CN110229091A - With 1, the 5- disubstituted indole derivative of leukotriene A 4 hydrolase inhibiting effect and application - Google Patents
With 1, the 5- disubstituted indole derivative of leukotriene A 4 hydrolase inhibiting effect and application Download PDFInfo
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- CN110229091A CN110229091A CN201910540367.5A CN201910540367A CN110229091A CN 110229091 A CN110229091 A CN 110229091A CN 201910540367 A CN201910540367 A CN 201910540367A CN 110229091 A CN110229091 A CN 110229091A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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- 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
Abstract
The present invention relates to a kind of 1, the 5- disubstituted indole derivative with leukotriene A 4 hydrolase inhibiting effect, 1, the 5- disubstituted indole derivative have the function of being able to suppress leukotriene A 4 hydrolase.This 1,5- disubstituted indole derivative is noval chemical compound and is to synthesize for the first time, active testing is carried out to it, the aminopeptidase activity of this analog derivative dialogue triolefin A4 hydrolase and hydrolysing activity have effect as the result is shown, the analog derivative synthetic route is short, and synthesis technology and purification process are simple, and yield is higher, 1, the 5- disubstituted indole derivative can be used in inflammation caused by inhibiting leukotriene A 4 hydrolase and the medicine preparation by the other diseases of inflammation initiation.
Description
Technical field
The invention belongs to noval chemical compound synthesis and medicinal application technical fields, are related to noval chemical compound preparation method and its white three
Alkene A4 hydrolyzes enzyme adjustment activity, especially a kind of 1,5- disubstituted indole derivative with leukotriene A 4 hydrolase inhibiting effect
And application.
Background technique
Arachidonic acid is metabolized through 5-LOX, and under the catalysis of 5- lipoxygenase activator protein (FLAP), is formed in unstable
Between product 5- hydroperoxyl-arachidonic acid, then generate unstable leukotriene A (leukotreines A4, LTA4)。
It is in leukotriene A 4 hydrolase (LTA4H leukotriene B4 (LTB is formed under) acting on4), LTA4It can be through leukotriene C (LTC4) synzyme
LTC is generated in conjunction with glutathione4, and then generate leukotriene D, leukotriene E4, LTB4It is a kind of important inflammatory mediator, has
More and more research report leukotrienes and inflammation generation are closely related, wherein with LTB4Status it is particularly important.
Leukotriene A 4 hydrolase is the difunctional metalloproteinases containing zinc with epoxide hydrolase and aminopeptidase activity,
The generation of many inflammation of wide participation, and it is closely related with the generation of kinds of tumors, it is the new target for researching and developing anti-inflammatory anti-tumor drug
Point.Therefore, it finds and designs synthesis LTA4H inhibitor becomes treatment inflammation and treatment by the one of inflammation mediated a variety of diseases
A new research direction.
By retrieval, such as next chapter patent publication us relevant to present patent application is found:
Difunctional inhibitor of leukotriene A 4 hydrolase and cyclooxygenase and application thereof (CN101874798B), is related to formula
(I) difunctional inhibitor of leukotriene A 4 hydrolase and cyclooxygenase shown in, containing the pharmaceutical compositions of the inhibitor and he
In the drug of the patient's condition that by leukotriene A 4 hydrolase and cyclooxygenase is mediated of the preparation for treating and preventing subject
Purposes, the purposes in the drug of inflammation of the preparation for treating, preventing or inhibiting subject, in preparation for inhibiting leukotriene
Purposes in A4 hydrolase and the drug of cyclooxygenase enzymatic activity.Wherein, Ar is represented: 2- pyridyl group, 4- pyridyl group, 6- nitro-
2- pyridyl group, 2- pyrazinyl and related hexa-atomic nitrogen-containing heterocycle, phenyl or the group (II) for representing following formula: in group (II)
P, Q is located at the 2 of phenyl ring, 3,4 two positions, may be the same or different, and respectively represents: hydrogen, halogen, amido, nitro, three
Methyl fluoride, mesyl, single methylsulfonyl amido, diformazan sulfoamido or sulfonyloxy methyl amido.
By comparison, there is essential difference in present patent application and above-mentioned patent publication us.
Summary of the invention
Place that the purpose of the present invention is to overcome the deficiency in the prior art provides a kind of with leukotriene A 4 hydrolase inhibition work
1,5- disubstituted indole derivative and application, 1, the 5- disubstituted indole derivative is noval chemical compound and is to synthesize for the first time,
Active testing is carried out to it, the aminopeptidase activity of this analog derivative dialogue triolefin A4 hydrolase and hydrolysing activity have as the result is shown
Effect, the analog derivative synthetic route is short, and synthesis technology and purification process are simple, and yield is higher, which spreads out
Biology can be used in inflammation caused by inhibiting leukotriene A 4 hydrolase and the medicine preparation by the other diseases of inflammation initiation.
