CN108689946B - 2-substituted sulfenyl acetamide compound and preparation method and application thereof - Google Patents
2-substituted sulfenyl acetamide compound and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a 2-substituted thioacetamide compound and a preparation method and application thereof, wherein the 2-substituted thioacetamide compound has a structure shown in a formula I, R is C1-C3 alkoxy, halogen or NR 1 R 2 Wherein R is 1 、R 2 Independently H, C1-C3 alkyl. The compound of the invention can effectively and selectively inhibit arginine methyltransferase 5 and can be used as a PRMT5 inhibitor.
Description
Technical Field
The invention relates to a 2-substituted sulfenyl acetamide compound and a preparation method and application thereof.
Background
The methylation of arginine, which is involved in the family of protein arginine methyltransferases (PRMTs), is a post-translational modification that is widespread in the nucleus and cytoplasm, and that uses S-adenosyl-methionine as a methyl donor, and that modifies the nitrogen atom of the protein arginine side chain by methylation, producing S-adenosylhomocysteine and methyl arginine. The substrates of PRMTs are glycine and arginine domain rich proteins. A total of 9 PRMTs (PRMT 1-9) are currently found in mammals, 8 of which are biologically active. Depending on the methylation product, it can be divided into types I and II: type I PRMT catalyzes the formation of monomethyl arginine (MMA) and asymmetric dimethyl arginine (dimethylarginine), and type II PRMT catalyzes the formation of MMA and symmetric dimethyl arginine (dimethylarginine). PRMT5 belongs to type ii PRMT.
PRMT5 may methylate different proteins involved in the regulation of physiological processes, for example PRMT5 may influence gene transcription processes by methylating histones and transcription elongation factors; it can methylate the tumor suppressor gene p53 to alter the activation state of p 53.
It has been found that overexpression of PRMT5 occurs in mantle cell lymphoma, acute myelogenous leukemia, lung cancer, colon cancer, diffuse large B-cell lymphoma, etc., and that inhibition of PRMT5 activity by small molecules can inhibit tumor cell proliferation in mantle cell lymphoma. In addition, it was found that PRMT5 is also highly likely to be a new therapeutic target for beta-thalassemia and sickle cell disease. PRMT5 is therefore a promising therapeutic target.
Disclosure of Invention
The purpose of the present invention is to provide a novel arginine methyltransferase 5 inhibitor.
In a first aspect of the invention, there is provided a compound of formula I, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or prodrug thereof:
in the formula, R is C1-C3 alkoxy, halogen or NR 1 R 2 Wherein R is 1 、R 2 Independently H, C1-C3 alkyl.
In another preferred embodiment, R is methoxy, ethoxy, fluoro, chloro, bromo, or dimethylamino.
In another preferred embodiment, the pharmaceutically acceptable salts are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
In a second aspect of the invention, there is provided a process for the preparation of a compound of formula I, said process comprising the steps of:
nucleophilic substitution of compound 2 and compound 4 to produce the compound of formula I, wherein R is as defined above.
In another preferred embodiment, the nucleophilic substitution reaction of the compound 2 and the compound 4 occurs under an alkaline condition, wherein the alkaline condition is one or a combination of more than two of potassium carbonate, sodium carbonate, potassium hydroxide and sodium hydroxide.
In another preferred embodiment, compound 2 is prepared by the following steps:
a) The compound 1 is reduced to become a substituted o-diamine intermediate;
b) The substituted o-diamine intermediate is reacted with carbon disulfide ring under basic condition to synthesize compound 2.
In another preferred embodiment, compound 3 is reacted with 2-chloroacetyl chloride to form compound 4, as follows:
in another preferred embodiment, the compound 3 is reacted with 2-chloroacetyl chloride under alkaline conditions, wherein the alkaline condition is selected from one or a combination of more than two of potassium carbonate, sodium carbonate and triethylamine.
As is well known to those skilled in the art,
and
as tautomers, they are used interchangeably as starting materials for the preparation of compounds of formula I.
In a third aspect of the invention, there is provided a pharmaceutical composition comprising a compound of formula I according to the first aspect, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or prodrug thereof; and a pharmaceutically acceptable carrier.
In another preferred embodiment, the dosage form of the pharmaceutical composition is a solid dosage form which is a capsule, a tablet, a granule, a pill or a powder; the liquid dosage form is a pharmaceutically acceptable emulsion, solution, suspension, syrup or tincture.
In a fourth aspect of the invention, there is provided a compound of formula I as described in the first aspect, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or prodrug thereof, for use in:
(i) Preparing arginine methyltransferase inhibitor 5 (PRMT 5 inhibitor);
(ii) Preparing a medicament for preventing and/or treating PRMT5 related diseases;
(iii) Preparing an MV4-11 apoptosis inducer;
(iv) Preparing MV4-11 cell proliferation inhibitor; or
(v) Preparing the medicine for preventing and/or treating acute monocytic leukemia.
In a fifth aspect of the present invention, there is provided a method for inducing apoptosis of MV4-11 in vitro, wherein the compound of formula I according to the first aspect or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or prodrug thereof is added to a MV4-11 cell culture system.
In a sixth aspect of the present invention, there is provided a method for inhibiting the proliferation of MV4-11 cells in vitro, by adding a compound of formula I as described in the first aspect or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or prodrug thereof to a MV4-11 cell culture system.
