CN108558743A - A kind of deuterated heterocyclic carbamate derivatives, preparation method and applications - Google Patents
A kind of deuterated heterocyclic carbamate derivatives, preparation method and applications Download PDFInfo
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Abstract
The present invention provides a kind of deuterated heterocyclic carbamate derivatives.The present invention also provides a kind of preparation method of formula (I) compound and include the medical composition and its use of the compounds of this invention.Pharmacokinetic trial shows that the compounds of this invention has good pharmacokinetic parameter and therapeutic effect.
Description
Technical field
The invention belongs to medicinal chemistry arts, and in particular to a new class of deuterated benzamide derivatives, preparation method
And composition containing the deuterated benzamide derivatives and the compound or composition go second as preparing histone
Purposes in deacerylase inhibitors class drug, the especially purposes of anticancer drug.
Background technology
Human body chromosome is made of many base units, and histone is exactly one of them, and the expression process of gene
In play decisive role is exactly modification after histone transcription, most important in method of modifying is exactly acetylation.
Many researchs have been found that the generation and acetylation of tumour are unbalance to have relationship, histon deacetylase (HDAC) to cross scale in cancer cell
Up to being the major reason for causing acetylation unbalance, so to inhibit tumour growth that can first inhibit HDAC.Recent years, research
HDAC is more and more deep, especially the research hotspot of antitumor drug has been locked in both at home and abroad the suppression of histon deacetylase (HDAC)
Preparation.Compared to the antitumor drug of the past, HDAC is a kind of completely new anti-tumor drugs targeting, is had on low cytotoxicity
Clear superiority.First HDACi drug is the vorinostat of U.S. FDA approval listing in 2006 in the world, can promptly be controlled
Treat acute skin T cell lymphoma.In addition natural products FK228 at 2009 and 2011 respectively go through listing and by
Treatment of the approval for t cell lymphoma.
Histon deacetylase (HDAC) (histone deacetylase, HDAC) is a kind of protease, to the knot of chromosome
Structure is modified and gene expression regulation plays an important role.Under normal circumstances, the acetylation of histone is conducive to DNA and group
The dissociation of eight aggressiveness of albumen, nucleosomal structure relaxation, to enable various transcription factors and collaboration transcription factor and DNA bound sites
Point specific binding, the transcription of activated gene.In nucleus, acetylation of histone is in dynamic with DNA methylase inhibitor process
State balances, and by acetylation of histone transferase (histone acetyltransferase, HAT) and DNA methylase inhibitor
Enzyme (histone deace- tylase, HDAC) regulates and controls jointly.HAT is by the acetyl grouptransfer of acetyl coenzyme A to histone amino
On the specific lysine residue in end, HDAC makes DNA methylase inhibitor, combines closely with negatively charged DNA, and chromatin causes
The transcription of close curling, gene is suppressed.
In cancer cell, the overexpression of HDAC leads to the enhancing that deacetylation acts on, by restoring histone positive charge,
To increase the gravitation between DNA and histone, so that loose nucleosome is become very close, be unfavorable for the table of specific gene
It reaches, including some tumor suppressor genes.Histon deacetylase (HDAC) inhibitor (histone deacetylase
Inhibitors, HDACi) to regulating cell apoptosis and it can then be divided by improving chromatin specific region acetylation of histone
Expression and stability, inducing cell apoptosis and the differentiation for changing GAP-associated protein GAP, become a new class of antitumor drug.HDACi is not only
There is good therapeutic effect to a variety of hematological system tumors and solid tumor, and with the relatively high selectivity of tumour cell and
The advantage of low toxicity.
Chidamide is a kind of target therapeutic agent, it is histon deacetylase (HDAC) inhibitor, and first indication is
Relapsed and refractory periphery T cell lymph cancer.
Currently, chidamide have been found to have in colon cancer, lung cancer, breast cancer, liver cancer and leukemia it is good anti-swollen
Tumor acts on, hence it is evident that improves the quality of life of cancer trouble.But the common adverse reactions observed in clinical test have：Hematology is not
Good reaction, including platelet count is reduced, leucocyte or neutrophil count reduction, hemoglobin reduce；Whole body is bad anti-
It answers, including weak, fever；Gastrointestinal side effect, including diarrhea, nausea and vomiting；Metabolism and trophic system adverse reaction, packet
Include loss of appetite, hypopotassaemia and hypocalcemia；And other adverse reactions, including dizziness, fash etc..
An effective way for reducing adverse drug reaction is with the isotope deuterium of hydrogen come modified medicaments.
