CN112079821A - Conjugate formed by orlistat and phenylaminopyrimidine compound and preparation method and application thereof - Google Patents

Conjugate formed by orlistat and phenylaminopyrimidine compound and preparation method and application thereof Download PDF

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CN112079821A
CN112079821A CN202010959460.2A CN202010959460A CN112079821A CN 112079821 A CN112079821 A CN 112079821A CN 202010959460 A CN202010959460 A CN 202010959460A CN 112079821 A CN112079821 A CN 112079821A
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pyrimidin
pyridin
phenyl
oxooxetan
hexyl
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张俊
李玲
王浩然
陈永基
杜志博
彭韪
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Zhongshan Wanyuan New Drugs Research And Development Co ltd
Zhongshan Wanhan Pharmaceutical Co ltd
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    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D403/14—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 three or more hetero rings
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    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

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Abstract

The invention provides a conjugate formed by orlistat and anilinopyrimidine compounds, and the specific definition of the conjugate is shown in the specification. In vitro test results show that the IC of the conjugate of the invention on various tumor cellsfaAre all significantly lower than the IC of a mixture of orlistat and the corresponding anilinopyrimidine in a molar ratio of 1:1faThe value is obtained.

Description

Conjugate formed by orlistat and phenylaminopyrimidine compound and preparation method and application thereof
Technical Field
The invention belongs to the field of biological medicines, and particularly relates to a conjugate formed by orlistat and a phenylaminopyrimidine compound, and a preparation method and application thereof.
Background
Orlistat, also known as tetrahydrolipstatin, is a lipase inhibitor type of weight-loss drug commonly used at present. In addition to lipase, orlistat has a certain inhibitory effect on Fatty Acid Synthase (FAS) which plays an important role in the proliferation of tumor cells, and thus in recent years, orlistat has attracted more and more attention, for example, orlistat has been evaluated systematically in "research progress on orlistat against tumors" by cheng sha et al (see medical review, 2015,21(15): 2735-2737).
US patent US5521184 discloses a number of anilinopyrimidine protein kinase inhibitors with anti-tumor effect, including imatinib mesylate, which is subsequently marketed for the treatment of chronic myelogenous leukemia. However, the inhibitory activity of the compounds disclosed in this patent on other tumor cells is to be further improved.
Song wenting in Zhang Yi medical academy discloses a nitrogen mustard conjugated 4-amino quinazoline derivative with synergistic anti-tumor effect in the Master thesis of construction and in vitro activity analysis of nitrogen mustard conjugated 4-amino quinazoline derivative double chemotherapy synergistic anti-tumor drug, and confirms the possibility of generating synergistic anti-tumor effect through drug-drug conjugate. However, it is well known in the art that trans-cell membrane transport is a prerequisite for drugs whose target of action is located intracellularly to exert their desired pharmacological effects, and active transport, which is the primary trans-cell membrane transport mode of most small molecule organic drugs, is highly structure-specific. Therefore, when the molecular structure of the drug is significantly changed due to conjugation, particularly when the molecular weight is greatly increased, it cannot be expected whether the conjugate can achieve the concentration required for the inhibitory effect in the cell.
In conclusion, there is no technical suggestion in the prior art that orlistat forms conjugates with anilinopyrimidines to produce synergistic antitumor effects.
Disclosure of Invention
The invention aims to provide a conjugate formed by orlistat and an anilinopyrimidine compound, and a preparation method and application thereof.
