CN115611901B - Azepine compound or pharmaceutically acceptable salt thereof, and preparation method and application thereof - Google Patents

Azepine compound or pharmaceutically acceptable salt thereof, and preparation method and application thereof Download PDF

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CN115611901B
CN115611901B CN202110809157.9A CN202110809157A CN115611901B CN 115611901 B CN115611901 B CN 115611901B CN 202110809157 A CN202110809157 A CN 202110809157A CN 115611901 B CN115611901 B CN 115611901B
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aza
pharmaceutically acceptable
compound
acceptable salt
cox
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CN115611901A (en
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祝诗发
刘子瑞
史秋
王永东
黄志鹏
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GENIFARM (GUANGZHOU) TECHNOLOGY Inc
Xinyuan Guangzhou Pharmaceutical Research Co ltd
South China University of Technology SCUT
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GENIFARM (GUANGZHOU) TECHNOLOGY Inc
Xinyuan Guangzhou Pharmaceutical Research Co ltd
South China University of Technology SCUT
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    • 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
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    • 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
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Abstract

The invention discloses an azaCompound or pharmaceutically acceptable salt thereof, preparation method and application thereof, and azaThe structural formula of the class of compounds is shown as a 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 groups on the A ring, said R 1 is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, C1-C6 ester, C1-C6 alkylamino, cyano or phenyl; when the number of R 1 is more than one, the two R 1 can be connected through saturated or unsaturated C1-C4 carbon chains; r 2 is selected from hydrogen, carbobenzoxy, t-butoxycarbonyl, fluorenylmethoxycarbonyl, phthaloyl, p-toluenesulfonyl, trifluoroacetyl, p-methoxybenzyl, benzyl or methanesulfonyl; r 3 is selected from hydrogen, phenyl or C1-C6 alkyl. The azaThe compound or pharmaceutically acceptable salt thereof has COX-2 inhibiting activity.

Description

Azepine compound or pharmaceutically acceptable salt thereof, and preparation method and application thereof
Technical Field
The invention relates to the technical field of pharmaceutical chemistry, in particular to an azaA compound or pharmaceutically acceptable salt thereof, and a preparation method and application thereof.
Background
In heterocyclic compounds, benzazepineThat is, the benzo-aza-seven-membered ring exists in the form of alkaloid in most of the nature, and has strong biological activity and medicinal value. For example trypsin (pancrracine) is isolated from PANCRRACINE MARITIMUM; galanthamine is separated from lycoris for treating senile dementia; cripowellins is separated from the root of Bao Shiwen Cryptophan (Crinum powellii) and has strong insecticidal activity; also, alkaloids isolated from erythrina plants are clinically useful as insect repellents and antiemetics.
Clinically, there are also a number of benzazepinesThe compounds have been used as medicaments for the treatment of central nervous system diseases. For example, chlorimipramine (Clomipramine) is an antidepressant manic drug, olanzapine (Olanzapine) is an antipsychotic drug, lorazepam (Lorazepam) is used to treat neurological, epileptic psychotic disorders, and Milbeine (MIANSERIN) is an antidepressant. Therefore, there is a need to further develop new aza/>And (3) a class of compounds.
Disclosure of Invention
The invention aims to provide an azaA class of compounds or pharmaceutically acceptable salts thereof. The aza/>The compounds or pharmaceutically acceptable salts thereof have novel parent nucleus structures and are capable of inhibiting COX-2 activity.
It is another object of the present invention to provide a process for the preparation of said compound or a pharmaceutically acceptable salt thereof.
It is a further object of the present invention to provide the use of said compound or a pharmaceutically acceptable salt thereof in the manufacture of a COX-2 inhibitor.
The above object of the present invention is achieved by the following technical scheme:
Aza A compound of the class or a pharmaceutically acceptable salt thereof, said aza/>The structural formula of the class of compounds is shown as a 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 groups on the A ring, said R 1 is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, C1-C6 ester, C1-C6 alkylamino, cyano or phenyl;
When the number of R 1 is more than one, the two R 1 can be connected through saturated or unsaturated C1-C4 carbon chains;
R 2 is selected from hydrogen, carbobenzoxy, t-butoxycarbonyl, fluorenylmethoxycarbonyl, phthaloyl, p-toluenesulfonyl, trifluoroacetyl, p-methoxybenzyl, benzyl or methanesulfonyl;
R 3 is selected from hydrogen, phenyl or C1-C6 alkyl.
