CN115611901A - An azepine compound or a pharmaceutically acceptable salt thereof, and preparation method and application thereof - Google Patents
An azepine compound or a pharmaceutically acceptable salt thereof, and preparation method and application thereof Download PDFInfo
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- CN115611901A CN115611901A CN202110809157.9A CN202110809157A CN115611901A CN 115611901 A CN115611901 A CN 115611901A CN 202110809157 A CN202110809157 A CN 202110809157A CN 115611901 A CN115611901 A CN 115611901A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
Abstract
The invention discloses a nitrogen-doped nitrogen compound
Class compound or pharmaceutically acceptable salt thereof, preparation method and application thereof, and nitrogen heterocyclic compound
The structural formula of the compound is shown as the formula (2): wherein X is a carbon atom or a nitrogen atom; n is selected from 1,2 or 3; r is 1 Is one or more radicals on the A ringGroup, said R 1 Independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, C1-C6 ester group, C1-C6 alkylamino, cyano or phenyl; when R is 1 When the number of (B) is plural, two R 1 Can be connected with each other through saturated or unsaturated C1-C4 carbon chains; r is 2 Selected from hydrogen, benzyloxycarbonyl, t-butoxycarbonyl, fluorenylmethyloxycarbonyl, phthaloyl, p-toluenesulfonyl, trifluoroacetyl, p-methoxybenzyl, benzyl or methanesulfonyl; r 3 Selected from hydrogen, phenyl or C1-C6 alkyl. The nitrogen heterocyclic compound
The compound or its pharmaceutically acceptable salt has COX-2 inhibiting activity.
Description
Technical Field
The invention relates to the technical field of medicinal chemistry, and particularly relates to aza
The compound or the pharmaceutically acceptable salt thereof, and a preparation method and application thereof.
Background
In heterocyclic compounds, benzazepines
Namely, the benzazepine seven-membered ring exists in the form of alkaloid mostly in nature, and has strong biological activity and medicinal value. For example, trypsin (pancrracine) is isolated from pancrracine maritimum; galantamine is separated from Bulbus Lycoridis Radiatae and can be used for treating senile dementia; cripobellins are obtained by separating from roots of Crinum bauhini (Crinum powellii), and have strong insecticidal activity; also from the genus erythrinaThe alkaloid separated from the extract can be used as anthelmintic and antiemetic.
Clinically, there are also a number of benzazepines
The compounds have been used as drugs for treating central nervous system diseases. For example, clomipramine (Clomipramine) is an antidepressant manic drug, olanzapine (Olanzapine) is an antipsychotic drug, lorazepam (Lorazepam) is used to treat neurological and epileptic mental disorders, and mirelin (Mianserin) is an antidepressant drug. Therefore, there is a need to further develop novel aza compounds
A compound of the class.
Disclosure of Invention
The invention aims to provide an aza
A compound of class or a pharmaceutically acceptable salt thereof. The nitrogen heterocyclic compound
The compound or its pharmaceutically acceptable salt has new mother-nucleus structure and can inhibit COX-2 activity.
Another object of the present invention is to provide a method for preparing the compound or a pharmaceutically acceptable salt thereof.
It is another object of the present invention to provide the use of said compounds or pharmaceutically acceptable salts thereof in the preparation of COX-2 inhibitors.
The above purpose of the invention is realized by the following technical scheme:
aza
Class of compounds or pharmaceutically acceptable salts thereof, said azepine
The structural formula of the compound is shown as the formula (2):
wherein X is a carbon atom or a nitrogen atom; n is selected from 1, 22 or 3;
R 1 is one or more radicals on the A ring, said R 1 Independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, C1-C6 ester group, C1-C6 alkylamino, cyano or phenyl;
when R is 1 When the number of (B) is plural, two R 1 Can be connected with each other through saturated or unsaturated C1-C4 carbon chains;
R 2 selected from hydrogen, benzyloxycarbonyl, t-butoxycarbonyl, fluorenylmethyloxycarbonyl, phthaloyl, p-toluenesulfonyl, trifluoroacetyl, p-methoxybenzyl, benzyl or methanesulfonyl;
R 3 selected from hydrogen, phenyl or C1-C6 alkyl.
Substituent definitions and general terms
The term "alkyl", as used herein, denotes a saturated, straight, branched or cyclic, monovalent hydrocarbon radical containing from 1 to 6 carbon atoms. In one embodiment, the alkyl group contains 1 to 6 carbon atoms; in another embodiment, the alkyl group contains 1 to 3 carbon atoms.
The term "halogen" refers to fluorine, chlorine, bromine, iodine.
The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein.
The term "ester group" means-C (= O) O-. The ester group may be linked to a substituent as described herein to form the corresponding ester substituent. Examples of ester groups include, but are not limited to, methyl, ethyl, propyl, butyl, and the like.
Preferably, said n is selected from 1 or 2.
Preferably, R 1 Selected from hydrogen, chlorine, bromine, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl or C1-C6 ester group.
Preferably, R 2 Selected from hydrogen, p-toluenesulfonyl or methanesulfonyl.
More preferably, the aza ring
The compounds are partially listed as follows:
preferably, the pharmaceutically acceptable salt is an aza
Pharmaceutically acceptable salts of the compounds with organic or inorganic acids.
More preferably, the pharmaceutically acceptable salt formed by the organic or inorganic acid is a hydrochloride, hydrobromide, sulphate, acetate, lactate, tartrate, citrate, trifluoroacetate, malate, maleate, succinate, p-toluenesulphonic acid or methanesulphonate.
The nitrogen heterocyclic compound
A preparation method of the compound or the pharmaceutically acceptable salt thereof comprises the following steps:
s1, heating a allene compound shown in a formula (1) in a solvent and reacting to obtain a compound shown in a formula (2);
s2, if necessary, converting the obtained compound shown in the formula (2) into pharmaceutically acceptable salt;
wherein X is a carbon atom or a nitrogen atom; n is selected from 1,2 or 3;
R 1 is one or more radicals on the A ring, said R 1 Independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, C1-C6 ester group, C1-C6 alkylamino, cyano or phenyl;
R 2 selected from hydrogen, benzyloxycarbonyl, tert-butoxycarbonyl, fluorenylmethyloxycarbonyl, phthaloyl, p-toluenesulfonyl, trifluoroacetyl, p-methoxybenzyl, benzyl or methanesulfonyl;
R 3 selected from hydrogen, phenyl or C1-C6 alkyl.
Preferably, the heating temperature is 60 to 120 ℃.
More preferably, the heating temperature is 70 to 90 ℃.
Preferably, the heating time is 4 to 48 hours.
More preferably, the heating time is 4 to 24 hours.
Preferably, the allene compound represented by the formula (1) is commercially available or can be synthesized according to conventional literature reports.