In a seventh aspect of the invention, there is provided a method of inhibiting arginine methyltransferase 5, which method comprises the step of contacting a cell with a compound of formula I as described in the first aspect, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or prodrug thereof.
In another preferred embodiment, the cells are cells cultured in vitro.
In an eighth aspect of the present invention, there is provided a method for selectively inhibiting arginine methyltransferase 5 in vitro, the method comprising the step of contacting a reaction system with a compound of formula I as described in the first aspect, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or prodrug thereof, wherein the reaction system comprises arginine methyltransferase 5 or a cell expressing arginine methyltransferase 5.
Preferably, the method is non-therapeutic and non-diagnostic.
In another preferred embodiment, the reaction system further comprises one or more of the following enzymes, or a cell expressing one or more of the following enzymes: PRMT1, NSD1, DNMT1, DOT1L, SET7/9, PRMT3, PRMT4, PRMT6, PRTM7, PRMT8.
In another preferred embodiment, PRMT5 selectivity is as follows.
| Protein | PRMT5selectivity |
| PRMT1 | >303 |
| NSD1 | >303 |
| DNMT1 | >303 |
| DOT1L | >303 |
| SET7/9 | >303 |
| PRMT3 | >303 |
| PRMT4 | >303 |
| PRMT6 | >303 |
| PRTM7 | >303 |
| PRMT8 | >303 |
The compound can selectively inhibit PRMT5, and can be used for preparing a medicament for preventing and/or treating PRMT5 related diseases.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Drawings
FIG. 1 is a graph showing the effect of Compound 1 on cell proliferation of MV4-11, RCH-ACV, REH, jeko, RS4.11, THP1, U937, NALM6, etc., with a detection time of 6 days.
FIG. 2 is a graph showing the effect of Compound 2 on the proliferation of MV4-11, RCH-ACV, REH, jeko, RS4.11, THP1, U937, NALM6, etc., with a detection time of 6 days
FIG. 3 is a graph showing the effect of Compound 1 on the proliferation of MV4-11 cells.
FIG. 4 is a graph showing the effect of Compound 1 on the amount of SDMA protein expressed on MV4-11 cells.
FIG. 5 is a graph showing the effect of Compound 2 on the expression level of SDMA proteins in MV4-11 cells.
FIG. 6 is a graph showing the effect of Compound 1 on apoptosis of MV4-11 cells.
Detailed Description
The inventors of the present application have made extensive and intensive studies and have for the first time developed an arginine methyltransferase 5 inhibitor having a novel structure, which is effective in inhibiting arginine methyltransferase 5 (PRMT 5). On the basis of this, the present invention has been completed.
Term(s) for
As used herein, "C1-C3 alkoxy" refers to-O (C1-C3 alkyl). Such as methoxy, ethoxy, propoxy, and the like.
As used herein, "halogen" refers to fluorine, chlorine, bromine or iodine.
As used herein, the "pharmaceutically acceptable salts" include pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
"pharmaceutically acceptable acid addition salts" refers to salts with inorganic or organic acids which retain the biological effectiveness of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, phosphate, and the like; organic acid salts include, but are not limited to, formates, acetates, propionates, glycolates, gluconates, lactates, oxalates, maleates, succinates, fumarates, tartrates, citrates, glutamates, aspartates, benzoates, methanesulfonates, p-toluenesulfonate, salicylates, and the like. These salts can be prepared by methods known in the art.
"pharmaceutically acceptable base addition salts" include, but are not limited to, salts with inorganic bases such as sodium, potassium, calcium, and magnesium salts, and the like. Including but not limited to salts with organic bases such as ammonium, triethylamine, lysine, arginine, and the like. These salts can be prepared by methods known in the art.
The term "tautomer" means that structural isomers having different energies may exceed the low energy barrier and thus be converted to each other. For example, proton tautomers (i.e., proton shift variants) include interconversion by proton shift, such as 1H-benzo [ d ] imidazole and 3H-benzo [ d ] imidazole, and valence tautomers include interconversion by recombination of some of the bonding electrons.
The term "solvate" as used herein refers to a complex formed by a compound of the present invention and a solvent. They either react in a solvent or precipitate out of a solvent or crystallize out.
The "hydrate" referred to in the present invention means a complex formed by the compound of the present invention and water.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are exemplary only.
A compound of formula I
In the present invention, a compound of formula I or a compound of formula (I) refers to a compound having the following formula I:
wherein R is as defined above.
The present invention includes prodrugs of the above compounds which are hydrolyzed under physiological conditions or released via an enzymatic reaction to yield the parent compound.
Pharmaceutical composition
The term "active substance of the present invention" or "active compound of the present invention" means a compound of formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a prodrug thereof, which has a remarkably selective PRMT5 inhibitory activity and is useful as a PRMT5 inhibitor for the prevention and/or treatment of PRMT 5-associated diseases. The PRMT5 related disease is acute monocytic leukemia.