Substituent definition and general terminology
The term "alkyl" as used herein, means 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 that the alkyl group is attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein.
The term "ester group" refers to-C (=o) O-. The ester groups may be linked to the substituents described herein to form the corresponding ester substituents. Examples of ester groups include, but are not limited to, methyl, ethyl, propyl, butyl, and the like.
Preferably, n is selected from 1 or 2.
Preferably, R 1 is selected from hydrogen, chlorine, bromine, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl or C1-C6 ester.
Preferably, R 2 is selected from hydrogen, p-toluenesulfonyl or methanesulfonyl.
More preferably, the azaClass of compounds, partially listed below:
preferably, the pharmaceutically acceptable salt is aza Pharmaceutically acceptable salts of the class of compounds with organic or inorganic acids.
More preferably, the pharmaceutically acceptable salt of the organic or inorganic acid is a hydrochloride, hydrobromide, sulfate, acetate, lactate, tartrate, citrate, trifluoroacetate, malate, maleate, succinate, p-toluenesulfonic acid or methanesulfonate salt.
The azaThe preparation method of the compound or the pharmaceutically acceptable salt thereof comprises the following steps:
s1, heating a diene 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 groups on the A ring, said R 1 is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, C1-C6 ester, C1-C6 alkylamino, cyano or phenyl;
R 2 is selected from hydrogen, carbobenzoxy, t-butoxycarbonyl, fluorenylmethoxycarbonyl, phthaloyl, p-toluenesulfonyl, trifluoroacetyl, p-methoxybenzyl, benzyl or methanesulfonyl;
R 3 is selected from hydrogen, phenyl or C1-C6 alkyl.
Preferably, the temperature of the heating 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 diene compound represented by the formula (1) is commercially available or synthesized by referring to a conventional report.
As an embodiment, the alkylene oxide compound represented by the formula (1) may be prepared by the following method: the dibromoolefin compound represented by the formula (3) is reacted with the alkylidene compound represented by the formula (4) to produce the alkynylamine alkylidene compound represented by the formula (1). Wherein the R 1、R2、R3 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 alkylene oxide compound represented by the formula (1) can be produced by the following operations: in a nitrogen atmosphere, sequentially adding a dibromoalkene compound shown in a formula (3), a binaphthyl compound shown in a formula (4), cuprous iodide, 1, 10-phenanthroline and cesium carbonate, adding dry tetrahydrofuran, and stirring at room temperature until the raw materials are completely reacted. After filtration, the solvent was evaporated in vacuo and purified by flash chromatography to give the alkylene compound of formula (1).
The azaThe application of a compound or pharmaceutically acceptable salt thereof in preparing COX-2 inhibitor.
Compared with the prior art, the invention has the beneficial effects that:
the present invention provides a novel series of aza-s The compound or the pharmaceutically acceptable salt thereof has the activity of inhibiting COX-2, so that the compound or the pharmaceutically acceptable salt thereof can be used for preparing COX-2 inhibitors. The invention also provides the aza/>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 industrialization value.
Detailed Description
Unless otherwise specified, the raw materials, reagents and solvents used in the present invention are commercially available without any treatment or may be prepared by literature methods. In order to more clearly illustrate the present invention, the present invention will be further described with reference to preferred embodiments. It is to be understood by persons skilled in the art that the following detailed description is illustrative and not restrictive, and that this invention is not limited to the details given herein.
