CN108218800B - 1, 2, 3-triazole aminopeptidase N inhibitor and preparation method and application thereof - Google Patents
1, 2, 3-triazole aminopeptidase N inhibitor and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a 1, 2, 3-triazole aminopeptidase N inhibitor and a preparation method and application thereof. The compound has a structure shown in a general formula (I) or (II). The invention also provides a preparation method of the 1, 2, 3-triazole compound and application of the compound in preparing a medicament for preventing or treating diseases related to the abnormal activity of aminopeptidase.
Description
Technical Field
The invention relates to a 1, 2, 3-triazole aminopeptidase N inhibitor, and a preparation method and application thereof, and belongs to the technical field of organic compound synthesis and medical application.
Background
Aminopeptidase N (APN, CD13) is a zinc ion-dependent metalloprotease, participates in degradation of N-terminal amino acid of a substrate, exists in a cell membrane in a homodimer form, and is proved to play an important role in tumorigenesis, development, invasion and metastasis, apoptosis and tumor angiogenesis. (1) Aminopeptidase N is expressed at high levels on the surface of tumor cells. The enzyme can degrade extracellular matrix, thereby promoting tumor cell invasion and metastasis. Tumor metastasis is an important cause of difficult tumor healing. Extracellular matrix plays a very important role in maintaining the stability of cell junctions and intercellular signaling. (2) Aminopeptidase N can stimulate vascular endothelial cells to release tumor microvascular formation related factors and promote angiogenesis of tumor cells. The new blood vessels can provide nutritional support for tumor tissue and carry away metabolic waste products. The APN is highly expressed in endothelial cells and sub-endothelial cells of new vessels, and can facilitate the endothelial cells to invade other surrounding tissues. Angiogenesis is the first step in tumor growth and metastasis. (3) Aminopeptidase N (CD13) is a surface marker of tumor stem cells and has a significant relationship with the survival of liver cancer stem cells (J Clin invest2010,120(9), 3326-3339). Tumor stem cells are a significant cause of tumor chemotherapy resistance, recurrence and metastasis. (4) APNs are involved in T lymphocyte-dependent inflammatory responses. Can be expressed on the surface of antigen presenting cells to degrade immunocompetent substances (such as interleukin-8); also reduces the recognition capability of the T cell surface to the antigen thereof, weakens the recognition and killing capability of macrophages and NK cells to tumor cells, and reduces the immunity of the organism.
Ubenimex is the only drug on the market so far, has a dipeptide-like structure of beta-amino acid, and is used as an immunopotentiator for treating leukemia. It is separated from the culture solution of Streptomyces olivaceus (Streptomyces olivoreticuli), and has high total synthesis cost and limited source. APN inhibitors, most of which are reported to be peptides, are sensitive to degradation by in vivo enzymes, and are poor in selectivity due to the existence of various aminopeptidases, carboxypeptidases or dipeptidylpeptidases in vivo, so that the APN inhibitors are difficult to develop into aminopeptidase N inhibitors with clinical application value. In addition, peptide inhibitors contain a plurality of chiral centers, so that the peptide inhibitors are difficult to synthesize, mostly come from natural products, and the limited sources are not favorable for deep scientific research and future large-scale production. Therefore, there is a great need to develop effective easily synthesized aminopeptidase N inhibitors.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a 1, 2, 3-triazole aminopeptidase N inhibitor and a preparation method thereof, and also provides pharmaceutical application of the compound.
The technical scheme of the invention is as follows:
1, 2, 3-triazole aminopeptidase N inhibitor
A compound having a structure represented by the following general formula (I) or (II), and optical isomers, diastereomers and racemic mixtures thereof, pharmaceutically acceptable salts, solvates or prodrugs thereof:
wherein the content of the first and second substances,
x is aliphatic hydrocarbon group, aromatic hydrocarbon group;
R1is aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl;
is in the S or R configuration, or a racemate thereof.
In accordance with a preferred aspect of the present invention,
wherein: x is
R1Is phenyl, substituted phenyl, pyridyl, naphthyl;
is in the S configuration.
According to a further preferred embodiment of the invention, the above compound is one of the following:
preparation method of di, 1, 2, 3-triazole aminopeptidase N inhibitor
The preparation method of the 1, 2, 3-triazole aminopeptidase N inhibitor comprises the following steps:
(1) the preparation method of the compound with the structure of the general formula (I) or (II) is as follows:
1) reacting leucine methyl ester hydrochloride 1 with triphosgene to generate isocyanate, then reacting with propargylamine under an alkaline condition to generate an intermediate 2, and reacting with hydroxylamine potassium to generate an intermediate 3; different aldehydes 4 are subjected to sodium borohydride reduction, mesylation and nucleophilic substitution by sodium azide to generate an intermediate 7; diazotizing different substituted arylamine 9, and performing nucleophilic substitution by sodium azide to generate an intermediate 10(10a-10 v); 2-nitrobenzaldehyde 12 is reduced by sodium borohydride and sodium sulfide to generate an intermediate 14; then diazotization and sodium azide nucleophilic substitution are carried out to generate an intermediate 15; acylation of intermediate 15 with different acid chlorides to yield intermediate 10(10aa-10 ii); the intermediate 7 or 10 respectively reacts with the intermediate 3 to generate a target compound 8 or 11; equation 1 is as follows:
reagents and conditions in equation 1 above: (a) triphosgene, sodium bicarbonate, dichloromethane, water, 0 ℃, 1.5 hours; (b) propargylamine, triethylamine, dichloromethane, 25 ℃,12 hours; (c) hydroxylamine potassium, methanol, 25 ℃, 0.5 hours; (d) sodium borohydride, methanol, 0 ℃,1 hour; (e) methanesulfonyl chloride, dichloromethane and triethylamine at 0 ℃ for 12 hours; (f) sodium azide, N' N-dimethylformamide, at 25 ℃ for 12 hours; (g) intermediate 3, copper sulfate pentahydrate, sodium ascorbate, and the volume ratio is 4: 1 dimethyl sulfoxide/water, 25 ℃, 2 hours; (h) i: sodium nitrite, 3.7% hydrochloric acid by mass fraction, 0 ℃, 0.5 hours, ii: sodium azide, 0 ℃, 0.5 hours; (i) sodium sulfide, water, 100 ℃,3 hours; (j) various acid chlorides, triethylamine, anhydrous tetrahydrofuran, 50 ℃,3 hours.
