CN116745270A - Process for preparing diphenylpyrazine derivatives - Google Patents

Process for preparing diphenylpyrazine derivatives Download PDF

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Publication number
CN116745270A
CN116745270A CN202280012079.2A CN202280012079A CN116745270A CN 116745270 A CN116745270 A CN 116745270A CN 202280012079 A CN202280012079 A CN 202280012079A CN 116745270 A CN116745270 A CN 116745270A
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butoxy
diphenylpyrazin
amino
calcium
prop
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龙尼·瓦尼尔肖特
阿兰·科拉斯
卡利娜·莱斯
科莱·范梅赫伦
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Actelion Pharmaceuticals Ltd
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Actelion Pharmaceuticals Ltd
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Priority claimed from PCT/EP2022/052084 external-priority patent/WO2022162163A1/en
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Abstract

The present invention relates to a process for preparing {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } calcium acetate, or a pharmaceutically acceptable hydrate or solvate thereof. Furthermore, it relates to high purity {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } calcium acetate, and crystalline forms of {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } calcium acetate and hydrates and solvates thereof. Furthermore, the present invention relates to the use of calcium 4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } acetate for the treatment or prophylaxis of, for example, pulmonary Arterial Hypertension (PAH) or chronic embolic pulmonary arterial hypertension (CTEPH).

Description

Process for preparing diphenylpyrazine derivatives
Technical Field
The present invention relates to a process for preparing {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } calcium acetate, or a pharmaceutically acceptable hydrate or solvate thereof:
the compound of formula (I) is the calcium salt of the metabolite of Sailexipa (Selexipag) (the calcium salt of ACT-333679), and has the formula Ca (C) 25 H 28 N 3 O 3 ) 2 C, i.e 50 H 56 N 6 O 6 Ca (MW: 877.109). In the present invention, the term "{4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino group ]Butoxy calcium acetate "; "2- [4- [ (5, 6-diphenylpyrazin-2-yl) (propan-2-yl) amino ]]Butoxy group]Calcium acetate "; "2- [4- [ (5, 6-diphenylpyrazin-2-yl) -isopropyl-amino ]]Butoxy group]Calcium acetate "; "2- [4- [ (5, 6-diphenylpyrazin-2-yl) - (propan-2-yl) amino ]]Butoxy calcium acetate "," {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino group]Calcium salt of butoxy } acetic acid "; "{4- [ (5, 6-diphenylpyrazin-2-yl) (isopropyl) amino group]Calcium salt of butoxy } acetic acid "; "calcium salt of 2- (4- ((5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino) butoxy) acetic acid"; "calcium salt of 2- (4- ((5, 6-diphenylpyrazin-2-yl) (isopropyl) amino) butoxy) acetic acid"; "bis [ [2- [4- [ (5, 6-diphenylpyrazin-2-yl) -isopropyl-amino ]]Butoxy group]Acetyl group]Oxy group]Calcium) "and the calcium salt of the celecoxib metabolite (calcium salt of ACT-333679) are used synonymously.
Sailexipa (INN) is 2- {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ]]Butoxy } -N- (methylsulfonyl) acetamide (A)CT-293987, NS-304, CAS:475086-01-2;2- {4- [ N- (5, 6-diphenylpyrazin-2-yl) -N-isopropylamino group]Butoxy } -N- (methylsulfonyl) acetamide), also known as Uptavi TM . The metabolite of celecoxib is 2- (4- ((5, 6-diphenylpyrazin-2-yl) (isopropyl) amino) butoxy) acetic acid (MRE-269, ACT-333679,2- {4- [ (5, 6-diphenylpyrazin-2-yl) -propan-2-ylamino) ]Butoxy } acetic acid; {4- [ (5, 6-diphenylpyrazin-2-yl) (isopropyl) amino group]Butoxy } acetic acid; {4- [ (5, 6-diphenylpyrazin-2-yl) - (propan-2-yl) amino ]]Butoxy } acetic acid; CAS:475085-57-5 (MW 419.52)).
The present invention relates to a process for preparing {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } calcium acetate, or a pharmaceutically acceptable hydrate or solvate thereof. Furthermore, it relates to high purity {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } calcium acetate, and crystalline forms of {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } calcium acetate, and hydrates and solvates thereof. Furthermore, the present invention relates to the use of calcium 4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } acetate for the treatment or prophylaxis of, for example, pulmonary Arterial Hypertension (PAH) or chronic embolic pulmonary arterial hypertension (CTEPH).
Background
The preparation and medical use of celecoxib and the active metabolite 2- (4- ((5, 6-diphenylpyrazin-2-yl) (isopropyl) amino) butoxy) acetic acid is described in WO2002/088084; WO2009/157396; WO2009/107736; WO2009/154246; WO2009/157397; WO2009/157398; WO2010/150865; WO2011/024874; nakamura et al, biorg Med Chem (2007), 15,7720-7725; kuwano et al J Pharmacol Exp Ther (2007), 322 (3), 1181-1188; kuwano et al J Pharmacol Exp Ther (2008), 326 (3), 691-699; sitbon et al, N Engl J Med (2015), 373,2522-33; asaki et al, bioorg Med Chem (2007), 15,6692-6704; asaki et al, j.med.chem (2015), 58,7128-7137. Salts of the celecoxib metabolite are described in JP 2019-149945.
Celecoxib has been shown to be beneficial in the treatment of pulmonary hypertension. In phase III clinical trials, the risk of the primary complex endpoint of mortality or complications associated with pulmonary hypertension in patients receiving celecoxib was significantly lower than in patients receiving placebo. Celecoxib is approved for example in the united states and is indicated for the treatment of pulmonary arterial hypertension (PAH, WHO group I) to delay disease progression and reduce risk of hospitalization for PAH.
To date, standard film coated tablet formulations of celecoxib intended for twice daily oral administration have been used, wherein the excipients include D-mannitol, corn starch, low substituted hydroxypropylcellulose, hydroxypropylcellulose and magnesium stearate; the tablets were film coated with a coating material containing a mixture of hypromellose, propylene glycol, titanium dioxide, carnauba wax, and iron oxide.
Furthermore, safety studies (NCT 03187678) have been conducted on the transition from oral celecoxib to intravenous injection of celecoxib in patients with PAH, whereby celecoxib is administered twice daily for approximately 87 minutes per infusion. For each patient, the dose was personalized to correspond to his/her current oral dose of celecoxib.
Celecoxib is believed to act as a prodrug (while retaining some agonistic activity of itself on the IP receptor) that exerts long-acting selective IP receptor agonist activity of the active metabolite 2- (4- ((5, 6-diphenylpyrazin-2-yl) (isopropyl) amino) butoxy) acetic acid in mammals, particularly humans. In vivo metabolism of celecoxib can effectively act as a class of 'sustained release mechanisms' that potentially prolong activity and reduce the typical side effects associated with high concentrations of PGI2 agonists (Kuwano et al, J Pharmacol Exp Ther (2007), 322 (3), 1181-1188).
In some cases, the use of oral formulations of celecoxib may be inappropriate or impossible, for example, in emergency care, or in cases where the patient is not able to swallow a tablet for some reason.
Furthermore, in general, it is desirable to reduce the drug burden, particularly for treatment regimens that may last for months or longer.
The number and/or volume of dosage forms containing the drug to be administered is often referred to as the "drug burden". High drug loading is undesirable for a number of reasons, such as frequency of administration, which is often combined with the inconvenience of having to swallow large dosage forms and the need to store and transport large or bulky pharmaceutical formulations. The high drug burden increases the risk that the patient does not take his full dose and is unable to follow the prescribed dosage regimen.
Thus, there is a need to develop a pharmaceutical composition or formulation whose efficacy is maintained for, for example, one week or more, or one month or more, whereby it only needs to be administered at long intervals, such as one week or more, or even one month or more (long acting formulation), i.e. three months.
Calcium {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } acetate, or a pharmaceutically acceptable hydrate or solvate thereof, prepared according to the method of the present invention is particularly suitable for long-acting formulations due to its low solubility in aqueous media. The present process allows {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } calcium acetate or a pharmaceutically acceptable hydrate or solvate thereof to be obtained in high purity.
Disclosure of Invention
It is an object of the present invention to provide an improved process for the preparation of {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } calcium acetate, or a pharmaceutically acceptable hydrate or solvate thereof. Furthermore, it is an object of the present invention to provide novel crystalline forms of {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } calcium acetate.
It has now been found that {4- [ (5, 6-diphenylpyrazin-2-yl) (propan-2-yl) amino group ]Calcium butoxy } acetate can be efficiently produced in high purity by the process of the present invention, i.e., avoiding excessive residual Ca in the final product 2+ I.e. calcium salts derived from raw materials, in particular Ca (OH) 2 . Furthermore, the novel process ensures an improved conversion of the starting celecoxib metabolite, i.e. a lower proportion of excess celecoxib metabolite in the product. Furthermore, new crystalline forms and hydrates/solvates have been prepared. The novel process can employ various calcium salts to provide high yields, high conversion of the calcium salt, and high purity {4- [ (5, 6-diphenylpyrazine-2 ]Radical) (propan-2-yl) amino group]Butoxy } calcium acetate.
Because of the low water solubility of the calcium salt of the celecoxib metabolite obtained by the method of the invention, the product and various crystalline forms are suitable for use in the preparation of long-acting formulations, such as, for example, long-acting injections. The improved process of the present invention allows the preparation of particularly pure products, which is important in the preparation of pharmaceutical compounds.
