CN110229091B - 1, 5-disubstituted indole derivatives with leukotriene A4 hydrolase inhibition effect and application thereof - Google Patents
1, 5-disubstituted indole derivatives with leukotriene A4 hydrolase inhibition effect and application thereof Download PDFInfo
- Publication number
- CN110229091B CN110229091B CN201910540367.5A CN201910540367A CN110229091B CN 110229091 B CN110229091 B CN 110229091B CN 201910540367 A CN201910540367 A CN 201910540367A CN 110229091 B CN110229091 B CN 110229091B
- Authority
- CN
- China
- Prior art keywords
- indole
- leukotriene
- hydrolase
- ethoxy
- nmr
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
Abstract
The invention relates to a 1, 5-disubstituted indole derivative with a leukotriene A4 hydrolase inhibition effect, wherein the 1, 5-disubstituted indole derivative has a function of inhibiting leukotriene A4 hydrolase. The 1, 5-disubstituted indole derivative is a new compound, is synthesized for the first time, and activity tests are carried out on the compound, and results show that the derivative has effects on aminopeptidase activity and hydrolytic activity of leukotriene A4 hydrolase, the derivative has short synthetic route, simple synthetic process and purification method and higher yield, and the 1, 5-disubstituted indole derivative can be used for inhibiting inflammation caused by leukotriene A4 hydrolase and preparing medicines for other diseases caused by inflammation.
Description
Technical Field
The invention belongs to the technical field of synthesis of new compounds and application of medicines, and relates to a preparation method of a new compound and leukotriene A4 hydrolase regulation activity of the new compound, in particular to a 1, 5-disubstituted indole derivative with leukotriene A4 hydrolase inhibition effect and application thereof.
Background
Arachidonic acid is metabolized by 5-LOX and catalyzed by 5-lipoxygenase activating protein (FLAP) to form unstable intermediate 5-peroxy compoundOxyhydroxy-arachidonic acid, followed by the formation of unstable leukotrienes A4 (Leukotenes A4, LTA) 4 ). It is in leukotriene A4 hydrolase (LTA) 4 H) Formation of leukotriene B4 (LTB) by action of 4 )，LTA 4 Can be processed by leukotriene C4 (LTC) 4 ) Synthesis of LTC by combining synthetase and glutathione 4 Further, leukotriene D4, leukotriene E4, LTB are produced 4 Is an important inflammatory mediator, and more studies have reported that leukotrienes are closely related to the occurrence of inflammation, among which LTB 4 Is particularly important.
The leukotriene A4 hydrolase is zinc-containing bifunctional metalloprotease with the activities of cycloxygenase and aminopeptidase, is widely involved in the generation of various inflammations, is closely related to the generation of various tumors, and is a new target for developing anti-inflammatory and antitumor drugs. Thus, synthetic LTA was sought and designed 4 H inhibitors have become a new direction in the treatment of inflammation and in the treatment of a variety of diseases mediated by inflammation.
Through searching, the following patent publications related to the patent application of the invention are found:
a bifunctional inhibitor of leukotriene A4 hydrolase and cyclooxygenase and its use (CN 101874798B), relates to a bifunctional inhibitor of leukotriene A4 hydrolase and cyclooxygenase shown in formula (I), a pharmaceutical composition containing the inhibitor, and their use in preparing medicaments for treating and preventing the conditions of subjects mediated by leukotriene A4 hydrolase and cyclooxygenase, the use in preparing medicaments for treating, preventing or inhibiting the inflammation of subjects, and the use in preparing medicaments for inhibiting the activities of leukotriene A4 hydrolase and cyclooxygenase. Wherein Ar represents: 2-pyridyl, 4-pyridyl, 6-nitro-2-pyridyl, 2-pyrazinyl and related six-membered nitrogen-containing heterocycles, phenyl, or a group (II) representing the formula: p and Q in the group (II) are respectively positioned at two positions of 2, 3 and 4 of the benzene ring, can be the same or different, and respectively represent: hydrogen, halogen, amine, nitro, trifluoromethyl, methanesulfonyl, monomethanesulfonamide, dimethylaminesulfonamide, or methanesulfonamide.
By contrast, the present patent application is intrinsically different from the above patent publications.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a 1, 5-disubstituted indole derivative with leukotriene A4 hydrolase inhibition effect and application thereof, wherein the 1, 5-disubstituted indole derivative is a new compound and is synthesized for the first time, and activity test is carried out on the derivative, and the result shows that the derivative has the effect on both aminopeptidase activity and hydrolysis activity of leukotriene A4 hydrolase, the derivative has short synthetic route, simple synthetic process and purification method and higher yield, and the 1, 5-disubstituted indole derivative can be used for preparing medicines for inhibiting inflammation caused by leukotriene A4 hydrolase and other diseases caused by the inflammation.
The technical scheme adopted by the invention for solving the technical problem is as follows:
a1, 5-disubstituted indole derivative having a leukotriene A4 hydrolase inhibitory action, said 1, 5-disubstituted indole derivative having a function capable of inhibiting leukotriene A4 hydrolase.
Furthermore, the structural general formula of the 1, 5-disubstituted indole derivative is as follows:
wherein R is 2 R 1 N is one of four to six membered heterocyclic rings; r 3 Is one of substituted aromatic rings; n =1-4.
And, the four-to six-membered heterocyclic ring is a tetrahydropyrrole ring group, a thiazolidine ring group, a morpholine ring group or a piperidine ring group; the substituted aromatic ring is benzyl, 3-bromobenzyl, 3-chlorobenzyl or 3-methoxybenzyl.
Moreover, the synthetic route of the synthetic method is as follows:
furthermore, the structural general formula of the 1, 5-disubstituted indole derivative is as follows:
wherein R is 1 Is one of cyano, 1-hydroxyethyl or acetoxy, namely, o, m and p (R1 substituent groups are at three different positions of a benzene ring); NR (nitrogen to noise ratio) 2 R 3 Is one of N, N-dimethylamino or four-to six-membered heterocycle; n =1-4.
And, the four-to six-membered heterocyclic ring is a tetrahydropyrrole ring group, a thiazolidine ring group, a morpholine ring group or a piperidine ring group.
Moreover, the synthetic route of the synthetic method is as follows:
furthermore, the structural formula of the 1, 5-disubstituted indole derivative is as follows:
use of the 1, 5-disubstituted indole derivatives having leukotriene A4 hydrolase inhibitory effect as described above for inhibiting leukotriene A4 hydrolase.
The 1, 5-disubstituted indole derivative with the leukotriene A4 hydrolase inhibition effect is applied to the anti-tumor aspect.
The invention has the advantages and positive effects that:
the 1, 5-disubstituted indole derivative is a new compound, is synthesized for the first time, and is subjected to activity test, the result shows that the derivative has the effect on both the aminopeptidase activity and the hydrolysis activity of leukotriene A4 hydrolase, the derivative has short synthetic route, simple synthetic process and purification method and higher yield, and the 1, 5-disubstituted indole derivative can be used for inhibiting inflammation caused by leukotriene A4 hydrolase and the preparation of medicaments for other diseases caused by the inflammation.
Drawings
FIG. 1 is a NMR chart of TM 7 in the present invention;
FIG. 2 is a NMR spectrum of TM 8 in the present invention;
FIG. 3 is a NMR spectrum of TM12 in the present invention;
FIG. 4 is a NMR chart of TM14 in the present invention;
FIG. 5 is a NMR spectrum of TM17 in the present invention;
FIG. 6 shows the NMR spectrum of TM 23 in the present invention.
Detailed Description
The following detailed description of the embodiments of the present invention is provided for the purpose of illustration and not limitation, and should not be construed as limiting the scope of the invention.
The raw materials used in the invention are conventional commercial products unless otherwise specified; the methods used in the present invention are, unless otherwise specified, conventional in the art.
A1, 5-disubstituted indole derivative having a leukotriene A4 hydrolase inhibitory action, said 1, 5-disubstituted indole derivative having a function of inhibiting leukotriene A4 hydrolase.
