.33 g,1.4 mmol), TEA (0.33 g,3.2 mmol) and heat the reaction mixture to 75℃for 12h. After the reaction, H 2 O (10 mL) was added to dilute the reaction solution, the reaction solution was extracted with EA (20 mE. Times.3), the organic phase was collected and dried, and the organic phase was concentrated under reduced pressure, followed by preparation, separation and purification (formic acid system) to give Compound BX20-6-041 (0.24 g, 49.9%) as a white powder. MS (ESI, m/z) =446.1 [ m+h ] +.
1H NMR(400MHz,DMSO-d6)δ＝9.15(s,1H),7(t,J＝8.0Hz,1H),7.66-7.62(m,1H),7.18(d,J＝8.00Hz,1H),6.48(d,J＝8.00Hz,1H),3.48-3.47(m,1H),3.15(q,J＝8.00Hz,2H),2.86-2.83(m,2H),2.45-2.40(m,2H),1.79-1.76(m,2H),1.46-1.38(m,2H).
EXAMPLE 17 Synthesis of BX20-6-042
First step, the synthesis of intermediate XR02002-S2
The synthetic route is shown in the following formula:
The procedure was as for solution A, triphosgene (2.0 g,6.9 mmol) was dissolved in DCM (20 mL) and N 2 was replaced. XR02002-S1 (3.0 g,15.4 mmol), TEA (2.3 g,23.0 mmol) was dissolved in DCM (30 mL) as solution B. And cooling the solution A to-78 ℃ by using a liquid nitrogen ethanol bath, slowly dropwise adding the solution B, and naturally heating to-10 ℃ for reaction for 1h. XR02002-S2 was obtained. XR02002-S2 is not treated and is directly put into the next step.
Second step, intermediate XR02002-S3 synthesis
The synthetic route is shown in the following formula:
The procedure was followed by taking A1 (3.0 g,15.4 mmol), TEA (2.3 g,23.0 mmol) in DCM (20 mL) as solution C. The reaction solution of XR02002-S2 was cooled to-78℃and solution C was slowly added dropwise followed by reaction at 25℃for 1h. After completion of the reaction, excess triphosgene was quenched by addition of H 2 O (10 mL), the organic phase was collected and dried, concentrated under reduced pressure and purified by column chromatography to give compound XR02002-S3 (4.6 g, 70.1%) as a white solid. MS (ESI, m/z) =422.2 [ m+h ] +.
Third step, XR02002-S4 synthesis
The synthetic route is shown in the following formula:
The procedure is to dissolve compound XR02002-S3 (4.6 g,10.9 mmol) in MeOH (14 mL) and add HCl/1,4-dioxane (13.6 mL,54.5 mmol) at 25℃and the reaction mixture is stirred at room temperature for 2h. After the reaction, it was concentrated directly under reduced pressure to give compound XR02002-S4 (3.0 g, crude) as a colourless oil. MS (ESI, m/z) =322.1 [ m+h ] +.
Fourth step, synthesizing BX20-6-042
The synthetic route is shown in the following formula:
The procedure is to dissolve compound XR02002-S4 (1.0 g,2.8 mmol) in DMF (6 mL), add A2 (0.84 g,3.6 mmol), TEA (0.84 g,8.4 mmol) and heat the reaction mixture to 75℃for 12h. After the completion of the reaction, H 2 O (25 mL) was added to dilute the reaction mixture, the reaction mixture was extracted with EA (20 mL. Times.3), the organic phase was collected and dried, and the organic phase was concentrated under reduced pressure, followed by preparation, separation and purification (formic acid system) to give Compound BX20-6-042 (670 mg) as a white powder. MS (ESI, m/z) =404.1 [ m+h ] +.
Example 18 Synthesis of BX20-6-043
First step, the synthesis of intermediate XR02003-S2
The synthetic route is shown in the following formula:
The procedure was followed by taking A1 (12.8 g,64.2 mmol), TEA (10.8 g,106.9 mmol) in DCM (150 mL) as solution A. XR02003-S1 (10.0 g,53.5 mmol) was dissolved in DCM (50 mL) as solution B. Solution a was cooled to 0 ℃, solution B was slowly added dropwise, followed by reaction at 25 ℃ for 2h. After the reaction, excess triphosgene was quenched by addition of H 2 O (10 mL), the organic phase was collected and dried, concentrated under reduced pressure and purified by beating to give compound XR02003-S2 (20 g, 96.5%) as a white solid. MS (ESI, m/z) =388.2 [ m+h ] +.