In general, a compound of the present invention or a pharmaceutically acceptable salt thereof, or a solvate, hydrate, or stereoisomer, or prodrug thereof, can be administered in a suitable dosage form with one or more pharmaceutically acceptable carriers. These dosage forms are suitable for oral, rectal, topical, intraoral, and other parenteral (e.g., subcutaneous, intramuscular, intravenous, etc.) administration. For example, dosage forms suitable for oral administration include capsules, tablets, granules, and syrups. The compounds of the invention contained in these formulations may be solid powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; water-in-oil or oil-in-water emulsions, and the like. The above-mentioned dosage forms can be prepared from the active compounds and one or more carriers or adjuvants by customary pharmaceutical methods. The above-mentioned carriers need to be compatible with the active compound or other adjuvants. For solid formulations, non-toxic carriers that are commonly used include, but are not limited to, mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, and the like. Carriers for liquid preparations include water, physiological saline, aqueous glucose solution, ethylene glycol, polyethylene glycol and the like. The active compound may be in solution or suspension with the carrier(s) mentioned above.
The pharmaceutical compositions of the present invention are formulated, dosed and administered in a manner consistent with medical practice specifications. The "therapeutically effective amount" of a compound to be administered will depend on, among other factors, the particular condition being treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.
A "therapeutically effective amount" refers to an amount that produces a function or activity in and is acceptable to humans and/or animals.
The pharmaceutical composition of the present invention contains the compound of the present invention or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a prodrug thereof in a therapeutically effective amount of preferably 0.1mg to 5g/kg (body weight).
The compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, or prodrug thereof, of the present invention may be used in combination with other drugs in certain diseases to achieve a desired therapeutic effect.
The features mentioned above with reference to the invention, or the features mentioned with reference to the embodiments, can be combined arbitrarily. All the features disclosed in this specification may be combined in any combination, and each feature disclosed in this specification may be replaced by alternative features serving the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, the features disclosed are merely generic examples of equivalent or similar features.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures without specific conditions noted in the following examples, molecular cloning is generally performed according to conventional conditions such as Sambrook et al: the conditions described in the Laboratory Manual (New York: cold Spring Harbor Laboratory Press, 1989), or according to the manufacturer's recommendations. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
Example 1
Preparation of Compound 1
2- (2- ((5-methoxy-1H-benzo [ d ] imidazol-2-yl) thio) acetylamino) benzoic acid methyl ester
Step 1: preparation of methyl 2- (2-chloroacetylamino) benzoate
After 400 mg of methyl anthranilate was dissolved in 10 ml of acetone, 438 mg of potassium carbonate was added, followed by addition of 0.25 ml of 2-chloroacetyl chloride, and stirred at room temperature for 4 hours, the reaction was quenched with water, extracted three times with ethyl acetate, combined with the organic phase, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (petroleum ether: ethyl acetate =95, V/V) to obtain methyl 2- (2-chloroacetamido) benzoate. 590 mg (98%) of white solid.
1 H NMR(300MHz,CDCl 3 )δ11.89(s,1H),8.70(d,J＝8.5Hz,1H),8.07(d,J＝8.0Hz,1H),7.57(t,J＝7.9Hz,1H),7.15(t,J＝7.7Hz,1H),4.21(s,2H),3.96(s,3H).
And 2, step: preparation of 5-methoxy-1H-benzo [ d ] imidazole-2 (3H) -thione
Dissolving 1.0 g of 5-methoxy-2-nitroaniline in 20 ml of methanol, adding 100 mg of 10% palladium carbon and 3.7 g of ammonium formate, heating to 55 ℃, heating and stirring for 4 hours, stopping the reaction, cooling, filtering, washing with methanol for several times, concentrating the filtrate to be dry, dissolving the filtrate in 20 ml of ethanol, adding 5 ml of carbon disulfide and 336 mg of potassium hydroxide (dissolved in 3 ml of water), heating to 70 ℃, stirring overnight, spin-drying the reaction solution, adding water, dissolving and filtering, washing the filter cake with water for several times to obtain 774 mg of brown solid, and obtaining the yield of 72%.
1 H NMR(300MHz,DMSO-d 6 )δ12.39(s,1H),12.35(s,1H),7.01(d,J＝8.6Hz,1H),6.70(dd,J＝8.6,2.3Hz,1H),6.65(d,J＝2.3Hz 1H),3.72(s,3H).
Step 2: preparation of methyl 2- (2- ((5-methoxy-1H-benzo [ d ] imidazol-2-yl) thio) acetylamino) benzoate
18 mg of 5-methoxy-1H-benzo [ d ] imidazole-2-thiol was dissolved in 3 ml of acetone, 20 mg of potassium carbonate was added, and after stirring at room temperature for 30 minutes, 22 mg of methyl 2- (2-chloroacetamido) benzoate was added, and after stirring at room temperature for 5 hours, the reaction was stopped, insoluble matter was filtered, methanol was washed, and after the filtrate was condensed, column chromatography (dichloromethane/methanol =95, V/V) gave 22 mg of the objective product as a white powder (80%).
1 H NMR(300MHz,CD 3 OD)δ8.49(d,J＝8.5Hz,1H),7.96(d,J＝7.8Hz,1H),7.54(t,J＝7.8Hz,1H),7.34(d,J＝9.0Hz,1H),7.14(t,J＝7.6Hz,1H),6.97(s,1H),6.81(d,J＝9.0Hz,1H),4.17(s,2H),3.80(s,3H),3.77(s,3H). 13 C NMR(126MHz,DMSO-d 6 )δ167.2,166.9,155.3,147.3,139.3,137.9,136.3,134.0,130.6,123.4,120.9,117.9,117.4,110.7,94.2,55.4,52.4,36.0.HRMS(ESI - )m/zcalcd for C 18 H 16 N 3 O 4 S[M-H] - :370.0862；found 370.0858.