As an embodiment, the allene compound represented by the formula (1) may be prepared by the following method: the dibromo-alkene compound represented by formula (3) reacts with the allene compound represented by formula (4) to produce an alkynylamine allene compound represented by formula (1). Wherein R is 1 、R 2 、R 3 The substituents are as defined herein.
Preferably, the solvent is selected from one or more of toluene, chlorobenzene, dimethyl sulfoxide, tetrahydrofuran, dichloromethane, 1, 2-dichloroethane, 1, 4-dioxane, methanol, ethanol, isopropanol, acetonitrile, water.
As an embodiment, the allene compound represented by the formula (1) can be produced by the following procedure: in a nitrogen atmosphere, adding a dibromo olefin compound shown in a formula (3), a dienyl compound shown in a formula (4), cuprous iodide, 1, 10-phenanthroline and cesium carbonate in sequence, adding dry tetrahydrofuran, and stirring at room temperature until the raw materials react completely. After filtration, the solvent was evaporated in vacuo and purified by flash chromatography to give a dialkylene compound represented by the formula (1).
The nitrogen heterocyclic compound
The application of the compound or the pharmaceutically acceptable salt thereof in preparing COX-2 inhibitors.
Compared with the prior art, the invention has the beneficial effects that:
the present invention provides a series of novel aza rings
The compound or the pharmaceutically acceptable salt thereof has COX-2 inhibiting activity, and therefore can be used for preparing COX-2 inhibitors. The invention also provides the aza ring
The preparation method of the compound or the pharmaceutically acceptable salt thereof has the advantages of simple operation, no need of metal catalysis, low cost and potential industrial value.
Detailed Description
Unless otherwise specified, the starting materials, reagents and solvents used in the present invention are all commercially available without any treatment or can be prepared by literature methods. In order to more clearly illustrate the present invention, the present invention is further described below in conjunction with preferred embodiments. It is to be understood by persons skilled in the art that the following detailed description is illustrative and not restrictive, and is not to be taken as limiting the scope of the invention.
Example 1
Example 1 provides a 1-tosyl-2, 3,5, 10-tetrahydrobenzo [ b ]]Pyrrolo [3,2-f]Aza derivatives
-4 (1H) -one (2 a), said preparation method being in particular as follows:
first, compound (3 a), compound (4 a) and allene compound (1 a) were prepared:
(1) Preparation of compound (3 a): 2-nitrobenzaldehyde (3 a-s1, 10g,66.2mmol, 1eq) was dissolved in dichloromethane (350 mL), carbon tetrabromide (23g, 69.5mmol, 1.1eq) was added, the solution was cooled to 0 ℃ in an ice bath, triphenylphosphine (36.4g, 139mmol) was added in portions to the above mixture, and the solution was stirred at 0 ℃. Completion of the reaction was monitored by TLC plates. Hexane (350 ml) was added to precipitate a phosphonium salt. The solution was filtered through silica gel, washed with 10% ethyl acetate (hexane), the filtrate was collected and the solvent was removed in vacuo and purified by column chromatography (petroleum ether: ethyl acetate =30: 1) to give 2- (2, 2-dibromovinyl) -1-nitrobenzene (18.3g, 90%).
(2) Preparation of Compound (4 a):
3-butyn-1-ol (4 a-s1, 50 mmol), dioxane (100 ml), paraformaldehyde (100 mmol) and cuprous bromide (35 mmol) were placed in a 250ml flask equipped with a reflux condenser and stirred at room temperature under nitrogen atmosphere for half an hour. Dicyclohexylamine (100 mmol) was added to the mixture and stirred for 1 hour before refluxing at 120 ℃ for 18 hours, the mixture was cooled to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was washed with 5% hydrochloric acid, and the reaction product was extracted with ethyl acetate, dried over magnesium sulfate, and the solvent was spin-dried. Purification by column chromatography (petroleum ether: ethyl acetate = 10).
To a dichloromethane solution (120 ml) of 4a-s2 (2.5g, 30mmol) at 0 ℃ were added triethylamine (2 eq) and p-methylbenzenesulfonyl chloride (1.2 eq) in this order, stirred at room temperature for 12 hours, and after completion of the reaction, the reaction mixture was washed with water, the resulting solution was extracted with dichloromethane, and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 15) to obtain compounds 4a-s3 (7.0 g, 98%).
After 4a-s3 (1.0 g, 4.2mmol) was taken, p-methylbenzenesulfonamide (1.0 eq), acetonitrile (20 ml) and potassium carbonate (2 eq) were added and stirred at 90 ℃ for 12 hours, the reaction mixture was washed with water, extracted with ethyl acetate, dried over sodium sulfate and concentrated in vacuo, and purified by column chromatography (petroleum ether: ethyl acetate = 5).
(3) Preparation of the allene compound (1 a):
sequentially adding 2- (2, 2-dibromovinyl) -1-nitrobenzene 3a (307mg, 1mmol, 1.0eq), compound 4a (237mg, 1eq), cuprous iodide (3%), 1, 10-phenanthroline (5%) and cesium carbonate (3 eq) and dried tetrahydrofuran (0.25M) in a nitrogen atmosphere, and stirring at room temperature until the raw materials are completely reacted. After filtration through silica gel, the solvent was evaporated in vacuo and purified by column chromatography (petroleum ether: ethyl acetate = 5).
1-tosyl-2, 3,5, 10-tetrahydrobenzo [ b ]]Pyrrolo [3,2-f]Aza derivatives
-4 (1H) -one (2 a), the preparation method comprising the steps of:
s1. Taking compound 1a (0.15mmol, 57.3mg), adding tetrahydrofuran (5 ml), stirring at 90 ℃ for 12 hours, concentrating the reaction liquid under reduced pressure, and purifying by column chromatography (petroleum ether: ethyl acetate = 3) to obtain compound 1-tosyl-2, 3,5, 10-tetrahydrobenzo [ b]Pyrrolo [3,2-f]Aza derivatives
-4 (1H) -one (2 a). Yield 81% (43 mg), grey solid, m.p.155.9-157.4 ℃, R f =0.6 (ethyl acetate/petroleum ether = 1. 1 H NMR(500MHz,CDCl 3 )δ9.00(s,1H),7.68(d,J＝8.0Hz,2H),7.31(d,J＝7.9Hz,3H),7.23(d,J＝6.5Hz,2H),7.16(d,J＝7.9Hz,1H),3.71(t,J＝8.4Hz,2H),3.60(s,2H),2.52(t,J＝8.4Hz,2H),2.42(s,3H). 13 C{ 1 H}NMR(126MHz,CDCl 3 )δ187.1,150.5,145.5,138.2,133.2,130.8,130.4,127.60,127.2,126.2,124.8,119.5,102.6,48.2,47.8,25.1,21.7.IR(KBr,cm -1 ):2924,1727,1627,1402,1266,1160,915,754,588,546.HRMS(ESI–TOF)/m/z:[M+Na] + calcd for C 20 H 20 N 2 O 3 SNa 391.1087；found 391.1085
Examples 2 to 5
The preparation methods and the starting materials of examples 2 to 5 differ from example 1 only in temperature, and the effect of the temperature of the reaction in step S1 on the yield was examined.