There are three types of isotopes for hydrogen：Protium (1H, Hydrogen, Protium), deuterium (2H, Deuterium) and tritium (3H,
Tritium).Wherein deuterium (2H or D) be to obtain one of most widely used isotope, it be hydrogen present in nature (1H, protium)
A kind of stable isotope, it is "dead", be to be found in water for the first time in 1932 by Urey.The atomic nucleus of deuterium is by a seed
It is formed with proton, and only there are one protons for hydrogen (protium).Content of the deuterium in nature is about 0.015%, current a large amount of deuterium
Element is separated in the form of deuterated water from water, and content is up to 99.9%.Deuterated water is called heavy water, is most to pass through at present
The deuterium source helped and be easy to get.
Deuterated drug be by the protium (H) in drug molecule with deuterium (D) replace, due to D-atom size and shape with
Hydrogen atom is almost the same, and hydrogen will not change the selectivity and biochemical activity of drug after being replaced by deuterium, but due to deuterium ratio
The chemical bond rupture of hydrogen weight, formation is difficult, therefore will produce prodigious influence to drug metabolism, is particularly in metabolism site
When, medicine can be improved well for effect and can substantially reduce adverse reaction.
Therefore, to provide a kind of noval chemical compound that can effectively reduce chidamide adverse reaction be necessary and can by deuterated
Capable.
Invention content
It is a kind of deuterated heterocyclic carbamate derivatives histon deacetylase (HDAC) inhibitor it is an object of the invention to it, with west
Drug effect up to this amine is identical, and is synthesizing new histone deacetylase with the pharmacokinetic property due to chidamide
Change enzyme inhibitor and new compound is provided.
Formula (I) compound represented provided by the invention or its pharmaceutically acceptable salt,
Wherein, X1~X8Separately it is selected from H or D, also, X1、X2、X3、X4、X5、X6、 X7、X8At least one
Selected from D.
Preferably, X5=X6、X7=X8。
Formula (I) compound represented is selected from such as lower structure：
And its pharmaceutically acceptable salt.
Patent CN03139760 reports a kind of preparation method of following chidamide：
The compounds of this invention refers to above-mentioned preparation method, provides preparation method as shown in Figure 1：
Compound 1 is selected from such as lower structure：
Wherein, 1e is commercially available obtains, and 1a and 1d can be prepared with reference to WO2018081211, and 1b can refer to WO
2017133360 1 are prepared, and 1c can be with bibliography Synlett (2004), (13), 2319-2322.
Compound 2 is selected from such as lower structure：
Wherein, 2b is commercially available obtains, and the preparation method of 2a is as follows：
Compound 4 is selected from such as lower structure：
Wherein 4b is commercially available to be obtained, and 4a is prepared with reference to WO2014062204.
The present invention also provides a kind of formula (I) compounds or its pharmaceutically acceptable salt to prepare histon deacetylase (HDAC)
Purposes in inhibitor class drug.
Further, the purposes of the drug or its pharmaceutically acceptable salt in the preparation of antitumor drugs.
The present invention also provides a kind of pharmaceutical compositions.
A kind of pharmaceutical composition, it is active constituent that it, which is by above compound or its pharmaceutically acceptable salt, in addition medicine
The preparation that common auxiliary material or complementary ingredient are prepared on.
In some of these embodiments, pharmaceutical composition of the present invention further includes that other are anti-swollen
Tumor medicine.
Compound shown in formula (I) of the present invention is on the basis of keeping former compound high anti-cancer active, by deuterated modification,
So that pharmacokinetic property of the compound in blood plasma be more preferable, blood peak concentration of drug is high, and effective blood drug concentration is held time length, can
To reduce dosage；By toxicity test, it is found that its toxic side effect is low, good security.
Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspect and its
The content of his aspect will make more specific complete description below.
Detailed description of the invention
Definition and general terms
The present invention will be corresponding to the content determining materialization document list in detail, embodiment is all accompanied by structure
The diagram of formula and chemical formula.The present invention, which has, expectedly covers all choices, variant and coordinate, these may be such as right
Existing invention field is included in defined in it is required that like that.Those skilled in the art will identify it is many similar or equivalent to
This described method and substance, these can be applied to the practice of the present invention.The present invention is limited to absolutely not method and substance
Description.There are many documents and similar substance to distinguish or contradict with the present patent application including but not limited to term
Definition, the usage of term, the technology of description or range as controlled by the present invention.
