MXPA01003432A - Vitreous form of known bradykinin antagonist - Google Patents

Abstract

This invention relates to a vitreous form of 8-[3-[N-[(E)-3- (6-acetamidopyridin-3-yl) acryloylglycyl]- N-methylamino]-2,6- dichlorobenzyloxy]-2- methylquinoline (FR173657) of formula (I). This vitreous form has good solid stability and, therefore, is useful for producing and supplying FR173657 products whose quality is stable enough to be suitable for medicines.

Description

FORM VITREA OF ANTAGONIST OF BRADYKININ KNOWN Technical Field The present invention relates to a form. vitrea of 8 - [3 - [N- [(E) -3- (6-acetamidopyridin-3-yl) acryloyl-glycyl] -N-ethylamino] -2,6-dichloro-benzyloxy] -2-methylquinoline ( hereinafter, referred to as FR173657) and with a pharmaceutical composition comprising it. Prior art FR 173657 is a compound of the following formula [I] and is disclosed in the Japanese Patent Laid-open No. 2780/1995 or in the Journal of Medicinal Chemi s try Medical Chemistry) 1998, Vol. 41, No.21, 4062-4079.

This possesses activity as a bradykinin antagonist and is useful as an agent for the prevention and / or treatment, for example, of allergy, inflammation, autoimmune disease, shock, pain or the like. FR173657 has an excellent activity as a bradykinin antagonist. However, FR173657 which is described in the aforementioned open specification is in an amorphous form, as obtained by solidification in a solvent. This amorphous form has a melting point that, in general terms, varies between 133 and 139 ° C and its stability in the solid state is deficient. Therefore, this is problematic in that products with a sufficiently stable quality to be acceptable as medicines are difficult to produce and supply. FR173657 comprises the crystallographic polymorphism from which crystalline hydrates have been found which have high purity and good stability in the solid state and which are easy to handle for the formulation in medicines, more preferably, three types of crystals which are referred to as type A crystal, type B crystal and type C crystal (Japanese Patent No. 316677/1998). However, although it has good stability in the solid state and good detachment, type A glass is problematic because it is often contaminated with type C glass, which makes production with a stable quality impossible. Type B glass is the most stable of all and there are no problems in the production of the same, although it is problematic because its detachment is much less than that of type A glass. Type C glass is also complicated, because its stability in The solid state is inferior to that of the type B crystal and its detachment is inferior to that of the type A crystal. Therefore, it is necessary to carry out further studies to try to find a new form of the FR173657 that is more suitable. Given this situation, FR173657 has been studied hard and as a result of the efforts, a vitreous form of FR173657 has been found that has high purity, good stability in solid state, good solubility and good detachment, and that is capable of production with stable quality and thus the present invention has been completed.

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1: Infrared absorption spectrum of the vitreous form of the FR173657 Fig. 2: Profile of the vitreous form of the FR173657 in Differential Scanning Calorimetry (DSC). Fig. 3: Infrared Absorption Spectrum of FR173657 Hydrate Crystal (Type A Crystal). Fig. 4: Infrared absorption spectrum of the hydrate crystal of FR173657 (crystal of type B). Fig. 5: Infrared absorption spectrum of the hydrate crystal of FR173657 (crystal of type C). Fig. 6: Results of the solubility test in Example 8.

BACKGROUND OF THE INVENTION The "vitreous form" indicates a solid amorphous substance that is in a state of fusion, without crystallizing it. In this specification, for reasons of coexistence, other amorphous substances that are not in a vitreous state are considered to be "amorphous forms." The vitreous formulations of FR173657 have the following physical properties.