Drawings
FIG. 1 shows the X-ray powder diffraction pattern of {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } calcium acetate in crystalline form 1. X-ray diffraction showed the following peaks: 5.1 ° (85%), 5.4 ° (20%), 8.8 ° (63%), 9.9 ° (100%), 11.4 ° (38%), 13.4 ° (21%), 13.8 ° (21%), 16.3 ° (65%), 18.1 ° (19%), 18.7 ° (27%), 19.7 ° (52%), 20.9 ° (51%), 21.4 ° (31%), 22.9 ° (51%), 23.6 ° (36%), 25.1 ° (37%).
The peaks listed above describe the experimental results of the X-ray powder diffraction pattern shown in figure 1. It should be understood that not all of these peaks are necessary to fully and explicitly characterize form 1.
FIG. 2 shows the X-ray powder diffraction pattern of {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } calcium acetate in crystalline form 2 obtained from example 5. X-ray diffraction showed the following peaks: 3.2 ° (100%), 6.3 ° (21%), 7.7 ° (21%), 9.3 ° (34%), 10.0 ° (35%), 10.4 ° (9%), 11.6 ° (5%), 12.7 ° (26%), 13.8 ° (7%), 15.7 ° (12%), 17.5 ° (8%), 19.2 ° (20%), 20.2 ° (12%), 21.3 ° (8%), 22.9 ° (17%), 23.4 ° (13%), 24.0 ° (14%), 25.2 ° -2 theta (6%).
The peaks listed above describe the experimental results of the X-ray powder diffraction shown in fig. 2. It should be understood that not all of these peaks are necessary to fully and explicitly characterize form 2.
FIG. 3 shows DSC curve of form 2
FIG. 4 shows the TGA curve of form 2
FIG. 5 shows the X-ray powder diffraction pattern of {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } calcium acetate in crystalline form 3 obtained from example 6. X-ray diffraction showed the following peaks: 4.5 ° (100%), 4.8 ° (60%), 5.0 ° (56%), 7.9 ° (36%), 8.8 ° (47%), 9.0 ° (53%), 10.0 ° (74%), 11.9 ° (46%), 14.9 ° (50%), 15.6 ° (69%), 17.1 ° (43%), 18.7 ° (100%), 19.7 ° (33%), 20.7 ° (30%), 21.1 ° (17%), 22.1 ° (38%), 22.7 ° (34%), 23.9 ° (22%), 24.5 ° (12%), 26.1 ° (2 theta (12%).
The peaks listed above describe the experimental results of the X-ray powder diffraction pattern shown in fig. 5. It should be understood that not all of these peaks are necessary to fully and explicitly characterize form 3.
FIG. 6 shows DSC curve of form 3
FIG. 7 shows the TGA curve of form 3
FIG. 8 shows the X-ray powder diffraction pattern of {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } calcium acetate in crystalline form 5 obtained from example 7. X-ray diffraction showed the following peaks: 4.9 ° (25%), 8.8 ° (49%), 9.8 ° (100%), 11.0 ° (44%), 12.8 ° (21%), 13.1 ° (23%), 13.3 ° (17%), 14.7 ° (12%), 15.7 ° (17%), 16.1 ° (8%), 16.7 ° (17%), 16.9 ° (29%), 17.8 ° (5%), 18.2 ° (4%), 18.7 ° (10%), 19.0 ° (8%), 19.5 ° (43%), 20.1 ° (11%), 20.6 ° (10%), 21.1 ° (38%), 21.5 ° (22%), 22.6 ° (20%), 23.6 ° (12%), 26.3 ° (10%), 30.3 °. 2theta (7%).
The peaks listed above describe the experimental results of the X-ray powder diffraction pattern shown in fig. 8. It should be understood that not all of these peaks are necessary to fully and explicitly characterize form 5.
In the X-ray diffraction diagrams of fig. 1, 2, 5 and 8, the refraction angle 2theta (2θ) is plotted on the horizontal axis and the counts are plotted on the vertical axis.
FIG. 9 shows the plasma concentrations over time of various study formulations containing celecoxib, the celecoxib metabolite (2- (4- ((5, 6-diphenylpyrazin-2-yl) (isopropyl) amino) -butoxy) acetic acid; ACT 333679) and the calcium salt of the celecoxib metabolite ({ 4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } calcium acetate; the calcium salt of ACT 333679).
Detailed Description
The present invention describes a process for the preparation of {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } calcium acetate of formula (I), or a pharmaceutically acceptable hydrate or solvate thereof:
the method comprises the following steps:
mixing {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } acetic acid and a first calcium source with a solvent (a) to obtain a mixture;
heating or maintaining the mixture at a temperature in the range of 20 ℃ to 85 ℃;
separating the solid product obtained;
optionally, reslurrying the isolated solid product in a solution of a second calcium source in solvent (b) at a temperature in the range of 20 ℃ to 85 ℃.
In some embodiments, the mixing step comprises mixing {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } acetic acid with solvent (a) to obtain a mixture; and heating or maintaining the mixture at a temperature in the range of 20 ℃ to 85 ℃ prior to adding the first calcium source.
In some embodiments of the present invention, in some embodiments,
the first calcium source was dissolved in the solvent (b) to obtain a solution (b), and then the solution (b) was added to a mixture of {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } acetic acid and the solvent (a).
The present invention relates to a process for the preparation of {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } calcium acetate of formula (I), or a pharmaceutically acceptable hydrate or solvate thereof:
the method comprises the following steps:
(a) {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } acetic acid was dissolved in the solvent (a)
To obtain a solution (a);
(b) Heating the solution (a) to a temperature in the range of 20 ℃ to 85 ℃;
(c) Dissolving a first calcium source in a solvent (b) to obtain a solution (b);
(d) Dosing the solution (b) into the solution (a);
(e) Separating the solid product obtained;
(f) Optionally reslurrying the product of step (e) in a solution of a second calcium source in solvent (b) at a temperature in the range 20 ℃ to 85 ℃.
In some embodiments, the first and optionally the second calcium source is Ca (OAc) 2 。
The starting material {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } acetic acid, i.e. the celecoxib metabolite (MRE-269, ACT-333679), can be prepared as known in the art, for example as described in EP1400518A1, example 42.
The {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } calcium acetate having the structure of the above formula (I) as shown above may be in an anhydrous form, or in a hydrate form or a pharmaceutically acceptable solvate form. The term "pharmaceutically acceptable solvent" refers to a solvent that retains the desired biological activity of the compound and exhibits minimal undesirable toxicological effects. Preferably in anhydrous form or in the form of a hydrate.
{4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } calcium acetate may be in the form of a hydrate. The hydrate form may be about 0.1 to about 1 water molecule/{ 4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } calcium acetate molecule. In some embodiments, the molar ratio of water to calcium {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } acetate ranges from about 0.1 to about 1, such as from about 0.1 to about 0.15, from about 0.15 to about 0.2, from about 0.2 to about 0.25, from about 0.25 to about 0.3, from about 0.3 to about 0.35, from about 0.35 to about 0.4, from about 0.4 to about 0.45, from about 0.45 to about 0.5, from about 0.5 to about 0.55, from about 0.55 to about 0.6, from about 0.6 to about 0.65, from about 0.65 to about 0.7, from about 0.7 to about 0.75, from about 0.75 to about 0.8, from about 0.8 to about 0.85, from about 0.85 to about 0.9, from about 0.9 to about 0.95, from about 0.95, and from about 0.95 to about 1. The molar ratio of water in the hydrate form may vary based on the storage conditions of the compound, the method of formation of the compound, and the crystal structure of the compound.
The solvent (a) used in step (a) to dissolve {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } -acetic acid may be an organic solvent or a mixture of one or more organic solvents with water. Solution (a) involves a solution of {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } -acetic acid in solvent (a).
The water used in the process is preferably purified water, such as standard Purified Water (PW).
Preferably, the organic solvent is miscible or partially soluble in water. In this context, miscible with water means a miscibility or solubility of at least 200g/L water. Preferably, the organic solvent is miscible with water. Suitable organic solvents may be selected from: acetone, tetrahydrofuran (THF), acetonitrile, MEK (methyl ethyl ketone), DMSO, DMF, 1, 4-dioxane, pyridine, dimethylacetamide (DMA), methyl acetate (MeOAc), methanol, ethanol, propanol (1-propanol, 2-propanol) and butanol (1-butanol, 2-methylpropan-1-ol, 2-methylpropan-ol). In one embodiment, the organic solvent may be selected from: acetone, THF, acetonitrile, MEK (methyl ethyl ketone), DMSO, DMF, 1, 4-dioxane, pyridine, dimethylacetamide (DMA), methyl acetate (MeOAc), propanol and butanol, or mixtures thereof. Preferred organic solvents are acetone and THF, in particular acetone.
The organic solvent in the solvent (a) may be mixed with water. The ratio is given in weight/weight%. Thus, the ratio of solvent (a)/water (weight/weight) may be 100/0 to 10/90, or 100/0 to 50/50, or 100/0 to 70/30. For example, the solvent (a) is a mixture of acetone/water in a ratio of 100/0 to 30/70, or a mixture of THF/water in a ratio of 100/0 to 10/90.
The solvent (a) may be, for example, acetone/water in a ratio of 100/0 to 80/20, or 99/1 to 90/10, for example, 95/5.
The concentration of the raw material {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } acetic acid in the solvent (a) is not particularly limited. The concentration may be selected from 60g {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } acetic acid per 100g solvent (a) or less, for example, in the range of 1g/100g solvent (a) to 60g/100g solvent (a), or 1g/100g solvent (a) to 50g/100g solvent (a), or 1g/100g solvent (a) to 40g/100g solvent (a). For example, the concentration may be from 1g of celecoxib metabolite/100 g of acetone/water (95/5) to 10.2g of celecoxib metabolite/100 g of acetone/water (95/5), such as from 8g to 9 g.+ -. 10% or from 8g to 9 g.+ -. 5% of celecoxib metabolite/100 g of acetone/water (95/5).
