阅读说明：本技术 含有异吲哚啉酮衍生物的组合物在制备用于治疗磷酸二酯酶介导的疾病的药物中的用途 (Use of compositions containing isoindolinone derivatives for the preparation of a medicament for the treatment of phosphodiesterase mediated diseases ) 是由 向飞 周小刚 于 2020-05-16 设计创作，主要内容包括：本发明提供了一种含有异吲哚啉酮衍生物的组合物在制备用于治疗磷酸二酯酶,尤其是磷酸二酯酶4所介导的疾病的药物中的用途,所述组合物对各种磷酸二酯酶亚型的抑制作用均显著优于化合物Ⅰ。动物试验结果显示,本发明所述组合物对关节炎性小鼠胫跗关节组织病理学参数的改善效果显著优于化合物Ⅰ。(The invention provides the use of a composition containing isoindolinone derivatives for the preparation of a medicament for the treatment of phosphodiesterase, particularly phosphodiesterase 4 mediated diseases, said composition having a significantly better inhibition of various phosphodiesterase subtypes than compound i. Animal test results show that the composition has a remarkably better effect on improving the histopathological parameters of the tibialis joint of the arthritic mouse than that of the compound I.)

1. Use of a composition comprising a first isoindolinone derivative and a second isoindolinone derivative, which are different from each other and are selected from the group consisting of compound 1 to compound 44, as described below, in the preparation of a medicament for the treatment of a phosphodiesterase mediated disease:

2. use according to claim 1, characterized in that the mass ratio of the first isoindolinone derivative to the second isoindolinone derivative is between 0.01:1 and 100: 1.

3. Use according to claim 1 or 2, characterized in that the medicament may further comprise pharmaceutically acceptable adjuvants.

4. The use according to claim 3, characterized in that the auxiliary material is at least one selected from lactose, microcrystalline cellulose, crospovidone, starch, hypromellose, aerosil and magnesium stearate.

5. Use according to claim 1 or 2, characterized in that the medicament is formulated as an oral solid preparation.

6. The use according to claim 5, wherein the oral solid preparation is one selected from the group consisting of tablets, capsules and granules.

7. Use according to claim 1 or 2, characterized in that said phosphodiesterase is one selected from the group consisting of phosphodiesterase 1, phosphodiesterase 2, phosphodiesterase 3, phosphodiesterase 4, phosphodiesterase 5, phosphodiesterase 6, phosphodiesterase 7B and phosphodiesterase 11A.

8. Use according to claim 7, characterized in that said phosphodiesterase is one selected from the group consisting of phosphodiesterase 4, phosphodiesterase 7B, phosphodiesterase 1 and phosphodiesterase 3.

9. Use according to claim 8, characterized in that said phosphodiesterase is phosphodiesterase 4.

10. Use according to claim 1 or 2, characterized in that the disease is arthritis.

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to application of a composition containing isoindolinone derivatives in preparation of medicines for treating phosphodiesterase-mediated diseases.

Background

Phosphodiesterases (PDEs) are widely distributed in various tissues in the body and mediate various physiological functions (see PMDA: overview Form of RevationTablets 20mg, P54). The PMDA approved Interview Form of Otezla Tablets 10mg/Otezla Tablets 20mg/Otezla Tablets 30mg discloses the inhibition of various PDE subtypes, especially the inhibition of PDE4, by compound I, which has been approved by various drug administration for the treatment of psoriatic arthritis, but the inhibitory activity of PDE4 still needs to be further improved.

Disclosure of Invention

The object of the present invention is to provide the use of a composition containing isoindolinone derivatives for the preparation of a medicament for the treatment of phosphodiesterase mediated diseases, said composition having a significantly better inhibition of various phosphodiesterase subtypes than compound i.

In order to achieve the above objects, the present invention provides, in one aspect, a use of a composition comprising a first isoindolinone derivative and a second isoindolinone derivative, which are different from each other and selected from the group consisting of compounds 1 to 44 as described below, for the preparation of a medicament for treating a phosphodiesterase-mediated disease:

preferably, the mass ratio of the first isoindolinone derivative to the second isoindolinone derivative in the composition of the invention is 0.01: 1-100: 1.