(2) The preparation method of the compound with the structure of the general formula (I) is as follows:
aldehyde or ketone 16 is subjected to sodium borohydride reduction, mesylation and nucleophilic substitution by sodium azide to generate an intermediate 19; the intermediate 19 and the intermediate 3 are subjected to click reaction to generate a target compound 20; equation 2 is as follows:
reagents and conditions in equation 2 above: (a) sodium borohydride, methanol, 0 ℃,1 hour; (b) methanesulfonyl chloride, dichloromethane and triethylamine at 0 ℃ for 12 hours; (c) sodium azide, N' N-dimethylformamide, at 25 ℃ for 12 hours; (d) intermediate 3, copper sulfate pentahydrate, sodium ascorbate, and the volume ratio is 4: 1 dimethyl sulfoxide/water, 25 ℃, 2 hours.
According to a preferred embodiment of the present invention, the compound having the structure of formula I is prepared as follows:
preparation of Compounds 8a-8w, 8aa-8ii and 20a-20e, exemplified by Compound 8 a.
A process for the preparation of (S) -2(3- ((1-benzyl-1H-1, 2, 3-triazol-4-yl) methyl) ureido) -N-hydroxy-4-methylpentanamide (8a) comprising the steps of:
1) preparation of methyl (prop-2-ynyl-1-ylcarbamoyl) -L-leucine (2)
Dissolving 11.81 g of L-leucine methyl ester hydrochloride into a mixed solvent of 40mL of dichloromethane and 40mL of saturated sodium bicarbonate, adding 0.98g of triphosgene in portions, reacting for 1.5 hours at 0 ℃, separating an organic phase, drying for 15 minutes by anhydrous magnesium sulfate, filtering, dropwise adding the filtered solution into 100mL of an anhydrous dichloromethane solution of 0.55g of propargylamine and 1.21g of triethylamine at 0 ℃, and reacting for 12 hours at 25 ℃; concentrating, dissolving the residue in 100mL of ethyl acetate, washing with 100mL of 3.7% hydrochloric acid for three times, washing with 100mL of saturated sodium bicarbonate for three times, washing with 100mL of saturated sodium chloride for three times, drying with anhydrous magnesium sulfate overnight, filtering, and concentrating to obtain a crude product; the crude product was recrystallized from ethyl acetate/petroleum ether to give 1.87g of a white solid, yield: 83 percent;
2) preparation of (S) -N-hydroxy-4-methyl-2- (3- (prop-2-ynyl-1-yl) ureido) propanamide (3)
Preparation of hydroxylamine potassium methanol solution: 28.00g of potassium hydroxide and 23.35g of hydroxylamine hydrochloride are dissolved in 70mL and 120mL of redistilled methanol respectively to obtain a solution A and a solution B; dropwise adding the solution A into the solution B, and stirring for 40 minutes at 0 ℃; filtering to obtain a new methanol solution of hydroxylamine potassium; dissolving 22.26 g of the compound in 20mL of the solution, reacting at 25 ℃ for 0.5 hour, concentrating, dissolving residues in water, and adjusting the pH value to 6 by using hydrochloric acid with the mass fraction of 3.7%; extracting with ethyl acetate 100mL for three times, combining organic phases, washing the organic phase with saturated sodium bicarbonate 100mL for three times, washing with saturated sodium chloride 100mL for three times, drying with anhydrous magnesium sulfate, filtering, and concentrating; after 50mL of methylene chloride was added to the residue, the mixture was left overnight at-18 ℃ to precipitate a solid, which was filtered and dried in vacuo to obtain 1.20g of a white solid, yield: 53 percent;
3) preparation of benzyl alcohol (5a)
1.06g of benzaldehyde 4a is dissolved in 10mL of methanol, 0.57g of sodium borohydride is added at 0 ℃ in portions, the mixture reacts for 1 hour at 0 ℃, the mixture is concentrated, and the residue is dissolved in 100mL of ethyl acetate; washing the organic phase with 100mL of water for three times, washing with 100mL of saturated sodium chloride for three times, drying with anhydrous magnesium sulfate, filtering, and concentrating to obtain 2.01g of colorless oil, wherein the crude product is directly put into the next reaction without further purification;
compounds 5b-5w, 5aa-5ii and 17a-17e were prepared in analogy to Compound 5 a;
4) benzyl methanesulfonate (6a)
Dissolving 1.08g of compound 5a and 1.52g of triethylamine in 100mL of anhydrous dichloromethane, dropwise adding 20mL of anhydrous dichloromethane solution containing 1.36g of methanesulfonyl chloride at 0 ℃, reacting at 0 ℃ for 12 hours, concentrating, dissolving the residue in 100mL of ethyl acetate, washing with 100mL of 3.7% hydrochloric acid for three times, washing with 100mL of saturated sodium bicarbonate for three times, washing with 100mL of saturated sodium chloride for three times, drying over-night with anhydrous magnesium sulfate, and concentrating to obtain 1.77g of yellow oil; the crude product is directly put into the next reaction without further purification;
compounds 6b-6w, 6aa-6ii and 18a-18e were prepared in analogy to Compound 6 a;
5) azidomethylbenzene (7a)
Dissolving 1.86g of a compound 6a in 10mL of N' N-dimethylformamide, adding 0.72g of sodium azide in several times, reacting for 12 hours at 25 ℃, pouring a reaction solution into ice water, extracting for three times by using 100mL of ethyl acetate, washing an organic phase by using 100mL of water for three times, washing by using 100mL of saturated sodium chloride for three times, drying over night by using anhydrous magnesium sulfate, concentrating to obtain 1.18g of colorless oil, and directly putting a crude product into the next reaction without further purification;
compounds 7b-7w, 7aa-7ii and 19a-19e were prepared in analogy to Compound 7 a;
6) ((S) -2(3- ((1-benzyl-1H-1, 2, 3-triazol-4-yl) methyl) ureido) -N-hydroxy-4-methylpentanamide (8a)
Dissolving 30.45 g of compound and 0.29g of compound 7a in 16mL of dimethyl sulfoxide, adding a solution of sodium ascorbate 59.4mg in 2mL of water and a solution of copper sulfate pentahydrate in 2mL of water, reacting at 25 ℃ for 2 hours, pouring the reaction solution into water, extracting with ethyl acetate 100mL for three times, combining organic phases, washing with saturated sodium chloride 100mL for three times, drying over-night anhydrous magnesium sulfate, and concentrating to obtain a colorless oil; the residue was dissolved in 20mL of methylene chloride and stirred at 25 ℃ for 2 hours, and the formed precipitate was filtered to obtain 0.35g of a white solid, yield: 48 percent;
compounds 8b-8w, 8aa-8ii and 20a-20e were prepared in analogy to Compound 8 a.