In step (b), the solution (a) is heated to a temperature in the range of 20 ℃ to 85 ℃. The temperature depends on the boiling point of solvent (a) and is selected to be high enough to dissolve the feedstock and low enough to prevent degradation of the feedstock. In some embodiments, a mixture of {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } acetic acid and solvent (a) is heated or maintained at a temperature in the range of 20 ℃ to 85 ℃. In some embodiments, a mixture of {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } acetic acid, the first calcium source, and the solvent (a) is heated or maintained at a temperature in the range of 20 ℃ to 85 ℃.
In one embodiment, the temperature of step (b) or the mixture is in the range of 20 ℃ to 85 ℃, 20 ℃ to 80 ℃, 20 ℃ to 75 ℃, 20 ℃ to 70 ℃, 20 ℃ to 65 ℃, 20 ℃ to 60 ℃, 20 ℃ to 55 ℃, e.g., 20 ℃ to 50±3 ℃. Preferably, the final temperature in step (b) or the mixture is above 20 ℃ and ranges from 40 ℃ to 85 ℃, 45 ℃ to 80 ℃, 45 ℃ to 75 ℃, 45 ℃ to 70 ℃, 45 ℃ to 65 ℃, 45 ℃ to 60 ℃, 45 ℃ to 55 ℃, e.g. 50 ℃ ± 3 ℃.
Preferably, the final temperature of step (b) or the mixture is reached by rapid heating (e.g. at 1K/min). Alternatively, the raw material may be added to the solvent (a) set at a desired temperature.
Optionally, the solution (a) or a mixture of {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } acetic acid and the solvent (a) may be subjected to a filtration step. Preferably, the optional filtration step is a polish filtration step. The mesh size of the filter may be 5 μm or less, for example in the range of 0.2 μm-5 μm, for example 0.5 μm.
Optionally, a seed crystal of {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } calcium acetate may be added to the solution (a) or the mixture. The addition of seed crystals is not mandatory, i.e. the process operates without seed crystals and provides the same crystalline form as without seed crystals. However, seeds may be added to optimize the crystallization process. The purity of the product is not affected by the addition of seed crystals.
Seed crystals may be optionally added, whereby the amount of seed crystals is not particularly limited. However, for economic reasons, the amount of seed crystals may be selected to be an amount of at most 25 wt/wt% relative to the amount of starting {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } acetic acid; or 0 to 25% w/w relative to the amount of the starting {4- [ (5, 6-diphenylpyrazin-2-yl) (propan-2-yl) amino ] butoxy } acetic acid. In one embodiment, the seed is added in an amount of 0.5 to 10 wt/wt%, or in an amount of 0.5 to 5 wt/wt%, or in an amount of 0.5 to 4 wt/wt%, or in an amount of 0.5 to 3 wt/wt%, for example in an amount of 1 wt/wt% ± 10% or 1% wt/wt% ± 5%.
In one embodiment, the seed crystal has an X-ray powder diffraction pattern in which at least five peaks, or at least seven peaks, or at least nine peaks, have a refractive angle 2theta (2 theta) value selected from the group consisting of: 5.1 °, 5.4 °, 8.8 °, 9.9 °, 11.4 °, 13.4 °, 13.8 °, 16.3 °, 19.7 °, 20.9 °, 21.4 °, 22.9 °, 25.1 °. In one embodiment, the seed crystal has an X-ray powder diffraction pattern in which at least five peaks, or at least seven peaks, or at least nine peaks, have a refractive angle 2theta (2 theta) value selected from the group consisting of: 5.1 °, 5.4 °, 8.8 °, 9.9 °, 11.4 °, 13.4 °, 13.8 °, 16.3 °, 18.1 °, 18.7 °, 19.7 °, 20.9 °, 21.4 °, 22.9 °, 23.6 °, 25.1 °. In particular, crystalline form 1 shows an X-ray powder diffraction pattern in which the following peaks, and their relative intensities given in brackets: 5.1 ° (85%), 5.4 ° (20%), 8.8 ° (63%), 9.9 ° (100%), 11.4 ° (38%), 13.4 ° (21%), 13.8 ° (21%), 16.3 ° (65%), 18.1 ° (19%), 18.7 ° (27%), 19.7 ° (52%), 20.9 ° (51%), 21.4 ° (31%), 22.9 ° (51%), 23.6 ° (36%), 25.1 ° (37%), wherein the X-ray powder diffraction pattern is obtained by using combined Cu kα1 and kα2 (Kalpha 2) radiation without kα2 stripping; and the accuracy of the 2theta (2 theta) value is in the range of 2theta +/-0.2 deg. (2 theta +/-0.2 deg.). Most preferably, the seed crystal shows an X-ray powder diffraction pattern as depicted in fig. 1. The crystalline form is shown herein as form 1.
Those skilled in the art are aware of the following facts: the relative peak intensities will show inter-device variability as well as variability due to crystallinity, preferred orientation, surface of the prepared sample, and other factors known to those skilled in the art, and should be considered merely qualitative measurements. Those of ordinary skill in the art will also appreciate that X-ray diffraction patterns may be obtained with measurement errors that depend on the measurement conditions employed. In particular, it is generally known that the intensity in an X-ray diffraction pattern may fluctuate depending on the measurement conditions employed. It should also be appreciated that the relative intensities may also vary depending on experimental conditions and, therefore, the exact intensity level should not be considered. In addition, the measurement error of the diffraction angle of the conventional X-ray diffraction pattern is generally about 5% or less, and the degree of the measurement error should be considered as related to the above-described diffraction angle.
Optionally, a waiting step may be performed after adding the seed crystal.
In some embodiments, the first calcium source is dissolved in solvent (b) and then added to solution (a). The dissolution of the starting celecoxib metabolite in solvent (a) and the dissolution of the calcium source in solvent (b) can be performed in parallel. The solution (b) relates to a solution of a calcium source in the solvent (b).
The first calcium source provides Ca 2+ Which is soluble in the solvent (b). In some embodiments, the first calcium source is selected from Ca (OAc) 2 Calcium propionate, calcium formate, and calcium pantothenate. In some embodiments, the first calcium source is selected from Ca (OAc) 2 Calcium propionate and armorAnd (3) acid calcium. In some embodiments, the first calcium source is Ca (OAc) 2 . In some embodiments, the first calcium source is calcium propionate. In some embodiments, the first calcium source is calcium formate. In some embodiments, the first calcium source is calcium pantothenate. The solvent (b) may be selected from water or a mixture of water and an organic solvent. The organic solvent may be one of the organic solvents listed above, or a mixture thereof. Thus, the ratio of water mixed with the organic solvent is higher, i.e., the ratio of water/organic solvent (weight/weight) is 100/0 to 50/50, or 100/0 to 55/45, or 100/0 to 70/30, or 100/0 to 75/25, or 100/0 to 80/20, or 100/0 to 90/10, or 100/0 to 95/5. Preferably, the solvent (b) is water.
The concentration of the first calcium source in the solvent (b) is not particularly limited. In one embodiment, the concentration of the first calcium source in the solution (b) is a saturated concentration or less, for example in the range of 0.5g of the first calcium source per 100g of the solvent (b) to 35g of the first calcium source per 100g of the solvent (b). In one embodiment, the concentration of the solution (b) is 35g of the first calcium source per 100g of the solvent (b) or less, for example between 1g of the first calcium source per 100g of the solvent (b) and 35g of the first calcium source per 100g of the solvent (b); or 1g of the first calcium source per 100g of the solvent (b) to 30g of the first calcium source per 100g of the solvent (b); or 1g of the first calcium source per 100g of the solvent (b) to 25g of the first calcium source per 100g of the solvent (b); or 1g of the first calcium source per 100g of the solvent (b) to 20g of the first calcium source per 100g of the solvent (b); or 1g of the first calcium source per 100g of the solvent (b) to 15g of the first calcium source per 100g of the solvent (b). For example, 35g of the first calcium source per 100g of water or less, for example, between 1g of the first calcium source per 100g of water and 35g of the first calcium source per 100g of water; or 1g of the first calcium source per 100g of water to 30g of the first calcium source per 100g of water; or 1g of the first calcium source per 100g of water to 25g of the first calcium source per 100g of water; or 1g of the first calcium source per 100g of water to 20g of the first calcium source per 100g of water; or in the range of 1g of the first calcium source per 100g of water to 15g of the first calcium source per 100g of water. For example, 5g of the first calcium source per 100g of water to 15g of the first calcium source per 100g of water; or 7g of the first calcium source per 100g of water to 13g of the first calcium source per 100g of water; or 9g + -5% of the first calcium source per 100g of water to 10g + -5% of the first calcium source per 100g of water.
The amount of the first calcium source added in step (c) and step (d) or to {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } acetic acid is 0.4mol/mol to 1mol/mol {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } acetic acid (raw material celecoxib metabolite), or 0.4mol/mol to 0.8mol/mol raw material, or 0.4mol/mol to 0.6mol/mol raw material, or 0.45mol/mol to 0.55mol/mol raw material, or 0.5mol/mol to 0.6mol/mol raw material, or 0.5mol/mol to 0.55mol/mol raw material, for example, 0.525mol/mol±5% mol/mol raw material.
Optionally, step (d) or the step of adding the first calcium source may be divided into two or more dosage steps. This means that the amount of the first calcium source is added in one or more doses. There may be a waiting step between the addition of the previous first calcium source dose and the subsequent first calcium source dose.
