CN107118209B - Pyridine a pair of horses going side by side [3,4-b] indoles carbamide compounds and its purposes as IDO inhibitor - Google Patents
Pyridine a pair of horses going side by side [3,4-b] indoles carbamide compounds and its purposes as IDO inhibitor Download PDFInfo
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
The invention discloses parallel [3,4-b] the indoles carbamide compounds of pyridine, specifically substituted in the position 9- of parallel [3, the 4-b] indoles of pyridine, and connecting bridge is ureas structure.The invention also discloses the preparation method of the compound and as the purposes of IDO inhibitor.The compound of the present invention can be used for preventing and/or treating a variety of diseases, such as Alzheimer disease, cataract, cellular immunity activate relevant infection, autoimmune disease, AIDS, cancer, depression or tryptophan metabolism abnormal.
Description
Technical field
The present invention relates to parallel [3,4-b] the indoles carbamide compounds of pyridine, further relate to preparation method and as IDO inhibitor
Purposes.
Background technique
Indoleamine 2,3-dioxygenase (Indoleamine 2,3-dioxygenase, IDO) is the indoles such as catalysis tryptophan
Indole ring oxicracking in amine molecule makes it by the rate-limiting enzyme of kynurenine approach catabolism.
IDO plays an important role in tumour immunity exemption and tumour generating process.Under normal circumstances, IDO is in vivo
Low expression level, and the high expression IDO that most of tumour cells can then form, convert N- formyl dog urinary ammonia for L-Trp
Acid reduces the Tryptophan concentration in cell micro-environment, so that the T cell synthesis that tryptophan relies on was stagnated in the G1 phase, T cell increases
It grows and is suppressed, to inhibit body immune system to the lethal effect of tumor tissues.Meanwhile IDO acts on lower tryptophan
There are cytotoxicities for metabolite, can generate direct dissolution to T cell.
Therefore, inhibit the activity of IDO that can effectively prevent the degradation of near tumor cells tryptophan, promote T cell
Proliferation, to enhance body to the attacking ability of tumour cell.Also, IDO inhibitor can also be shared with chemotherapeutics, be reduced
The drug resistance of tumour cell, to enhance the anti-tumor activity of conventional cytotoxic therapy.Taking IDO inhibitor simultaneously also can be improved
The curative effect of the therapeutic vaccine of cancer patient.
In addition to being played an important role in terms of tumor cell drug resistance, IDO also to it is a variety of related with cellular immunity activation
Disease pathogenesis it is closely related.IDO have been found be infection relevant to cellular immunity activation, malignant tumour, itself
The target of the major diseases such as immunity disease, AIDS.Meanwhile inhibiting IDO still for the nervous system disease such as depression
Disease, the critical treatment strategy of the patient of Alzheimer disease.Therefore, IDO inhibitor has wide potential applicability in clinical practice.
Summary of the invention
To solve the above problems, they are pyridines invention broadly provides a kind of novel IDO inhibitor class drug
Parallel [3,4-b] indoles carbamide compounds.It is specifically substituted in the position 9- of parallel [3, the 4-b] indoles of pyridine, and connecting bridge is ureas
Structure.
The present invention provides a kind of compound or its pharmaceutically acceptable salt or its solvate, the knots of the compound
Shown in structure such as formula (I):
A indicate without orOn ring adjacent-OH and-COOH replace orOne on ring
Or multiple substituent groups；The substituent group is selected from halogen, alkyl, alkoxy, ester group ,-OH ,-COOH ,-SO3H or-SO2NH2；
X indicates carbon or nitrogen；
N indicates 0 or 1.
In specifically a kind of specific embodiment of the invention, when X is selected from nitrogen,For 3- pyridyl group.
Further, A indicate without orOn ring adjacent-OH and-COOH replace orRing
On one or more substituent groups；The substituent group is selected from-COOH or ester group-COOR, R are selected from the alkyl of C1~4.
Further, the quantity of the substituent group is 1 or 2.
Further, it is characterised in that: n is selected from 0.
Further, it is characterised in that: A is indicatedOn at least one-COOH replace.
Further, the structure of the compound is such as one of flowering structure:
The present invention also provides a kind of methods of compound shown in preparation formula (I), it is characterised in that: includes the following steps:
(1)
Compound 2 is prepared using (tertbutyloxycarbonyl) ethylaminoethanol and paratoluensulfonyl chloride as raw material；
(2)
It is that compound 3 is prepared in raw material with compound 1 and compound 2, the blocking group sloughed on amino obtains chemical combination
Object 4；
(3)
Compound 5-ic is prepared using compound 5 and Triphosgene as raw material；N=0 or 1；
(4)
Compound shown in formula (I) is prepared using compound 4 and compound 5-ic as raw material；
Wherein, when the group that A is indicated includes-COOH structure, the raw material 5 used in step (3) is its ester-formin, and
And further include the steps that hydrolyzing the ester group after step (4).
In some specific embodiments of the present invention, A is selected from-COOR.The ester type compound of final product can be used as
When A is selected from-COOH, respective compound prepares intermediate, such as compound can be used as of 6bEt, 6cEt, 6gEt, 6hEt
That closes object 6b, 6c, 6g and 6h prepares intermediate, and further by the ester hydrolysis technological means of this field routine, ester hydrolysis is anti-
It should be prepared.In another example being compound 6d in invention specific embodiment when A indicates adjacent hydroxyl and carboxyl
And 6e, the starting material of step (3) are its lactone form.
The present invention also provides the compounds or its pharmaceutically acceptable salt or its prodrug or its solvate to exist
Prepare the purposes on IDO inhibitor class drug.
Further, the drug is prevention and/or treatment Alzheimer disease, cataract, cellular immunity activation correlation
Infection, autoimmune disease, AIDS, cancer, depression or tryptophan metabolism exception drug.
The present invention also provides a kind of pharmaceutical compositions, it is to be with the compound or its pharmaceutically acceptable salt
Active constituent, in addition the preparation that pharmaceutically acceptable auxiliary material is prepared.
Wherein, the composition is to treat or prevent and/or treat Alzheimer disease, cataract, cellular immunity activation
Relevant infection, autoimmune disease, AIDS, cancer, depression or tryptophan metabolism exception drug
The prodrug is the derivative of aforesaid compound, and their own may have weaker activity or even without work
Property, but upon administration, (such as passing through metabolism, solvolysis or other mode) is converted to accordingly in physiological conditions
Biologically active form.
The preparation may include injection or oral preparation.
Key intermediate and compound in the present invention are separated and are purified, and used mode is normal in organic chemistry
Isolation and purification method.
One or more compounds of the invention can be used in conjunction with one another, and also be may be selected the compound of the present invention and appointed
What other active agent is used in combination, and is used to prepare IDO inhibitor.It, can be by these if using one group of compound
Compound simultaneously, respectively or is in an orderly manner administered study subject.
Pharmaceutically acceptable auxiliary material of the present invention refers in addition to the active ingredient (s include substance in dosage form.
Tests prove that parallel [3,4-b] the indoles carbamide compounds of pyridine provided by the invention have excellent inhibition to IDO
Effect, can be used for preventing and/or treating a variety of diseases, as Alzheimer disease, cataract, cellular immunity activate relevant sense
Dye, autoimmune disease, AIDS, cancer, depression or tryptophan metabolism exception etc..
In the present invention, the connotation of english abbreviation is as follows:
Ts: p-toluenesulfonyl.
Boc: tert- butoxy carbonyl.
Obviously, above content according to the present invention is not being departed from according to the ordinary technical knowledge and customary means of this field
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
The specific embodiment of form by the following examples remakes further specifically above content of the invention
It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to example below.It is all to be based on above content of the present invention
The technology realized all belongs to the scope of the present invention.
Specific embodiment
The reagent and raw material are all from commercially available commodity, in addition to the starting material for being specially labelled with source, remaining reagent
It is purchased from Chengdu Ke Long chemical reagents corporation.
The preparation of 1 the compounds of this invention key intermediate of embodiment
1, the synthesis of (1- (tert- butoxy carbonyl) amino) ethyl alcohol-(4- toluenesulfonic acid) ester (2)
To buy in Rui Ouke science and technology CAS is 26690-80-2；Product number is raw material (the tertiary fourth oxygen of R0K11845-2
Carbonyl) ethylaminoethanol (5.00g, 31.06mmol) and TsCl (11.88g, 62.12mmol) be dissolved in 20mL pyridine, and room temperature is stirred
Reaction 12h is mixed, TLC detects fully reacting.
Vacuum distillation removes a part of pyridine, adds water, is extracted with ethyl acetate 3 times, and organic layer is dried over magnesium sulfate, is concentrated
Crude product purifies to obtain compound as white solid 2 (4.89g, yield through silica gel column chromatography (petroleum ether: ethyl acetate=3:1) afterwards
50%).
2, the synthesis of t-butoxy (2- (9H- pyrido [3,4-b] indoles -9- base) ethyl) carbamate (3)
It is 244-63-3 by lark prestige CAS；The raw material compound 1 (0.50g, 2.98mmol) that product number is 230515
It sets in a round bottom flask with 60%NaH (0.24g, 5.96mmol), then is dissolved with 10mLDMF, after 45 DEG C of stirring 2h, then will
Compound 2 (2.81g, 8.94mmol) is added in above-mentioned reaction solution, 16h is stirred at room temperature, it is complete that TLC detects raw material fundamental reaction.
Add water, be extracted with ethyl acetate 3 times, organic layer is dried over magnesium sulfate, after concentration crude product through silica gel column chromatography
(CH2Cl2:CH3OH=30:1 faint yellow solid compound 3 (0.74g, yield 77%)) is purified to obtain.
Compound 3:1H NMR(400MHz,CDCl3): δ (ppm) 8.92 (s, 1H), 8.49 (d, J=5.2Hz, 1H), 8.17
(d, J=7.8Hz, 1H), 7.98 (dd, J=5.2Hz, 0.8Hz, 1H), 7.62 (t, J=7.2Hz, 1H), 7.55 (d, J=
8.3Hz, 1H), 7.33 (t, J=7.8Hz, 1H), 4.65 (s, br, 1H), 4.59 (t, J=5.7Hz, 2H), 3.62 (q, J=
6.0Hz,2H),1.45(s,9H).
3, the synthesis of 2- (9H- pyrido [3,4-b] indoles -9- base) ethyl -1- amino (4)
First use the CH of 10mL2Cl2Compound 3 (0.21g, 0.66mmol) is dissolved, 1.60mL tri- is added under stirring at room temperature
Fluoroacetic acid, after reacting 5h, TLC detects raw material fully reacting.
Vacuum distillation removes solvent, with saturation NaHCO3Being adjusted to pH is 8, and ethyl acetate extracts 3 times, and organic layer is through magnesium sulfate
Faint yellow solid compound 4 (0.12g, yield 86%) is obtained after dry, concentration.
The synthesis of 2 1- of embodiment (2- (9H- pyrido [3,4-b] indoles -9- base) ethyl) -3- phenylurea (6a)
15mLCH is dissolved in by aniline 5a (0.02mL, 2.19mmol)2Cl2NaHCO is saturated with 15mL3The mixing of aqueous solution
It in solvent, is added with stirring at 0 DEG C Triphosgene (0.22g, 0.72mmol), TCL is shown completely after equality of temperature is stirred to react 15min
Reaction.
Reaction solution is poured into separatory funnel, collected organic layer, it is dry, it is concentrated to give phenylisocyanate crude product, it is not purified
It directly throws in next step.
Phenylisocyanate (0.02g, 0.15mmol) and compound 4 (0.03g, 0.14mmol) are dissolved in 4mLCH2Cl2,
It is placed in 0 DEG C and is stirred to react TCL after 10h and show complete reaction.
Reaction solution is directly spin-dried for obtaining crude product, crude product chromatographs (CH through column2Cl2:CH3OH=15:1 white solid) is purified to obtain
Powder 6a (0.05g, yield 98%).
Compound 6a: purity is 99% through HPLC test；1H NMR(400MHz,CDCl3):δ(ppm)8.81(s,1H),
8.25 (d, J=5.2Hz, 1H), 8.12 (d, J=7.8Hz, 1H), 7.86 (d, J=5.2Hz, 1H), 7.62-7.55 (m, 2H),
7.33-7.29 (m, 2H), 7.20 (t, J=8.0Hz, 2H), 7.09 (d, J=7.6Hz, 2H), 7.01 (t, J=6.0Hz, 2H),
5.26 (t, J=5.8Hz, 1H), 4.55 (t, J=5.8Hz, 2H), 3.65 (q, J=5.8Hz, 2H)13C NMR(400MHz,
DMSO-d6):δ(ppm)156.0,141.5,140.7,138.5,136.8,132.8,129.1,128.9,127.9,122.5,
121.7,120.8,120.1,118.4,115.1,110.6,43.1,39.0.ESI-MS m/z:331.15[M+H]。
3 1- of embodiment (2- (9H- pyrido [3,4-b] indoles -9- base) ethyl) -3- (3- carbethoxyl group)-phenylurea
The synthesis of (6bEt) and 1- (2- (9H- pyrido [3,4-b] indoles -9- base) ethyl) -3- (3- carboxyl)-phenylurea (6b)
3- aminobenzoic acid (0.04g, 0.27mmol) is dissolved with 3mL ethyl alcohol, 0 DEG C is added with stirring thionyl chloride
(0.05mL, 0.68mmol) is warmed to room temperature and is stirred to react 7h, and TCL shows complete reaction.
Solvent is removed in rotation, with saturation NaHCO3PH to 7~8 is adjusted, ethyl acetate extracts 3 times, with saturated common salt water washing, does
Dry, concentration obtains light yellow oil 3- benzocaine (0.04g, yield 84%).
According to the method for embodiment 2, aniline is replaced with 3- benzocaine 5b, compound 1- (2- (9H- pyridine is made
And [3,4-b] indoles -9- base) ethyl) -3- (3- carbethoxyl group)-phenylurea 6bEt, white solid (0.09g, yield 98%).
With 5mL water and 5mL ethyl alcohol by 1- (2- (9H- pyrido [3,4-b] indoles -9- base) ethyl) -3- (3- ethoxy carbonyl
Base)-phenylurea (0.08g, 0.21mmol) and NaOH (0.03g, 0.63mmol) dissolution, 100 DEG C of reaction 2h are warming up to, TLC is examined
Survey raw material fully reacting.
Reaction solution is cooled to room temperature later, vacuum distillation removes solvent, adds water, has when pH being adjusted to 6~7 with dilute HCl
White solid be precipitated, filtering, vacuum oven it is dry white solid 6b (0.07g, yield 90%).
Compound 6bEt: purity is 99% through HPLC test；1H NMR(400MHz,DMSO-d6):δ(ppm)12.80(s,
Br, 1H), 9.07 (s, 1H), 8.78 (s, 1H), 8.38 (d, J=5.2Hz, 1H), 8.28 (d, J=7.8Hz, 1H), 8.13 (d, J
=5.2Hz, 1H), 8.03 (s, 1H), 7.75 (d, J=8.4Hz, 1H), 7.63-7.56 (m, 2H), 7.49 (d, J=7.8Hz,
1H), 7.36-7.27 (m, 2H), 6.31 (t, J=6.0Hz, 1H), 4.61 (t, J=6.0Hz, 2H), 4.44 (q, J=6.8Hz,
2H), 3.55 (q, J=6.0Hz, 2H), 1.20 (t, J=6.8Hz, 3H)
Compound 6b: purity is 99% through HPLC test；1H NMR(400MHz,DMSO-d6):δ(ppm)12.80(s,br,
1H), 9.07 (s, 1H), 8.78 (s, 1H), 8.38 (d, J=5.2Hz, 1H), 8.28 (d, J=7.8Hz, 1H), 8.13 (d, J=
5.2Hz, 1H), 8.03 (s, 1H), 7.75 (d, J=8.4Hz, 1H), 7.63-7.56 (m, 2H), 7.49 (d, J=7.8Hz, 1H),
7.36-7.27 (m, 2H), 6.31 (t, J=6.0Hz, 1H), 4.61 (t, J=6.0Hz, 2H), 3.55 (q, J=6.0Hz, 2H)
.13C NMR(400MHz,DMSO-d6):δ(ppm)168.2,155.9,141.3,141.0,138.9,136.8,133.1,
132.2,129.2,128.8,127.7,122.5,122.4,122.3,120.9,120.0,119.0,115.0,110.5,43.0,
39.0.ESI-MS m/z:375.14[M+H]。
4 1- of embodiment (2- (9H- pyrido [3,4-b] indoles -9- base) ethyl) -3- (4- carbethoxyl group)-phenylurea
The synthesis of (6cEt) and 1- (2- (9H- pyrido [3,4-b] indoles -9- base) ethyl) -3- (4- carboxyl)-phenylurea (6c)
According to the method for embodiment 3,3- Aminobenzoate 5b is substituted with 4-aminobenzoic acid ethyl ester 5c.
Obtain compound 1- (2- (9H- pyrido [3,4-b] indoles -9- base) ethyl) -3- (4- carbethoxyl group)-phenylurea
6cEt, white solid (0.10g, total recovery 92%).
Compound 1- (2- (9H- pyrido [3,4-b] indoles -9- base) ethyl) -3- (4- carboxyl)-phenylurea 6c, it is white
Color solid (0.09g, four step yields 90%).
Compound 6cEt: purity is 99% through HPLC test；1H NMR(400MHz,DMSO-d6):δ(ppm)9.07(s,
1H), 8.95 (s, 1H), 8.38 (s, 1H), 8.27 (d, J=7.2Hz, 1H), 8.14 (s, 1H), 7.81 (d, J=7.6Hz, 2H),
7.74 (d, J=7.6Hz, 1H), 7.61 (t, J=6.0Hz, 1H), 7.46 (d, J=7.6Hz, 2H), 7.29 (t, J=6.0Hz,
1H), 6.43 (s, 1H), 4.62 (t, J=6.0Hz, 2H), 4.44 (q, J=6.8Hz, 2H), 3.55 (q, J=6.0Hz, 2H),
1.20 (t, J=6.8Hz, 3H)
Compound 6c: purity is 99% through HPLC test；1H NMR(400MHz,DMSO-d6):δ(ppm)9.07(s,1H),
8.95 (s, 1H), 8.38 (s, 1H), 8.27 (d, J=7.2Hz, 1H), 8.14 (s, 1H), 7.81 (d, J=7.6Hz, 2H), 7.74
(d, J=7.6Hz, 1H), 7.61 (t, J=6.0Hz, 1H), 7.46 (d, J=7.6Hz, 2H), 7.29 (t, J=6.0Hz, 1H),
6.43 (s, 1H), 4.62 (t, J=6.0Hz, 2H), 3.55 (q, J=6.0Hz, 2H)13C NMR(400MHz,DMSO-d6):δ
(ppm)167.6,155.6,145.1,141.4,138.7,137.0,132.9,130.9,128.8,127.8,123.4,122.4,
120.9,120.0,117.3,115.1,110.5,43.0,39.0.ESI-MS m/z:375.14[M+H]。
5 1- of embodiment (2- (9H- pyrido [3,4-b] indoles -9- base) ethyl) -3- (3- hydroxyl -4- carboxyl)-phenyl
The synthesis of urea (6d)
According to the method for embodiment 2, with 6- amino -2,2- dimethyl -4- oxygen -4H- benzo [1,3] dioxin -4- ketone 5d
(being made by WO2006125805 method) substitution aniline 5a, obtains compound 1- (2- (9H- pyrido [3,4-b] indoles -9- base) second
Base) -3- (2,2- dimethyl -4- oxygen -4H- benzo [1,3] dioxin -7- base) urea (0.05g, total recovery 98%).
By 1- (2- (9H- pyrido [3,4-b] indoles -9- base) ethyl) -3- (2,2- dimethyl -4- oxygen -4H- benzo [1,
3] dioxin -7- base) urea (0.05g, 0.12mmol) is dissolved in 1mL tetrahydrofuran, be added 1mL KOH (0.03g,
0.6mmol) aqueous solution is stirred at reflux overnight.
It is cooled to room temperature, it is 1 that reaction solution, which is acidified to pH, and ethyl acetate extracts 3 times, merges organic layer, through saturated salt solution
Washing, it is dry, it is concentrated to give white solid 6d (0.04g, yield 90%)
Compound 6d: purity is 99% through HPLC test；1H NMR(400MHz,DMSO-d6):δ(ppm)12.50(br,
1H), 9.07 (s, 1H), 8.95 (s, 1H), 8.38 (s, 1H), 8.27 (d, J=7.2Hz, 1H), 8.18 (s, 1H), 7.89 (s,
1H), 7.77 (d, J=7.6Hz, 1H), 7.61 (t, J=6.0Hz, 1H), 7.49 (d, J=7.6Hz, 2H), 7.29 (t, J=
6.0Hz, 1H), 6.43 (s, 1H), 4.62 (t, J=6.0Hz, 2H), 3.55 (q, J=6.0Hz, 2H) .ESI-MS m/z:
389.13[M-H]。
6 1- of embodiment (2- (9H- pyrido [3,4-b] indoles -9- base) ethyl) -3- (3- carboxyl -4- hydroxyl)-phenyl
The synthesis of urea (6e)
1- (2- (9H- pyrido [3,4-b] Yin is obtained with compound 5e alternative compounds 5d according to the method for embodiment 5
Diindyl -9- base) ethyl) -3- (3- carboxyl -4- hydroxyl)-phenylurea 6e white solid (0.05g, total recovery 98%).
Compound 6e: purity is 99% through HPLC test；1H NMR(400MHz,DMSO-d6):δ(ppm)12.50(br,
1H), 9.07 (s, 1H), 8.95 (s, 1H), 8.38 (s, 1H), 8.27 (d, J=7.2Hz, 1H), 8.18 (s, 1H), 7.85 (s,
1H), 7.73 (d, J=7.6Hz, 1H), 7.64 (t, J=6.0Hz, 1H), 7.52 (d, J=7.6Hz, 2H), 7.23 (t, J=
6.0Hz, 1H), 6.43 (s, 1H), 4.62 (t, J=6.0Hz, 2H), 3.55 (q, J=6.0Hz, 2H) .ESI-MS m/z:
389.13[M-H]。
The synthesis of 7 1- of embodiment (2- (9H- pyrido [3,4-b] indoles -9- base) ethyl) -3- benzyl urea (6f)
According to the method for embodiment 2, aniline 5a is substituted with benzylamine 5f, obtains 1- (2- (9H- pyrido [3,4-b] indoles -9-
Base) ethyl) -3- benzyl urea 6f white solid (0.06g, total recovery 92%).
Compound 6f: purity is 99% through HPLC test；1H NMR(400MHz,DMSO-d6):δ(ppm)9.05(s,1H),
8.41 (d, J=5.2Hz, 1H), 8.27 (d, J=7.8Hz, 1H), 8.15 (d, J=5.2Hz, 1H), 7.81 (s, 1H), 7.80
(d, J=7.0Hz, 1H), 7.64 (d, J=8.3Hz, 1H), 7.52 (t, J=7.6Hz, 1H), 7.40-7.42 (m, 2H), 7.23
(t, J=7.6Hz, 1H), 6.51 (t, J=5.8Hz, 1H), 6.13 (t, J=5.6Hz, 1H), 4.51 (t, J=6.0Hz, 2H),
4.20 (d, J=5.8Hz, 2H), 3.41 (q, J=6.0Hz, 2H)13C NMR(400MHz,DMSO-d6):δ(ppm)158.6,
141.9,141.5,138.7,136.7,133.0,132.0,131.2,128.9,128.8,128.3,128.0,127.8,
122.4,120.8,119.9,115.0,110.6,43.4,43.0.ESI-MS m/z:345.15[M+H]。
8 1- of embodiment (2- (9H- pyrido [3,4-b] indoles -9- base) ethyl) -3- (3- carbethoxyl group)-benzyl urea
(6gEt) 1- (2- (9H- pyrido [3,4-b] indoles -9- base) ethyl) -3- (3- carboxyl)-benzyl urea (6g) synthesis
According to the method for embodiment 3,3- carboxyanilino (i.e. 3- aminobenzoic acid) is substituted with 3- carboxyl benzylamine 5g.
Obtain compound 1- (2- (9H- pyrido [3,4-b] indoles -9- base) ethyl) -3- (4- carbethoxyl group)-phenylurea
6gEt white solid (0.07g, total recovery 91%).
It is white to obtain compound 1- (2- (9H- pyrido [3,4-b] indoles -9- base) ethyl) -3- (3- carboxyl)-benzyl urea 6g
Color solid (0.06g, total recovery 90%).
Compound 6gEt: purity is 99% through HPLC test；1H NMR(400MHz,DMSO-d6):δ(ppm)12.80(br,
1H), 9.06 (s, 1H), 8.40 (d, J=5.2Hz, 1H), 8.28 (d, J=7.8Hz, 1H), 8.16 (d, J=5.2Hz, 1H),
7.85 (s, 1H), 7.81 (d, J=7.0Hz, 1H), 7.70 (d, J=8.3Hz, 1H), 7.58 (t, J=7.6Hz, 1H), 7.46-
7.40 (m, 2H), 7.28 (t, J=7.6Hz, 1H), 6.56 (t, J=5.8Hz, 1H), 6.15 (t, J=5.6Hz, 1H), 4.54
(t, J=6.0Hz, 2H), 4.44 (q, J=6.8Hz, 2H), 4.25 (d, J=5.8Hz, 2H), 3.48 (q, J=6.0Hz, 2H),
1.20 (t, J=6.8Hz, 3H)
Compound 6g: purity is 99% through HPLC test；1H NMR(400MHz,DMSO-d6):δ(ppm)12.80(br,
1H), 9.06 (s, 1H), 8.40 (d, J=5.2Hz, 1H), 8.28 (d, J=7.8Hz, 1H), 8.16 (d, J=5.2Hz, 1H),
7.85 (s, 1H), 7.81 (d, J=7.0Hz, 1H), 7.70 (d, J=8.3Hz, 1H), 7.58 (t, J=7.6Hz, 1H), 7.46-
7.40 (m, 2H), 7.28 (t, J=7.6Hz, 1H), 6.56 (t, J=5.8Hz, 1H), 6.15 (t, J=5.6Hz, 1H), 4.54
(t, J=6.0Hz, 2H), 4.25 (d, J=5.8Hz, 2H), 3.48 (q, J=6.0Hz, 2H)13C NMR(400MHz,DMSO-
d6):δ(ppm)167.9,158.6,141.9,141.5,138.7,136.7,133.0,132.0,131.2,128.9,128.8,
128.3,128.0,127.8, 122.4,120.8,119.9,115.0,110.6,43.4,43.0.ESI-MS m/z:387.15
[M-H]。
9 1- of embodiment (2- (9H- pyrido [3,4-b] indoles -9- base) ethyl) -3- (4- carbethoxyl group)-benzyl urea
(6hEt) and 1- (2- (9H- pyrido [3,4-b] indoles -9- base) ethyl) -3- (4- carboxyl)-benzyl urea (6h) synthesis
According to the method for embodiment 4,4- carboxyanilino is substituted with 4- carboxyl benzylamine 5h.
Obtain compound 1- (2- (9H- pyrido [3,4-b] indoles -9- base) ethyl) -3- (4- carbethoxyl group)-benzyl urea
6hEt white solid (0.07g, total recovery 93%).
It is white to obtain compound 1- (2- (9H- pyrido [3,4-b] indoles -9- base) ethyl) -3- (4- carboxyl)-benzyl urea 6h
Color solid (0.06g, total recovery 90%).
Compound 6hEt: purity is 99% through HPLC test；1H NMR(400MHz,DMSO-d6):δ(ppm)12.80(s,
Br, 1H), 9.07 (s, 1H), 8.41 (d, J=5.2Hz, 1H), 8.28 (d, J=7.8Hz, 1H), 8.16 (d, J=5.2Hz,
1H), 7.88 (d, J=8.2Hz, 2H), 7.71 (d, J=8.3Hz, 1H), 7.59 (t, J=7.8Hz, 1H), 7.31-7.28 (m,
1H), 7.25 (d, J=8.2Hz, 2H), 6.52 (t, J=6.0Hz, 1H), 6.17 (t, J=6.0Hz, 2H), 4.55 (t, J=
6.0Hz, 2H), 4.44 (q, J=6.8Hz, 2H), 4.24 (t, J=6.0Hz, 2H), 3.50 (q, J=6.0Hz, 2H), 1.20 (t,
J=6.8Hz, 3H)
Compound 6h: purity is 99% through HPLC test；1H NMR(400MHz,DMSO-d6):δ(ppm)12.80(s,br,
1H), 9.07 (s, 1H), 8.41 (d, J=5.2Hz, 1H), 8.28 (d, J=7.8Hz, 1H), 8.16 (d, J=5.2Hz, 1H),
7.88 (d, J=8.2Hz, 2H), 7.71 (d, J=8.3Hz, 1H), 7.59 (t, J=7.8Hz, 1H), 7.31-7.28 (m, 1H),
7.25 (d, J=8.2Hz, 2H), 6.52 (t, J=6.0Hz, 1H), 6.17 (t, J=6.0Hz, 2H), 4.55 (t, J=6.0Hz,
2H), 4.24 (t, J=6.0Hz, 2H), 3.50 (q, J=6.0Hz, 2H)13C NMR(400MHz,DMSO-d6):δ(ppm)
167.7,158.6,146.6,141.5,138.5,136.8,132.9,129.8,129.5,128.8,127.9,127.3,
122.4,120.8,119.9,115.1,110.6,43.5,43.1.ESI-MS m/z:387.15[M-H]。
10 1- of embodiment (2- (9H- pyrido [3,4-b] indoles -9- base) ethyl) -3- (3- pyridine) methylurea (6j)
Synthesis
According to the method for embodiment 2, aniline is substituted with 3- aminomethyl-pyridine 5j, obtain compound 1- (2- (9H- pyrido [3,
4-b] indoles -9- base) ethyl) -3- (3- pyridine) methylurea 6j white solid (0.06g, yield 98%)
Compound 6j: purity is 98% through HPLC test；1H NMR(400MHz,CDCl3):δ(ppm)8.80(s,1H),
8.45 (d, J=5.2Hz, 1H), 8.39 (d, J=4.7Hz, 1H), 8.28 (d, J=1.7Hz, 1H), 8.14 (d, J=7.8Hz,
1H), 7.92 (d, J=5.2Hz, 1H), 7.52 (t, J=7.6Hz, 1H), 7.40-7.42 (m, 2H), 7.23 (t, J=7.6Hz,
1H), 7.46-7.43 (m, 2H), 7.38 (t, J=7.6Hz, 1H), 7.16 (q, J=7.7Hz, J=4.6Hz, 1H), 6.42 (s,
Br, 1H), 5.06 (s, 2H), 4.51 (t, J=6.0Hz, 2H), 3.41 (q, J=6.0Hz, 2H) .LC-MS m/z:346.16 [M+
H]。
Inhibitory activity of 11 the compounds of this invention of embodiment to IDO albumen
Recombined human IDO albumen through Bacillus coli expression, nickel affinity chromatographic purifying and obtain.Compound is real to IDO inhibitory activity
It tests using L-Trp as substrate.Untested compound is dissolved in 10%DMSO solution and is configured to dilution.Take 5uL dilution
It is added in 100 μ L reaction systems.Contain 0.5%DMSO, 40nmol/L IDO, 900 μm of ol/L L- in 100 μ L reaction systems
Tryptophan and other reactions concurrent (kaliumphosphate buffer, ascorbic acid, catalase, methylene blue).Reaction mixing
Object is cultivated 180 minutes under 37 degree, is added trichloroacetic acid and is terminated reaction.Existed using Tecan Infinite M1000 microplate reader
The concentration for the N- formoxyl kynurenin that measurement generates at 321nm, to evaluate compound to the inhibitory activity of IDO.It is negative right
It is that IDO is replaced with the buffer of 5 μ L according to object.The IDO inhibitor INCB024360 of clinical III phase is as positive control, and verifying is originally
Whether effective test the IDO Activity determination system established.
Each concentration sets up three wells.Data analysis is carried out using software Graphpad Prism.Be free of test compounds
In the reaction solution of object, absorbance (At) it is defined as 100% activity.In the reaction solution without IDO, absorbance (Ab) it is defined as 0%
Activity.For untested compound, active calculation formula are as follows: %activity=[(A-Ab)/(At-Ab)] × 100, wherein A be
The absorbance of reaction solution containing untested compound.The calculation formula of inhibiting rate are as follows: %inhibition=100-%activity.
By the above experimental method, the inhibitory activity that the part of compounds in the present invention is directed to IDO is tested.Specific portion
It closes inhibitory activity of the object under 1 μM, 10 μM, 100 μM of concentration and is shown in Table 1.
Wherein A indicates that inhibiting rate is greater than 80%, B and indicates that inhibiting rate is 20-80%, and C indicates that inhibiting rate is 10-19%；D table
Show inhibiting rate less than 10%；Inhibiting rate of the positive control when concentration is 0.05 μM is 46%.
Inhibitory activity of 1 the compounds of this invention of table to IDO
Pyridine [3,4-b] indoles carbamide compounds show the inhibitory activity different degrees of to IDO.When the fragrance on side chain
When ring non-polar group, activity is mostly relatively low；When the aromatic rings on side chain has carboxyl, hydroxyl replaces, activity is obviously increased；When
Aromatic rings on side chain be between carboxyl replace when (6b), obtain preferably activity, under 100 μM of concentration inhibiting rate be greater than 80%.Together
When, the result of 6i and 6j are also shown, when group aromatic rings or aromatic heterocycle on side chain, inhibitory activity is suitable.
Tests prove that parallel [3,4-b] the indoles carbamide compounds of pyridine provided by the invention have excellent inhibition to IDO
Effect, can be used for preventing and/or treating a variety of diseases, as Alzheimer disease, cataract, cellular immunity activate relevant sense
Dye, autoimmune disease, AIDS, cancer, depression or tryptophan metabolism exception etc..
Claims (5)
1. a kind of compound or its pharmaceutically acceptable salt, the structure of the compound are as follows:
2. a kind of method for preparing compound shown in claim 1, it is characterised in that: include the following steps:
(1)
Compound 2 is prepared using (tertbutyloxycarbonyl) ethylaminoethanol and paratoluensulfonyl chloride as raw material；
(2)
It is that compound 3 is prepared in raw material with compound 1 and compound 2, sloughs the blocking group on amino and obtain compound 4；
(3)
Compound 5-ic is prepared using compound 5 and Triphosgene as raw material；N=0；X is carbon；A be phenyl ring between carboxyl
Replace；
(4)
Compound shown in formula (I) is prepared using compound 4 and compound 5-ic as raw material；
Wherein, the raw material 5 used in step (3) is its ester-formin, also, further includes hydrolyzing the ester group after step (4)
Step.
3. the purposes of compound described in claim 1 or its pharmaceutically acceptable salt on preparation IDO inhibitor class drug.
4. purposes according to claim 3, it is characterised in that: the drug be prevention and/or treatment Alzheimer disease,
Cataract, cellular immunity activate relevant infection, autoimmune disease, AIDS, cancer, depression or tryptophan metabolism different
Normal drug.
5. a kind of pharmaceutical composition, it is characterised in that: it is with compound described in claim 1 or its is pharmaceutically acceptable
Salt is active constituent, in addition the preparation that pharmaceutically acceptable auxiliary material is prepared.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101932325A (en) * | 2007-11-30 | 2010-12-29 | 新联基因公司 | Ido inhibitors |
| CN105906531A (en) * | 2015-12-23 | 2016-08-31 | 嘉实（湖南）医药科技有限公司 | Preparation method of pimavanserin intermediate |
-
2016
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101932325A (en) * | 2007-11-30 | 2010-12-29 | 新联基因公司 | Ido inhibitors |
| CN105906531A (en) * | 2015-12-23 | 2016-08-31 | 嘉实（湖南）医药科技有限公司 | Preparation method of pimavanserin intermediate |
Non-Patent Citations (2)
| Title |
|---|
| 2-Pyridinyl-4(3H)-Quinazolinone: A Scaffold for Anti-influenza A Virus Compounds;Shixu Liu et al.;《Chem Biol Drug Des》;20151231;第86卷;第1221-1225页 |
| Potent aza-peptide derived inhibitors of HCV NS3 protease;Srikanth Venkatraman et al.;《Bioorganic & Medicinal Chemistry Letters》;20090617;第19卷;第4760–4763页 |
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