CN110478352A - 5- cyano -6- phenyl-pyrimidine compound containing triazolyl is inhibiting application and LSD1 inhibitor in LSD1 - Google Patents

5- cyano -6- phenyl-pyrimidine compound containing triazolyl is inhibiting application and LSD1 inhibitor in LSD1 Download PDF

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Publication number
CN110478352A
CN110478352A CN201910813548.0A CN201910813548A CN110478352A CN 110478352 A CN110478352 A CN 110478352A CN 201910813548 A CN201910813548 A CN 201910813548A CN 110478352 A CN110478352 A CN 110478352A
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lsd1
cyano
phenyl
compound containing
chlorine
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刘宏民
马立英
郑一超
王豪杰
游英华
刘月娇
郑甲信
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Zhengzhou University
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Zhengzhou University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D401/14—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 three or more hetero rings

Abstract

The invention belongs to medicinal chemistry arts, the present invention provides a kind of, and the 5- cyano -6- phenyl-pyrimidine compound containing triazolyl is inhibiting application and LSD1 inhibitor in LSD1,5- cyano -6- phenyl-pyrimidine the compound containing triazolyl has structure shown in Formulas I, R in the Formulas I1For H, 3,4,5 ,-trimethoxy, methyl, isopropyl, chlorine, bromine or thiophene, R2For H, methyl, isopropyl, fluorine, chlorine, nitro, trifluoromethyl or methoxyl group.5- cyano -6- phenyl-pyrimidine compound containing triazolyl of the invention can significantly inhibit the activity of LSD1, it is thus possible to be used to prepare the inhibitor of LSD1, can be used as the candidate further developed or lead compound is used to prepare anticancer drug.