For example, in the first dosing step, the amount of the first calcium source may be from 5% to 50% of the total amount of the first calcium source, or from 5% to 40% of the total amount of the first calcium source, or from 5% to 35% of the total amount of the first calcium source, or from 5% to 30% of the total amount of the first calcium source, or from 5% to 25% of the total amount of the first calcium source, or from 10% to 20% of the total amount of the first calcium source, such as about 15% of the total amount of the first calcium source (it is understood that "about" means ± 10% of 15% is dissolved in the solvent (b)).
Optionally, a waiting or maturation step may be performed after the dosing step. For example, a waiting or maturation step of 1 to 48 hours may be performed after a first dose of 5 to 50% of the total amount of the first calcium source. The duration of the waiting step depends on the scale of the preparation batch and may be even longer. The waiting or curing step may range, for example, from 1 hour to 48 hours, from 1 hour to 24 hours, from 1 hour to 15 hours, from 1 hour to 12 hours, or from 1 hour to 10 hours.
In case only a part of the total amount of the first calcium source is added in the first dosing step, the remaining amount of the first calcium source may be added in the second or subsequent dosing steps. Preferably, the remaining amount of the first calcium source is added in the second dosing step.
The dosing of the first calcium source is preferably controlled linearly in each dose step.
Preferably, the mixture obtained in step (d) or the mixture of {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } acetic acid, the first calcium source and the solvent (a) is stirred for an additional at least 30 minutes, for example 30 minutes to 48 hours, 30 minutes to 24 hours, 30 minutes to 12 hours, or 30 minutes to 10 hours.
The solid product obtained is then isolated in step (e), for example by filtration or centrifugation.
Optionally, the product obtained in step (e) or the isolated solid product is washed with a solvent (c), preferably a mixture of water and an organic solvent, wherein the organic solvent is selected from the group of organic solvents as described above. The ratio is given in weight/weight%. Thus, the ratio of solvent (a)/water (weight/weight) may be 100/0 to 10/90, or 100/0 to 50/50, or 100/0 to 70/30. For example, the solvent (a) is a mixture of acetone/water in a ratio of 100/0 to 50/50, or a mixture of THF/water in a ratio of 100/0 to 10/90.
The addition and separation steps of each of steps (d) to (e) or the first calcium source and optional filtration and waiting/stirring steps are performed at a temperature of 20 ℃ to 85 ℃, e.g. at the temperature selected in step (b), e.g. at the final temperature of step (b) or at a lower temperature.
The resulting product may then be subjected to a drying step, preferably under vacuum and nitrogen purge. Preferably, the drying temperature is from 20 ℃ to 85 ℃, or from 25 ℃ to 85 ℃, e.g. from 30 ℃ to 80 ℃, or from 40 ℃ to 55 ℃, or from 45 ℃ to 55 ℃, e.g. at 50 ℃ ± 3 ℃.
Optionally, the process for preparing {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } calcium acetate of formula (I) may comprise a reslurrying step (f). This reslurrying step is suitable in case the product of step (e) contains an excess of starting {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } acetic acid, i.e. free {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } acetic acid, e.g. more than 2% of starting {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } acetic acid.
In this case, the product of step (e) or the isolated solid product may be reslurried in a solution of the second calcium source in solvent (b), preferably in a solution of the second calcium source in water, at a temperature in the range of 20 ℃ to 85 ℃.
The second calcium source provides Ca 2+ Which is soluble in the solvent (b). In some embodiments, the second calcium source is selected from Ca (OAc) 2 Calcium propionate, calcium formate, and calcium pantothenate. In some embodiments, the second calcium source is selected from Ca (OAc) 2 Calcium propionate, calcium formate. In some embodiments, the second calcium source is Ca (OAc) 2 . In some embodiments, the second calcium source is calcium propionate. In some embodiments, the second calcium source is calcium formate. In some embodiments, the second calcium source is calcium pantothenate.
The general conditions of the reslurry step are comparable to those of steps (c) to (e), although the conditions need not be chosen exactly the same as those of the preceding step, but may vary within the general ranges given above. This means that the temperature is preferably the same as the temperature in step (b), e.g. the final temperature of step (b). Furthermore, the solvent and concentration of the second calcium source are preferably the same as in step (c), e.g. the solvent is water.
The product obtained in step (f) is isolated in the same way as in step (e), preferably with purified water and under the same drying conditions as the primary crystals are isolated.
{4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino group of formula (I) obtained by the process of the present invention]Calcium butoxy acetate is characterized by high purity, in particular with regard to excess Ca originating from the preparation process, i.e. from the inorganic calcium salt used as starting material 2+ . For example, ca (OH) is used 2 The process as starting material produces excess residual Ca (OH) 2 It remains in the product. This can be avoided by the present method. {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino group of formula (I) obtainable by the present process]Calcium butoxy acetate characterized by Ca 2+ The content is 7.0.+ -. 0.1 wt./wt.% or less, or Ca 2+ The content is 6.0.+ -. 0.1 wt./wt.% or less, or Ca 2+ The content is 5.5.+ -. 0.1 wt./wt.% or less, or Ca 2+ The content is 5.0.+ -. 0.1 wt./wt.% or less. For example, ca 2+ The content is 7.0 + -0.1 wt/wt% to 4.0±0.1 wt/wt%, or 7.0±0.1 wt/wt% to 4.1±0.1 wt/wt%, or 6.0±0.1 wt/wt% to 4.0±0.1 wt/wt%, or 6.0±0.1 wt/wt% to 4.1±0.1 wt/wt%, or 5.5±0.1 wt/wt% to 4.0±0.1 wt/wt%, or 5.5±0.1 wt/wt% to 4.1±0.1 wt/wt%, or 5.0±0.1 wt/wt% to 4.0±0.1 wt/wt%, or 5.0±0.1 wt/wt% to 4.1±0.1 wt/wt%. Ca (Ca) 2+ The content is measured by ion chromatography, as is well known in the art. Suitable measurement methods are exemplified in the experimental section.
The invention thus also relates to a product obtainable by the process described herein.
The products obtainable by the process according to the invention are particularly suitable for the preparation of long-acting formulations. This is shown in example 8, demonstrating the feasibility of a long-acting formulation of calcium {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } acetate compared to celecoxib and the celecoxib metabolite {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } acetic acid.
Furthermore, the following crystalline forms of {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } calcium acetate are disclosed:
(i) Crystalline form 2 of {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } -acetic acid calcium of formula (I) has an X-ray powder diffraction pattern in which at least five peaks have a refraction angle 2θ (2 theta) value selected from the group consisting of: 3.2 °, 6.3 °, 7.7 °, 9.3 °, 10.4 °, 11.6 °, 24.0 ° 2theta; preferably at least five peaks, or at least seven peaks, or at least nine peaks are selected from: 3.2 °, 6.3 °, 7.7 °, 9.3 °, 10.0 °, 10.4 °, 11.6 °, 12.7 °, 19.2 °, 22.9 °, 24.0 ° 2theta; in particular, at least five peaks, or at least seven peaks, or at least nine peaks are selected from: 3.2 °, 6.3 °, 7.7 °, 9.3 °, 10.0 °, 10.4 °, 11.6 °, 12.7 °, 13.8 °, 15.7 °, 17.5 °, 19.2 °, 20.2 °, 21.3 °, 22.9 °, 23.4 °, 24.0 °, 25.2 °, 2theta,
Wherein the X-ray powder diffraction pattern is obtained by using Cu ka 1 radiation (in the case of ka 2 exfoliation); and the accuracy of the 2theta (2 theta) value is in the range of 2theta +/-0.2 deg. (2 theta +/-0.2 deg.).
In particular, crystalline form 2 shows an X-ray powder diffraction pattern in which the following peaks, and their relative intensities given in brackets: 3.2 ° (100%), 6.3 ° (21%), 7.7 ° (21%), 9.3 ° (34%), 10.0 ° (35%), 10.4 ° (9%), 11.6 ° (5%), 12.7 ° (26%), 13.8 ° (7%), 15.7 ° (12%), 17.5 ° (8%), 19.2 ° (20%), 20.2 ° (12%), 21.3 ° (8%), 22.9 ° (17%), 23.4 ° (13%), 24.0 ° (14%), 25.2 ° -2 theta (6%).
(ii) Crystalline form 3 of {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } -acetic acid calcium of formula (I) has an X-ray powder diffraction pattern, wherein the peak has a refraction angle 2θ (2 theta) value selected from the group consisting of: 4.5 °, 7.9 °, or 11.9 ° 2θ; preferably at least five peaks, or at least seven peaks, or at least nine peaks are selected from: 4.5 °, 4.8 °, 5.0 °, 7.9 °, 10.0 °, 11.9 °, 14.9 °, 15.6 °, 17.1 °, 18.7 °, 22.1 °, and 22.7 ° 2theta; in particular, at least five peaks, or at least seven peaks, or at least nine peaks are selected from: 4.5 °, 4.8 °, 5.0 °, 7.9 °, 8.8 °, 9.0 °, 10.0 °, 11.9 °, 14.9 °, 15.6 °, 17.1 °, 18.7 °, 19.7 °, 20.7 °, 21.1 °, 22.1 °, 22.7 °, 23.9 °, 24.5 °, 26.1 °, 2theta,
Wherein the X-ray powder diffraction pattern is obtained by using combined Cu ka 1 and ka 2 (Kalpha 2) radiation without ka 2 stripping; and the accuracy of the 2theta (2 theta) value is in the range of 2theta +/-0.2 deg. (2 theta +/-0.2 deg.).
