Clazosentan disodium salt, its preparation and pharmaceutical composition containing same

Abstract

The present invention relates to clazosentan disodium salt and a process for preparing the same.

Description

[Technical field]

[0001] The present invention relates to clazosentan disodium salt. The present invention further relates to a novel process for the preparation of a compound of formula (I) ... A pharmaceutical composition containing clazosentan and a method for treating a disease involving an endothelin receptor or in the prevention and / or treatment of disorders, in particular aneurysmal subarachnoid hemorrhage. Cerebral vasospasm after aSAH cerebral vasospasm (VSP) and / or subsequent ischemic effects / Endothelin receptor antagonists for use in the prevention and / or treatment of conditions This document relates to their use as a tool for [Background technology]

[0002] aSAH is a sudden, life-threatening bleeding event in the subarachnoid space between the brain and skull. , caused by the rupture of an aneurysm. To stop the bleeding, endovascular coil embolization (e Indovascular coiling or microsurgical clipping of aneurysms Emergency surgical treatment with crosurgical clipping may be required. Mortality from aSAH is high (approximately 25%), and a significant proportion of survivors experience neurological impairment. VSP is a potent blockade of the arteries surrounding the bleeding site that reduces blood flow and oxygen to nearby brain regions. This contraction occurs 4 to 14 days after aneurysm securing. Delayed cerebral ischemia, in which brain tissue dies due to insufficient blood supply, can occur. Complications such as cerebral ischemia and / or cerebral infarction may progress after VSP. do.

[0003] Clazosentan is a potent endothelin (ET A It is a selective receptor antagonist. Several clinical trials (e.g., NCT00111085, NCT0055831 ... CT00940095, NCT02560532, NCT03585270, Japic CTI-163369 and JapicCTI-163368) SP and / or subsequent ischemic effects / symptoms have been evaluated. Sentan (brand name Pivlaz) was approved in 2022 (Lee A. Clazocenta N:First Approval.Drugs.2022 Apr;82(6):69 7-702.Doi:10.1007 / s40265-022-01708-0.PMI D:35362854).

[0004] Clazosentan disodium salt (hereinafter also referred to as the compound of formula 6) is a 5-methyl -Pyridine-2-sulfonic acid N-{6-(2-hydroxy-ethoxy)-5-(2-methyl- Toxic-phenoxy)-2-[2-(1H-tetrazol-5-yl)-pyridine-4- yl]-pyrimidin-4-yl}-amide disodium salt or 5-methyl-pyridine- 2-Sulfonic acid N-{6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenyl (1H-tetrazol-5-yl)-pyridin-4-yl)-pyridine It is known by several systematic names, such as {midin-4-yl}-amide sodium salt (1:2) Clazosentan has been recognized in the art for its laboratory code. codes), e.g., ACT-108475 (free acid), AXV-034343 (free Disodium salt), AXV-034343A (disodium salt), ACT-108475A (disodium salt) sodium salt), VML588 and Ro61-1790; It may be represented as:

[0005] [ka] EP0979822 discloses clazosentan disodium salt and its preparation (Example 9) WO9619459 discloses a laboratory-scale preparation of clazosentan free acid. (Example 29) Clazosentan disodium salt was used in Example Cb) of WO9619459. However, there is no description of the manufacturing method. The present invention relates to a method for the preparation of 2,5-disubstituted pyridines that may be used in the preparation of lazosentan free acid. (For example,

[0018] ,

[0024] and

[0032] ). EP0897914 is , mainly concerns the first step of the manufacturing process of clazosentan. 35 and W02000052007 disclose heterocyclic compounds as inhibitors of endothelin receptors. Vorbrueggen et al.: Synthesis 1983 (4):316-319, DOI:10.1055 / s-1983-30321;TS Akamoto et al.: Chem. Pharm. Bull. 33, 565-571 (1985 ); and A. Kubo et al.: Chem. Pharm. Bull. 36, 4355-4363 (1988) discusses the cyanation of heterocyclic-N-oxides. Summary of the Invention