Conditions for measurement * Infrared absorption spectrum: According to the Nujol method. * Differential scanning calorimetry (DSC): heating rate: 10 ° C / minute. Co-chemical physiological properties of the vitreous form of FR173657 (a) Specific peaks in the infrared absorption spectrum: 1684, 1662, 1524, 1236 and 836 cm "1. The infrared absorption spectrum is shown in the Figure. 1. (b) C to 1 or differential scanning imetry (DSC): The endothermic peak due to the transition of the glass appears in a temperature comprised in the approximate range of 115 to 122 ° C (where its maximum peak occurs around 126 to 128 ° C). The profile in differential scanning calorimetry (DSC) is shown in the Figure. 2. The vitreous form of FR173657 of the invention can be produced by heating an amorphous form, a crystalline form, or a mixture thereof of FR173657 or its solvate [ie hydrate, ethanolate, etc.] at a temperature not less than its melting point, followed by cooling in the melting state. The melting point varies according to the condition of the FR173657 or its solvate to be processed (if it is amorphous or crystalline, or the ratio of the mixture thereof), but for this process, any temperature at which the FR1 73657 in the initial stage or its solvate melts is adequate. In general, the initial stage of FR173657 or its solvate melts in a range of temperatures that fluctuates between 130 and 220 ° C. The method of heating FR173657 in its initial stage or its solvate at a temperature not lower than its melting point does not have a specific limitation. For example, the initial FR173657 or its solvate is introduced into a container under cooling, at room temperature or under heating, and then heated until it reaches a temperature not less than its melting point so as to melt; or, it is introduced into a container that has been heated to a temperature close to its melting point or at a higher temperature, so that it melts. Once it has melted in this way, it can be cooled immediately. Preferably, however, it remains in a melting state for about: 20 to 40 minutes and then cooled. The cooling method has no specific limitation. In general, the system that has been heated simply lets itself cool down. The vitreous form obtained in this way from FR173657 can be crushed or ground mechanically for the manufacture of the pharmaceutical preparations. The FR173657 in its initial stage or its solvate can be amorphous, crystalline or a mixture thereof. The crystal of a solvate of FR173657 can be prepared by any of the conventional methods, such as for example: a method comprising the stirring of FR173657 in a solvent, while warming or heating, and the subsequent stirring to obtain a crystalline precipitate; a method that includes the dissolution of FR173657 in a solvent in an acidic condition, followed by the addition of a base thereto and, optionally, water or a water solvent, to neutralize it, thus obtaining a crystalline precipitate; a method that includes exposure to the crystal of FR173657 for the evaporation or vaporization of an organic solvent; a method comprising any of these methods in combination, or the like, wherein FR173657 can be obtained as an amorphous form, according to a known method, for example, which is described in Japanese Patent Laid-open No. 2780/1995. The solvent to be used to precipitate the crystal may include: water; conventional organic solvents, such as alcohols, for example, methanol, ethanol, isopropyl alcohol, etc., acetone, N, N-dimethyldimethylformamide, dioxane, tetrahydrofuran, ethyl acetate, acetonitrile, dimethyl sulfoxide, or the like; and a mixture of them. Hydric alcohols, such as hydrous methanol, hydrous ethanol, etc., are preferred.; water acetone; and solvents in a mixture of water and an organic solvent, such as, for example, a combination of water and ethyl acetate. - - The type A crystal, the type B crystal and the type C crystal mentioned above can also be prepared, for example, according to the methods described in the following preparations or similar ways to the same. . The vitreous form of FRI 73657 of the invention possesses a marked activity as an antagonist of bradykinin and is useful in the treatment and / or prevention of diseases mediated by bradykinin or its analogues, such as allergy, inflammation, autoimmune disease, shock, pain or the like, both in humans and in animals. For therapeutic purposes, the vitreous form of FRI 73657 of the present invention can be used in the form of a pharmaceutical preparation containing one of said compounds, as an active ingredient, in admixture with a pharmaceutically acceptable carrier, such as, for example, an excipient. solid, semi-solid or suitable organic or inorganic liquid, for oral, parenteral administration -such as, for example, intravenous, intramuscular, subcutaneous or intra-articular-; external, as for example, topical, enteric, in t r a r c t a 1, vaginal, inhalant, ophthalmic, nasal or hypoglossal. The pharmaceutical preparations can be capsules, tablets, tablets, granules, suppositories, solution, lotion, suspension, emulsion, ointment, gel, cream or the like. If desired, auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and other additives that are commonly used may be included in these preparations. Although the dosage of the vitreous form of FR173657 will vary according to the age and condition of the patient, a single average dose of approximately 0.1 mg, 1 mg, 10 mg, SO mg, 100 mg, 250 mg, 500 mg and 1000 mg of the vitreous form of FR173657 can be effective for the prevention and / or treatment of the diseases mentioned above. In general, amounts between 0.1 mg / body and about 1,000 mg / body can be administered on a daily basis. Normally, it is said that a vitreous form crystallizes extremely fast and that its stability is weak. However, it has been found that the vitreous form of FR173657 of the invention neither crystallizes nor decomposes at all, even if it is exposed to heat or humidity or if it is subjected to a physical treatment and is quite stable.