In particular, crystalline form 3 shows an X-ray powder diffraction pattern in which the following peaks, and their relative intensities given in brackets: 4.5 ° (100%), 4.8 ° (60%), 5.0 ° (56%), 7.9 ° (36%), 8.8 ° (47%), 9.0 ° (53%), 10.0 ° (74%), 11.9 ° (46%), 14.9 ° (50%), 15.6 ° (69%), 17.1 ° (43%), 18.7 ° (100%), 19.7 ° (33%), 20.7 ° (30%), 21.1 ° (17%), 22.1 ° (38%), 22.7 ° (34%), 23.9 ° (22%), 24.5 ° (12%), 26.1 ° (2 theta (12%).
Crystalline form 3 is a isomorphic solvate.
(iii) Crystalline form 5 of {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } calcium acetate of formula (I) has an X-ray powder diffraction pattern in which at least five peaks, or at least seven peaks, or at least nine peaks, have refractive angle 2θ (2θ) values selected from: 4.9 °, 8.8 °, 9.8 °, 11.0 °, 12.8 °, 13.1 °, 16.9 °, 19.5 °, 21.1 °, 21.5 °, and 22.6 ° 2theta; in particular, at least 5 peaks, or at least 7 peaks, or at least 9 peaks, have a refraction angle 2θ (2θ) value selected from: 4.9 °, 8.8 °, 9.8 °, 11.0 °, 12.8 °, 13.1 °, 13.3 °, 14.7 °, 15.7 °, 16.1 °, 16.7 °, 16.9 °, 17.8 °, 18.2 °, 18.7 °, 19.0 °, 19.5 °, 20.1 °, 20.6 °, 21.1 °, 21.5 °, 22.6 °, 23.6 °, 26.3 °, 30.3 °, 2theta,
Wherein the X-ray powder diffraction pattern is obtained by using Cu ka 1 radiation (in the case of ka 2 exfoliation); and the accuracy of the 2theta (2 theta) value is in the range of 2theta +/-0.2 deg. (2 theta +/-0.2 deg.).
In particular, crystalline form 5 shows an X-ray powder diffraction pattern in which the following peaks, and their relative intensities given in brackets: 4.9 ° (25%), 8.8 ° (49%), 9.8 ° (100%), 11.0 ° (44%), 12.8 ° (21%), 13.1 ° (23%), 13.3 ° (17%), 14.7 ° (12%), 15.7 ° (17%), 16.1 ° (8%), 16.7 ° (17%), 16.9 ° (29%), 17.8 ° (5%), 18.2 ° (4%), 18.7 ° (10%), 19.0 ° (8%), 19.5 ° (43%), 20.1 ° (11%), 20.6 ° (10%), 21.1 ° (38%), 21.5 ° (22%), 22.6 ° (20%), 23.6 ° (12%), 26.3 ° (10%), 30.3 °. 2theta (7%).
It will be appreciated that the crystalline form of {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } -acetic acid calcium salt of formula (I) may comprise non-coordinating and/or coordinating solvents. The coordinating solvent is used herein as a term for crystalline solvates. Likewise, non-coordinating solvents are used herein as terms for physically adsorbing or physically trapping solvents (according to Polymorphismin the Pharmaceutical Industry (R. Hilfiker, eds., VCH, 2006), chapter 8: U.J. Griesser: the Importance of Solvates).
In particular, crystalline form 1 is a hydrate. Containing about 0.25 equivalent of H 2 O (about mean ± 10%, e.g. ± 5%).
In particular, crystalline form 2 is anhydrous, i.e., it does not contain coordinated water, but may contain non-coordinated methanol.
In particular, crystalline form 3 is an isomorphic solvate, i.e., it contains coordinated anisole or toluene.
In particular, crystalline form 5 is anhydrate.
Furthermore, one embodiment relates to a pharmaceutical composition comprising {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } -calcium acetate in crystalline form 2, crystalline form 3 or crystalline form 5 as described herein.
One embodiment relates to {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } -calcium acetate of formula (I) as prepared by the methods described herein for the prevention and/or treatment of a disease and/or disorder selected from the group consisting of: ulcers, finger ulcers, diabetic gangrene, diabetic foot ulcers, pressure ulcers (bedsores), hypertension, pulmonary arterial hypertension, chronic embolic pulmonary arterial hypertension, fang Tan disease and pulmonary hypertension associated with Fang Tan disease, sarcoidosis and pulmonary hypertension associated with sarcoidosis, peripheral circulatory disorders (e.g., chronic arterial occlusion, intermittent claudication, peripheral embolism, shock syndrome, raynaud's disease), connective tissue diseases (e.g., systemic lupus erythematosus, scleroderma, mixed connective tissue diseases, vasculitis syndrome), post Percutaneous Transluminal Coronary Angioplasty (PTCA) reocclusion/restenosis, arteriosclerosis, thrombosis (e.g., acute cerebral thrombosis, pulmonary embolism), transient cerebral ischemic attacks (TIAs), diabetic neuropathy, ischemic conditions (e.g., cerebral infarction, myocardial infarction), angina (e.g., stable angina, unstable angina), chronic kidney disease including glomerulonephritis and diabetic nephropathy at any stage, allergies, bronchial asthma, coronary interventions such as atherectomy and restenosis after stent implantation, thrombocytopenia due to dialysis, diseases involving organ or tissue fibrosis (e.g., kidney diseases such as tubular interstitial nephritis), respiratory diseases (e.g., interstitial pneumonia, (idiopathic) pulmonary fibrosis, chronic obstructive pulmonary disease), digestive system diseases (e.g., liver cirrhosis, viral hepatitis, chronic pancreatitis and hard gastric cancer), cardiovascular diseases (e.g., myocardial fibrosis), bone and joint diseases (e.g., myelofibrosis and rheumatoid arthritis), skin diseases (e.g., postoperative scars, scald scars, keloids, and hypertrophic scars), obstetric diseases (e.g., uterine fibroids), urinary system diseases (e.g., prostatic hyperplasia), other diseases (e.g., alzheimer's disease, sclerosing peritonitis, type I diabetes, and postoperative organ adhesions), erectile dysfunction (e.g., diabetic erectile dysfunction, cardiac erectile dysfunction, psychotic erectile dysfunction, erectile dysfunction associated with chronic kidney failure, post-pelvic surgical erectile dysfunction for removal of the prostate, and vascular erectile dysfunction associated with aging and arteriosclerosis), inflammatory bowel diseases (e.g., ulcerative colitis, crohn's disease, intestinal tuberculosis, ischemic colitis, and intestinal ulcers associated with white plug disease), gastritis, gastric ulcers, ischemic ocular diseases (e.g., retinal artery occlusion, retinal vein occlusion, ischemic optic neuropathy), sudden ear necrosis, non-vascular osteonecrosis, and inflammatory lesions associated with the administration of non-vascular osteogenic agents, and symptoms associated with the stenosis.
Preferred diseases and/or disorders are selected from: ulcers, finger ulcers, diabetic gangrene, diabetic foot ulcers, pulmonary hypertension, pulmonary arterial hypertension, chronic embolic pulmonary arterial hypertension, fang Tan disease and pulmonary hypertension associated with Fang Tan disease, sarcoidosis and pulmonary hypertension associated with sarcoidosis, peripheral circulatory disorders, connective tissue disease, chronic kidney disease including glomerulonephritis and diabetic nephropathy at any stage, diseases involving fibrosis of organs or tissues, or respiratory diseases.
Pulmonary Arterial Hypertension (PAH) is particularly preferred. Particularly preferred is chronic embolic pulmonary arterial hypertension (CTEPH),
the {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } -acetic acid calcium of formula (I) prepared by the process described herein has high purity. This is particularly important for the preparation of injectables, such as long-acting injectables.
Thus, the {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } -calcium acetate obtainable by the methods described herein is particularly useful in the treatment of the above-described diseases and/or disorders, preferably in intramuscular or subcutaneous injection. Thus, the injection is a long-acting injection (LAI). The term "long-acting injection" is used herein for administration intervals of one week to three months, or 1 week to two months, or 1 week to one month, or 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks.
The present invention also relates to a method of treating a subject suffering from the above-described diseases and/or disorders, particularly PAH, comprising administering a therapeutically effective amount of {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } -calcium acetate obtainable by the methods described herein. Preferably, the method comprises administering {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } -calcium acetate obtainable by a method as described herein via intramuscular injection or subcutaneous injection.
The term "therapeutically effective amount" refers to an amount or concentration of {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } -calcium acetate which produces effective plasma levels for treatment of the indicated disease, particularly PAH. For example, a therapeutically effective amount may be from 1mg to 200mg, such as from 2mg to 150mg or from 5mg to 100mg, and especially from 25mg to 100mg of {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } calcium acetate per month. By "effective plasma levels" is meant those plasma levels of {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } acetic acid which provide effective treatment or effective prevention of the indicated diseases and/or disorders, particularly PAH.
In particular, the term "subject" relates to a human.
All documents cited herein are incorporated by reference in their entirety.
The following examples are intended to illustrate the invention and should not be construed as limiting the invention thereto.
Where present, all ranges are inclusive and combinable. That is, a reference to a value specified in a range includes every value within that range. For example, a range defined as 400ppm to 450ppm includes 400ppm and 450ppm as separate embodiments. The ranges of 400ppm to 450ppm and 450ppm to 500ppm can be combined into the range of 400ppm to 500 ppm.