TABLE 1 data for examples 2 to 5
| Examples | Temperature/. Degree.C | Yield/%) |
| 2 | 60 | 20 |
| 3 | 70 | 33 |
| 4 | 100 | 75 |
| 5 | 120 | 80 |
Examples 6 to 8
The preparation methods and the raw materials of examples 6 to 8 were the same as example 1 except for the reaction time in step S1, and the influence of the reaction time in step S1 on the yield was examined.
TABLE 2 data for examples 6 to 8
| Examples | Reaction time/h | Yield/%) |
| 6 | 4 | 41 |
| 7 | 24 | 80 |
| 8 | 48 | 79 |
Examples 9 to 14
The preparation methods and starting materials of examples 9 to 14 differ from example 1 only in the solvent in step S1, and the influence of the solvent on the yield was investigated.
TABLE 3 data for examples 9 to 14
Example 16
Example 16 provides a 8-fluoro-1-tosyl-2, 3,5, 10-tetrahydrobenzo [ b ]]Pyrrole [3,2-f ]]Aza derivatives
-4 (1H) -one (2 b), prepared as follows:
4-fluoro-2-nitrobenzaldehyde was used in place of 2-nitrobenzaldehyde in step (1) of example 1, and the remainder was unchanged to give 8-fluoro-1-tosyl-2, 3,5, 10-tetrahydrobenzo [ b]Pyrrole [3,2-f ]]Aza derivatives
-4 (1H) -one (2 b). Yield 70% (55.8 mg), grey solid, m.p.155.8-156.6 ℃ C. R f =0.4 (ethyl acetate/petroleum ether = 1. 1 H NMR(500MHz,CDCl 3 )δ8.96(s,1H),7.67(d,J＝8.1Hz,2H),7.34(d,J＝8.1Hz,2H),7.18(dd,J＝8.5,6.0Hz,1H),6.97–6.86(m,2H),3.71(t,J＝8.5Hz,2H),3.57(s,2H),2.52(t,J＝8.5Hz,2H),2.44(s,3H). 13 C{ 1 H}NMR(126MHz,CDCl 3 )δ187.0,162.7(C-F, 1 J C-F ＝247.0Hz),160.8(C-F, 1 J C-F ＝247.0Hz),150.2,145.6,139.34(C-F, 3 J C-F ＝10.1Hz),139.26(C-F, 3 J C-F ＝10.1Hz),133.1,132.14(C-F, 3 J C-F ＝8.9Hz),132.07(C-F, 3 J C-F ＝8.9Hz),130.5,127.2,120.58(C-F, 4 J C-F ＝2.5Hz),120.56(C-F, 4 J C-F ＝2.5Hz),113.3(C-F, 2 J C-F ＝21.4Hz),113.1(C-F, 2 J C-F ＝21.4Hz),106.7(C-F, 2 J C-F ＝24.1Hz),106.5(C-F, 2 J C-F ＝24.1Hz),102.8,47.8,47.5,25.1,21.7. 19 F NMR(471MHz,CDCl 3 )δ-114.57.IR(KBr,cm -1 ):3327,3057,2976,2923,2246,1729,1614,1496,1400,1266,1164,971,745,583,543.HRMS(ESI–TOF)/m/z:[M+Na] + calcd for C 19 H 17 FN 2 O 3 SNa 395.0836；found 395.0832.
Example 17
Example 17 provides an 8-bromo-1-tolyl-2, 3,5, 10-tetrahydrobenzo [ b ]]Pyrrolo [3, 2-f)]Aza derivatives
-4 (1H) -one (2 c), the preparation method being in particular as follows:
the 2-nitrobenzaldehyde in step (1) of example 1 was replaced with 4-bromo-2-nitrobenzaldehyde, and the remainder was carried out without changing to give 8-bromo-1-tolyl-2, 3,5, 10-tetrahydrobenzo [ b ] b]Pyrrolo [3, 2-f)]Aza derivatives
-4 (1H) -one (2 c). Yield 80% (52 mg), brown solid, m.p.162.5-163.9 ℃ C f =0.5 (ethyl acetate/petroleum ether = 1. 1 H NMR(500MHz,CDCl 3 )δ8.96(s,1H),7.68(d,J＝8.1Hz,2H),7.37–7.30(m,4H),7.09(d,J＝8.0Hz,1H),3.70(t,J＝8.5Hz,2H),3.55(s,2H),2.52(t,J＝8.5Hz,2H),2.44(s,3H). 13 C{ 1 H}NMR(126MHz,CDCl 3 )δ186.5,150.2,145.7,139.5,133.1,132.1,130.5,129.1,127.2,123.8,122.4,120.6,102.9,47.8,25.1,21.7.IR(KBr,cm -1 ):2979,1603,1573,1531,1484,1354,1402,1159,1114,1086,1159,1114,1086,741,667,591.HRMS(ESI–TOF)/m/z:[M+H] + calcd for C 19 H 18 BrN 2 O 3 S 433.0216；found 433.0211.
Example 18
Example 18 provides a4-oxo-1-tosyl-1, 2,3,4,5, 10-hexahydrobenzo [ b ]]Pyrrole [3,2-f ]]Aza derivatives
-8-Carboxylic acid methyl ester (2 d), the preparation method being specified below:
4-Carboxylic acid carbomethoxy-2-nitrobenzaldehyde was used in place of 2-nitrobenzaldehyde in step (1) of example 1, and the remaining operations were not changed to give 4-oxo-1-toluenesulfonyl-1, 2,3,4,5, 10-hexahydrobenzo [ b ] b]Pyrrole [3,2-f ]]Aza derivatives
-8-carboxylic acid methyl ester (2 d). Yield 75% (46 mg) of brown liquid R f =0.3 (ethyl acetate/petroleum ether = 1. 1 H NMR(500MHz,CDCl 3 )δ9.12(s,1H),7.90–7.83(m,2H),7.70(d,J＝8.1Hz,2H),7.36–7.26(m,4H),3.96(s,3H),3.72(t,J＝8.4Hz,2H),3.66(s,2H),2.54(t,J＝8.5Hz,2H). 13 C{ 1 H}NMR(126MHz,CDCl 3 )δ186.0,166.1,150.6,145.6,138.3,133.1,131.0,130.4,129.8,129.6,127.2,127.1,120.8,102.9,52.4,48.4,47.8,25.1,21.7.IR(KBr,cm -1 ):2953,1727,1602,1541,1497,1437,1355,1295,1226,1159,1108,814,761,667,592,542.HRMS(ESI–TOF)/m/z:[M+H] + calcd for C 19 H 18 BrN 2 O 3 S 435.0985；found 435.0980.
Example 19
Example 19 provides a 7-chloro-1-tolyl-2, 3,5, 10-tetrahydrobenzo [ b ]]Pyrrolo [3, 2-f)]Aza derivatives
-4 (1H) -one (2 e), prepared as follows:
5-chloro-2-nitrobenzaldehyde was used in place of 2-nitrobenzaldehyde in step (1) of example 1, and the remainder was carried out unchanged to give 7-chloro-1-tolyl-2, 3,5, 10-tetrahydrobenzo [ b]Pyrrolo [3, 2-f)]Aza derivatives
-4 (1H) -one (2 e). Yield 83% (48 mg), brown solid, m.p.149.5-152.2 ℃ C. R f =0.6 (ethyl acetate/petroleum ether = 1. 1 H NMR(500MHz,CDCl 3 )δ8.97(s,1H),7.66(d,J＝8.0Hz,2H),7.33(d,J＝8.0Hz,2H),7.29–7.27(m,1H),7.22(s,1H),7.10(d,J＝8.4Hz,1H),3.70(t,J＝8.4Hz,2H),3.56(s,2H),2.51(t,J＝8.4Hz,2H),2.43(s,3H). 13 C{ 1 H}NMR(126MHz,CDCl 3 )δ186.2,150.4,145.7,136.9,133.1,131.3,130.5,130.4,127.6,127.2,126.4,120.7,102.8,47.9,47.8,25.1,21.7.IR(KBr,cm -1 ):2953,1727,1602,1541,1497,1437,1355,1295,1226,1159,1108,814,761,667,592,542.HRMS(ESI–TOF)/m/z:[M+H] + calcd for C 19 H 17 ClN 2 O 3 SNa 411.0541；found 411.0537.
Example 20
Example 20 provides an 8-chloro-1-tolyl-2, 3,5, 10-tetrahydrobenzo [ b ]]Pyrrolo [3, 2-f)]Aza derivatives
-4 (1H) -one (2 f), the preparation method being in particular as follows:
the 2-nitrobenzaldehyde in step (1) of example 1 was replaced with 4-chloro-2-nitrobenzaldehyde, and the remainder was carried out unchanged to give 8-chloro-1-tolyl-2, 3,5, 10-tetrahydrobenzo [ b]Pyrrolo [3, 2-f)]Aza derivatives
-4 (1H) -one (2 e). Yield 82% (48 mg), brown solid, m.p.151.2-152.6 ℃ C f =0.6 (ethyl acetate/petroleum ether = 1. 1 H NMR(500MHz,CDCl 3 )δ8.97(s,1H),7.68(d,J＝7.9Hz,2H),7.34(d,J＝7.9Hz,2H),7.21–7.12(m,3H),3.70(t,J＝8.4Hz,2H),3.57(s,2H),2.52(t,J＝8.5Hz,2H),2.44(s,3H). 13 C{ 1 H}NMR(126MHz,CDCl 3 )δ186.6,150.2,145.7,139.2,133.1,133.0,131.9,130.5,127.2,126.2,123.3,119.5,47.8,25.1,21.7.IR(KBr,cm -1 ):1606,1533,1485,1401,1352,1241,1159,1096,811,737,668,587.HRMS(ESI–TOF)/m/z:[M+H] + calcd for C 19 H 17 ClN 2 O 3 SNa 411.0541；found 411.0536.
Example 21
Example 21 provides an 8-methoxy-1-tolyl-2, 3,5, 10-tetrahydrobenzo [ b ]]Pyrrolo [3,2-f]Aza derivatives
-4 (1H) -one (2 g), prepared as follows:
the 2-nitrobenzaldehyde in step (1) of example 1 was replaced with 4-methoxy-2-nitrobenzaldehyde, and the remainder was unchanged to give 8-methoxy-1-tolyl-2, 3,5, 10-tetrahydrobenzo [ b]Pyrrolo [3,2-f]Aza derivatives
-4 (1H) -one (2 g). Yield 72% (41 mg) of brown liquid, R f =0.4 (ethyl acetate/petroleum ether = 1. 1 H NMR(500MHz,CDCl 3 )δ8.92(s,1H),7.69(d,J＝8.1Hz,2H),7.32(d,J＝8.0Hz,2H),7.12(d,J＝8.4Hz,1H),6.78(dd,J＝8.4,2.4Hz,1H),6.67(d,J＝2.4Hz,1H),3.83(s,3H),3.69(t,J＝8.4Hz,2H),3.52(s,2H),2.51(t,J＝8.4Hz,2H),2.43(s,3H).. 13 C{ 1 H}NMR(126MHz,CDCl 3 )δ187.7,159.2,150.3,145.5,139.0,133.1,131.6,130.4,127.2,116.9,112.2,104.8,102.4,55.7,47.8,47.3,25.2,21.7.IR(KBr,cm -1 ):2963,1608,1499,1405,1351,1277,1116,1034,812,739,670,582,541.HRMS(ESI–TOF)/m/z:[M+H] + calcd for C 20 H 20 N 2 O 4 SNa 407.1036；found 407.1031.
Example 22
Example 22 provides a 7-fluoro-1-tolyl-2, 3,5, 10-tetrahydrobenzo [ b ]]Pyrrolo [3,2-f]Aza derivatives
-4 (1H) -one (2 k), prepared as follows:
5-fluoro-2-nitrobenzaldehyde was used in place of 2-nitrobenzaldehyde in step (1) of example 1, and the remainder was unchanged to give 7-fluoro-1-tolyl-2, 3,5, 10-tetrahydrobenzo [ b]Pyrrolo [3,2-f]Aza derivatives
-4 (1H) -one (2H). Yield 72% (40 mg), grey solid, m.p.93.5-94.7 ℃, R f =0.4 (ethyl acetate/petroleum ether = 1. 1 H NMR(500MHz,CDCl 3 )δ8.94(s,1H),7.67(d,J＝8.1Hz,2H),7.33(d,J＝8.0Hz,2H),7.13(dd,J＝8.7,4.7Hz,1H),7.05–6.92(m,2H),3.70(t,J＝8.4Hz,2H),3.57(s,2H),2.51(t,J＝8.4Hz,2H),2.43(s,3H). 13 C{ 1 H}NMR(126MHz,CDCl 3 )δ186.2,161.7(C-F, 1 J C-F ＝247.7Hz),159.8(C-F, 1 J C-F ＝247.7Hz),150.7,145.6,134.5(C-F, 4 J C-F ＝3.8Hz),134.4(C-F, 4 J C-F ＝3.8Hz),133.1,130.4,127.2,127.1(C-F, 2 J C-F ＝8.9Hz),127.0(C-F, 3 J C-F ＝8.9Hz),120.9(C-F, 3 J C-F ＝7.6Hz),120.8(C-F, 2 J C-F ＝7.6Hz),117.0(C-F, 2 J C-F ＝24.1Hz),116.8(C-F, 2 J C-F ＝24.1Hz),114.6(C-F, 2 J C-F ＝22.9Hz),114.4(C-F, 2 J C-F ＝22.9Hz),102.42,48.03,47.81,25.07,21.67. 19 F NMR(471MHz,CDCl 3 )δ-116.91.IR(KBr,cm -1 ):2923,1586,1497,1402,1353,1246,1159,1105,814,737,667,587,546.HRMS(ESI–TOF)/m/z:[M+Na] + calcd for C 19 H 17 FN 2 O 3 SNa 395.0836；found 395.0834
Example 23
Example 23 provides a series of 7-methoxy-1-tolyl-2, 3,5, 10-tetrahydrobenzo [ b ]]Pyrrolo [3,2-f]Aza derivatives
-4 (1H) -one (2 i) prepared as follows:
the 2-nitrobenzaldehyde in step (1) of example 1 was replaced with 7-methoxy-2-nitrobenzaldehyde, and the remainder was carried out without changing to give 7-methoxy-1-tolyl-2, 3,5, 10-tetrahydrobenzo [ b ] b]Pyrrolo [3,2-f]Aza derivatives
-4 (1H) -one (2 i). Yield 64% (37 mg), brown liquid, m.p.143.6-144.0 ℃ R f =0.8 (ethyl acetate/petroleum ether = 1. 1 H NMR(500MHz,CDCl 3 )δ8.88(s,1H),7.67(d,J＝8.1Hz,2H),7.31(d,J＝8.0Hz,2H),7.08(d,J＝8.7Hz,1H),6.85(dd,J＝8.7,2.8Hz,1H),6.75(d,J＝2.7Hz,1H),3.80(s,3H),3.70(t,J＝8.4Hz,2H),3.56(s,2H),2.50(t,J＝8.4Hz,2H),2.42(s,3H). 13 C{ 1 H}NMR(126MHz,CDCl 3 )δ186.7,158.1,150.8,145.5,133.3,131.5,130.4,127.2,126.4,120.6,114.5,113.8,101.8,55.6,48.4,47.9,25.1,21.7.IR(KBr,cm -1 ):3337,2918,2215,1586,1532,1500,1353,1248,1158,1035,812,666,585.HRMS(ESI–TOF)/m/z:[M+Na] + calcd for C 20 H 20 N 2 O 4 SNa 407.1036；found 407.1031
Example 24
Example 24 provides an 8-methyl-1-tolyl-2, 3,5, 10-tetrahydrobenzo [ b ]]Pyrrolo [3, 2-f)]Aza derivatives
-4 (1H) -one (2 j), prepared as follows:
the 2-nitrobenzaldehyde in step (1) of example 1 was replaced with 4-methyl-2-nitrobenzaldehyde, and the remainder was carried out without changing to give 8-methyl-1-tolyl-2, 3,5, 10-tetrahydrobenzo [ b ] b]Pyrrolo [3,2-f]Aza derivatives
-4 (1H) -one (2 j). Yield 75% (41 mg), brown solid, m.p.101.8-102.1, R f =0.4 (ethyl acetate/petroleum ether = 1. 1 H NMR(500MHz,CDCl 3 )δ8.94(s,1H),7.69(d,J＝8.1Hz,2H),7.32(d,J＝8.1Hz,2H),7.10(d,J＝7.8Hz,1H),7.03(d,J＝7.8Hz,1H),6.96(s,1H),3.69(t,J＝8.4Hz,2H),3.55(s,2H),2.51(t,J＝8.5Hz,2H),2.42(s,3H),2.38(s,3H). 13 C{ 1 H}NMR(126MHz,CDCl 3 )δ187.4,150.4,145.5,138.0,137.7,133.2,130.6,130.4,127.3,127.1,121.7,119.9,102.3,47.8,25.1,21.7,20.9. 19 F NMR(471MHz,CDCl 3 )δ-116.16.IR(KBr,cm -1 ):2922,1605,1499,1402,1351,1240,1160,1115,814,735,670,587.HRMS(ESI–TOF)/m/z:[M+Na] + calcd for C 20 H 20 N 2 O 3 SNa 391.1087；found 391.1082
Example 25
Example 25 provides a 6-fluoro-1-tolyl-2, 3,5, 10-tetrahydrobenzo [ b ]]Pyrrolo [3,2-f]Aza derivatives
-4 (1H) -one (2 k), prepared as follows:
the 2-nitrobenzaldehyde in step (1) of example 1 was replaced with 6-fluoro-2-nitrobenzaldehyde, and the remainder of the procedure was unchanged,to give 6-fluoro-1-tolyl-2, 3,5, 10-tetrahydrobenzo [ b ]]Pyrrolo [3,2-f]Aza derivatives
-4 (1H) -one (2 k). Yield 59% (33 mg) of a brown liquid, R f =0.4 (ethyl acetate/petroleum ether = 1. 1 H NMR(500MHz,CDCl 3 )δ9.03(s,1H),7.67(d,J＝8.1Hz,2H),7.32(d,J＝8.0Hz,2H),7.26–7.22(m,1H),7.02–6.93(m,2H),3.71(t,J＝8.5Hz,2H),3.64(s,2H),2.52(t,J＝8.5Hz,2H),2.43(s,3H). 13 C{ 1 H}NMR(126MHz,CDCl 3 )δ186.3,161.5(C-F, 1 J C-F ＝248.9Hz),159.5(C-F, 1 J C-F ＝248.9Hz),150.2,145.6,140.42(C-F, 3 J C-F ＝5.08Hz),140.38(C-F, 3 J C-F ＝5.08Hz),133.0,130.4,128.2(C-F, 3 J C-F ＝10.2),128.1(C-F, 3 J C-F ＝10.2),127.2,115.00(C-F, 4 J C-F ＝3.8),114.97(C-F, 4 J C-F ＝3.8),113.0(C-F, 2 J C-F ＝20.3),112.9(C-F, 2 J C-F ＝20.3),112.3(C-F, 2 J C-F ＝22.9),112.2(C-F, 2 J C-F ＝22.9),103.5,47.8,38.5,38.5,25.2. 19 F NMR(471MHz,CDCl 3 )δ-116.16.IR(KBr,cm -1 ):2923,1614,1476,1399,1354,1261,1161,1984,782,669,586.HRMS(ESI–TOF)/m/z:[M+Na] + calcd for C 19 H 17 FN 2 O 3 SNa 395.0836；found 395.0831
Example 26
Example 26 provides a 1-tosyl-8- (trifluoromethyl) -2,3,5, 10-tetrahydrobenzo [ b ]]Pyrrolo [3, 2-f)]Aza derivatives
-4 (1H) -one (2 l) prepared as follows:
with 4-trifluoromethyl-2-nitro compoundBenzaldehyde instead of 2-nitrobenzaldehyde in step (1) of example 1, the remaining operations were unchanged to give 1-tosyl-8- (trifluoromethyl) -2,3,5, 10-tetrahydrobenzo [ b]Pyrrolo [3, 2-f)]Aza derivatives
-4 (1H) -one (2 l). Yield 60% (38 mg), grey solid, R f =0.4 (ethyl acetate/petroleum ether = 1. 1 H NMR(500MHz,CDCl 3 )δ9.11(s,1H),7.69(d,J＝8.1Hz,2H),7.47(d,J＝8.0Hz,1H),7.40(s,1H),7.38–7.31(m,3H),3.73(t,J＝8.5Hz,2H),3.66(s,2H),2.56(t,J＝8.5Hz,2H),2.44(s,3H).δ185.9,150.4,145.8,138.6,133.1,131.5,130.16(q,J＝33.1Hz),130.0,129.8,128.5,127.2,122.70(q,J＝3.7Hz),116.67(q,J＝3.7Hz,103.21,48.13,47.77,24.99,21.66. 19 F NMR(471MHz,CDCl 3 )δ-116.16.IR(KBr,cm -1 ):2923,1614,1476,1399,1354,1261,1161,1984,782,669,586.HRMS(ESI–TOF)/m/z:[M+Na] + calcd for C 19 H 17 FN 2 O 3 SNa 395.0836；found 395.0831
Example 27
Example 27 provides a 4-oxo-1-tosyl-1, 2,3,4,5, 10-hexahydrobenzo [ b ]]Pyrrole [3,2-f ]]Aza derivatives
-7-Carboxylic acid methyl ester (2 m), prepared as follows:
5-carbomethoxy-2-nitrobenzaldehyde was used in place of 2-nitrobenzaldehyde in step (1) of example 1, and the remainder was unchanged to give 4-oxo-1-toluenesulfonyl-1, 2,3,4,5, 10-hexahydrobenzo [ b ] b]Pyrrole [3,2-f ]]Aza derivatives
-7-carboxylic acid methyl ester (2 m). Yield 68% (42 mg) of a yellow liquid, R f =0.3 (ethyl acetate/petroleum ether = 1. 1 H NMR(500MHz,CDCl 3 )δ9.14(s,1H),8.02–7.92(m,2H),7.67(d,J＝8.1Hz,2H),7.32(d,J＝8.1Hz,2H),7.21(d,J＝8.3Hz,1H),3.92(s,3H),3.72(t,J＝8.5Hz,2H),3.65(s,2H),2.53(t,J＝8.5Hz,2H),2.43(s,3H). 13 C{ 1 H}NMR(126MHz,CDCl 3 )δ186.4,166.2,149.7,145.7,142.1,133.0,132.7,130.5,129.1,127.8,127.2,124.2,119.5,103.6,52.2,48.1,47.8,25.2,21.7.IR(KBr,cm -1 ):2922,1605,1499,1402,1351,1240,1160,1115,814,735,670,587.HRMS(ESI–TOF)/m/z:[M+Na] + calcd for C 20 H 20 N 2 O 3 SNa 391.1087；found 391.1082.
Example 28
Example 28 provides a 5-phenyl-1-tosyl-2, 3,5, 10-tetrahydrobenzo [ b ]]Pyrrolo [3, 2-f)]Aza derivatives
-4 (1H) -one (2 n) prepared as follows:
the remaining operations were carried out without changing benzaldehyde instead of paraformaldehyde in step (2) of example 1 to give 5-phenyl-1-toluenesulfonyl-2, 3,5, 10-tetrahydrobenzo [ b ]]Pyrrolo [3,2-f]Aza derivatives
-4 (1H) -one (2 n). Yield 47% (30 mg), grey solid, rf =0.4 (ethyl acetate/petroleum ether = 1. 1 H NMR(500MHz,CDCl 3 )δ9.09(s,1H),7.42(t,J＝7.6Hz,1H),7.33(t,J＝10.1Hz,4H),7.24–7.13(m,6H),6.88(d,J＝7.5Hz,2H),5.03(s,1H),3.75(td,J＝10.4,3.8Hz,1H),3.32(q,J＝10.0Hz,1H),2.72–2.56(m,2H),2.39(s,3H). 13 C NMR(126MHz,CDCl 3 )δ188.5,148.5,145.0,138.1,137.6,132.9,132.7,130.3,128.4,128.2,127.0,126.7,126.6,126.3,125.5,120.5,100.8,63.9,47.4,25.2,21.6.IR(KBr,cm -1 ):2958,2862,1575,1542,1493,1450,1409,1352,1303,1160,1120,1080,912,912,753,668,628,586.HRMS(ESI–TOF)/m/z:[M+H] + calcd for C 25 H 23 N 2 O 3 S 431.1424；found 431.1421.
Example 29
Example 29 provides a 5-Ethyl-1-tosyl-2, 3,5, 10-tetrahydrobenzo [ b ]]Pyrrolo [3,2-f]Aza derivatives
-4 (1H) -one (2 o), prepared as follows:
by substituting propionaldehyde for paraformaldehyde in step (2) of example 1 and carrying out the other operations unchanged, 5-ethyl-1-toluenesulfonyl-2, 3,5, 10-tetrahydrobenzo [ b ] is obtained]Pyrrolo [3, 2-f)]Aza derivatives
-4 (1H) -one (2 o). Yield 75% (43 mg), grey solid, rf =0.4 (ethyl acetate/petroleum ether = 1. 1 H NMR(500MHz,CDCl 3 )δ9.02(s,1H),7.67(d,J＝7.9Hz,2H),7.30(q,J＝8.6,8.0Hz,3H),7.24–7.11(m,3H),3.82–3.73(m,1H),3.68(q,J＝9.8Hz,1H),3.43(t,J＝8.0Hz,1H),2.62–2.54(m,1H),2.54–2.46(m,1H),1.82–1.72(m,1H),1.65–1.55(m,1H),0.76(t,J＝7.4Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ190.79,148.38,145.45,136.78,133.15,131.35,130.32,127.58,127.43,127.24,125.79,119.99,100.91,60.93,47.82,25.41,23.31,21.63,12.01.IR(KBr,cm -1 ):2964,2926,2871,1604,1539,1490,1402,1352,1225,1161,1093,1052,755,669,587.HRMS(ESI–TOF)/m/z:[M+H] + calcd for C 21 H 23 N 2 O 3 S 383.1424；found 383.1430.
Example 30
Example 30 provides a 6-tosyl-5, 7,8, 10-tetrahydropyrido [3,2-b ]]Pyrrolo [3,2-f]Aza derivatives
-9 (6H) -one (2 p), preparationThe method comprises the following steps:
the 2-nitrobenzaldehyde of step (1) in example 1 was replaced with 3-nitropyridinylaldehyde, and the remaining operations were not changed to give 6-tosyl-5, 7,8, 10-tetrahydropyrido [3,2-b ]]Pyrrolo [3, 2-f)]Aza derivatives
-9 (6H) -one (2 p). Yield 53% (28 mg), grey solid, rf =0.6 (ethyl acetate/petroleum ether = 1. 1 H NMR(500MHz,CDCl 3 )δ8.87(s,1H),8.48(d,J＝4.6Hz,1H),7.66(d,J＝8.3Hz,2H),7.48(s,1H),7.33(d,J＝8.1Hz,2H),3.90(s,2H),3.75–3.68(m,2H),2.56(t,J＝8.5Hz,2H),2.44(s,4H). 13 C NMR(126MHz,CDCl 3 )δ185.4,149.5,147.3,145.7,144.0,134.0,133.0,130.5,129.3,128.7,127.2,126.9,122.2,103.6,51.7,47.8,25.2,21.7.IR(KBr,cm -1 ):2922,1733,1598,1568,1489,1352,1268,1160,1113,1083,810,752,668,587,544.HRMS(ESI–TOF)/m/z:[M+H] + calcd for C 18 H 18 N 3 O 3 S 356.1064；found 356.1068.
Example 31
Example 31 provides a 1- (methylsulfonyl) -2,3,5, 10-tetrahydrobenzo [ b ]]Pyrrolo [3,2-f]Aza derivatives
-4 (1H) -one (2 q) prepared as follows:
replacement of p-methylbenzenesulfonyl chloride in step (2) of example 1 with methanesulfonyl chloride and the remainder of the procedures were unchanged to give 1- (methanesulfonyl) -2,3,5,10-tetrahydrobenzo [ b ]]Pyrrolo [3,2-f]Aza derivatives
-4(1H) -a ketone (2 q). Yield 62% (26 mg), grey solid, rf =0.4 (ethyl acetate/petroleum ether = 1. 1 H NMR(500MHz,CDCl 3 )δ8.67(s,1H),7.26–7.18(m,3H),7.04(d,J＝7.7Hz,1H),3.87(t,J＝8.6Hz,2H),3.65(s,2H),3.07(s,3H),2.84(t,J＝8.6Hz,2H). 13 C NMR(126MHz,CDCl 3 )δ187.20,150.08,137.92,130.83,127.60,126.37,124.80,119.57,101.92,48.31,48.22,38.04,25.35.IR(KBr,cm -1 ):3054,3008,1647,1607,1575,1538,1409,1346,1240,1154,1115,1068,1036,965,755.HRMS(ESI–TOF)/m/z:[M+H] + calcd for C 13 H 15 N 2 O 3 S 279.0798；found 279.0798.
Example 32
Example 32 provides a 1-p-toluenesulfonyl-1, 2,3,4,6, 11-hexahydro-5H-benzo [ b ]]Pyrido [3,2-f ]]Aza derivatives
-5-ketone (2 r), prepared as follows:
the 3-butyn-1-ol from step (2) of example 1 was replaced with 4-pentyn-1-ol and the remainder was unchanged to give 1-p-toluenesulfonyl-1, 2,3,4,6, 11-hexahydro-5H-benzo [ b ]]Pyrido [3,2-f]Aza derivatives
-5-ketone (2 r). Yield 73% (40 mg), brown liquid, R f =0.6 (ethyl acetate/petroleum ether = 1. 1 H NMR(500MHz,CDCl 3 )δ8.71(s,1H),7.57(d,J＝8.1Hz,2H),7.36–7.30(m,2H),7.29(t,J＝2.8Hz,1H),7.24(d,J＝8.0Hz,2H),3.70(d,J＝15.0Hz,4H),2.38(s,3H),2.03(t,J＝7.3Hz,2H),1.31–1.22(m,3H). 13 C{ 1 H}NMR(126MHz,CDCl 3 )δ189.3,149.4,145.1,138.8,135.5,130.3,129.1,128.4,127.5,127.0,126.6,119.8,105.1,48.2,46.9,21.6,21.1,20.8.IR(KBr,cm -1 ):2927,1580,1524,1490,1369,1156,1089,1009,756,669,560.HRMS(ESI–TOF)/m/z:[M+Na] + calcd for C 20 H 20 N 2 O 3 SNa 391.1087；found 391.1085.
Biological activity assay
The compounds prepared in the above examples were tested for biological activity
1. Preparation of samples: an appropriate amount of the compound prepared in the examples of the present invention was prepared into gradient concentrations of 1000uM, 100uM, 10uM, and 1uM using cyclooxygenase-2 Assay Buffer (COX-2 Assay Buffer), milli-Q grade purified water, dimethyl sulfoxide, and other appropriate solvents.
2. Preparation of the kit:
a. melting all other reagents except human recombinant COX-2 (recombinant human COX-2, rhCOX-2) to room temperature, centrifuging to precipitate the solution to the bottom of the tube, and mixing. COX-2Probe (COX-2 Probe), COX-2Cofactor (COX-2 Cofactor) (50X), and COX-2Substrate (COX-2 Substrate) (50X) were formulated in DMSO and melt facilitated in a 37 deg.C water bath for 2 min. After use, the mixture is immediately stored at-20 ℃ in the dark.
Preparing a COX-2 accessory factor (COX-2 Cofactor) working solution: an appropriate amount of COX-2Cofactor (COX-2 Cofactor) working solution was prepared at a rate such that 5. Mu.L of COX-2Cofactor working solution was required for each sample. mu.L of COX-2Cofactor (COX-2 Cofactor) (50X) was taken and diluted with COX-2Assay Buffer at a ratio of 1. The prepared COX-2Cofactor (COX-2 Cofactor) working solution can be stored at 4 ℃ and is only used in the same day.
C, preparing COX-2 working solution: and preparing a proper amount of COX-2 working solution according to the proportion that 5 mu L of COX-2 working solution is needed for each sample. An appropriate amount of human recombinant COX-2 (recombinant human COX-2, rhCOX-2) (25X) was diluted with COX-2Assay Buffer at a ratio of 1. The prepared COX-2 working solution can be temporarily stored on an ice bath, and the enzyme activity is basically stable within 1 hour. Note: all manipulations involving COX-2 should be performed on ice.