Example 2
Preparation of Compound 2
2- (2- ((5-ethoxy-1H-benzo [ d ] imidazol-2-yl) thio) acetylamino) benzoic acid methyl ester
Step 1: preparation of 5-ethyl-1H-benzo [ d ] imidazole-2 (3H) -thione
5-methoxy-2-nitroaniline is replaced by 5-ethoxy-2-nitroaniline, and the other required raw materials, reagents and preparation method are the same as the step 2 in the example 1, so as to obtain 5-ethoxy-1H-benzo [ d ] imidazole-2 (3H) -thione. White solid (45%).
1 H NMR(300MHz,DMSO-d 6 )δ12.35(s,2H),6.99(d,J＝8.7Hz,1H),6.68(d,J＝8.7Hz,1H),6.63(s,1H),3.96(q,J＝6.9Hz,2H),1.29(t,J＝6.9Hz,3H).
Step 2: preparation of methyl 2- (2- ((5-ethoxy-1H-benzo [ d ] imidazol-2-yl) thio) acetylamino) benzoate
5-methoxy-1H-benzo [ d ] imidazole-2 (3H) -thione was replaced with 5-ethoxy-1H-benzo [ d ] imidazole-2 (3H) -thione, and the remaining required starting materials, reagents and preparation were the same as in step 3 of example 1 to give a white solid (84%).
1 H NMR(300MHz,CD 3 OD)δ8.47(d,J＝8.3Hz,1H),7.91(d,J＝7.9Hz,1H),7.50(t,J＝7.6Hz,1H),7.32(d,J＝8.7Hz,1H),7.09(t,J＝7.4Hz,1H),6.93(s,1H),6.78(d,J＝8.9Hz,1H),4.16(s,2H),3.98(q,J＝6.9Hz,2H),3.75(s,3H),1.36(t,J＝6.9Hz,3H). 13 C NMR(126MHz,DMSO-d 6 )δ167.2,166.9,154.5,147.3,139.3,137.8,136.2,134.0,130.6,123.5,120.9,117.8,117.5,110.8,95.0,63.4,52.4,36.0,14.7.HRMS(ESI - )m/z calcd for C 19 H 18 N 3 O 4 S[M-H] - :384.1018；found 384.1005.
Example 3
Preparation of Compound 3
2- (2- ((5-propoxy-1H-benzo [ d ] imidazol-2-yl) thio) acetylamino) benzoic acid methyl ester
Step 1: preparation of 5-propoxy-2-nitroaniline
After 600 mg of 5-fluoro-2-nitroaniline was dissolved in 10 ml of acetone, 2.0 ml of propanol and 1.1 g of potassium hydroxide were added, and the mixture was heated to 80 ℃ and stirred for 24 hours, the reaction solution was concentrated and subjected to column chromatography (petroleum ether/ethyl acetate =90, 10, V/V) to obtain a yellow solid (420 mg, 56%).
1 H NMR(300MHz,CDCl 3 )δ8.07(d,J＝9.5Hz,1H),6.28(dd,J＝9.5,2.4Hz,1H),6.13(d,J＝2.4Hz,1H),3.93(t,J＝6.5Hz,2H),1.90–1.72(m,2H),1.03(t,J＝7.4Hz,3H).
And 2, step: preparation of 5-propoxy-1H-benzo [ d ] imidazole-2 (3H) -thione
5-methoxy-2-nitroaniline was replaced with 5-propoxy-2-nitroaniline, and the remaining required raw materials, reagents and preparation method were the same as in step 2 of example 1, to obtain 5-propoxy-1H-benzo [ d ] imidazole-2 (3H) -thione. Beige solid (75%).
1 H NMR(300MHz,DMSO-d 6 )δ12.37(s,1H),12.34(s,1H),6.99(d,J＝8.6Hz,1H),6.69(d,J＝8.6Hz,1H),6.64(s,1H),3.87(t,J＝6.5Hz,2H),1.69(m,2H),0.95(t,J＝7.4Hz,3H).
And 3, step 3: preparation of methyl 2- (2- ((5-propoxy-1H-benzo [ d ] imidazol-2-yl) thio) acetylamino) benzoate
5-methoxy-1H-benzo [ d ] imidazole-2 (3H) -thione was replaced with 5-propoxy-1H-benzo [ d ] imidazole-2 (3H) -thione, and the remaining required starting materials, reagents and preparation were the same as in step 3 of example 1 to give a white solid (66%).
1 H NMR(300MHz,CD 3 OD)δ8.48(d,J＝8.4Hz,1H),7.96(d,J＝8.0Hz,1H),7.55(d,J＝8.4Hz,1H),7.34(d,J＝8.7Hz,1H),7.14(t,J＝7.7Hz,1H),6.96(s,1H),6.81(dd,J＝8.9,2.2Hz,1H),4.17(s,2H),3.92(t,J＝6.4Hz,2H),3.77(s,3H),1.78(m,2H),1.04(t,J＝7.4Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ168.6,168.5,156.0,147.2,140.5,134.7,131.1,123.7,121.0,116.1,112.6,70.3,52.6,38.1,22.7,10.7.HRMS(ESI - )m/z calcd for C 20 H 20 N 3 O 4 S[M-H] - :398.1175；found 398.1176.