According to a preferred embodiment of the present invention, the compound having the structure of formula II is prepared as follows:
(1) a process for producing compounds 11a to 11v, for example, compound 11 a.
A process for the preparation of (S) -N-hydroxy-4-methyl-2- (3- ((1-phenyl-1H-1, 2, 3-triazol-4-yl) methyl) ureido) pentanamide (11a) comprising the steps of:
1) azidobenzene (10a)
0.93g of aniline 9a is dissolved in hydrochloric acid with the mass fraction of 3.7%, 0.74g of sodium nitrite is added at 0 ℃ to react for 0.5 hour at 0 ℃, then 0.72g of sodium azide is added to continue to react for 0.5 hour at 0 ℃, 50mL of ethyl acetate is extracted for three times, organic phase anhydrous magnesium sulfate is dried, filtered and concentrated to obtain yellow oil, and the crude product is directly put into the next reaction without further purification;
compounds 10b-10v were prepared in analogy to Compound 10 a;
2) (S) -N-hydroxy-4-methyl-2- (3- ((1-phenyl-1H-1, 2, 3-triazol-4-yl) methyl) ureido) pentanamide (11a)
30.45 g of the compound and 0.26g of the compound 10a were dissolved in 16mL of dimethyl sulfoxide, a solution of 59.4mg of sodium ascorbate in 2mL of water and a solution of 25mg of copper sulfate pentahydrate in 2mL of water were added, the reaction mixture was poured into water, 100mL of ethyl acetate was extracted three times, the organic phases were combined, 100mL of saturated sodium chloride was washed three times, anhydrous magnesium sulfate was dried overnight, and the mixture was concentrated to obtain a colorless oil, the residue was dissolved in 20mL of dichloromethane and stirred at 25 ℃ for 2 hours, and the precipitate formed was filtered to obtain 0.33g of a white solid, yield: and 47 percent.
Compounds 11b-11v were prepared in analogy to Compound 11 a.
(2) The preparation method of the compounds 11aa-11ii takes the compound 11aa as an example.
A process for the preparation of (S) -2- (4- ((3- (1-hydroxyamino) -4-methyl-1-oxopentan-2-yl) ureido) methyl) -1H-1, 2, 3-triazol-1-yl) benzylacetate (11aa) comprising the steps of:
1) (2-Nitrophenyl) methanol (13)
121.51 g of 2-nitrobenzaldehyde is dissolved in 10mL of methanol, 0.57g of sodium borohydride is added at 0 ℃ in a plurality of times, the mixture reacts for 1 hour at 0 ℃, the mixture is concentrated, the residue is dissolved in 100mL of ethyl acetate, the organic phase is washed with 50mL of water for three times, the saturated sodium chloride is washed with 50mL of water for three times, anhydrous magnesium sulfate is dried overnight, the mixture is filtered and concentrated to obtain 1.45g of yellow solid, and the crude product is directly put into the next reaction without further purification;
2) (2-aminophenyl) methanol (14)
Adding 131.53 g of compound into 100mL of water solution containing 21.60g of sodium sulfide, reacting for 3 hours at 100 ℃, extracting the water phase with 50mL of ethyl acetate for three times, washing the organic phase with 50mL of water for three times, washing the organic phase with 50mL of saturated sodium chloride for three times, drying the mixture over night by anhydrous magnesium sulfate, filtering and concentrating to obtain 1.05g of white solid, and directly putting the crude product into the next reaction without further purification;
3) (2-azidophenyl) methanol (15)
141.23 g of compound is dissolved in hydrochloric acid with the mass fraction of 3.7%, 0.74g of sodium nitrite is added at 0 ℃, the reaction is carried out for 0.5 hour at 0 ℃, then 0.72g of sodium azide is added, the reaction is continued for 0.5 hour at 0 ℃, 50mL of ethyl acetate is extracted for three times, the organic phase anhydrous magnesium sulfate is dried, filtered and concentrated to obtain yellow oil, and the crude product is directly put into the next reaction without further purification;
4) 2-azidobenzyl acetate (10aa)
151.49 g of compound and 1.51g of triethylamine are dissolved in 50mL of anhydrous tetrahydrofuran, 10mL of anhydrous tetrahydrofuran solution of acetyl chloride 0.94g is added dropwise at 0 ℃, the reaction is carried out for 3 hours at 50 ℃, the concentration is carried out, the residue is dissolved in 50mL of ethyl acetate, the organic phase is washed by 50mL of hydrochloric acid with the mass fraction of 3.7% for three times, saturated sodium bicarbonate is washed for three times, saturated sodium chloride is washed for three times, anhydrous magnesium sulfate is dried overnight, the filtration and the concentration are carried out, 1.07g of yellow oily matter is obtained, and the crude product is directly put into the next reaction without further purification;
compounds 10bb-10ii are prepared analogously to Compound 10 aa;
5) (S) -2- (4- ((3- (1-hydroxyamino) -4-methyl-1-oxopentan-2-yl) ureido) methyl) -1H-1, 2, 3-triazol-1-yl) benzyl acetate (11aa)
30.45 g of the compound and 10aa 0.42g of the compound were dissolved in 16mL of dimethyl sulfoxide, a solution of 59.4mg of sodium ascorbate in 2mL of water and a solution of 25mg of copper sulfate pentahydrate in 2mL of water were added, the reaction mixture was poured into water, 100mL of ethyl acetate was extracted three times, the organic phases were combined, 100mL of saturated sodium chloride was washed three times, anhydrous magnesium sulfate was dried overnight, and the mixture was concentrated to obtain a colorless oil, the residue was dissolved in 20mL of dichloromethane and stirred at 25 ℃ for 2 hours, and the resulting precipitate was filtered and dried in vacuo to obtain 0.44g of a white solid, yield: 53 percent.