The technical solution adopted by the present invention to solve the technical problems is:
A kind of 1,5- disubstituted indole derivative with leukotriene A 4 hydrolase inhibiting effect, 1, the 5- bis- replace Yin
Diindyl derivative has the function of being able to suppress leukotriene A 4 hydrolase.
Moreover, the general structure of 1, the 5- disubstituted indole derivative is as follows:
Wherein, R2R1N is one of four to hexa-member heterocycle；R3For one of substituted aroma ring；N=1-4.
Moreover, described four to hexa-member heterocycle be nafoxidine ring group, tetrahydro-thiazoles ring group, morpholine ring group or piperidines ring group；
The substituted aroma ring is benzyl, 3- bromobenzyl, 3- chlorobenzyl or 3- methoxy-benzyl.
Moreover, the synthetic route of its synthetic method are as follows:
Moreover, the general structure of 1, the 5- disubstituted indole derivative is as follows:
Wherein, R1It is cyano, one of 1- hydroxyethyl or acetoxyl group are that is, o-, m-, to (R1 substituent group is in benzene
Three kinds of different locations of ring)；NR2R3For N, N- dimethylamino or four is one of to hexa-member heterocycle；N=1-4.
Moreover, described four to hexa-member heterocycle be nafoxidine ring group, tetrahydro-thiazoles ring group, morpholine ring group or piperidine ring
Base.
Moreover, the synthetic route of its synthetic method are as follows:
Moreover, the structural formula of 1, the 5- disubstituted indole derivative are as follows:
1,5- disubstituted indole derivative as described above with leukotriene A 4 hydrolase inhibiting effect is inhibiting white three
Application in terms of alkene A4 hydrolase.
1,5- disubstituted indole derivative as described above with leukotriene A 4 hydrolase inhibiting effect is in antitumor side
Application in face.
The advantages of present invention obtains and good effect are as follows:
The present invention 1,5- disubstituted indole derivative is noval chemical compound and is to synthesize for the first time, and active testing is carried out to it, is tied
Fruit shows that the aminopeptidase activity of this analog derivative dialogue triolefin A4 hydrolase and hydrolysing activity have effect, analog derivative synthesis
Route is short, and synthesis technology and purification process are simple, and yield is higher, which can be used in inhibiting white three
In inflammation caused by alkene A4 hydrolase and the medicine preparation by the other diseases of inflammation initiation.
Detailed description of the invention
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of TM 7 in the present invention；
Fig. 2 is the hydrogen nuclear magnetic resonance spectrogram of TM 8 in the present invention；
Fig. 3 is the hydrogen nuclear magnetic resonance spectrogram of TM 12 in the present invention；
Fig. 4 is the hydrogen nuclear magnetic resonance spectrogram of TM 14 in the present invention；
Fig. 5 is the hydrogen nuclear magnetic resonance spectrogram of TM 17 in the present invention；
Fig. 6 is the hydrogen nuclear magnetic resonance spectrogram of TM 23 in the present invention.
Specific embodiment
The embodiment of the present invention is described in detail below, it should be noted that the present embodiment is narrative, is not limited
, this does not limit the scope of protection of the present invention.
Raw material used in the present invention is unless otherwise specified conventional commercial product；Used in the present invention
Method is unless otherwise specified the conventional method of this field.
A kind of 1,5- disubstituted indole derivative with leukotriene A 4 hydrolase inhibiting effect, 1, the 5- bis- replace Yin
Diindyl derivative has the function of being able to suppress leukotriene A 4 hydrolase.
More preferably, the general structure of 1, the 5- disubstituted indole derivative is as follows:
Wherein, R2R1N is one of four to hexa-member heterocycle；R3For one of substituted aroma ring；N=1-4.
More preferably, described four to hexa-member heterocycle be nafoxidine ring group, tetrahydro-thiazoles ring group, morpholine ring group or piperidine ring
Base；The substituted aroma ring is benzyl, 3- bromobenzyl, 3- chlorobenzyl or 3- methoxy-benzyl.
More preferably, the synthetic route of synthetic method are as follows:
I.e. by known compound 5-OHi by the acylation reaction of N, nucleophilic substitution and etc., synthesize whole production
Object I.
More preferably, the general structure of 1, the 5- disubstituted indole derivative is as follows:
Wherein, R1It is cyano, one of 1- hydroxyethyl or acetoxyl group are that is, o-, m-, to (R1 substituent group is in benzene
Three kinds of different locations of ring)；NR2R3For N, N- dimethylamino or four is one of to hexa-member heterocycle；N=1-4.
More preferably, described four to hexa-member heterocycle be nafoxidine ring group, tetrahydro-thiazoles ring group, morpholine ring group or piperidine ring
Base.
More preferably, the synthetic route of synthetic method are as follows:
I.e. by known compound 5-OHi by the acylation reaction of N, nucleophilic displacement of fluorine, the reaction such as reduction has synthesized end
Product II and II '.
More preferably, the structural formula of 1, the 5- disubstituted indole derivative are as follows:
1,5- disubstituted indole derivative as described above with leukotriene A 4 hydrolase inhibiting effect can be applied
Inhibit in terms of leukotriene A 4 hydrolase.