Preferably, the structural general formula of the 1, 5-disubstituted indole derivative is as follows:
wherein R is 2 R 1 N is one of four to six membered heterocyclic rings; r 3 Is one of substituted aromatic rings；n＝1-4。
Preferably, the four-to six-membered heterocyclic ring is tetrahydropyrrole ring, thiazolidine ring, morpholine ring or piperidine ring; the substituted aromatic ring is benzyl, 3-bromobenzyl, 3-chlorobenzyl or 3-methoxybenzyl.
Preferably, the synthetic route of the synthetic method is as follows:
namely, the known compound 5-hydroxyindole is subjected to N acylation reaction, nucleophilic substitution reaction and other steps to synthesize the final product I.
Preferably, the 1, 5-disubstituted indole derivative has the following structural formula:
wherein R is 1 Is one of cyano, 1-hydroxyethyl or acetoxy, namely, o, m and p (R1 substituent is at three different positions of a benzene ring); NR (nitrogen to noise ratio) 2 R 3 Is one of N, N-dimethylamino or four-to six-membered heterocycle; n =1-4.
Preferably, the four-to six-membered heterocyclic ring is a tetrahydropyrrole ring group, a thiazolidine ring group, a morpholine ring group or a piperidine ring group.
Preferably, the synthetic route of the synthetic method is as follows:
namely, the known compound 5-hydroxyindole is subjected to reactions such as N acylation reaction, nucleophilic substitution, reduction and the like to synthesize final products II and II'.
Preferably, the structural formula of the 1, 5-disubstituted indole derivative is as follows:
the 1, 5-disubstituted indole derivatives having leukotriene A4 hydrolase inhibitory action as described above can be used in the inhibition of leukotriene A4 hydrolase.
The 1, 5-disubstituted indole derivatives having leukotriene A4 hydrolase inhibitory effect as described above can be used in antitumor applications.
Specifically, the related specific structures and the related examples of the synthesis method of the 1, 5-disubstituted indole derivative are as follows:
example 1: synthesis of 5-hydroxy-1-tert-butyloxycarbonyl-1H-indole (a):
5g (37.5 mmol) of 5-hydroxyindole is dissolved in 50ml of MeCN, 21ml (91.4 mmol) of di-tert-butyl dicarbonate and 0.46g (3.7 mmol) of DMAP are added under stirring at room temperature, the reaction of the raw materials is completed for 10 minutes at room temperature, the solvent is dried by spinning, 100ml of methanol is added for dissolution, 15g (108.5 mmol) of potassium carbonate is added, after stirring at room temperature for 4 hours, the pH is adjusted to about 7 by glacial acetic acid, and then the system is diluted by adding water. Extraction with EA, washing of the organic phase with saturated sodium chloride, drying over anhydrous sodium sulfate, concentration under reduced pressure, chromatography with column chromatography, PE/EA =30:1 7.95g of white solid is obtained, yield 90%.
1 H NMR(400MHz,DMSO-d 6 )δ1.61(s,9H),6.54(d,J＝3.6Hz,1H),6.77(dd,J＝8.8Hz,J＝2Hz,1H),6.91(d,J＝2Hz,1H),7.56(d,J＝3.6Hz,1H),7.82(d,J＝8.8Hz,1H),9.17(s,1H).
Example 2: synthesis of 5- (2-chloroethoxy) -1-tert-butyloxycarbonyl-1H-indole (b):
dissolving 2g (8.6 mmol) of 5-hydroxy-1-tert-butyloxycarbonyl-1H-indole (a) in 5ml of DMF, adding 3.56g (25.8 mmol) of potassium carbonate, stirring at room temperature for 10 minutes, then adding 14.3ml (172 mmol) of 1-bromo-2-chloroethane, stirring at 100 ℃ for 10 hours, diluting with water, extracting with DCM, washing with saturated sodium chloride, drying over anhydrous sodium sulfate, concentrating under reduced pressure, column chromatography with a stir-column, PE/EA =200: 1.3g of a white solid are obtained, yield 52%.
1 H NMR(400MHz,DMSO-d 6 )δ1.61(s,9H),3.95(t,J＝5.2Hz,2H),4.27(t,J＝5.2Hz,2H),6.62(d,J＝3.6Hz,1H),6.96(dd,J＝9.2Hz,J＝2.8Hz,1H),7.18(d,J＝2.4Hz,1H),7.63(d,J＝3.6Hz,1H),7.94(d,J＝9.2Hz,1H).
Example 3: synthesis of 5- (2- (1-pyrrolidine) ethoxy) -1-tert-butyloxycarbonyl-1H-indole (c-1):
2g (6.8 mmol) of 5- (2-chloroethoxy) -1-tert-butyloxycarbonyl-1H-indole (b) are dissolved in 5ml of DMF, 2.8g (20.4 mmol) of potassium carbonate are added, stirring is carried out at normal temperature for 10 minutes, 0.56g (3.4 mmol) of potassium iodide and 1.67ml (20.4 mmol) of pyrrolidine are added, stirring is carried out at 100 ℃ for 9 hours, dilution with water is carried out, DCM extraction is carried out, washing is carried out with saturated sodium chloride, drying is carried out with anhydrous sodium sulfate, concentration is carried out under reduced pressure, column chromatography is carried out with stirring, DCM/MeOH =400: 1.81g of oil are obtained, yield 82%.
1 H NMR(400MHz,DMSO-d 6 )δ1.89(s,9H),1.94-1.98(m,4H),2.78-2.80(m,4H),3.08(t,J＝6Hz,2H),4.36(t,J＝6Hz,2H),6.89(d,J＝3.6Hz,1H),7.20(dd,J＝9.2Hz,J＝2.4Hz,1H),7.42(d,J＝2Hz,1H),7.90(d,J＝3.6Hz,1H),8.20(d,J＝8.8Hz,1H).
Example 4: synthesis of 5- (2- (1-piperidine) ethoxy) -1-tert-butyloxycarbonyl-1H-indole (c-2):
the procedure is as in example 3, except that piperidine is used instead of pyrrolidine, in 98% yield.
1 H NMR(400MHz,DMSO-d 6 )δ1.38(t,J＝6Hz,2H),1.45-1.52(m,4H),1.61(s,9H),2.42(s,4H),2.65(t,J＝6Hz,2H),4.06(t,J＝6Hz,2H),6.60(d,J＝3.6Hz,1H),6.91(dd,J＝9.2Hz,J＝2.4Hz,1H),7.13(d,J＝2.4Hz,1H),7.60(d,J＝3.6Hz,1H),7.91(d,J＝8.8Hz,1H).
Example 5: synthesis of 5- (2- (1-thiazolidine) ethoxy) -1-tert-butyloxycarbonyl-1H-indole (c-3):
the procedure is as in example 3, except that thiazolidine is used instead of pyrrolidine, in 36% yield.
1 H NMR(400MHz,DMSO-d 6 )δ1.61(s,9H),2.69(t,J＝6Hz,2H),2.81(t,J＝6.4Hz,2H),3.08(t,J＝6Hz,2H),4.09-4.12(m,4H),6.62(d,J＝3.6Hz,1H),6.94(dd,J＝9.2Hz,J＝2.4Hz,1H),7.16(d,J＝2.4Hz,1H),7.62(d,J＝3.6Hz,1H),7.92(d,J＝9.2Hz,1H).
Example 6: synthesis of 5- (2- (1-morpholine) ethoxy) -1-tert-butyloxycarbonyl-1H-indole (c-4):
the procedure is as in example 3, except that morpholine is used instead of pyrrolidine, giving a yield of 97%.
1 H NMR(400MHz,DMSO-d 6 )δ1.60(s,9H),2.47(s,4H),2.69(t,J＝6Hz,2H),3.57(t,J＝4.8Hz,4H),4.09(t,J＝5.6Hz,2H),6.61(d,J＝3.6Hz,1H),6.92(dd,J＝8.8Hz,J＝2.4Hz,1H),7.14(d,J＝2.4Hz,1H),7.61(d,J＝4Hz,1H),7.92(d,J＝9.2Hz,1H).