Compounds 11bb-11ii were prepared in analogy to Compound 11 aa.
The target compound of reaction formula 1 has the following structural formula:
the target compound of reaction formula 2 has the following structural formula:
the specific procedures for the compounds are described in detail in the examples.
The skilled person can vary the above steps to increase the yield, and can determine the synthetic route according to the basic knowledge in the art, such as choice of reactants, solvents and temperature, and can increase the efficiency by using various conventional protecting groups to avoid side reactions. These conventional protection methods can be found, for example, in T.Greene, Protecting Groups in Organic Synthesis.
Application of tris, 1, 2, 3-triazole aminopeptidase N inhibitor
The invention also provides application of the 1, 2, 3-triazole aminopeptidase N inhibitor in preparing a medicament for preventing or treating diseases related to the abnormal activity of aminopeptidase; the diseases related to the abnormal activity of the aminopeptidase comprise: various hematologic or solid tumors, inflammation, multiple sclerosis, various tissue ulcers or tissue ulcerative conditions, periodontal disease, epidermolysis bullosa, malaria.
In addition, the invention also includes a pharmaceutical composition suitable for oral or parenteral administration comprising a compound of formula I or II and one or more pharmaceutically acceptable carriers or excipients.
Drawings
FIG. 1 is a representative picture of inhibition of tubular structure formation of human umbilical vein endothelial cells.
FIG. 2 is a bar graph of the rate of inhibition of tubular structure formation; the analysis of the statistics is carried out,*P<0.05, 8v (100. mu.M) group to ubenimex (100. mu.M) group.
Fig. 3 is a representative picture of inhibition of rat aortic annulus microangiogenesis.
FIG. 4 is a bar graph of the inhibition rate of rat aortic ring microvascular formation; the analysis of the statistics is carried out,*P<0.05, 8v (100. mu.M) group to ubenimex (100. mu.M) group.
Fig. 5 is a representative picture of lobe surface nodules from mouse H22 liver cancer lung metastases.
FIG. 6 is a histogram of the surface nodules of lung lobes from lung metastases of mouse H22 liver cancer; the analysis of the statistics is carried out,*P<0.05, 8v (60mg/kg) dose group to blank group, ubenimex (60mg/kg) dose group to blank group.
Detailed Description
The present invention will be further described with reference to the following examples, but is not limited thereto.
Example 1 (1) preparation of compounds 8a-8w, 8aa-8ii and 20a-20e, exemplified by compound 8 a.
