CN107176927A - Histone demethylase lsd1 inhibitor - Google Patents
Histone demethylase lsd1 inhibitor Download PDFInfo
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- CN107176927A CN107176927A CN201610139700.8A CN201610139700A CN107176927A CN 107176927 A CN107176927 A CN 107176927A CN 201610139700 A CN201610139700 A CN 201610139700A CN 107176927 A CN107176927 A CN 107176927A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/07—Optical isomers
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Abstract
Histone demethylase LSD1 inhibitor, the present invention relates to Formulas I containing piperazine compounds or its pharmaceutically acceptable salt and its purposes as LSD1 inhibitor:
Description
Technical field
The invention belongs to medicinal chemistry art, and in particular to a class contains piperazine compounds or its medicinal acceptable salt
And its it is used as the application of istone lysine demethylase LSD1 inhibitor.
Background technology
The improper expression or regulation and control of apparent gene albumen can cause many diseases including cancer.For example, a lot
The lesion of cancer cell tissue relates to the improper expression or regulation and control of one or more apparent gene albumen.By to being related to disease
The apparent gene albumen of change carries out interference suppression, can suppress or even reverse pathological process, so as to reach alleviation or cure disease
Purpose.There are multiple cancer therapy drug listings using apparent gene albumen as target in the world now.Apparent modification is usually
Refer to DNA methylation and the modification to histone, histone modification include acetylation, methylate, phosphorylation, extensive, glycosylation,
ADP- pentoseizations and carbonating etc..These apparent modifications occur in many different but special sites, and produce various different groups
The modification of conjunction, so as to influence the expression of gene.As histone methylated modification contributes to as heterochromatin formation, X chromosomes lose
Living, genetic transcription regulation, the maintenance of stem cell and differentiation etc..The imbalance of apparent gene modification generally results in some gene expressions
Imbalance, so as to cause disease.Increasing drugmaker starts to develop apparent gene of the small-molecule drug to imbalance at present
State is interfered, to find the new way for effectively treating some major diseases such as cancer.Particularly to istone lysine
The research of demethylation is obtaining increasing concern, and the exploitation of the inhibitor has important strategic importance, will turned into
The new focus of one of the new approaches and drug development for the treatment of cancer and tumour.
In the research and development of epigenetic medicine, istone lysine demethylase plays extremely important role,
And therefore obtained the attention of numerous researchers.Histone lysine methylation generally occur H3K4, H3K9, H3K27,
On H3K36, H3K79 and H4K20, H1 N-terminal can be also betided.Methylating for H3K4, H3K36 and H3K79 generally turns with gene
The activation of record is related, and H3K9, H3K27 are generally related to the suppression of genetic transcription to methylating for H4K20（Martin, C.;
Zhang,Y. Nat Rev Mol Cell Biol, 2005,6(11), 838-849）.Single first can occur for istone lysine
Base (Me1), di-methylation (Me2) and tri-methylated (Me3), every kind of different methylation state can play different lifes
Thing effect.The modification that methylates of histone had been considered as once once an irreversible, permanent histidine tag mistake
Journey, however, first (Lysine specific of lysine specific histone demethylase 1 in 2004
Demethylase 1, LSD1) discovery（Shi, Y.; et al. Cell2004, 119(7), 941-953）, it was confirmed that
Histone methylated is a regulatable process.The addition to methyl under being aided in by ZNFN3A1, and go
Methylase specifically removes the interaction of the single, double middle methyl group that methylates, and can dynamically adjust the first of histone
The activation and suppression of base state, the interaction of regulation histone and other functional proteins, and then controlling gene transcription, X dyes
The biological processes such as colour solid inactivation（Shi ,Y.; Whetstine, J. R. Mol Cell, 2007, 25(1),1-14;
Klose, R. J.; Zhang, Y. Nat Rev Mol Cell Biol, 2007,8(4), 307- 318）.
LSD1 also known as KIAA0601, KDM1, AOF2, BHC110, p110b and NPAO, are a kind of dependence flavin adenines two
The amine oxidase of nucleotides (Flavin adenine dinulcleotide, FAD), the C-N of the amine oxidase energy oxidation substrates
Key, generation amido, formaldehyde and hydrogen peroxide（H2O2）。Often H in catalytic process is tested in biological test by means of laboratory facilities2O2's
Yield, come the anti-activity value for pushing away its inhibitor small molecule tested.When LSD1 and substrate react, FAD is from methylating
Istone lysine obtain proton, generate FADH2, the lysine methylated lose proton generation imines intermediate product, FADH2
It is oxidized to FAD and H2O2, generation amido and formaldehyde after imines intermediate product adds water.Because the formation of intermediate product imines must
The nitrogen of a protonation must be needed, and tri-methylated lysine can not be containing the nitrogen protonated, therefore LSD1 can only be catalyzed list
The lysine substrate demethyl methylated with di-methylation.Trimethyl modification is removed then by another kind of containing JmjC domains
Protein family is completed, and the protein family of JmjC domains is relied on supplemented by Fe (II) and α-ketoglutaric acid (α-ketoglutarate)
Factor catalytic oxidation removes methyl group（Tsukada ,Y.; Fang, J. Nature2006, 439(7078),811−
816）.It is relevant with chromatinic Transcription inhibition to the process of H3K4me1 and H3K4me2 catalysis demethylation, wherein
H3K4me2 is the gene promoter of nuclear chromatin activated transcription, and tumour base can be suppressed by means of LSD1 demethylation effect
The expression of cause, plays an important role during human cytotoxic（Huang, Y.; et al. Proc Natl Acad Sci
U S A2007,104(19),8023-8028）.As can be seen here, to further cancer therapy drug of the research using LSD1 as target spot, exploitation
Compound with independent intellectual property right has important Research Significance.
