CN111514135A - Use of compositions containing isoindolinone derivatives for the preparation of a medicament for the treatment of phosphodiesterase mediated diseases - Google Patents

Use of compositions containing isoindolinone derivatives for the preparation of a medicament for the treatment of phosphodiesterase mediated diseases Download PDF

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CN111514135A
CN111514135A CN202010415339.3A CN202010415339A CN111514135A CN 111514135 A CN111514135 A CN 111514135A CN 202010415339 A CN202010415339 A CN 202010415339A CN 111514135 A CN111514135 A CN 111514135A
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phosphodiesterase
mix
medicament
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向飞
周小刚
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis

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Abstract

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.

Description

Use of compositions containing isoindolinone derivatives for the preparation of a medicament for the treatment of phosphodiesterase mediated diseases
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.
Figure BDA0002494807700000011
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:
Figure BDA0002494807700000012
Figure BDA0002494807700000021
Figure BDA0002494807700000031
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
Figure BDA0002494807700000041
Figure BDA0002494807700000051
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
Figure BDA0002494807700000052
Figure BDA0002494807700000061
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
Figure BDA0002494807700000062
Figure BDA0002494807700000071
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
Figure BDA0002494807700000072
Figure BDA0002494807700000081
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
Figure BDA0002494807700000082
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.
Example 1 preparation of solid preparation of isoindolinone derivative-containing composition
Prescription
Figure BDA0002494807700000083
Figure BDA0002494807700000091
Preparation method
Taking the active ingredients and the auxiliary materials according to the prescription amount, and sieving the active ingredients and the auxiliary materials with a 100-mesh sieve. Mixing active ingredients, lactose, microcrystalline cellulose, polyvinylpolypyrrolidone and starch thoroughly; taking the hydroxypropyl methylcellulose with the prescription amount, preparing a solution with the concentration of 10% based on the hydroxypropyl methylcellulose, adjusting the pH to 3.0-4.0 by using lactic acid, adding the solution into the mixed material to prepare a soft material, granulating by using a 16-mesh sieve, and drying for 3-4 h at 80 ℃. Granulating with 16 mesh sieve, adding prescription amount of silica gel micropowder and magnesium stearate, mixing, and encapsulating into capsule with weight of about 500 mg;
taking the active ingredients and the auxiliary materials according to the prescription amount, and sieving the active ingredients and the auxiliary materials with a 100-mesh sieve. Mixing active ingredients, lactose, microcrystalline cellulose, polyvinylpolypyrrolidone and starch thoroughly; taking the hydroxypropyl methylcellulose with the prescription amount, preparing a solution with the concentration of 10% based on the hydroxypropyl methylcellulose, adjusting the pH to 3.0-4.0 by using lactic acid, adding the solution into the mixed material to prepare a soft material, granulating by using a 16-mesh sieve, and drying for 3-4 h at 80 ℃. Sieving with a 16-mesh sieve, adding the aerosil and magnesium stearate according to the formula amount, mixing uniformly, and subpackaging into granules with the weight of about 5g per bag;
taking the active ingredients and the auxiliary materials according to the prescription amount, and sieving the active ingredients and the auxiliary materials with a 100-mesh sieve. Mixing active ingredients, lactose, microcrystalline cellulose, polyvinylpolypyrrolidone and starch thoroughly; taking the hydroxypropyl methylcellulose with the prescription amount, preparing a solution with the concentration of 10% based on the hydroxypropyl methylcellulose, adjusting the pH to 3.0-4.0 by using lactic acid, adding the solution into the mixed material to prepare a soft material, granulating by using a 16-mesh sieve, and drying for 3-4 h at 80 ℃. Sieving with 16 mesh sieve, adding prescription amount of silica gel micropowder and magnesium stearate, mixing, and making into tablet with weight of about 500 mg.

Claims (10)

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:
Figure FDA0002494807690000011
Figure FDA0002494807690000021
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.
CN202010415339.3A 2020-05-16 2020-05-16 Use of compositions containing isoindolinone derivatives for the preparation of a medicament for the treatment of phosphodiesterase mediated diseases Withdrawn CN111514135A (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113173878A (en) * 2021-04-20 2021-07-27 梯尔希（南京）药物研发有限公司 Preparation method of apremilast impurity
CN113956189A (en) * 2021-11-08 2022-01-21 深圳菲斯生物科技有限公司 Preparation method of lenalidomide impurity D
CN114644586A (en) * 2022-04-12 2022-06-21 江苏豪森药业集团有限公司 Preparation method of lenalidomide related substance
WO2023015944A1 (en) * 2021-08-13 2023-02-16 苏州璞正医药有限公司 Substituted isoindolin-1,3-dione pde4 inhibitor and pharmaceutical use thereof

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113173878A (en) * 2021-04-20 2021-07-27 梯尔希（南京）药物研发有限公司 Preparation method of apremilast impurity
CN113173878B (en) * 2021-04-20 2022-03-15 梯尔希（南京）药物研发有限公司 Preparation method of apremilast impurity
WO2023015944A1 (en) * 2021-08-13 2023-02-16 苏州璞正医药有限公司 Substituted isoindolin-1,3-dione pde4 inhibitor and pharmaceutical use thereof
CN113956189A (en) * 2021-11-08 2022-01-21 深圳菲斯生物科技有限公司 Preparation method of lenalidomide impurity D
CN114644586A (en) * 2022-04-12 2022-06-21 江苏豪森药业集团有限公司 Preparation method of lenalidomide related substance

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Application publication date: 20200811