A process for the preparation of (S) -2(3- ((1-benzyl-1H-1, 2, 3-triazol-4-yl) methyl) ureido) -N-hydroxy-4-methylpentanamide (8a) comprising the steps of:
1) preparation of methyl (prop-2-ynyl-1-ylcarbamoyl) -L-leucine (2)
L-leucine methyl ester hydrochloride 1(1.81g, 10mmol) was dissolved in a mixed solvent of dichloromethane (40mL) and saturated sodium bicarbonate (40 mL). Triphosgene (0.98g, 3.3mmol) was added in portions. The reaction was carried out at 0 ℃ for 1.5 hours. The organic phase was separated and dried over anhydrous magnesium sulfate for 15 minutes. Filtration was carried out, and at 0 ℃ the filtrate was added dropwise to propargylamine (0.55g, 10mmol) and triethylamine (1.21g, 12mmol) in dry dichloromethane (100 mL). After dropping, the reaction was carried out at 25 ℃ for 12 hours. Concentrate and dissolve the residue in ethyl acetate (100 mL). 3.7% hydrochloric acid (3X 100mL), saturated sodium bicarbonate (3X 100mL), saturated sodium chloride (3X 100mL), anhydrous magnesium sulfate and dried overnight. Filtering, concentrating to obtain crude product. The crude product was recrystallized from ethyl acetate/petroleum ether to give 1.87g of a white solid. Yield: 83%, mp: 102.9-104.2 ℃;1H NMR(300MHz，DMSO-d6)：6.37(d，J＝8.4Hz，1H)，6.25(t，J＝5.7Hz，1H)，4.17(q，J＝8.4Hz，1H)，3.78(dd，J＝5.7Hz，J＝2.4Hz，2H)，3.61(s，3H)，3.05(t，J＝2.4Hz，1H)，1.68-1.54(m，1H)，1.47-1.42(m，2H)，0.89-0.84(m，6H)；ESI-MS m/z 227.4[M+H]+。
2) preparation of (S) -N-hydroxy-4-methyl-2- (3- (prop-2-ynyl-1-yl) ureido) propanamide (3)
Preparation of hydroxylamine potassium methanol solution: potassium hydroxide (28.00g, 509mmol) and hydroxylamine hydrochloride (23.35g, 343 mmol)mmol) were dissolved in 70mL and 120mL of redistilled methanol, respectively, to obtain solution A and solution B. Solution A was added dropwise to solution B, and stirred at 0 ℃ for 40 minutes. Filtration gave fresh methanolic potassium hydroxylamine solution. Compound 2(2.26g, 10mmol) was dissolved in the above solution (20 mL). The reaction was carried out at 25 ℃ for 0.5 hour. And (5) concentrating. The residue was dissolved in water, and the pH was adjusted to 6 with 3.7% by mass of hydrochloric acid. Extraction with ethyl acetate (3X 100mL) and combination of the organic phases. The organic phase was washed with saturated sodium bicarbonate (3X 100mL) and saturated sodium chloride (3X 100 mL). Dried over anhydrous magnesium sulfate. Filtering and concentrating. Dichloromethane (50mL) was added to the residue, and the mixture was left at-18 ℃ overnight. The solid precipitated, was filtered and dried under vacuum to give 1.20g of a white solid. Yield: 53%, mp: 124.5-126.2 ℃;1H NMR(600MHz,DMSO-d6)：10.68(s，1H)，8.80(s，1H)，6.24(t，J＝5.7Hz，1H)，6.16(d，J＝8.4Hz，1H)，4.05(q，J＝8.4Hz，1H)，3.78(dd，J＝5.7Hz，J＝2.4Hz，2H)，3.05(t，J＝2.4Hz，1H)，1.54-1.50(m，1H)，1.34-1.32(m，2H)，0.89-0.84(m，6H)；ESI-MS m/z 226.3[M-H]-。
3) preparation of benzyl alcohol (5a)
Benzaldehyde 4a (1.06g, 10mmol) was dissolved in methanol (10mL) and sodium borohydride (0.57g, 15mmol) was added in portions at 0 ℃. The reaction was carried out at 0 ℃ for 1 hour. Concentrate and dissolve the residue in ethyl acetate (100 mL). The organic phase was washed with water (3X 100mL), saturated sodium chloride (3X 100mL) and dried over anhydrous magnesium sulfate. Filtration and concentration gave a colourless oil (2.01g), which was directly taken to the next reaction without further purification of the crude product.
Compounds 5b-5w, 5aa-5ii and 17a-17e were prepared in analogy to Compound 5 a.
4) Benzyl methanesulfonate (6a)
Compound 5a (1.08g, 10mmol) and triethylamine (1.52g, 15mmol) were dissolved in anhydrous dichloromethane (100mL) and a solution of methanesulfonyl chloride (1.36g, 12mmol) in anhydrous dichloromethane (20mL) was added dropwise at 0 ℃. The reaction was carried out at 0 ℃ for 12 hours. The mixture was concentrated, and the residue was dissolved in ethyl acetate (100mL), washed with 3.7% by mass hydrochloric acid (3X 100mL), saturated sodium bicarbonate (3X 100mL), saturated sodium chloride (3X 100mL), and dried over anhydrous magnesium sulfate overnight. Concentration gave a yellow oil (1.77 g). The crude product was directly used in the next reaction without further purification.
Compounds 6b-6w, 6aa-6ii and 18a-18e were prepared in analogy to Compound 6 a.
5) Azidomethylbenzene (7a)
Compound 6a (1.86g, 10mmol) was dissolved in N' N-dimethylformamide (10mL) and sodium azide (0.72g, 11mmol) was added in portions. The reaction was carried out at 25 ℃ for 12 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate (3X 100 mL). The organic phase was washed with water (3X 100mL), saturated sodium chloride (3X 100mL) and dried over anhydrous magnesium sulfate overnight. Concentration gave a colorless oil (1.18 g). The crude product was directly used in the next reaction without further purification.
Compounds 7b-7w, 7aa-7ii and 19a-19e were prepared in analogy to compound 7 a.
6) (S) -2(3- ((1-phenyl-1H-1, 2, 3-triazol-4-yl) methyl) ureido) -N-hydroxy-4-methylpentanamide (8a)
Compound 3(0.45g, 2mmol) and compound 7a (0.29g, 2.2mmol) were dissolved in dimethyl sulfoxide (16mL), and a solution of sodium ascorbate (59.4mg, 0.3mmol) in water (2mL) and a solution of copper sulfate pentahydrate (25mg, 0.1mmol) in water (2mL) were added. The reaction was carried out at 25 ℃ for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate (3X 100 mL). The combined organic phases were washed with saturated sodium chloride (3X 100mL) and dried over anhydrous magnesium sulfate overnight. Concentration gave a colorless oil. The residue was dissolved in methylene chloride (20mL), and the mixture was stirred at 25 ℃ for 2 hours. The resulting precipitate was filtered to give 0.35g of a white solid. Yield: 48%, mp: 184.8-186.2 ℃.1H NMR(600MHz,DMSO-d6)：10.67(s，1H)，8.79(s，1H)，7.90(s，1H)，7.37(t，J＝6.6Hz，2H)，7.32(t，J＝6.6Hz，1H)，7.30(d，J＝6.6Hz，2H)，6.36(t，J＝6Hz，1H)，6.11(d，J＝8.4Hz，1H)，5.56(s，2H)，4.21-4.20(m，2H)，4.06(q，J＝8.4Hz，1H)，1.51-1.49(m，1H)，1.33-1.30(m，2H)，0.86-0.82(m，6H)；13C-NMR(100MHz,DMSO-d6)：169.9，157.6，146.6，136.5，129.1，128.5，128.3，122.9，53.1，49.5，42.9，35.4，24.6，23.2，22.6；HRMS(AP-ESI)m/z calcd for C17H25N6O3[M+H]+361.1988，found 361.1992。
Compounds 8b-8w, 8aa-8ii and 20a-20e were prepared in analogy to Compound 8 a.