On the other hand, the medicament of the invention can further contain pharmaceutically acceptable auxiliary materials; on the other hand, the auxiliary material is preferably at least one selected from lactose, microcrystalline cellulose, crospovidone, starch, hydroxypropyl methylcellulose, aerosil and magnesium stearate.

On the other hand, the medicament can be prepared into oral solid preparations; further preferably, the oral solid preparation is one selected from tablets, capsules and granules.

In another aspect, the phosphodiesterase of the present invention is preferably one selected from the group consisting of phosphodiesterase 1, phosphodiesterase 2, phosphodiesterase 3, phosphodiesterase 4, phosphodiesterase 5, phosphodiesterase 6, phosphodiesterase 7B and phosphodiesterase 11A; further preferably, the phosphodiesterase is one selected from the group consisting of phosphodiesterase 4, phosphodiesterase 7B, phosphodiesterase 1 and phosphodiesterase 3; most preferably, the phosphodiesterase is phosphodiesterase 4.

In another preferred aspect, the disease of the invention is arthritis.

In vitro test results show that the IC of the composition of the invention has inhibition effect on various phosphodiesterase subtypes₅₀Are all obviously lower than the lowest compounds of the compounds I to IV. Animal test results show that the composition has a remarkably better effect on improving the histopathological parameters of the tibialis joint of the arthritic mouse than that of the compound I.

Detailed Description

The following description of the embodiments is only intended to aid in the understanding of the method of the invention and its core ideas. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention. The following description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described.

Test example 1 compositions containing isoindolinone derivatives as IC inhibitors of Phosphodiesterase (PDE)₅₀Measurement of (2)

The invention adopts a method disclosed in the research on the inhibition effect of chemical components of Nanling oak and on phosphodiesterase (J. New Chinese medicine, 2010,19(02):147-151.) of Ling-Si Kai et al to determineMIX (X-Y) (X is selected from 1-44, and X ≠ Y) obtained by mixing compound X and compound Y in a specific mass ratio R inhibits IC of various phosphodiesterase subtypes shown in Table 1₅₀Values (in ng/mL, based on the total mass of compound X and compound Y) are shown in tables 2 to 9

TABLE 1 phosphodiesterase for use in the invention and sources thereof

Enzyme

PDE1

PDE2

PDE3

PDE4

PDE5

PDE6

PDE7B

PDE11A

Origin of origin

Rat heart

Ox adrenal gland

Dog heart

Canine lung

Canine lung

Bovine retina

Recombination

Recombination

TABLE 2 IC of PDE1 inhibition by test substances₅₀Value of

Test article	R	IC50
			MIX(2-11)	0.01	506.406
MIX(3-4)	0.1	602.989
			MIX(5-21)	1	655.805
MIX(8-19)	10	1467.378
			MIX(9-23)	100	480.757
MIX(11-16)	0.01	903.393
			MIX(13-40)	0.1	1522.150
MIX(15-15)	1	1348.668
			MIX(18-44)	10	1045.798
MIX(19-24)	100	805.571
			MIX(21-33)	0.01	1787.554
MIX(23-24)	0.1	1491.666
			MIX(26-1)	1	1330.965
MIX(27-19)	10	544.695
			MIX(30-14)	100	1708.481
MIX(32-36)	0.01	583.075
			MIX(33-4)	0.1	1029.858
MIX(35-42)	1	576.350
			MIX(37-17)	10	927.669
MIX(40-11)	100	1759.717
			MIX(42-6)	0.01	1571.215
MIX(44-34)	0.1	1841.475