The vitreous form of the FR173657 of the invention has higher purity and better stability in the solid state, compared to the known FR1736S7 and has greater solubility and better detachment than the crystallographic polymorphic FR173657. Consequently, it is useful to produce and supply the products of FR173657, whose quality is stable enough to be suitable for medicines.

EXAMPLES The invention is explained in a more specific way, through the following Preparations and Examples, which, however, do not intend to restrict the scope of the invention.

Preparation 1 To a mixture of 8 - [3 - (N-g 1 ici 1-N-methylamino) -2,6-dichlorobenzyloxy] -2-methylquinoline (100 mg), acid (E) -3-10 (6 - acet ami dop iri di n-3-yl) acrylic (56.1 mg) and, N-d ime ti 1 fo rmami da (2 ml) were added l-hydroxy-benzotriazole (43.4 mg) and hydrochloride of 1 - eti 1 - 3 - (3-dime ti 1 ami not -pr op i 1) ca rb od iimi da (56.9 mg) in nitrogen vapor at 0 ° C and the resulting mixture was stirred at room temperature, during 2 hours. The reaction mixture was poured into water and extracted with chloroform. The organic layer was washed with an aqueous solution of saturated sodium hydrogen carbonate, water and brine successively and dried over magnesium sulfate and subsequently, the solvent was removed under reduced pressure. The residue was purified by preparative thin layer chromatography (methanol: di-1 = 1:10, v / v) and solidified with diethyl ether and ethyl acetate to obtain 8 - [3 - [ N- [(E) -3- (6-Acetamidopyridin-3-yl) acryloyl-glycyl] - N -methylamino] -2,6-dichlorobenzyloxy] -2-methylquinoline (FR173657) (78.8 mg) as a gray white solid. P. Fusion: 133- 139 ° C. NMR (CDC13, d): 2.22 (3H, s), 2.74 (3H, s), 3.27 (3H, s), 3.67 (1H, dd, J = 16.5, 5, 5 Hz), 3.96 (1H, dd, J = 16.5, 5.5 Hz), 5.62 (1H, d, J = 11.0 Hz), 5.67 (lH, d, J = 11.0Hz), 6.46 (1H, d, J = 16.0 Hz), 6.73 (1H, br t, J = 5.5 Hz), 7.2t- 7.33 (3H, m) , 7.38-7.51 (3H, m), 7.52 (1H, d, J = 16.0 Hz), 7.82 (1H, dd, J = 8.5, 1.5 Hz), 8.03 (1H, d, J = 8.5 Hz), 8.13-8.25 (2H,), 8.33 (1H, d, J = 1.5Hz).