Up to the present, have been demonstrated can be as LSD1 inhibitor for only a small number of existing compounds.LSD1 active site
Structure and monoamine oxidase class A and B (MAO A and MAO B), acetyl polyamine oxidase (APAO) and spermine oxidase (SMO)
There is sizable sequence homology（Shi, Y.; et al. Cell2004, 119 (7), 941-953; Lee, M. G.;
et al. Chem Biol 2006,13 (6), 563-567; Schmidt, D. M.; McCafferty, D. G.
Biochemistry2007, 46(14), 4408-4416）.Research shows that MAO inhibitor can also press down to a certain extent
LSD1 processed, wherein testing multiple choices comprising Lee et al. and non-selective MAOI, it was demonstrated that non-selection
Property MAOI have and suppress the effect of LSD1 demethylations, wherein acting on particularly bright with antidepressant parnitene
It is aobvious（Lee, M. G.;Et al. Chem Biol, 2006,13 (6), 563-567), the material is clinically to apply length
Up to the anti-depression drug Parnate (tranylcypromine) of 40 years active component；McCafferty et al. has synthesized one
The analog of the parnitene of row, after tested to LSD1 inhibition constant KiBetween 188-566 μM（Gooden, D.
M.; et al. Bioorg Med Chem Lett 2008, 18(10), 3047-3051）, while these analogs are directed to
MAO A and MAO B suppression efficiency improve the 1-2 order of magnitude.Recent years, Ueda and his colleague identify some anti-benzene
Cyclopropylamine analog its there is selective depression effect to LSD1 and MAO A, MAO B（Ueda, R.; et al. J Am
Chem Soc2009,131(48),17536-17537）.Binda et al. some parnitene analogs are identified with
Afterwards, it is found that it embodies partial selective inhibition to LSD1 and a kind of new histone demethylase LSD2（Binda,
C.; et al. J Am Chem Soc 2010, 132, ePub 10.1021/jal01557k）.LSD2 is similar with LSD1, has
Can specifically be removed in vitro under FAD participation H3K4 monomethyl and dimethyl modification, but biology propose LSD2 with
LSD1 difference is that in vitro, the albumen such as LSD2 and CoREST can not form compound, up to the present be included at any one
LSD2 can not be all found in LSD1 protein complexes（Yang, Z.; et al. Cell. Res 2010,20(3), 276-
287）.
In the patent and document for the relevant LSD1 inhibitor announced at present, most of invention all surrounds parnitene
As the leading skeleton of molecule, the inhibitor molecules for having finer selection inhibition for LSD1 are designed on this basis.
Wherein protruded the most with Hispanic Oryzon Genomics companies especially, though the scheme of the invention that they propose is with parnitene
For the inhibitor of frame design, but great lifting is obtained in the selectivity to LSD1 inhibitions.
The present invention is had found using computer virtual screening and Computer Aided Design, the method for Binding experiment detection and has been synthesized one
Series, as the inhibitor for having preferable inhibition to LSD1 activity, can be used for and histone demethyl containing piperazine compounds
Change the prevention and treatment of the disease and symptom of the activity correlation of enzyme.
The content of the invention
It is used to develop the lead drug for suppressing LSD1 activity it is an object of the invention to provide a class compound.
There is below formula containing piperazine compounds or its pharmaceutically acceptable salt present invention firstly provides one kind：
Ⅰ
Wherein：
A is hydrogen, carbonyl or thiocarbonyl；
R1For cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl；Wherein cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl select 0-3 respectively
Individual R ' substituents replace to it；
R2For H, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl；Wherein alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl
Base selects 0-3 R ' substituent to replace it respectively；
R3For aryl or heteroaryl；The wherein optional 0-3 R ' substituents of aryl or heteroaryl replace to it；
R ' is：C1-C6Alkyl, halogen, hydroxyl, alkoxy, amino, nitro, cyano group, acyl group, carboxyl, phenyl, benzyl, ether or
Carboxylic acid ester groups.
The medicinal acceptable salt includes acetate, sulfate, hydrochloride, oxalates and phosphate.
If general formula can be obtained when limiting A in formula I as=O：
Ⅱ
Wherein：
R1For cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl；The wherein optional 0-3 of cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl
Individual R ' substituents replace to it；
R2For H, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl or halogen；Wherein alkyl, cycloalkyl, Heterocyclylalkyl, virtue
The optional 0-3 R ' substituents of base or heteroaryl replace to it；
R3For aryl or heteroaryl；The wherein optional 0-3 R ' substituents of aryl or heteroaryl replace to it；
R ' is：C1-C6Alkyl, halogen, hydroxyl, amino, nitro, cyano group, acyl group, carboxyl, phenyl, benzyl, ether or carboxylate
Base.
Such as limit the R in formula II3General formula can be obtained during for substituted-phenyl：
Ⅲ
Wherein：
R1For cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl；The wherein optional 0- of cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl
3 R ' substituents replace to it；
R2For H, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl or halogen；Wherein alkyl, cycloalkyl, Heterocyclylalkyl, virtue
The optional 0-3 R ' substituents of base or heteroaryl replace to it；
X is hydroxyl, alkoxy or halogen.