In order to achieve the above object, the present invention provides, in one aspect, a conjugate selected from the group consisting of:
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((5-benzoylamino-2-methylphenyl) (4- (pyridin-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((4- (pyridin-4-yl) pyrimidin-2-yl) (3- (1,1,2, 2-tetrafluoroethoxy) phenyl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((3-nitrophenyl) (4- (pyridin-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((3- (4-chlorobenzoylamino) phenyl) (4- (pyridin-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((3-benzoylaminophenyl) (4- (pyridin-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((3- (pyridine-2-carboxamido) phenyl) (4- (pyridine-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((3- (pyridine-3-carboxamido) phenyl) (4- (pyridine-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((3- (isopropylpyridin-3-carboxamido) phenyl) (4- (pyridin-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((3- (perfluorobenzoylamino) phenyl) (4- (pyridin-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
2- ((3- (3- ((S) -1- (((S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl) oxy) -4-methyl-1-oxopent-2-yl) -1- (4- (pyridin-3-yl) pyrimidin-2-yl) ureido) phenyl) carbamoyl) benzoic acid,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((3-hexanoylaminophenyl) (4- (pyridin-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((3-nitrophenyl) (4- (pyridin-2-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((3-nitrophenyl) (4- (pyridin-4-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((3- (2-methoxybenzamido) phenyl) (4- (pyridin-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((3- (4-fluorobenzamido) phenyl) (4- (pyridin-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((3- (4-cyanobenzoylamino) phenyl) (4- (pyridin-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((4- (pyridin-3-yl) pyrimidin-2-yl) (3- (thiophene-2-carboxamido) phenyl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((3- (cyclohexanecarboxamido) phenyl) (4- (pyridin-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((3- (4-methylbenzamido) phenyl) (4- (pyridin-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((3- (4-chlorobenzoylamino) phenyl) (4- (pyridin-4-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((3- (4- ((4-methylpiperazin-1-yl) methyl) benzoylamino) phenyl) (4- (pyridin-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((3- (4-methylbenzamido) phenyl) (4- (pyridin-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((5- (2-naphthocarboxamido) -2-methylphenyl) (4- (pyridin-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((5- (4-chlorobenzoylamino) -2-methylphenyl) (4- (pyridin-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((5- (2-methoxybenzamido) -2-methylphenyl) (4- (pyridin-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((4- (pyridin-3-yl) pyrimidin-2-yl) (3- (trifluoromethoxy) phenyl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((4- (pyridin-3-yl) pyrimidin-2-yl) (3- (1,1,2, 2-tetrafluoroethoxy) phenyl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((3-methyl-5-nitrophenyl) (4- (pyridin-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((3-nitro-5- (trifluoromethyl) phenyl) (4- (pyridin-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
3- (2- (3- ((S) -1- (((S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl) oxy) -4-methyl-1-oxopent-2-yl) -1- (3-nitrophenyl) ureido) pyrimidin-4-yl) pyridine 1-oxide,
3- (2- (1- (5-benzoylamino-2-methylphenyl) -3- ((S) -1- (((S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl) oxy) -4-methyl-1-oxopent-2-yl) ureido) pyrimidin-4-yl) pyridine 1-oxide,
4- (2- (3- ((S) -1- (((S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl) oxy) -4-methyl-1-oxopent-2-yl) -1- (3- (1,1,2, 2-tetrafluoroethoxy) phenyl) ureido) pyrimidin-4-yl) pyridine 1-oxide,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((4- (1H-indol-3-yl) pyrimidin-2-yl) (3- (1,1,2, 2-tetrafluoroethoxy) phenyl) carbamoyl) -L-leucine ester, with
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((2-methyl-5- (4- ((4-methylpiperazin-1-yl) methyl) benzoylamino) phenyl) (4- (pyridin-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester.