Example 1
Example 1 provides a 1-tosyl-2, 3,5, 10-tetrahydrobenzo [ b ] pyrrolo [3,2-f ] aza-4 (1H) -ketone (2 a), said preparation method being specifically as follows:
first, compound (3 a), compound (4 a) and alkylene oxide compound (1 a) are prepared:
(1) Preparation of compound (3 a): 2-nitrobenzaldehyde (3 a-s1, 10g,66.2mmol,1 eq) was dissolved in dichloromethane (350 mL), carbon tetrabromide (23 g,69.5mmol,1.1 eq) was added, the solution was cooled to 0℃in an ice bath, triphenylphosphine (36.4 g,139 mmol) was added in portions to the above mixture, and the solution was stirred at 0 ℃. The reaction was monitored by TLC plate. Hexane (350 ml) was added to precipitate the phosphine salt. The solution was filtered through silica gel, rinsed with 10% ethyl acetate (hexane) solution, the filtrate collected and the solvent removed in vacuo and purified by column chromatography (petroleum ether: ethyl acetate=30:1) to give 2- (2, 2-dibromovinyl) -1-nitrobenzene (18.3 g, 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 under nitrogen at room temperature for half an hour. Dicyclohexylamine (100 mmol) was added to the mixture, stirred for 1 hour, then refluxed 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, the reaction product was extracted with ethyl acetate, dried over magnesium sulfate, and the solvent was dried. Purification by column chromatography (petroleum ether: ethyl acetate=10:1) afforded compound 4a-s2 (2.5 g, 60%).
Triethylamine (2 eq) and p-toluenesulfonyl chloride (1.2 eq) were added sequentially to a dichloromethane solution (120 ml) of 4a-s2 (2.5 g,30 mmol) at 0℃and stirred at room temperature for 12 hours, after complete reaction the reaction mixture was washed with water, the resulting solution extracted with dichloromethane, the combined organic layers were washed with brine and dried over sodium sulfate, filtered and concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate=15:1) to give compounds 4a-s3 (7.0 g, 98%).
4A-s3 (1.0 g,4.2 mmol) was taken, p-methylbenzenesulfonamide (1.0 eq), acetonitrile (20 ml) and potassium carbonate (2 eq) were added and stirred at 90℃for 12 hours, after completion of 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=5:1) to give compound 4a (890mg, 90%).
(3) Preparation of the alkylene oxide compound (1 a):
2- (2, 2-Dibromovinyl) -1-nitrobenzene 3a (307 mg,1mmol,1.0 eq), compound 4a (237 mg,1 eq), cuprous iodide (3%), 1, 10-phenanthroline (5%) and cesium carbonate (3 eq) were added sequentially under nitrogen atmosphere, dried tetrahydrofuran (0.25M) and stirred at room temperature until the starting materials were reacted completely. After filtration through silica gel, the solvent was evaporated in vacuo and purified by column chromatography (petroleum ether: ethyl acetate=5:1) to give compound 1a (311 mg, 83%).
1-Tosyl-2, 3,5, 10-tetrahydrobenzo [ b ] pyrrolo [3,2-f ] aza-4 (1H) -ketone (2 a), the preparation method comprising the steps of:
S1. Compound 1a (0.15 mmol,57.3 mg) was taken, tetrahydrofuran (5 ml) was added and stirred at 90℃for 12 hours, the reaction solution was concentrated under reduced pressure, and the compound 1-tosyl-2, 3,5, 10-tetrahydrobenzo [ b ] pyrrolo [3,2-f ] aza was obtained by purification by column chromatography (Petroleum ether: ethyl acetate=3:1) -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).1H NMR(500MHz,CDCl3)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).13C{1H}NMR(126MHz,CDCl3)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 C20H20N2O3SNa 391.1087;found 391.1085
Examples 2 to 5
The preparation methods and starting materials of examples 2 to 5 were the same as in example 1, except that the temperature was used to investigate the effect of the temperature of the reaction in step S1 on the yield.
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 starting materials of examples 6 to 8 were the same as in example 1, except that the reaction time in step S1 was used to investigate the effect of the reaction time in step S1 on the yield.
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 raw materials of examples 9 to 14 were the same as those of example 1 except that the solvent in step S1 was used to investigate the effect of the solvent on the yield.