If limiting the R in general formula III2For benzyl, X can obtain the structure or its isomers of general formula when being OH：
IV
Wherein：
R1For cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl；The wherein optional 0- of cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl
3 R ' substituents replace to it；
R ' is：C1-C6Alkyl, halogen, hydroxyl, alkoxy, amino, nitro, cyano group, acyl group, carboxyl, phenyl, benzyl, ether or
Carboxylic acid ester groups.
If limiting the R in formula IV1During for 2- pyrrolidines, the structure or its isomers of general formula can be obtained：
V。
If general formula can be obtained when limiting the A in formula I as hydrogen：
VI
Wherein：
R1For cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl；The wherein optional 0- of cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl
3 R ' substituents replace to it；
R2For H, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl or halogen；Wherein alkyl, cycloalkyl, Heterocyclylalkyl, virtue
The optional 0-3 R ' substituents of base or heteroaryl replace to it；
R3For aryl or heteroaryl；The wherein optional 0-3 R ' substituents of aryl or heteroaryl replace to it；
R ' is：C1-C6Alkyl, halogen, hydroxyl, alkoxy, amino, nitro, cyano group, acyl group, carboxyl, phenyl, benzyl, ether or
Carboxylic acid ester groups.
Such as limit the R in formula VI3General formula can be obtained during for substituted-phenyl：
VII
Wherein：
R1For cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl；Wherein cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl it is optional
0-3 R ' substituent replaces to it；
R2For H, alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl or halogen；Wherein alkyl, cycloalkyl, Heterocyclylalkyl, virtue
The optional 0-3 R ' substituents of base or heteroaryl replace to it；
X is hydroxyl, alkoxy or halogen.
R ' is：C1-C6Alkyl, halogen, hydroxyl, alkoxy, amino, nitro, cyano group, acyl group, carboxyl, phenyl, benzyl, ether
Base or carboxylic acid ester groups.
If limiting the R in formula VII2For phenyl, X can obtain the structure or its isomers of general formula when being OH：
VII
Wherein：
R1For cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl；The wherein optional 0- of cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl
3 R ' substituents replace to it；
R ' is：C1-C6Alkyl, halogen, hydroxyl, alkoxy, amino, nitro, cyano group, acyl group, carboxyl, phenyl, benzyl, ether or
Carboxylic acid ester groups.
R in restriction formula VIII1During for N- propyl group -2- pyrrolidines, described has IX institutes containing piperazine compounds
The structure shown or its configurational isomer：
IX。
Containing piperazine compounds or its medicinal acceptable salt histone is being prepared present invention also offers described
Application in methylase LSD1 inhibitor medicaments.
External LSD1 active suppression tests show that the piperazine compounds cited by the present invention have obvious to LSD1 activity
Inhibitory action, can as active component be used for prepare LSD1 inhibitor medicaments.
Embodiment
The present invention is as follows for the NMR and mass spectrographic device information of test compound：
NMR：
Instrument production man title：BRUKER
INSTRUMENT MODEL (Model): AVANCE Ⅱ 400
Instrument frequency：400 MHz
The conventional deuterated reagent of test：CDCl3, d6-DMSO
LC-MS:
Instrument production man title：WATERS
INSTRUMENT MODEL (Model):UPLC-SQD
The conventional solvent orange 2 A of test：0.1% Formic acid+ Water
The conventional solvent B of test: 0.1% Formic acid + Acetonitrile.
The formula of embodiment 1（I）The preparation of shown derivative (compound -1)
4- ((R) -3- phenyl -4- (((R) -1- propyl pyrrole quinoline -2- bases) methylene) piperazine -1- bases) phenol（Hereinafter referred to as change
Compound 1）Preparation
Compound -1
The compound can be made by the steps：
The preparation of 1.1 (R) -2- (2- (benzyloxycarbonyl amino) acetylamino) -2- phenylacetates (1-2)
2- benzyloxycarbonyl aminos acetic acid (1-1)（2.98 g）With R-2- amino -2- phenylacetate hydrochlorides（3.0 g,
14.3 mmol）It is suspended in anhydrous methylene chloride（30 mL）, add HBTU (6.66 g) and DIEA (7.4 g, 57.4
mmol).After reaction mixture is stirred overnight at room temperature, water is added（10 mL）, divide after liquid, organic phase is extracted twice with dichloromethane
（10 mL×2）, the organic phase of merging washed once with saturated common salt, with anhydrous sodium sulfate drying, is concentrated under reduced pressure to give after filtering
Crude product.Obtain 3 grams of colorless oil (R) -2- (2- (benzyloxycarbonyl amino) acetylamino) -2- phenyl second after purification with silicagel column
Sour methyl esters (1-2).LC-MS (ESI): m/z (M+1) 357.2.
The preparation of phenylpiperazine -2,5- diketone (1-3)
(R) -2- (2- (benzyloxycarbonyl amino) acetylamino) -2- phenylacetates (1-2)（3.0 g）And palladium carbon（300
mg）Suspend in methyl alcohol（50 mL）, under conditions of hydrogen, 6 hours of reaction are stirred at room temperature in reaction mixture.LC-MS is tracked
Reaction, raw material reaction is complete, then filters, and filtrate continues to be stirred and heated to 60 DEG C overnight.It is concentrated under reduced pressure after removing organic solvent
Obtain 1.5 grams of white solid (R) -3- phenylpiperazine -2,5- diketone (1-3). LC-MS (ESI): m/z (M+1) 191.1.
