CN118005717A - 6-Diazonium-5-oxo-hexanamide derivative for preparing glutamine antagonist - Google Patents

6-Diazonium-5-oxo-hexanamide derivative for preparing glutamine antagonist Download PDF

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CN118005717A
CN118005717A CN202410166432.3A CN202410166432A CN118005717A CN 118005717 A CN118005717 A CN 118005717A CN 202410166432 A CN202410166432 A CN 202410166432A CN 118005717 A CN118005717 A CN 118005717A
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diazonium
oxo
pharmaceutically acceptable
acceptable salt
hexanamide
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范为正
张薰以
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Sanojin Pharmaceutical Technology Wuxi Co ltd
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Sanojin Pharmaceutical Technology Wuxi Co ltd
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Abstract

The invention discloses a 6-diazonium-5-oxo-hexanamide derivative for preparing a glutamine antagonist, belonging to the field of chemical medicine. The invention provides a 6-diazonium-5-oxo-hexanamide derivative shown in a general formula (I) or pharmaceutically acceptable salt thereof, which has excellent glutamine antagonism, and can effectively treat tumors by inhibiting glutamine metabolism and destroying tumor cell metabolism. Meanwhile, the compound provided by the invention has better GI stability, and can reduce the occurrence rate of adverse events.

Description

6-Diazonium-5-oxo-hexanamide derivative for preparing glutamine antagonist
Technical Field
The invention belongs to the field of chemical medicine, and in particular relates to a 6-diazonium-5-oxo-hexanamide derivative for preparing a glutamine antagonist.
Background
The metabolic processes of cancer cells are very different from those of normal cells. As early as 100 years ago, german scientists discovered that cancer cells, even under oxygen-rich conditions, could utilize active glycolysis processes to convert glucose to lactic acid (Warburg effect), and although this discovery revealed a significant difference in metabolism between cancer cells and healthy cells, it did not lead to effective anticancer therapies.
Normal cells stop proliferating when nutrient deficiency occurs, whereas cancer cells continue to rely on nutrient supply due to oncogene driving, and thus, theoretically targeting cancer metabolism can trigger cell death in cancer cells.
Cellular metabolism can be divided into glucose, amino acids, lipids, etc. Glucose is the major source of energy for cells, and cancer cells use glucose at rates tens or hundreds of times higher than normal cells because of the Warburg effect of tumor cells, which use a anaplerotic process to supplement the TCA cycle's metabolites in order to maintain normal mitochondrial function.
Glutamine is the amide of glutamic acid, is the most abundant circulating amino acid in blood and human body, and has the concentration 10-100 times of other amino acids. Many tumors, including pancreatic, ovarian and breast cancers, rely on glutamine as the primary source of energy to meet the TCA cycle, which is "glutamine addiction" (Li T, le A. Glutamine Metabolismin Cancer [ J ]. 2018).
The dependence of tumor cells on glutamine metabolism makes them a potential target for anticancer drugs a research hotspot in recent years, but most of these compounds are still in preclinical stages.
Disclosure of Invention
Problems to be solved by the invention
In order to solve the above problems in the prior art, the present invention provides a 6-diazonium-5-oxo-hexanamide derivative or pharmaceutically acceptable salt thereof, which can treat tumor by inhibiting glutamine metabolism and destroying the vital activity of tumor cells.
The invention also provides a pharmaceutical composition comprising the above compound or a pharmaceutically acceptable salt thereof.
Furthermore, the present invention provides the use of the above compound or a pharmaceutically acceptable salt thereof.
Solution for solving the problem
The invention firstly provides a 6-diazonium-5-oxo-hexanamide compound with a structure shown in a general formula (I) or pharmaceutically acceptable salt thereof;
In the method, in the process of the invention,
R 1、R1' are each independently selected from H, C 1-5 straight or branched chain alkyl, substituted or unsubstituted aryl; substituents on the aryl group are selected from C 1-5 straight or branched alkyl, C 3-6 cycloalkyl, C 1-5 straight or branched alkyl substituted with halogen atoms, and C 3-6 cycloalkyl substituted with halogen atoms;
R 2 is selected from H, -COR a、-COCH2NRbRc;Ra is C 1-5 linear or branched alkyl, R b、Rc is each independently selected from H, C 1-4 linear or branched alkyl;
R 3 is selected from hydroxy, C 1-5 straight or branched alkyl, C 3-6 cycloalkyl, C 1-5 straight or branched alkyl substituted by halogen atom, and C 3-6 cycloalkyl substituted by halogen atom.