Example 4
Preparation of Compound 4
2- (2- ((5-chloro-1H-benzo [ d ] imidazol-2-yl) thio) acetylamino) benzoic acid methyl ester
Step 1: preparation of 5-chloro-1H-benzo [ d ] imidazole-2 (3H) -thione
Dissolving 1 g of 4-chloro-o-phenylenediamine in 15 ml of ethanol, adding 1.5 ml of carbon disulfide and 615 mg of potassium hydroxide (dissolved in 2ml of water), heating to 70 ℃, stirring for 6 hours, stopping reaction, adding water for dissolving after reaction liquid is concentrated, acidifying with dilute hydrochloric acid, separating out solid, filtering, washing a filter cake for a plurality of times with water, and drying to obtain the 5-chloro-1H-benzo [ d ] imidazole-2 (3H) -thione. Grey solid (73%).
1 H NMR(300MHz,DMSO-d 6 )δ12.64(s,2H),7.12(s,3H).
Step 2: preparation of methyl 2- (2- ((5-chloro-1H-benzo [ d ] imidazol-2-yl) thio) acetylamino) benzoate
5-methoxy-1H-benzo [ d ] imidazole-2 (3H) -thione was replaced with 5-chloro-1H-benzo [ d ] imidazole-2 (3H) -thione, and the remaining required starting materials, reagents and preparation were the same as in step 3 of example 1 to give a yellow solid (83%).
1 H NMR(300MHz,DMSO-d 6 )δ11.21(s,1H),8.32(d,J＝8.4Hz,1H),7.89(d,J＝7.7Hz,1H),7.60(t,J＝7.4Hz,1H),7.50(s,1H),7.43(d,J＝8.4Hz,1H),7.16(m,2H),4.28(s,2H),3.77(s,3H). 13 C NMR(126MHz,DMSO-d 6 )δ167.2,166.6,151.1,139.3,134.0,130.6,125.9,123.5,121.6,121.0,117.5,114.6,52.3,35.9.HRMS(ESI - )m/z calcd for C 17 H 13 N 3 O 3 SCl[M-H] - :374.0366；found374.0366.
Example 5
Preparation of Compound 5
2- (2- ((5-bromo-1H-benzo [ d ] imidazol-2-yl) thio) acetylamino) benzoic acid methyl ester
Step 1: preparation of 5-bromo-1H-benzo [ d ] imidazole-2 (3H) -thione
The 4-chloro-o-phenylenediamine is replaced by 4-bromo-o-phenylenediamine, and the remaining required raw materials, reagents and preparation methods are the same as in step 1 of example 4, to obtain 5-bromo-1H-benzo [ d]Imidazole-2 (3H) -thiones. Brown solid (65%). 1 HNMR(300MHz,DMSO-d 6 )δ12.67(s,1H),12.63(s,1H),7.25(m),7.06(d,J＝8.9Hz,1H).
Step 2: preparation of methyl 2- (2- ((5-bromo-1H-benzo [ d ] imidazol-2-yl) thio) acetylamino) benzoate
5-methoxy-1H-benzo [ d ] imidazole-2 (3H) -thione was replaced with 5-bromo-1H-benzo [ d ] imidazole-2 (3H) -thione, and the remaining required starting materials, reagents and preparation were the same as in step 3 of example 1, giving a yellow solid (76%).
1 H NMR(300MHz,CD 3 OD)δ8.50(d,J＝7.6Hz,1H),7.97(dd,J＝8.0,1.5Hz,1H),7.62(s,1H),7.59–7.51(m,1H),7.37(d,J＝8.5Hz,1H),7.28(dd,J＝8.5,1.8Hz,1H),7.19–7.11(m,1H),4.24(s,2H),3.77(s,3H). 13 C NMR(126MHz,CDCl 3 )δ168.6,168.3,150.1,140.4,134.7,131.1,125.6,123.8,120.9,117.7,116.1,115.6,52.7,37.6.HRMS(ESI - )m/z calcd for C 17 H 13 N 3 O 3 SBr[M-H] - :417.9861；found 417.9871.
Example 6
Preparation of Compound 6
2- (2- ((5- (dimethylamino) -1H-benzo [ d ] imidazol-2-yl) thio) acetylamino) benzoic acid methyl ester
Step 1: preparation of 5- (dimethylamino) -1H-benzo [ d ] imidazole-2 (3H) -thione
5-methoxy-2-nitroaniline was replaced with 5- (dimethylamino) -2-nitroaniline, and the remaining required raw materials, reagents and preparation were the same as in example 1, step 2,5- (dimethylamino) -1H-benzo [ d ] imidazole-2 (3H) -thione, dark purple solid (62%).
1 H NMR(300MHz,DMSO-d 6 )δ12.16(s,2H),6.95(d,J＝8.8Hz,1H),6.58(d,J＝8.8Hz,1H),6.39(s,1H),2.84(s,6H).
And 2, step: preparation of methyl 2- (2- ((5- (dimethylamino) -1H-benzo [ d ] imidazol-2-yl) sulfanyl) acetylamino) benzoate
5-methoxy-1H-benzo [ d ] imidazole-2 (3H) -thione was replaced with 5- (dimethylamino) -1H-benzo [ d ] imidazole-2 (3H) -thione, and the remaining required starting materials, reagents and preparation were the same as in step 3 of example 1 to give a yellow solid (63%).