Example 7: synthesis of 5- (2- (1-pyrrolidine) ethoxy) -1H-indole (d-1):
1.8g (5.5 mmol) of 5- (2- (1-pyrrolidine) ethoxy) -1-tert-butyloxycarbonyl-1H-indole (c-1) are dissolved in MeOH, THF and H 2 To O, 4.57g (110 mmol) of LiOH. H was added 2 Stirring O at rt for 72 h, spin-drying the solvent, diluting with water, extracting with DCM, washing with saturated sodium chloride, drying over anhydrous sodium sulfate, concentrating under reduced pressure, chromatography on pad column, DCM/MeOH =20: 1.19g of oil are obtained in 95% yield.
1 H NMR(400MHz,DMSO-d 6 )δ1.64-1.67(m,4H),2.48-2.52(m,4H),2.76(t,J＝6Hz,2H),4.01(t,J＝6Hz,4H),6.31(t,J＝2Hz,1H),6.71(dd,J＝8.8Hz,J＝2.4Hz,1H),7.02(d,J＝2.4Hz,1H),7.25(d,J＝2.4Hz,1H),7.26(d,J＝3.6Hz,1H),10.89(s,1H).
Example 8: synthesis of 5- (2- (1-piperidine) ethoxy) -1H-indole (d-2):
the procedure is as in example 7, using 5- (2- (1-piperidine) ethoxy) -1-tert-butyloxycarbonyl-1H-indole (c-2) instead of 5- (2- (1-pyrrolidine) ethoxy) -1-tert-butyloxycarbonyl-1H-indole (c-1), giving a solid in 85% yield.
1 H NMR(400MHz,DMSO-d 6 )δ1.39(t,J＝6Hz,2H),1.47-1.53(m,4H),2.43(s,4H),2.65(t,J＝6Hz,2H),4.03(t,J＝6Hz,2H),6.31(s,1H),6.71(dd,J＝8.8Hz,J＝2.4Hz,1H),7.03(d,J＝2Hz,1H),7.24-7.26(m,2H),10.89(s,1H).
Example 9: synthesis of 5- (2- (1-thiazolidine) ethoxy) -1H-indole (d-3):
the procedure is as in example 7, substituting 5- (2- (1-pyrrolidine) ethoxy) -1-tert-butyloxycarbonyl-1H-indole (c-3) for 5- (2- (1-pyrrolidine) ethoxy) -1-tert-butyloxycarbonyl-1H-indole (c-1), 85% yield.
1 H NMR(400MHz,DMSO-d 6 )δ2.68(t,J＝5.6Hz,2H),2.82(t,J＝6.4Hz,2H),3.08(t,J＝6.4Hz,2H),4.06(t,J＝5.6Hz,2H),4.12(s,2H),6.33(s,1H),6.74(dd,J＝8.8Hz,J＝2.4Hz,1H),7.05(d,J＝2.4Hz,1H),7.27-7.29(m,2H),10.90(s,1H).
Example 10: synthesis of 5- (2- (1-morpholine) ethoxy) -1H-indole (d-4):
the procedure is as in example 7, substituting 5- (2- (1-pyrrolidine) ethoxy) -1-tert-butyloxycarbonyl-1H-indole (c-4) for 5- (2- (1-pyrrolidine) ethoxy) -1-tert-butyloxycarbonyl-1H-indole (c-1), giving a yield of 80%.
1 H NMR(400MHz,DMSO-d 6 )δ2.46-2.50(m,4H),2.68(t,J＝6Hz,2H),3.58(t,J＝4.8Hz,4H),4.05(t,J＝6Hz,2H),6.31(t,J＝2Hz,1H),6.72(dd,J＝8.8Hz,J＝2.4Hz,1H),7.04(d,J＝2Hz,1H),7.25-7.27(m,2H),10.88(s,1H).
Example 11: synthesis of 5- (2- (1-pyrrolidine) ethoxy) -1-benzyl-1H-indole (TM 1):
0.47g (2 mmol) of 5- (2- (1-pyrrole) ethoxy) -1H-indole (d-1) was dissolved in 2ml of DMF, 0.49g (20 mmol) of NaH was added, stirring was carried out at 0 ℃ for 30 minutes, 0.36ml (3 mmol) of benzyl bromide was added, 0.51g (3 mmol) of KI was added, stirring was carried out at room temperature for 6 hours, quenching was carried out with ice water, extraction was carried out with DCM, washing with saturated sodium chloride, drying over anhydrous sodium sulfate, concentration under reduced pressure, column chromatography with stirring, DCM/MeOH =10:1 0.33g of oil was obtained in 51% yield.
1 H NMR(400MHz,DMSO-d 6 )δ1.67-1.70(m,4H),2.55(d,J＝5.2Hz,4H),2.82(t,J＝6.0Hz,2H),4.05(d,J＝6.0Hz,2H),5.36(s,2H),6.39(d,J＝2.8Hz,1H),6.74(dd,J＝2.4Hz,J＝8.8Hz,1H),7.07(d,J＝2.4Hz,1H),7.16-7.18(m,2H),7.21-7.31(m,4H),7.44(d,J＝3.2Hz,1H).
Example 12: synthesis of 5- (2- (1-piperidine) ethoxy) -1-benzyl-1H-indole (TM 2):
the procedure is as in example 11, 5- (2- (1-pyrrolidine) ethoxy) -1H-indole (d-2) is used instead of 5- (2- (1-pyrrolidine) ethoxy) -1H-indole (d-1), yield 90%.
1 H NMR(400MHz,DMSO-d 6 )δ1.39(d,J＝5.2Hz,2H),1.49-1.54(m,4H),2.50(d,J＝1.6Hz,4H),2.71(s,2H),4.05(t,J＝6Hz,2H),5.36(s,2H),6.38(d,J＝3.2Hz,1H),6.73(dd,J＝2.4Hz,J＝8.8Hz,1H),7.07(d,J＝2Hz,1H),7.16(d,J＝7.2Hz,2H),7.21-7.24(m,1H),7.29(m,3H),7.44(d,J＝2.8Hz,1H).
Example 13: synthesis of 5- (2- (1-thiazolidine) ethoxy) -1-benzyl-1H-indole (TM 3):
the procedure is as in example 11, 5- (2- (1-pyrrolidine) ethoxy) -1H-indole (d-3) is used instead of 5- (2- (1-pyrrolidine) ethoxy) -1H-indole (d-1), yield 36%.
1 H NMR(400MHz,CDCl 3 )δ2.91(t,J＝5.6Hz,2H),3.02(t,J＝6.4Hz,2H),3.27(t,J＝6.4Hz,2H),4.24(t,J＝5.6Hz,2H),4.28(s,2H),5.36(s,2H),6.57(d,J＝2.8Hz,1H),6.96(dd,J＝2Hz,J＝8.8Hz,1H),7.18-7.24(m,5H),7.33-7.40(m,3H).
Example 14: synthesis of 5- (2- (1-morpholine) ethoxy) -1-benzyl-1H-indole (TM 4):
the procedure is as in example 11, 5- (2- (1-pyrrolidine) ethoxy) -1H-indole (d-4) is used instead of 5- (2- (1-pyrrolidine) ethoxy) -1H-indole (d-1), yield 64%.
1 H NMR(400MHz,DMSO-d 6 )δ2.47(t,J＝4.4Hz,4H),2.68(t,J＝6.0Hz,2H),3.57(t,J＝4.8Hz,4H),4.05(d,J＝6.0Hz,2H),5.36(s,2H),6.38(d,J＝2.4Hz,1H),6.74(dd,J＝2Hz,J＝8.8Hz,1H),7.07(d,J＝2.4Hz,1H),7.16(d,J＝6.8Hz,2H),7.21-7.24(m,1H),7.27-7.31(m,3H),7.44(d,J＝3.2Hz,1H).
Example 15: synthesis of 5- (2- (1-pyrrolidine) ethoxy) -1- (3-chlorobenzyl) -1H-indole (TM 5):
the procedure is as in example 11, 3-chlorobenzyl bromide is used instead of benzyl bromide, yield 64%.