In one embodiment of the present invention, the aryl group is a benzene ring or an indole ring.
In one embodiment of the present invention, R 1 is further preferably a C 4-5 straight or branched chain alkyl, substituted or unsubstituted aryl.
In one embodiment of the invention, R 1 is specifically selected from phenyl, 3-indolyl, isopropyl, R 1' is H; or R 1、R1' are both methyl.
In one embodiment of the invention, R 2 is specifically selected from H, -COCH 3 or-COCH 2NMe2.
In one embodiment of the invention, the above-mentioned compound is selected from:
In one embodiment of the present invention, the pharmaceutically acceptable salt is an inorganic salt or an organic salt, and the inorganic salt includes hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, bisulfate, nitrate, phosphate, and acid phosphate; the organic salt is selected from formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, succinate, glutarate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, salicylate, p-toluenesulfonate, ascorbate. Still further, the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, sulfate, succinate, or mesylate salts.
The invention also provides a pharmaceutical composition comprising the compound of the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, excipient or diluent.
In one embodiment of the invention, the pharmaceutical compositions may be formulated for systemic or sequential administration, and may be formulated for delivery of the compound or pharmaceutical composition to the tumor site in any effective manner of administration. Such modes of administration include, but are not limited to, oral compounds or compositions, by topical, transdermal, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal injection, intranasal instillation, by intracavitary or intravesical instillation, intraocular, intraarterial, intralesional or by application to mucous membranes such as nasal, laryngeal and bronchial mucosal tubes.
The invention also provides application of the compound or pharmaceutically acceptable salt thereof in preparing a medicament for inhibiting glutamine.
The invention also provides application of the compound or pharmaceutically acceptable salt thereof in preparing medicines for inhibiting tumor cell metabolism.
The invention also provides application of the compound or pharmaceutically acceptable salt thereof in preparing antitumor drugs.
In one embodiment of the present invention, the tumor is a tumor such as breast cancer, ovarian cancer, lung cancer, pancreatic cancer, etc.
The invention also provides an antitumor drug which is characterized by comprising the compound or pharmaceutically acceptable salt thereof and pharmaceutic adjuvant.
The beneficial effects are that:
The invention provides a 6-diazonium-5-oxo-hexanamide derivative or pharmaceutically acceptable salt thereof, which can inhibit glutamine metabolism and destroy the vital movement of tumor cells, thereby realizing the purpose of effectively treating tumors. The compound has strong antagonism to glutamine, has good GI stability and can reduce the occurrence rate of adverse events.
Detailed Description
The following examples illustrate, but do not limit, the synthesis of compounds of formula (I). The temperatures are in degrees celsius. All the evaporation was carried out under reduced pressure, if not otherwise stated. Reagents were purchased from commercial suppliers and used without further purification, if not otherwise indicated. The structure of the end products, intermediates and starting materials is confirmed by standard analytical methods, such as elemental analysis, spectroscopic characterization, such as MS, NMR. Abbreviations used are conventional in the art.
Example 1: (S) -2- ((S) -2-acetamido-3-phenylpropionamide) -6-diaza-N- (methylsulfonyl) -5-oxohexanamide
Preparation of (S) -N- (methylsulfonyl) -5-oxopyrrolidine-2-carboxamide (Compounds 1-2):
After L-pyroglutamic acid (compound 1-1,1g,7.74mmol,1.0 eq) and methanesulfonamide (0.88 g,9.29mmol,1.2 eq) were dissolved in DCM at room temperature, a catalytic amount of DMAP was added in an N 2 atmosphere and a solution of DCC in DCM was slowly added dropwise under an ice bath. After the completion of the reaction, the mixture was filtered, and the filtrate was concentrated to obtain crude product, which was subjected to column chromatography to obtain Compound 1-2 (1.46 g, yield: 91.3%).
MS-ESI(m/z)：207.05[M+l]+。
Preparation of (S) -1- (acetyl-L-phenylpropionyl) -N- (methylsulfonyl) -5-oxopyrrolidine-2-carboxamide (compounds 1-3):
To a round bottom flask was added compound 1-2 (1 g,4.85mmol,1 eq), DMAP (4-dimethylaminopyridine) (0.59 g,4.85mmol,1 eq), DIPEA (N, N-diisopropylethylamine) (1.25 g,9.70mmol,2 eq) was dissolved in 30mL anhydrous ACN and stirred in an ice water bath for 15min, then acetyl-L-phenylalanine (2.01 g,9.70mmol,2 eq) was slowly added to the round bottom flask and the reaction was allowed to resume after stirring in an ice water bath for 2 h. After completion of the reaction, rotary evaporation concentration gave a brown solid. The solid was dissolved in 50mL of dichloromethane, washed with saturated brine (30 mL x 3) and the organic phase was dried, concentrated and chromatographed to give compound 1-3 (1.69 g, yield: 87.9%).