Example 2 preparation of Compounds 11a-11v, compound 11a is exemplified.
A process for the preparation of (S) -N-hydroxy-4-methyl-2- (3- ((1-phenyl-1H-1, 2, 3-triazol-4-yl) methyl) ureido) pentanamide (11a) comprising the steps of:
1) azidobenzene (10a)
Aniline 9a (0.93g, 10mmol) was dissolved in 3.7% by mass hydrochloric acid, and sodium nitrite (0.74g, 10.7mmol) was added at 0 ℃. After 0 ℃ for 0.5 h, sodium azide (0.72g, 11mmol) was added. The reaction was continued at 0 ℃ for 0.5 hour. Ethyl acetate (3X 50mL) was extracted and the organic phase was dried over anhydrous magnesium sulfate. Filtering and concentrating to obtain yellow oil, and directly putting the crude product into the next reaction without further purification.
Compounds 10b-10v were prepared in analogy to compound 10 a.
2) (S) -N-hydroxy-4-methyl-2- (3- ((1-phenyl-1H-1, 2, 3-triazol-4-yl) methyl) ureido) pentanamide (11a)
Compound 3(0.45g, 2mmol) and compound 10a (0.26g, 2.2mmol) were dissolved in dimethyl sulfoxide (16mL), and a solution of sodium ascorbate (59.4mg, 0.3mmol) in water (2mL) and copper sulfate pentahydrate (25mg, 0.1mmol) in water (2mL) were added. The reaction was carried out at 25 ℃ for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate (3X 100 mL). The combined organic phases were washed three times with saturated sodium chloride (3X 100mL) and dried over anhydrous magnesium sulfate overnight. Concentration gave a colorless oil. The residue was dissolved in methylene chloride (20mL), and the mixture was stirred at 25 ℃ for 2 hours. The precipitate formed was filtered to give 0.33g of a white solid, yield: and 47 percent.1H NMR(300MHz,DMSO-d6)：10.69(s，1H)，8.81(s，1H)，8.58(s，1H)，7.90-7.87(m，2H)，7.62-7.57(m，2H)，7.51-7.46(m，1H)，6.48(t，J＝5.7Hz，1H)，6.18(d，J＝8.7Hz，1H)，4.34-4.31(m，2H)，4.08(q，J＝8.7Hz，1H)，1.66-1.43(m，1H)，1.37-1.32(m，2H)，0.88-0.84(m，6H)；13C-NMR(75MHz，DMSO-d6)：169.4，157.2，146.9，136.6，129.8，128.5，120.6，119.9，49.1，42.3，34.8，24.1，22.7，22.1；HRMS(AP-ESI)m/z calcd for C16H23N6O3[M+H]+347.1832，found 347.1826。
Compounds 11b-11v were prepared in analogy to Compound 11 a.
Example 3 preparation of Compounds 11aa-11ii, taking Compound 11aa as an example.
A process for the preparation of (S) -2- (4- ((3- (1- (hydroxylamine) -4-methyl-1-oxopentan-2-yl) ureido) methyl) -1H-1, 2, 3-triazol-1-yl) benzyl acetate (11aa) comprising the steps of:
1) (2-Nitrophenyl) methanol (13)
2-nitrobenzaldehyde 12(1.51g, 10mmol) was dissolved in methanol (10mL) and sodium borohydride (0.57g, 15mmol) was added in portions at 0 ℃. The reaction was carried out at 0 ℃ for 1 hour. Concentrate and dissolve the residue in ethyl acetate (100 mL). The organic phase was washed with water (3X 50mL), saturated sodium chloride (3X 50mL) and dried over anhydrous magnesium sulfate overnight. Filtration and concentration gave a yellow solid (1.45 g). The crude product was directly used in the next reaction without further purification.
2) (2-aminophenyl) methanol (14)
Compound 13(1.53g, 10mmol) was added to a solution of sodium sulfide (21.60g, 90mmol) in water (100 mL). The reaction was carried out at 100 ℃ for 3 hours. The aqueous phase was extracted with ethyl acetate (3X 50 mL). The organic phase was washed with water (3X 50mL), saturated sodium chloride (3X 50mL) and dried over anhydrous magnesium sulfate overnight. Filtration and concentration gave a white solid (1.05 g). The crude product was directly used in the next reaction without further purification.
3) (2-azidophenyl) methanol (15)
Compound 14(1.23g, 10mmol) was dissolved in 3.7% by mass hydrochloric acid, and sodium nitrite (0.74g, 10.7mmol) was added at 0 ℃. After 0 ℃ for 0.5 h, sodium azide (0.72g, 11mmol) was added. The reaction was continued at 0 ℃ for 0.5 hour. Ethyl acetate (3X 50mL) was extracted and the organic phase was dried over anhydrous magnesium sulfate. Filtering and concentrating to obtain yellow oil, and directly putting the crude product into the next reaction without further purification.
