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CN112110937B - A kind of thieno[2,3-D]pyrimidin-4(3H)-one derivative and its preparation method and use - Google Patents

A kind of thieno[2,3-D]pyrimidin-4(3H)-one derivative and its preparation method and use Download PDF

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CN112110937B
CN112110937B CN201911311365.5A CN201911311365A CN112110937B CN 112110937 B CN112110937 B CN 112110937B CN 201911311365 A CN201911311365 A CN 201911311365A CN 112110937 B CN112110937 B CN 112110937B
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杨胜勇
李琳丽
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Abstract

本发明提供了式I所示化合物、或其药学上可接受的盐、或其溶剂合物、或其光学异构体。本发明还提供了上述化合物的制备方法和用途。实验结果表明，本发明提供的式I所示的结构新颖的噻吩并[2,3‑D]嘧啶‑4(3H)‑酮衍生物，能够有效抑制蛋白激酶ROCK 1和/或ROCK 2的活性，能够抑制ROCK的磷酸化活性，在制备治疗需要干预平滑肌收缩的疾病(包括青光眼、心血管疾病、勃起障碍等疾病)药物中具有非常好的前景。

Figure DDA0002324621190000011

Figure 201911311365

The present invention provides a compound represented by formula I, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or an optical isomer thereof. The present invention also provides preparation methods and uses of the above compounds. The experimental results show that the novel thieno[2,3-D]pyrimidine-4(3H)-ketone derivatives shown in formula I provided by the present invention can effectively inhibit the activity of protein kinase ROCK 1 and/or ROCK 2 , can inhibit the phosphorylation activity of ROCK, and has a very good prospect in the preparation of drugs for the treatment of diseases that require intervention in smooth muscle contraction (including glaucoma, cardiovascular diseases, erectile dysfunction and other diseases).