Preparation 2 FR173657 (7 g) was added to methanol (720 ml) at 6 ° C, and stirred under reflux for 5 minutes. The mixture was cooled to a temperature lower than 30 ° C and the duxant was stirred for 2 hours at a range between 20 and 30 ° C, to obtain a precipitate. The mixture containing the crystalline precipitate was filtered and the crystalline precipitate obtained was washed with methanol (14 ml) and dried in vacuo at 40 ° C, to obtain a crude anhydrous crystal of FR173657 (6.3 g) (hereinafter called the crystal of FR173657 crude). The crystal contained approximately 5% methanol.

Preparation 3 To a mixture of the crystal of crude FR173657 (100 g) and pure water (500 ml) was added concentrated hydrochloric acid (28.1 ml) stirring at less than 10 ° C to dissolve the crystal. Carbon powder (5 g) was added thereto and the mixture was stirred for 2.5 hours. The carbon powder was removed by filtration and washed with pure water (200 ml) and concentrated hydrochloric acid (1.4 ml). The resulting filtrate was incorporated into 'an m &' The acetone (700 ml) and triethylamine (35.87 g) were added at 55 ° C, stirred at the same temperature for 5 minutes and then refluxed for 20 minutes. After the mixture was cooled to 40 ° C, the crystal was collected by filtration. The crystal was washed with 50% acetone and dried in vacuo to obtain a FR173657 hydrate crystal (type A crystal) (88.7 g). Infrared absorption spectrum As shown in Fig. 3.

Preparation 4 To a mixture of the crystal of crude FR173657 (50 g) and pure water (250 ml) was added concentrated hydrochloric acid (14.1 ml) with stirring at 5 ° C to dissolve the crystal. There carbon powder (2.5 g) was added and the mixture was stirred for 30 minutes. The carbon powder was removed by filtration and washed with dilute hydrochloric acid. The resulting filtrate was added to a mixture of ethyl acetate (350 ml) and triethylamine (17.93 g) at 70 ° C and stirred at reflux for 2 hours. Then, the mixture was cooled to 20 ° C and then stirred at the same temperature for two more hours; The resulting crystal was collected by filtration. The crystal was vented with ethyl acetate (100 ml) and pure water (100 ml) and dried in vacuo at 40 ° C to obtain a crystal of hydrate of FRI 73657 (crystal of type B) (44.51 g). Infrared absorption spectrum As shown in Fig. 4.

P raparation 5 _ To a mixture of the crystal of crude FR173657 (260 g) and pure water (1300 ml) was added concentrated hydrochloric acid (73 ml), stirring for 10 minutes at 5 ° C to dissolve the crystal. After filtering, the residue was washed with dilute hydrochloric acid. The resulting filtrate was added dropwise to a mixture of acetone (6500 ml), pure water (4680 ml) and triethylamine (93.3 g) over a period of 30 minutes at 20 ° C, to which a seed crystal was added. of type C (26 mg). The resulting mixture was stirred at the same temperature for two and a half hours more, then cooled to 3 ° C and stirred for two more hours. The crystal was collected by filtration, washed with 50% acetone (520 ml) and dried in vacuo at 40 ° C to obtain a hydrate crystal of FR 173657 (crystal of type C) (236.68 g).

Infrared absorption spectrum As shown in Fig. 5.

EXAMPLE 1 _ A tray was placed in a thermostat with hot air circulation, baked at 230 ° C empty and then cooled to a lower temperature than 100 ° C. This was again heated to a fixed temperature of 160 ° C. Then ie confirm the fixed temperature of the tray, the hydrate crystal of FR173657 (type A glass) was spread evenly on the tray and heated on it. After the temperature of the substance reached 160 ° C, this was maintained for 30 minutes and then allowed to cool to obtain a vitreous form of FR173657. Infrared absorption spectrum As shown in Fig. 1. Profile in differential scanning calorimetry (DSC) As shown in Fig. 2.