In another aspect, the present invention provides a process for the preparation of a conjugate as hereinbefore described, characterised in that the process has the reaction formula:
Figure BDA0002679947400000041
wherein the compound represented by formula I is selected from:
n- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide,
4- (pyridin-4-yl) -N- (3- (1,1,2, 2-tetrafluoroethoxy) phenyl) pyrimidin-2-amine,
n- (3-nitrophenyl) -4- (pyridin-3-yl) pyrimidin-2-amine,
4-chloro-N- (3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide,
n- (3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide,
n- (3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) pyridine-2-carboxamide,
n- (3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) pyridine-3-carboxamide,
n- (3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) bipyridine-3-carboxamide,
2,3,4,5, 6-pentafluoro-N- (3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide,
2- ((3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) carbamoyl) benzoic acid,
n- (3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) hexanamide,
n- (3-nitrophenyl) -4- (pyridin-2-yl) pyrimidin-2-amine,
n- (3-nitrophenyl) -4- (pyridin-4-yl) pyrimidin-2-amine,
2-methoxy-N- (3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide,
4-fluoro-N- (3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide,
4-cyano-N- (3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide,
n- (3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) thiophene-2-carboxamide,
n- (3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) cyclohexanecarboxamide,
4-methyl-N- (3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide,
4-chloro-N- (3- ((4- (pyridin-4-yl) pyrimidin-2-yl) amino) phenyl) benzamide,
4- ((4-methylpiperazin-1-yl) methyl) -N- (3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide,
4-methyl-N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide,
n- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) -2-naphthamide,
4-chloro-N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide,
2-methoxy-N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide,
4- (pyridin-3-yl) -N- (3- (trifluoromethoxy) phenyl) pyrimidin-2-amine,
4- (pyridin-3-yl) -N- (3- (1,1,2, 2-tetrafluoroethoxy) phenyl) pyrimidin-2-amine,
n- (3-methyl-5-nitrophenyl) -4- (pyridin-3-yl) pyrimidin-2-amine,
n- (3-nitro-5- (trifluoromethyl) phenyl) -4- (pyridin-3-yl) pyrimidin-2-amine,
3- (2- ((3-nitrophenyl) amino) pyrimidin-4-yl) pyridine 1-oxide,
3- (2- ((5-benzoylamino-2-methylphenyl) amino) pyrimidin-4-yl) pyridine 1-oxide,
n- [3- (1,1,2, 2-tetrafluoroethoxy) phenyl ] -4- (N-oxy-4-pyridyl) -2-pyrimidin-amine,
4- (1H-indol-3-yl) -N- (3- (1,1,2, 2-tetrafluoroethoxy) phenyl) pyrimidin-2-amine with
One of N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) -4- ((4-methylpiperazin-1-yl) methyl) benzamide.
The invention further provides compositions containing the conjugates as described above.
In one aspect, the composition of the present invention preferably further comprises pharmaceutically acceptable excipients; further preferably, the pharmaceutically acceptable auxiliary material is at least one selected from tartaric acid, starch slurry, talcum powder and liquid paraffin
In one aspect, the composition of the present invention can be prepared into oral solid preparation; further preferably, the oral solid preparation is one selected from the group consisting of tablets, capsules and granules.
In another aspect, the invention provides the use of a conjugate or composition as hereinbefore described in the manufacture of a medicament for use against a tumour. Preferably, the tumor of the present invention is one selected from the group consisting of lung cancer, colon cancer, leukemia, melanoma, nasopharyngeal cancer, ovarian cancer, breast cancer, liver cancer, stomach cancer and prostate cancer.
The in vitro test results show that the IC of the conjugate of the invention on various tumor cells50Is obviously lower than the IC when orlistat and the corresponding anilinopyrimidine compound are combined at the molar ratio of 1:150。
Detailed Description
Compound preparation example: preparation and structure confirmation of conjugate formed by orlistat and anilinopyrimidine compound
0.1mol of the anilinopyrimidine compound shown in Table 1 is dissolved in tetrahydrofuran to obtain a saturated solution, the saturated solution is cooled to-78 ℃, then a saturated tetrahydrofuran solution containing 0.1mol of Lithium hexamethizaliazine is added dropwise into the solution under stirring, and the reaction is stirred at-78 ℃ until the TLC tracing shows that the reaction is complete. After warming to 25 ℃, a saturated tetrahydrofuran solution containing 0.15mol of di-tert-butyl dicarbonate was added dropwise to the reaction solution, and the mixture was stirred at 25 ℃ until completion of the reaction by TLC. The obtained reaction solution is slowly heated to 60 ℃, then a saturated tetrahydrofuran solution containing 0.1mol of triethylamine and 0.1mol of (S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecane-2-yl L-leucine ester is slowly and dropwise added into the reaction solution, and the reaction solution is stirred at 60 ℃ in the dark until TLC tracking shows that the reaction is complete. The reaction solvent was removed by rotary evaporation and the product was purified by HPLC to give the various conjugates shown in table 1. Of the various compounds described in Table 11H-NMR(CD3Cl, 500Hz) data (ppm) are shown in Table 2.