Figure DDA0002324621190000011

Figure 201911311365

Description

Thieno [2,3-D ] pyrimidine-4 (3H) -ketone derivative and preparation method and application thereof
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a thieno [2,3-D ] pyrimidine-4 (3H) -ketone derivative, and a preparation method and application thereof.
Background
ROCK kinase (Rho-associated coiled coil formation kinase), also known as Rho-associated coiled coil formation protein kinase, belongs to a serine/threonine protein kinase, and has been discovered for the first time in the 90 s of the 20 th century, and its important role has become one of the most studied kinases in this field. There are two subtypes of ROCK kinase: ROCK1 and ROCK2, both of which have 65% homology in protein primary sequence, with up to 92% homology in the catalytic domain, ROCK1 being expressed predominantly in non-neural tissues, such as liver, lung, and ROCK2 being expressed predominantly in the nervous system, such as brain, spinal cord. ROCK is located in the downstream signaling pathway of Rho protein, and when activated by GTP-bound Rho protein, it can produce a series of physiological effects such as alteration of cell morphology, regulation of cell proliferation, cytoskeleton, and the like, by phosphorylating its downstream signaling factors such as Myosin Light Chains (MLC), myosin targeting subunit 1 of myosin phosphatase (MYPT 1), adducin, and LIM kinase, and the like. Among the numerous downstream proteins, MLC and MYPT1 are the most important substrates for ROCK, and elevated levels of MLC phosphorylation promote actin-myosin inter-motility, highly correlated with smooth muscle contraction.
Therefore, Rho/ROCK signaling pathway is considered as an important target for treating diseases requiring intervention of smooth muscle contraction, including glaucoma, cardiovascular diseases, erectile dysfunction and the like, and the compound capable of inhibiting the phosphorylation activity of ROCK has great potential in preparing medicines requiring intervention of smooth muscle contraction, including glaucoma, cardiovascular diseases, erectile dysfunction and the like. Therefore, it is important to develop more novel compounds having a significant inhibitory effect on the phosphorylation activity of ROCK.
Disclosure of Invention
The invention aims to provide a thieno [2,3-D ] pyrimidine-4 (3H) -ketone derivative, and a preparation method and application thereof.
The invention provides a compound shown as a formula I, or a pharmaceutically acceptable salt, a solvate or an optical isomer thereof:
Figure BDA0002324621170000011
wherein n is an integer of 1-5;
R1n R2Each independently selected from H, amino, carboxyl,Halogen, substituted or unsubstituted C1-10 alkoxy, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cycloalkyl, aryl; wherein the substituents are selected from halogen, alkoxy, alkyl, amino;
R3、R4each independently selected from H, amino, carboxyl, halogen, substituted or unsubstituted C1-10 alkoxy, substituted or unsubstituted C1-10 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cycloalkyl and aryl; wherein the substituents are selected from halogen, alkoxy, alkyl, amino; or, R3、R4Together with the carbon atom to which they are each attached, form a ring.
"n number of R2Each independently selected from "means n R2The choices of (a) and (b) are not mutually interfered, and can be the same or different.
Further, the air conditioner is provided with a fan,
n is an integer of 1 to 3;
R1n R2Each independently selected from H, amino, carboxyl, halogen, substituted or unsubstituted C1-5 alkoxy, substituted or unsubstituted C1-5 alkyl; wherein the substituent is selected from halogen, C1-5 alkoxy, C1-5 alkyl and amino;
R3、R4each independently selected from H, amino, carboxyl, halogen, substituted or unsubstituted C1-5 alkoxy, substituted or unsubstituted C1-5 alkyl; wherein the substituent is selected from halogen, C1-5 alkoxy, C1-5 alkyl and amino; or, R3、R4Together with the carbon atoms to which they are each attached, form a 5-to 6-membered unsaturated ring.
Further, the air conditioner is provided with a fan,
the structure of the compound is shown as formula II:
Figure BDA0002324621170000021
wherein R is1Is H;