The present invention will apply defined below unless other aspects show.Purpose according to the present invention, chemical element is according to member
Plain periodic table, CAS versions and Chemical Physics handbook, 75th Ed., 1994 define.In addition, organic chemistry General Principle is shown in
" Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito：1999, and
" March ' s Advanced Organic Chemistry ", Michael B.Smith and Jerry March,
John wiley ＆ sons, New York：2007, therefore all contents have all merged bibliography.
Any atom of compound of the present invention is such as not specifically noted, and refers to the isotope of the atom of its stable state.
Unless otherwise specified, when " H " or " hydrogen " are selected as in a site on molecular structure, which should be understood that have
The natural abundance of hydrogen isotope.Similarly, if not otherwise specified, when " D " or " deuterium " are selected as in a site, which should
It is understood to that its deuterium isotope abundance is at least 3000 times (deuterium natural abundance of isotopes is 0.015%) of its natural abundance.
" isotope enrichment factor " means the isotope and the ratio of its natural isotope in the present invention.
More preferably, it is natural to be at least it for the abundance of the D-atom in each deuterated site of the deuterated compound in the present invention
3500 times (52.5% D-atom enrichments) of abundance, more preferably, at least 4500 times (67.5% D-atom enrichments) are more excellent
, at least 5000 times (75% D-atom enrichments), more preferably, at least 6000 times (90% D-atom enrichments) are more excellent
, at least 6333 times (95% D-atom enrichments), more preferably, at least 6466.7 times (97% D-atom enrichments), more
Excellent, at least 6600 times (99% D-atom enrichments), more preferably, at least 6633.3 times (99.5% D-atom is rich
Collection).
Term " isotope isomer " refers to there was only isotope difference in its structure and other structures are completely the same not
Same molecule.
Term " compound " is referred in addition to only existing the isotope difference still molecule with identical chemical constitution.
The present invention also provides a kind of compound pharmaceutically acceptable salts.Pharmaceutically acceptable salt includes inorganic
Hydrochlorate and acylate, inorganic acid salt include bisulfites, hydrochloride, hydrobromate, hydriodate, sulfate, phosphate,
Perchlorate, borate, bisulphate, Hemisulphate, nicotinate, nitrate；Organic acid such as tosilate, tartaric acid
Salt, malate, citrate, maleate, acetate, oxalates, succinate, malonate, adipate, alginic acid
Salt, ascorbate, aspartate, benzene sulfonate, benzoate, butyrate, camphor hydrochlorate, camsilate, cyclopenta
Propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, gluceptate are sweet
Oleophosphoric acid salt, gluconate, enanthate, caproate, hydriodate, 2- hydroxy-ethanesulfonate salts, lactobionate, lactic acid
Salt, laruate, lauryl sulfate, mesylate, 2- naphthalene sulfonates, oleate, palmitate, pamoate, pectate,
Persulfate, 3- phenylpropionic acid salt, picrate, pivalate, propionate, stearate, rhodanate, undecylate, penta
Hydrochlorate, etc..
Pharmaceutically acceptable salt further includes having the compound of acidic-group such as carboxyl by including alkali with alkali appropriate
Metal, such as lithium, sodium, potassium；Alkaline earth metal hydroxide, such as calcium, magnesium；And other metal hydroxides, such as calcium hydroxide, hydroxide
Zinc；Ammonia, organic amine, such as pyridine, dicyclohexyl amine, tri-n-butylamine, diethylamine, triethylamine, N, N- dimethylethanolamines, triethanolamine,
Meglumine, thiomorpholine, piperidines, pyrroles；The salt of the formation such as amino acid such as glycine, lysine.The present invention, which is also intended to contemplate, to be appointed
The compound of the group of what included N is formed by quaternary ammonium salt.Water-soluble or oil-soluble or dispersion product can be by quaternized
Effect obtains.Alkali or alkaline earth metal salt includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further comprises
The ammonium cation that appropriate, nontoxic ammonium, quaternary ammonium salt and gegenions are formed, such as halide, hydroxide, carboxylate, sulphur
Acidulants, phosphoric acid compound, nitric acid compound, C1-8 azochlorosulfonate acid compounds and aromatic sulphonic acid compound.