1 H NMR(400MHz,CDCl 3 )δ1.87(s,4H),2.73(s,4H),3.00(t,J＝5.6Hz,2H),4.22(t,J＝5.6Hz,2H),5.21(s,2H),6.52(s,1H),6.91-6.95(m,2H),7.10-7.14(m,3H),7.19-7.26(m,3H).
Example 16: synthesis of 5- (2- (1-pyrrolidine) ethoxy) -1- (3-bromobenzyl) -1H-indole (TM 6):
the procedure is as in example 11, substituting benzyl bromide with 3-bromobenzyl bromide in 29% yield.
1 H NMR(400MHz,DMSO-d 6 )δ1.67-1.70(m,4H),2.57(s,4H),2.83(t,J＝6Hz,2H),4.05(t,J＝6Hz,2H),5.38(s,2H),6.40(d,J＝2.8Hz,1H),6.75(dd,J＝8.8Hz,J＝2.4Hz,1H),7.07(d,J＝2.4Hz,1H),7.15(d,J＝7.6Hz,1H),7.25(t,J＝8Hz,1H),7.31(d,J＝8.8Hz,1H),7.35(s,1H),7.43(d,J＝8Hz,1H),7.46(d,J＝3.2Hz,1H).
Example 17: synthesis of 5- (2- (1-pyrrolidine) ethoxy) -1- (3-methoxybenzyl) -1H-indole (TM 7):
the procedure is as in example 11, 3-methoxybenzyl bromide is used instead of benzyl bromide, yield 71%.
1 H NMR(400MHz,DMSO-d 6 )δ1.67-1.70(m,4H),2.54(s,4H),2.80(t,J＝6Hz,2H),3.68(s,3H),4.04(t,J＝6Hz,2H),5.33(s,2H),6.38(d,J＝3.2Hz,1H),6.70-6.75(m,3H),6.80(dd,J＝8.8Hz,J＝2.4Hz,1H),7.07(d,J＝2.4Hz,1H),7.20(t,J＝8Hz,1H),7.30(d,J＝9.2Hz,1H),7.43(d,J＝3.2Hz,1H).
Example 18: synthesis of 5- (2- (1-piperidine) ethoxy) -1- (3-chlorobenzyl) -1H-indole (TM 8):
the procedure is as in example 11, 5- (2- (1-piperidine) ethoxy) -1H-indole (d-2) is used instead of 5- (2- (1-pyrrolidine) ethoxy) -1H-indole (d-1) and benzyl bromide is replaced by 3-chlorobenzyl bromide in 57% yield.
1 H NMR(400MHz,DMSO-d 6 )δ1.37(d,J＝4.8z,2H),1.47-1.52(m,4H),2.45(s,4H),2.67(t,J＝5.6Hz,2H),4.04(t,J＝5.6Hz,2H),5.38(s,2H),6.40(d,J＝2.8Hz,1H),6.75(dd,J＝2.4Hz,J＝8.8Hz,1H),7.08(d,J＝2.4Hz,1H),7.11(d,J＝6.8Hz,2H),7.20(s,1H),7.27-7.33(m,3H),7.46(d,J＝2.8Hz,1H).
Example 19: synthesis of 5- (2- (1-piperidine) ethoxy) -1- (3-bromobenzyl) -1H-indole (TM 9):
the procedure is as in example 11, 5- (2- (1-piperidine) ethoxy) -1H-indole (d-2) is used instead of 5- (2- (1-pyrrolidine) ethoxy) -1H-indole (d-1) and 3-bromobenzyl bromide is used instead of benzyl bromide, yield 34%.
1 H NMR(400MHz,DMSO-d 6 )δ1.38(t,J＝5.2Hz,2H),1.47-1.53(m,4H),2.46(s,4H),2.68(t,J＝5.2Hz,2H),4.04(t,J＝6Hz,2H),5.38(s,2H),6.39(d,J＝3.2Hz,1H),6.75(dd,J＝2.4Hz,J＝8.8Hz,1H),7.07(d,J＝2Hz,1H),7.15(d,J＝7.6Hz,1H),7.25(t,J＝7.6Hz,1H),7.31(d,J＝8.8Hz,1H),7.36(s,1H),7.43(d,J＝7.6Hz,1H),7.46(d,J＝3.2Hz,1H).
Example 20: synthesis of 5- (2- (1-piperidine) ethoxy) -1- (3-methoxybenzyl) -1H-indole (TM 10):
the procedure is as in example 11, 5- (2- (1-piperidine) ethoxy) -1H-indole (d-2) is used instead of 5- (2- (1-pyrrolidine) ethoxy) -1H-indole (d-1) and benzyl bromide is replaced by 3-methoxybenzyl bromide in 13% yield.
1 H NMR(400MHz,DMSO-d 6 )δ1.53(s,2H),1.74(s,4H),2.50(t,J＝1.6Hz,2H),3.45(d,J＝4Hz,4H),3.68(s,3H),4.30(t,J＝5.2Hz,2H),5.35(s,2H),6.41(d,J＝2.8Hz,1H),6.71(d,J＝7.6Hz,1H),6.74(s,1H),6.79-6.83(m,2H),7.16(d,J＝2.4Hz,1H),7.20(t,J＝8Hz,1H),7.36(d,J＝8.8Hz,1H),7.49(d,J＝3.2Hz,1H).
Example 21: synthesis of 5- (2- (1-thiazolidine) ethoxy) -1- (3-chlorobenzyl) -1H-indole (TM 11):
the procedure is as in example 11, 5- (2- (1-thiazolidine) ethoxy) -1H-indole (d-3) is used instead of 5- (2- (1-pyrrolidine) ethoxy) -1H-indole (d-1) and benzyl bromide is replaced by 3-chlorobenzyl bromide in 65% yield.
1 H NMR(400MHz,DMSO-d 6 )δ2.68(t,J＝5.6Hz,2H),2.81(t,J＝6.4Hz,2H),3.07(t,J＝6.4Hz,2H),4.07(t,J＝5.6Hz,2H),4.11(s,2H),5.39(s,2H),6.40(d,J＝2.8Hz,1H),6.76(dd,J＝2.4Hz,J＝8.8Hz,1H),7.08(d,J＝2.4Hz,1H),7.11(d,J＝6.8Hz,1H),7.20(s,1H),7.31(t,J＝2Hz,1H),7.33(d,J＝2Hz,1H),7.47(d,J＝3.2Hz,1H).
Example 22: synthesis of 5- (2- (1-thiazolidine) ethoxy) -1- (3-bromobenzyl) -1H-indole (TM 12):
the procedure is as in example 11, 5- (2- (1-thiazolidine) ethoxy) -1H-indole (d-3) is used instead of 5- (2- (1-pyrrolidine) ethoxy) -1H-indole (d-1) and benzyl bromide is replaced by 3-bromobenzyl bromide in 80% yield.
1 H NMR(400MHz,DMSO-d 6 )δ2.68(t,J＝5.6Hz,2H),2.81(t,J＝6.4Hz,2H),3.07(t,J＝6.4Hz,2H),4.07(t,J＝5.6Hz,2H),4.11(s,2H),5.38(s,2H),6.57(d,J＝2.8Hz,1H),6.96(dd,J＝2Hz,J＝8.8Hz,1H),7.18-7.24(m,5H),7.33-7.40(m,3H).
Example 23: synthesis of 5- (2- (1-thiazolidine) ethoxy) -1- (3-methoxybenzyl) -1H-indole (TM 13):
the procedure is as in example 11, 5- (2- (1-thiazolidine) ethoxy) -1H-indole (d-3) is used instead of 5- (2- (1-pyrrolidine) ethoxy) -1H-indole (d-1) and benzyl bromide is replaced by 3-methoxybenzyl bromide in 76% yield.