R3selected from H, methyl, methoxy, halogen, amino；
n is selected from 1 or 2, n R2Each independently selected from methoxy, halogen, preferably F, halomethyl, preferably-CF3；
Or, the structure of the compound is shown as formula III:
Figure BDA0002324621170000022
Figure BDA0002324621170000031
wherein R is1Is H;
n is selected from 1 or 2, n R2Each independently selected from methoxy, halogen, preferably F, halomethyl, preferably-CF3。
Further, the air conditioner is provided with a fan,
the compound is selected from the following structures:
Figure BDA0002324621170000032
Figure BDA0002324621170000041
。
the invention also provides a preparation method of the compound, which comprises the following steps:
(1) compounds a and Br2Reacting to obtain a compound b;
(2) reacting the compound b with NaH and a compound c to obtain a compound d;
(3) reacting the compound d with the compound e to obtain the compound;
wherein the structure of the compound a is
Figure BDA0002324621170000042
The structure of the compound b is
Figure BDA0002324621170000043
The structure of the compound c is
Figure BDA0002324621170000044
The structure of the compound d is
Figure BDA0002324621170000045
The structure of the compound e is
Figure BDA0002324621170000046
Wherein n and R1、R2、R3、R4As described above.
Further, the air conditioner is provided with a fan,
in the step (1), the solvent for the reaction is an organic solvent, the reaction temperature is 40-60 ℃, the reaction time is 3-5 h, and the compounds a and Br2The mass-to-volume ratio of (1.0 g): (0.5-1.5) mL;
in the step (2), the reaction process is as follows: reacting the compound c with NaH at 0 ℃ for 30 minutes, then adding the compound d, and continuing the reaction, wherein the reaction temperature is room temperature and the reaction time is 12 hours; the solvent of the reaction is an organic solvent, and the mass-volume ratio of the compound c, NaH and the compound d is 100 mg: (30-35) mg: (60-65) mu L;
in the step (3), the reaction is carried out in the presence of tetrakis (triphenylphosphine) palladium and potassium carbonate, the reaction is carried out under the protection of nitrogen, the solvent of the reaction is a mixed solution of 1, 4-dioxane and water, the reaction temperature is 80-120 ℃, the reaction time is 10-15 hours, and the mass ratio of the compound d to the compound e to the tetrakis (triphenylphosphine) palladium to the potassium carbonate is 35: (15-20): (20-25): (40-45).
Further, the air conditioner is provided with a fan,
in the step (1), the solvent for the reaction is glacial acetic acid, the reaction temperature is 50 ℃, the reaction time is 4h, and the compound a and Br2The mass-to-volume ratio of (1.0 g): 1.0 mL;
in the step (2), the solvent for the reaction is N, N-dimethylformamide, and the mass-to-volume ratio of the compound c, NaH and the compound d is 100 mg: 32 mg: 62 mu L of the solution;
in the step (3), the solvent for the reaction is a solvent with a volume ratio of 5: 1, and water, wherein the reaction temperature is 100 ℃, the reaction time is 12 hours, and the mass ratio of the compound d to the compound e to the tetrakis (triphenylphosphine) palladium to the potassium carbonate is 35: 18: 23: 42.
the invention also provides the use of the compound, or a pharmaceutically acceptable salt, solvate or optical isomer thereof, for preparing an inhibitor of Rho-associated coiled coil-forming protein kinase, preferably the Rho-associated coiled coil-forming protein kinase is ROCK1 or ROCK 2.
The invention also provides the application of the compound or the pharmaceutically acceptable salt thereof, or the solvate thereof, or the optical isomer thereof in preparing a medicament for treating diseases related to smooth muscle contraction, preferably, the diseases are glaucoma, cardiovascular diseases or erectile dysfunction.
The invention also provides a pharmaceutical composition, which is prepared by taking the compound, or pharmaceutically acceptable salt, solvate or optical isomer thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials.