Examples
Abbreviations (as used herein and in the description above):
ADME absorption, distribution, metabolism, and excretion
API active pharmaceutical ingredient
aq. Water-containing
h hours
HPLC high performance liquid chromatography
Ion chromatography of IC Ca for calcium determination
IM intramuscular injection
International naming of INCI cosmetic ingredients
INN International nonproprietary name
IP receptor prostacyclin receptor
ISO International organization for standardization
LAI long-acting injection
LC assay liquid chromatography-quantitative analysis
min
mM millimoles
PAH pulmonary hypertension
CTEPH chronic embolic pulmonary hypertension
pK pharmacokinetics
PVP polyvinylpyrrolidone
Proper amount (enough)
RH relative humidity
RT room temperature
SC subcutaneous
UPLC ultra-high performance liquid chromatography
WFI (Water-Fidelity) injection water
WHO world health organization
w/v weight/volume
w/w weight/weight
weight by weight
XRPD X-ray powder diffraction
X-ray powder diffraction analysis (XRPD)
XRPD method：
XRPD diffractograms of form 1 were collected on a PANalytical (Philips) X' PertPRO MPD diffractometer. The instrument is equipped with a Cu LFF X-ray tube.
The compounds were coated on zero background sample holders.
Instrument parameters
Generator voltage: 45kV
Generator current: 40mA
Geometry: bragg-Brentano
Stage: rotational phase
Measurement conditions
Scanning mode: continuous scanning
Scanning range: 3 DEG to 50 DEG 2theta
Step size: 0.02 DEG/step
Counting time: 30 seconds/step
Rotation time of the rotator: 1 second
Radiation type: cuKa
XRPD diffractograms of form 2 were collected on a Bruker D8 diffractometer using Cu ka radiation (40 kv,40 ma) and a theta-2θ (theta-2 theta) goniometer equipped with a Ge monochromator. The incident beam passes through a 2.0mm diverging slit, followed by a 0.2mm anti-scatter slit and knife edge (knifeedge). The diffracted beam passed through an 8.0mm receiving slit with a 2.5 ° soxhlet slit, followed by a lynxey detector. The software used for data collection and analysis was Diffrac Plus XRD Commander and Diffrac Plus EVA, respectively.
Samples were run under ambient conditions as flat plate samples using powder. Samples were prepared on polished zero background (510) silicon wafers by gently pressing onto a flat surface or loading into a dicing chamber. The sample rotates on its own plane.
Detailed information：
-angular range 2 DEG to 42 DEG 2theta (theta)
Step size: 0.05 degree 2theta (theta)
Collection time: 0.5 seconds/step (total collection time: 6.40 minutes)
In transmission geometry, XRPD diffractograms of form 3 were collected on a PANalytical Empyrean diffractometer using Cu ka radiation (40 kv,40 ma). A 0.5 ° slit, a 4mm mask, and a 0.04rad soller slit and focusing mirror were used on the incident beam. PIXcel placed on diffracted beam 3D The detector was equipped with a receiving slit and a 0.04raf soller slit. The software for data collection is an X 'Pert data collector using an X' Pert operator interface. Data was analyzed and presented using Diffrac Plus EVA or HighScore Plus. Samples were prepared and analyzed in a transmission mode in a metal 96-well plate. An X-ray transparent film was used between the metal sheets on the metal orifice plate, and a powder (about 1mg-2 mg) was used.
The scanning mode of the metal plate uses a gonio scanning axis, whereas a 2 theta (theta) scan is used for the microplate.
Detailed information of standard screening data collection method:
-angular range: 2.5 DEG to 32.0 DEG 2 theta (theta)
Step size: 0.0130 degree 2 theta (theta)
Collection time: 12.75 seconds/step (total collection time: 2.07 minutes)
XRPD diffractograms of form 5 were collected on a Bruker D8 diffractometer (Bruker D8 Advance).
XRPD method：
A detector: LYNXEYE_XE_T (1D mode)
Opening angle: 2.94 degree
Scanning mode: continuous PSD fast
Radiation: cu/K- α1 (γ=1.5418 angstroms)
X-ray generator power: 40kV,40mA
Step size: 0.02 degree
Time per step: 0.12 seconds per step
Scanning range: 3 DEG to 40 DEG
Primary beam path slit: double-main electric slit 10.0mm SollerMountaxial soller 2.5.5 deg. based on sample length
Secondary beam path slit: detector optics mount soller slit 2.5 °; double-secondary electric slit 5.2mm
Sample rotation speed: 15rpm
Differential scanning calorimetric analysis (DSC)
DSC data of form 2 (and form 3, respectively) were collected on a TA instrument Q2000 equipped with a 50-bit autosampler. 1.5mg of form 2 material (1.7 mg in the case of form 3) was weighed into a pinhole aluminum pan and heated from 25 ℃ to 250 ℃ at 10 ℃/min. A nitrogen purge of 50mL/min was maintained on the sample. The peak temperature of the melting point was recorded.
Thermogravimetric analysis (TGA)
TGA data of form 2 (and form 3, respectively) were collected on TA instrument Q500 equipped with a 16-bit autosampler. About 5mg to 10mg of the sample (7.7 mg in the case of form 2; 6.0mg in the case of form 3) is typically loaded onto a pre-tared aluminum pan and heated from 25 ℃ to 350 ℃ at 10 ℃/min. A nitrogen purge of 60mL min-1 was maintained on the sample.
Ion chromatography
The calcium content was determined using ion chromatography. By firing at 50mL10mg of the sample was weighed in a bottle for sample preparation. Approximately 25mL MeOH, H was added 2 O (50:50 v/v) then a few drops of concentrated aqueous HCl solution were added until a homogeneous solution was obtained (the solution turned yellow). MeOH H was used 2 O (50: 50 v/v) further dilutes the sample to volume. The resulting solution was diluted 2-fold by pipetting 10mL into a 20mL flask and diluting with the same dilution solvent. Analysis was performed using Thermoscientific Dionex IC 5000+ ion chromatography using a conductivity detector operating at 35 ℃. The separation was performed on a Dionex IonPac CS12A (2 mmx250 mm) analytical column coupled with a Dionex IonPac CG12A (2 mmx250 mm) guard column using a column temperature of 30 ℃. The eluent generator cartridge was used to generate eluent methanesulfonic acid (MSA) delivered at a constant concentration of 20mM at a flow rate of 0.25mL/min during 15 minutes. Inhibition was performed using a Dionex CDR 600 2mm inhibitor operating at 15 mA. Calibration was performed using standard cationic solutions containing Li, na, K, mg and Ca at 0.5ppm, 1.0ppm, 2.5ppm, 5.0ppm and 10ppm weight/weight. They were prepared from commercially available 10ppm IC cation standard solutions (Merck) by dilution with MilliQ water. Analysis was performed using a sample volume of 10 μl. The analytical error was 0.1%. Ca (Ca) 2+ Results are provided in weight/weight%. The concentration of the analyte was calculated automatically by Chromeleon software.
In the case of products containing water or other residual solvents, or in the presence of a slight excess of the celecoxib metabolite, ca 2+ The content may be below the theoretical 4.5693 wt/wt%.
Examples：
Example 1: preparation of {4- [ (5, 6-diphenylpyrazin-2-yl) (propan-2-yl) amino ] without seeding]Butyl Calcium oxy } acetate：
12g (28.604 mmol) of {4- [ (5, 6-diphenylpyrazin-2-yl) (propan-2-yl) amino group]Butoxy } acetic acid was added to a two-piece 400ml reactor and 145.34g acetone/water (95/5 wt/wt%). Gradual stirring was applied to a speed of 400rpm and the reactor was heated to 50℃at 1K/min and held at that temperature for 30 minutes. Then, at 30 minutes15 vol% (4.2 ml) Ca (OAc) was added thereto 2 ×1/2H 2 O-dissolved solution in Water (2.51 g (15.012 mmol) Ca (OAc) in 26.66g water) 2 ×1/2H 2 O stock solution)). The mixture was kept for 8 hours. Then, the remaining Ca (OAc) was added over 2 hours 2 A stock solution dissolved in water. The mixture was stirred for 7.75 hours and the resulting solid was filtered off and washed with 24g (2 g/g) acetone/water 80/20 wt/wt% at 50 ℃. Vacuum and N at 50deg.C 2 After drying under a purge, 12.46g of crystalline {4- [ (5, 6-diphenylpyrazin-2-yl) (propan-2-yl) amino are obtained]-calcium butoxy } acetate (99.3%) (crystalline form 1). IC Ca 2+ 4.41 wt./wt.%.
Example 2: preparation of {4- [ (5, 6-diphenylpyrazin-2-yl) (propan-2-yl) amino ] in the case of Vaccination]-butyl Calcium oxy } acetate：
Stage 1: dissolving
1.6kg (3.814 mol) of {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } acetic acid were dissolved in 17.7776kg of acetone/purified water 95/5 wt/wt%. The reactor was heated to a reactor temperature of 50℃at 1K/min and then stirred for a further 30 minutes.
Stage 2: polishing and filtering
A polish filtration step (0.5 micron CUNO filter) was performed and the reactor was heated to a reactor temperature of 50 ℃ as quickly as possible. The polishing filter was washed with 0.8kg acetone/purified water 95/5 wt/wt%.
2 Stage 3: inoculation and first dosing of Ca (OAc)
Then, 16g of {4- [ (5, 6-diphenylpyrazin-2-yl) (propan-2-yl) amino group was used]Crystals of calcium butoxy } acetate (1 wt/wt%, based on 1.6kg of raw material) were inoculated into the solution and left to stand for 90 minutes. Then, 15 wt% Ca (OAc) 2 ×1/2H 2 O in purified water (containing 317.64g (1.900 mol) Ca (OAc) in 3.5552kg of water) 2 Stock solution of x 1/2H 2O) was dosed linearly into the mixture over 70 minutes. The mixture was cured for 17 hours.
2 Stage 4: second dosing of Ca (OAc)
Then, the remaining 85% by weight of Ca (OAc) was dosed linearly over 271 minutes 2 A solution dissolved in purified water. The mixture was stirred for 19 hours.
Stage 5: filtering and drying
The solid obtained was filtered and the filtrate was washed with 3.2kg acetone/purified water 80/20 wt/wt% at 50 ℃. Vacuum and N at 50deg.C 2 Dried under purge and homogenized on a 2mm sieve. 1.481kg of {4- [ (5, 6-diphenylpyrazin-2-yl) (propan-2-yl) amino group were obtained]Butoxy calcium acetate (as defined in formula (I)) (88.5% yield).
Optional reslurry stage 6：
In the case where the product of stage 5 has a content of free {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } acetic acid of greater than 2%, then the reslurry step can be performed as follows:
the product obtained above (1.481 kg) (after stage 5) was purified at 3.2kg Ca (OAc) 2 Reslurry (concentration=10 g/100 g) in solution in purified water. It was heated to 50℃at a rate of 1K/min, after which it was stirred for 12 hours. Then cooled to 20℃at a rate of 0.5K/min and stirred for 4 hours. It was filtered and washed 2 times with 16kg of purified water at 50℃under vacuum and N 2 Drying under purging. After drying, it was homogenized on a 2mm sieve. Yield: 1.377kg (yield=93.0%) IC Ca 2 + :4.20 wt./wt.%
2 Example 3: preparation of {4- [ (5, 6-diphenylpyrazin-2-yl) (propan-2-yl) amino Using Ca (OH)]-butoxy Calcium radical } acetate
59.9g of {4- [ (5, 6-diphenylpyrazin-2-yl) (propan-2-yl) amino group was reacted with]Butoxy } acetic acid, 10.6g calcium hydroxide (1 molar equivalent) and 1.5L EtOH/water 50/50 vol% were added to the reactor. It was dissolved at 50℃and stirred for 2 days. After 2 hours, the solution was cooled to 20 ℃. The solids were isolated by vacuum filtration and air dried for 5 minutesAnd then dried in a vacuum oven at 50 c for 16 hours. 64g (102%) of {4- [ (5, 6-diphenylpyrazin-2-yl) (propan-2-yl) amino are isolated]Calcium-butoxy } acetate (still containing residual Ca (OH) 2 )。IC Ca 2+ :7.57 wt./wt.%
Example 4: preparation of {4- [ (5, 6-diphenylpyrazin-2-yl) (propan-2-yl) amino in amorphous form]Butoxy (butoxy) Calcium radical } acetate
Calcium 4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } acetate (30 g) (obtained from a batch similar to example 3) was heated in an oven to 210 ℃ for 20 minutes until the sample melted. The molten material was then rapidly cooled to-18 ℃ to obtain glass.
The anhydrous form remained physically stable (amorphous) after storage for 7 days at 25 ℃/97% rh and 40 ℃/75% rh.
Example 5: preparation of {4- [ (5, 6-diphenylpyrazin-2-yl) (propan-2-yl) amino ] form 2]Butoxy acetic acid Calcium
To amorphous {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } calcium acetate (30 mg) was added 0.6mL of methanol, and the sample was slurried in a platform shaker incubator at 60 ℃ for 6 days, and the resulting solid was isolated as form 2.
Form 2 is an anhydrous form which melts at 175.6 ℃ with a heat of fusion of 46J/g. It contains an additional endotherm (5J/g) at 122.9 ℃. TGA analysis showed a weight loss due to water loss of 0.3% between RT-100 ℃ and 1.0% between 100 ℃ and 200 ℃.
Form 2 is slightly hygroscopic (showing a reversible 2% mass change between 0% and 90% rh) and physically stable after 7 days of storage at 25 ℃/97% rh and 40 ℃/75% rh.
The X-ray pattern, DCS and TGA are shown in fig. 2, 3 and 4.
Example 6: preparation of {4- [ (5, 6-diphenylpyrazin-2-yl) (propan-2-yl) amino ] form 3]Butoxy acetic acid Calcium
To amorphous {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } calcium acetate (300 mg) was added 6mL anisole, and the sample was stirred at 60℃for 8 days at 500 rpm. The resulting white suspension was isolated by filtration and dried overnight in a vacuum oven at room temperature to give form 3.
Form 3 is shown as a set of isomorphic solvates separated from toluene and anisole, i.e. it is also obtained by the same procedure using toluene.
TGA analysis showed a weight loss of 10.8% (RT-190 ℃) and 1.1% (between 190 ℃ and 270 ℃) (total mass loss 10.9%, equal to 0.5 molar equivalent anisole). DSC shows a broad endothermic signal with a maximum (87J/g) at 164.9 ℃ due to melting/disintegration of solvated form. An additional endothermic signal was observed at 196.2 ℃ (3J/g) during further heating and corresponds to melting of form 1.
The X-ray pattern, DSC and TGA of form 3 are shown in figures 5,6 and 7.
Example 7: preparation of {4- [ (5, 6-diphenylpyrazin-2-yl) (propan-2-yl) amino ] form 5]Butoxy acetic acid Calcium
Form 5 is the dehydration product of form 1 and is obtained from variable temperature XRD experiments performed on form 1. Form 1 is converted to form 5 at a temperature of 190 ℃ (RT to 190 ℃ and hold for 2 minutes; 190 ℃ to 25 ℃ and hold for 2 minutes); when the temperature returns to 25 ℃, form 5 is converted back to form 1. The results also indicate that hydrate form 1 exhibits reversible dehydration-hydration behavior.
The X-ray pattern of form 5 is shown in fig. 8.
Example 8: feasibility pK rat study
Initial pK rat studies were performed to demonstrate the LAI potential of aqueous microsuspensions of {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } calcium acetate. For this study, an aqueous microsuspension of calcium celecoxib, {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } acetic acid, {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } acetate was prepared. An overview of the study design can be found in table 1.
TABLE 1 pK rat study design (ADME) showing LAI feasibility
The release profile and average AUC for the different formulations are depicted in figure 9.
As shown in fig. 9, the study group taking the calcium salt of ACT-333679 exhibited significantly lower plasma concentrations than the other two groups, which exhibited a long-acting release profile of up to 336 hours (i.e., 14 days), and AUC increased up to 720 hours. Sailexipa and its metabolites (group F and group H) do not exhibit long-acting release profile due to their high solubility and high dissolution rate.
Example 9: preparation of {4- [ (5, 6-diphenylpyrazin-2-yl) (propan-2- ] using other calcium sources with high water solubility Radical) amino group]-butoxy } acetic acid calcium salt：
6.9g {4- [ (5, 6-diphenylpyrazin-2-yl) (propan-2-yl) amino ] butoxy } acetic acid was dissolved in 100g acetone/purified water 95/5 wt./wt.% at 50 ℃. A first calcium source (0.5 mol/mol) dissolved in water was added to the mixture at a rate of 0.1mL/min until the acetone/water ratio was 70/30 wt/wt%. The mixture was stirred for 4 hours. The solids were separated at 50℃and washed with 2g/g acetone/water 70/30 wt/wt%. The product was dried at 50 ℃. The results are shown in Table 2.
TABLE 2：
Calcium source IC Ca LC assay LC impurity Yield (% F/F) XRD pattern
Calcium propionate 4.31％ 99.5％ Without any means for 92.8％ Form 1
Calcium formate 4.31％ 101.6％ Without any means for 86.1％ Form 1
Calcium hypophosphite 22.0％ 0.40％ Without any means for 15.3％ *
Calcium pyruvate 8.17％ 63.7％ Without any means for 23.6％ Form 1
L-calcium lactate hydrate 5.73％ 78.7％ Without any means for 63.1％ Form 1
* Indicating the form of unidentified material due to low yield
Example 10: preparation of {4- [ (5, 6-diphenylpyrazin-2-yl) (propan- ] using other calcium sources with high water solubility 2-yl) amino group]-butoxy } acetic acid calcium salt：
6.9g {4- [ (5, 6-diphenylpyrazin-2-yl) (propan-2-yl) amino ] butoxy } acetic acid was dissolved in 100g acetone/purified water 80/20 wt/wt% at 50 ℃. A first calcium source (0.5 mol/mol) dissolved in water was added to the mixture at a rate of 0.1mL/min until the acetone/water ratio was 55/45 wt/wt%. The mixture was stirred for 4 hours. The solid was isolated at 50℃and washed with 2g/g acetone/water 55/45 wt/wt%. The product was dried at 50 ℃. The results are shown in Table 3.
TABLE 3 Table 3：
Example 11: preparation of {4- [ (5, 6-diphenylpyrazine-2- ] using other calcium sources with moderate water solubility in water Radical) (propan-2-yl) amino group]Butoxy acetic acid calcium salt：
1g {4- [ (5, 6-diphenylpyrazin-2-yl) (propan-2-yl) amino ] butoxy } acetic acid was dissolved in 100g acetone/purified water 80/20 wt/wt% at 50 ℃. A first calcium source (0.5 mol/mol) dissolved in water was added to the mixture over 4 hours until the acetone/water ratio was 55/45 wt/wt%. The mixture was stirred for 17-22 hours. The solid was isolated at 50℃and washed with 2g/g acetone/water 55/45 wt/wt%. The product was dried at 50 ℃. The results are shown in Table 4.