1 H NMR(300MHz,CD 3 OD)δ8.46(d,J＝8.5Hz,1H),7.90(d,J＝7.9Hz,1H),7.48(t,J＝7.9Hz,1H),7.31(d,J＝9.5Hz,1H),7.08(t,J＝7.6Hz,1H),6.79(d,J＝5.9Hz,2H),4.12(s,2H),3.75(s,3H),2.86(s,6H). 13 C NMR(126MHz,CD 3 OD)δ169.2,169.0,149.5,147.6,141.3,135.1,131.9 124.6,122.0,118.0,116.2,112.8,52.8,42.4(2C),38.2.
HRMS(ESI - )m/z calcd for C 19 H 19 N 4 O 3 S[M-H] - :383.1178；found 383.1176.
Example 7
Effect of Compounds on PRMT5 enzymatic Activity
The enzyme activity inhibitory activity of the compounds was tested by means of radioisotopes. The experimental method is as follows:
1. preparing 1x experiment buffer (modified Tris-HCl buffer);
2. diluting the compound to the desired concentration in a 96-well plate;
3. protein solutions were prepared, also with 1 × assay buffer;
4. adding a substrate into 1x experiment buffer solution to prepare a substrate solution;
5. will 2 3 H]Preparation of SAM by addition to 1X test buffer 3 H]-a SAM solution;
6. adding SAM to 1x experiment buffer solution to prepare cold SAM solution;
7. removing 10. Mu.L of the protein solution into a 96-well plate containing the compound;
8. incubation for 15 minutes at room temperature;
9. add 10. Mu.L of substrate solution to each well;
10. to each well, 10. Mu.L of 3 H]-the SAM solution initiates the reaction;
11. incubation at room temperature for 240 min;
12. add 10. Mu.L of cold SAM solution to each well to stop the reaction;
13. transferring 40 mu L of reaction mixed solution to a GF/B plate, and washing for 3 times by using triple distilled water in vacuum;
14. reading data on a Microbeta liquid scintillation/luminescence counter;
15. the inhibition rate is calculated according to a formula,
% Inh = (maximum signal-compound signal)/(maximum signal-minimum signal) × 100
The maximum signal is obtained from the reaction of the enzyme and the substrate and the minimum signal is obtained from the substrate.
Data were plotted after processing using GraphPad prism 5.0. Known SAH was used as a positive control.
The results of the experiment are shown in table 1.
TABLE 1 inhibitory Activity of Compounds on PRMT5 enzyme Activity
| Compound (I) | R | IC 50 (μM) |
| 1 | Methoxy radical | 0.33 |
| 2 | Ethoxy radical | 0.35 |
| 3 | Propoxy group | 0.53 |
| 4 | Chlorine | 0.5 |
| 5 | Bromine compound | 0.34 |
| 6 | Dimethylamino group | 0.33 |
| Positive control SAH | 0.34 |
Example 8
Effect of Compounds on the Activity of other members of the PRMT family and other SAM-cofactor methyltransferases
Selecting a compound 1 (R is methoxyl), and testing the influence of the PRMT5 active small molecule on the activity of other PRMT family members and other methyl transferase taking SAM as a cofactor by adopting an Alpha Screening and radioisotope method. The test concentration was 100. Mu.M. The test methods are as follows, and the results are shown in table 2.
The inhibitory activity of compound 1 on PRMT1, PRMT7, NSD1, DNMT1 was tested as follows:
1. preparing 1x experiment buffer (modified Tris-HCl buffer);
2. diluting the compound to the desired concentration in a 96-well plate;
3. preparing a protein solution, and using 1x experiment buffer solution;
4. combining a substrate and [ 2 ] 3 H]-SAM added to 1x assay buffer to prepare substrate solution;
5. adding SAM to 1x experiment buffer solution to prepare cold SAM solution;
6. removing 10. Mu.L of the protein solution into a 96-well plate containing the compound;
7. incubation for 15 minutes at room temperature;
8. add 10 μ L of substrate solution to each well;
9. to each well, 10. Mu.L of 3 H]-the SAM solution initiates the reaction;
10. incubation at room temperature for 240 min;
11. the reaction was stopped by adding 10. Mu.L of cold SAM solution to each well;
12. transferring 40 mu L of reaction mixed solution to a GF/B plate, and washing for 3 times by using triple distilled water in vacuum;
13. reading data on a Microbeta liquid scintillation/luminescence counter;
14. the inhibition rate is calculated according to a formula,
% Inh = (maximum signal-compound signal)/(maximum signal-minimum signal) × 100
The maximum signal is obtained from the reaction of the enzyme and the substrate and the minimum signal is obtained from the substrate.
Data processing was followed by fitting IC with GraphPad Prism5.0 50 The value is obtained. SAH was used as a positive control.