Experimental results show that the thieno [2,3-D ] pyrimidine-4 (3H) -ketone derivative with a novel structure can effectively inhibit the activity of protein kinase ROCK1 and/or ROCK2, can inhibit the phosphorylation activity of ROCK, and has a very good prospect in preparing medicaments for treating diseases (including glaucoma, cardiovascular diseases, erectile dysfunction and other diseases) needing intervention of smooth muscle contraction.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
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FIG. 1 shows the effect of the compound 7 of the present invention on the phosphorylation level of the ROCK downstream protein MYPT1, wherein, the graph A is a Western blot picture, and the graph B is the statistical result of the gray value of Western blot scanning.
Detailed Description
The raw materials and equipment used in the invention are known products and are obtained by purchasing commercial products.
EXAMPLE 1 preparation of Compound 1 of the present invention
Compound 1 of the present invention was prepared according to the following synthetic route:
Figure BDA0002324621170000061
(a) preparation of intermediate 1
Figure BDA0002324621170000062
Starting material 1 (thieno [2, 3-D)]Pyrimidin-4 (3H) -one, 1g) was dissolved in glacial acetic acid, to which the starting material 2 (Br) was slowly added21mL) was added, and the reaction was stirred at 50 ℃ for 4 hours. After the reaction is finished, the reaction solution is filtered to obtain a yellow filter cake, the filter cake is fully washed by saturated sodium bicarbonate water solution and water, and the intermediate 1 is obtained after drying, wherein the yield is about 90%.1H NMR(400MHz,DMSO)δ12.64(s,1H),8.15(d,J＝2.5Hz,1H),7.56(s,1H).
(b) Preparation of intermediate 2
Figure BDA0002324621170000063
100mg of intermediate 1 was dissolved in N, N-dimethylformamide, and to this was added slowly starting material 3(NaH, 32mg) at 0 ℃ and stirred for 30 minutes, followed by dropwise addition of starting material 4 (3-methoxybenzyl bromide, 62. mu.L) to the reaction solution, heating to room temperature and stirring for reaction for 12 hours.After completion of the reaction, the reaction solution was spin-dried under reduced pressure, extracted with water and methylene chloride, and the organic phase was washed with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The organic phase was concentrated under reduced pressure, petroleum ether/ethyl acetate 3: 1 was isolated as intermediate 2 in about 41% yield.1H NMR(400MHz,DMSO)δ8.65(s,1H),7.59(s,1H),7.26(t,J＝7.9Hz,1H),6.94(s,1H),6.87(dd,J＝10.8,5.0Hz,2H),5.16(s,2H),3.73(s,3H).
(c) Preparation of Compound 1
Figure BDA0002324621170000071
35mg of intermediate 2, raw material 5 (pyridine-4-boronic acid, 18mg), raw material 6 (tetrakis (triphenylphosphine) palladium, 23mg) and raw material 7 (potassium carbonate, 42mg) were placed in a two-necked flask, added with 1, 4-dioxane and water (v/v ═ 5/1) and dissolved at room temperature, and heated to 100 ℃ under nitrogen atmosphere for 12 hours. After the reaction was completed, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure, and the mixture was extracted with ethyl acetate 1: 3 to obtain a light yellow solid, namely the compound 1, and the yield is about 53 percent.1H NMR(400MHz,DMSO)δ8.70(s,1H),8.63(d,J＝4.6Hz,2H),8.16(s,1H),7.78(d,J＝4.6Hz,2H),7.27(t,J＝7.9Hz,1H),6.97(s,1H),6.92(d,J＝7.3Hz,1H),6.88(d,J＝8.3Hz,1H),5.20(s,2H),3.74(s,3H).
EXAMPLE 2 preparation of Compounds 2 to 18 of the invention
Referring to the method of example 1, compounds 2-17 of the present invention were prepared by substituting the starting materials of example 1 with the starting materials corresponding to compounds 2-17 according to the following general formula I. For example, in the synthesis of compound 7: step (a) was the same as in example 1 to obtain intermediate 1; step (b) was the same as in example 1 to give intermediate 2; replacing the starting material 5 from step (c) with pyridine-4-boronic acid
Figure BDA0002324621170000072
Compound 7 was prepared under the same reaction conditions.
Figure BDA0002324621170000073
Further, referring to the procedure of example 1, intermediate 2 was synthesized, and then starting material 5 in step (c) of example 1 was replaced with pyridine-4-boronic acid
Figure BDA0002324621170000074
Compound 18 was prepared under the same reaction conditions.