[0006] The present invention provides a novel method suitable for large-scale production of clazosentan and its disodium salt. A method has been found which is particularly advantageous in that it has suitable reagents / solvents, high yields, high conversion rates and short reaction times. low temperature and pressure; high safety and reliability; and / or good filterability of intermediate / final products, etc. This method will provide advantageous process characteristics / conditions. In addition, this method will provide advantageous purity, impurity profile, and / or clazosentan disodium salt with appropriate sodium content. The method also provides a method for producing a compound according to the present invention, The use of said beneficial crystalline forms may be advantageous in raw material processing / manufacturing. Simplify and reduce transportation / storage / testing costs; reduce mass variation Simplify dosing in drug product manufacturing; reduce aggregate formation under storage conditions and / or improve the uniformity of the bulk feedstock. iscolored) to provide clazosentan disodium salt. [Brief description of the drawings]

[0007] [Figure 1]FIG. 1 shows the powder X-ray diffractogram of crystalline form A of 5-methyl-pyridine-2-sulfonic acid {6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-[2-(1H-tetrazol-5-yl)-pyridin-4-yl]-pyrimidin-4-yl}-amide disodium salt, which is expressed as a function of the refraction angle 2θ for CuKα radiation. The X-ray diffractogram in FIG. 1 shows peaks with the following percentage relative intensities (relative peak intensities are given in parentheses) compared to the most intense peak in the diffractogram at the indicated refraction angles 2-theta (selected peaks with a relative intensity of 10% or greater from the 5-35° 2-theta range are reported): 9.4° (100%), 12.0° (19%), 13.2° (15%), 17.7° (16%), 18.4° (20%), 19.8° (18%), 21.2° (23%), 21.9° (35%) and 24.9° (15%). [Diagram 2] FIG. 2 shows the powder X-ray diffractogram of 5-methyl-pyridine-2-sulfonic acid 6-chloro-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-ylamide (free acid) as a function of the refraction angle 2θ of CuKα radiation. The X-ray diffractogram in FIG. 2 shows peaks with the following percentage relative intensities (relative peak intensities are given in parentheses) compared to the most intense peak in the diffractogram at the indicated refraction angles 2-theta (selected peaks with a relative intensity of 7% or greater from the 5-35° 2-theta range are reported): 8.3° (100%), 9.1° (34%), 12.3° (10%), 16.7° (11%), 18.1° (10%), 20.2° (26%), 20.5° (11%), 25.0° (27%), 25.6° (7%) and 27.1° (18%). [Diagram 3]FIG. 3 shows the powder X-ray diffractogram of 5-methyl-pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-ylamide sodium salt, which is expressed as a function of the refraction angle 2θ of CuKα radiation. The X-ray diffractogram in FIG. 3 shows peaks with the following percentage relative intensities (relative peak intensities are given in parentheses) compared to the most intense peak in the diffractogram at the indicated refraction angles 2-theta (selected peaks with a relative intensity of 4% or greater from the 5-35° 2-theta range are reported): 9.8° (100%), 10.4° (11%), 18.2° (21%), 18.8° (7%), 19.2° (4%), 20.9° (10%), 23.1° (17%), 26.2° (11%), 27.1° (10%) and 29.0° (12%). [Figure 4] FIG. 4 shows the powder X-ray diffractogram of 5-methyl-pyridine-2-sulfonic acid 2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-ylamide as a function of the refraction angle 2θ of CuKα radiation. The X-ray diffractogram in FIG. 4 shows peaks with the following percentage relative intensities (relative peak intensities are given in parentheses) compared to the most intense peak in the diffractogram at the indicated refraction angles 2-theta (selected peaks with a relative intensity of 10% or greater from the 5-35° 2-theta range are reported): 7.0° (100%), 8.6° (38%), 11.6° (17%), 12.6° (25%), 13.8° (54%), 18.2° (34%), 21.4° (63%), 23.1° (30%), 25.3° (26%) and 26.7° (42%). [Diagram 5]FIG. 5 shows the powder X-ray diffractogram of 5-methyl-pyridine-2-sulfonic acid {6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-[2-(1H-tetrazol-5-yl)-pyridin-4-yl]-pyrimidin-4-yl}-amide, which is expressed as a function of the refraction angle 2θ of CuKα radiation. The X-ray diffractogram in FIG. 5 shows peaks with the following percentage relative intensities (relative peak intensities are given in parentheses) compared to the most intense peak in the diffractogram at the indicated refraction angles 2-theta (selected peaks with a relative intensity of 20% or greater from the 5-35° 2-theta range are reported): 6.0° (100%), 9.0° (34%), 12.7° (29%), 17.7° (35%), 18.0° (48%), 20.7° (36%), 23.0° (31%), 24.6° (66%), 25.8° (54%) and 27.2 (31%). [Figure 6] FIG. 6 shows the powder X-ray diffractogram of 5-methyl-pyridine-2-sulfonic acid {6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-[2-(1H-tetrazol-5-yl)-pyridin-4-yl]-pyrimidin-4-yl}-amide tetrahydrofuran solvate, which is expressed as a function of the refraction angle 2θ of CuKα radiation. The X-ray diffractogram in FIG. 6 shows peaks with the following percentage relative intensities (relative peak intensities are given in parentheses) compared to the most intense peak in the diffractogram at the indicated refraction angles 2-theta (selected peaks with a relative intensity of 5% or greater from the 5-35° 2-theta range are reported): 9.0° (100%), 15.4° (11%), 17.2° (6%), 19.0° (14%), 21.7° (10%), 23.6° (9%), 24.2° (19%), 24.4° (12%), 25.8° (10%) and 27.9° (15%).