MS-ESI(m/z)：396.13[M+l]+
Preparation of (S) -2- ((S) -2-acetamido-3-phenylpropionamide) -6-diaza-N- (methylsulfonyl) -5-oxohexanamide (example 1):
compound 1-3 (500 mg,1.26mmol,1.0 eq) was dissolved in 5mL anhydrous tetrahydrofuran and cooled to-116 ℃. TMS (trimethylsilyl diazomethane) (0.76ml,2M in hexane,1.51mmol,1.2eq) was additionally dissolved in 5mL of anhydrous tetrahydrofuran and cooled to-98 ℃. n-BuLi (0.60mL,2.5M in hexane,1.51mmol,1.2eq) was slowly added dropwise to the TMS solution and reacted for 30 minutes. Then, a mixed solution of TMS and n-BuLi was added to the solution of compounds 1 to 3, and the temperature was slowly raised from-116℃to-78℃and the reaction was continued for 30 minutes. After the reaction, 5mL of an aqueous solution was added to quench the reaction. Three extractions were performed with ethyl acetate (15 ml x 3). Then, the organic phases were dried over anhydrous magnesium sulfate, concentrated, and subjected to column chromatography to give example 1. (371 mg, yield: 67.2%).
MS-ESI(m/z)：438.15[M+l]+。
1H NMR(400MHz,CDCl3)δ:7.21-7.15(m,5H),4.93(m,1H),4.43(m,1H),4.25(s,1H),3.45(m,1H),3.20(m,1H),2.95(s,3H),2.37(t,2H),2.14-2.11(m,2H),1.85(s,3H).
Examples 2 to 12 (see Table 1) were obtained in a manner similar to the basic operation of example 1.
Table 1: structure and data of examples 2 to 12
Example 13: antiproliferative activity of P493B lymphoma cells
P493B lymphoma cells were seeded in 96-well plates at a density of 20000 cells/well; then adding basal medium based on 1640Serial dilutions of examples 1 to 14 or DRP-104, prepared under the trade designation C11875500 BT), were incubated for 72 hours; after 72 hours of incubation, 20 μ L CELL TITER AQueous was added to each well for 2 hours of incubation, absorbance was measured at 490nm and relative cell viability was calculated from the absorbance difference.
Table 2: data on antiproliferative activity of P493B lymphoma cells
Antiproliferative experiments were performed on this series of compounds. A total of 3 replicates were run and the results averaged. As shown in Table 2, the results of the experiments show that examples 1 to 12 all have equivalent or stronger inhibitory activity than the control DRP-104.
Example 14: evaluation of Compound stability
Intestinal tissue was homogenized with potassium phosphate buffer (0.1M) at a ratio of 1:9. To 100. Mu.l of plasma or tissue homogenates were added DRP-104 or 1640 basal medium solution of examples 1-12 (final concentration 10. Mu.M), incubated in triplicate for 0 and 60 minutes. At each time point, the reaction was stopped with 300 μl of methanol containing internal standard (losartan, 0.5 μΜ). The mixture was vortexed for 30s and centrifuged at 10000g for 10min at 4℃and the supernatant was used for subsequent analysis (peak area ratio of the test object and internal standard was determined by liquid chromatography-mass spectrometry (LC-MS)), yielding a Plasma stability (Plasma stability) index or a GI stability (intestinal stability) index, respectively.
Wherein, the specific LC-MS measurement conditions are as follows:
liquid chromatographic column: thermo BDS HYPERSIL C, 30x2.0mm,3 μm with guard column m.p., buffer: 25mM formic acid buffer, pH 3.5;
Aqueous phase (a): 90% water, 10% buffer;
Organic phase (B): 90% acetonitrile, 10% buffer;
flow rate: 300 microliters/min
Automatic sample injector: injection volume 10 microliters
Gradient procedure is seen in table 3.
Table 3: gradient program
Time (minutes) ％A ％B
0.0 100 0
1.5 0 100
2.0 0 100
2.1 100 0
3.5 100 0
The specific stability evaluation results are shown in table 4.
Table 4: compound stability results
As described in the present invention, examples 1 to 12 all showed good plasma stability, comparable to DRP-104. Examples 1 to 12 also exhibited good GI stability, especially examples 1 to 2, examples 4 to 6, examples 8 to 12, significantly better than DRP-104. Given that the gastrointestinal tract is the primary site of toxicity in the DON clinical study, good GI stability makes them potentially useful in reducing the incidence of adverse events.
From the stability data of the compounds of examples 1 to 12, it is clear that the R 3 substituted sulfonamide group significantly increases the GI stability of the compound for the compound of formula (I), while the steric hindrance of the R 1 substituent also has a certain effect on the stability of the compound.
The above examples are not intended to limit the scope of the invention nor the order of execution of the steps described. The present invention is obviously modified by a person skilled in the art in combination with the prior common general knowledge, and falls within the scope of protection defined by the claims of the present invention.