1,5- disubstituted indole derivative as described above with leukotriene A 4 hydrolase inhibiting effect can be applied
In anti-tumor aspect.
Specifically, the related specific structure of the present invention 1,5- disubstituted indole derivative and synthetic method related embodiment be such as
Under:
The synthesis of embodiment 1:5- hydroxyl -1- tert-butyl ester base -1H- indoles (a):
5g (37.5mmol) 5-OHi is dissolved in 50ml MeCN, lower addition 21ml (91.4mmol) is stirred at room temperature
Di-tert-butyl dicarbonate and 0.46g (3.7mmol) DMAP react 10 minutes raw material end of reaction under room temperature, are spin-dried for solvent, add
The dissolution of 100ml methanol, adds 15g (108.5mmol) potassium carbonate, after being stirred at room temperature 4 hours, adjusts pH with glacial acetic acid and arrives
7 or so, then it is diluted with water system.It is extracted with EA, organic phase is washed with saturated sodium-chloride, and anhydrous sodium sulfate is dry, is depressurized dense
Contracting, mixes sample column chromatography, and PE/EA=30:1 obtains white solid 7.95g, yield 90%.
1H NMR(400MHz,DMSO-d6) δ 1.61 (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).
The synthesis of embodiment 2:5- (2- chloroethoxy) -1- tert-butyl ester base -1H- indoles (b):
2g (8.6mmol) 5- hydroxyl -1- tert-butyl ester base -1H- indoles (a) is dissolved in 5ml DMF, 3.56g is added
(25.8mmol) potassium carbonate is stirred at room temperature 10 minutes, the bromo- 2- chloroethanes of 14.3ml (172mmol) 1- is then added, in
After being stirred 10 hours at 100 DEG C, it is diluted with water, DCM extraction, saturated sodium-chloride washing, anhydrous sodium sulfate is dry, it is concentrated under reduced pressure,
Sample column chromatography is mixed, PE/EA=200:1 obtains white solid 1.3g, yield 52%.
1H NMR(400MHz,DMSO-d6) δ 1.61 (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)
The synthesis of embodiment 3:5- (2- (1- pyrrolidines) ethyoxyl) -1- tert-butyl ester base -1H- indoles (c-1):
2g (6.8mmol) 5- (2- chloroethoxy) -1- tert-butyl ester base -1H- indoles (b) is dissolved in 5ml DMF, is added
2.8g (20.4mmol) potassium carbonate stirs 10 minutes under room temperature, and 0.56g (3.4mmol) potassium iodide and 1.67ml is added
(20.4mmol) pyrrolidines is stirred 9 hours at 100 DEG C, is diluted with water, DCM extraction, saturated sodium-chloride washing, anhydrous slufuric acid
Sodium is dry, is concentrated under reduced pressure, and mixes sample column chromatography, and DCM/MeOH=400:1 obtains grease 1.81g, yield 82%.
1H NMR(400MHz,DMSO-d6)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)
The synthesis of embodiment 4:5- (2- (1- piperidines) ethyoxyl) -1- tert-butyl ester base -1H- indoles (c-2):
Operating process only replaces pyrrolidines, yield 98% with piperidines with embodiment 3.
1H NMR(400MHz,DMSO-d6) δ 1.38 (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).
The synthesis of embodiment 5:5- (2- (1- tetrahydro-thiazoles) ethyoxyl) -1- tert-butyl ester base -1H- indoles (c-3):
Operating process only replaces pyrrolidines, yield 36% with tetrahydro-thiazoles with embodiment 3.
1H NMR(400MHz,DMSO-d6) δ 1.61 (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)
The synthesis of embodiment 6:5- (2- (1- morpholine) ethyoxyl) -1- tert-butyl ester base -1H- indoles (c-4):
Operating process only replaces pyrrolidines, yield 97% with morpholino with embodiment 3.
1H NMR(400MHz,DMSO-d6) δ 1.60 (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)
The synthesis of embodiment 7:5- (2- (1- pyrrolidines) ethyoxyl) -1H- indoles (d-1):
1.8g (5.5mmol) 5- (2- (1- pyrrolidines) ethyoxyl) -1- tert-butyl ester base -1H- indoles (c-1) is dissolved in
MeOH, THF and H2In O, 4.57g (110mmol) LiOH.H is added2O is stirred 72 hours at room temperature, is spin-dried for solvent, adds water dilute
It releases, DCM extraction, saturated sodium-chloride washing, anhydrous sodium sulfate is dry, is concentrated under reduced pressure, and mixes sample column chromatography, and DCM/MeOH=20:1 is obtained
To grease 1.19g, yield 95%.
1H NMR(400MHz,DMSO-d6) δ 1.64-1.67 (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)
The synthesis of embodiment 8:5- (2- (1- piperidines) ethyoxyl) -1H- indoles (d-2):
Operating method is replaced with embodiment 7 with 5- (2- (1- piperidines) ethyoxyl) -1- tert-butyl ester base -1H- indoles (c-2)
5- (2- (1- pyrrolidines) ethyoxyl) -1- tert-butyl ester base -1H- indoles (c-1), obtains solid, yield 85%.