[0008] For the avoidance of any doubt, the above peaks are shown in the powder X-ray diffraction patterns shown in Figures 1-6. In contrast to the above peak list, the results of the peak chromatogram of the crystalline form of the present invention are described below. Only selected characteristic peaks are required to fully and unambiguously characterize the corresponding compounds. It should be understood that is necessary. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] Detailed Description of the Invention 1) One aspect of the present invention is a method for producing a method for manufacturing a semiconductor device comprising the steps of: (a) A compound of formula 1

[0010] [ka] 5-methyl-pyridine-2-sulfonamide or a salt thereof (especially a and reacting with an alkali metal salt; especially a potassium salt) to give a compound of formula 2 or a salt thereof (especially an alkali metal salt; especially a potassium salt). Potassium metal salts; especially potassium salts

[0011] [ka] obtaining the above compound; The present invention relates to a method having the following structure:

[0012] As used herein, the term "basic conditions" refers to 5-methyl-pyridine-2-sulfonyl This means the presence of a compound capable of deprotonating the sulfonamide group in sulfonamide. Such compounds include, for example, basic alkali metal salts, alkali metal hydroxides, tri- C 1-4 -Alkylamines, 1,4-diazabicyclo[2.2.2]octane (DABC O), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,5 -Diazabicyclo(4.3.0)non-5-ene (DBN) and other amidine bases, unsubstituted Or 1, 2 or 3 C 1-4-Alkyl (especially methyl) substituted pyridines Preferably, basic alkali metal salts, alkali metal hydroxides and tri-C 1-4 -alkylamines. Particularly preferred are basic alkali metal salts or alkali metal hydroxides. It's a monster.

[0013] As used herein, "Tri-C 1-4 The term "-alkylamine" refers to an amine having the formula NR 1 R 2 R 3 (R 1 , R 2 and R 3 are independently 1-4 - represents alkyl. C 1-4 The term alkyl refers to a branched or straight chain alkyl group having 1 to 4 carbon atoms. C means a monovalent saturated hydrocarbon group. 1-4 Examples of -alkyl groups are methyl, ethyl, n -propyl, isopropyl, n-butyl, tert-butyl, sec-butyl and isobutyl Chill; especially ethyl.

[0014] Basic alkali metal salts hydrolyze in water to form solutions with pH values ​​above 7. Examples of such salts are the carbonates, bicarbonates, sulfides, etc. of alkali metals. In particular, lithium, sodium or potassium carbonates or Suitable alkali metal hydroxides are sodium, potassium, lithium or are hydroxides of cesium; in particular, sodium hydroxide, potassium hydroxide and lithium hydroxide It is.

[0015] 2) In another embodiment, step (a) is carried out in the presence of a basic alkali metal salt (particularly potassium carbonate). The present invention relates to a method according to embodiment 1), which is carried out in

[0016] 3) In another embodiment, the basic alkali metal salt (particularly potassium carbonate) is a compound of the formula 1 In the method according to embodiment 2), the amount of the amine is about 1 equivalent to about 3 equivalents (particularly about 2 equivalents) relative to the amount of the compound. do.

