CN106986874B - (1H- pyrazoles [3,4-d] pyrimidine) -4- aminoderivative and its purposes as IDO inhibitor in medicine preparation - Google Patents
(1H- pyrazoles [3,4-d] pyrimidine) -4- aminoderivative and its purposes as IDO inhibitor in medicine preparation Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The invention discloses a kind of (1H- pyrazoles [3,4-d] pyrimidine) -4- aminoderivatives, also disclose the preparation method of the compound and the purposes as 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 1H- pyrazoles [3,4-d] pyrimidines) -4- aminoderivative, further relate to preparation method and as IDO
The purposes of inhibitor.
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 (1H- invention broadly provides a kind of novel IDO inhibitor class drug
Pyrazoles [3,4-d] pyrimidine) -4- aminoderivative is the substitution on ammonia nitrogen.
The present invention provides a kind of compound or its pharmaceutically acceptable salt or its solvate, the compound
Shown in structure such as formula (I):
Wherein, R1Selected from H, halogen or C1~C4Alkyl；
R2Selected from substituted or non-substituted aryl, naphthenic base, heteroaryl or heterocycle, the substituted aryl, cycloalkanes
Base, heteroaryl or heterocycle are separately by one or more selected from-(CH2)mCOOH, halogen, hydroxyl, amino, nitro, alkane
Replaced the substituent group of base；
N=1,2 or 3；
M=0,1,2 or 3.
Further, the R2Selected from phenyl or substituted phenyl, the substituted phenyl by one or more selected from-
(CH2)mCOOH, halogen, hydroxyl, amino, nitro, alkyl substituent group replaced；M=0 or 1.
Further, the R2Selected from one of following radicals:
Further, R1Selected from H or methyl.
Further, the structure of the compound is as follows:
The present invention also provides a kind of methods for preparing the formula (I) compound, comprising the following steps:
It is raw material with compound 9 and compound 10, is dissolved in organic solvent, it is anti-in the presence of inert gas environment and alkali
It answers, purifying obtains formula (I) compound.
As a kind of specific embodiment, when reaction, compound 9 is slightly excessive.Compound 9 can be according to of the invention specific real
The method synthesis applied in mode can also be synthesized according to method in the prior art.
Further, the alkali is selected from organic base or inorganic base, and the organic base is selected from triethylamine or pyridine, described inorganic
Alkali selects sodium bicarbonate, sodium carbonate or sodium hydroxide.
Further, the organic solvent is selected from dimethylformamide, tetrahydrofuran, ethyl acetate, acetone or dichloromethane
Alkane.
For example, above compound 1a, 1b, 1c and 1d are prepared by following routes in specific embodiment of the present invention
It obtains:
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 that the compound or its pharmaceutically acceptable salt are to live
Property ingredient, 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
C of the present invention1~C4Alkyl refer to the alkyl of the linear chain or branched chain with 1~4 carbon atom, including first
Base, ethyl, propyl, isopropyl, butyl, isobutyl group, tert-butyl, sec-butyl etc..
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 pyrido [3, the 4-b] indole derivatives of 9- substitution provided by the invention are to IDO with excellent
Inhibiting effect, can be used for preventing and/or treating a variety of diseases, as Alzheimer disease, cataract, cellular immunity activate phase
Infection, autoimmune disease, AIDS, cancer, depression or tryptophan metabolism exception of pass etc..
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
Raw materials and reagents are that analysis is pure: raw materials used to be purchased from Chengdu Rui Ouke Science and Technology Ltd., reagent is purchased from Chengdu
Ke Long Reagent Company.
The synthesis of intermediate 6- methyl-1 H- pyrazoles [3,4-d] pyrimidine -4 (7H) -one (8b) of the present invention of embodiment 1
Synthetic route is as follows:
Glacial acetic acid (6mL) and polyphosphoric acids is added in compound (7) (CAS:5334-31-6,1.0g, 7.94mmol)
In the mixed solution of (6mL), reacted 7 hours at 120 DEG C.Reaction solution is cooled to room temperature, and is poured into 70mL water, with 50%
It is 5 that NaOH aqueous solution, which adjusts pH, there is white solid precipitation, is filtered, and filter cake is rinsed with a large amount of water.Filter cake is suspended in methyl alcohol,
Stirring 10 minutes, filtering, filter cake are washed with 50mL ethyl acetate.Filter cake reduced vacuum it is dry white solid 887.5mg, yield
76%.
The preparation of 2 the compounds of this invention 1a of embodiment
Synthetic route is as follows:
8a (CAS:315-30-0) can directly be bought.
1, the synthesis of compound 9a
Compound 8a (0.5g, 3.68mmol) is protected into lower instillation thionyl chloride (15ml) and DMF (1.5mL) in argon gas,
80 DEG C of back flow reactions are warming up to after being added dropwise 2 hours.Reaction solution is cooled to room temperature, and is poured slowly into the 150mL ice being vigorously stirred
In water, three times with the extraction of 100mL ethyl acetate, merges organic phase, washed with saturated common salt, anhydrous magnesium sulfate is dry, is spin-dried for
Yellow powder 9a 367mg, yield 64%.
2, the synthesis of compound 1a
Compound 9a (0.32mmol) and compound 10a (40.6mg, 0.27mmol) are dissolved in DMF (1.5mL), are added
Triethylamine (66.8 μ L, 0.484mmol) reacts 4 hours under argon gas protection in 80 DEG C.Solvent to the greatest extent is revolved in decompression, and 8mL is added in residue
Ethyl acetate, three times with 4mL water washing.Organic phase is dry through anhydrous magnesium sulfate, was spin-dried for column (DCM:MeOH=10:1), and obtained light
Yellow solid 31.1mg, yield 43%.
3- ((1H- pyrazoles [3,4-d] pyrimidine -4- amino) methyl) benzoic acid (1a)1H-NMR(400MHz,d6-DMSO,
ppm):δ13.44(br,2H,COOH and pyrazole NH),8.81(m,1H,amino),8.23(s,1H,
), pyrimidine-CH 8.17 (s, 1H, pyrazole-CH), 7.94 (s, 1H, Ar-H2), 7.83 (d, 1H, J=7.6Hz, Ar-
), H6 7.46 (d, 1H, J=7.6Hz, Ar-H4), 7.46 (t, 1H, J=7.6Hz, Ar-H5), 4.80 (d, 2H, J=6.0Hz,
benzyl-CH2).ESI-MS:270.09[M+H].
The preparation of 3 the compounds of this invention 1b of embodiment
Compound 1b is synthesized according to method similar in embodiment 2, difference is to obtain with compound 9b alternative compounds 9a
Yellow solid 1b, yield 41%.
4- ((1H- pyrazoles [3,4-d] pyrimidine -4- amino) methyl) benzoic acid (1b)1H-NMR(400MHz,d6-DMSO,
ppm):δ14.50(s,1H,br,COOH),13.41(s,1H,pyrazole NH),8.79(m,1H,amino),8.23(s,1H,
Pyrimidine CH), 8.17 (s, 1H, pyrazole CH), 7.91 (d, 2H, J=7.6Hz, Ar-H2 and Ar-H6),
7.46 (d, 2H, J=7.6Hz, Ar-H3 and Ar-H5), 4.82 (d, 2H, J=5.2Hz, benzyl-CH2).ESI-MS:
270.09[M+H].
The preparation of 4 the compounds of this invention 1c of embodiment
Compound 1c is synthesized according to similar method in embodiment 2, difference is with compound 9b alternative compounds 9a, with
Compound 10b alternative compounds 10a, obtains yellow solid 1c, yield 36%
3- ((6- methyl 1H- pyrazoles [3,4-d] pyrimidine -4- amino) methyl) benzoic acid (1c)1H-NMR(400MHz,d6-
DMSO, ppm): δ 14.58 (s, 1H, pyrazole-NH), 12.92 (br, 1H, COOH), 11.43 (t, 1H, J=6.0Hz,
), amino 8.52 (s, 1H, pyrazole-CH), 8.02 (s, 1H, Ar-H2), 7.98 (d, 1H, J=7.6Hz, Ar-H6), 7.56
(d, 1H, J=7.6Hz, Ar-H4), 7.50 (t, 1H, J=7.6Hz, Ar-H5), 5.02 (d, 2H, J=6.0Hz, benzyl-
CH2),2.33(s,1H,CH3).ESI-MS:284.11[M+H].
The preparation of 5 the compounds of this invention 1d-k of embodiment
Compound 1d is synthesized according to similar method in embodiment 2, difference is with compound 9b alternative compounds 9a, with
Compound 10b alternative compounds 10a, obtains yellow solid 1d, yield 39%.
4- ((6- methyl-1 H- pyrazoles [3,4-d] pyrimidine -4- amino) methyl) benzoic acid (1d)1H-NMR(400MHz,d6-
DMSO, ppm): δ 14.74 (s, 1H, pyrazole-NH), 12.94 (br, 1H, COOH), 11.39 (t, 1H, J=6.0Hz,
), amino 8.55 (s, 1H, pyrazole-CH), 7.93 (d, 2H, J=8.3Hz, Ar-H2 and Ar-H6), 7.46 (d, 2H, J
=8.3Hz, Ar-H3 and Ar-H5), 5.08 (d, 2H, J=6.0Hz, benzyl-CH2),2.34(s,1H,CH3).ESI-MS:
284.11[M+H].
Corresponding raw material is selected, compound 1e-k is prepared in a similar way, as a result and is characterized as below:
Yellow solid, yield 41%.1H-NMR(400MHz,d6-DMSO,ppm):δ13.52(s,1H,pyrazole NH),
8.64(m,1H,amino),8.17(s,1H,pyrimidine CH),8.11(s,1H,pyrazole CH),7.45-6.67(m,
5H, Ar-H), 4.12 (d, 2H, J=5.2Hz, benzyl-CH2).ESI-MS:226.09[M+H].
Yellow solid, yield 49%.1H-NMR(400MHz,d6-DMSO,ppm):δ13.52(s,1H,pyrazole NH),
8.64(m,1H,amino),8.19(s,1H,pyrimidine CH),8.12(s,1H,pyrazole CH),7.45(d,2H,J
=7.6Hz, Ar-H2 and Ar-H6), 7.12 (d, 2H, J=7.6Hz, Ar-H3 and Ar-H5), 4.01 (d, 2H, J=
5.2Hz,benzyl-CH2),2.33(s,3H,CH3).ESI-MS:240.12[M+H].
Yellow solid, yield 46%.1H-NMR(400MHz,d6-DMSO,ppm):δ13.44(s,1H,pyrazole NH),
8.80(m,1H,amino),8.25(s,1H,pyrimidine CH),8.19(s,1H,pyrazole CH),7.98(d,2H,J
=7.6Hz, Ar-H2 and Ar-H6), 7.42 (d, 2H, J=7.6Hz, Ar-H3 and Ar-H5), 4.85 (d, 2H, J=
5.2Hz,benzyl-CH2).ESI-MS:260.06[M+H].
Yellow solid, yield 52%.1H-NMR(400MHz,d6-DMSO,ppm):δ13.52(s,1H,pyrazole NH),
8.45(m,1H,amino),8.07(s,1H,pyrimidine CH),8.01(s,1H,pyrazole CH),7.23(d,2H,J
=7.6Hz, Ar-H2 and Ar-H6), 7.07 (d, 2H, J=7.6Hz, Ar-H3 and Ar-H5), 4.03 (d, 2H, J=
5.2Hz,benzyl-CH2).ESI-MS:242.12[M+H].
Yellow solid, yield 55%.1H-NMR(400MHz,d6-DMSO,ppm):δ14.59(s,1H,pyrazole-NH),
12.93 (br, 1H, COOH), 11.41 (t, 1H, J=6.0Hz, amino), 8.51 (s, 1H, pyrazole-CH), 8.00 (s,
1H, Ar-H2), 7.87 (d, 1H, J=7.6Hz, Ar-H6), 7.34 (d, 1H, J=7.6Hz, Ar-H5), 4,98 (d, 2H, J=
6.0Hz,benzyl-CH2).ESI-MS:286.10[M+H].
Yellow solid, yield 46%.1H-NMR(400MHz,d6-DMSO,ppm):δ14.74(s,1H,pyrazole-NH),
12.94 (br, 1H, COOH), 11.23 (t, 1H, J=6.0Hz, amino), 8.51 (s, 1H, pyrazole-CH), 7.86 (d,
2H, J=8.3Hz, Ar-H2 and Ar-H6), 7.23 (d, 2H, J=8.3Hz, Ar-H3 and Ar-H5), 4.89 (d, 2H, J
=6.0Hz, CH2NH),3.68(s,2H,CH2COOH),2.34(s,1H,CH3).ESI-MS:298.11[M+H].
Yellow solid, yield 41%.1H-NMR(400MHz,d6-DMSO,ppm):δ14.51(s,1H,pyrazole-NH),
12.93 (br, 1H, COOH), 11.41 (t, 1H, J=6.0Hz, amino), 8.53 (s, 1H, pyrazole-CH), 8.02 (s,
1H, Ar-H2), 7.95 (d, 1H, J=7.6Hz, Ar-H6), 7.52 (d, 1H, J=7.6Hz, Ar-H4), 7.54 (t, 1H, J=
7.6Hz,Ar-H5),4.23(m,2H,CH2),2.94(m,2H,CH2).ESI-MS:284.11[M+H].
Inhibitory activity of 6 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 30%, B and indicates that inhibiting rate 20%-30%, C indicate that inhibiting rate is 10%-20%；D
Indicate that inhibiting rate is 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
The results show that the compound of the present invention has certain inhibitory activity to IDO.Wherein R2It is selected fromWhen, effect is preferable.
In conclusion (1H- pyrazoles [3,4-d] pyrimidine) -4- aminoderivative provided by the invention, has IDO excellent
Inhibiting effect, can be used for preventing and/or treating a variety of diseases, as Alzheimer disease, cataract, cellular immunity activate phase
Infection, autoimmune disease, AIDS, cancer, depression or tryptophan metabolism exception of pass etc..
Claims (8)
1. a kind of compound or its pharmaceutically acceptable salt, the structure of the compound are as follows:
2. the method for preparing compound described in claim 1, it is characterised in that: the following steps are included:
It is raw material with compound 9 and compound 10, is dissolved in organic solvent, is reacted in the presence of inert gas environment and alkali,
Purifying obtains compound described in claim 1；
Wherein, compound 9 isCompound 10 is
3. according to the method described in claim 2, it is characterized by: the alkali is selected from organic base or inorganic base, the organic base
Selected from triethylamine or pyridine, the inorganic base selection sodium bicarbonate, sodium carbonate or sodium hydroxide.
4. according to the method in claim 2 or 3, it is characterised in that: the organic solvent is selected from dimethylformamide, tetrahydro
Furans, ethyl acetate, acetone or methylene chloride.
5. according to the method described in claim 2, it is characterized by: the temperature of the reaction is 25 DEG C -100 DEG C.
6. the purposes of compound described in claim 1 or its pharmaceutically acceptable salt on preparation IDO inhibitor class drug.
7. purposes according to claim 6, it is characterised in that: the drug be prevention and/or treatment Alzheimer disease,
Cataract, cellular immunity activate relevant infection, autoimmune disease, AIDS, depression or tryptophan metabolism exception
Drug.
8. 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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| CN102746306A (en) * | 2012-07-09 | 2012-10-24 | 四川国康药业有限公司 | Allopurinol derivative and preparation method and application thereof |
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