The inhibitory activity of compound 1 against PRMT3, PRMT4, PRMT6, PRMT8, DOT1L and SET7/9 was tested as follows:
1. preparing 1x experiment buffer (modified Tris-HCl buffer);
2. transfer 100nL of compound to a 96-well plate;
3. preparing a 1x protein solution;
4. preparing a 1x substrate solution by using a Tris-HCl buffer solution;
5. transfer 5 μ L of protein solution to a 96-well plate;
6. incubation for 15 minutes at room temperature;
7. adding 5 mu L of substrate solution into a 96-well plate to initiate reaction;
8. incubation at room temperature for 60 minutes;
9. preparing an acceptor and donor beads by using 1x experiment buffer solution;
10. adding 15 mu L of acceptors and donor beads into a 96-well plate, and incubating for 60 minutes at room temperature in a dark place;
11. reading data values with Alpha mode in Enspire;
12. data processing:
% Inh = (maximum signal-compound signal)/(maximum signal-minimum signal) × 100
The maximum signal is obtained from the reaction of the enzyme and the substrate and the minimum signal is obtained from the substrate.
13. Fitting of IC with Graphpad Prism5.0 50 。
Selectivity formula calculation of IC from Compounds on other proteins 50 IC of compound on PRMT5 50 And (6) calculating.
TABLE 2. Compound 1 methyl conversion to other members of the PRMT family and other SAM cofactors
Effect of transferase Activity
| Protein | IC 50 (μΜ) | PRMT5selectivity |
| PRMT1 | >100 | >303 |
| NSD1 | >100 | >303 |
| DNMT1 | >100 | >303 |
| DOT1L | >100 | >303 |
| SET7/9 | >100 | >303 |
| PRMT3 | >100 | >303 |
| PRMT4 | >100 | >303 |
| PRMT6 | >100 | >303 |
| PRTM7 | >100 | >303 |
| PRMT8 | >100 | >303 |
Experimental results show that the compound 1 has strong selectivity on PRMT5, and can selectively inhibit the enzyme activity of PRMT 5.
Example 9
Effect of Compounds on tumor cell proliferation
1. Cell culture
MV4-11 (acute myeloid leukemia cell), jeko (acute lymphoma cell), KOPN8 (acute lymphoma cell), RCH-ACV (acute lymphoma cell), REH (acute lymphoma cell), RS4.11, THP1 (acute myeloid leukemia cell), U937 (histiocyte lymphoma cell), NALM6 (acute myeloid leukemia cell) cell culture medium is RPMI 1640+10% fetal bovine serum, and in order to prevent bacterial contamination, 100U/mL penicillin and 100 μ g/mL streptomycin were added to the culture medium. At 37 ℃ C, 5% CO 2 Saturated humidity conditionIn the lower culture, the experimental cells are all in the logarithmic growth phase.
2. Cell proliferation Activity assay
Adjusting the cell concentration to 1X 10 5 And inoculating the culture medium in a 24-well culture plate with 1mL of each well volume, and establishing a control group and an experimental group, wherein DMSO is added in the control group, a PRMT5 active small molecule inhibitor is added in the experimental group, and the final concentration is 0-100 mu M. Set 3 detection time points for MV4-11 cells, 4, 8 and 12 days respectively; RCH-ACV, MV4-11, REH, jeko, RS4.11, KOPN8, THP1, U937, NALM6 cells were set for a 6 day detection time point. The cells were cultured in a CO2-culture chamber at 37 ℃ and 5% to each time point, and the amount of viable cells was measured using CellTiter-Glo reagent.
3. Results of the experiment
The results are shown in FIG. 1, compound 1 vs MV4-11 (IC) 50 ＝11.7μM)、Jeko(IC 50 ＝47.2μM)、KOPN8(IC 50 =26.7 μ M), wherein the proliferation inhibitory activity to MV4-11 is strongest, and the selectivity is shown, and the result of 12 days is shown in fig. 3, IC 50 6.53. Mu.M.
Example 10
Effect of Compounds on intracellular SDMA
Detection of SDMA expression by Western Blot
Adjusting the concentration of MV4-11 cells to 5X 10 5 Perml and inoculated in 6-well culture plates, 2ml per well volume, control group to which only DMSO was added and experimental group to which Compound 1 was added to give a final concentration of 3.125-12.5. Mu.M were set. Cells were incubated at 37 ℃ 5% 2 And culturing in an incubator for 96h, and collecting to obtain the total cell protein. Adding 2 x SDS to the protein sample at a certain ratio, mixing well, denaturing at 98 ℃ for 10min, and separating by SDS-PAGE at 4-12%. The protein was electroporated into nitrocellulose membrane and blocked with 5% skim milk for 0.5h at room temperature. SDMA and GADPH antibodies were blocked overnight at 4 ℃. Washing with 1 × TBST for 3 times, 5 minutes each time; diluted horseradish peroxidase labelThe secondary antibody of (4) was incubated at room temperature for 1 hour. Wash 3 times 1 × TBST for 5 minutes each. Color development was performed using ECL Western Blot luminescent detection reagents and an assay system.
The influence of the compound on intracellular symmetric dimethylarginine is researched by detecting the protein expression amount of SDMA through a Western blot Western blot hybridization experiment. Studies have shown that SmD3 protein is a substrate for PRMT5 and can be modified by PRMT5 methylation, and thus SmD3 can be used to track changes in PRMT5 intracellularly after administration. The results of the experiment (fig. 4) show that intracellular SmD3me2s is significantly inhibited, so that it can be assumed that the anti-cell proliferation effect of the series of compounds is a direct result of PRMT5 being inhibited, which also indicates that the compounds of the present invention are not off-target intracellularly. As shown in FIG. 4, after 3.125-12.5. Mu.M of Compound 1 was allowed to act on MV4-11 cells for 96 hours, intracellular SmD3me2s signal was inhibited in a concentration-dependent manner. Consistent with the positive compound EPZ015666 causing greater than 50% inhibition of intracellular SmD3me2s signaling.