Pharmaceutical preparation can be in unit dosage forms, and each unit dose contains the active constituent of predetermined amount.The change of present disclosure
The dosage level of object is closed between about 0.01 mg/kg (mg/kg) body weight/day and about 250 mg/kg body weight/days,
Preferably in the range of about between 0.05mg/kg body weight/days and about 100mg/kg body weight/days, usually it is used to prevent or control with monotherapy
Treat thyroid cancer.It usually can be by daily about 1 to about 5 time or as the pharmaceutical composition for continuously giving present disclosure.It is this kind of
Dose regimen can be used as therapy in long or short term.The amount that the active constituent to prepare single formulation is mixed with carrier material will be according to waiting for
Disease, the severity of disease, administration time, administration route, the discharge rate of compound used therefor, treatment time and the trouble for the treatment of
Person's age, gender, weight and situation and change.Preferred unit dosage forms are the daily doses containing hereinbefore active constituent or divide
The unit dosage forms of dosage or its appropriate fraction.It can start to treat with the low dose of already clearly below compound optimal dose.Hereafter, with
Smaller increment carrys out escalated dose until reaching optimum efficiency in this case.In general, most desirably giving compound
Concentration level be that usually can provide effective result without regard to causing any harmful or toxic secondary make in anti-virus aspect
With.
When present disclosure composition include present disclosure compound and one or more other treatment drugs or
When the combination of prophylactic agent, the dosage level of compound and other drug accounts for normal administration usually in monotherapy scheme
The about 10-15% of dosage, more preferably accounts for about the 10% to 80% of normal dosage.Pharmaceutical preparation is suitable for by any suitable
Approach is administered, such as passes through oral (including oral cavity or sublingual), rectum, nose, part (including oral cavity, sublingual or percutaneous), vagina
Or parenteral (including in subcutaneous, intradermal, intramuscular, intra-articular, intrasynovial, breastbone, under intrathecal, intralesional, intravenous or corium
Injection or infusion) approach.Can prepare this kind of preparation by any known method of art of pharmacy, for example, by by active constituent with
Carrier or excipient mixing.It is preferred that oral medication or drug administration by injection.
Pharmaceutical preparation suitable for oral medication is provided by independent unit, such as capsule or tablet；Powder or granule；
Solution in aqueous or non-aqueous liquid or suspension；Edible foam formulations or foaming preparations (whip)；Or oil-in-water breast
Liquor or water in oil emulsion liquor.
It by preparing pulverulent mixture as described above, and is loaded into the gelatin shell of forming, to prepare capsule.It is filling
It fills out before operation, it can be by glidant and lubricant (such as colloidal silicon dioxide, talcum powder, magnesium stearate, calcium stearate or solid-state
Polyethylene glycol) it is added in pulverulent mixture.Can also be added when taking capsule by improve drug utilizability disintegrant or
Solubilizer (such as agar, calcium carbonate or sodium carbonate).
When needing in addition or is required, also suitable adhesive, lubricant, disintegrant and colorant can be mixed mixture
In.Suitable adhesive includes starch, gelatin, natural sugar (such as glucose or beta lactose), corn sweetener, natural and synthesis
Gummy (such as gum arabic, tragacanth or mosanom), carboxymethyl cellulose, polyethylene glycol etc..For these dosage forms
Lubricant includes enuatrol, sodium chloride etc..Disintegrant includes but is not limited to starch, methylcellulose, agar, bentonite, xanthan
Glue etc..For example, by the way that pulverulent mixture, granulation or pre- tabletting is made, lubricant and disintegrant is added, it is tabletted, to make
Piece agent.By the compound suitably crushed and diluent as described above or base-material, optionally with adhesive, (such as carboxymethyl is fine
Tie up element, alginates, gelatin or polyvinylpyrrolidone), dissolve inhibitor (such as paraffin), absorbsion accelerator (quaternary salt) and/or
Absorbent (such as bentonite, kaolin or Dicalcium Phosphate) mixes, to prepare pulverulent mixture.Useful binders (such as syrup,
Starch slurry, mucialga of arabic gummy (acadiamucilage) or cellulosic material or polymeric material solution) wetting after pressurize sieving, will
Pulverulent mixture is pelletized.Granulation an alternative be, can be by pulverulent mixture by tablet press machine, the result is that will be formed bad
Agglomerate smash particle is made again.Can be by the way that stearic acid, stearate be added, talcum powder or mineral oil make particle lubrication to prevent
It adheres on the punch die of tablet press machine.Then the mixture through lubrication is tabletted.The compound of present disclosure can also be with freedom
The inert carrier of flowing mixes, can be tabletted without passing through granulation or pre- tableting step.It can provide transparent or opaque
The protectiveness being made of shellac seal coat, sugar-coat or polymeric material clothing and wax polishing clothing (polish coating of wax)
Coating material.Dyestuff can be added in these coating materials and distinguish different unit doses.