TABLE 1 Compound Numbers and chemical names
Figure BDA0002679947400000061
Figure BDA0002679947400000071
Figure BDA0002679947400000081
Figure BDA0002679947400000091
Figure BDA0002679947400000101
TABLE 21H-NMR data
Figure BDA0002679947400000102
Figure BDA0002679947400000111
Figure BDA0002679947400000121
Figure BDA0002679947400000131
Figure BDA0002679947400000141
Figure BDA0002679947400000151
Figure BDA0002679947400000161
Test example 1 antitumor Activity test
The inhibition effect of the following test substances on the proliferation of various tumor cell strains is investigated by adopting a method disclosed by Zhang Xiong of Nanjing Chinese medicinal university in the Master thesis screening of anti-liver cancer active ingredients of rhubarb and hibernating insect pills and the research of pharmacokinetics thereof:
a test substance (i): the conjugates described in Table 1, are designated "Compound xP" (x is selected from 1 to 34)
A test object (c): the mixture of the anilinopyrimidine compound and Orlistat (ORL) in a molar ratio of 1:1 shown in Table 1 is "Compound yS-ORL" (y is selected from 1 to 34)
The results are shown in tables 3.1 to 3.10.
TABLE 3.1 inhibition of Lung cancer A549 cell line proliferation by each test substance
Figure BDA0002679947400000162
Figure BDA0002679947400000171
TABLE 3.2 inhibition of proliferation of colon cancer CT26 cell line by each test substance
Figure BDA0002679947400000172
Figure BDA0002679947400000181
TABLE 3.3 inhibition of the proliferation of the leukemia K562 cell line by each test substance
Figure BDA0002679947400000182
Figure BDA0002679947400000191
TABLE 3.4 inhibition of proliferation of melanoma A375 cell line by each test substance
Figure BDA0002679947400000192
Figure BDA0002679947400000201
TABLE 3.5 inhibitory Effect of each test substance on proliferation of nasopharyngeal carcinoma CNE-2 cell line
Figure BDA0002679947400000202
Figure BDA0002679947400000211
TABLE 3.6 inhibition of proliferation of the SK-OV-3 cell line in ovarian cancer by each test substance
Figure BDA0002679947400000212
Figure BDA0002679947400000221
TABLE 3.7 inhibition of proliferation of breast cancer MDA-MB-231 cell line by each test substance
Figure BDA0002679947400000222
Figure BDA0002679947400000231
TABLE 3.8 inhibition of proliferation of the hepatocarcinoma SMMC-7721 cell line by each test substance
Figure BDA0002679947400000232
Figure BDA0002679947400000241
TABLE 3.9 inhibition of gastric cancer SGC-7901 cell line proliferation by each test substance
Figure BDA0002679947400000242
Figure BDA0002679947400000251
TABLE 3.10 inhibition of prostate cancer PC-3 cell line proliferation by each test substance
Test article IRmax Cmax Slope of Intercept of a beam fa ICfa R
Compound 1P 80.79％ 80 0.5539 -0.2311 66.87％ 42.1214 0.1480
Compound 4P 86.53％ 200 0.3061 0.1557 83.70％ 168.1464 0.3286
Compound 8P 84.63％ 200 0.3718 -0.0090 77.32％ 126.9334 0.3875
Compound 11P 91.99％ 50 0.4657 0.1232 87.61％ 41.3851 0.2052
Compound 14P 84.23％ 100 0.3529 0.0972 71.13％ 54.9792 0.3769
Compound 18P 82.65％ 80 0.5919 -0.3056 67.74％ 45.7763 0.1790
Compound 20P 84.55％ 300 0.5676 -0.5495 76.31％ 205.4372 0.3605