[0017] 4) In another embodiment, step (a) is carried out using a polar aprotic organic solvent or a mixture of such solvents. (especially acetonitrile, 1,4-dioxane or a mixture thereof; especially acetonitrile The present invention relates to a method according to any one of aspects 1) to 3), which is carried out in

[0018] The term "polar aprotic organic solvent" in the context of the present invention means a polar aprotic organic solvent (measured at 25° C.) A dielectric constant greater than 15, especially greater than 20. It is an organic solvent that has an acidic hydrogen atom and lacks an acidic hydrogen atom. The solvents used are acetone, ethyl acetate, dimethyl sulfoxide, 1,4-dioxane, acetone, The solvent may be trinitrile, N-methyl-pyrrolidone or dimethyl-formamide.

[0019] 5) In another embodiment, the amount of 5-methyl-pyridine-2-sulfonamide is In any of the embodiments 1) to 4), the amount is about 1 equivalent to about 1.5 equivalents (particularly about 1 equivalent) relative to the amount of the compound. It concerns the method of following one of them.

[0020] 6) In another embodiment, the compound of formula 2 is in the form of a potassium salt, i.e. a compound of formula 2a (especially its hydrate),

[0021] [ka] or, especially in the form of the free acid, The present invention relates to a method according to any one of embodiments 1) to 5), wherein the compound is isolated.

[0022] The process according to any one of embodiments 1) to 6) may be used to prepare a compound of formula 6.

[0023] 7) Another aspect of the present invention is (b) a compound of formula 2 or a salt thereof (especially an alkali metal salt; especially a potassium salt)

[0024] [ka] in the presence of an alkali metal hydroxide (especially sodium hydroxide), with ethylene glycol to produce a compound of formula 3 or a salt thereof (especially the sodium salt; especially the sodium salt hydrate). thing)

[0025] [ka] obtaining the above compound; The present invention relates to a method having the following structure:

[0026] 8) Another embodiment is reacting a compound of formula 2 (i.e., a compound of formula 2 in the free acid form) , embodiment 7).

[0027] 9) In another embodiment, the amount of the alkali metal hydroxide (particularly sodium hydroxide) is a compound represented by the formula [ 2] at least about 4 equivalents (particularly at least about 5 equivalents; more particularly at least about 5 equivalents 0.7 equivalents).

[0028] 10) In another embodiment, step (b) comprises the step of adding at least one free radical scavenger (free radical scavenger) (especially 2,6-di-tert-butyl According to any one of the embodiments 7) to 9), the reaction is carried out in the presence of 1-4-methylphenol. In particular, the free radical scavenger is a compound of formula 2 in the free acid form The compound is present in an amount of about 0.1 to about 1 equivalent (particularly about 0.5 equivalent) relative to the compound.

[0029] The term "free radical scavenger" in the context of the present invention refers to Compounds that prevent the formation of by-products by reacting with free radical species formed during An example of such a compound is 2,6-di-tert-butyl-4-methylphenol. (BHT), 2-(1,1-dimethylethyl)-1,4-benzenediol, 1,2-di Hydro-6-ethoxy-2,2,4-trimethylquinoline, tert-butylhydroquinone (t tertiary butylhydroquinone (TBHQ), propyl gallate gallic acid, dodecyl gallate, gallic acid, or 2-tert-butyl-4-hydroxyanisole Butyl hydroxyanisole such as a mixture of isomers of 3-tert-butyl-4-hydroxyanisole BHA; especially 2,6-di-tert-butyl-4-methylphenyl 6-Di-tert-butyl-4-methylphenol and other free If a radical scavenger is used, toluene may be added to the reaction mixture.

[0030] 11) In another embodiment, the compound of formula 3 is a sodium salt (particularly a hydrate thereof), i.e. Compound 3a (especially its hydrate)

[0031] [ka] The present invention relates to a method according to any one of embodiments 7) to 10), wherein the compound is isolated in the form of

[0032] The method according to any one of embodiments 7) to 11) may be used to prepare a compound of formula 6.