The preparation of phenylpiperazine (1-4)
(R) -3- phenylpiperazines -2,5- diketone (1-3)（1.5 g）It is dissolved in anhydrous THF（20 mL）In, 0 DEG C is cooled to, four are added
Hydrogen lithium aluminium（1.49 g）.Reaction mixture is slowly raised to room temperature after 0 DEG C is reacted 30 minutes, is then heated to 70 DEG C overnight.It is cold
To room temperature, water is added（1.5 mL）Reaction is quenched, adds sodium hydroxide solution 1.5mL, adds water after 4mL, filter and use second
Acetoacetic ester washes solid, and 1.1 grams of yellow solid (R) -2- phenylpiperazines (1-4) are obtained after filtrate decompression concentration. LC-MS (ESI):
m/z (M+1) 163.1。
Tertiary butyl dimethyl Si) phenyl) -3- phenylpiperazines (1-5) preparation
(R) -2- phenylpiperazines (1-4)（300 mg）And 1-（Tertiary butyl dimethyl Si base）- 4- bromobenzenes（372 mg）It is suspended in
Toluene（5 mL）In, add Pd2(dba)3(84 mg), Dave-phose (48 mg) and sodium tert-butoxide（540 mg）.Reaction is mixed
Close liquid and be heated to 100 DEG C of 1 hours of reaction under nitrogen protection.It is as cold as after room temperature, is concentrated under reduced pressure, silica gel column chromatography separating purification
Oily (R) -1- (4- (tertiary butyl dimethyl Si) phenyl) -3- phenylpiperazines (1-5) of 300mg yellow are obtained afterwards. LC-MS
(ESI): m/z (M+1) 369.2。
Tertiary butyl dimethyl Si) phenyl) -2- phenylpiperazine -1- bases) methyl) pyrrolin -1- carboxylic acid tert-butyl esters (1-6)
Preparation
(R) -1- (4- (tertiary butyl dimethyl Si) phenyl) -3- phenylpiperazines (1-5)（200 mg）With N-Boc-D- dried meat ammonia
Aldehyde（130 mg）It is dissolved in dichloromethane（5 mL）In, add Sodium triacetoxyborohydride（345 mg）.Reaction mixture is in room temperature
2 hours of stirring reaction, saturated sodium bicarbonate solution is added, is extracted with dichloromethane, the organic phase saturated aqueous common salt of merging
Wash, after anhydrous sodium sulfate drying, be concentrated under reduced pressure to give crude product.Then silica gel column chromatography separating purification is used, colourless oil is obtained
Shape thing (R) -2- (((R) -4- (4- (tertiary butyl dimethyl Si) phenyl) -2- phenylpiperazine -1- bases) methyl) pyrrolin -1- carboxylics
The mg of tert-butyl acrylate (1-6) 140. LC-MS (ESI): m/z (M+1) 552.3.
Tertiary butyl dimethyl Si) phenyl) -2- phenyl -1- ((R)-nafoxidine -2- methylenes) piperazine (1-7)
Prepare
(R) -2- (((R) -4- (4- (tertiary butyl dimethyl Si) phenyl) -2- phenylpiperazine -1- bases) methyl) pyrrolin -1- carboxylics
Tert-butyl acrylate (1-6)（140 mg）It is dissolved in 1,4- dioxane（1 mL）, add 4N hydrochloric acid dioxane（5 mL）, reaction
Reaction 30 minutes is stirred at room temperature in mixed liquor, and the removing solvent that is concentrated under reduced pressure obtains (R) -4- (4- (tertiary butyl dimethyl Si) benzene
Base) -2- phenyl -1- ((R)-nafoxidine -2- methylenes) piperazine (1-7), it is directly used in next step reaction.LC-MS
(ESI): m/z (M+1) 452.3。
Tertiary butyl dimethyl Si base) phenyl) -2- phenyl -1- (((R) -1- propyl pyrrole quinoline -2- bases) methylene) piperazine
The preparation of (1-8)
(R) -4- (4- (tertiary butyl dimethyl Si) phenyl) -2- phenyl -1- ((R)-nafoxidine -2- methylenes) piperazine
(1-7)（114 mg）With positive propionic aldehyde（18 mg）Colourless grease is obtained using with step 1.5 identical Examination on experimental operation
(R) -4- (4- (tertiary butyl dimethyl Si base) phenyl) -2- phenyl -1- (((R) -1- propyl pyrrole quinoline -2- bases) methylene) piperazine
The mg of piperazine (1-8) 110. LC-MS (ESI): m/z (M+1) 494.3.