The structures and the characteristics of the compounds 2 to 18 of the invention are shown in Table 1.
TABLE 1 structures and1H NMR
Figure BDA0002324621170000081
Figure BDA0002324621170000091
Figure BDA0002324621170000101
Figure BDA0002324621170000111
the beneficial effects of the compounds of the present invention are demonstrated by the following experimental examples.
Experimental example 1 in vitro kinase assay of the Compound of the present invention
The experimental method is briefly described as follows: the test small molecule, i.e. compound 1-17 (0.001-10. mu.M), the test protein kinase (ROCK 1, ROCK 2), and the reagent containing substrate, 10mM magnesium acetate and [ gamma-33P-ATP]The reaction was started by adding Mg \ ATPmix and after a period of incubation at room temperature, the reaction was stopped by adding 3% phosphate solution to the buffer. Then, 10. mu.L of the reaction mixture was quantitatively pipetted onto a P30 filter paper and washed 3 times with 75mM phosphate solutionAnd then washed once by methanol, and the P30 filter paper is dried in the air and then added with scintillation liquid for scintillation counting. Half inhibitory concentration IC for inhibitory Activity of Compounds50To represent, IC50Values were fitted from the inhibition ratios corresponding to each concentration gradient. The results are shown in tables 2 and 3.
It can be seen that the compounds of the present invention are effective in inhibiting the activity of the protein kinases ROCK1 and/or ROCK 2. In particular IC of Compound 7 against ROCK150<10nM, IC of compounds 6-8, 13-18 on ROCK150<10nM, the inhibitory effect is very significant.
TABLE 2 inhibitory Activity of the Compounds of the present invention on ROCK1
Figure BDA0002324621170000112
Figure BDA0002324621170000121
TABLE 3 inhibitory Activity of the Compounds of the present invention on ROCK2
Figure BDA0002324621170000122
Experimental example 2 in vitro cell assay of the Compound of the present invention
1 materials of the experiment
The main equipment comprises: electrophoresis apparatus
The main reagents are as follows: 6 well plates (CORNING), DMEM medium (Life Technologies, USA), fetal bovine serum (Life Technologies, USA)
Cell line: 293T cell
2 method of experiment
1)293T cell culture
293T cells were cultured in DMEM medium and 10% fetal bovine serum, passaged every other day, and the experiment was started in the third generation after recovery.
2) Western blot detection of influence of compound 7 on phosphorylation level of ROCK downstream protein MYPT1
293T cells at 1X 105The cells were plated in 6-well plates overnight, pretreated with the phosphatase inhibitor Cocktail for 2 hours to allow easy detection of the phosphorylation level of MYPT1, followed by addition of compound 7 to treat the cells for 5 hours and protein quantification after sonication. Proteins were separated by SDS-PAGE gels, then proteins on the gels were transferred to PVDF membrane and blocked, primary and secondary antibody incubations followed by cell visualization. Wherein the primary antibodies are Anti-phospho-MYPT1(Thr696), Anti-MYPT1 and Anti-GAPDH, and the secondary antibodies are labeled with horseradish peroxidase (HRP).
3 results of the experiment
Compound 7 was able to significantly reduce the phosphorylation level of ROCK substrate MYPT 1. Western blot results show that the phosphorylation level of MYPT1 can be stabilized by treating with phosphatase inhibitor Cocktail, and after treating with compound 7 at a concentration of 10 μ M, the decrease in phosphorylation level of MYPT1 can be detected in both phosphatase inhibitor pretreatment and non-treatment groups, and the statistical difference is shown (FIG. 1), which indicates that the compound 7 can significantly inhibit the phosphorylation activity of ROCK.
In conclusion, the invention provides a thieno [2,3-D ] pyrimidin-4 (3H) -one derivative with a novel structure, which can effectively inhibit the activity of protein kinase ROCK1 and/or ROCK2, can inhibit the phosphorylation activity of ROCK, and has a very good prospect in preparing medicaments for treating diseases requiring intervention of smooth muscle contraction (including glaucoma, cardiovascular diseases, erectile dysfunction and other diseases).