Oral liquid such as solution, syrup and elixir can be prepared with dosage unit form, to which specified rate contains
There is the compound of predetermined amount.Syrup can be prepared by the way that compound to be dissolved in suitably seasoned aqueous solution, and elixir can lead to
It crosses and is prepared using non-toxic vehicle.Solubilizer and emulsifier (such as ethoxylated isostearyl alcohols and polyoxyethylene mountain can also be added
Pears alcohol ether), preservative, flavoring additive (such as peppermint oil or natural sweetener or saccharin or other artificial sweeteners) etc..
It if appropriate, can be by the dosage unit preparations microencapsulation for oral medication.Also preparation can be made and is prolonged
When or sustained release, such as by being coated or being embedded in the microparticle materials such as polymer, wax.
Formula (I) compound and its pharmaceutically acceptable salt can be given with liposome delivery systems, such as small single layer fat
Plastid, big unilamellar liposome and multilamellar liposome.Liposome can be by a variety of phosphatide (such as cholesterol, octadecylamine or phosphatide
Phatidylcholine) it constitutes.
Formula (I) compound and its pharmaceutically acceptable salt also can be by using monoclonal antibodies as individual carrier
(compound molecule is coupled) passs medicine.Compound also can with as can target medicine carrier soluble polymer be coupled.This
Type of Collective object may include polyvinylpyrrolidone, pyran co-polymer, poly- hydroxypropyhnethacrylamide phenol, poly-hydroxyethyl asparagus fern
Amidophenol or the polyethylene-oxide polylysine replaced by palmitoyl residues.In addition, compound can be with a kind of biodegradable
Polymer coupling, the controlled release for reaching drug, this kind of polymer such as polylactic acid, poly-epsilon-caprolactone, polyhydroxybutyrate, poly-
The cross-linked copolymer or amphiphilic block of ortho esters, polyacetals, poly- dihydropyran, polybutylcyanoacrylate and hydrogel
Object.
The abbreviation that the present invention uses：
K2CO3Potassium carbonate
Pd(AcO)2Palladium
DMF N,N-dimethylformamides
N2Nitrogen
THF tetrahydrofurans
CDI N, N- carbonyl dimidazoles
DCC dicyclohexylcarbodiimides
DMSO dimethyl sulfoxide (DMSO)s
Description of the drawings
Fig. 1 is the synthesis flow of deuterated heterocyclic carbamate derivatives.
Specific implementation mode
Embodiment 1
101 synthesis：
Step 1:The synthesis of compound 3
By compound 1b (1.57g, 10mmol), 2b (0.86g, 10mmol), K2CO3(1.66g, 12mmol), Pd
(AcO)2(0.1g) is added in DMF (40ml), N2Displacement, is heated to 130 DEG C, is stirred to react 4h, and the reaction was complete for point board monitoring,
It is concentrated under reduced pressure and removes DMF, be cooled to room temperature, NaOH aqueous solutions (NaOH is added:0.8g, water：20ml), ethyl alcohol is added
(10ml) is heated to 70 DEG C, is stirred to react 2h, the reaction was complete for point board monitoring, is cooled to room temperature, and filters, is added dropwise into filtrate dense
Hydrochloric acid has white solid precipitation to pH=7, filtering, and filter cake is washed with a small amount of cold absolute ethyl alcohol, dry, obtains white solid
Compound 3 (1.26g, yield 84.6%).
1H NMR(400MHz,DMSO-d6)：δppm10.90(s,1H),9.12(s,1H), 8.36(d,1H),7.78(d,
1H), 7.65 (d, 1H), 6.37 (d, 1H).
Step 2：The synthesis of compound 5
Compound 3 (1.25g, 8.3mmol) is added in anhydrous THF (20ml), is cooled to 10 DEG C, CDI is added
(1.34g, 8.3mmol), is stirred to react 1h, add be dissolved in 1N NaOH aqueous solutions (10ml) compound 4 (1.25g,
8.3mmol), 6h is reacted at room temperature, the reaction was complete for point board monitoring, is concentrated under reduced pressure and removes THF, water (15ml) is added into residue,
PH=6.8 is adjusted with concentrated hydrochloric acid, white solid is precipitated, 2~4 DEG C is cooled to overnight, then filters, filter cake is washed with ice water, is done
It is dry, obtain compound 5 (1.87g, yield 79.8%).
1H NMR(400MHz,DMSO-d6)：δppm11.27(s,1H), 8.47(s,1H),8.15(dd,2H),7.59(d,
1H), 7.52 (d, 1H), 7.39 (d, 1H), 7.18 (dd, 2H), 6.38 (d, 1H), 5.74 (s, 1H), 4.61 (s, 2H).