4) 2-azidobenzyl acetate (10aa)
Compound 15(1.49g, 10mmol) and triethylamine (1.51g, 15mmol) were dissolved in anhydrous tetrahydrofuran (50mL), and a solution of acetyl chloride (0.94g, 12mmol) in anhydrous tetrahydrofuran (10mL) was added dropwise at 0 ℃. The reaction was carried out at 50 ℃ for 3 hours. Concentrate and dissolve the residue in ethyl acetate (50 mL). The organic phase was washed with 3.7% by mass hydrochloric acid (3X 50mL), saturated sodium bicarbonate (3X 50mL), saturated sodium chloride (3X 50mL), and dried over anhydrous magnesium sulfate overnight. Filtration and concentration gave a yellow oil (1.07 g). The crude product was directly used in the next reaction without further purification.
Compounds 10bb-10ii were prepared in analogy to Compound 10 aa.
5) (S) -2- (4- ((3- (1-hydroxyamino) -4-methyl-1-oxopentan-2-yl) ureido) methyl) -1H-1, 2, 3-triazol-1-yl) benzyl acetate (11aa)
Compound 3(0.45g, 2mmol) and compound 10aa (0.42g, 2.2mmol) were dissolved in dimethyl sulfoxide (16mL), and a solution of sodium ascorbate (59.4mg, 0.3mmol) in water (2mL) and copper sulfate pentahydrate (25mg, 0.1mmol) in water (2mL) were added. The reaction was carried out at 25 ℃ for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate (3X 100 mL). The combined organic phases were washed with saturated sodium chloride (3X 100mL) and dried over anhydrous magnesium sulfate overnight. Concentration gave a colorless oil. The residue was dissolved in methylene chloride (20mL), and the mixture was stirred at 25 ℃ for 2 hours. The precipitate formed was filtered and dried in vacuo to give 0.44g of a white solid in yield: 53 percent.1H NMR(300MHz，DMSO-d6)：10.68(s，1H)，8.80(s，1H)，8.26(s，1H)，7.67-7.49(m，4H)，6.48(t，J＝5.7Hz，1H)，6.19(d，J＝9Hz，1H)，4.99(s，2H)，4.40-4.28(m，2H)，4.08(q，J＝9Hz，1H)，1.96(s，3H)，1.60-1.32(m，1H)，1.24-1.17(m，2H)，0.88-0.84(m，6H)；13C-NMR(75MHz，DMSO-d6)：169.8，169.3，157.1，146.0，135.5，131.1，129.9，129.8，129.3，125.8，124.1，61.6，49.1，42.3，34.7，24.1，22.7，22.1，20.4；HRMS(AP-ESI)m/z calcd for C19H27N6O5[M+H]+419.2043，found 419.2039。
Compounds 11bb-11ii were prepared in analogy to Compound 11 aa.
Example 4 in vitro inhibition of the Activity of aminopeptidase N
1) Experimental materials:
porcine aminopeptidase N was purchased from Biocol, and the substrate L-leucyl-p-nitroaniline was purchased from Sigma.
Preparation of buffer, 12.89g Na2HPO4 .12H2O and 2.18g NaH2PO4 .2H2O, dissolved in a 1000mL volumetric flask, added with freshly boiled and cooled distilled water to a constant volume to obtain a 50mM phosphate buffer solution with pH of 7.2, and left at room temperature for later use.
The substrate was dissolved in dimethyl sulfoxide to prepare a solution of 16 mmol/mL.
Aminopeptidase N was dissolved in the buffer solution to prepare a solution of 0.15IU/mL, and the solution was left at 4 ℃ in a refrigerator for further use.
2) The experimental method comprises the following steps:
TABLE 1 various ratios of reagents added in vitro enzyme inhibition experiments
In a 96-well plate, the enzyme, substrate, inhibitor and phosphate buffer were added in the amounts shown in the table above. Incubate at 37 ℃ for 0.5 hours. The absorbance at 405nm was measured and the inhibition was calculated according to the following formula:
according to the concentration and the inhibition rate of the compound, origin 8.0 software is used for fitting a curve to obtain IC50The value is obtained.
3) The experimental results are as follows:
the aminopeptidase N inhibitory activities of some compounds in the general formulas (I) and (II) and the positive ubenimex are shown in the following table 2:
TABLE 2 aminopeptidase N inhibitory Activity of part of the Compounds
[a]The experimental results are expressed as mean ± standard deviation from three independent experiments.
The results of in vitro enzyme inhibition experiments show that: most compounds exhibit aminopeptidase N inhibitory activity at micromolar or submicromolar levels. The activity of all the compounds is superior to that of positive drug ubenimex (Bestatin). Wherein, the activity of the compounds 8b, 8e, 8h, 8k, 8l, 8s, 8t, 8w, 8aa, 8bb, 8cc, 11a, 11b, 11e, 11h, 11k-11q, 11s, 11u, 11v, 11aa-11ee, 11hh and 20d is one order of magnitude better than that of ubenimex; the activity of compounds 8v, 11ff and 11ii was two orders of magnitude better than ubenimex.
Example 5 in vitro inhibition of tumor cell proliferation assay
1) Experimental materials:
cell lines:
human leukemia K562 cell line, human liver cancer PLC/PRF/5 cell line, human prostate cancer PC-3 cell line, human ovarian clear cell carcinoma ES-2 cell line, human breast cancer A549 cell line, human breast cancer MDA-MB-231 cell line and human colon cancer HCT116 cell line in logarithmic growth phase.
Reagent: MTT was dissolved in 1 XPBS to make a 5mg/mL solution, dimethylsulfoxide.
2) The experimental method comprises the following steps:
spreading cells (100 μ L) in logarithmic growth phase at the bottom of 96-well plate (suspension cells 8,000 cells/well, adherent cells 4,000 cells/well), adding inhibitor (100 μ L) with different concentrations at 37 deg.C and 5% CO after cell adherent extension (suspension cells directly added inhibitor)2Incubate for 48 hours. MTT (20. mu.L) solution was then added and incubation continued for 4 hours. And (4) centrifuging. Add dimethyl sulfoxide (200. mu.L) and mix well for 15 minutes. Absorbance at 570nm was measured. The cell proliferation inhibition rate was calculated according to the following formula:
fitting a curve by utilizing origin 8.0 software according to the concentration and the corresponding inhibition rate of the inhibitor to obtain IC50The value is obtained.