1 H NMR(400MHz,DMSO-d 6 )δ2.68(t,J＝5.6Hz,2H),2.81(t,J＝6.4Hz,2H),3.07(t,J＝6.4Hz,2H),3.68(s,3H),4.06(t,J＝5.6Hz,2H),4.11(s,2H),5.33(s,2H),6.38(d,J＝2.8Hz,1H),6.71(d,J＝7.6Hz,1H),6.74-6.76(m,2H),6.80(dd,J＝2.4Hz,J＝8.8Hz,1H),7.07(d,J＝2Hz,1H),7.20(t,J＝8Hz,1H),7.31(d,J＝8.8Hz,1H),7.44(d,J＝2.8Hz,1H).
Example 24: synthesis of 5- (2- (1-morpholine) ethoxy) -1- (3-chlorobenzyl) -1H-indole (TM 14):
the procedure is as in example 11, 5- (2- (1-morpholine) ethoxy) -1H-indole (d-4) is used instead of 5- (2- (1-pyrrolidine) ethoxy) -1H-indole (d-1) and benzyl bromide is replaced by 3-chlorobenzyl bromide in 82% yield.
1 H NMR(400MHz,DMSO-d 6 )δ2.47(s,4H),2.68(t,J＝6.0Hz,2H),3.57(t,J＝4.4Hz,4H),4.06(d,J＝6.0Hz,2H),5.38(s,2H),6.40(d,J＝2.8Hz,1H),6.75(dd,J＝2.4Hz,J＝8.8Hz,1H),7.08(d,J＝2Hz,1H),7.11(d,J＝6.8Hz,1H),7.20(s,1H),7.29(d,J＝8Hz,1H),7.33(d,J＝6.8Hz,1H),7.46(d,J＝2.8Hz,1H).
Example 25: synthesis of 5- (2- (1-morpholine) ethoxy) -1- (3-bromobenzyl) -1H-indole (TM 15):
the procedure is as in example 11, 5- (2- (1-morpholine) ethoxy) -1H-indole (d-4) is used instead of 5- (2- (1-pyrrolidine) ethoxy) -1H-indole (d-1) and 3-bromobenzyl bromide is used instead of benzyl bromide, yield 73%.
1 H NMR(400MHz,DMSO-d 6 )δ2.47(t,J＝4.0Hz,4H),2.68(t,J＝6.0Hz,2H),3.58(t,J＝4.4Hz,4H),4.06(d,J＝6.0Hz,2H),5.38(s,2H),6.40(d,J＝3.2Hz,1H),6.75(dd,J＝2.4Hz,J＝8.8Hz,1H),7.08(d,J＝2Hz,1H),7.15(d,J＝8.0Hz,1H),7.25(t,J＝8.0Hz,1H),7.31(d,J＝8.8Hz,1H),7.36(s,1H),7.43(d,J＝8.0Hz,1H),7.46(d,J＝2.8Hz,1H).
Example 26: synthesis of 5- (2- (1-morpholine) ethoxy) -1- (3-methoxybenzyl) -1H-indole (TM 16):
the procedure is as in example 11, 5- (2- (1-morpholine) ethoxy) -1H-indole (d-4) is used instead of 5- (2- (1-pyrrolidine) ethoxy) -1H-indole (d-1) and 3-methoxybenzyl bromide is used instead of benzyl bromide, 54% yield.
1 H NMR(400MHz,DMSO-d 6 )δ2.47(t,J＝4.4Hz,4H),2.68(t,J＝6.0Hz,2H),3.58(t,J＝4.4Hz,4H),3.68(s,3H),4.05(t,J＝6.0Hz,2H),5.32(s,2H),6.38(d,J＝3.2Hz,1H),6.71(d,J＝7.6Hz,1H),6.73-6.75(m,2H),6.80(dd,J＝2.4Hz,J＝8.0Hz,1H),7.07(d,J＝2.4Hz,1H),7.20(t,J＝8.0Hz,1H),7.30(d,J＝8.8Hz,1H),7.43(d,J＝2.8Hz,1H).
Example 27: synthesis of 5- (4-acetoxyphenoxy) -1-tert-butyloxycarbonyl-1H-indole (e-1):
dissolving 100mg (0.4 mmol) of 5-hydroxy-1-tert-butyloxycarbonyl-1H-indole (a) in 1ml of DMF, adding 0.5ml (4 mmol) of p-fluoroacetophenone and 0.96g (0.8 mmol) of potassium tert-butoxide, stirring at 100 ℃ for 7 hours, diluting with water, EA extracting, washing with saturated sodium chloride, drying over anhydrous sodium sulfate, concentrating under reduced pressure, column chromatography with stirring, PE: EA =150:1 an oil was obtained in 46% yield.
1 H NMR(400MHz,DMSO-d 6 )δ1.64(s,9H),2.53(s,3H),6.71(d,J＝3.6Hz,1H),7.02(d,J＝8.8Hz,2H),7.11(dd,J＝8.8Hz,J＝2.0Hz,1H),7.39(d,J＝2Hz,1H),7.74(d,J＝3.6Hz,1H),7.87(d,J＝8.4Hz,2H),8.10(d,J＝9.2Hz,1H).
Example 28: synthesis of 5- (2-acetoxyphenoxy) -1-tert-butyloxycarbonyl-1H-indole (e-2):
the procedure is as in example 27, substituting 2-fluoroacetophenone for p-fluoroacetophenone to give a yield of 38%.
1 H NMR(400MHz,DMSO-d 6 )δ1.63(s,9H),2.59(s,3H),6.69(d,J＝3.6Hz,1H),6.89(d,J＝8.4Hz,2H),7.10(dd,J＝8.8Hz,J＝2.4Hz,1H),7.19-7.23(m,1H),7.30(d,J＝2.4Hz,1H),7.49-7.54(m,1H),7.71-7.74(m,1H),8.08(d,J＝9.2Hz,1H).
Example 29: synthesis of 5- (4-cyanophenoxy) -1-tert-butyloxycarbonyl-1H-indole (e-3):
the procedure is as in example 27 except that p-fluoroacetonitrile is used instead of p-fluoroacetophenone, in a yield of 74%.
1 H NMR(400MHz,DMSO-d 6 )δ1.63(s,9H),6.71(d,J＝4.0Hz,1H),7.06(dd,J＝6.8Hz,J＝2.0Hz,2H),7.12(dd,J＝8.8Hz,J＝2.4Hz,1H),7.41(d,J＝2.4Hz,1H),7.75(d,J＝3.6Hz,1H),7.80(dd,J＝6.8Hz,J＝2.0Hz,2H),8.11(d,J＝9.2Hz,1H).
Example 30: synthesis of 5- (2-cyanophenoxy) -1-tert-butyloxycarbonyl-1H-indole (e-4):
the procedure is as in example 27 except that 2-fluorobenzonitrile is used in place of p-fluoroacetophenone in a yield of 85%.
1 H NMR(400MHz,DMSO-d 6 )δ1.63(s,9H),6.71(d,J＝3.6Hz,1H),6.87(d,J＝8.4Hz,1H),7.15(dd,J＝8.8Hz,J＝2.4Hz,1H),7.24-7.26(m,1H),7.42(d,J＝2.4Hz,1H),7.59-7.63(m,1H),7.74(d,J＝4.0Hz,1H),7.88(dd,J＝7.6Hz,J＝1.6Hz,1H),8.11(d,J＝9.2Hz,1H).
Example 31: synthesis of 5- (4-acetoxyphenoxy) -1H-indole (f-1):
0.72g (2.1 mmol) of 5- (4-acetoxyphenoxy) -1-tert-butyloxycarbonyl-1H-indole (e-1) are dissolved in MeOH, THF and H 2 To O, 1.76g (42 mmol) of LiOH. H was added 2 Stirring for 2 hr at room temperature, spin-drying solvent, diluting with water, extracting with DCM, washing with saturated sodium chloride, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and mixing with sampleColumn chromatography, PE/EA =10:1 white solid 0.41g was obtained in 80% yield.
1 H NMR(400MHz,DMSO-d 6 )δ2.51(s,3H),6.43(t,J＝2.4Hz,1H),6.87(dd,J＝8.8Hz,J＝2.4Hz,1H),6.96(dd,J＝7.2Hz,J＝2.0Hz,2H),7.29(d,J＝2.4Hz,1H),7.42(t,J＝2.8Hz,1H),7.46(d,J＝8.8Hz,1H),7.93(dd,J＝6.8Hz,J＝2.0Hz,2H),11.22(s,1H).