[0033] 12) Another aspect of the present invention is a method for producing ... composition comprising the steps of: (c) a compound of formula 3 or a salt thereof (especially the sodium salt; especially the sodium salt hydrate):

[0034] [ka] Mono-, di- or tri-C 1-4 - The presence of alkylamines (especially triethylamine) In the presence of trimethylsilyl cyanide to produce a compound of formula 4

[0035] [ka] obtaining the above compound; The present invention relates to a method having the following structure:

[0036] 13) Another embodiment is the compound of formula 3 in the form of a salt, in particular its sodium salt (formula 3a) The process according to embodiment 12) relates to a process according to embodiment 12), in which

[0037] 14) In another embodiment, step (c) is Any one of embodiments 12) or 13), wherein the reaction is carried out in the presence of In particular, the amount of chlorotrimethylsilane is [relative to the compound of formula 3 / 3a] and about 1 to about 2 equivalents (particularly about 1.3 equivalents).

[0038] If additional alcohol groups, such as residual ethylene glycol, are present in the starting material, Further increases in the amount of chlorotrimethylsilane may be used.

[0039] 15) In another embodiment, the amount of trimethylsilyl cyanide is According to any one of the embodiments 12) to 14), the amount of the hydroxyl group is about 3 to about 6 (particularly about 4.5) equivalents. It concerns the method.

[0040] 16) Another embodiment is a mono-, di- or tri-C 1-4 - The amount of alkylamine is 3 / 3a] about 2 to about 4 (particularly 3.1) equivalents, This relates to a method according to any one of the following:

[0041] 17) In another embodiment, step (c) is carried out at atmospheric pressure. re) (i.e., greater than about 1 bar; in particular, from about 2 to about 10 bar; The method according to any one of the embodiments 12) to 16), wherein the reaction is carried out under a pressure of about 6 bar. do.

[0042] 18) In another embodiment, step (c) is carried out at about 70° C. to about 110° C. (particularly about 80° C. to about 100° C.). ℃, in particular about 93 ° C) according to any one of the embodiments 12) to 17) It concerns the method.

[0043] The method according to any one of embodiments 12) to 18) may be used to prepare a compound of formula 6 .

[0044] 19) Another aspect of the present invention is a method for producing a method for the treatment of atopic dermatitis. (d) Compound of Formula 4

[0045] [ka] It is reacted with alkali metal azide (especially sodium azide) in the presence of ammonium chloride. to give a compound of formula 5 or a solvate thereof (particularly a tetrahydrofuran solvate).

[0046] [ka] obtaining the above compound; The present invention relates to a method having the following structure:

[0047] 20) In another embodiment, the compound of formula 5 is adsorbed onto a filter aid. and isolating the filter aid (by solid-liquid separation), According to embodiment 19) having activated carbon or perlite; in particular diatomaceous earth It concerns the method.

[0048] Isolation of the solid residue of the compound of formula 5 means separating the solid phase of the suspension from its liquid phase. The isolation may be carried out by filtration (e.g., gravity filtration, especially vacuum filtration). The separation may be carried out by any method for solid-liquid separation, such as solid-liquid separation (solid-liquid separation), or by filtration.

[0049] As used herein, the term "filter aid" refers to a material that, for example, reduces the compressibility of the cake. and / or improving cake permeability / porosity to improve flow rate and / or filtrate clarity ( Filtration refers to a carrier made of solid particles that improves the filtration clarity of a substance. The auxiliary has porous particles and is added to the suspension to be filtered or the suspension to be filtered is An example of a filter aid is Hyflo® S. Diatomaceous earth such as Super Cel® NF aceous earth or diatomite), activated charcoal, Yarn, (wood) cellulose, agricultural fibers, Saw dust, (burnt) rice hull ash or Paper fibers (e.g. fibers from old newspapers); in particular suitable The filter aid is diatomaceous earth, activated carbon or perlite; especially diatomaceous earth.

[0050] 21) In another embodiment, the amount of filter aid used is at least about 1% of the amount of the compound of formula 4. 0% w / w (particularly at least about 50% w / w; more particularly at least 75% w / w; especially 20) wherein the concentration of the cation exchange resin is at least 100%.

[0051] 22) In another embodiment, step (d) is carried out at a temperature of less than about 110° C. (particularly, from about 80° C. to about 110° C. ; in particular at a temperature of about 95° C.) according to any one of embodiments 19) to 21). Regarding the law.

[0052] 23) Another embodiment is the method of any one of embodiments 19) to 19), in which step (d) is carried out in dimethylformamide. 22) according to any one of the methods described above.