TABLE 4 Table 4：
* Form of undetermined material due to low yield
n.d. =form of undetermined material
Example 12: preparation of {4- [ (5, 6-diphenylpyrazin-2-yl) (propan- ] using other calcium sources with low water solubility 2-yl) amino group]-butoxy } acetic acid calcium salt：
1g {4- [ (5, 6-diphenylpyrazin-2-yl) (propan-2-yl) amino ] butoxy } acetic acid was stirred in 100g acetone/purified water 70/30 wt./wt.% and 0.5mol/mol of the first calcium source at 50℃for 5 days. The solids were separated at 50℃and washed with 2g/g acetone/water 70/30 wt/wt%. The product was dried at 50 ℃. The results are shown in Table 5.
TABLE 5：
* Form of undetermined material due to low yield
n.d. =form of undetermined material

Claims (23)

1. A process for preparing {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } calcium acetate of formula (I), or a pharmaceutically acceptable hydrate or solvate thereof:
the method comprises the following steps:
mixing {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } acetic acid and a first calcium source with a solvent (a) to obtain a mixture;
heating or maintaining the mixture at a temperature in the range of 20 ℃ to 85 ℃;
separating the solid product obtained; and
optionally, reslurrying the separated solid product in a solution of the second calcium source in solvent (b) at a temperature in the range of 20 ℃ to 85 ℃.
2. The method of claim 1, wherein the step of mixing comprises:
mixing {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } acetic acid with solvent (a) to obtain a mixture; and
the mixture is heated or maintained at a temperature in the range of 20 ℃ to 85 ℃ prior to the addition of the first calcium source.
3. The process according to claim 1, wherein the first calcium source is dissolved in a solvent (b) to obtain a solution (b), and then the solution (b) is added to a mixture of {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } acetic acid and the solvent (a).
4. The method of claim 1, wherein the steps include:
(1) Dissolving {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } acetic acid in solvent (a) to obtain solution (a);
(2) Heating the solution (a) to a temperature in the range of 20 ℃ to 85 ℃;
(3) Dissolving a first calcium source in a solvent (b) to obtain a solution (b);
(4) Dosing the solution (b) into the solution (a);
(5) Separating the solid product obtained; and
(6) The product of step (5) is reslurried in a solution of a second calcium source in solvent (b), optionally at a temperature in the range of 20 ℃ to 85 ℃.
5. The method of claim 1, wherein the first calcium source is added in an amount of 0.4 to 1mol/mol {4- [ (5, 6-diphenylpyrazin-2-yl) (propan-2-yl) amino ] butoxy } acetic acid, or 0.4 to 0.8mol/mol {4- [ (5, 6-diphenylpyrazin-2-yl) (propan-2-yl) amino ] butoxy } acetic acid, or 0.4 to 0.6mol/mol {4- [ (5, 6-diphenylpyrazin-2-yl) (propan-2-yl) amino ] butoxy } acetic acid, or 0.45 to 0.55mol/mol {4- [ (5, 6-diphenylpyrazin-2-yl) (propan-2-yl) amino ] butoxy } acetic acid, or 0.5 to 0.6mol {4- [ (5, 6-diphenylpyrazin-2-yl) (propan-2-yl) amino ] butoxy } acetic acid.
6. The method of any one of claims 1 to 5, wherein the first calcium source is added in two or more doses.
7. The process according to any one of claims 1 to 6, wherein the solvent (a) is an organic solvent or an organic solvent mixed with water.
8. The method of claim 7, wherein the organic solvent in solvent (a) is selected from the group consisting of: acetone, tetrahydrofuran (THF), acetonitrile, MEK (methyl ethyl ketone), DMSO, DMF, 1, 4-dioxane, pyridine, dimethylacetamide (DMA), methyl acetate (MeOAc), methanol, ethanol, propanol (1-propanol or 2-propanol) and butanol (1-butanol, 2-methylpropan-1-ol or 2-methylpropan-ol).
9. The method of claim 4, wherein the solution (a) is subjected to a filtration step.
10. The process according to any one of claims 1 to 9, wherein solvent (b) is selected from water or a mixture of water and an organic solvent, preferably water.
11. The process according to any one of claims 1 to 10, wherein the seed crystals of calcium {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } acetate of formula (I) are added to the solution (a) or the mixture in an amount of up to 25 wt/wt% relative to the amount of {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } acetic acid used as starting material.
12. The method according to claim 11, wherein the seed crystals of {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } calcium acetate of formula (I) have an X-ray powder diffraction pattern in which at least five peaks, or at least seven peaks, or at least nine peaks, having an angle of refraction 2Θ (2 theta) value selected from: 5.1 °, 5.4 °, 8.8 °, 9.9 °, 11.4 °, 13.4 °, 13.8 °, 16.3 °, 19.7 °, 20.9 °, 21.4 °, 22.9 °, 25.1 °, wherein the X-ray powder diffraction pattern is obtained by using Cu ka radiation, wherein the accuracy of the 2θ (2theta) values is within a range of 2θ +/-0.2 ° (2theta +/-0.2 °).
13. The method of any one of claims 1 to 12, wherein the first calcium source, the second calcium source, or both calcium sources are selected from Ca (OAc) sources 2 Calcium propionate, calcium formate, and calcium pantothenate.
14. The method of claim 13, wherein the first and optionally the second calcium source is Ca (OAc) 2 。
15. A product obtained by the method according to any one of claims 1 to 14.
16. {4- [ (5, 6-diphenylpyrazin-2-yl) (propan-2-yl) amino group of formula (I)]Butoxy calcium acetate, wherein Ca 2+ The content is 7.0.+ -. 0.1 wt./wt.% or less, preferably 7.0.+ -. 0.1 wt./wt.% to 4.0.+ -. 0.1 wt./wt.%.
17. A crystalline form 2 of {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } calcium acetate of formula (I), which crystalline form shows an X-ray powder diffraction pattern, wherein at least five peaks have refractive angle 2Θ (2 theta) values selected from: 3.2 °, 6.3 °, 7.7 °, 9.3 °, 10.4 °, 11.6 °, 24.0 ° 2theta; preferably at least five peaks, or at least seven peaks, or at least nine peaks are selected from: 3.2 °, 6.3 °, 7.7 °, 9.3 °, 10.0 °, 10.4 °, 11.6 °, 12.7 °, 19.2 °, 22.9 °, 24.0 ° 2theta; wherein the X-ray powder diffraction pattern is obtained by using Cu ka radiation; and the accuracy of the 2theta (2 theta) value is in the range of 2theta +/-0.2 deg. (2 theta +/-0.2 deg.).
18. A crystalline form 3 of {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } calcium acetate of formula (I), which crystalline form shows an X-ray powder diffraction pattern, wherein the peaks have refractive angle 2Θ (2 theta) values selected from: 4.5 °, 7.9 °, or 11.9 ° 2theta; preferably at least five peaks, or at least seven peaks, or at least nine peaks are selected from: 4.5 °, 4.8 °, 5.0 °, 7.9 °, 10.0 °, 11.9 °, 14.9 °, 15.6 °, 17.1 °, 18.7 °, 22.1 °, and 22.7 ° 2theta; wherein the X-ray powder diffraction pattern is obtained by using Cu ka radiation; and the accuracy of the 2theta (2 theta) value is in the range of 2theta +/-0.2 deg. (2 theta +/-0.2 deg.).
19. A crystalline form 5 of {4- [ (5, 6-diphenylpyrazin-2-yl) (prop-2-yl) amino ] butoxy } calcium acetate of formula (I), which crystalline form shows an X-ray powder diffraction pattern, wherein at least five peaks, or at least seven peaks, or at least nine peaks, have a refraction angle 2Θ (2 theta) value selected from: 4.9 °, 8.8 °, 9.8 °, 11.0 °, 12.8 °, 13.1 °, 16.9 °, 19.5 °, 21.1 °, 21.5 °, and 22.6 ° 2theta; wherein the X-ray powder diffraction pattern is obtained by using Cu ka 1 radiation; and the accuracy of the 2theta (2 theta) value is in the range of 2theta +/-0.2 deg. (2 theta +/-0.2 deg.).
20. A pharmaceutical composition comprising the product of any one of claims 17 to 19.
21. The pharmaceutical composition of claim 20, in the form of an intramuscular or subcutaneous injection.
22. The product according to any one of claims 17 to 19 for use in the treatment or prevention of ulcers, finger ulcers, diabetic gangrene, diabetic foot ulcers, pulmonary hypertension, pulmonary arterial hypertension, chronic embolic pulmonary arterial hypertension, fang Tan disease and pulmonary hypertension associated with Fang Tan disease, sarcoidosis and pulmonary hypertension associated with sarcoidosis, peripheral circulatory disorders, connective tissue disease, chronic kidney disease including glomerulonephritis and diabetic nephropathy at any stage, diseases involving fibrosis of organs or tissues, or respiratory diseases, preferably Pulmonary Arterial Hypertension (PAH) or chronic embolic pulmonary arterial hypertension (CTEPH).
23. A method for preventing and/or treating ulcers, finger ulcers, diabetic gangrene, diabetic foot ulcers, pulmonary hypertension, pulmonary arterial hypertension, chronic embolic pulmonary arterial hypertension, fang Tan disease and pulmonary hypertension associated with Fang Tan disease, sarcoidosis and pulmonary hypertension associated with sarcoidosis, peripheral circulatory disorders, connective tissue diseases, chronic kidney diseases including glomerulonephritis and diabetic nephropathy at any stage, diseases involving fibrosis of organs or tissues, or respiratory diseases, the method comprising administering to a human subject in need thereof a pharmaceutical composition according to claim 20 or 21.
CN202280012079.2A 2021-01-29 2022-01-28 Process for preparing diphenylpyrazine derivatives Pending CN116745270A (en)

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