Phenyl -4- (((R) -1- propyl pyrrole quinoline -2- bases) methylene) piperazine -1- bases) phenol (compound 1) preparation
(R) -4- (4- (tertiary butyl dimethyl Si base) phenyl) -2- phenyl -1- (((R) -1- propyl pyrrole quinoline -2- bases) methylenes
Base) piperazine (1-8)（110 mg）It is dissolved in Isosorbide-5-Nitrae-dioxane（0.5 mL）, add 4N hydrochloric acid dioxane（5 mL）, reaction solution
It is stirred overnight at room temperature.After being concentrated under reduced pressure, methanol is dissolved in（3 mL）, add ammoniacal liquor and neutralize, directly with preparation HPLC separation（It is anti-phase
C18 posts, mobile phase：10 to 95% acetonitrile and water, containing 0.1% formic acid）Obtain white solid 4- ((R) -3- phenyl -4- (((R) -1-
Propyl pyrrole quinoline -2- bases) methylene) piperazine -1- bases) 35 mg of phenol (compound 1).LC-MS (ESI): m/z (M+1)
380.2。
1 (400 MHz, DMSO) δ 8.19 (s, 1H), 7.45 – 7.24 (m, 5H), 6.76 (d, J =
8.9 Hz, 2H), 6.62 (d, J = 8.9 Hz, 2H), 3.42 (d, J = 11.0 Hz, 2H), 3.31 – 3.25
(m, 3H), 3.00 – 2.94 (m, 1H), 2.77 – 2.67 (m, 2H), 2.58 – 2.52 (m, 2H), 2.42
– 2.37 (m, 1H), 2.35 – 2.29 (m, 1H), 2.01 – 1.92 (m, 2H), 1.87 – 1.78 (m,
1H), 1.65 – 1.49 (m, 2H), 1.43 – 1.22 (m, 3H), 0.76 (t, J = 7.4 Hz, 3H)。
The formula of embodiment 2（I）The preparation of shown derivative (compound -2)
(R) -4- (3- phenyl -4- (piperidin-4-yl methylene) piperazine -1- bases) phenol（Hereinafter referred to as compound 2）Preparation
Compound -2
The compound can be made by the steps：
2.1 (R)-1-（4-（N- t-butoxycarbonylpiperidin bases）Methylene）- 2- phenyl -4- (4- (tertiary butyl dimethyl Si base)
Phenyl)）The preparation of piperazine (2-1)
(R) -1- (4- (tertiary butyl dimethyl Si) phenyl) -3- phenylpiperazines (1-5)（100 mg）With 1- tertbutyloxycarbonyl piperazines
Pyridine -4- formaldehyde（69 mg）(R) -1- is obtained using with step 1.5 identical Examination on experimental operation（4-（N- t-butoxycarbonylpiperidins
Base）Methylene）- 2- phenyl -4- (4- (tertiary butyl dimethyl Si base) phenyl)）Piperazine（2-1）130 mg.LC-MS (ESI):
m/z (M+1) 566.4。
Phenyl -4- (piperidin-4-yl methylene) piperazine -1- bases) phenol (Compound 2) preparation
(R)-1-（4-（N- t-butoxycarbonylpiperidin bases）Methylene）- 2- phenyl -4- (4- (tertiary butyl dimethyl Si base) benzene
Base)）Piperazine（2-1）（130 mg）(R) -4- (3- phenyl -4- (piperazines are obtained using with step 1.8 identical Examination on experimental operation
Pyridine -4- methylenes) piperazine -1- bases) phenol (Compound 2)9 mg。 LC-MS (ESI): m/z (M+1) 352.2。
1 (400 MHz, DMSO) δ 8.85 (br, 1H), 8.42 (s, 1H), 7.42 – 7.23 (m, 5H),
6.76 (d, J = 9.0 Hz, 2H), 6.62 (d, J = 8.9 Hz,2H), 3.51-3.41 (m, 1H), 3.34 –
3.22 (m, 4H), 3.20 – 3.13 (m, 1H), 3.06 – 2.95 (m, 2H), 2.76 – 2.68 (m, 1H),
2.62 – 2.57 (m, 1H), 2.27 – 2.18 (m, 1H), 2.14 – 2.06 (m, 1H), 2.00 – 1.93
(m, 1H), 1.83 – 1.69 (m, 2H), 1.50 – 1.41 (m, 1H), 0.95 – 0.75 (m, 2H)。
The formula of embodiment 3（I）The preparation of shown derivative (compound -3)
(S) -4- (4- (4- hydroxybenzyls) -3- phenylpiperazine -1- bases) phenol（Hereinafter referred to as compound 3）Preparation
Compound -3
The compound can be made by the steps：
The preparation of 3.1 (S) -2- (2- (benzyloxycarbonyl amino) acetylamino) -2- phenylacetates (3-2)
2- benzyloxycarbonyl aminos acetic acid (3-1)（2.98 g）With S-2- amino -2- phenylacetate hydrochlorides（3.0 g）It is molten
In dry DMF（30 mL）, add HBTU (6.66 g) and DIEA (7.4 g).After reaction mixture is stirred overnight at room temperature,
Add water（30 mL）And ethyl acetate（10 mL）, divide after liquid, aqueous phase is extracted with ethyl acetate（10 mL X 3）, merging has
Machine is washed 3 times with salt, and with anhydrous sodium sulfate drying, crude product is concentrated under reduced pressure to give after filtering.5 are obtained after purification with silicagel column
Gram colorless oil (S) -2- (2- (benzyloxycarbonyl amino) acetylamino) -2- phenylacetates (3-2).LC-MS (ESI):
m/z (M+1) 357.2。
The preparation of phenylpiperazine -2,5- diketone (3-3)
(S) -2- (2- (benzyloxycarbonyl amino) acetylamino) -2- phenylacetates (3-2)（5 g）Using with step 1.2 phase
Same Examination on experimental operation obtains (S) -3- phenylpiperazine -2,5- diketone（3-3）2.6 gram. LC-MS (ESI): m/z (M+
1) 191.1。
The preparation of phenylpiperazine (3-4)
(S) -3- phenylpiperazines -2,5- diketone（3-3）（200 mg）Obtained using with step 1.3 identical Examination on experimental operation
(S) -2- phenylpiperazines（3-4）150 mg.LC-MS (ESI): m/z (M+1) 163.1.
The preparation of 3.4 (S) -1- (4- (tertiary butyl dimethyl Si) phenyl) -3- phenylpiperazines (3-5)
((S) -2- phenylpiperazines（3-4）（100 mg）(S) -1- (4- are obtained using with step 1.4 identical Examination on experimental operation
(tertiary butyl dimethyl Si) phenyl) -3- phenylpiperazines（3-5）100mg.LC-MS (ESI): m/z (M+1) 369.2.
