阅读说明：本技术 2-(6-甲基-吡啶-2-基)-3-基-[6-酰胺基-喹啉-4-基]-5,6-二氢-4H-吡咯并[1,2-b]吡唑的共晶，其制备方法和药物组合物 (Co-crystals of 2- (6-methyl-pyridin-2-yl) -3-yl- [ 6-amido-quinolin-4-yl ] -5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazole, processes for their preparation and pharmaceutical compositions containing them ) 是由 盛晓红 盛晓霞 汪晶 于 2017-03-21 设计创作，主要内容包括：本发明涉及式(I)所示的2-(6-甲基-吡啶-2-基)-3-基-[6-酰胺基-喹啉-4-基]-5,6-二氢-4H-吡咯并[1,2-b]吡唑(Galunisertib或LY2157299)与共晶形成物形成的共晶,与Galunisertib已知的固体形式相比,本发明的共晶在稳定性、溶解度等方面具有优势。本发明还涉及所述共晶的晶型及其制备方法,其药物组合物及其在制备用于预防和/或治疗与TGF-β有关的疾病中的用途。<Image he="472" wi="700" file="DDA0002259668310000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention relates to 2- (6-methyl-pyridine-2-yl) -3-yl- [ 6-amido-quinoline-4-yl group shown as the formula (I)]-5, 6-dihydro-4H-pyrrolo [1,2-b]The co-crystals formed by pyrazole (gallunertinib or LY2157299) with the co-crystal composition have advantages in terms of stability, solubility, etc. compared to the known solid forms of gallunertinib. The invention also relates to a crystal form of the eutectic crystal, a preparation method thereof, a pharmaceutical composition thereof and application thereof in preparing medicines for preventing and/or treating TGF-beta related diseases.)

Cocrystals of 2- (6-methyl-pyridin-2-yl) -3-yl- [ 6-amido-quinolin-4-yl ] -5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazole with succinic acid.

The co-crystal according to claim 1, wherein the molar ratio of 2- (6-methyl-pyridin-2-yl) -3-yl- [ 6-amido-quinolin-4-yl ] -5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazole to succinic acid is 1: 0.5.

the co-crystal according to claim 2, characterized in that it contains 1 mole of water.

A co-crystal according to any one of claims 1 to 3, characterized in that a crystalline form of the co-crystal has characteristic peaks in the X-ray powder diffraction pattern at 2 Θ values of 10.8 ° ± 0.2 °, 11.6 ° ± 0.2 °, 15.5 ° ± 0.2 ° and 20.2 ° ± 0.2 ° using Cu-ka radiation.

The co-crystal of claim 4, wherein a crystalline form of the co-crystal uses Cu-Ka radiation and has an X-ray powder diffraction pattern further comprising characteristic peaks at one or more of 2 θ values of 12.3 ° ± 0.2 °, 16.8 ° ± 0.2 °, 18.0 ° ± 0.2 °, 21.3 ° ± 0.2 °, 21.7 ° ± 0.2 °, 22.0 ° ± 0.2 °, 24.6 ° ± 0.2 ° and 25.2 ° ± 0.2 °.

The co-crystal of claim 5, characterized in that the X-ray powder diffraction pattern of the crystalline form of the co-crystal further has characteristic peaks at 2 Θ values of 12.3 ° ± 0.2 °, 16.8 ° ± 0.2 °, 18.0 ° ± 0.2 °, 21.3 ° ± 0.2 °, 21.7 ° ± 0.2 °, 22.0 ° ± 0.2 °, 24.6 ° ± 0.2 ° and 25.2 ° ± 0.2 °.

The co-crystal of any one of claims 4 to 6, wherein the co-crystal has a Fourier infrared spectrum at a wave number of 3473cm^-1±2cm^-1、3141cm^-1±2cm^-1、1693cm^-1±2cm^-1、1580cm^-1±2cm-1、1429cm^-1±2cm^-1、1322cm^-1±2cm^-1、1189cm^-1±2cm^-1、864cm^-1±2cm-1、831cm^-1±2cm^-1、806cm^-12cm-1 and 609cm^-1±2cm^-1Has characteristic peaks.