Step 3：The synthesis of compound 101
Compound 5 (1.85g, 6.4mmol) and the fluoro- 1,2- phenylenediamines (0.8g, 6.4mmol) of 4- are added to 1,4- bis-
In six ring of oxygen (25ml), DCC (1.34g, 6.5mmol) is added, reaction 10h is stirred at room temperature, there is white solid precipitation, contact plate prison
The reaction was complete for control, is filtered to remove insoluble matter, filtrate decompression concentration, and residue alcohol crystal obtains target compound 101
(1.67g, 67%).
1H NMR(400MHz,DMSO-d6)：δppm9.58(brs,1H), 8.75(brs,1H),7.53(m,5H),7.32
(m,4H), 7.02(t,1H),6.77(m,2H),6.62(t,1H),4.93(brs,2H),4.41(d,2H)。
ESI/MS：M/z=392 (M+H)+.
Embodiment 2
102 synthesis
Step 1~3 refer to 101 synthesis step respectively, are made 102.
1H NMR(400MHz,DMSO-d6)：δppm9.57(brs,1H),8.74(brs,1H), 8.24(s,1H),7.51
(m,5H),7.33(m,3H), 7.01(t,1H),6.77(m,2H),6.61(t,1H),4.94(brs,2H),4.40(d,2H)。
ESI/MS：M/z=392 (M+H)+.
Embodiment 3
103 synthesis
Step 1~3 refer to 101 synthesis step respectively, are made 103.
1H NMR(400MHz,DMSO-d6)：δppm9.57(brs,1H),8.75(brs,1H), 8.26(d,1H),7.50
(m,5H),7.32(m,3H),7.02(t,1H),6.77(m,2H), 6.62(t,1H),4.93(brs,2H),4.41(d,2H)。
ESI/MS：M/z=392 (M+H)+.
Embodiment 4
104 synthesis
Step 1~3 refer to 101 synthesis step respectively, are made 104.
1H NMR(400MHz,DMSO-d6)：δppm9.57(brs,1H),8.75(brs,1H), 7.51(m,5H),7.02
(t,1H),6.76(m,2H), 6.61(t,1H),4.94(brs,2H),4.41(d,2H)。
ESI/MS：M/z=395 (M+H)+.
Embodiment 5
105 synthesis
Step 1~3 refer to 101 synthesis step respectively, are made 105.
1H NMR(400MHz,DMSO-d6)：δppm9.57(brs,1H),8.76(brs,1H), 7.50(m,5H),7.33
(m,4H),6.74(m,2H), 4.92(brs,2H),4.40(d,2H)。
ESI/MS：M/z=393 (M+H)+.
Embodiment 6
106 synthesis
Step 1~3 refer to 101 synthesis step respectively, are made 106.
1H NMR(400MHz,DMSO-d6)：δppm9.57(brs,1H),8.76(brs,1H), 7.50(m,5H),7.33
(m,5H),6.74(m,2H), 6.23(d,1H),4.92(brs,2H)。
ESI/MS：M/z=393 (M+H)+.
Embodiment 7
201 synthesis
Step 1~3 refer to 101 synthesis step respectively, are made 201.
1H NMR(400MHz,DMSO-d6)：δppm9.56(brs,1H),8.75(brs,1H), 7.51(m,5H),7.34
(m,4H),4.91(brs,2H),4.40(s,2H)。
ESI/MS：M/z=394 (M+H)+.
Embodiment 8
202 synthesis
Step 1~3 refer to 101 synthesis step respectively, are made 202.
1H NMR(400MHz,DMSO-d6)：δppm9.56(brs,1H),8.76(brs,1H), 7.52(m,5H),7.35
(m,4H),4.92(brs,2H),4.41(s,2H)。
ESI/MS：M/z=394 (M+H)+.
Embodiment 9
203 synthesis
Step 1~3 refer to 101 synthesis step respectively, are made 203.
1H NMR(400MHz,DMSO-d6)：δppm9.55(brs,1H),8.74(brs,1H), 7.51(m,5H),7.36
(m,4H),4.92(brs,2H),4.40(s,2H)。
ESI/MS：M/z=394 (M+H)+.
Embodiment 10
204 synthesis
Step 1~3 refer to 101 synthesis step respectively, are made 204.
1H NMR(400MHz,DMSO-d6)：δppm9.56(brs,1H),8.77(brs,1H), 7.52(m,3H),7.36
(m,2H),7.04(d,2H),4.93(brs,2H), 4.40(s,2H)。
ESI/MS：M/z=397 (M+H)+.
Embodiment 11
205 synthesis
Step 1~3 refer to 101 synthesis step respectively, are made 205.