Tertiary butyl dimethyl Si base) phenyl) -2- phenylpiperazine -1- bases) methylene) phenol (3-6) preparation
(S) -1- (4- (tertiary butyl dimethyl Si) phenyl) -3- phenylpiperazines (3-5)（100 mg）With 4- hydroxy benzaldehydes（40
mg）Using with step 1.5 identical Examination on experimental operation obtain (S) -4- ((4- (4- (tertiary butyl dimethyl Si base) phenyl) -
2- phenylpiperazine -1- bases) methylene) 60 mg of phenol (3-6). LC-MS (ESI): m/z (M+1) 475.2.
Hydroxybenzyl) -3- phenylpiperazine -1- bases) phenol (Compound 3) preparation
(S) -4- ((4- (4- (tertiary butyl dimethyl Si base) phenyl) -2- phenylpiperazine -1- bases) methylene) phenol (3-6)
（60 mg, 0.13 mmol）(S) -4- (4- (4- hydroxybenzyls) -3- are obtained using with step 1.8 identical Examination on experimental operation
Phenylpiperazine -1- bases) 17 mg of phenol (compound 3).LC-MS (ESI): m/z (M+1) 361.2.
1 (400 MHz, DMSO) δ 9.79 (s, 1H), 8.20 (s,1H), 7.54 (d, J = 7.4 Hz,
2H), 7.40 (t, J = 7.5 Hz, 2H), 7.31 (t, J = 7.3 Hz, 1H), 7.04 (d, J = 8.3 Hz,
2H), 6.64-6.78 (m, 4H), 6.61 (d, J = 8.9 Hz, 2H), 3.59 – 3.52 (m, 1H), 3.44 –
3.33 (m,3H), 2.88 – 2.74 (m, 2H), 2.68 – 2.53 (m, 2H), 2.29 – 2.18 (m, 1H)。
The formula of embodiment 4（I）The preparation of shown derivative (compound -4)
(R) -4- (3- phenyl -4- (piperidin-4-yl methylene) piperazine -1- bases) phenol（Hereinafter referred to as compound -4）Preparation
Compound -4
The compound can be made by the steps：
The preparation of 4.1 (S) -4- (benzyloxycarbonyl amino) -3- oxygen -5- phenylvaleric acids methyl esters (4-2)
(S) -2- (benzyloxycarbonyl amino) -3- phenylpropionic acids (4-1)（3 g）Used and step 1.1 phase with 2- methyl aminoacetates
Same Examination on experimental operation obtains 1.5 grams of (S) -4- (benzyloxycarbonyl amino) -3- oxygen -5- phenylvaleric acids methyl esters (4-2). LC-MS
(ESI): m/z (M+1) 356.2。
The preparation of benzyl diethylenediamine -2,5- diketone (4-3)
(S) -4- (benzyloxycarbonyl amino) -3- oxygen -5- phenylvaleric acids methyl esters (4-2)（1.5 g）Using real with step 1.2 identical
Test operating method and obtain (S) -3- benzyl diethylenediamine -2,5- diketone (4-3) 800 mg. LC-MS (ESI): m/z (M+1)
205.1。
The preparation of benzyl diethylenediamine (4-4)
((S) -3- benzyl diethylenediamine -2,5- diketone (4-3)（800 mg）Obtained using with step 1.3 identical Examination on experimental operation
(S) -2- benzyl diethylenediamines（4-4）560 mg. LC-MS (ESI): m/z (M+1) 177.1.
The preparation of 4.4 (S) -3- benzyls -1- (4- (tertiary butyl dimethyl Si base) phenyl) piperazine (4-5)
(S) -2- benzyl diethylenediamines（4-4）（100 mg）Using with step 1.4 identical Examination on experimental operation obtain (S) -3- benzyls -
The mg of 1- (4- (tertiary butyl dimethyl Si base) phenyl) piperazine (4-5) 100. LC-MS (ESI): m/z (M+1) 383.2.
Tertbutyloxycarbonyl pyrrolinyl)-(2- (R)-carbonyl)) -2- ((S) -2- benzyls) -4- (4- (tert-butyldimethyl silyls
Epoxide) phenyl) piperazine (4-6) preparation
(S) -3- benzyls -1- (4- (tertiary butyl dimethyl Si base) phenyl) piperazine (4-5)（100 mg）With Boc-D- proline
（57 mg）1- ((N- tertbutyloxycarbonyls pyrrolinyl)-(2- (R)-carbonyl are obtained using with step 1.1 identical Examination on experimental operation
Base)) 130 mg of -2- ((S) -2- benzyls) -4- (4- (tertiary butyl dimethyl Si base) phenyl) piperazine (4-6). LC-MS
(ESI): m/z (M+1) 380.4。
Pyrrolin -2- carbonyls) (S) -2- benzyls -4- (4- hydroxy phenyls) piperazines (compound -4) preparation
1- ((N- tertbutyloxycarbonyls pyrrolinyl)-(2- (R)-carbonyl)) -2- ((S) -2- benzyls) -4- (4- (fert-butyidimethylsilyls
Siloxy) phenyl) piperazine (4-6)（130 mg）(S) -4- (4- (4- are obtained using with step 1.8 identical Examination on experimental operation
Hydroxybenzyl) -3- phenylpiperazine -1- bases) 30 mg of phenol (compound 4). LC-MS (ESI): m/z (M+1) 366.2.