Description

5- cyano -6- phenyl-pyrimidine compound containing triazolyl is inhibiting answering in LSD1 With and LSD1 inhibitor
Technical field
The present invention relates to field of pharmaceutical chemistry technology more particularly to a kind of 5- cyano -6- phenyl-pyrimidines containing triazolyl Compound is inhibiting application and LSD1 inhibitor in LSD1.
Background technique
Istone lysine specificity demethylase 1 (LSD1) is Harvard University Yang Shi professor seminar 2004 First histone demethylase of year discovery is capable of the single pair of methylation of the removal H3K4 and H3K9 of specificity, to adjust The interaction of histone and other albumen is saved, and influences the activation and inhibition of genetic transcription, the life processes such as x chromosome inactivation.
LSD1 belongs to the amine oxidase superfamily of flavin adenine dinucleotide (FAD) (FAD) dependence, it removes H3K4, H3K9 Single double methylations are the processes that a FAD is relied on.The similarity of it and polyamine oxidase is 22.4% and monoamine oxidase A and B Similarity be 17.6%.
Numerous studies prove that LSD1 is overexpressed in Several Kinds of Malignancy, play in the generation of tumour, proliferation and transfer Very important effect.It is a variety of swollen in Acute Meyloid type leukaemia, lymthoma, prostate cancer, breast cancer, neuroblastoma etc. The expression quantity of LSD1 is all significantly higher than normal cell in tumor.It is demonstrated experimentally that by inhibiting the expression quantity of LSD1 or reducing LSD1's Activity can inhibit the growth and transfer of kinds of tumor cells and solid tumor.LSD1 has become new point of tumor prevention and treatment Sub- target, design synthesis of selective is good, and the inhibitor of high-efficiency low-toxicity is the new way for the treatment of cancer.
Summary of the invention
The purpose of the present invention is to provide a kind of, and the 5- cyano -6- phenyl-pyrimidine compound containing triazolyl is inhibiting Application and a kind of LSD1 inhibitor in LSD1, the 5- cyano -6- phenyl-pyrimidine compound energy of the invention containing triazolyl Enough activity for effectively inhibiting LSD1.
In order to achieve the above-mentioned object of the invention, the present invention the following technical schemes are provided:
The present invention provides a kind of, and the 5- cyano -6- phenyl-pyrimidine compound containing triazolyl is inhibiting answering in LSD1 With the 5- cyano -6- phenyl-pyrimidine compound containing triazolyl has structure shown in Formulas I:
In the Formulas I, R1For H, 3,4,5 ,-trimethoxy, methyl, isopropyl, chlorine, bromine or thiophene, R2For H, methyl, different Propyl, fluorine, chlorine, nitro, trifluoromethyl or methoxyl group.
Preferably, work as R in the Formulas I1When for methyl, isopropyl, chlorine or bromine, R1Replace for contraposition.
Preferably, R in the Formulas I1=p-CH (CH3)2And R2=p-F；R1=p-CH (CH3)2And R2=p-OCH3；R1= p-CH(CH3)2And R2=p-CH3；R1=p-CH3And R2=p-OCH3；R1=p-CH3And R2=o-OCH3；R1=p-CH3And R2= p-CH3；R1=p-CH3And R2=m-Cl；R1=p-CH3And R2=m-CF3；R1=p-CH3And R2=p-Cl；R1=m, p, m- triOCH3And R2=p-CH3；R1=m, p, m-triOCH3And R2=m-CF3；R1=m, p, m-triOCH3And R2=p-Cl；R1=
m,p,m-triOCH3And R2=m-Cl；R1=m, p, m-triOCH3And R2=m-CH3；R1=p-Cl and R2=p- CH3；R1=p-Cl and R2=p-CH (CH3)2；R1=p-Br and R2=m-Cl；R1=p-Br and R2=p-CH3；R1=p-Br and R2 =p-CH (CH3)2Or R1=H and R2=p-CH3。
The present invention provides a kind of LSD1 inhibitor, including active component and pharmaceutically acceptable auxiliary material；The activity Group is divided into the 5- cyano -6- phenyl-pyrimidine compound containing triazolyl with structure shown in Formulas I:
In the Formulas I, R1For H, 3,4,5 ,-trimethoxy, methyl, isopropyl, chlorine, bromine or thiophene, R2For H, methyl, different Propyl, fluorine, chlorine, nitro, trifluoromethyl or methoxyl group.
The present invention provides a kind of, and the 5- cyano -6- phenyl-pyrimidine compound containing triazolyl is inhibiting answering in LSD1 With the 5- cyano -6- phenyl-pyrimidine compound containing triazolyl has structure shown in Formulas I:
In the Formulas I, R1For H, 3,4,5 ,-trimethoxy, methyl, isopropyl, chlorine, bromine or thiophene, R2For H, methyl, different Propyl, fluorine, chlorine, nitro, trifluoromethyl or methoxyl group.5- cyano -6- phenyl-pyrimidine compound containing triazolyl of the invention The activity of LSD1 can be significantly inhibited, it is thus possible to be used to prepare the inhibitor of LSD1, can be used as the candidate further developed or Person's lead compound is used to prepare anticancer drug.
Embodiment the result shows that, the 5- cyano -6- phenyl-pyrimidine compound of the invention containing triazolyl is to LSD1's IC50Value is 0.183 ± 0.0023 to 5.62 ± 0.75 μM, and existing LSD1 inhibitor 2-PCPA is to the IC of LSD150Value is 27.83±2.64μM；Illustrate that the compound of the present invention significantly inhibits the activity of LSD1, and is better than positive control Compound 2-PCPA can be used to prepare LSD1 inhibitor for the compound of invention as active constituent.
Specific embodiment
The present invention provides a kind of, and the 5- cyano -6- phenyl-pyrimidine compound containing triazolyl is inhibiting answering in LSD1 With the 5- cyano -6- phenyl-pyrimidine compound containing triazolyl has structure shown in Formulas I:
In the Formulas I, R1For H, 3,4,5 ,-trimethoxy, methyl, isopropyl, chlorine, bromine or thiophene, R2For H, methyl, different Propyl, fluorine, chlorine, nitro, trifluoromethyl or methoxyl group；It is preferred that R1For H, 3,4,5 ,-trimethoxy or contraposition replace " methyl, Isopropyl, chlorine or bromine ", works as R1For H, 3,4,5, when " methyl, isopropyl, chlorine or bromine " that-trimethoxy or contraposition replace, R2For H, methyl, isopropyl, fluorine, chlorine, nitro, trifluoromethyl or methoxyl group.In the present invention, R1And R2Most preferably: R1=p-CH (CH3)2And R2=p-F；R1=p-CH (CH3)2And R2=p-OCH3；R1=p-CH (CH3)2And R2=p-CH3；R1=p-CH3And R2 =p-OCH3；R1=p-CH3And R2=o-OCH3；R1=p-CH3And R2=p-CH3；R1=p-CH3And R2=m-Cl；R1=p-CH3 And R2=m-CF3；R1=p-CH3And R2=p-Cl；R1=m, p, m-triOCH3And R2=p-CH3；R1=m, p, m-triOCH3And R2=m-CF3；R1=m, p, m-triOCH3And R2=p-Cl；R1=m, p, m-triOCH3And R2=m-Cl；R1=m, p, m- triOCH3And R2=m-CH3；R1=p-Cl and R2=p-CH3；R1=p-Cl and R2=p-CH (CH3)2；R1=p-Br and R2=m- Cl；R1=p-Br and R2=p-CH3；R1=p-Br and R2=p-CH (CH3)2Or R1=H and R2=p-CH3。
The present invention comes to the 5- cyano -6- phenyl-pyrimidine compound containing triazolyl with structure shown in formula 1 Source does not have particular/special requirement, can arbitrarily obtain the source of the compound；The present invention is preferably according to Li-YingMa.Bioorg Method disclosed in Med Chem Lett.25 (2015) 1124-1128 is prepared.
The present invention provides a kind of LSD1 inhibitor, including active component and pharmaceutically acceptable auxiliary material；The activity Group is divided into the 5- cyano -6- phenyl-pyrimidine compound containing triazolyl with structure shown in Formulas I:
In the Formulas I, R1For H, 3,4,5 ,-trimethoxy, methyl, isopropyl, chlorine, bromine or thiophene, R2For fluorine, chlorine, bromine, Methyl, isopropyl, methoxyl group or trifluoromethyl；It is preferred that R1For H, 3,4,5, " methyl, isopropyl of-trimethoxy or contraposition substitution Base, chlorine or bromine ", works as R1For H, 3,4,5, when " methyl, isopropyl, chlorine or bromine " that-trimethoxy or contraposition replace, R2For H, first Base, isopropyl, fluorine, chlorine, nitro, trifluoromethyl or methoxyl group.In the present invention, R1And R2Most preferably: R1=p-CH (CH3)2 And R2=p-F；R1=p-CH (CH3)2And R2=p-OCH3；R1=p-CH (CH3)2And R2=p-CH3；R1=p-CH3And R2=p- OCH3；R1=p-CH3And R2=o-OCH3；R1=p-CH3And R2=p-CH3；R1=p-CH3And R2=m-Cl；R1=p-CH3And R2 =m-CF3；R1=p-CH3And R2=p-Cl；R1=m, p, m-triOCH3And R2=p-CH3；R1=m, p, m-triOCH3And R2= m-CF3；R1=m, p, m-triOCH3And R2=p-Cl；R1=m, p, m-triOCH3And R2=m-Cl；R1=m, p, m-triOCH3 And R2=m-CH3；R1=p-Cl and R2=p-CH3；R1=p-Cl and R2=p-CH (CH3)2；R1=p-Br and R2=m-Cl；R1= P-Br and R2=p-CH3；R1=p-Br and R2=p-CH (CH3)2Or R1=H and R2=p-CH3。
The present invention does not have particular/special requirement to the content of active component in the LSD1 inhibitor, and those skilled in the art can root It is selected according to experience.The present invention does not have particular/special requirement to the specific type of the pharmaceutically acceptable auxiliary material, using ability Pharmaceutically acceptable auxiliary material known to field technique personnel.The present invention does not have special want to the dosage form of the LSD1 inhibitor Ask, those skilled in the art can the dosage form according to actual needs to the LSD1 inhibitor select.
The present invention does not have particular/special requirement, medicine preparation mode well known in the art to the preparation method of the LSD1 inhibitor .
5- cyano -6- phenyl-pyrimidine the compound provided by the invention containing triazolyl is being pressed down below with reference to embodiment Application and LSD1 inhibitor in LSD1 processed are described in detail, but they cannot be interpreted as to the scope of the present invention Restriction.
Embodiment 1
According to Bo Wang, the preparation of method disclosed in Li-Ying Ma.J.Med.Chem.2018,61,5988-6001 has 5- cyano -6- phenyl-pyrimidine the compound containing triazolyl of structure shown in Formulas I, by after purification, being used for following experiments, respectively The specific structure of compound is shown in Table 1.
Experimental method:
3~5mg sample is weighed in EP pipe, then with DMSO (dimethyl sulfoxide) be configured to concentration be 20nM solution, 4 It DEG C saves and to place, when experiment is diluted according to required concentration with DMSO.By sample to be tested and LSD1 albumen after incubation at room temperature, it is added LSD1 reactant H3K4me2 and incubation reaction are eventually adding fluorescent dye Amplex and horseradish peroxidase HPR incubation at room temperature, (exciting light 530nm emits light 590nm) the detection fluorescence values in microplate reader, calculate inhibiting rate according to Formula II, and use SPSS Software calculates IC50Value, the results are shown in Table 1；
In addition, the present invention, using identical method, obtains 2-PCPA using existing LSD1 inhibitor 2-PCPA as control IC50Value；It the results are shown in Table 1.
The inhibition data of 1 the compounds of this invention of table and 2-PCPA to LSD1
As can be seen from the data in table 1, the 5- cyano -6- phenyl-pyrimidine compound of the invention containing triazolyl is to LSD1's IC50Value is 0.183 ± 0.0023 to 5.62 ± 0.75 μM, and currently used LSD1 inhibitor 2-PCPA is to the IC of LSD150Value It is 27.83 ± 2.64 μM；Illustrate that the compound of the present invention significantly inhibits the activity of LSD1, and right better than positive According to compound 2-PCPA, LSD1 inhibitor can be used to prepare using the compound of invention as active constituent.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered It is considered as protection scope of the present invention.