3) The experimental results are as follows:
the activities of partial compounds in the general formulas (I) and (II) and positive ubenimex for inhibiting the proliferation of various tumor cell strains are shown in the following table 3:
TABLE 3 antitumor cell proliferation Activity of part of the Compounds
[a]The experimental results are expressed as mean ± standard deviation from three independent experiments.
The cell proliferation activity showed: the inhibition effect of the compounds 8v and 8w on seven cell strains is obviously better than that of positive drug ubenimex, and the compounds have the effect of resisting tumor cell proliferation.
Example 6 in vitro anti-angiogenic experiments
(1) Experiment for inhibiting formation of tubular structure of endothelial cells of human umbilical vein in vitro
1) An experimental model: forming tubular structure of endothelial cells of umbilical vein in vitro;
2) experimental materials: primary isolated human umbilical vein endothelial cells, Matrigel (Matrigel, available from BD Bioscience, inc.), M199 cell culture medium;
3) the experimental method comprises the following steps:
mu.L of matrigel was added to a 96-well plate and left at 37 ℃ for 0.5 hour, and after the gel was solidified, 50. mu.L of M199 medium containing human umbilical vein endothelial cells (20,000 cells/well) and various concentrations of inhibitor was added. 37 ℃ and 5% CO2Incubate for 4 hours. Observing and photographing under a microscope, randomly selecting five visual fields to count branch points of the tubular structure, calculating an average value, and comparing with the ubenimex group. This experiment was repeated three times.
4) The experimental results are as follows:
the experimental results are shown in figure 1 and figure 2. Compound 8v exhibited dose-dependent inhibition of human umbilical vein endothelial cell tube formation. When the compound 8v is at 10 mu M, the effect of inhibiting the formation of a tubular structure is equivalent to that when the positive drug ubenimex is at 100 mu M; compound 8v almost completely inhibited the formation of tubular structures at 100 μ M. Compound 8v showed anti-angiogenic effects in vitro, with further development value.
(2) Experiment for inhibiting generation of micro-vessels in aortic annulus of rat in vitro
1) An experimental model: in vitro rat aortic ring microvascular generation;
2) experimental materials: 8-10 weeks old rats, Matrigel (Matrigel, available from BD Bioscience), M199 cell culture medium;
3) the experimental method comprises the following steps:
the aorta of the rat is divided and cut into aortic rings about 1mm for standby. Matrigel (100 μ L) was added to a 96-well plate, left at 37 ℃ for 0.5 hour, and after the gel was solidified, the divided aortic ring was added, followed by covering with matrigel (100 μ L). Standing at 37 deg.C for 0.5 hr, adding inhibitor with different concentrations at 37 deg.C and 5% CO after gelation2Incubate for 9 days. The pictures were photographed by observation under a microscope, processed with Image-pro Plus 6.0 software, and the inhibition ratio was calculated. Cell culture medium was changed every three days. This experiment was repeated three times.
4) The experimental results are as follows:
the experimental results are shown in figures 3 and 4. The compound 8v has a dose-dependent inhibitory effect on rat aortic ring microangiogenesis. When the compound 8v is at 10 mu M, the effect of inhibiting the micro-angiogenesis is equivalent to that when the positive drug ubenimex is at 100 mu M; compound 8v almost completely inhibited the production of microvessels at 100 μ M. Compound 8v showed anti-angiogenic effects in vitro, with further development value.
Example 7 in vivo inhibition of tumor Lung metastasis
1) An experimental model: mouse H22 hepatoma cell lung metastasis;
2) experimental materials: kunming mouse 6 weeks old, mouse H22 hepatoma cell;
3) the experimental method comprises the following steps:
mouse tail vein injection of H22 cells (7.5X 10) suspended in 1 XPBS (0.1mL)60.1 mL). After injection, mice were randomly divided into blank and medicated groups. The medicine is an intraperitoneal injection inhibitor or ubenimex, and the dosage is 60 mg/kg/d. Blank groups were injected i.p. with 1 × PBS. After 12 days of administration, the mice were sacrificed by cervical pulling, the lung lobes were separated, fixed in Bouin's fixative, the lung nodules on the surface of the lung lobes were counted, and the inhibition rate was calculated.
4) The experimental results are as follows:
the experimental results are shown in figures 5 and 6. When the compound 8v and ubenimex are injected into the abdominal cavity and the dosage is 60mg/kg/d, the inhibition effect on H22 lung metastasis is 71 percent and 64 percent respectively. No obvious hepatosplenic toxicity was seen with the group of 8v drugs. The compound 8v shows the function of inhibiting tumor metastasis in vivo and has further development value.
Claims (4)
1, 2, 3-triazole aminopeptidase N inhibitors, characterized by being a compound of the structure:
。
2. use of the 1, 2, 3-triazole aminopeptidase N inhibitor of claim 1 for the preparation of a medicament for preventing or treating a disease associated with abnormal aminopeptidase activity.
3. The diseases associated with the abnormality of aminopeptidase activity according to claim 2, which are: various hematologic or solid tumors, inflammation, multiple sclerosis, various tissue ulcers or tissue ulcerative conditions, periodontal disease, epidermolysis bullosa, malaria.
4. A pharmaceutical composition suitable for oral or parenteral administration comprising a 1, 2, 3-triazole aminopeptidase N inhibitor of claim 1 and one or more pharmaceutically acceptable carriers or excipients.
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