TABLE 3 data for examples 9-14
Example 16
Example 16 provides an 8-fluoro-1-toluenesulfonyl-2, 3,5, 10-tetrahydrobenzo [ b ] pyrrole [3,2-f ] aza-4 (1H) -ketone (2 b), the preparation method is specifically as follows:
the 2-nitrobenzaldehyde in step (1) of example 1 was replaced with 4-fluoro-2-nitrobenzaldehyde, and the remaining operations were unchanged to give 8-fluoro-1-tosyl-2, 3,5, 10-tetrahydrobenzo [ b ] pyrrole [3,2-f ] aza-s -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).1H NMR(500MHz,CDCl3)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).13C{1H}NMR(126MHz,CDCl3)δ187.0,162.7(C-F,1JC-F＝247.0Hz),160.8(C-F,1JC-F＝247.0Hz),150.2,145.6,139.34(C-F,3JC-F＝10.1Hz),139.26(C-F,3JC-F＝10.1Hz),133.1,132.14(C-F,3JC-F＝8.9Hz),132.07(C-F,3JC-F＝8.9Hz),130.5,127.2,120.58(C-F,4JC-F＝2.5Hz),120.56(C-F,4JC-F＝2.5Hz),113.3(C-F,2JC-F＝21.4Hz),113.1(C-F,2JC-F＝21.4Hz),106.7(C-F,2JC-F＝24.1Hz),106.5(C-F,2JC-F＝24.1Hz),102.8,47.8,47.5,25.1,21.7.19F NMR(471MHz,CDCl3)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 C19H17FN2O3SNa 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-4 (1H) -ketone (2 c), the preparation method is specifically as follows:
The 2-nitrobenzaldehyde in step (1) of example 1 was replaced with 4-bromo-2-nitrobenzaldehyde, and the remaining operation was unchanged to give 8-bromo-1-tolyl-2, 3,5, 10-tetrahydrobenzo [ b ] pyrrolo [3,2-f ] aza -4 (1H) -one (2 c). Yield 80% (52 mg), brown solid, m.p.162.5-163.9 ℃ R f = 0.5 (ethyl acetate/petroleum ether) ＝1:1).1H NMR(500MHz,CDCl3)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).13C{1H}NMR(126MHz,CDCl3)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 C19H18BrN2O3S 433.0216;found 433.0211.
Example 18
Example 18 provides a 4-oxo-1-tosyl-1, 2,3,4,5, 10-hexahydrobenzo [ b ] pyrrole [3,2-f ] aza-Methyl 8-carboxylate (2 d), the preparation method is specifically as follows:
The 2-nitrobenzaldehyde in step (1) of example 1 was replaced with methyl 4-formate-2-nitrobenzaldehyde, and the remaining operations were unchanged to give 4-oxo-1-tosyl-1, 2,3,4,5, 10-hexahydrobenzo [ b ] pyrrole [3,2-f ] aza -Methyl 8-carboxylate (2 d). Yield 75% (46 mg) brown liquid, R f =0.3 (ethyl acetate/petroleum ether) ＝1:1).1H NMR(500MHz,CDCl3)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).13C{1H}NMR(126MHz,CDCl3)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 C19H18BrN2O3S 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-4 (1H) -ketone (2 e) prepared as follows:
The 2-nitrobenzaldehyde in step (1) of example 1 was replaced with 5-chloro-2-nitrobenzaldehyde, and the remaining operations were unchanged to give 7-chloro-1-tolyl-2, 3,5, 10-tetrahydrobenzo [ b ] pyrrolo [3,2-f ] aza -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).1H NMR(500MHz,CDCl3)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).13C{1H}NMR(126MHz,CDCl3)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 C19H17ClN2O3SNa 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-4 (1H) -ketone (2 f), the preparation method is specifically as follows:
The 2-nitrobenzaldehyde in step (1) of example 1 was replaced with 4-chloro-2-nitrobenzaldehyde, and the remaining operations were unchanged to give 8-chloro-1-tolyl-2, 3,5, 10-tetrahydrobenzo [ b ] pyrrolo [3,2-f ] aza -4 (1H) -one (2 e). Yield 82% (48 mg), brown solid, m.p.151.2-152.6 ℃ C. R f = 0.6 (ethyl acetate/petroleum ether) ＝1:1).1H NMR(500MHz,CDCl3)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).13C{1H}NMR(126MHz,CDCl3)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 C19H17ClN2O3SNa 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-4 (1H) -ketone (2 g), prepared as follows:
The 2-nitrobenzaldehyde in step (1) of example 1 was replaced with 4-methoxy-2-nitrobenzaldehyde, and the remaining operations were unchanged to give 8-methoxy-1-tolyl-2, 3,5, 10-tetrahydrobenzo [ b ] pyrrolo [3,2-f ] aza -4 (1H) -one (2 g). Yield 72% (41 mg), brown liquid, R f =0.4 (ethyl acetate/petroleum ether) ＝1:1).1H NMR(500MHz,CDCl3)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)..13C{1H}NMR(126MHz,CDCl3)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 C20H20N2O4SNa 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-4 (1H) -ketone (2 k), prepared as follows:
the 2-nitrobenzaldehyde of step (1) of example 1 was replaced with 5-fluoro-2-nitrobenzaldehyde, and the remaining operations were unchanged to give 7-fluoro-1-tolyl-2, 3,5, 10-tetrahydrobenzo [ b ] pyrrolo [3,2-f ] aza -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).1H NMR(500MHz,CDCl3)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).13C{1H}NMR(126MHz,CDCl3)δ186.2,161.7(C-F,1JC-F＝247.7Hz),159.8(C-F,1JC-F＝247.7Hz),150.7,145.6,134.5(C-F,4JC-F＝3.8Hz),134.4(C-F,4JC-F＝3.8Hz),133.1,130.4,127.2,127.1(C-F,2JC-F＝8.9Hz),127.0(C-F,3JC-F＝8.9Hz),120.9(C-F,3JC-F＝7.6Hz),120.8(C-F,2JC-F＝7.6Hz),117.0(C-F,2JC-F＝24.1Hz),116.8(C-F,2JC-F＝24.1Hz),114.6(C-F,2JC-F＝22.9Hz),114.4(C-F,2JC-F＝22.9Hz),102.42,48.03,47.81,25.07,21.67.19F NMR(471MHz,CDCl3)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 C19H17FN2O3SNa 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-4 (1H) -ketone (2 i) prepared by the following method:
Substituting 7-methoxy-2 nitrobenzaldehyde for 2-nitrobenzaldehyde in step (1) of example 1, the remaining operations remain unchanged, to give 7-methoxy-1-tolyl-2, 3,5, 10-tetrahydrobenzo [ b ] pyrrolo [3,2-f ] aza -4 (1H) -one (2 i). Yield 64% (37 mg), brown liquid, m.p.143.6-144.0 ℃ C. R f = 0.8 (ethyl acetate/petroleum ether) ＝1:2).1H NMR(500MHz,CDCl3)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).13C{1H}NMR(126MHz,CDCl3)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 C20H20N2O4SNa 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-4 (1H) -ketone (2 j) prepared by the following method:
The 2-nitrobenzaldehyde of step (1) of example 1 was replaced with 4-methyl-2-nitrobenzaldehyde, and the remaining operations were unchanged to give 8-methyl-1-tolyl-2, 3,5, 10-tetrahydrobenzo [ b ] pyrrolo [3,2-f ] aza -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).1H NMR(500MHz,CDCl3)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).13C{1H}NMR(126MHz,CDCl3)δ187.4,150.4,145.5,138.0,137.7,133.2,130.6,130.4,127.3,127.1,121.7,119.9,102.3,47.8,25.1,21.7,20.9.19F NMR(471MHz,CDCl3)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 C20H20N2O3SNa 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-4 (1H) -ketone (2 k) prepared by the following method:
the 2-nitrobenzaldehyde in step (1) of example 1 was replaced with 6-fluoro-2-nitrobenzaldehyde, and the remaining operations were unchanged to give 6-fluoro-1-tolyl-2, 3,5, 10-tetrahydrobenzo [ b ] pyrrolo [3,2-f ] aza -4 (1H) -one (2 k). Yield 59% (33 mg), brown liquid, R f =0.4 (ethyl acetate/petroleum ether) ＝1:1).1H NMR(500MHz,CDCl3)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).13C{1H}NMR(126MHz,CDCl3)δ186.3,161.5(C-F,1JC-F＝248.9Hz),159.5(C-F,1JC-F＝248.9Hz),150.2,145.6,140.42(C-F,3JC-F＝5.08Hz),140.38(C-F,3JC-F＝5.08Hz),133.0,130.4,128.2(C-F,3JC-F＝10.2),128.1(C-F,3JC-F＝10.2),127.2,115.00(C-F,4JC-F＝3.8),114.97(C-F,4JC-F＝3.8),113.0(C-F,2JC-F＝20.3),112.9(C-F,2JC-F＝20.3),112.3(C-F,2JC-F＝22.9),112.2(C-F,2JC-F＝22.9),103.5,47.8,38.5,38.5,25.2.19F NMR(471MHz,CDCl3)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 C19H17FN2O3SNa 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-4 (1H) -ketone (2 l) prepared as follows:
The 2-nitrobenzaldehyde in step (1) of example 1 was replaced with 4-trifluoromethyl-2-nitrobenzaldehyde, and the remaining operations were unchanged to give 1-tosyl-8- (trifluoromethyl) -2,3,5, 10-tetrahydrobenzo [ b ] pyrrolo [3,2-f ] aza -4 (1H) -one (2 l). Yield 60% (38 mg), grey solid, R f =0.4 (ethyl acetate/petroleum ether) ＝1:1).1H NMR(500MHz,CDCl3)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,103.21,48.13,47.77,24.99,21.66.19F NMR(471MHz,CDCl3)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 C19H17FN2O3SNa 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-Methyl 7-carboxylate (2 m) prepared as follows:
The 2-nitrobenzaldehyde in step (1) of example 1 was replaced with methyl 5-formate-2-nitrobenzaldehyde, and the remaining operations were unchanged to give 4-oxo-1-tosyl-1, 2,3,4,5, 10-hexahydrobenzo [ b ] pyrrole [3,2-f ] aza -Methyl 7-carboxylate (2 m). Yield 68% (42 mg), yellow liquid, R f =0.3 (ethyl acetate/petroleum ether) ＝1:1).1H NMR(500MHz,CDCl3)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).13C{1H}NMR(126MHz,CDCl3)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 C20H20N2O3SNa 391.1087;found 391.1082./>
Example 28
Example 28 provides a 5-phenyl-1-toluenesulfonyl-2, 3,5, 10-tetrahydrobenzo [ b ] pyrrolo [3,2-f ] aza-4 (1H) -ketone (2 n) prepared by the following method:
The paraformaldehyde in step (2) of example 1 was replaced with benzaldehyde, and the remaining operations were unchanged, to give 5-phenyl-1-tosyl-2, 3,5, 10-tetrahydrobenzo [ b ] pyrrolo [3,2-f ] aza -4 (1H) -one (2 n). Yield 47% (30 mg), grey solid, rf=0.4 (ethyl acetate/petroleum ether) ＝1:4).1H NMR(500MHz,CDCl3)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).13C NMR(126MHz,CDCl3)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 C25H23N2O3S 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-4 (1H) -ketone (2 o) prepared as follows:
substitution of propionaldehyde for paraformaldehyde in step (2) of example 1, the remainder of the procedure being unchanged, gives 5-ethyl-1-tosyl-2, 3,5, 10-tetrahydrobenzo [ b ] pyrrolo [3,2-f ] aza -4 (1H) -one (2 o). Yield 75% (43 mg), grey solid, rf=0.4 (ethyl acetate/petroleum ether) ＝1:4).1H NMR(500MHz,CDCl3)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).13C NMR(126MHz,CDCl3)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 C21H23N2O3S 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-9 (6H) -ketone (2 p) prepared by the following method:
3-nitropyridine aldehyde is used to replace 2-nitrobenzaldehyde in the step (1) of the example 1, and the rest operation is unchanged, so that 6-tosyl-5,7,8,10-tetrahydropyrido [3,2-b ] pyrrolo [3,2-f ] aza-is obtained -9 (6H) -one (2 p). Yield 53% (28 mg), grey solid, rf=0.6 (ethyl acetate/petroleum ether) ＝1:1).1H NMR(500MHz,CDCl3)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).13C NMR(126MHz,CDCl3)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 C18H18N3O3S 356.1064;found 356.1068.