EXAMPLE 2 A tray was placed in a thermostat with hot air circulation, baked at 230 ° C empty and then cooled to. a temperature less than 100 ° C. This was again heated to a fixed temperature of 160 ° C. After confirming the fixed temperature of the tray, the FR173657 hydrate crystal (type B glass) spread evenly on the tray and heated on it. After the temperature of the substance reached 220 ° C, this was maintained for 30 minutes and then it was allowed to cool to obtain a vitreous form of FR 173657. Both its infrared absorption spectrum and its profile in differential scanning calorimetry ( DSC) were equal to those of the vitreous form obtained in Example 1.

EXAMPLE 3 A tray was placed in a thermostat with circulating hot air, baked at 230 ° C empty and then cooled to a temperature of less than 100 ° C. This was again heated to a fixed temperature of 160 ° C. After confirming the fixed temperature of the tray, the FR173657 hydrate crystal (type C glass) was spread evenly on the tray and heated on it. After the temperature of the substance reached 160 ° C, this was maintained for 30 minutes and then allowed to cool to obtain a vitreous form of FR173657. Both its infrared absorption spectrum and its profile in differential scanning calorimetry (DSC) were equal to those of the vitreous form obtained in Example 1.

EXAMPLE 4 A tray was placed in a thermostat with hot air circulation, baked at 230 ° C empty and then cooled to a temperature less than 100C. This was again heated to a fixed temperature of 160 ° C. After confirming the fixed temperature of the tray, the FR173657 hydrate crystal (a mixture of type A glass and type C glass) was spread evenly on the tray and heated on it. After the temperature of the substance reached 160 ° C, this was maintained for 30 minutes and then allowed to cool to obtain a vitreous form of FR173657. Both its infrared absorption spectrum and its profile in differential scanning calorimetry (DSC) were equal to those of the vitreous form obtained in Example 1.

The above components were granulated and tabletted in an entional manner, to prepare uncoated tablets, which were coated with a film in a conventional manner, in order to obtain tablets coated with a film containing the vitreous form of FR. 73657.

The above components were granulated and tabletted in a conventional manner, to prepare uncoated tablets, which were coated with a film in a conventional manner, for the purpose of obtaining tablets coated with a film containing the vitreous form.

The above components were granulated and tabletted in an entional manner, to prepare uncoated tablets, which were coated with a film in a conventional manner, in order to obtain film-coated tablets containing the vitreous form of FR173657.

EXAMPLE 8 Solubility Test Method A solubility test was conducted in accordance with the dissolution test of the Japanese Pharmacopoeia (JP) XIII, paddle method. 900 ml of distilled water was used as the test solution. The speed of the pallet was set at 50 rpm. The vitreous form of FR173657 (100 g) was added to the test solution and 10 ml aliquots of the test solution were taken as samples in each measurement. Each sample was filtered through a 0.45 mm filter and analyzed by high performance liquid chromatography. As a control, type A crystal, type B crystal, type C crystal and a mixture of crystals of types A and C of hydrate of FR173657 were used.

Results The results of the test are shown in Fig. 6. From these results it is evident that the vitreous form of FR173657 of the invention has greater solubility than any crystallographic polymorphic FR173657.

EXAMPLE 9 Stability test The results of the vitreous stability test of mechanically ground FR 173657 are shown in the following Table. 40 ° C 30 ° C 25 ° C Relative humidity 75% Relative humidity: 75% Humidity 3 months 3 relative months: 60% 3 months ditto ditto ditto ditto ditto ditto From these results it is evident that the vitreous form of FR173657 of the invention neither "crystallizes nor decomposes at all under heat or humidity conditions, or if it is subjected to a physical treatment, and is quite stable in storage. long-term.

Claims (12)

RE VINDICAC ONES

1. A vitreous form of 8 - [3 - [N - [(E) - 3 - (6-acetamido-pyridin-3-yl) acryloyl-glycyl] -N-methylamino] -2,6-dichloro-benzyloxy] - 2-methylquinoline.