Second step, intermediate XR02003-S3 synthesis
The synthetic route is shown in the following formula:
The procedure is to dissolve compound XR02003-S3 (20 g,51.7 mmol) in MeOH (100 mL) and add HCl/1,4-dioxane (100 mL,400 mmol) at 25℃and stir the reaction mixture at room temperature for 12h. After the reaction, the mixture was concentrated under reduced pressure and purified by beating with acetone to give compound XR02003-S3 (14.7 g, 87.8%) as pale white solid. MS (ESI, m/z) =288.1 [ m+h ] +.
Third step, synthesis of BX20-6-043
The synthetic route is shown in the following formula:
The procedure is to dissolve compound XR02003-S3 (3.0 g,9.3 mmol) in DMF (30 mL), add A2 (2.8 g,12.1 mmol), TEA (2.8 g,27.8 mmol) and heat the reaction mixture to 75℃for 12h. After the reaction, H 2 O (10 mL) was added to dilute the reaction solution, the reaction solution was extracted with EA (20 mL. Times.3), the organic phase was collected and dried, and the organic phase was concentrated under reduced pressure and purified by column chromatography to give Compound BX20-6-043 (1.3 g, 38.0%) as a white powder. MS (ESI, m/z) =370.1 [ m+h ] +.
Example 19 Synthesis of BX20-6-045
Reference is made to the synthesis of BX20-6-024, MS (ESI, m/z) 431.15[ M+H ] +
Example 20 Synthesis of BX20-6-046
Reference is made to the synthesis of BX20-6-024, MS (ESI, m/z) 445.16[ M+H ] +
Example 21 Synthesis of BX20-6-047
Reference BX20-6-024 Synthesis method, MS (ESI, m/z) 430.11[ M+H ] +
Synthesis of reference compound 1:
reference WO2013116690, example 12, method of synthesis, reference Compound 1 was synthesized
1H NMR(400MHz,DMSO-d6)δ＝8.55(d,J＝11.2Hz,1H),7.47(d,J＝7.6Hz,2H),7.21(d,J＝7.6Hz,2H),6.28(t,J＝8.0Hz,1H),4.23-4.21(m,1H),3.89-3.86(m,1H),3.72-3.69(m,1H),3.17-3.14(m,1H),2.84-2.68(m,2H),1.87-1.80(m,2H),1.55-1.54(m,1H),1.31-1.17(m,3H),0.97(t,J＝7.6Hz,3H),0.83-0.78(m,3H).
Biological test evaluation
The invention is explained below in further detail in connection with test examples
Test example 1 test of the inhibitory Activity of the Compounds of the invention against human soluble cyclooxygenase (IC 50)
1. Purpose of experiment
The IC 50 values of the compounds of the invention for human recombinant soluble cyclooxygenase (sEH) inhibitory activity were determined using a sensitive fluorescence-based assay.
2. Laboratory instrument and reagent
2.1 Experimental sample
The embodiment of the invention and the reference compound are self-made.
2.2 Laboratory apparatus
Multifunctional enzyme label instrument (Tecan Spark 20M)
Microplate incubator (Thermo; PST-60 HL-4)
384 Kong Baiban (Cisbio 66PL 384025)
2.3 Experimental reagents
3-Phenyl-cyano (6-methoxy-2-naphthyl) methyl ester-2-oxiraneacetic acid (PHOME) (Cayman)
AUDA (Positive compound) (Cayman)
Tris Buffer (Tris-hydroxy methyl aminomethane hydrochloride) (pH 7.0,25mM, sigma)
Human soluble cyclooxygenase (hsEH) (Cayman)
3. Experimental procedure
Determination of IC50 values using sensitive fluorescence-based assays
1) HsEH formulated with Tris Buffer at 2. Mu.g/mL was added to 384 blackboard at 8. Mu.L/well (final concentration 1. Mu.g/mL).
2) The formulated compound and positive control were then added to the plate at 4 μl/well. After mixing, the mixture was centrifuged at 1000rpm for 1min. Incubate at 30 ℃ for 5min. Positive (no compound added) and negative control wells (no sEH added) were set simultaneously.
3) The formulated fluorogenic substrate PHOME was then added to the plate at 4 μl/well ([ S ] = 1 μΜ). After mixing, the mixture was centrifuged at 1000rpm for 1min. Incubate at 30 ℃ for 15min.