2- (6-methyl-pyridine-2-yl) -3-yl- [ 6-acylamino-quinoline-4-yl]-5, 6-dihydro-4H-pyrrolo [1,2-b]Eutectic single crystal of pyrazole and succinic acid, characterized in that it is of the crystalline form according to any one of claims 4 to 7, belonging to the triclinic system, space group P1, having the following single crystal unit cell parameters:

a process for the preparation of a co-crystal according to any one of claims 4 to 7, which process comprises any one of the following:

(1) adding a solvent into a mixture of LY2157299 monohydrate and succinic acid, and grinding to dryness to obtain the eutectic crystal; the solvent is selected from methanol, acetonitrile or water;

preferably, the molar ratio of LY2157299 monohydrate to succinic acid is 1: 0.5-1: 1.2, more preferably 1: 0.5-1: 0.6;

preferably, the mass-to-volume ratio of the LY2157299 monohydrate to the solvent is 80mg:1 mL-200 mg:1mL, more preferably 80mg:1 mL-150 mg:1 mL;

preferably, the grinding temperature is 10-40 ℃, and more preferably 10-30 ℃;

(2) forming a suspension of a mixture of LY2157299 monohydrate and succinic acid in a solvent, stirring for crystallization, separating crystals, and drying to obtain the eutectic crystal; the solvent is selected from C₁～C₄Alcohol, ethyl acetate or acetone;

preferably, the solvent is methanol;

preferably, the molar ratio of LY2157299 monohydrate to succinic acid is 1: 0.5-1: 1.2, more preferably 1: 1.0-1: 1.2;

preferably, the mass-to-volume ratio of the LY2157299 monohydrate to the solvent is 50-100 mg/mL;

preferably, the temperature for stirring and crystallizing is 10-40 ℃, and more preferably 10-30 ℃;

preferably, the stirring crystallization time is 4-16 hours.

Cocrystals of 2- (6-methyl-pyridin-2-yl) -3-yl- [ 6-amido-quinolin-4-yl ] -5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazole with fumaric acid.

The co-crystal according to claim 10, wherein the molar ratio of 2- (6-methyl-pyridin-2-yl) -3-yl- [ 6-amido-quinolin-4-yl ] -5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazole and fumaric acid is 1: 0.5.

the co-crystal according to any one of claims 10 to 11, wherein a crystalline form of the co-crystal uses Cu-ka radiation and has an X-ray powder diffraction pattern with characteristic peaks at 2 Θ values of 8.3 ° ± 0.2 °, 9.8 ° ± 0.2 °, 16.7 ° ± 0.2 °.

The co-crystal of claim 12, wherein the crystalline form of the co-crystal further has an X-ray powder diffraction pattern having characteristic peaks at one or more of 2 Θ values of 15.5 ° ± 0.2 °, 16.4 ° ± 0.2 °, 23.4 ° ± 0.2 °, 23.7 ° ± 0.2 °, 24.2 ° ± 0.2 °, 27.1 ° ± 0.2 ° and 28.3 ° ± 0.2 °: .

The co-crystal of claim 13, wherein the X-ray powder diffraction pattern of the crystalline form of the co-crystal further comprises characteristic peaks at 2 Θ values of 15.5 ° ± 0.2 °, 16.4 ° ± 0.2 °, 23.4 ° ± 0.2 °, 23.7 ° ± 0.2 °, 24.2 ° ± 0.2 °, 27.1 ° ± 0.2 ° and 28.3 ° ± 0.2 °.

The co-crystal of any one of claims 12 to 14, wherein the co-crystal has a Fourier infrared spectrum at a wavenumber of 3350cm^-1±2cm^-1、3153cm^-1±2cm^-1、1681cm^-1±2cm^-1、1588cm^-1±2cm^-1、1395cm^-1±2cm^-1、1320cm^-1±2cm^-1、1149cm^-1±2cm^-1、971cm^-1±2cm^-1、870cm^-1±2cm^-1、835cm^-1±2cm^-1、747cm^-1±2cm^-1And 634cm^-1±2cm^-1Has characteristic peaks.