As shown in fig. 5, compound 2 was able to inhibit intracellular SmD3me2s signal in a concentration-dependent manner after being allowed to act on MV4-11 cells for 96 hours by the same detection method, and the effect was consistent with that of the positive compound EPZ015666 which caused more than 50% inhibition of intracellular SmD3me2s signal.
Example 11
Effect of Compounds on cell cycle and apoptosis
1. Experimental methods
Adjusting MV4-11 cell concentration to 2X 10 5 And inoculating the cells in 12-well culture plates with 1mL of each well, setting a control group and an experimental group, wherein DMSO is added to the control group as a negative control, and the compound 1 is added to the experimental group respectively so as to obtain a final concentration of 0-15 mu M. The 48h treated cells were harvested by centrifugation (1000 rpm for 5 min), the cells were washed 2 times with PBS (1000 rpm for 5 min), the supernatant harvested cells were discarded, fixed overnight with 70% ethanol, the cells were washed again with pre-cooled PBS, and incubated with cell cycle reagents for 10min for re-suspension. In the apoptosis test, cells after 72 hours of treatment were collected by centrifugation (1000 rpm for 5 min), the cells were washed 2 times with PBS (1000 rpm for 5 min), the supernatant was discarded, and 500. Mu.L of biningbuffer suspension cells were added. Adding 5 μ L Annexin V-FITC and 55 μ L PI, mixing, and cooling at room temperatureAnd reacting for 10min in the dark. Cell cycle and apoptosis detection assays were performed on a BD flow cytometer.
2. Results of the experiment
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (18)
1. A compound of formula I or a pharmaceutically acceptable salt thereof:
wherein R is C3 alkoxy, fluorine or NR 1 R 2 Wherein R is 1 、R 2 Independently H, C1-C3 alkyl.
2. The compound of formula I according to claim 1, wherein R is fluoro or dimethylamino.
3. The compound of formula I according to claim 1, wherein the pharmaceutically acceptable salts are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
4. A process for the preparation of a compound of formula I, said process comprising the steps of:
nucleophilic substitution of compound 2 with compound 4 to produce a compound of formula I, wherein R is as defined in claim 1.
5. The preparation method according to claim 4, wherein the nucleophilic substitution reaction of the compound 2 and the compound 4 is performed under an alkaline condition, wherein the alkaline condition is one or a combination of more than two of potassium carbonate, sodium carbonate, potassium hydroxide and sodium hydroxide.
6. The method of claim 4, wherein compound 2 is prepared by:
a) The compound 1 is reduced to become a substituted o-diamine intermediate;
b) And (3) synthesizing the compound 2 from the substituted o-diamine intermediate and carbon disulfide ring under alkaline conditions.
7. The method of claim 4, wherein Compound 4 is prepared by:
the compound 3 reacts with 2-chloroacetyl chloride to generate a compound 4.
8. The method according to claim 7, wherein the compound 3 is reacted with 2-chloroacetyl chloride under basic conditions, wherein the base used in the basic conditions is one or a combination of more than two of potassium carbonate, sodium carbonate and triethylamine.
9. The method of claim 4, wherein Compound 2 is reacted with
As tautomers, are used interchangeably as starting materials for the preparation of compounds of formula I.
10. A pharmaceutical composition comprising a compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
11. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition is in a solid dosage form that is a liquid dosage form, wherein the solid dosage form is a capsule, tablet, granule, pill, or powder; the liquid dosage form is a pharmaceutically acceptable emulsion, solution, suspension, syrup or tincture.
12. Use of a compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 10 for:
(i) Preparing an arginine methyltransferase inhibitor 5, i.e., a PRMT5 inhibitor;
(ii) Preparing a medicament for preventing and/or treating PRMT5 related diseases;
(iii) Preparing an MV4-11 apoptosis inducer;
(iv) Preparing MV4-11 cell proliferation inhibitor; or
(v) Preparing the medicine for preventing and/or treating acute monocytic leukemia.
13. A method for the non-therapeutic, non-diagnostic induction of apoptosis in MV4-11 cells in vitro, characterized in that a compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof is added to the MV4-11 cell culture system.
14. A method for the non-therapeutic, non-diagnostic inhibition of MV4-11 cell proliferation in vitro, characterized in that a compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof is added to the MV4-11 cell culture system.
15. A method of non-therapeutically non-diagnostically inhibiting arginine methyltransferase 5 in vitro comprising the step of contacting a cell with a compound of formula I, or a pharmaceutically acceptable salt thereof, according to claim 1.
16. The method of claim 15, wherein the cell is a cell cultured in vitro.
17. A method of non-therapeutically non-diagnostically selectively inhibiting arginine methyltransferase 5 in vitro, comprising the step of contacting a reaction system with a compound of formula I of claim 1, or a pharmaceutically acceptable salt thereof, wherein the reaction system comprises arginine methyltransferase 5 or a cell expressing arginine methyltransferase 5.
18. The method of claim 17, wherein the reaction system further comprises one or more of the following enzymes, or cells expressing one or more of the following enzymes: PRMT1, NSD1, DNMT1, DOT1L, SET7/9, PRMT3, PRMT4, PRMT6, PRTM7, PRMT8.
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