1 (400 MHz, CDCl3) δ 8.61 (s, 1H), 7.28 – 7.16 (m, 5H), 6.79 (d, J =
8.3 Hz, 2H), 6.65 (d, J = 8.3 Hz, 2H), 4.93 (s, 1H), 4.62 (s, 1H), 3.43 –
3.24 (m, 3H), 3.22 – 2.95 (m, 5H), 2.31 – 2.24 (m, 1H), 2.21 – 2.10 (m, 1H),
2.07 – 1.98 (m, 1H), 1.93 – 1.82 (m, 1H), 1.53 – 1.42 (m, 1H), 1.16 – 1.04
(m, 1H).
The external enzyme inhibition activities of LSD1 of the above-claimed cpd of embodiment 5 are determined：
1. experimental method
Using the LSD1 Fluorimetric Drug Discovery Kit purchased from Enzo Life Sciences
（Instruction Manual BML-AK544）Kit tests above-claimed cpd（Also known as implement compound）To LSD1 activity
Influence.I.e. with the H3-K4 peptides (H3K4me2) of di-methylation（BML-P256）It is used as substrate.LSD1（BML-SE544）It can be catalyzed
H3K4me2 produces H2O2, in CELLestialTMIn the presence of Red matrix (BML-KI565), catalase
（HRP）H can be catalyzed2O2Produce fluorescence signal（Excite：530-570nm, transmitting：590nm）.This fluorescence signal and LSD1 activity are in
Positive correlation, fluorescence intensity is stronger, and enzymatic activity is stronger, and the inhibitory activity for surveying compound to enzyme is lower.
Specifically, using parnitene as positive control, to be not added with any compound as negative control, each concentration weight
Again twice, first added in 384 orifice plates by 27.2 μ L assay buffer, 0.1 μ g/ μ L the μ L of LSD1 enzymes 5 and gradient dilution
Implementation compound 0.8 μ L or dH2The μ L of O 0.8 or parnitene（TCP）" 2 × the Enzymes ", in room of 0.8 μ L compositions
Under temperature（23°C）Reaction 30 minutes, is added by 6.7 μ L assay buffer, 0.5 mM H3K4me2 substrates 1.6 μ L, and 100
× CELLestialTMRed 0.4 μ L and 50 × HRP 0.8 μ L composition " after 2 × Substrates ", use at once
SpectraMax （Excite：530-570nm, transmitting：590nm）Dynamic reads fluorescent value, surveys data and uses SoftMax Pro again
6.2.2 software fitting is so as to obtain the IC50 values of surveyed compound.
2. experimental result
What following table was listed is the active situation of the external LSD1 enzymes experiment of the compounds of this invention.
The active situation of the compounds of this invention vitro enzyme of table 1 experiment
Implementation compound -1 can be seen that by IC50 (uM) value of table 1, -2, -3, -4 couples of LSD1 rejection ability is respectively
102 times of TCP, 31 times, 19 times and 76 times, therefore compound -1, -2, -3 and -4 belong to LSD1 highly efficient depressor.
The LSD1 inhibitor that embodiment 6 has been screened is in inhibitory action of the cellular level to LSD1 activity:
1. implement compound to liver cancer cells（HepG2）Inhibition test（MTT experiment）
HepG2 cells are cultivated in 96 orifice plates for adding 100 μ L DMEM culture mediums/hole, make cell dense
Degree reaches 1 × 104Cells/well, using final concentration of 0.02% DMSO as negative control, using TCP as positive control, with
The implementation compound nurse cell of gradient concentration is after 48 hours, according to the MTT Cell Proliferation of green skies company
and Cytotoxicity Assay Kit（C0009）Operation requires configuration, and 5mg/ml MTT solution adds 10 μ L per hole
MTT solution, continues to be incubated 4 hours in cell culture incubator, 100 μ L Formanzan lysates is added per hole, in cell culture
It is further continued for being incubated in case.Until observation finds that Formazan all dissolves under ordinary optical microscope.Usual 37 DEG C of incubations 4 are small
When or so, after purple crystal can all dissolve, absorbance is determined in 570nm.According to light absorption value, using Graph Pad Prism5
Software, mapping, can obtain the IC50 values of the inhibitory action of compound on intracellular.
2. experimental result
What following table was listed is inhibitory action situation of the compounds of this invention to HepG2 cells.The result of table 2 shows, noval chemical compound 1-4
There is inhibitory action to HepG2 liver cancer cell lines.The compound concentration of gradient dilution is respectively 10.00,3.00,0.90,0.27,
0.08,0.02 and 0.007 micromole, extent of cell growth inhibition and compound dose proportional.Numeral is maximum to produce in table
Suppress 50% when compound concentration be IC50 values.TCP is used as positive control for known LSD1 inhibitor.
Inhibitory action of the compounds of this invention of table 2 to HepG2 cells
Claims (10)
1. one kind contains piperazine compounds or its medicinal acceptable salt, it is characterised in that：It is described to have containing piperazine compounds
There are the structure or its configurational isomer shown in formula I,
Ⅰ
Wherein：
A is hydrogen, carbonyl or thiocarbonyl；
R1For cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl；Wherein cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl select 0-3 R '
Substituent replaces to it；
R2For H, alkyl, cycloalkyl, heterocycloalkylaryl or heteroaryl；Wherein alkyl, cycloalkyl, heterocycloalkylaryl or heteroaryl
Base selects 0-3 R ' substituent to replace it；
R3For aryl or heteroaryl；Wherein aryl or heteroaryl select 0-3 R ' substituent to replace it；
R ' is C1-C6Alkyl, halogen, hydroxyl, alkoxy, amino, nitro, cyano group, acyl group, carboxyl, phenyl, benzyl, ether or carboxylic
Perester radical.