[0053] 24) Another embodiment is to dissolve the adsorbed compound of formula 5 in a suitable solvent, e.g., in tetrahydrofuran at a temperature above about 50° C., particularly at about 66° C. The compound of formula 5 is desorbed by solvating the compound in, for example, tetrahydrofuran. and isolating the product (in particular by precipitation and / or crystallization from a suitable solvent, such as tetrahydrofuran). for example at temperatures below about 20° C., particularly at about 10° C.; the compound is particularly The product is isolated by separation, and optionally reacted in a suitable solvent (e.g., tetrahydrofuran), particularly at reflux. The method according to any one of aspects 19) to 23) is further slurried while the mixture is being stirred. Regarding.

[0054] The method according to any one of embodiments 19) to 24) may be used to prepare a compound of formula 6 .

[0055] 25) Another aspect relates to a method having the steps of: (e) A compound of formula 5 or a solvate thereof (especially a tetrahydrofuran solvate; especially a tetrahydrofuran solvate). tetrahydrofuran monosolvate)

[0056] [ka] with a sodium-containing base (especially sodium alkoxide, sodium hydride or sodium hydroxide) Sodium alkoxides; in particular sodium alkoxides having 1 to 4 carbon atoms; especially sodium thorium methoxide) to give a compound of formula 6

[0057] [ka] obtaining the above compound; (f) Optionally, (f1) [Step (e)] Treating a compound of formula 6 at a pH of 7 or more (particularly at a pH of 10 or more; recrystallization in water at a pH of about 14; and / or (f2) [Step (e) or Step (f1)] Reacting the compound of formula 6 with a lower alcohol or grinding in a solvent selected from a mixture of alcohols; purifying the compound of formula 6 by (g) optionally drying the compound of formula 6.

[0058] In a preferred subembodiment of embodiment 25), steps (f) and (g) are according to embodiment 25). Included in the method (i.e., steps (f) and (g) are not optional). In a further preferred subembodiment of step (f) and step (g) are the process according to embodiment 25). (i.e., steps (f) and (g) are not optional), and step (f) is included in step ( In yet a further preferred embodiment, step (f1) is present and step (f2) is absent. Steps (f) and (g) are included in the method according to embodiment 25) (i.e., steps (f) and (g) are included in the method according to embodiment 26). (g) is not optional), and step (f) includes steps (f1) and (f2). In yet another preferred subembodiment of 5), steps (f) and (g) are according to embodiment 25). (i.e., steps (f) and (g) are not optional), and step (f) is The method includes step (f2) and does not include step (f1).

[0059] As used herein, the term "sodium-containing base" refers to an organic compound having sodium. and / or inorganic Bronsted bases; in particular, the bases are those which are capable of converting the proton from the compound of formula 5 Ton (H + ion) to produce a compound of formula 6. The Bronsted base is a sodium alkoxide (e.g., sodium methoxide, sodium Sodium ethoxide, sodium n-propoxide, sodium isopropoxide and / or is sodium butoxide), sodium hydride, sodium oxide and / or sodium hydroxide in particular sodium alkoxides, sodium hydride or sodium hydroxide; Sodium alkoxides having 1 to 4 carbon atoms; especially sodium methoxide. That's fine.

[0060] As used herein, the term "recrystallizing" refers to the compound of formula (e) obtained in step (e). Compound 6 (solid residue) is subjected to high temperature (e.g., about 60-80° C.) at a pH of 7 or higher, in water (particularly in a weight ratio of the compound of formula 6 / water of about 1 to 3) and cooling the solution. means isolating (in particular by solid-liquid separation) the (solid residue of) compound of formula 6. In the recrystallization process of 25), the pH value of 7 or more (especially the pH value of 10 or more; A pH value of about 14 can be achieved by the addition of bases such as alkali metal bases; especially sodium hydroxide. This may be achieved by the addition of

[0061] As used herein, the term "triturating" refers to a process that It refers to a process used to purify a crude organic compound having soluble impurities. Insoluble in the product and soluble in the undesirable by-product, or vice versa. For example, if the impurities are soluble and the desired product is not, the crude product may be soluble. The purified product is obtained in solid form by washing the product with the solvent and filtering it. Leave the material in solution. In particular, "grinding" (slurrying) as used herein The term "slurring" is used to describe - reacting the (solid residue of) compound of formula 6 [obtained in step (f1) or step (e)] with a lower alkyl group suspending the mixture in a solvent selected from the group consisting of alcohol and a mixture of lower alcohols; Optionally, the suspension is subjected to agitation, in particular under heating, for a given period of time. ) (e.g., stirring); and - isolating the (solid residue of) compound of formula 6; means.