Compound 24P 91.90％ 300 0.5417 -0.3993 87.43％ 224.3417 0.3826
Compound 26P 89.79％ 100 0.4121 0.0217 82.15％ 87.2430 0.3233
Compound 29P 80.80％ 30 0.3309 0.3411 74.84％ 17.0214 0.1113
Compound 32P 93.98％ 300 0.4939 -0.2679 75.24％ 116.3255 0.2216
Compound 33P 86.27％ 100 0.4608 -0.1151 72.55％ 66.7175 0.1228
Compound 1S-ORL 66.87％ 300 0.3398 -0.1652 66.87％ 284.6821
Compound 4S-ORL 83.70％ 500 0.3731 -0.1737 83.70％ 511.6330
Compound 8S-ORL 77.32％ 300 0.4225 -0.2896 77.32％ 327.5461
Compound 11S-ORL 87.61％ 200 0.4212 -0.0946 87.61％ 201.6867
Compound 14S-ORL 71.13％ 100 0.5458 -0.4698 71.13％ 145.8574
Compound 18S-ORL 67.74％ 300 0.4967 -0.5185 67.74％ 255.7839
Compound 20S-ORL 76.31％ 600 0.5548 -0.7658 76.31％ 569.9174
Compound 24S-ORL 87.43％ 600 0.4866 -0.4726 87.43％ 586.4251
Compound 26S-ORL 82.15％ 300 0.4171 -0.1925 82.15％ 269.8749
Compound 29S-ORL 74.84％ 200 0.5295 -0.4082 74.84％ 152.9157
Compound 32S-ORL 75.24％ 500 0.4143 -0.3744 75.24％ 524.8427
Compound 33S-ORL 72.55％ 500 0.3278 -0.1711 72.55％ 543.2815
Example 2 oral solid preparation containing conjugate and method for preparing the same
Prescription
Figure BDA0002679947400000261
Tablet preparation method
The conjugate with the amount of the prescription is taken and mixed with starch with the amount of 1/3 evenly, 15% of starch slurry (containing tartaric acid) is added to prepare soft materials for 10-15 min, or wet granules are prepared by a 14-mesh sieve, the mixture is dried at 70 ℃, the dry granules are prepared by a 12-mesh sieve, then the granules, the residual starch (dried at 100-105 ℃ in advance) and the talcum powder absorbed with liquid paraffin are mixed evenly and then pass through the 12-mesh sieve, and after the content of the granules is determined to be qualified, the granules are tabletted into tablets with the weight of about 200mg each tablet.
Capsule preparation method
The conjugate with the amount of the prescription is taken and evenly mixed with starch with the amount of 1/3, 15% of starch slurry (containing tartaric acid) is added to prepare soft materials for 10-15 min, or wet granules are prepared by a 14-mesh sieve, the mixture is dried at 70 ℃, the dried granules are prepared by a 12-mesh sieve, then the granules, the residual starch (dried at 100-105 ℃ in advance) and the talcum powder absorbed with liquid paraffin are evenly mixed together and then pass through the 12-mesh sieve, and the granules are filled into capsules with the weight of about 200mg after the content is determined to be qualified.
Preparation method of granules
The conjugate with the amount of the prescription is taken and evenly mixed with starch with the amount of 1/3, 15% of starch slurry (containing tartaric acid) is added to prepare soft materials for 10-15 min, or wet granules are prepared by a 14-mesh sieve, the mixture is dried at 70 ℃, the dry granules are prepared by a 12-mesh sieve, then the granules, the residual starch (dried at 100-105 ℃ in advance) and the talcum powder absorbed with liquid paraffin are evenly mixed together and then pass through the 12-mesh sieve, and the granules are subpackaged into granules with the weight of about 5g per bag after the content is determined to be qualified.