Example 32: synthesis of 5- (2-acetoxyphenoxy) -1H-indole (f-2):
the procedure is as in example 31, substituting 5- (4-acetoxyphenoxy) -1-tert-butoxycarbonyl-1H-indole (e-1) with 5- (2-acetoxyphenoxy) -1-tert-butoxycarbonyl-1H-indole (e-2), yielding 97%.
1 H NMR(400MHz,DMSO-d 6 )δ2.63(s,3H),6.41(t,J＝2.0Hz,1H),6.79(t,J＝8.4Hz,1H),6.90(dd,J＝8.8Hz,J＝2.4Hz,1H),7.11-7.15(m,1H),7.24(d,J＝2.4Hz,1H),7.40(t,J＝2.8Hz,1H),7.43-7.47(m,2H),7.69(dd,J＝8.0Hz,J＝2.0Hz,1H),11.20(s,1H).
Example 33: synthesis of 5- (4-cyanophenoxy) -1H-indole (f-3):
the procedure is as in example 31, substituting 5- (4-acetyloxyphenoxy) -1-tert-butoxycarbonyl-1H-indole (e-3) for 5- (4-acetyloxyphenoxy) -1-tert-butoxycarbonyl-1H-indole (e-1) in 74% yield.
1 H NMR(400MHz,DMSO-d 6 )δ6.44(t,J＝2.0Hz,1H),6.87(dd,J＝8.8Hz,J＝2.4Hz,1H),7.00(dd,J＝6.8Hz,J＝2.0Hz,2H),7.31(d,J＝2.4Hz,1H),7.43(t,J＝2.8Hz,1H),7.48(d,J＝8.4Hz,1H),7.77(dd,J＝6.8Hz,J＝2.0Hz,2H),11.25(s,1H).
Example 34: synthesis of 5- (2-cyanophenoxy) -1H-indole (f-4):
the procedure is as in example 31, substituting 5- (2-cyanophenoxy) -1-tert-butoxycarbonyl-1H-indole (e-4) for 5- (4-acetoxyphenoxy) -1-tert-butoxycarbonyl-1H-indole (e-1), yield 85%.
1 H NMR(400MHz,DMSO-d 6 )δ6.45(t,J＝2.0Hz,1H),6.77(d,J＝8.4Hz,1H),6.92(dd,J＝8.8Hz,J＝2.4Hz,1H),7.17(t,J＝7.6Hz,1H),7.34(t,J＝2.0Hz,1H),7.44(t,J＝2.8Hz,1H),7.49(d,J＝8.4Hz,1H),7.53-7.57(m,1H),7.83(dd,J＝7.6Hz,J＝1.6Hz,1H),11.27(s,1H).
Example 35: synthesis of 5- (4-acetoxyphenoxy) -1- [2- (dimethylamino) ethyl) ] -1H-indole (TM 17):
after 0.2g (0.8 mmol) of 5- (4-acetoxyphenoxy) -1H-indole (f-1) was dissolved in 5ml of DMF, 0.2g (8 mmol) of NaH was added, and after stirring at 0 ℃ for 30 minutes, 0.2g (1.6 mmol) of dimethylaminoethyl chloride hydrochloric acid was added, 0.2g (1.2 mmol) of KI was added, and after stirring at room temperature for 6 hours, quenching was performed with ice water, EA extraction was performed, washing with saturated sodium chloride, drying over anhydrous sodium sulfate, concentration under reduced pressure, column chromatography with stirring, DCM/MeOH =150:1 0.18g of oil is obtained in 69% yield. 1 H NMR(400MHz,DMSO-d 6 )δ2.18(s,6H),2.50(s,3H),2.61(t,J＝6.8Hz,2H),4.26(t,J＝6.8Hz,2H),6.41(d,J＝2.8Hz,1H),6.90(dd,J＝8.8Hz,1H),6.93-6.97(m,2H),7.28(d,J＝2.4Hz,1H),7.45(d,J＝3.2Hz,1H),7.54(d,J＝8.8Hz,1H),7.90-7.93(m,2H).
Example 36: synthesis of 5- [4- (1-hydroxyethyl) phenoxy ] -1- [2- (dimethylamino) ethyl) ] -1H-indole (TM 18):
after 0.26g (0.8 mmol) of 5- (4-acetoxyphenoxy) -1- [2- (dimethylamino) ethyl) ] -1H-indole (TM 17) was dissolved in 3ml of ethanol, 0.18g (4.8 mmol) of sodium borohydride was added with stirring, and after stirring at room temperature for 15 minutes, the reaction was quenched with ice water, the solvent was dried under reduced pressure, extracted with EA, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, column-chromatographed with DCM/MeOH =50:1 0.24g of oil was obtained in 92% yield.
1 H NMR(400MHz,DMSO-d 6 )δ1.30(d,J＝6.4Hz,3H),2.19(s,6H),2.60(t,J＝6.8Hz,2H),4.24(t,J＝6.8Hz,2H),4.68(m,1H),5.08(d,J＝3.6Hz,1H),6.37(d,J＝2.8Hz,1H),6.86(dd,J＝8.8Hz,3H),7.16(d,J＝2.4Hz,1H),7.28(d,J＝8.4Hz,2H),7.41(d,J＝3.2Hz,1H),7.48(d,J＝8.8Hz,1H).
Example 37: synthesis of 5- (4-cyanophenoxy) -1- [2- (dimethylamino) ethyl) ] -1H-indole (TM 19):
the procedure is as in example 35, substituting 5- (4-acetoxyphenoxy) -1H-indole (f-1) with 5- (4-cyanophenoxy) -1H-indole (f-3) in 70% yield.
1 H NMR(400MHz,DMSO-d 6 )δ2.19(s,6H),2.62(t,J＝6.8Hz,2H),4.27(t,J＝6.8Hz,2H),6.42(d,J＝2.8Hz,1H),6.92(dd,J＝8.4Hz,J＝2.0Hz,1H),6.99-7.03(m,2H),7.31(d,J＝2.4Hz,1H),7.47(d,J＝3.2Hz,1H),7.55(d,J＝16.8Hz,1H),7.75-7.79(m,2H).
Example 38: synthesis of 5- (2-acetoxyphenoxy) -1- [2- (dimethylamino) ethyl) ] -1H-indole (TM 20):
the procedure is as in example 35, substituting 5- (4-acetoxyphenoxy) -1H-indole (f-1) with 5- (2-acetoxyphenoxy) -1H-indole (f-2), yield 95%.
1 H NMR(400MHz,DMSO-d 6 )δ2.19(s,6H),2.60-2.63(m,5H),4.26(t,J＝6.8Hz,2H),6.39(d,J＝2.8Hz,1H),6.80(d,J＝8Hz,1H),6.94(dd,J＝8.8Hz,J＝2.4Hz,2H),7.12-7.16(m,1H),7.24(d,J＝2.4Hz,1H),7.43-7.48(m,2H),7.54(d,J＝8.8Hz,1H),7.70(dd,J＝1.6Hz,J＝6Hz,1H).
Example 39: synthesis of 5- [2- (1-hydroxyethyl) phenoxy ] -1- [2- (dimethylamino) ethyl) ] -1H-indole (TM 21):
the procedure is as in example 36, 5- (2-acetoxyphenoxy) -1- [2- (dimethylamino) ethyl) ] -1H-indole (TM 20) is used instead of 5- (4-acetoxyphenoxy) -1- [2- (dimethylamino) ethyl) ] -1H-indole (TM 17) in 57% yield.
1 H NMR(400MHz,DMSO-d 6 )δ1.36(d,J＝6.0Hz,3H),2.19(s,6H),2.61(t,J＝6.8Hz,2H),4.24(t,J＝6.8Hz,2H),5.12(m,1H),6.35(d,J＝2.8Hz,1H),6.66(dd,J＝8.0Hz,J＝1.2Hz,1H),6.84(dd,J＝2.0Hz,J＝8.8Hz,1H),7.05-7.08(m,2H),7.11-7.15(m,1H),7.39(d,J＝2.8Hz,1H),7.47(d,J＝8.8Hz,1H),7.58(dd,J＝2.0Hz,J＝7.6Hz,1H).