4) The detection of the machine is carried out, wherein the excitation wavelength is 330nm, and the emission wavelength is 465nm.
4. Data analysis
Using GRAPHPAD PRISM analysis of the data, IC 50 values for the compounds were calculated by fitting the percent inhibition and ten point concentration data to a parametric nonlinear logic formula.
5. Experimental results
The results of the test of the human soluble cyclooxygenase inhibiting activity of the compounds of the present invention are shown in Table 1.
TABLE 1
6. Conclusion of the experiment
According to the scheme, partial compounds show better inhibition effect on recombinant human soluble cyclooxygenase.
Test example 2 in vivo pharmacokinetic assay of Compounds of the invention in SD rats
1. Purpose of test
The pharmacokinetic behavior of plasma in rats orally administered at a dose of 6mg/kg was studied in the compound example using SD rats as test animals.
2. Test method
2.1. Test drug
The embodiment of the invention and the reference compound are self-made.
2.2. Test animals
Male SPF-grade SD rats, body weight (200+ -20) g, st Bei Fu (Beijing) Biotechnology Co., ltd., animal production license number SCXK (Beijing) 2019-0010.
2.3. Preparation of test drug
The medicine is prepared, the concentration of the prepared medicine is 0.3mg/mL or 0.6mg/mL, and the prepared solution is 0.5 percent CMC solution.
The preparation is carried out by weighing 4.5mg or 9mg of each drug by a precise balance of one part per million, and uniformly suspending in 15mL of 0.5% CMC solution. Care is taken to prevent the drug from adhering to the stirring rod or tube wall during the drug formulation process.
2.4. Administration:
Male SPF SD rats were fed with the drug for 3-4 days, followed by additional gavage at a dose of 3mg/kg or 6mg/kg and a drug administration volume of 10mL/kg.
2.5. Sample collection
Before (0 h) and after administration, rats are subjected to blood sampling at 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h and 24h, the rats are subjected to fundus puncture blood sampling, the blood sampling amount is about 0.5mL, the rats are placed in an EDTA-K2 anticoagulation test tube with a labeled, the blood sampling tube is immediately and lightly reversed for 3 times to be uniformly mixed with the anticoagulation agent, the rats are immediately and uniformly placed in an ice-water bath at 4500rpm under the condition of 4 ℃, the rats are centrifuged for 10min, and after the centrifugation operation is finished, blood plasma is taken and timely packaged in an EP tube with the labeled corresponding label, and the blood plasma is stored in a refrigerator at-80 ℃.
2.6. Sample detection
The concentration of example X and example Y in plasma after administration was determined in this experiment using a simplified validated HPLC-MS/MS method.
2.6.1. Sample treatment, namely taking 2 mu L of blank plasma in a 96 deep hole plate, adding 400 mu L of precipitator methanol, swirling for 10min, centrifuging for 15min at 4000rpm, taking 250 mu L of supernatant in the 96 deep hole plate, and carrying out HPLC-MS/MS analysis, wherein the sample injection volume is 5 mu L.
2.6.2. Liquid analysis:
1) Liquid phase conditions
Waters XSelect CHS C18,2.1 x 50mm,1.8/5 μm;
pre-column, waters on-line filter/Fimbrance AJO-4287;
Mobile phase A0.1% formic acid &5mM ammonium acetate in water;
Mobile phase B is 0.1% acetonitrile formate solution;
Flow Rate (Flow Rate) 0.6mL/min;
Column temperature (Column Temperature) 40 ℃;
Autoinjector Temperature (SAMPLE TRAY Temperature): 4 ℃;
Sample Volume (Injection Volume) 5.0 μl;
An automatic sample injection cleaning mode (Rinse Mode) before sample injection and after sample injection (Before and after aspiration);
the needle washing volume (Rinsing Volume) of the automatic injector is 500.0 mu L;
Soaking time (RINSE DIP TIME) of the automatic injector during cleaning of the sample injection needle is 5sec;
An automatic injector sample needle cleaning method (Rinse Method) Rinse Port Only;
The cleaning time RINSE TIME of the sample injection needle of the automatic sample injector is 2sec
The autosampler cleaning solution (Rinse Pump and Port Wash Solution) is 50% acetonitrile/50% methanol aqueous solution.