Claims (9)

1. A conjugate, wherein said conjugate is selected from the group consisting of:
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((5-benzoylamino-2-methylphenyl) (4- (pyridin-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((4- (pyridin-4-yl) pyrimidin-2-yl) (3- (1,1,2, 2-tetrafluoroethoxy) phenyl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((3-nitrophenyl) (4- (pyridin-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((3- (4-chlorobenzoylamino) phenyl) (4- (pyridin-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((3-benzoylaminophenyl) (4- (pyridin-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((3- (pyridine-2-carboxamido) phenyl) (4- (pyridine-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((3- (pyridine-3-carboxamido) phenyl) (4- (pyridine-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((3- (isopropylpyridin-3-carboxamido) phenyl) (4- (pyridin-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((3- (perfluorobenzoylamino) phenyl) (4- (pyridin-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
2- ((3- (3- ((S) -1- (((S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl) oxy) -4-methyl-1-oxopent-2-yl) -1- (4- (pyridin-3-yl) pyrimidin-2-yl) ureido) phenyl) carbamoyl) benzoic acid,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((3-hexanoylaminophenyl) (4- (pyridin-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((3-nitrophenyl) (4- (pyridin-2-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((3-nitrophenyl) (4- (pyridin-4-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((3- (2-methoxybenzamido) phenyl) (4- (pyridin-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((3- (4-fluorobenzamido) phenyl) (4- (pyridin-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((3- (4-cyanobenzoylamino) phenyl) (4- (pyridin-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((4- (pyridin-3-yl) pyrimidin-2-yl) (3- (thiophene-2-carboxamido) phenyl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((3- (cyclohexanecarboxamido) phenyl) (4- (pyridin-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((3- (4-methylbenzamido) phenyl) (4- (pyridin-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((3- (4-chlorobenzoylamino) phenyl) (4- (pyridin-4-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((3- (4- ((4-methylpiperazin-1-yl) methyl) benzoylamino) phenyl) (4- (pyridin-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((3- (4-methylbenzamido) phenyl) (4- (pyridin-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((5- (2-naphthocarboxamido) -2-methylphenyl) (4- (pyridin-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((5- (4-chlorobenzoylamino) -2-methylphenyl) (4- (pyridin-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((5- (2-methoxybenzamido) -2-methylphenyl) (4- (pyridin-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((4- (pyridin-3-yl) pyrimidin-2-yl) (3- (trifluoromethoxy) phenyl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((4- (pyridin-3-yl) pyrimidin-2-yl) (3- (1,1,2, 2-tetrafluoroethoxy) phenyl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((3-methyl-5-nitrophenyl) (4- (pyridin-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((3-nitro-5- (trifluoromethyl) phenyl) (4- (pyridin-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester,
3- (2- (3- ((S) -1- (((S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl) oxy) -4-methyl-1-oxopent-2-yl) -1- (3-nitrophenyl) ureido) pyrimidin-4-yl) pyridine 1-oxide,
3- (2- (1- (5-benzoylamino-2-methylphenyl) -3- ((S) -1- (((S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl) oxy) -4-methyl-1-oxopent-2-yl) ureido) pyrimidin-4-yl) pyridine 1-oxide,
4- (2- (3- ((S) -1- (((S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl) oxy) -4-methyl-1-oxopent-2-yl) -1- (3- (1,1,2, 2-tetrafluoroethoxy) phenyl) ureido) pyrimidin-4-yl) pyridine 1-oxide,
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((4- (1H-indol-3-yl) pyrimidin-2-yl) (3- (1,1,2, 2-tetrafluoroethoxy) phenyl) carbamoyl) -L-leucine ester, with
(S) -1- ((2S,3S) -3-hexyl-4-oxooxetan-2-yl) tridecan-2-yl ((2-methyl-5- (4- ((4-methylpiperazin-1-yl) methyl) benzoylamino) phenyl) (4- (pyridin-3-yl) pyrimidin-2-yl) carbamoyl) -L-leucine ester.