1H NMR(400MHz,DMSO-d6)：δppm9.56(brs,1H),8.77(brs,1H), 8.04(s,1H),7.52
(m,5H),7.36(m,4H),7.04(d,2H),4.93(brs,2H)。
ESI/MS：M/z=397 (M+H)+.
Embodiment 12
206 synthesis
Step 1~3 refer to 101 synthesis step respectively, are made 206.
1H NMR(400MHz,DMSO-d6)：δppm9.56(brs,1H),8.77(brs,1H), 8.04(s,1H),7.96
(s,1H),7.52(m,4H),7.36(m,4H),7.04(d,2H), 4.93(brs,2H)。
ESI/MS：M/z=394 (M+H)+.
Embodiment 13
207 synthesis
Step 1~3 refer to 101 synthesis step respectively, are made 207.
1H NMR(400MHz,DMSO-d6)：δppm9.56(brs,1H),8.77(brs,1H), 8.04(s,1H),7.96
(d,1H),7.52(m,4H),7.36(m,4H),7.04(d,2H), 4.93(brs,2H)。
ESI/MS：M/z=394 (M+H)+.
Embodiment 14
208 synthesis
Step 1~3 refer to 101 synthesis step respectively, are made 208.
1H NMR(400MHz,DMSO-d6)：δppm9.56(brs,1H),8.77(brs,1H), 7.52(m,4H),7.36
(m,3H),7.04(d,2H),4.93(brs,2H)。
ESI/MS：M/z=397 (M+H)+.
Embodiment 15
301 synthesis
Step 1~3 refer to 101 synthesis step respectively, are made 301.
1H NMR(400MHz,DMSO-d6)：δppm9.56(brs,1H),8.77(brs,1H), 7.52(m,4H),7.36
(m,3H),7.04(d,2H),4.93(brs,2H)。
ESI/MS：M/z=396 (M+H)+.
Embodiment 16
302 synthesis
Step 1~3 refer to 101 synthesis step respectively, are made 302.
1H NMR(400MHz,DMSO-d6)：δppm9.56(brs,1H),8.77(brs,1H), 8.04(s,1H),7.52
(m,3H),7.36(m,3H),7.04(d,2H), 4.93(brs,2H)。
ESI/MS：M/z=396 (M+H)+.
Embodiment 17
303 synthesis
Step 1~3 refer to 101 synthesis step respectively, are made 303.
1H NMR(400MHz,DMSO-d6)：δppm9.56(brs,1H),8.77(brs,1H), 8.04(d,1H),7.52
(m,3H),7.36(m,3H),7.04(d,2H), 4.93(brs,2H)。
ESI/MS：M/z=396 (M+H)+.
Embodiment 18
304 synthesis
Step 1~3 refer to 101 synthesis step respectively, are made 304.
1H NMR(400MHz,DMSO-d6)：δppm9.56(brs,1H),8.77(brs,1H), 7.52(m,3H),7.36
(m,2H),7.04(d,2H),4.93(brs,2H)。
ESI/MS：M/z=399 (M+H)+.
Embodiment 19：
Pharmacokinetics in rats is tested
In order to comprehensively be understood the compound for newly designing and synthesizing, we are to compound 101,201 and compound
304 have carried out pharmacokinetic studies.In addition, in order to prove that newly-designed compound exists than chidamide (Chidamide)
Certain characteristic aspects improve to some extent, and chidamide has also been carried out test of the medicine for parameter by we, and its reference as a comparison
Object.
Compound 101,201,304 and chidamide are dissolved in 5% DMSO, 10% CremophorELP first, and
The solution of 2 mg/litres is made in 85% saline solution, this solution can be used to carry out intravenous injection or mouth to animal
Clothes.It is 190 grams to 215 grams that male Spraque Dawley rats, weight are used in this experiment.The dosage of intra arterial injection is 4 millis
G/kg；And oral dosage is 15 mgs/kg.Allow animal into after medicine, by jugular vein in different times point (0,
0.25,0.5,1,2,4,6,8,24 hour) extract blood sample, each data point uses the average value of three different rats
It obtains.Before analysis and test, all samples and compound doses are stored in minus 20 degree of refrigerator Celsius, chemical combination
Concentration of the object in blood plasma is measured by instrument HPLC (Shimadzu) and MS/MS (API3000).
The processing method of blood plasma is as follows：0.05 milliliter of blood plasma is put, and to 250 microlitres of IS solution in test tube, are added, (10 receive
Grams per milliliter, Quetiapine), it was vortexed by 1 minute and 5 minutes centrifugal treatings, 2 microlitres of supernatant liquor is injected LC/MS/MS instrument
In device.
Table 1 lists chidamide and compound 101,201 and 304 on rat by after intravenous injection obtained one
Serial medicine codes or data, table 2 have collected chidamide, and compound 101,201 and 304 passes through oral rear obtained one in rat
Serial medicine codes or data.
Table -1：Pharmacokinetic parameter compares (animal：Mouse；Into prescription method：Intravenous injection；Dosage：4 mgs/kg)
AUC：Area under blood drug concentration-time curve；
T1/2：Blood medicine eliminates half-life period；
Tmax：Peak time of drug refers to required time when single reaches peak value into blood concentration after medicine；
Cmax：Peak concentration of drug refers to the maximum concentration of blood medicine；
CL：Blood medicine clearance rate.
Table -2：Pharmacokinetic parameter compares (animal：Mouse；Into prescription method：It is oral；Dosage：15 mgs/kg)
AUC：Area under blood drug concentration-time curve；
T1/2：Blood medicine eliminates half-life period；
Tmax：Peak time of drug refers to required time when single reaches peak value into blood concentration after medicine；
Cmax：Peak concentration of drug refers to the maximum concentration of blood medicine；
F：Bioavailability.
From in the data of table 1 it is found that with same dose of compound by being injected intravenously rat after, compound 201,
Area (AUC) is obviously higher than chidamide under 304 blood drug concentration-time curve；The blood medicine elimination half-life period of compound 101 reaches with west
This amine is similar, but 201,304 blood medicine elimination half-life period is substantially higher than chidamide；In addition, the medicine of compound 201,304
Cmax is more much higher than chidamide, and its blood medicine clearance rate is more much lower than chidamide.
One group of pharmacokinetic data that experiment has obtained table 3 is carried out to rat with oral, can be obtained down from table
Row conclusion：Area is 1-1.6 times of chidamide under the blood drug concentration-time curve of compound 100,101,103；Compound 201,304
It is longer than chidamide that blood medicine eliminates half-life period；Peak time of drug does not have too big difference substantially in four compounds；Compound 201,304
Peak concentration of drug be the 1.38 of chidamide, 1.89 times；In addition, the bioavailability of compound 201,304 is Xi Daben respectively
1.36,1.66 times of amine.
Therefore the compounds of this invention has better pharmacokinetic parameter in animal body, thus with more preferable
Pharmacodynamics and therapeutic effect.
Embodiment 20：
Pharmaceutical composition
304 10g of compound
Starch 50g
Microcrystalline cellulose 25g
According to a conventional method, above-mentioned substance is packed into common gelatine capsule after mixing, 1000 capsules are made.
Claims (7)
1. a kind of deuterated heterocyclic carbamate derivatives, which is characterized in that shown in its structure such as formula (I)：
And its pharmaceutically acceptable salt,
Wherein, X1~X8Separately it is selected from H or D, also, X1、X2、X3、X4、X5、X6、X7、X8At least one is selected from D.
2. a kind of deuterated heterocyclic carbamate derivatives according to claim 1, which is characterized in that X5=X6、X7=X8。
3. a kind of deuterated heterocyclic carbamate derivatives according to claims 1 to 2, which is characterized in that chemical combination shown in formula (I)
Object is selected from such as lower structure：
And its pharmaceutically acceptable salt.
4. a kind of pharmaceutical composition, including therapeutically effective amount compound according to claims 1 to 3 or its can pharmaceutically connect
The salt and pharmaceutical acceptable carrier or diluent received.
5. compound or its pharmaceutically acceptable salt are preparing DNA methylase inhibitor described in claims 1 to 3 any one
Purposes in enzyme inhibitor class drug.
6. purposes according to claim 5, which is characterized in that the drug is antitumor drug.
7. according to the purposes described in claim 5~6, which is characterized in that the antitumor range includes：Breast cancer, colon cancer,
Uterine cancer, cancer of pancreas, lung cancer, gastric cancer, leukemia, lymph cancer, prostate cancer, liver cancer, cervical carcinoma, nerve metrocyte carcinoma, melanin
Tumor, solid tumor or intracranial tumors.
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| WO2023011416A1 (en) * | 2021-08-04 | 2023-02-09 | 中国海洋大学 | Multi-target inhibitor targeting hdac and nad synthesis and use of multi-target inhibitor |
| CN115703736A (en) * | 2021-08-04 | 2023-02-17 | 中国海洋大学 | Multi-target inhibitors targeting HDAC and NAD synthesis and uses thereof |
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