Claims (13)

1. A compound of formula I, or a pharmaceutically acceptable salt, or an optical isomer thereof:
Figure FDA0003444224650000011
wherein n is an integer of 1-3;
R1n R2Each independently selected from H, amino, carboxyl, halogen, substituted or unsubstituted C1-5 alkoxy, substituted or unsubstituted C1-5 alkyl; wherein the taking is carried outThe substituent is selected from halogen, C1-5 alkoxy, C1-5 alkyl and amino;
R3、R4each independently selected from H, amino, carboxyl, halogen, substituted or unsubstituted C1-5 alkoxy, substituted or unsubstituted C1-5 alkyl; wherein the substituent is selected from halogen, C1-5 alkoxy, C1-5 alkyl and amino; or, R3、R4Together with the carbon atoms to which they are each attached, form a 5-to 6-membered unsaturated ring.
2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, wherein: the structure of the compound is shown as formula II:
Figure FDA0003444224650000012
wherein R is1Is H;
R3selected from H, methyl, methoxy, halogen, amino;
n is selected from 1 or 2, n R2Each independently selected from methoxy, halogen, halomethyl;
or, the structure of the compound is shown as formula III:
Figure FDA0003444224650000013
wherein R is1Is H;
n is selected from 1 or 2, n R2Each independently selected from methoxy, halogen, halomethyl.
3. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, wherein: the halogen is F, and the halomethyl is-CF3。
4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, wherein: the compound is selected from the following structures:
Figure FDA0003444224650000021
5. the following compounds, or pharmaceutically acceptable salts thereof, or optical isomers thereof:
Figure FDA0003444224650000022
6. a process for the preparation of a compound according to any one of claims 1 to 4, characterized in that: the method comprises the following steps:
(1) compounds a and Br2Reacting to obtain a compound b;
(2) reacting the compound b with NaH and a compound c to obtain a compound d;
(3) reacting the compound d with the compound e to obtain the compound;
wherein the structure of the compound a is
Figure FDA0003444224650000031
The structure of the compound b is
Figure FDA0003444224650000032
The structure of the compound c is
Figure FDA0003444224650000033
The structure of the compound d is
Figure FDA0003444224650000034
The structure of the compound e is
Figure FDA0003444224650000035
Wherein n and R1、R2、R3、R4The method according to any one of claims 1 to 4.
7. The method of claim 6, wherein: in the step (1), the solvent for the reaction is an organic solvent, the reaction temperature is 40-60 ℃, the reaction time is 3-5 h, and the compounds a and Br2The mass-to-volume ratio of (1.0 g): (0.5-1.5) mL;
in the step (2), the reaction process is as follows: reacting the compound c with NaH at 0 ℃ for 30 minutes, then adding the compound d, and continuing the reaction, wherein the reaction temperature is room temperature and the reaction time is 12 hours; the solvent of the reaction is an organic solvent, and the mass-volume ratio of the compound c, NaH and the compound d is 100 mg: (30-35) mg: (60-65) mu L;
in the step (3), the reaction is carried out in the presence of tetrakis (triphenylphosphine) palladium and potassium carbonate, the reaction is carried out under the protection of nitrogen, the solvent of the reaction is a mixed solution of 1, 4-dioxane and water, the reaction temperature is 80-120 ℃, the reaction time is 10-15 hours, and the mass ratio of the compound d to the compound e to the tetrakis (triphenylphosphine) palladium to the potassium carbonate is 35: (15-20): (20-25): (40-45).
8. The method of claim 7, wherein: in the step (1), the solvent for the reaction is glacial acetic acid, the reaction temperature is 50 ℃, the reaction time is 4h, and the compound a and Br2The mass-to-volume ratio of (1.0 g): 1.0 mL;
in the step (2), the solvent for the reaction is N, N-dimethylformamide, and the mass-to-volume ratio of the compound c, NaH and the compound d is 100 mg: 32 mg: 62 mu L of the solution;
in the step (3), the solvent for the reaction is a solvent with a volume ratio of 5: 1, and water, wherein the reaction temperature is 100 ℃, the reaction time is 12 hours, and the mass ratio of the compound d to the compound e to the tetrakis (triphenylphosphine) palladium to the potassium carbonate is 35: 18: 23: 42.
9. use of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or an optical isomer thereof, for the manufacture of a Rho-associated coiled coil forming protein kinase inhibitor.
10. Use according to claim 9, characterized in that: the Rho-associated coiled coil-forming protein kinase is ROCK1 or ROCK 2.
11. Use of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, for the manufacture of a medicament for the treatment of a disorder associated with smooth muscle contraction.
12. Use according to claim 11, characterized in that: the disease is glaucoma, cardiovascular disease or erectile dysfunction.
13. A pharmaceutical composition characterized by: the pharmaceutical composition is prepared by taking the compound of any one of claims 1 to 5, or pharmaceutically acceptable salt or optical isomer thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials.
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CN109180702B (en) * 2018-10-29 2021-11-30 四川大学 Thienopyrimidone compound and application thereof

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