2. A process for the preparation of a conjugate according to claim 1, characterized in that the process has the formula:
Figure FDA0002679947390000031
wherein the compound represented by formula I is selected from:
n- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide,
4- (pyridin-4-yl) -N- (3- (1,1,2, 2-tetrafluoroethoxy) phenyl) pyrimidin-2-amine,
n- (3-nitrophenyl) -4- (pyridin-3-yl) pyrimidin-2-amine,
4-chloro-N- (3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide,
n- (3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide,
n- (3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) pyridine-2-carboxamide,
n- (3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) pyridine-3-carboxamide,
n- (3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) bipyridine-3-carboxamide,
2,3,4,5, 6-pentafluoro-N- (3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide,
2- ((3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) carbamoyl) benzoic acid,
n- (3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) hexanamide,
n- (3-nitrophenyl) -4- (pyridin-2-yl) pyrimidin-2-amine,
n- (3-nitrophenyl) -4- (pyridin-4-yl) pyrimidin-2-amine,
2-methoxy-N- (3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide,
4-fluoro-N- (3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide,
4-cyano-N- (3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide,
n- (3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) thiophene-2-carboxamide,
n- (3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) cyclohexanecarboxamide,
4-methyl-N- (3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide,
4-chloro-N- (3- ((4- (pyridin-4-yl) pyrimidin-2-yl) amino) phenyl) benzamide,
4- ((4-methylpiperazin-1-yl) methyl) -N- (3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide,
4-methyl-N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide,
n- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) -2-naphthamide,
4-chloro-N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide,
2-methoxy-N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide,
4- (pyridin-3-yl) -N- (3- (trifluoromethoxy) phenyl) pyrimidin-2-amine,
4- (pyridin-3-yl) -N- (3- (1,1,2, 2-tetrafluoroethoxy) phenyl) pyrimidin-2-amine,
n- (3-methyl-5-nitrophenyl) -4- (pyridin-3-yl) pyrimidin-2-amine,
n- (3-nitro-5- (trifluoromethyl) phenyl) -4- (pyridin-3-yl) pyrimidin-2-amine,
3- (2- ((3-nitrophenyl) amino) pyrimidin-4-yl) pyridine 1-oxide,
3- (2- ((5-benzoylamino-2-methylphenyl) amino) pyrimidin-4-yl) pyridine 1-oxide,
n- [3- (1,1,2, 2-tetrafluoroethoxy) phenyl ] -4- (N-oxy-4-pyridyl) -2-pyrimidin-amine,
4- (1H-indol-3-yl) -N- (3- (1,1,2, 2-tetrafluoroethoxy) phenyl) pyrimidin-2-amine with
One of N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) -4- ((4-methylpiperazin-1-yl) methyl) benzamide.
3. A composition comprising a conjugate according to claim 1.
4. The composition of claim 3, wherein said composition further comprises a pharmaceutically acceptable excipient; further preferred are
5. The composition according to claim 3 or 4, wherein the pharmaceutically acceptable excipient is at least one selected from the group consisting of tartaric acid, starch slurry, talc, and liquid paraffin
6. The composition according to claim 3 or 4, wherein said composition is formulated as a solid preparation for oral administration.
7. The composition of claim 6, wherein the oral solid preparation is one selected from the group consisting of tablets, capsules and granules.
8. Use of a conjugate according to claim 1 or a composition according to claim 3 or 4 for the preparation of a medicament for use against tumors.
9. The use according to claim 8, wherein said tumor is one selected from the group consisting of lung cancer, colon cancer, leukemia, melanoma, nasopharyngeal carcinoma, ovarian cancer, breast cancer, liver cancer, stomach cancer, and prostate cancer.
CN202010959460.2A 2020-09-14 2020-09-14 Conjugate formed by orlistat and phenylaminopyrimidine compound and preparation method and application thereof Pending CN112079821A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4931463A (en) * 1984-12-21 1990-06-05 Hoffmann-La Roche Inc. Oxetanones
CN110559299A (en) * 2019-09-22 2019-12-13 黄泳华 composition containing pyridyl pyrimidinamine compound and application thereof
CN111329863A (en) * 2020-03-04 2020-06-26 黄泳华 Use of a composition containing a heterocyclic compound for the preparation of a medicament for the treatment of leukemia

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4931463A (en) * 1984-12-21 1990-06-05 Hoffmann-La Roche Inc. Oxetanones
CN110559299A (en) * 2019-09-22 2019-12-13 黄泳华 composition containing pyridyl pyrimidinamine compound and application thereof
CN111329863A (en) * 2020-03-04 2020-06-26 黄泳华 Use of a composition containing a heterocyclic compound for the preparation of a medicament for the treatment of leukemia

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MYKHAILO SYTNYK ET AL.: "Cellular interfaces with hydrogen-bonded organic semiconductor hierarchical nanocrystals", 《NATURE COMMUNICATIONS》 *
张希琼: "大黄蛰虫丸抗肝癌活性成分筛选及其药动学研究", 《中国优秀硕士学位论文全文数据库医药卫生科技辑》 *

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