Preparing a COX-2Substrate (COX-2 Substrate) working solution: an appropriate amount of COX-2Substrate (COX-2 Substrate) working solution was prepared at a rate of 5 μ L of COX-2Substrate (COX-2 Substrate) working solution per sample. mu.L of COX-2Substrate (COX-2 Substrate) (50X) was added to an equal volume of Substrate Buffer and mixed well by vortexing, and the mixture was diluted again with Milli-Q grade pure water or redistilled water according to the ratio of 1. The prepared COX-2Substrate (COX-2 Substrate) working solution was stored temporarily on an ice bath.
e. Preparation of a positive inhibitor Celecoxib solution: the positive control inhibitor Celecoxib concentration provided by the kit is 100 μ M and is formulated in DMSO.
3. Sample detection: (1) Referring to table 4, the control wells and the sample wells were set using a 96-well blackboard, and the samples and the respective solutions were added in order as follows. After the addition of the sample to be tested, the mixture was mixed well and incubated at 37 ℃ for 10 minutes.
TABLE 4 data sheet
(2) COX-2Probe (COX-2 Probe) was added to each well at 5. Mu.L.
(3) Add 5 μ L of COX-2Substrate (COX-2 Substrate) working solution into each well rapidly, mix well.
(4) Fluorescence measurements were performed after incubation for 5 minutes at 37 ℃ in the dark. The excitation wavelength was 560nm and the emission wavelength was 590nm. When the fluorescence reading is low, the incubation time can be prolonged to 10-20 minutes.
4. Calculation (1) the mean fluorescence value for each sample well and blank control well was calculated and recorded as RFU blank control, RFU100% enzyme activity control, RFU positive inhibitor control, and RFU sample, respectively. RFU, relative Fluorescence Unit. (2) The percent inhibition was calculated for each sample. The calculation formula is as follows: inhibition (%) = (RFU 100% enzyme activity control-RFU sample)/(RFU 100% enzyme activity control-RFU blank) × 100%. IC50 values were fitted using compucon.
The experimental data are shown in table 5:
data for the compounds of Table 5
The experimental result shows that the nitrogen-containing impurities prepared by the invention
The compound has certain inhibition effect on COX-2 and has the potential of preparing COX-2 inhibitors.
It should be understood that the above-described embodiments of the present invention are merely examples for clearly illustrating the present invention and are not intended to limit the embodiments of the present invention. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. This need not be, nor should it be exhaustive of all embodiments. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.
Claims (10)
1. Aza
A compound of the class (I) or a pharmaceutically acceptable salt thereof, wherein the aza is as defined above
The structural formula of the compound is shown as the formula (2):
wherein X is a carbon atom or a nitrogen atom; n is selected from 1,2 or 3;
R 1 is one or more radicals on the A ring, said R 1 Independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, C1-C6 ester group, C1-C6 alkylamino, cyano or phenyl;
when R is 1 Is a plurality ofWhen two R are present 1 Can be connected with each other through saturated or unsaturated C1-C4 carbon chains;
R 2 selected from hydrogen, benzyloxycarbonyl, t-butoxycarbonyl, fluorenylmethyloxycarbonyl, phthaloyl, p-toluenesulfonyl, trifluoroacetyl, p-methoxybenzyl, benzyl or methanesulfonyl;
R 3 selected from hydrogen, phenyl or C1-C6 alkyl.
2. The azepine of claim 1
A compound of the class I or a pharmaceutically acceptable salt thereof, wherein n is selected from 1 or 2.
3. The azepine of claim 1
A compound of the class R or a pharmaceutically acceptable salt thereof, wherein R is 1 Selected from hydrogen, chlorine, bromine, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl or C1-C6 ester group.
4. The azepine of claim 1
A compound of the class R or a pharmaceutically acceptable salt thereof, wherein R is 2 Selected from hydrogen, p-toluenesulfonyl or methanesulfonyl.
5. The azepine of claim 1
A compound or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is aza
Pharmaceutically acceptable salts of the compounds with organic or inorganic acids.
6. The compound of any one of claims 1 to 5
A preparation method of the compound or the pharmaceutically acceptable salt thereof is characterized by comprising the following steps:
s1, heating a allene compound shown in a formula (1) in a solvent and reacting to obtain a compound shown in a formula (2);
s2, if necessary, converting the obtained compound shown as the formula (2) into pharmaceutically acceptable salt;
wherein X is a carbon atom or a nitrogen atom; n is selected from 1,2 or 3;
R 1 is one or more groups on the A ring, said R 1 Independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, C1-C6 ester group, C1-C6 alkylamino, cyano or phenyl;
R 2 selected from hydrogen, benzyloxycarbonyl, t-butoxycarbonyl, fluorenylmethyloxycarbonyl, phthaloyl, p-toluenesulfonyl, trifluoroacetyl, p-methoxybenzyl, benzyl or methanesulfonyl;
R 3 selected from hydrogen, phenyl or C1-C6 alkyl.
7. The azepine of claim 6
The preparation method of the compound or the pharmaceutically acceptable salt thereof is characterized in that the solvent is selected from toluene, chlorobenzene, dimethyl sulfoxide, tetrahydrofuran, dichloromethane, 1, 2-dichloroethane, 1, 4-dioxane, methanol, ethanol and isopropylAlcohol, acetonitrile and water.
8. The azepine of claim 6
The preparation method of the compound or the pharmaceutically acceptable salt thereof is characterized in that the heating temperature is 60-120 ℃.
9. The azepine of claim 6
The preparation method of the compound or the pharmaceutically acceptable salt thereof is characterized in that the heating time is 4-48 h.
10. The azepine of any one of claims 1 to 5
The application of the compound or the pharmaceutically acceptable salt thereof in preparing COX-2 inhibitors.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1278263A (en) * | 1997-09-05 | 2000-12-27 | 葛兰素集团有限公司 | 2,3-diaryl-pyrazolo [1,5-B] pyridazines derivatives, their prepn. and use as cyclooxygenase 2 (cox-2) inhibitors |
| CN1323301A (en) * | 1998-08-22 | 2001-11-21 | 株式会社太平洋 | Diarylbenzopyran derivatives as cyclooxygenase-2 inhibitors |
| CN1612865A (en) * | 2001-11-09 | 2005-05-04 | 藤泽药品工业株式会社 | Triazole derivatives as cyclooxygenase (COX) inhibitors |
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2021
- 2021-07-16 CN CN202110809157.9A patent/CN115611901A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1278263A (en) * | 1997-09-05 | 2000-12-27 | 葛兰素集团有限公司 | 2,3-diaryl-pyrazolo [1,5-B] pyridazines derivatives, their prepn. and use as cyclooxygenase 2 (cox-2) inhibitors |
| CN1323301A (en) * | 1998-08-22 | 2001-11-21 | 株式会社太平洋 | Diarylbenzopyran derivatives as cyclooxygenase-2 inhibitors |
| CN1612865A (en) * | 2001-11-09 | 2005-05-04 | 藤泽药品工业株式会社 | Triazole derivatives as cyclooxygenase (COX) inhibitors |
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