1H NMR(400MHz,DMSO-d6) δ 1.39 (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)
The synthesis of embodiment 9:5- (2- (1- tetrahydro-thiazoles) ethyoxyl) -1H- indoles (d-3):
Operating method is with embodiment 7, with 5- (2- (1- tetrahydro-thiazoles) ethyoxyl) -1- tert-butyl ester base -1H- indoles (c-3)
Instead of 5- (2- (1- pyrrolidines) ethyoxyl) -1- tert-butyl ester base -1H- indoles (c-1), yield 85%.
1H NMR(400MHz,DMSO-d6) δ 2.68 (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)
The synthesis of embodiment 10:5- (2- (1- morpholine) ethyoxyl) -1H- indoles (d-4):
Operating method is replaced with embodiment 7 with 5- (2- (1- morpholine) ethyoxyl) -1- tert-butyl ester base -1H- indoles (c-4)
5- (2- (1- pyrrolidines) ethyoxyl) -1- tert-butyl ester base -1H- indoles (c-1), yield 80%.
1H NMR(400MHz,DMSO-d6) δ 2.46-2.50 (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)
The synthesis of embodiment 11:5- (2- (1- pyrrolidines) ethyoxyl) -1- benzyl -1H- indoles (TM1):
0.47g (2mmol) 5- (2- (1- pyrroles) ethyoxyl) -1H- indoles (d-1) 2ml DMF is dissolved, is added
0.49g (20mmol) NaH is stirred 30 minutes at 0 DEG C, and 0.36ml (3mmol) cylite is added, and is added 0.51g (3mmol)
KI is stirred 6 hours at room temperature, and ice water is quenched, and DCM extraction, saturated sodium-chloride washing, anhydrous sodium sulfate is dry, is concentrated under reduced pressure,
Sample column chromatography is mixed, DCM/MeOH=10:1 obtains grease 0.33g, yield 51%.
1H NMR(400MHz,DMSO-d6) δ 1.67-1.70 (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)
The synthesis of embodiment 12:5- (2- (1- piperidines) ethyoxyl) -1- benzyl -1H- indoles (TM 2):
Operating method replaces 5- (2- (1- pyrrole with embodiment 11, with 5- (2- (1- piperidines) ethyoxyl) -1H- indoles (d-2)
Cough up alkane) ethyoxyl) -1H- indoles (d-1), yield 90%.
1H NMR(400MHz,DMSO-d6) δ 1.39 (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)
The synthesis of embodiment 13:5- (2- (1- tetrahydro-thiazoles) ethyoxyl) -1- benzyl -1H- indoles (TM 3):
Operating method replaces 5- (2- with embodiment 11, with 5- (2- (1- tetrahydro-thiazoles) ethyoxyl) -1H- indoles (d-3)
(1- pyrrolidines) ethyoxyl) -1H- indoles (d-1), yield 36%.
1H NMR(400MHz,CDCl3) δ 2.91 (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)
The synthesis of embodiment 14:5- (2- (1- morpholine) ethyoxyl) -1- benzyl -1H- indoles (TM 4):
Operating method replaces 5- (2- (1- pyrrole with embodiment 11, with 5- (2- (1- morpholine) ethyoxyl) -1H- indoles (d-4)
Cough up alkane) ethyoxyl) -1H- indoles (d-1), yield 64%.
1H NMR(400MHz,DMSO-d6) δ 2.47 (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)
The synthesis of embodiment 15:5- (2- (1- pyrrolidines) ethyoxyl) -1- (3- chlorobenzyl) -1H- indoles (TM 5):
Operating method replaces cylite, yield 64% with embodiment 11, with 3- chlorine cylite.
1H NMR(400MHz,CDCl3) δ 1.87 (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).
The synthesis of embodiment 16:5- (2- (1- pyrrolidines) ethyoxyl) -1- (3- bromobenzyl) -1H- indoles (TM 6):
Operating method replaces cylite, yield 29% with embodiment 11, with 3- bromine cylite.
1H NMR(400MHz,DMSO-d6) δ 1.67-1.70 (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)
The synthesis of embodiment 17:5- (2- (1- pyrrolidines) ethyoxyl) -1- (3- methoxy-benzyl) -1H- indoles (TM 7):
Operating method replaces cylite, yield 71% with embodiment 11, with 3- methoxyl group cylite.
1H NMR(400MHz,DMSO-d6) δ 1.67-1.70 (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)
The synthesis of embodiment 18:5- (2- (1- piperidines) ethyoxyl) -1- (3- chlorobenzyl) -1H- indoles (TM 8):
Operating method replaces 5- (2- (1- pyrrole with embodiment 11, with 5- (2- (1- piperidines) ethyoxyl) -1H- indoles (d-2)
Cough up alkane) ethyoxyl) -1H- indoles (d-1), cylite, yield 57% are replaced with 3- chlorine cylite.
1H NMR(400MHz,DMSO-d6) δ 1.37 (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)
The synthesis of embodiment 19:5- (2- (1- piperidines) ethyoxyl) -1- (3- bromobenzyl) -1H- indoles (TM 9):
Operating method replaces 5- (2- (1- pyrrole with embodiment 11, with 5- (2- (1- piperidines) ethyoxyl) -1H- indoles (d-2)
Cough up alkane) ethyoxyl) -1H- indoles (d-1), cylite, yield 34% are replaced with 3- bromine cylite.
1H NMR(400MHz,DMSO-d6) δ 1.38 (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)
The synthesis of embodiment 20:5- (2- (1- piperidines) ethyoxyl) -1- (3- methoxy-benzyl) -1H- indoles (TM10):
Operating method replaces 5- (2- (1- pyrrole with embodiment 11, with 5- (2- (1- piperidines) ethyoxyl) -1H- indoles (d-2)
Cough up alkane) ethyoxyl) -1H- indoles (d-1), cylite, yield 13% are replaced with 3- methoxyl group cylite.
1H NMR(400MHz,DMSO-d6) δ 1.53 (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)
The synthesis of embodiment 21:5- (2- (1- tetrahydro-thiazoles) ethyoxyl) -1- (3- chlorobenzyl) -1H- indoles (TM11):
Operating method replaces 5- (2- with embodiment 11, with 5- (2- (1- tetrahydro-thiazoles) ethyoxyl) -1H- indoles (d-3)
(1- pyrrolidines) ethyoxyl) -1H- indoles (d-1), cylite, yield 65% are replaced with 3- chlorine cylite.
1H NMR(400MHz,DMSO-d6) δ 2.68 (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)
The synthesis of embodiment 22:5- (2- (1- tetrahydro-thiazoles) ethyoxyl) -1- (3- bromobenzyl) -1H- indoles (TM12):
Operating method replaces 5- (2- with embodiment 11, with 5- (2- (1- tetrahydro-thiazoles) ethyoxyl) -1H- indoles (d-3)
(1- pyrrolidines) ethyoxyl) -1H- indoles (d-1), cylite, yield 80% are replaced with 3- bromine cylite.
1H NMR(400MHz,DMSO-d6) δ 2.68 (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)
The conjunction of embodiment 23:5- (2- (1- tetrahydro-thiazoles) ethyoxyl) -1- (3- methoxy-benzyl) -1H- indoles (TM13)
At:
Operating method replaces 5- (2- with embodiment 11, with 5- (2- (1- tetrahydro-thiazoles) ethyoxyl) -1H- indoles (d-3)
(1- pyrrolidines) ethyoxyl) -1H- indoles (d-1), cylite, yield 76% are replaced with 3- methoxyl group cylite.
1H NMR(400MHz,DMSO-d6) δ 2.68 (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)
The synthesis of embodiment 24:5- (2- (1- morpholine) ethyoxyl) -1- (3- chlorobenzyl) -1H- indoles (TM14):
Operating method replaces 5- (2- (1- pyrrole with embodiment 11, with 5- (2- (1- morpholine) ethyoxyl) -1H- indoles (d-4)
Cough up alkane) ethyoxyl) -1H- indoles (d-1), cylite, yield 82% are replaced with 3- chlorine cylite.
1H NMR(400MHz,DMSO-d6) δ 2.47 (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)
The synthesis of embodiment 25:5- (2- (1- morpholine) ethyoxyl) -1- (3- bromobenzyl) -1H- indoles (TM15):
Operating method replaces 5- (2- (1- pyrrole with embodiment 11, with 5- (2- (1- morpholine) ethyoxyl) -1H- indoles (d-4)
Cough up alkane) ethyoxyl) -1H- indoles (d-1), cylite, yield 73% are replaced with 3- bromine cylite.
1H NMR(400MHz,DMSO-d6) δ 2.47 (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)
The synthesis of embodiment 26:5- (2- (1- morpholine) ethyoxyl) -1- (3- methoxy-benzyl) -1H- indoles (TM16):
Operating method replaces 5- (2- (1- pyrrole with embodiment 11, with 5- (2- (1- morpholine) ethyoxyl) -1H- indoles (d-4)
Cough up alkane) ethyoxyl) -1H- indoles (d-1), cylite, yield 54% are replaced with 3- methoxyl group cylite.
1H NMR(400MHz,DMSO-d6) δ 2.47 (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)
The synthesis of embodiment 27:5- (4- acetoxyl group phenoxy group) -1- tert-butyl ester base -1H- indoles (e-1):
100mg (0.4mmol) 5- hydroxyl -1- tert-butyl ester base -1H- indoles (a) 1ml DMF is dissolved, 0.5ml is added
(4mmol) to fluoro acetophenone and 0.96g (0.8mmol) potassium tert-butoxide, stir 7 hours, be diluted with water at 100 DEG C, EA extraction
It taking, saturated sodium-chloride washing, anhydrous sodium sulfate is dry, is concentrated under reduced pressure, and mixes sample column chromatography, and PE:EA=150:1 obtains grease,
Yield 46%.
1H NMR(400MHz,DMSO-d6) δ 1.64 (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)
The synthesis of embodiment 28:5- (2- acetoxyl group phenoxy group) -1- tert-butyl ester base -1H- indoles (e-2):
Operating method is replaced with 2- fluoro acetophenone to fluoro acetophenone, yield 38% with embodiment 27.
1H NMR(400MHz,DMSO-d6) δ 1.63 (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)
The synthesis of embodiment 29:5- (4- cyano-benzene oxygen) -1- tert-butyl ester base -1H- indoles (e-3):
Operating method is replaced with to fluorobenzonitrile to fluoro acetophenone, yield 74% with embodiment 27.
1H NMR(400MHz,DMSO-d6) δ 1.63 (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)
The synthesis of embodiment 30:5- (2- cyano-benzene oxygen) -1- tert-butyl ester base -1H- indoles (e-4):
Operating method is replaced with 2- fluorobenzonitrile to fluoro acetophenone, yield 85% with embodiment 27.
1H NMR(400MHz,DMSO-d6) δ 1.63 (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).
The synthesis of embodiment 31:5- (4- acetoxyl group phenoxy group) -1H- indoles (f-1):
0.72g (2.1mmol) 5- (4- acetoxyl group phenoxy group) -1- tert-butyl ester base -1H- indoles (e-1) is dissolved in
MeOH, THF and H2In O, 1.76g (42mmol) LiOH.H is added2O is stirred 2 hours at room temperature, is spin-dried for solvent, is diluted with water,
DCM extraction, saturated sodium-chloride washing, anhydrous sodium sulfate is dry, is concentrated under reduced pressure, and mixes sample column chromatography, and PE/EA=10:1 obtains white
Solid 0.41g, yield 80%.
1H NMR(400MHz,DMSO-d6) δ 2.51 (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)
The synthesis of embodiment 32:5- (2- acetoxyl group phenoxy group) -1H- indoles (f-2):
Operating method is replaced with embodiment 31 with 5- (2- acetoxyl group phenoxy group) -1- tert-butyl ester base -1H- indoles (e-2)
5- (4- acetoxyl group phenoxy group) -1- tert-butyl ester base -1H- indoles (e-1), yield 97%.
1H NMR(400MHz,DMSO-d6) δ 2.63 (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)
The synthesis of embodiment 33:5- (4- cyano-benzene oxygen) -1H- indoles (f-3):
Operating method replaces 5- with embodiment 31, with 5- (4- cyanophenoxy) -1- tert-butyl ester base -1H- indoles (e-3)
(4- acetoxyl group phenoxy group) -1- tert-butyl ester base -1H- indoles (e-1), yield 74%.
1H NMR(400MHz,DMSO-d6) δ 6.44 (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)
The synthesis of embodiment 34:5- (2- cyano-benzene oxygen) -1H- indoles (f-4):
Operating method replaces 5- with embodiment 31, with 5- (2- cyanophenoxy) -1- tert-butyl ester base -1H- indoles (e-4)
(4- acetoxyl group phenoxy group) -1- tert-butyl ester base -1H- indoles (e-1), yield 85%.
1H NMR(400MHz,DMSO-d6) δ 6.45 (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).
The conjunction of embodiment 35:5- (4- acetoxyl group phenoxy group) -1- [2- (dimethylamino) ethyl)] -1H- indoles (TM17)
At:
0.2g (0.8mmol) 5- (4- acetoxyl group phenoxy group) -1H- indoles (f-1) 5ml DMF is dissolved, is added
0.2g (8mmol) NaH after stirring 30 minutes at 0 DEG C, is added 0.2g (1.6mmol) dimethylamino chloroethene heptane hydrochloride, is added
0.2g (1.2mmol) KI, after stirring 6 hours at room temperature, ice water is quenched, EA extraction, saturated sodium-chloride washing, anhydrous sodium sulfate
It is dry, it is concentrated under reduced pressure, mixes sample column chromatography, DCM/MeOH=150:1 obtains grease 0.18g, yield 69%.1H NMR
(400MHz,DMSO-d6) δ 2.18 (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)
Embodiment 36:5- [4- (1- hydroxyethyl) phenoxy group] -1- [2- (dimethylamino) ethyl)] -1H- indoles (TM18)
Synthesis:
By 0.26g (0.8mmol) 5- (4- acetoxyl group phenoxy group) -1- [2- (dimethylamino) ethyl)] -1H- indoles
(TM17) it is dissolved with 3ml ethyl alcohol, is added with stirring 0.18g (4.8mmol) sodium borohydride, after stirring 15 minutes at room temperature, ice
Water quenching reaction, decompression are spin-dried for solvent, and EA extraction, saturated sodium-chloride washing, anhydrous sodium sulfate is dry, is concentrated under reduced pressure, mixes sample column
Chromatography, DCM/MeOH=50:1 obtain grease 0.24g, yield 92%.
1H NMR(400MHz,DMSO-d6) δ 1.30 (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)
The synthesis of embodiment 37:5- (4- cyano-benzene oxygen) -1- [2- (dimethylamino) ethyl)] -1H- indoles (TM19):
Operating method replaces 5- (4- acetyloxy phenyl with embodiment 35, with 5- (4- cyano-benzene oxygen) -1H- indoles (f-3)
Oxygroup) -1H- indoles (f-1), yield 70%.
1H NMR(400MHz,DMSO-d6) δ 2.19 (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)
Embodiment 38:5- (2- acetoxyl group phenoxy group) -1- [2- (dimethylamino) ethyl)] -1H- indoles (TM 20)
Synthesis:
Operating method replaces 5- (4- acetyl oxygen with embodiment 35, with 5- (2- acetoxyl group phenoxy group) -1H- indoles (f-2)
Phenoxyl) -1H- indoles (f-1), yield 95%.
1H NMR(400MHz,DMSO-d6) δ 2.19 (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)
Embodiment 39:5- [2- (1- hydroxyethyl) phenoxy group] -1- [2- (dimethylamino) ethyl)] -1H- indoles (TM
21) synthesis:
Operating method is with embodiment 36, with 5- (2- acetoxyl group phenoxy group) -1- [2- (dimethylamino) ethyl)] -1H- Yin
Diindyl (TM20) replaces 5- (4- acetoxyl group phenoxy group) -1- [2- (dimethylamino) ethyl)] -1H- indoles (TM17), yield
57%.
1H NMR(400MHz,DMSO-d6) δ 1.36 (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)
The synthesis of embodiment 40:5- (2- cyano-benzene oxygen) -1- [2- (dimethylamino) ethyl)] -1H- indoles (TM 22):
Operating method replaces 5- (4- acetyloxy phenyl with embodiment 35, with 5- (2- cyano-benzene oxygen) -1H- indoles (f-4)
Oxygroup) -1H- indoles (f-1), yield 33%.
1H NMR(400MHz,DMSO-d6) δ 2.19 (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).
The synthesis of embodiment 41:5- (4- cyano-benzene oxygen) -1- [2- (morpholine) ethyl)] -1H- indoles (TM 23):
Operating method replaces 5- (4- acetyloxy phenyl with embodiment 35, with 5- (4- cyano-benzene oxygen) -1H- indoles (f-3)
Oxygroup) -1H- indoles (f-1), replaces dimethylamino chloroethene heptane hydrochloride, yield 34% with N- (2- chloroethyl) morpholino.
1H NMR(400MHz,DMSO-d6) δ 2.44 (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)
The synthesis of embodiment 42:5- (4- cyano-benzene oxygen) -1- [2- (nafoxidine) ethyl)] -1H- indoles (TM 24):
Operating method replaces 5- (4- acetyloxy phenyl with embodiment 35, with 5- (4- cyano-benzene oxygen) -1H- indoles (f-3)
Oxygroup) -1H- indoles (f-1), dimethylamino chloroethene heptane hydrochloride, yield 75% are replaced with N- (2- chloroethyl) pyrrolidines.
1H NMR(400MHz,DMSO-d6) δ 1.64-1.68 (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).
The synthesis of embodiment 43:5- (2- cyano-benzene oxygen) -1- [2- (nafoxidine) ethyl)] -1H- indoles (TM 25):
Operating method replaces 5- (4- acetyloxy phenyl with embodiment 35, with 5- (2- cyano-benzene oxygen) -1H- indoles (f-4)
Oxygroup) -1H- indoles (f-1), dimethylamino chloroethene heptane hydrochloride, yield 46% are replaced with N- (2- chloroethyl) pyrrolidines.
1H NMR(400MHz,DMSO-d6) δ 1.65-1.67 (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)
The synthesis of embodiment 44:5- (2- cyano-benzene oxygen) -1- [2- (morpholine) ethyl)] -1H- indoles (TM 26):
Operating method replaces 5- (4- acetyloxy phenyl with embodiment 35, with 5- (2- cyano-benzene oxygen) -1H- indoles (f-4)
Oxygroup) -1H- indoles (f-1), replaces dimethylamino chloroethene heptane hydrochloride, yield 50% with N- (2- chloroethyl) morpholino.
1H NMR(400MHz,DMSO-d6) δ 2.43 (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)
Coherent detection of the invention:
1, active testing:
LTA has been carried out to part of compounds 17-224The measurement of the inhibitory activity of H.
Compound inhibits LTA4Using DMSO as negative control in the experiment of H hydrolytic enzyme activities, to have listed LTA4H inhibitor
Bestatin is as positive control.Compound concentration is arranged to 0.1 μM, 1 μM, 10 μM, 100 μM of four concentration gradients simultaneously,
Use LTB4Detection kit detects LTA4H acts on LTA4When LTB4Production quantity, with compound group LTB4Production quantity relative to
DMSO group LTB4The percentage of production quantity measures compound group to LTA4The inhibitory effect of H hydrolyzing activity, and finally calculate phase
Corresponding IC50。
1 compound of table inhibits hydrolytic enzyme activities to test IC50
IC50 for Compound Inhibition of Hydrolase Activity Test
It the results are shown in Table 1, from table 1 it follows that this 6 compounds all show lower IC50It is worth, wherein compound
17,19,22 be even more to have relatively low IC50, illustrate these three compounds to LTA4There is H hydrolase preferable inhibition to make
With, the results showed that this kind of indole derivatives have preferable inhibition LTA4The effect of H hydrolase.
2, compound inhibits LTA4The detection of H aminopeptidase activity
Compound inhibits LTA4Using DMSO as negative control in the experiment of H aminopeptidase activity, to have listed LTA4H inhibitor
Bestatin is as positive control.Compound concentration is arranged to 0.1 μM, 1 μM, 10 μM, 100 μM of four concentration gradients inspections simultaneously
Survey LTA4H acts on the amount of the free paranitroanilinum of l-Alanine paranitroanilinum generation, and with compound group eachization
The production quantity for closing paranitroanilinum under object concentration measures compound relative to the percentage of DMSO group paranitroanilinum production quantity
Group is to LTA4The inhibitory effect of H aminopeptidase activity.
2 l-Alanine of table-paranitroanilinum substrate method evaluates aminopeptidase activity
Evaluation of aminopeptidase activity by L-alanine-p-nitroaniline
substrate method
It the results are shown in Table 2, although from Table 2, it can be seen that the IC that 6 compound aminopeptidases inhibit50Not as good as reference material
Bestatin, but be also that all there is lower IC50Value is obtained in combination with the activity data of inhibition hydrolase, in the present invention
Compound have certain inhibition LTA4The effect of H.
Although disclosing the embodiment of the present invention for the purpose of illustration, it will be appreciated by those skilled in the art that: not
Be detached from the present invention and spirit and scope of the appended claims in, various substitutions, changes and modifications be all it is possible, therefore, this
The range of invention is not limited to the embodiment and attached drawing disclosure of that.
Claims (10)
1. a kind of 1,5- disubstituted indole derivative with leukotriene A 4 hydrolase inhibiting effect, it is characterised in that: described 1,
5- disubstituted indole derivative has the function of being able to suppress leukotriene A 4 hydrolase.
2. 1, the 5- disubstituted indole derivative according to claim 1 with leukotriene A 4 hydrolase inhibiting effect,
Be characterized in that: the general structure of 1, the 5- disubstituted indole derivative is as follows:
Wherein, R2R1N is one of four to hexa-member heterocycle；R3For one of substituted aroma ring；N=1-4.
3. 1, the 5- disubstituted indole derivative according to claim 2 with leukotriene A 4 hydrolase inhibiting effect,
Be characterized in that: described four to hexa-member heterocycle be nafoxidine ring group, tetrahydro-thiazoles ring group, morpholine ring group or piperidines ring group；It is described
Substituted aroma ring is benzyl, 3- bromobenzyl, 3- chlorobenzyl or 3- methoxy-benzyl.
4. 1, the 5- disubstituted indole derivative according to claim 2 or 3 with leukotriene A 4 hydrolase inhibiting effect,
It is characterized by: the synthetic route of its synthetic method are as follows:
5. 1, the 5- disubstituted indole derivative according to claim 1 with leukotriene A 4 hydrolase inhibiting effect,
Be characterized in that: the general structure of 1, the 5- disubstituted indole derivative is as follows:
Wherein, R1It is cyano, one of 1- hydroxyethyl or acetoxyl group are that is, o-, m-, right；NR2R3For N, N- diformazan ammonia
Base or four is one of to hexa-member heterocycle；N=1-4.
6. 1, the 5- disubstituted indole derivative according to claim 5 with leukotriene A 4 hydrolase inhibiting effect,
Be characterized in that: described four to hexa-member heterocycle be nafoxidine ring group, tetrahydro-thiazoles ring group, morpholine ring group or piperidines ring group.
7. 1, the 5- disubstituted indole derivative according to claim 5 or 6 with leukotriene A 4 hydrolase inhibiting effect,
It is characterized by: the synthetic route of its synthetic method are as follows:
8. 1, the 5- disubstituted indole derivative according to claim 1 with leukotriene A 4 hydrolase inhibiting effect,
It is characterized in that: the structural formula of 1, the 5- disubstituted indole derivative are as follows:
9. 1, the 5- disubstituted indole as claimed in any one of claims 1 to 8 with leukotriene A 4 hydrolase inhibiting effect spreads out
Biology in terms of inhibit leukotriene A 4 hydrolase in application.
10. 1, the 5- disubstituted indole as claimed in any one of claims 1 to 8 with leukotriene A 4 hydrolase inhibiting effect spreads out
Application of the biology in anti-tumor aspect.
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