Example 31
Example 31 provides a 1- (methylsulfonyl) -2,3,5, 10-tetrahydrobenzo [ b ] pyrrolo [3,2-f ] aza-4 (1H) -ketone (2 q) prepared by the following method:
Replacement of the p-toluenesulfonyl chloride in step (2) of example 1 with methanesulfonyl chloride, the remainder of the procedure being unchanged, gives 1- (methanesulfonyl) -2,3,5, 10-tetrahydrobenzo [ b ] pyrrolo [3,2-f ] aza -4 (1H) -one (2 q). Yield 62% (26 mg), grey solid, rf=0.4 (ethyl acetate/petroleum ether) ＝1:4).1H NMR(500MHz,CDCl3)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).13C NMR(126MHz,CDCl3)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 C13H15N2O3S 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-5-Ketone (2 r) prepared by the following method: /(I)
Substitution of 4-pentyn-1-ol for 3-butyn-1-ol from step (2) of example 1, the remainder of the procedure being unchanged, gives 1-p-toluenesulfonyl-1, 2,3,4,6, 11-hexahydro-5H-benzo [ b ] pyrido [3,2-f ] aza-5-Ketone (2 r). Yield 73% (40 mg), brown liquid, R f =0.6 (ethyl acetate/petroleum ether) ＝1:1).1H NMR(500MHz,CDCl3)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).13C{1H}NMR(126MHz,CDCl3)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 C20H20N2O3SNa 391.1087;found 391.1085.
Biological Activity test
The compounds prepared in the above examples pass the bioactivity test
1. Sample preparation: a proper amount of the compound prepared in the embodiment of the invention is prepared into gradient concentrations of 1000uM, 100uM, 10uM and 1uM by using a proper solvent such as cyclooxygenase-2 test Buffer (COX-2 Assay Buffer), milli-Q grade pure water, dimethyl sulfoxide and the like.
2. Preparation of the kit:
a. All reagents except human recombinant COX-2 (recombinant human COX-2, rhCOX-2) were thawed to room temperature, centrifuged slightly to precipitate the solution to the bottom of the tube, and then mixed well for use. The COX-2Probe (COX-2 Probe), COX-2cofactor (COX-2 Cofactor) (50X) and COX-2Substrate (COX-2 Substrate) (50X) were formulated in DMSO and water-bath at 37℃for 2min to promote melting. And (5) immediately after the use, keeping the materials away from light at the temperature of minus 20 ℃.
Preparation of COX-2cofactor (COX-2 Cofactor) working solution: a suitable amount of COX-2cofactor (COX-2 Cofactor) working solution was prepared in a ratio of 5. Mu.L of COX-2cofactor (COX-2 Cofactor) working solution per sample. mu.L of COX-2cofactor (COX-2 Cofactor) (50X) was taken and diluted with COX-2Assay Buffer in a 1:49 ratio. The prepared COX-2cofactor (COX-2 Cofactor) working solution can be stored at 4 ℃ and is only used for the same day.
Preparing COX-2 working solution: a proper amount of COX-2 working solution was prepared in a proportion of 5. Mu.L of COX-2 working solution per sample. An appropriate amount of human recombinant COX-2 (recombinant human COX-2, rhCOX-2) (25X) was taken and diluted with COX-2Assay Buffer at a 1:24 ratio. The prepared COX-2 working solution can be temporarily stored on an ice bath, and the enzyme activity is basically stable within 1 hour. And (3) injection: all operations involving COX-2 should be performed on ice.
Preparation of COX-2Substrate (COX-2 Substrate) working solution: a proper amount of COX-2Substrate (COX-2 Substrate) working solution was prepared in a ratio of 5. Mu.L of COX-2Substrate (COX-2 Substrate) working solution per sample. mu.L of COX-2Substrate (COX-2 Substrate) (50X) was taken, an equal volume of Substrate Buffer was added, vortexed thoroughly, and the mixture was diluted with Milli-Q grade pure water or redistilled water in a 1:24 ratio and vortexed thoroughly. The formulated COX-2Substrate working solution was temporarily stored on an ice bath.
E. Preparation of a Positive inhibitor Celecoxib solution: the positive control inhibitor, celecoxib, was provided in the kit at a concentration of 100 μm and formulated in DMSO.
3. Sample detection: (1) Referring to table 4, control wells and sample wells were set using a 96-well blackboard, and samples and solutions were added sequentially according to the following table. After the sample to be measured was added, the mixture was homogenized and incubated at 37℃for 10 minutes.
Table 4 data sheet
(2) Each well was added with 5. Mu.L of a COX-2Probe (COX-2 Probe).
(3) Each well was quickly filled with 5. Mu.L of COX-2Substrate (COX-2 Substrate) working solution, and mixed well.
(4) Fluorescence measurement was performed after incubation at 37℃for 5 minutes in the absence of light. The excitation wavelength is 560nm and the emission wavelength is 590nm. When the fluorescence reading is low, the incubation time can also be suitably prolonged to 10-20 minutes.
4. Calculation ① the average fluorescence values for each sample well and control well were calculated and recorded as RFU control blank, RFU100% enzyme activity control, RFU positive inhibitor control and RFU sample, respectively. RFU Relative Fluorescence Unit. ② 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 fit using compuSyn.
Experimental data are shown in table 5:
data for the compounds of Table 5
Experimental results show that the nitrogen-containing impurity prepared by the inventionThe compound has a certain inhibition effect on COX-2, and has the potential of preparing COX-2 inhibitors.
It is to be understood that the above examples of the present invention are provided by way of illustration only and not by way of limitation of the embodiments of the present invention. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. It is not necessary here nor is it exhaustive of all embodiments. Any modification, equivalent replacement, improvement, etc. which come within the spirit and principles of the invention are desired to be protected by the following claims.

Claims (8)

1. AzaA compound or a pharmaceutically acceptable salt thereof, characterized in that the aza/>The structural formula of the class of compounds is shown as a formula (2):
wherein X is a carbon atom; n is selected from 1, 2 or 3;
R 1 is one or more groups on the A ring, said R 1 is independently selected from hydrogen, halogen, C1-C6 alkyl or C1-C6 alkoxy;
r 2 is selected from p-toluenesulfonyl;
r 3 is selected from hydrogen.
2. An aza according to claim 1A compound or a pharmaceutically acceptable salt thereof, wherein n is selected from 1 or 2.
3. An aza according to claim 1A compound or a pharmaceutically acceptable salt thereof, characterized in that the pharmaceutically acceptable salt is aza/>Pharmaceutically acceptable salts of the class of compounds with organic or inorganic acids.
4. An aza according to any one of claims 1 to 3The preparation method of the compound or the pharmaceutically acceptable salt thereof is characterized by comprising the following steps:
s1, heating a diene compound shown in a formula (1) in a solvent and reacting to obtain a compound shown in a formula (2);
Or also include
S2, converting the obtained compound shown in the formula (2) into pharmaceutically acceptable salt;
wherein X is a carbon atom; n is selected from 1, 2 or 3;
R 1 is one or more groups on the A ring, said R 1 is independently selected from hydrogen, halogen, C1-C6 alkyl or C1-C6 alkoxy;
r 2 is selected from p-toluenesulfonyl;
r 3 is selected from hydrogen.
5. An aza according to claim 4The preparation method of the compound or the pharmaceutically acceptable salt thereof is characterized in that 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 and water.
6. An aza according to claim 4The preparation method of the compound or the pharmaceutically acceptable salt thereof is characterized in that the heating temperature is 60-120 ℃.
7. An aza according to claim 4The preparation method of the compound or the pharmaceutically acceptable salt thereof is characterized in that the heating time is 4-48 h.
8. An aza according to any one of claims 1 to 3The application of a compound or pharmaceutically acceptable salt thereof in preparing COX-2 inhibitor.
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Citations (3)

* Cited by examiner, † Cited by third party
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

Patent Citations (3)

* Cited by examiner, † Cited by third party
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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