2. according to claim 1 contain piperazine compounds or its medicinal acceptable salt, it is characterised in that：When formula I
In A be carbonyl when, the structure or its configurational isomer having containing piperazine compounds shown in formula II：
Ⅱ。
3. according to claim 2 contain piperazine compounds or its medicinal acceptable salt, it is characterised in that：When formula II
In R3During for substituted-phenyl, the structure or its configurational isomer having containing piperazine compounds shown in formula III：
Ⅲ
Wherein：
X is hydroxyl, alkoxy or halogen.
4. according to claim 3 contain piperazine compounds or its medicinal acceptable salt, it is characterised in that：Work as formula
R in III2For benzyl, when X is hydroxyl, the structure or its configuration isomery having containing piperazine compounds shown in formula IV
Body：
IV。
5. according to claim 4 contain piperazine compounds or its medicinal acceptable salt, it is characterised in that：Work as formula IV
In R1During for 2- pyrrolidines, the structure or its configurational isomer having containing piperazine compounds shown in V：
V。
6. according to claim 1 contain piperazine compounds or its medicinal acceptable salt, it is characterised in that：When formula I
In A be hydrogen when, the structure or its configurational isomer having containing piperazine compounds shown in Formula IV：
VI。
7. according to claim 6 contain piperazine compounds or its medicinal acceptable salt, it is characterised in that：Work as Formula IV
In R3During for substituted-phenyl, the structure or its configurational isomer having containing piperazine compounds shown in Formula VII：
VII
Wherein：
X is hydroxyl, alkoxy or halogen.
8. according to claim 7 contain piperazine compounds or its medicinal acceptable salt, it is characterised in that：Work as formula
R in VII2It is described to have structure or its configuration shown in Formula VIII different containing piperazine compounds when X is hydroxyl for phenyl
Structure body：
VIII。
9. according to claim 8 contain piperazine compounds or its medicinal acceptable salt, it is characterised in that：Work as formula
R in VIII1It is described to have structure or its configuration shown in IX different containing piperazine compounds during for N- propyl group -2- pyrrolidines
Structure body：
IX。
10. as claimed in any one of claims 1-9 wherein containing piperazine compounds or its medicinal acceptable salt in preparation group
Application in albumen demethylase LSD1 inhibitor medicaments.
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Cited By (7)
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| WO2018083189A1 (en) | 2016-11-03 | 2018-05-11 | Oryzon Genomics, S.A. | Biomarkers for determining responsiveness to lsd1 inhibitors |
| US10800757B2 (en) | 2017-10-27 | 2020-10-13 | Boehringer Ingelheim International Gmbh | Inhibitors of TRPC6 |
| WO2021004610A1 (en) | 2019-07-05 | 2021-01-14 | Oryzon Genomics, S.A. | Biomarkers and methods for personalized treatment of small cell lung cancer using kdm1a inhibitors |
| WO2022214303A1 (en) | 2021-04-08 | 2022-10-13 | Oryzon Genomics, S.A. | Combinations of lsd1 inhibitors for treating myeloid cancers |
| WO2023217784A1 (en) | 2022-05-09 | 2023-11-16 | Oryzon Genomics, S.A. | Methods of treating nf1-mutant tumors using lsd1 inhibitors |
| WO2023217758A1 (en) | 2022-05-09 | 2023-11-16 | Oryzon Genomics, S.A. | Methods of treating malignant peripheral nerve sheath tumor (mpnst) using lsd1 inhibitors |
| WO2024110649A1 (en) | 2022-11-24 | 2024-05-30 | Oryzon Genomics, S.A. | Combinations of lsd1 inhibitors and menin inhibitors for treating cancer |
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|---|---|---|---|---|
| WO2018083189A1 (en) | 2016-11-03 | 2018-05-11 | Oryzon Genomics, S.A. | Biomarkers for determining responsiveness to lsd1 inhibitors |
| US10800757B2 (en) | 2017-10-27 | 2020-10-13 | Boehringer Ingelheim International Gmbh | Inhibitors of TRPC6 |
| US10889568B2 (en) | 2017-10-27 | 2021-01-12 | Boehringer Ingelheim International Gmbh | Inhibitors of TRPC6 |
| USRE49699E1 (en) | 2017-10-27 | 2023-10-17 | Boehringer Ingelheim International Gmbh | Inhibitors of TRPC6 |
| WO2021004610A1 (en) | 2019-07-05 | 2021-01-14 | Oryzon Genomics, S.A. | Biomarkers and methods for personalized treatment of small cell lung cancer using kdm1a inhibitors |
| WO2022214303A1 (en) | 2021-04-08 | 2022-10-13 | Oryzon Genomics, S.A. | Combinations of lsd1 inhibitors for treating myeloid cancers |
| WO2023217784A1 (en) | 2022-05-09 | 2023-11-16 | Oryzon Genomics, S.A. | Methods of treating nf1-mutant tumors using lsd1 inhibitors |
| WO2023217758A1 (en) | 2022-05-09 | 2023-11-16 | Oryzon Genomics, S.A. | Methods of treating malignant peripheral nerve sheath tumor (mpnst) using lsd1 inhibitors |
| WO2024110649A1 (en) | 2022-11-24 | 2024-05-30 | Oryzon Genomics, S.A. | Combinations of lsd1 inhibitors and menin inhibitors for treating cancer |
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