Claims (10)

1. A 6-diazonium-5-oxo-hexanamide compound of the structure shown in formula (I):
In the method, in the process of the invention,
R 1、R1' are each independently selected from H, C 1-5 straight or branched chain alkyl, substituted or unsubstituted aryl; substituents on the aryl group are selected from C 1-5 straight or branched alkyl, C 3-6 cycloalkyl, C 1-5 straight or branched alkyl substituted with halogen atoms, and C 3-6 cycloalkyl substituted with halogen atoms;
R 2 is selected from H, -COR a、-COCH2NRbRc;Ra is C 1-5 linear or branched alkyl, R b、Rc is each independently selected from H, C 1-4 linear or branched alkyl;
R 3 is selected from hydroxy, C 1-5 straight or branched alkyl, C 3-6 cycloalkyl, C 1-5 straight or branched alkyl substituted by halogen atom, and C 3-6 cycloalkyl substituted by halogen atom.
2. The 6-diazonium-5-oxo-hexanamide compound or pharmaceutically acceptable salt thereof according to claim 1, wherein aryl is benzene ring, indole ring.
3. The 6-diazonium-5-oxo-hexanamide compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the 6-diazonium-5-oxo-hexanamide compound is selected from the group consisting of:
4. The 6-diazonium-5-oxo-hexanamide compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the pharmaceutically acceptable salt is an inorganic or organic salt; wherein the inorganic salt is selected from hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, bisulfate, nitrate, phosphate, and acid phosphate; the organic salt is selected from formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, succinate, glutarate, fumarate, maleate, lactate, malate, citrate, tartrate, mesylate, ethanesulfonate, benzenesulfonate, salicylate, p-toluenesulfonate, ascorbate.
5. A pharmaceutical composition comprising a 6-diazonium-5-oxo-hexanamide compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or diluent.
6. A glutamine antagonist comprising a 6-diazonium-5-oxo-hexanamide compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.
7. Use of a 6-diazonium-5-oxo-hexanamide compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting glutamine metabolism.
8. Use of a 6-diazonium-5-oxo-hexanamide compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting tumor cell metabolism.
9. Use of a 6-diazonium-5-oxo-hexanamide compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating cancer.
10. The use according to claim 9, wherein the tumor is breast cancer, ovarian cancer, lung cancer, pancreatic cancer or the like.
CN202410166432.3A 2024-02-06 2024-02-06 6-Diazonium-5-oxo-hexanamide derivative for preparing glutamine antagonist Pending CN118005717A (en)

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