Example 40: synthesis of 5- (2-cyanophenoxy) -1- [2- (dimethylamino) ethyl) ] -1H-indole (TM 22):
the procedure is as in example 35, substituting 5- (2-cyanophenoxy) -1H-indole (f-4) for 5- (4-acetoxyphenoxy) -1H-indole (f-1) in 33% yield.
1 H NMR(400MHz,DMSO-d 6 )δ2.19(s,6H),2.62(t,J＝6.8Hz,2H),4.27(t,J＝6.8Hz,2H),6.43(d,J＝3.2Hz,1H),6.78(d,J＝8.8Hz,1H),6.96(dd,J＝2.4Hz,J＝8.8Hz,2H),7.16-7.20(m,1H),7.33(d,J＝2.4Hz,1H),7.48(d,J＝3.2Hz,1H),7.54-7.58(m,2H),7.83-7.86(m,1H).
Example 41: synthesis of 5- (4-cyanophenoxy) -1- [2- (morpholino) ethyl) ] -1H-indole (TM 23):
the procedure is as in example 35, 5- (4-cyanophenoxy) -1H-indole (f-3) is used instead of 5- (4-acetoxyphenoxy) -1H-indole (f-1) and N- (2-chloroethyl) morpholine is used instead of dimethylaminoethyl chloride hydrochloric acid in 34% yield.
1 H NMR(400MHz,DMSO-d 6 )δ2.44(s,4H),2.67(t,J＝6.8Hz,2H),3.55(t,J＝4.4Hz,4H),4.31(t,J＝6.8Hz,2H),6.43(d,J＝2.8Hz,1H),6.92(dd,J＝8.8Hz,J＝2.4Hz,1H),7.01(d,J＝8.8Hz,2H),7.31(d,J＝2.4Hz,1H),7.49(d,J＝2.8Hz,1H),7.58(d,J＝8.8Hz,1H),7.77(d,J＝8.8Hz,2H).
Example 42: synthesis of 5- (4-cyanophenoxy) -1- [2- (tetrahydropyrrole) ethyl) ] -1H-indole (TM 24):
the procedure is as in example 35, 5- (4-cyanophenoxy) -1H-indole (f-3) is used instead of 5- (4-acetoxyphenoxy) -1H-indole (f-1) and N- (2-chloroethyl) pyrrolidine is used instead of dimethylaminoethyl chloride hydrochloric acid in 75% yield.
1 H NMR(400MHz,DMSO-d 6 )δ1.64-1.68(m,4H),2.48-2.50(m,4H),2.80(t,J＝6.8Hz,2H),4.30(t,J＝6.8Hz,2H),6.43(d,J＝2.8Hz,1H),6.92(dd,J＝8.8Hz,J＝2.4Hz,1H),6.99-7.02(m,2H),7.31(d,J＝2.0Hz,1H),7.48(d,J＝3.2Hz,1H),7.56(d,J＝8.8Hz,1H),7.75-7.79(m,2H).
Example 43: synthesis of 5- (2-cyanophenoxy) -1- [2- (tetrahydropyrrole) ethyl) ] -1H-indole (TM 25):
the procedure is as in example 35, 5- (2-cyanophenoxy) -1H-indole (f-4) is used instead of 5- (4-acetoxyphenoxy) -1H-indole (f-1) and N- (2-chloroethyl) pyrrolidine is used instead of dimethylaminoethyl chloride hydrochloric acid in a yield of 46%.
1 H NMR(400MHz,DMSO-d 6 )δ1.65-1.67(m,4H),2.49-2.50(m,4H),2.80(t,J＝6.8Hz,2H),4.30(t,J＝6.8Hz,2H),6.43(d,J＝2.8Hz,1H),6.77(d,J＝8.4Hz,1H),6.96(dd,J＝8.8Hz,J＝2.0Hz,1H),7.16-7.20(m,1H),7.33(d,J＝2.0Hz,1H),7.49(d,J＝3.2Hz,1H),7.54-7.58(m,2H),7.85(dd,J＝8.0Hz,J＝1.6Hz,1H).
Example 44: synthesis of 5- (2-cyanophenoxy) -1- [2- (morpholino) ethyl) ] -1H-indole (TM 26):
the procedure is as in example 35, 5- (2-cyanophenoxy) -1H-indole (f-4) is used instead of 5- (4-acetoxyphenoxy) -1H-indole (f-1) and N- (2-chloroethyl) morpholine is used instead of dimethylaminoethyl chloride hydrochloric acid in 50% yield.
1 H NMR(400MHz,DMSO-d 6 )δ2.43(s,4H),2.67(t,J＝6.8Hz,2H),3.54-3.56(m,4H),4.31(t,J＝6.8Hz,2H),6.44(d,J＝2.8Hz,1H),6.77(d,J＝8.4Hz,1H),6.97(dd,J＝8.8z,J＝2.4Hz,1H),7.19(t,J＝7.6Hz,1H),7.33(d,J＝2.4Hz,1H),7.49(d,J＝2.8Hz,1H),7.55-7.60(m,2H),7.85(dd,J＝7.6Hz,J＝1.6Hz,1H).
Correlation detection of the invention:
1. and (3) activity test:
LTA of partial Compounds 17-22 4 Measurement of H inhibitory Activity.
Compounds inhibit LTA 4 DMSO was used as a negative control in H hydrolase activity experiments, and LTA was marketed 4 The H inhibitor Bestatin served as a positive control. While the concentration of the compound was set to four concentration gradients of 0.1. Mu.M, 1. Mu.M, 10. Mu.M and 100. Mu.M with LTB 4 Detection of LTA by detection kit 4 H on LTA 4 Time-dependent LTB 4 In the amount of compound group LTB 4 LTB produced in the DMSO group 4 Percent formation measurement of Compound group to LTA 4 The inhibition effect of H hydrolase activity is calculated, and finally the corresponding IC is calculated 50 。
TABLE 1 Compound inhibition of hydrolase Activity test IC 50
IC 50 for Compound Inhibition of Hydrolase Activity Test
The results are shown in Table 1, and it can be seen from Table 1 that all of the 6 compounds exhibited lower IC 50 Of these, compounds 17, 19 and 22 furthermore have a relatively low IC 50 Illustrates the three compounds to LTA 4 H hydrolase has better inhibiting effect, and the result shows that the indole derivatives have better LTA inhibiting effect 4 Action of H hydrolase.
2. Compounds that inhibit LTA 4 H aminopeptidase Activity detection
Compounds that inhibit LTA 4 DMSO was used as a negative control in the H aminopeptidase activity assay, and LTA was marketed 4 The H inhibitor Bestatin served as a positive control. LTA was detected by simultaneously setting the concentration of the compound to four concentration gradients of 0.1. Mu.M, 1. Mu.M, 10. Mu.M and 100. Mu.M 4 H acts on the amount of free p-nitroaniline generated by L-alanine p-nitroaniline, and the amount of the generated p-nitroaniline under each compound concentration of the compound group is used for measuring the percentage of the generated p-nitroaniline by the DMSO group 4 Inhibitory effect of H aminopeptidase Activity.
TABLE 2 evaluation of aminopeptidase Activity by L-alanine-p-nitroaniline substrate method
Evaluation of aminopeptidase activity by L-alanine-p-nitroaniline substrate method
The results are shown in Table 2, and from Table 2, it can be seen that although 6 compounds had aminopeptidase inhibited IC 50 Is not as good asThe reference Bestatin, but all also have a lower IC 50 Values, combined with data on hydrolase inhibition activity, indicate that the compounds of the invention have certain LTA inhibition 4 H, the effect of the compound.
Although the embodiments of the present invention have been disclosed for illustrative purposes, those skilled in the art will appreciate that: various substitutions, changes and modifications are possible without departing from the spirit and scope of the invention and the appended claims, and therefore the scope of the invention is not limited to the disclosure of the embodiments and the accompanying drawings.