2- (6-methyl-pyridine-2-yl) -3-yl- [ 6-acylamino-quinoline-4-yl]-5, 6-dihydro-4H-pyrrolo [1,2-b]Eutectic single crystal of pyrazole and fumaric acid, characterized in that the eutectic is a crystalline form according to any of claims 12 to 15, said eutectic single crystal being of the triclinic system, space group P1, having the following unit cell parameters:α＝99.9°±0.2°；β＝102.3°±0.2°；γ＝108.4°±0.2°。

a method of preparation of the co-crystal of any one of claims 12 to 15, the method comprising any one of the following:

(1) adding a solvent into a mixture of LY2157299 monohydrate and fumaric acid, and grinding to be dry to obtain the eutectic crystal; the solvent is selected from methanol, acetonitrile or water;

preferably, the mass-volume ratio of the mixture to the solvent is 60mg:1 mL-160 mg:1 mL;

preferably, the molar ratio of LY2157299 monohydrate to fumaric acid is 1: 0.5-1: 1.2, more preferably 1: 0.5-1: 0.6;

preferably, the grinding temperature is 10-40 ℃, and more preferably 10-30 ℃;

(2) forming a suspension of a mixture of LY2157299 monohydrate and fumaric acid in a solvent, stirring for crystallization, separating crystals, and drying to obtain the eutectic crystal; the solvent is selected from C₁～C₄Alcohol, ethyl acetate or acetone;

preferably, the solvent is methanol;

preferably, the molar ratio of LY2157299 monohydrate to fumaric acid is 1: 0.5-1: 1.2, more preferably 1: 1.0-1: 1.2;

preferably, the mass-to-volume ratio of the LY2157299 monohydrate to the solvent is 50-100 mg/mL;

preferably, the temperature for stirring and crystallizing is 10-40 ℃, and more preferably 10-30 ℃;

preferably, the stirring crystallization time is 4-16 hours.

A pharmaceutical composition comprising a therapeutically effective amount of a co-crystal of 2- (6-methyl-pyridin-2-yl) -3-yl- [ 6-amido-quinolin-4-yl ] -5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazole and succinic acid according to any one of claims 1 to 8, a co-crystal of 2- (6-methyl-pyridin-2-yl) -3-yl- [ 6-amido-quinolin-4-yl ] -5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazole and fumaric acid according to any one of claims 10 to 15, and at least one pharmaceutically acceptable carrier or auxiliary.

The pharmaceutical composition of claim 18, wherein the pharmaceutical composition is in a form selected from the group consisting of a formulation suitable for oral, rectal, topical, subcutaneous or parenteral administration, such as injection, including a tablet, powder, capsule, lozenge, emulsion, cream, syrup, sublingual tablet, sachet, cachet, elixir, gel, suspension, injectable solution, aerosol, ointment, suppository and combinations thereof.

Use of a co-crystal of 2- (6-methyl-pyridin-2-yl) -3-yl- [ 6-amido-quinolin-4-yl ] -5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazole and succinic acid according to any one of claims 1 to 8, a co-crystal of 2- (6-methyl-pyridin-2-yl) -3-yl- [ 6-amido-quinolin-4-yl ] -5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazole and fumaric acid according to any one of claims 10 to 15 in the preparation of a medicament for the treatment or prevention of a disease associated with TGF- β; the TGF-beta related diseases comprise cancer, precancerous lesions, nephropathy, fibrosis, eye diseases and the like.

A method for the treatment and/or prevention of a TGF- β related disease comprising administering to a patient in need thereof a therapeutically and/or prophylactically effective amount of one or more co-crystals selected from 2- (6-methyl-pyridin-2-yl) -3-yl- [ 6-amido-quinolin-4-yl ] -5, 6-dihydro-4H-pyrrolo [1,2-b ] pyrazole according to any one of claims 1 to 8 and succinic acid, 2- (6-methyl-pyridin-2-yl) -3-yl- [ 6-amido-quinolin-4-yl ] -5, 6-dihydro-4H-pyrrolo [1,2-b ] a co-crystal of pyrazole and fumaric acid or a pharmaceutical composition according to any one of claims 18 to 19; the TGF-beta related diseases comprise cancer, precancerous lesions, nephropathy, lung fibrosis, eye diseases and the like.