TABLE 3 IC inhibition of PDE2 by test substances₅₀Value of

TABLE 4 IC inhibition of PDE3 by test substances₅₀Value of

Test article	R	IC50
			MIX(2-24)	0.01	1569.594
MIX(3-38)	0.1	4246.401
			MIX(6-14)	1	2919.628
MIX(7-10)	10	2246.679
			MIX(9-33)	100	2680.024
MIX(12-29)	0.01	1467.861
			MIX(13-21)	0.1	4123.848
MIX(15-33)	1	3070.629
			MIX(18-44)	10	3286.526
MIX(19-9)	100	3357.767
			MIX(22-6)	0.01	1748.145
MIX(24-22)	0.1	1073.265
			MIX(25-24)	1	2368.949
MIX(28-11)	10	3221.152
			MIX(29-32)	100	3507.724
MIX(32-44)	0.01	1343.124
			MIX(33-37)	0.1	4379.706
MIX(36-25)	1	1153.324
			MIX(38-23)	10	3783.514
MIX(40-24)	100	2574.262
			MIX(42-42)	0.01	1498.500
MIX(44-36)	0.1	2403.140

TABLE 5 IC of test Agents for inhibition of PDE4₅₀Value of

TABLE 6 IC of PDE5 inhibition by test substances₅₀Value of

Test article	R	IC50
			MIX(1-15)	0.01	5867.188
MIX(3-24)	0.1	5107.765
			MIX(6-7)	1	3755.489
MIX(8-11)	10	7345.820
			MIX(10-12)	100	6489.109
MIX(12-29)	0.01	3662.293
			MIX(13-8)	0.1	4331.098
MIX(16-38)	1	4122.800
			MIX(17-23)	10	6841.805
MIX(20-30)	100	5218.341
			MIX(21-34)	0.01	5909.825
MIX(23-37)	0.1	9422.182
			MIX(26-22)	1	2536.502
MIX(27-30)	10	5224.371
			MIX(29-20)	100	9118.557
MIX(32-22)	0.01	2277.765
			MIX(34-12)	0.1	7818.583
MIX(35-41)	1	9255.071
			MIX(38-11)	10	10240.750
MIX(39-4)	100	5417.213
			MIX(42-1)	0.01	8008.129
MIX(43-32)	0.1	6725.909

TABLE 7 IC of PDE6 inhibition by test substances₅₀Value of

TABLE 8 IC inhibition of PDE7B by test substances₅₀Value of

Test article	R	IC50
			MIX(2-41)	0.01	502.190
MIX(3-11)	0.1	526.961
			MIX(6-25)	1	697.005
MIX(7-37)	10	1027.149
			MIX(9-16)	100	913.004
MIX(11-25)	0.01	937.590
			MIX(14-2)	0.1	1015.981
MIX(16-33)	1	728.038
			MIX(18-11)	10	897.844
MIX(20-34)	100	216.239
			MIX(22-30)	0.01	703.324
MIX(24-12)	0.1	369.385
			MIX(25-11)	1	930.655
MIX(27-40)	10	616.611
			MIX(30-37)	100	378.030
MIX(31-16)	0.01	783.125
			MIX(34-43)	0.1	739.347
MIX(36-27)	1	267.575
			MIX(37-9)	10	521.864
MIX(40-1)	100	1012.838
			MIX(41-7)	0.01	438.567
MIX(43-22)	0.1	398.895

TABLE 9 IC inhibition of PDE11A by test substances₅₀Value of

As a control, the present invention also determined IC of various phosphodiesterase subtypes shown in Table 1 of Compound I in the same manner₅₀(ng/mL) and the results are shown in Table 10.

Watch 10

	PDE1	PDE2	PDE3	PDE4	PDE5	PDE6	PDE7B	PDE11A
									IC50	41080.53	819786.80	99443.75	86.67	210292.74	3152712.51	22577.10	112050.44

Test example 2 Effect of isoindolinone derivative-containing composition on the histopathological characteristics of the tibetan Joint of arthritic mice

The effect of a mixture of compound 8 and compound 30 at a mass ratio of 10 (MIX (8-30) (R ═ 10)) and compound i on the histopathological characteristics of the tibialis joint of arthritic mice was examined using the method disclosed in McCann FE et al (Arthritis Res ther. 2010; 12(3): R107), and the results are shown in table 11.

TABLE 11 Effect of each drug on the histopathology of the tibiotarsal joints in arthritic mice

As can be seen from table 11, when MIX (8-30) (R ═ 10) was administered at a dose of only 1/10 for compound i, the tibioarticular histopathology scores of the former-treated mice were significantly lower in part than compound i, while no statistical difference was observed in part compared to compound i.