2. The vitreous form according to claim 1, characterized in that it is substantially free of a crystalline form of the 8- [3- [N- [(E) -3- (6-acetamido-pyridin-3-yl)] acrylo-ylglycyl] -N-met-il-amino] -2,6-dichlorobenzyloxy] -2-methylquinoline.

3. A vitreous form of the 8- [3- [N- [(E) -3- (6-acetamido-pyridin-3-yl) acryloylglycyl] -N-methyl-amino] -2,6-dichloro-benzyloxy ] -2-methylquinoline, characterized in that it is obtained by heating an amorphous form, a crystalline form or a mixture thereof of the 8- [3- [N- [(E) -3- (6-acetamido-pyridine -3-yl) -acyloyl-glycyl] -N-methylamino] -2,6-dichlorobenzyloxy] -2-methylquinoline or its solvate, at a temperature not lower than its melting point, after which cooling is carried out Of the same.

4. The vitreous form according to claim 3, characterized in that it is obtained by heating a crystal of the type A, or a mixture of the crystal of the type A and the crystal of the type C, of the hydrate of the 8 - [3 - [- [ (E) - 3 - (6 - a ce t ami do -piri di n-3 -i 1) acryloyl-glycyl] -N-methylamino] -2,6-dichloro-benzyl 1 oxy] - 2 -methyl 1 qui nol ina at a temperature not less than its melting point, which is followed by cooling it.

5. A vitreous form of the 8 - [3 - [N - [(E) - 3 - (6-acetamido-pyridin-3-yl) acryloylglycyl] -N-methylamino] -2,6-dichlorobenzyloxy] -2- methyl-quinoline, characterized in that the maximum endothermic peak due to the transition of the glass appears at a temperature comprised in the approximate range that varies between 126 and 128 ° C in the differential scanning calorimetry (DSC) heating rate: 10 ° C / minute).

6. A vitreous form of the 8- [3- [N- [(E) -3- (6-acetamidopyridin-3-yl) acryloylglycyl] -N-methylamino] -2,6-dichlorobenzyloxy] -2-methylquinoline, characterized by not being crystallized neither totally nor partially nor decomposed during a long term storage.

7. A process for preparing the vitreous form of the 8 - [3 - [N- [(E) - 3 - (6 - a ce t ami dop iri din-3-yl) acryloylglycyl] -N-methylamino] -2 , 6-dichloro-b-en-1-oxy] -2-methyl-1-quinoline, characterized in that it comprises heating an amorphous form, a crystalline form or a mixture thereof of the 8- [3- [N- [( E) -3- (6-Acetamidopyridin-3-yl) acryloylglycyl] - N -methylamino] -2,6-dichloro-benzyloxy] -2-methylquinoline, or its solvate, at a temperature not less than its point of fusion, followed by cooling it.

8. A process according to claim 7, characterized in that it comprises heating the crystal of type A, or a mixture of the crystal of type A and the crystal of type C of the hydrate of the 8- [3- [N-I - (E ) -3- (6-acetamidopyridin-3-yl) acryloyl-glycyl] -N-methylamino] -2,6-dichlorobenzyloxy] -2-methylquinoline, at a temperature not lower than its melting point, followed by cooling of the my smo

9. A pharmaceutical composition characterized in that it comprises the vitreous form according to claims 1, 2, 3, 4, 5 or 6 as an active ingredient, in association with a pharmaceutically acceptable excipient or carrier, substantially non-toxic.

10. An agent for the prevention and / or treatment of diseases mediated by bradykinin or its analogs, characterized in that it comprises a vitreous form according to claims 1, 2, 3, 4, 5 or 6 as an active ingredient.

11. The use of a vitreous form according to claims 1, 2, 3, 4, 5 or 6 as a medicament.

12. The use of a vitreous form according to claims 1, 2, 3, 4, 5 or 6 for the manufacture of a medicament for the prevention and / or treatment of diseases mediated by bradykinin or its analogues.