Elution mode gradient elution
2) Mass spectrometry conditions:
ion source Electrospray Ionization (ESI);
ionization mode (Ionization) Positive ion mode (Positive);
detection Mode (Mode) multiple reaction detection (MRM);
Collision cell gas (CAD): 8psi;
air Curtain Gas (CurtainGas Type) 35-45 psi;
Atomizing gas (GS 1) 50psi;
auxiliary gas (GS 2) of 50 to 60psi;
The electrospray voltage (Ion Spray Voltage) is 3000-4500V;
the vortex ion spraying temperature (Turbo Ion Spray Temperature) is 600-650 ℃;
Mass spectrum resolution: unit;
3. test results and analysis
The main pharmacokinetic parameters were calculated using WinNonlin 7.0 and the rat pharmacokinetic results are shown in table 2 below.
TABLE 2 rat drug substitution test results (6 mg/kg dose)
4. Conclusion of the experiment
From the results of the rat drug generation test in the table, the compounds of the examples of the present invention show good metabolic properties.
Test example 3 study of the efficacy of neuropathic pain in diabetes
1. Purpose of test
It was investigated whether the compounds of the examples could improve diabetic neuropathic pain symptoms in rats.
2. Test materials
Male SD rats, S Bei Fu (Beijing) Biotechnology Co., ltd., weight: 180-220 g, streptozotocin (sigma), example Compounds
3. Diabetes pain model establishment
After adaptive feeding, rats were tested for basal pain threshold using von Frey needle stick pain test kit (IITC Inc, woodland Hills CA). The tail vein injection of 55mg/kg streptozotocin solution induced diabetic status, followed by the development of neuropathic pain in the rats. And 7-10 days after molding, the rats have pain onset symptoms.
4. Administration of drugs
During the onset of pain in rats, diabetic neuropathic pain rats were grouped, no less than 6 per group, and the example compound (10 mg/kg) and reference compound 1 (30 mg/kg) were administered by gavage, and mechanical stinging threshold tests were performed on each group of rats at different times after administration.
5. Results
In a study of efficacy using a diabetic rat pain model, according to fig. 1, the compounds of the present disclosure showed higher potency and higher efficacy than the reference compound.
Effect of example compounds on the mechanical pain threshold of diabetic neuropathic pain rats. The examples have a higher pain-suppressing effect than the reference compound 1. Each group showed "×" P <0.05; "×" P <0.01 compared to pre-dose (0 h).
Claims (18)
1. A compound shown as a formula I-1 or pharmaceutically acceptable salt thereof is characterized in that,
Wherein R 1 is "cyclohexyl substituted with 1R 1-2" or "6 membered nitrogen containing heterocycloalkyl substituted with 1R 1-1";
R 1-1 is "C 1-C6 alkyl substituted by 3 halogens" or
R 1-1-1 isOr C 1-C6 alkyl;
R 1-1-1-1 is C 1-C6 alkyl;
R 1-2 is
R 1-2-1 is phenyl or "phenyl substituted with 1R 1-2-1-1";
R 1-2-1-1 is carboxyl.
2. A compound or pharmaceutically acceptable salt thereof according to claim 1,
In R 1, the "6-membered nitrogen-containing heterocycloalkyl substituted by 1R 1-1" isWherein nitrogen is attached to R 1-1;
or, in R 1-1, the C 1-C6 alkyl group in the "C 1-C6 alkyl group substituted with 3 halogens" is a C 1-C4 alkyl group;
Or, in R 1-1, halogen in the "C 1-C6 alkyl substituted with 3 halogens" is fluorine, chlorine, bromine or iodine;
Or, in R 1-1-1, the C 1-C6 alkyl is C 1-C4 alkyl;
Or, in R 1-1-1-1, the C 1-C6 alkyl is C 1-C4 alkyl.
3. A compound or pharmaceutically acceptable salt thereof according to claim 2,
In R 1-1, the C 1-C4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl;
Or, in R 1-1, the "C 1-C6 alkyl substituted with 3 halogens" is "C 1-C6 alkyl substituted with 3 fluorine";
Or, in R 1-1-1, the C 1-C6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl;
Or, in R 1-1-1-1, the C 1-C6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.
4. A compound or pharmaceutically acceptable salt thereof according to claim 3,
In R 1-1, the C 1-C4 alkyl is methyl, ethyl, n-propyl or isopropyl;
Or, in R 1-1, the "C 1-C6 alkyl substituted with 3 halogens" is trifluoromethyl,
Or, in R 1-1-1, the C 1-C6 alkyl is isobutyl or isopropyl;
Or, in R 1-1-1-1, the C 1-C6 alkyl is methyl, ethyl or isopropyl.