Claims (4)
1.1, 5-disubstituted indole derivatives having leukotriene A4 hydrolase inhibitory action, characterized in that: the 1, 5-disubstituted indole derivative has a function of inhibiting leukotriene A4 hydrolase;
the structural general formula of the 1, 5-disubstituted indole derivative is as follows:
wherein R is 1 Is one of cyano, 1-hydroxyethyl or acetyl at ortho-position or para-position; NR 2 R 3 Is N, N-dimethylamino; n =2;
the structural formula of the 1, 5-disubstituted indole derivative is as follows:
17 Or 18, or 19, or
20 Or 21, or 22.
2. The 1, 5-disubstituted indole derivative having a leukotriene A4 hydrolase inhibitory effect according to claim 1, which is characterized in that: the synthetic route of the synthetic method is as follows:
3. use of the 1, 5-disubstituted indole derivatives having leukotriene A4 hydrolase inhibitory effect according to claim 1 or 2 for the preparation of a medicament for inhibiting leukotriene A4 hydrolase.
4. Use according to claim 3, characterized in that: the medicine is an anti-tumor medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910540367.5A CN110229091B (en) | 2019-06-21 | 2019-06-21 | 1, 5-disubstituted indole derivatives with leukotriene A4 hydrolase inhibition effect and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910540367.5A CN110229091B (en) | 2019-06-21 | 2019-06-21 | 1, 5-disubstituted indole derivatives with leukotriene A4 hydrolase inhibition effect and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110229091A CN110229091A (en) | 2019-09-13 |
| CN110229091B true CN110229091B (en) | 2022-11-22 |
Family
ID=67856415
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910540367.5A Active CN110229091B (en) | 2019-06-21 | 2019-06-21 | 1, 5-disubstituted indole derivatives with leukotriene A4 hydrolase inhibition effect and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110229091B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111620942B (en) * | 2020-06-12 | 2021-10-15 | 中国科学院昆明动物研究所 | Mature peptide of batus brucei leukotriene A4hydrolase inhibitor Motisin and application thereof |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101189012A (en) * | 2005-03-31 | 2008-05-28 | 詹森药业有限公司 | Phenyl and pyridyl LTA4H modulators |
| CN101874798A (en) * | 2010-06-29 | 2010-11-03 | 北京大学 | Difunctional inhibitor of leukotriene A4 hydrolase and cyclooxygenase and application thereof |
| CN102491933A (en) * | 2011-12-19 | 2012-06-13 | 天津科技大学 | Substituted 5-acrylic acid indole dione derivative, as well as preparation method and application thereof |
| CN102491979A (en) * | 2011-12-21 | 2012-06-13 | 天津科技大学 | 1-hydroxyethyl-5-substituted indolone derivative and preparation method and application thereof |
| WO2014014874A1 (en) * | 2012-07-17 | 2014-01-23 | Boehringer Ingelheim International Gmbh | Pyrazole derivatives which inhibit leukotriene production |
| CN105916841A (en) * | 2013-11-25 | 2016-08-31 | 诺沃根公司 | Functionalised and substituted indoles as anti-cancer agents |
| WO2016187667A1 (en) * | 2015-05-27 | 2016-12-01 | Novogen Limited | Functionalised and substituted indoles as anti-cancer agents |
| CN106661005A (en) * | 2014-07-16 | 2017-05-10 | 诺沃根公司 | Functionalised and substituted indoles as anti-cancer agents |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007073405A1 (en) * | 2005-12-21 | 2007-06-28 | Decode Genetics Ehf | N-linked aryl heteroaryl inhibitors of lta4h for treating inflammation |
-
2019
- 2019-06-21 CN CN201910540367.5A patent/CN110229091B/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101189012A (en) * | 2005-03-31 | 2008-05-28 | 詹森药业有限公司 | Phenyl and pyridyl LTA4H modulators |
| CN101874798A (en) * | 2010-06-29 | 2010-11-03 | 北京大学 | Difunctional inhibitor of leukotriene A4 hydrolase and cyclooxygenase and application thereof |
| CN102491933A (en) * | 2011-12-19 | 2012-06-13 | 天津科技大学 | Substituted 5-acrylic acid indole dione derivative, as well as preparation method and application thereof |
| CN102491979A (en) * | 2011-12-21 | 2012-06-13 | 天津科技大学 | 1-hydroxyethyl-5-substituted indolone derivative and preparation method and application thereof |
| WO2014014874A1 (en) * | 2012-07-17 | 2014-01-23 | Boehringer Ingelheim International Gmbh | Pyrazole derivatives which inhibit leukotriene production |
| CN105916841A (en) * | 2013-11-25 | 2016-08-31 | 诺沃根公司 | Functionalised and substituted indoles as anti-cancer agents |
| CN106661005A (en) * | 2014-07-16 | 2017-05-10 | 诺沃根公司 | Functionalised and substituted indoles as anti-cancer agents |
| WO2016187667A1 (en) * | 2015-05-27 | 2016-12-01 | Novogen Limited | Functionalised and substituted indoles as anti-cancer agents |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110229091A (en) | 2019-09-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2150812C (en) | Catechol diethers as selective pde iv inhibitors | |
| JP4580240B2 (en) | Substituted aminophenylacetic acids, derivatives thereof, their preparation and their use as cyclooxygenase 2 (COX-2) inhibitors | |
| KR100810468B1 (en) | 1H-indole derivatives as a highly selective cyclooxygenase-2 inhibitor | |
| Yang et al. | 4, 6-Substituted-1H-Indazoles as potent IDO1/TDO dual inhibitors | |
| KR20100074288A (en) | Histone deacetylase inhibitors | |
| US4772703A (en) | 2-(phenoxymethyl)-quinazolines as antiallergic and antiinflammatory agents | |
| CN101723896B (en) | Tyrosine derivative histone deacetylases inhibitor and application thereof | |
| JP7301433B2 (en) | Naphthalenesulfonamide compounds, methods of preparation, and uses | |
| Wang et al. | Development of novel ferulic acid derivatives as potent histone deacetylase inhibitors | |
| KR100686531B1 (en) | Arylaminomethyl propenyl benzhydroxyamide derivatives with inhibitory activity against histone deacetylase and method for the preparation thereof | |
| Wang et al. | Design, synthesis and preliminary bioactivity studies of imidazolidine-2, 4-dione derivatives as Bcl-2 inhibitors | |
| ES2428539T9 (en) | New histone deacetylase inhibitors | |
| CN105566241A (en) | 1-sulfonamide-4-aryloxy compound, preparation method and medical application of 1-sulfonamide-4-aryloxy compound | |
| CN108101821A (en) | Naphthalene sulfonamide amino acid derivativges, preparation method and its medical usage | |
| CN104592145B (en) | Benzofuroxan histone deacetylase inhibitor as well as preparation method and application thereof | |
| CN114805205A (en) | Acridine compound and preparation method and application thereof | |
| CN110229091B (en) | 1, 5-disubstituted indole derivatives with leukotriene A4 hydrolase inhibition effect and application thereof | |
| CN112920208A (en) | Boric acid-containing indole aryl sulfone derivative and preparation method and application thereof | |
| Bertinaria et al. | Synthesis and anti‐Helicobacter pylori properties of NO‐donor/metronidazole hybrids and related compounds | |
| CN105541806A (en) | Barbiturate compound, preparing method and application thereof | |
| JP2021510152A (en) | Compounds that simultaneously target and inhibit LSD1 and HDAC and their uses | |
| US6136848A (en) | Flavone derivative and medicine comprising the same | |
| JP2018510904A5 (en) | ||
| KR100814100B1 (en) | Alkylcarbamoyl naphthalenyloxyprophenyl hydroxybenzamide derivatives having inhibitory activity against histone deacetylase, method for the preparation thereof, and anticancer composition comprising the same | |
| US12098119B2 (en) | Compound used as SIRT6 small-molecule allosteric activator and pharmaceutical composition thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |