CN106146467A - Isoquinilone derivatives and its preparation method and application - Google Patents

Isoquinilone derivatives and its preparation method and application Download PDF

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CN106146467A
CN106146467A CN201610573019.4A CN201610573019A CN106146467A CN 106146467 A CN106146467 A CN 106146467A CN 201610573019 A CN201610573019 A CN 201610573019A CN 106146467 A CN106146467 A CN 106146467A
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卢学春
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Shanxi Kembs Sen Biotechnology Co Ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

The present invention relates to isoquinilone derivatives or its pharmaceutically acceptable salt that logical formula (I) represents, wherein Y represents carbonyl or sulfonyl.The invention still further relates to the preparation method of this compound, and the application in the medicine of preparation treatment NK/T cell malignancies.

Description

Isoquinilone derivatives and its preparation method and application
Technical field
The present invention relates to a kind of isoquinilone derivatives with treatment NK/T cell malignancies effect and salt thereof, and should The preparation method of isoquinilone derivatives.
Background technology
NKT/t cell lymphoma (NK/T cell lymphoma, NKTCL) belongs in non-Hodgkin lymphoma (NHL) relatively Rare hypotype, major part malignant cell derives from NK cell, but also has a little part to derive from expression EBV+、CD56-Thin Cytotoxic T cells.NKTCL is mainly in Asia and Latin America, accounts for T-cell non-Hodgkin's (T-NHL) in China 30.1%.Tying outer NKTCL common with young man clinically, its course advancement is very fast, insensitive to chemotherapy, late period poor prognosis. According to the literature, the complete remission rate of NKTCL is 44.8～56.0%, 5 years overall survivals (OS) 18～50%.NKTCL pathological changes is normal For limitation I phase or II phase, during first visit, mostly there is lymphatic metastasis.
The nose NK/T cell lymphoma of more than 90% has EBV to infect.In WHO classification (2008), nasal cavity NKTCL is defined as Upper respiratory tract is originated, and the outer NKTCL of nasal cavity is defined as the outer NKTCL of upper respiratory tract.The outer position of the modal primary knot of the latter includes Webster ring, skin, gastrointestinal tract, testis, kidney and soft tissue etc., China is most commonly seen with Webster ring.
By stages the most extremely important to selecting therapeutic regimen.Associating Radiotherapy chemotherapy is for Limited-stage (I phase or II phase) NKTCL has preferable curative effect；But for III/IV phase patient, either nasal cavity, it is also non-nasal cavity and invasive hypotype, Although high intensity chemotherapy is its primary treatments, but prognosis mala.Although Comprehensive Treatment can make the patient's prognosis of part NKTCL change Kind, but be not obviously prolonged total life cycle, the chemotherapy combined with radiotherapy of such as high intensity and the use of ASP are equal Patient can be made to be benefited.Although there being document to report, high-dose chemotherapy associating hematopoietic stem cell transplantation can also be as its recurrence for the treatment of A kind of means to save the situation in refractory late period, but Most patients inapplicable.Study novel, toxic and side effects is little and the controlling of determined curative effect Treat medicine, be the task of top priority of China's NK/T cell lymphoma (leukemia).
For early stage NKTCL patient, there is no the therapeutic scheme of standard, between different doctors, in terms of its treatment, have bigger difference Not.Therapeutic modality includes after chemotherapy, radiation alone, radiotherapy radiotherapy or Synchronous chemoradiotherapy after chemotherapy, chemotherapy.Existing evidence Showing, for early stage nasal cavity and Webster ring NKTCL, radiotherapy is essential therapeutic arsenals.The overall efficiency of radiation alone (ORR) being 77～100%, complete remission rate (CR) 52～100%, the patient that radiotherapy is invalid is less than 17%, and the overwhelming majority is less than 10%. But regrettably, a lot of patients mostly are late period when making a definite diagnosis, and early stage patient proportion is the least.
Late period, the treatment of NK/t cell lymphoma included following several respects: L-asparaginase, bortezomib chemotherapy, Hemopoietic Stem Cell Transplantation.
Although both at home and abroad current research finds, radiotherapy add the chemotherapy regimen of L-asparaginase (L-ASP) in early days and Late period, NKTCL demonstrated preferable curative effect, but all these research is small sample (multinomial research is all less than 50 examples), though closely Phase response rate increases, but Overall survival have no prolongation, and program toxic and side effects is serious, the patient of 72.3% can occur Serious leukopenia, the nearlyest 10% patient dies from treatment.Additionally, the patient by L-asparaginase chemotherapy may Anaphylaxis occur, even there is anaphylactic shock in severe patient.
Bortezomib is as first proteasome inhibitor being applied to clinic, by affecting various kinds of cell cycle regulating Albumen and NF-KB activation plays antitumor action.Recent research indicate that, combine bortezomib+CHOP Regimen Chemotherapy late stages of T cell Lymphoma or NKTCL Lymphoma, bortezomib maximum uses 1.6mg/m2, overall CR leads 61.5%, but NKTCL group It is 33.3% that OR leads, and is minimum in all subgroups.This research is only I phase clinical research, and the patient's number included in is less.
Use Hemopoietic Stem Cell Transplantation NKTCL at present still in exploratory stage, the case load that great majority research includes Seldom.Additionally, due to patient is heterogeneous, test into group standard, most preferably transplant opportunity, pretreating scheme, derived from hematopoietic precursor cells Etc. the difference of situation, hematopoietic stem cell transplantation curative effect in NKTCL treats is difficult to evaluate.
In a word, the most not yet there is the NKTCL Therapeutic Method of standard.For nose type NKTCL in early days, it is intended to local is put Treat, non-anthracyclines chemotherapy can be combined；Can be with some newer chemotherapy regimens to late period or patients with recurrent.But how to enter One step improves the curative effect of NKTCL, remains an important problem.
Summary of the invention
It is an object of the invention to provide a kind of isoquinilone derivatives, and the preparation method of this derivant.Prepared by the present invention Isoquinilone derivatives have treatment NK/T cell malignancies effect.
The invention provides a kind of isoquinilone derivatives represented by following logical formula (I) or its pharmaceutically acceptable salt:
Wherein:
Y represents carbonyl or sulfonyl；
R represents C1-C4Alkyl；C1-C10Alkyl-carbonyl；Aryl；N, O or S heteroaryl；The substituted cycloalkyl of N, O or S；Or cycloalkanes The substituted C of base1-C4Alkyl.
Specifically, described R can be expressed as the saturated alkyls such as methyl, ethyl, isopropyl, the tert-butyl group, or hexamethylene The alkyl of the cycloalkyl substituted such as ylmethyl, Pentamethylene. base ethyl；Formoxyl, acetyl group, propiono, butyryl can also be expressed as The alkyl-carbonyls such as base, 2-methylbutyryl base, 2-propyl group valeryl；Be also denoted as phenyl, p-methylphenyl, p-methoxyphenyl, The aryl such as o-tolyl, halogenophenyl, naphthyl, or pyridine radicals, furyl, pyranose, imidazole radicals, isoxazolyl etc. containing N, O or the heteroaryl of S atom；Can also is that the substituted cycloalkyl of N, O or S such as piperidyl, piperazinyl, morpholinyl.
Present invention also offers the preparation method of the isoquinilone derivatives that described logical formula (I) represents, described method includes:
1) compound represented with logical formula (II) is as raw material, carries out what the logical formula (III) of halogenating reaction synthesis represented with thionyl chloride Compound；
2) compound represented by logical formula (III) again and homopiperazine carry out aminating reaction and obtain the compound that logical formula (IV) represents；
Described method also includes:
3) prepare, with any one method following, the isoquinilone derivatives that logical formula (I) represents:
3-1) compound represented by logical formula (IV) and RX carry out halogenating reaction；
3-2) compound represented by logical formula (IV) and RCOOH carry out condensation reaction.
Y in above-mentioned logical formula (II), (III) and (IV) represents carbonyl or sulfonyl.
In described compound R X and RCOOH, R represents C1-C4Alkyl；C1-C10Alkyl-carbonyl；Aryl；N, O or S heteroaryl； The substituted cycloalkyl of N, O or S；Or the C of cycloalkyl substituted1-C4Alkyl.
X therein is halogen.
The above-mentioned preparation method of the present invention can represent by following reaction equation.
Wherein, specifically, the halogenating reaction of described step 1) is preferably carried out in DMF dicyandiamide solution, Reaction temperature 80～120 DEG C.
More specifically, in the halogenating reaction of described step 1), the consumption mol ratio of each raw material is: the change that logical formula (II) represents Compound: DMF: thionyl chloride=1: 1: (10～20), response time 3～6 hours.
And then, described step 2) aminating reaction in, it is preferred to use dichloromethane as dicyandiamide solution, logical formula (III) table The compound shown is 1 with the consumption mol ratio of homopiperazine: (2～5), described aminating reaction preferably enters under the conditions of 20～40 DEG C OK, the response time 24～48 hours.
Step 3) of the present invention can select the compound using RX or RCOOH and logical formula (IV) to represent carry out reacting with Obtain target product.Specifically chosen any method, usually pays the utmost attention to the complexity that raw material obtains, considers former and then Material cost.Such as, when substituent R described in target product is acetyl group, it is all feasible for selecting chloroacetic chloride or acetic acid to carry out reacting , but from cost consideration, should preferably be such that with chloroacetic chloride be the halogenating reaction of raw material.But when substituent R is 2-propyl group valeryl, Owing to raw material valproic acid is readily available, but it is difficult to obtain the 2-propyl group valeric chloride product of commercialization, therefore should be excellent Choosing uses valproic acid to be the condensation reaction of raw material.
Further, when described step 3) use condensation reaction time, be preferably used DMAP (DMAP) with The mixed catalyst of EDCI (1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride), in triethylamine solvent system React.Described reaction is carried out at normal temperatures, response time 48～72 hours.
Further, in above-mentioned reaction system, preferred raw material dosage mol ratio is the chemical combination that logical formula (IV) represents Thing: RCOOH: DMAP: EDCI: triethylamine=1: (1～2): (1～2): (1～2): (3～5).
Preferably, in isoquinilone derivatives of the present invention or its pharmaceutically acceptable salt, described R is 2-propyl group penta Acyl group.
It is highly preferred that in isoquinilone derivatives of the present invention or its pharmaceutically acceptable salt, described Y is sulphonyl Base, R is 2-propyl group valeryl, and its structural formula is as follows.
The molecular formula of this compound is C22H31N3O3S, chemical name 1-(4-(isoquinolin-5-sulfonyl)-Isosorbide-5-Nitrae-phenodiazine Zhuo-1-base)-2-valpromide, molecular weight 417.6, oily compound, it is soluble in dichloromethane, ethanol, methanol, acetonitrile etc. molten In agent.
The preparation process of this compound is as follows.
Present invention also offers described isoquinilone derivatives or its pharmaceutically acceptable salt at preparation treatment NK/T cell Application in the medicine of malignant tumor.
The medicine of described treatment NK/T cell malignancies includes isoquinilone derivatives or its medicine of medicine effective quantity Acceptable salt on, and the pharmaceutical carrier of routine.
Suspension Jurkat cell system is acted on, it is possible to observe along with isoquinolin spreads out with isoquinilone derivatives of the present invention The increase of biological agent concentration, substantially increases the inhibitory action of Jurkat cell.
Accompanying drawing explanation
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram that embodiment 1 prepares product.
Fig. 2 is that embodiment 1 prepares the product inhibitory action curve chart to suspension Jurkat cell.
Detailed description of the invention
Following embodiment is only the preferred technical solution of the present invention, is not used to the present invention is carried out any restriction.For For those skilled in the art, the present invention can have various modifications and variations.All within the spirit and principles in the present invention, made Any modification, equivalent substitution and improvement etc., should be included within the scope of the present invention.
Embodiment 1
Weigh 5g raw material A (5-sulfonic group isoquinolin), be placed in 50ml round-bottomed flask, be sequentially added into 0.5ml DMF, 25ml dichloro Sulfoxide, 80 DEG C of back flow reaction 3h.It is down to room temperature, evaporated under reduced pressure thionyl chloride and DMF, adds ethyl acetate 20ml and dissolve, filter, steam Dry solvent ethyl acetate, obtains intermediate product B (5-sulfonic acid chloride isoquinolin) 5.1g.
250ml round-bottomed flask added with 8.8g homopiperazine is placed under ice bath, adds 100ml dichloromethane, is produced from centre Thing B 5.1g is dissolved in 50ml dichloromethane, is slowly added dropwise in the dichloromethane solution of above-mentioned homopiperazine, reacts under room temperature 24h, add water 50ml stopped reaction.With dichloromethane/H2The extract 100ml extractive reaction liquid of O (V/V)=20: 1, collects extraction Liquid evaporated under reduced pressure, upper silica gel column chromatography, with methylene chloride/methanol (V/V)=50: 1～20: 1 eluting, eluent is evaporated and obtains 3.1g intermediate product C (hexahydro-1-(5-isoquinolinesulfonylcompounds)-1H-1,4-diazepine), productivity 44.5%.
Intermediate product C 3.1g, valproic acid 1.84g, DMAP 1.599g, EDCI is added in 250ml round-bottomed flask 2.446g, triethylamine 5.8ml, room temperature reaction 48h.Evaporated under reduced pressure solvent, with dichloromethane/H2O (V/V)=20: 1 100ml altogether enters Row extraction, evaporated under reduced pressure, upper silica gel column chromatography, with methylene chloride/methanol (V/V)=120: 1～100: 1 eluting, eluent steams Dry, obtain product D (1-(4-(isoquinolin-5-sulfonyl)-Isosorbide-5-Nitrae-phenodiazine Zhuo-1-base)-2-valpromide) brown oil liquid 2g, Productivity 45%.
The hydrogen nuclear magnetic resonance spectrogram of product D is as it is shown in figure 1, wherein:1H NMR (500 MHz, Chloroform-d) δ 9.37 (d, J = 4.0 Hz, 1H), 8.71 (t, J = 5.6 Hz, 1H), 8.41 (t, J = 5.7 Hz, 1H), 8.34 (ddd, J = 11.2, 7.4, 1.1 Hz, 1H), 8.22 (dd, J = 8.2, 4.9 Hz, 1H), 7.71 (td, J = 7.8, 4.5 Hz, 1H), 3.82-3.65 (m, 4H), 3.51-3.32 (m, 4H), 2.55 (dtd, J = 13.7, 8.2, 5.5 Hz, 1H), 2.00 (dt, J = 10.2, 6.2 Hz, 2H), 1.67-1.51 (m, 2H), 1.39 (dddd, J = 15.5, 12.9, 8.3, 6.0 Hz, 2H), 1.29-1.16 (m, 4H), 0.87 (td, J =7.3,2.1 Hz, 6H), it was demonstrated that really synthesize object construction compound.
Embodiment 2～7
Embodiment 2～7 has been respectively synthesized the target compound that following table structural formula represents, wherein synthesis step 1) and step 2) with real Executing example 1 identical, the raw material of step 3) use and reaction condition are as described in table.
The hydrogen nuclear magnetic resonance modal data of each embodiment is as follows.
Embodiment 2:1H NMR (500 MHz, Chloroform-d) δ 9.37 (d, J = 4.0 Hz, 1H), 8.71 (t, J = 5.6 Hz, 1H), 8.41 (t, J = 5.7 Hz, 1H), 8.34 (ddd, J = 11.2, 7.4, 1.1 Hz, 1H), 8.22 (dd, J = 8.2, 4.9 Hz, 1H), 7.71 (td, J = 7.8, 4.5 Hz, 1H), 3.82 - 3.65 (m, 4H), 3.51 - 3.32 (m, 4H), 2.00 (dt, J = 10.2, 6.2 Hz, 2H), 1.90(s, 3H)。
Embodiment 3:1H NMR (500 MHz, Chloroform-d) δ 9.37 (d, J = 4.0 Hz, 1H), 8.71 (t, J = 5.6 Hz, 1H), 8.41 (t, J = 5.7 Hz, 1H), 8.34 (ddd, J = 11.2, 7.4, 1.1 Hz, 1H), 8.22 (dd, J = 8.2, 4.9 Hz, 1H), 7.71 (td, J = 7.8, 4.5 Hz, 1H), 3.82 - 3.65 (m, 4H), 3.51 - 3.32 (m, 4H), 2.18(q,2H), 2.00 (dt, J = 10.2, 6.2 Hz, 2H), 1.10(t,3H)。
Embodiment 4:1H NMR (500 MHz, Chloroform-d) δ 9.37 (d, J = 4.0 Hz, 1H), 8.71 (t, J = 5.6 Hz, 1H), 8.41 (t, J = 5.7 Hz, 1H), 8.34 (ddd, J = 11.2, 7.4, 1.1 Hz, 1H), 8.22 (dd, J = 8.2, 4.9 Hz, 1H), 7.71 (td, J = 7.8, 4.5 Hz, 1H), 3.82 - 3.65 (m, 4H), 3.51 - 3.32 (m, 4H), 2.90(t, 2H), 2.00 (dt, J = 10.2, 6.2 Hz, 2H), 1.68(m, 2H), 0.98(t, 3H).
Embodiment 5:1H NMR (500 MHz, Chloroform-d) δ 9.37 (d, J = 4.0 Hz, 1H), 8.71 (t, J = 5.6 Hz, 1H), 8.41 (t, J = 5.7 Hz, 1H), 8.34 (ddd, J = 11.2, 7.4, 1.1 Hz, 1H), 8.22 (dd, J = 8.2, 4.9 Hz, 1H), 7.71 (td, J = 7.8, 4.5 Hz, 1H), 3.82 - 3.65 (m, 4H), 3.51 - 3.32 (m, 4H), 2.55 (dtd, J = 13.7, 8.2, 5.5 Hz, 1H), 2.00 (dt, J = 10.2, 6.2 Hz, 2H), 1.72(m, 2H), 1.21(d, 3H), 0.76(t, 3H)。
Embodiment 6:1H NMR (500 MHz, Chloroform-d) δ 9.37 (d, J = 4.0 Hz, 1H), 8.71 (t, J = 5.6 Hz, 1H), 8.41 (t, J = 5.7 Hz, 1H), 8.34 (ddd, J = 11.2, 7.4, 1.1 Hz, 1H), 8.22 (dd, J = 8.2, 4.9 Hz, 1H), 7.71 (td, J = 7.8, 4.5 Hz, 1H), 3.82 - 3.65 (m, 4H), 3.51 - 3.32 (m, 4H), 2.00 (dt, J = 10.2, 6.2 Hz, 2H), 2.53(q,2H),1.03(t,3H)。
Embodiment 7:1H NMR (500 MHz, Chloroform-d) δ 9.37 (d, J = 4.0 Hz, 1H), 8.71 (t, J = 5.6 Hz, 1H), 8.41 (t, J = 5.7 Hz, 1H), 8.34 (ddd, J = 11.2, 7.4, 1.1 Hz, 1H), 8.22 (dd, J = 8.2, 4.9 Hz, 1H), 7.71 (td, J = 7.8, 4.5 Hz, 1H), 7.25(m,2H), 6.92(m, 2H), 6.84(tt, 1H), 3.82 - 3.65 (m, 4H), 3.51 - 3.32 (m, 4H), 2.00 (dt, J = 10.2, 6.2 Hz, 2H)。
Application examples 1:Jurkat cell line Inhibition test
CCK-8 detection kit, the embodiment 1 of detection variable concentrations is used to prepare product to people's Pancytopenia The inhibitory action of cell strain Jurkat cell activity.
Tested cell line: Jurkat cell system (purchased from bio tech ltd of Nanjing section one hundred).
The Jurkat suspension cell liquid that inoculated and cultured is good on 96 orifice plates, liquid measure 200 μ l on every hole, containing cell 7 × 103 Individual/hole.In hole, add different amounts of tested medicine so that it is comprehensive concentration be respectively 0.4 μM, 1.2 μMs, 3.7 μMs, 11.1 μMs, 33.3 μMs and 100 μMs, it is placed in 37 DEG C, 5%CO2Cultivate 72 hours in saturated humidity incubator.Each concentration arranges 3 multiple holes, with Time blank group is set.
Abandoning the 200 outmoded liquid of μ l in each hole, (90 μ l culture medium+10 μ l CCK-8 are former to add 100 μ l working solutions Liquid), it is placed in incubator about 1 hour, takes out, detect each hole inner cell liquid absorbance at 450nm wavelength with microplate reader.Inspection During survey, every hole adds 10 μ l CCK-8, cultivates 2～3 hours.
According to testing result, calculate the Jurkat cell survival rate after tested medicine effect, with tested drug level be Abscissa, cells survival rate is vertical coordinate mapping, obtains the curve chart shown in Fig. 2.According to Fig. 2 it can be seen that along with medicine is dense The increase of degree, the survival rate of Jurkat cell is remarkably decreased, and presents the dependency of drug dose and effect, it was demonstrated that medicine of the present invention Thing has significant inhibitory action to Jurkat cell.
Embodiment 8
Weigh 5g raw material A (isoquinolin-5-formic acid), be placed in 50ml round-bottomed flask, be sequentially added into 0.5ml DMF, 25ml dichloro Sulfoxide, 80 DEG C of back flow reaction 3h.It is down to room temperature, evaporated under reduced pressure thionyl chloride and DMF, adds ethyl acetate 20ml and dissolve, filter, steam Dry solvent ethyl acetate, obtains intermediate product B (isoquinolin-5-formyl chloride) 5.1g.
250ml round-bottomed flask added with 8.8g homopiperazine is placed under ice bath, adds 100ml dichloromethane, is produced from centre Thing B 5.1g is dissolved in 50ml dichloromethane, is slowly added dropwise in the dichloromethane solution of above-mentioned homopiperazine, reacts under room temperature 24h, add water 50ml stopped reaction.With dichloromethane/H2The extract 100ml extractive reaction liquid of O (V/V)=20: 1, collects extraction Liquid evaporated under reduced pressure, upper silica gel column chromatography, with methylene chloride/methanol (V/V)=50: 1～20: 1 eluting, eluent is evaporated and obtains 3.8g intermediate product C (hexahydro-1-(5-isoquinolin formoxyl)-1H-1,4-diazepine), productivity 57%.
Intermediate product C 3.8g, valproic acid 1.84g, DMAP 1.599g, EDCI is added in 250ml round-bottomed flask 2.446g, triethylamine 5.8ml, room temperature reaction 48h.Evaporated under reduced pressure solvent, with dichloromethane/H2O (V/V)=20: 1 100ml altogether enters Row extraction, evaporated under reduced pressure, upper silica gel column chromatography, with methylene chloride/methanol (V/V)=120: 1～100: 1 eluting, eluent steams Dry, obtain product D (1-(4-(isoquinolin-5-sulfonyl)-Isosorbide-5-Nitrae-phenodiazine Zhuo-1-base)-2-valpromide) brown oil liquid 4.1g, productivity 72%.
Embodiment 9～14
Embodiment 9～14 has been respectively synthesized the target compound that following table structural formula represents, wherein synthesis step 1) and step 2) with Embodiment 8 is identical, and the raw material of step 3) use and reaction condition are as described in table.
The hydrogen nuclear magnetic resonance modal data of each embodiment is as follows.
Embodiment 9:1H NMR (500 MHz, Chloroform-d) δ 9.37 (d, J = 4.0 Hz, 1H), 8.71 (t, J = 5.6 Hz, 1H), 8.41 (t, J = 5.7 Hz, 1H), 8.34 (ddd, J = 11.2, 7.4, 1.1 Hz, 1H), 8.22 (dd, J = 8.2, 4.9 Hz, 1H), 7.71 (td, J = 7.8, 4.5 Hz, 1H), 3.84 - 3.62 (m, 4H), 3.49 - 3.30 (m, 4H), 2.00 (dt, J = 10.2, 6.2 Hz, 2H), 1.90(s, 3H)。
Embodiment 10:1H NMR (500 MHz, Chloroform-d) δ 9.37 (d, J = 4.0 Hz, 1H), 8.71 (t, J = 5.6 Hz, 1H), 8.41 (t, J = 5.7 Hz, 1H), 8.34 (ddd, J = 11.2, 7.4, 1.1 Hz, 1H), 8.22 (dd, J = 8.2, 4.9 Hz, 1H), 7.71 (td, J = 7.8, 4.5 Hz, 1H), 3.84 - 3.62 (m, 4H), 3.49 - 3.30 (m, 4H), 2.18(q,2H), 2.00 (dt, J = 10.2, 6.2 Hz, 2H), 1.10(t,3H)。
Embodiment 11:1H NMR (500 MHz, Chloroform-d) δ 9.37 (d, J = 4.0 Hz, 1H), 8.71 (t, J = 5.6 Hz, 1H), 8.41 (t, J = 5.7 Hz, 1H), 8.34 (ddd, J = 11.2, 7.4, 1.1 Hz, 1H), 8.22 (dd, J = 8.2, 4.9 Hz, 1H), 7.71 (td, J = 7.8, 4.5 Hz, 1H), 3.84 - 3.62 (m, 4H), 3.49 - 3.30 (m, 4H), 2.90(t, 2H), 2.00 (dt, J = 10.2, 6.2 Hz, 2H), 1.68(m, 2H), 0.98(t, 3H).
Embodiment 12:1H NMR (500 MHz, Chloroform-d) δ 9.37 (d, J = 4.0 Hz, 1H), 8.71 (t, J = 5.6 Hz, 1H), 8.41 (t, J = 5.7 Hz, 1H), 8.34 (ddd, J = 11.2, 7.4, 1.1 Hz, 1H), 8.22 (dd, J = 8.2, 4.9 Hz, 1H), 7.71 (td, J = 7.8, 4.5 Hz, 1H), 3.84 - 3.62 (m, 4H), 3.49 - 3.30 (m, 4H), 2.55 (dtd, J = 13.7, 8.2, 5.5 Hz, 1H), 2.00 (dt, J = 10.2, 6.2 Hz, 2H), 1.72(m, 2H), 1.21(d, 3H), 0.76(t, 3H)。
Embodiment 13:1H NMR (500 MHz, Chloroform-d) δ 9.37 (d, J = 4.0 Hz, 1H), 8.71 (t, J = 5.6 Hz, 1H), 8.41 (t, J = 5.7 Hz, 1H), 8.34 (ddd, J = 11.2, 7.4, 1.1 Hz, 1H), 8.22 (dd, J = 8.2, 4.9 Hz, 1H), 7.71 (td, J = 7.8, 4.5 Hz, 1H), 3.84 - 3.62 (m, 4H), 3.49 - 3.30 (m, 4H), 2.00 (dt, J = 10.2, 6.2 Hz, 2H), 2.53(q,2H),1.03(t,3H)。
Embodiment 14:1H NMR (500 MHz, Chloroform-d) δ 9.37 (d, J = 4.0 Hz, 1H), 8.71 (t, J = 5.6 Hz, 1H), 8.41 (t, J = 5.7 Hz, 1H), 8.34 (ddd, J = 11.2, 7.4, 1.1 Hz, 1H), 8.22 (dd, J = 8.2, 4.9 Hz, 1H), 7.71 (td, J = 7.8, 4.5 Hz, 1H), 7.25(m,2H), 6.92(m, 2H), 6.84(tt, 1H), 3.84 - 3.62 (m, 4H), 3.49 - 3.30 (m, 4H), 2.00 (dt, J = 10.2, 6.2 Hz, 2H)。

Claims (10)

1. the isoquinilone derivatives represented by following logical formula (I) or its pharmaceutically acceptable salt:
Wherein:
Y represents carbonyl or sulfonyl；
R represents C1-C4Alkyl；C1-C10Alkyl-carbonyl；Aryl；N, O or S heteroaryl；The substituted cycloalkyl of N, O or S；Or cycloalkyl Substituted C1-C4Alkyl.
Isoquinilone derivatives the most according to claim 1 or its pharmaceutically acceptable salt, wherein R is 2-propyl group valeryl Base.
Isoquinilone derivatives the most according to claim 1 or its pharmaceutically acceptable salt, wherein Y is sulfonyl, and R is 2- Propyl group valeryl.
4. the preparation method of isoquinilone derivatives described in claim 1, be the compound represented with logical formula (II) as raw material, with two Chlorine sulfoxide carries out the compound that the halogenating reaction logical formula (III) of synthesis represents, then the compound that represented by logical formula (III) and homopiperazine Carry out aminating reaction and obtain the compound that logical formula (IV) represents, and, prepare logical formula (I) table with any one method following The isoquinilone derivatives shown:
1) compound represented by logical formula (IV) and RX carry out halogenating reaction；
2) compound represented by logical formula (IV) and RCOOH carry out condensation reaction；
Y in described logical formula (II), (III) and (IV) represents carbonyl or sulfonyl；
In described compound R X and RCOOH, R represents C1-C4Alkyl；C1-C10Alkyl-carbonyl；Aryl；N, O or S heteroaryl；N, O or The substituted cycloalkyl of S；Or the C of cycloalkyl substituted1-C4Alkyl；
X is halogen.
Preparation method the most according to claim 4, is characterized in that the compound represented according to logical formula (II): N, N-dimethyl Methanamide: thionyl chloride=1: 1: the mol ratio of (10～20), carries out logical formula (II) in DMF dicyandiamide solution Represent the halogenating reaction of compound, reaction temperature 80～120 DEG C, response time 3～6 hours.
Preparation method the most according to claim 4, is characterized in that compound and the homopiperazine represented according to logical formula (III) Mol ratio is 1: (2～5), carries out described aminating reaction in dichloromethane solvent system, and reaction temperature 20～40 DEG C, during reaction Between 24～48 hours.
Preparation method the most according to claim 4, is characterized in that described condensation reaction uses the mixing of DMAP with EDCI to urge Agent.
Preparation method the most according to claim 4, is characterized in that described condensation reaction is carried out in triethylamine solvent system, Response time 48～72 hours.
9. isoquinilone derivatives described in claim 1 or its pharmaceutically acceptable salt are at preparation treatment NK/T cell malignancies Medicine in application.
10. treat a medicine for NK/T cell malignancies, include isoquinolin described in the claim 1 of medicine effective quantity and spread out Biology or its pharmaceutically acceptable salt, and the pharmaceutical carrier of routine.
CN201610573019.4A 2016-07-20 2016-07-20 Isoquinilone derivatives and its preparation method and application Pending CN106146467A (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4678783A (en) * 1983-11-04 1987-07-07 Asahi Kasei Kogyo Kabushiki Kaisha Substituted isoquinolinesulfonyl compounds

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4678783A (en) * 1983-11-04 1987-07-07 Asahi Kasei Kogyo Kabushiki Kaisha Substituted isoquinolinesulfonyl compounds
US4678783B1 (en) * 1983-11-04 1995-04-04 Asahi Chemical Ind Substituted isoquinolinesulfonyl compounds

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