5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein in R 1, the number of heteroatoms in the 6-membered nitrogen-containing heterocycloalkyl is 1 or 2;
Or R 1-1 is "C 1-C4 alkyl substituted with 3 fluorine groups" or
Or R 1-1-1 isOr C 1-C4 alkyl;
or, R 1-1-1-1 is C 1-C4 alkyl.
6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I-1 is according to the following scheme:
R 1 is "6 membered nitrogen containing heterocycloalkyl substituted with 1R 1-1";
R 1-1 is "C 1-C4 alkyl substituted by 3 fluorine" or
R 1-1-1 isOr C 1-C4 alkyl;
R 1-1-1-1 is C 1-C4 alkyl.
7. A compound or pharmaceutically acceptable salt thereof according to claim 1,
R 1 is
Or R 1-1 is
8. A compound which is a compound of formula (I),
9. A preparation method of a compound shown as a formula I-1 is characterized by comprising the following steps of carrying out condensation reaction of a compound shown as a formula II and an amine compound in a solvent in the presence of alkali, wherein R 1 is defined as any one of claims 1-7;
10. Use of a substance Z for the preparation of a medicament for the treatment and/or prophylaxis of diseases which are associated with soluble cyclooxygenase, characterized in that the substance Z is a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.
11. The use according to claim 10, wherein the disease is hypertension, pain, cardiomyopathy, inflammation, adult respiratory distress syndrome, diabetic complications, kidney disease or raynaud's syndrome.
12. The use according to claim 10, wherein the disease is arthritis.
13. The use according to claim 11, wherein the pain is neuropathic pain and/or inflammatory pain.
14. The use of claim 11, wherein the kidney disease is end stage renal disease.
15. The use according to claim 11, wherein the hypertension is renal hypertension, liver hypertension or pulmonary hypertension.
16. The use according to claim 11, wherein the inflammation is kidney inflammation, vascular inflammation or lung inflammation.
17. Use of a substance Z for the preparation of a soluble cyclooxygenase inhibitor, wherein said substance Z is a compound according to any one of claims 1-8 or a pharmaceutically acceptable salt thereof.
18. A pharmaceutical composition comprising a substance Z and a pharmaceutically acceptable adjuvant, wherein the substance Z is a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.
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| WO2009086426A2 (en) * | 2007-12-28 | 2009-07-09 | Arete Therapeutics, Inc. | Soluble epoxide hydrolase inhibitors for the treatment of endothelial dysfunction |
| WO2010025043A1 (en) * | 2008-08-29 | 2010-03-04 | Arete Therapeutics, Inc. | Use of soluble epoxide hydrolase inhibitors in the treatment of inflammatory vascular diseases |
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| JP2018020989A (en) * | 2016-08-05 | 2018-02-08 | 宇部興産株式会社 | Urea compounds |
| CN115819319A (en) * | 2021-09-16 | 2023-03-21 | 武汉熙瑞医药科技有限公司 | A kind of amide compound, its preparation method and its application |
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| TW200808723A (en) * | 2006-03-13 | 2008-02-16 | Univ California | Conformationally restricted urea inhibitors of soluble epoxide hydrolase |
| US20200079786A1 (en) * | 2015-07-28 | 2020-03-12 | Universitat De Barcelona | Analogs of adamantylureas as soluble epoxide hydrolase inhibitors |
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| CN101679258A (en) * | 2007-03-13 | 2010-03-24 | 亚瑞特医疗公司 | 4-piperidinylurea compounds as soluble epoxide hydrolase inhibitors |
| WO2009086426A2 (en) * | 2007-12-28 | 2009-07-09 | Arete Therapeutics, Inc. | Soluble epoxide hydrolase inhibitors for the treatment of endothelial dysfunction |
| WO2010025043A1 (en) * | 2008-08-29 | 2010-03-04 | Arete Therapeutics, Inc. | Use of soluble epoxide hydrolase inhibitors in the treatment of inflammatory vascular diseases |
| WO2010053829A1 (en) * | 2008-11-04 | 2010-05-14 | Arete Therapeutics, Inc. | Soluble epoxide hydrolase inhibitors for treatment of metabolic syndrome and related disorders |
| JP2018020989A (en) * | 2016-08-05 | 2018-02-08 | 宇部興産株式会社 | Urea compounds |
| CN115819319A (en) * | 2021-09-16 | 2023-03-21 | 武汉熙瑞医药科技有限公司 | A kind of amide compound, its preparation method and its application |
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