Claims (4)

1. a kind of 5- cyano -6- phenyl-pyrimidine compound containing triazolyl is inhibiting the application in LSD1, which is characterized in that 5- cyano -6- phenyl-pyrimidine the compound containing triazolyl has structure shown in Formulas I:
In the Formulas I, R1For H, 3,4,5 ,-trimethoxy, methyl, isopropyl, chlorine, bromine or thiophene, R2For H, methyl, isopropyl, Fluorine, chlorine, nitro, trifluoromethyl or methoxyl group.
2. application according to claim 1, which is characterized in that work as R in the Formulas I1When for methyl, isopropyl, chlorine or bromine, R1Replace for contraposition.
3. application according to claim 1 or 2, which is characterized in that R in the Formulas I1=p-CH (CH3)2And R2=p-F；R1 =p-CH (CH3)2And R2=p-OCH3；R1=p-CH (CH3)2And R2=p-CH3；R1=p-CH3And R2=p-OCH3；R1=p-CH3 And R2=o-OCH3；R1=p-CH3And R2=p-CH3；R1=p-CH3And R2=m-Cl；R1=p-CH3And R2=m-CF3；R1=p- CH3And R2=p-Cl；R1=m, p, m-triOCH3And R2=p-CH3；R1=m, p, m-triOCH3And R2=m-CF3；R1=m, p, m-triOCH3And R2=p-Cl；R1=m, p, m-triOCH3And R2=m-Cl；R1=m, p, m-triOCH3And R2=m-CH3；R1 =p-Cl and R2=p-CH3；R1=p-Cl and R2=p-CH (CH3)2；R1=p-Br and R2=m-Cl；R1=p-Br and R2=p- CH3；R1=p-Br and R2=p-CH (CH3)2Or R1=H and R2=p-CH3。
4. a kind of LSD1 inhibitor, which is characterized in that including active component and pharmaceutically acceptable auxiliary material；The active component For the 5- cyano -6- phenyl-pyrimidine compound containing triazolyl with structure shown in Formulas I:
In the Formulas I, R1For H, 3,4,5 ,-trimethoxy, methyl, isopropyl, chlorine, bromine or thiophene, R2For H, methyl, isopropyl, Fluorine, chlorine, nitro, trifluoromethyl or methoxyl group.
CN201910813548.0A 2019-08-30 2019-08-30 5- cyano -6- phenyl-pyrimidine compound containing triazolyl is inhibiting application and LSD1 inhibitor in LSD1 Pending CN110478352A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022214303A1 (en) 2021-04-08 2022-10-13 Oryzon Genomics, S.A. Combinations of lsd1 inhibitors for treating myeloid cancers
WO2023217758A1 (en) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Methods of treating malignant peripheral nerve sheath tumor (mpnst) using lsd1 inhibitors
WO2023217784A1 (en) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Methods of treating nf1-mutant tumors using lsd1 inhibitors

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104119319A (en) * 2014-06-27 2014-10-29 郑州大学 Pyrimidine derivative containing 1,2,3-triazole and urea structure unit as well as preparation method and application thereof
CN104402831A (en) * 2014-10-24 2015-03-11 郑州大学 Ureide structural unit-containing 5-cyano pyrimidine derivatives and preparation method and use thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104119319A (en) * 2014-06-27 2014-10-29 郑州大学 Pyrimidine derivative containing 1,2,3-triazole and urea structure unit as well as preparation method and application thereof
CN104402831A (en) * 2014-10-24 2015-03-11 郑州大学 Ureide structural unit-containing 5-cyano pyrimidine derivatives and preparation method and use thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BO WANG等: "Discovery of 5‑Cyano-6-phenylpyrimidin Derivatives Containing an", 《J. MED. CHEM.》 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022214303A1 (en) 2021-04-08 2022-10-13 Oryzon Genomics, S.A. Combinations of lsd1 inhibitors for treating myeloid cancers
WO2023217758A1 (en) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Methods of treating malignant peripheral nerve sheath tumor (mpnst) using lsd1 inhibitors
WO2023217784A1 (en) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Methods of treating nf1-mutant tumors using lsd1 inhibitors

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Application publication date: 20191122