[0062] The suspension step is preferably carried out at a temperature above room temperature, especially at about 70°C. The stirring step is preferably carried out at a temperature higher than room temperature, in particular under reflux. A cooling step is performed prior to the isolation step, to a temperature below room temperature, particularly below 0° C. Furthermore, isolating the compound of formula 6 (solid residue) means separating the solid phase of the suspension from its liquid phase. This means isolating the material by filtration (e.g., centrifugal, gravity or vacuum filtration). By any method for solid-liquid separation such as filtration, settling, decantation and / or centrifugation. This may be accomplished by gravity or vacuum filtration among others.

[0063] The drying in step (g) may be carried out at a temperature higher than room temperature (particularly about 25°C to about 75°C). and optionally under vacuum.

[0064] The term "lower alcohol" as used above and below means an alcohol having 1 to 5 Linear or branched monovalent saturated alkyl groups having 1 to 3 carbon atoms; in particular 1 or 2 Examples of lower alcohols are methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, isobutanol, 2-methyl-propane-2- ol, 2-methyl-propan-1-ol, 1-pentanol, 2-pentanol or 3-Pentanol.

[0065] 26) Another embodiment is the sodium-containing base (especially sodium alkoxide; (sodium methoxide) is used in an amount of 2 to 3 (particularly about 2.5) equivalents relative to the compound of formula 5. The present invention relates to a method according to embodiment 25).

[0066] 27) In another embodiment, step (e) is carried out by using a lower alcohol or a mixture of lower alcohols (particularly , methanol, ethanol, 1-propanol, 2-propanol or mixtures thereof ;especially methanol, ethanol or mixtures thereof;especially 1 wt. of methanol and 3 wt. of ethanol), This relates to how to follow the

[0067] 28) In another embodiment, the solvent used in the grinding in step (f2) is methanol, ethanol, or the like. 1-propanol, 2-propanol or mixtures thereof [in particular methanol, ethanol or mixtures thereof; in particular mixtures of methanol and ethanol ( In particular, a mixture of 1 wt. of methanol and 3 wt. of ethanol), and embodiments 25) to 2 7) in accordance with any one of the following:

[0068] The method according to any one of embodiments 25) to 28) may be used to prepare a compound of formula 6 .

[0069] 29) Another aspect of the invention relates to a method for preparing a compound of formula 6, which method comprises the steps of embodiment 25) 28), comprising step (e) and optionally steps (f) and (g). death; The method further comprises the steps of: - step (d) according to any one of embodiments 19) to 24); Or, - step (d) according to any one of embodiments 19) to 24); and Step (c) according to any one of aspects 12) to 18) [particularly any one of aspects 14) to 18] or step (c)]; Or, - step (d) according to any one of embodiments 19) to 24); Step (c) according to any one of aspects 12) to 18) [particularly any one of aspects 14) to 18] or one of steps (c)]; and Step (b) according to any one of aspects 7) to 11) [particularly any one of aspects 9) to 11] Step (b)]; Or, - step (d) according to any one of embodiments 19) to 24); Step (c) according to any one of aspects 12) to 18) [particularly any one of aspects 14) to 18] or step (c)]; Step (b) according to any one of aspects 7) to 11) [particularly any one of aspects 9) to 11] Step (b)]; and step (a) according to any one of embodiments 1) to 6).

[0070] 30) Another aspect of the present invention relates to a method according to any one of aspects 25) to 28), comprising the steps (e The present invention relates to a method for preparing a compound of formula 6 having the formula (i), (ii), (iii) and (iv), the method comprising the steps of: Further have; - step (d) according to any one of embodiments 19) to 24); Or, - step (d) according to any one of embodiments 19) to 24); and Step (c) according to any one of aspects 12) to 18) [particularly any one of aspects 14) to 18] or step (c)]; Or, - step (d) according to any one of embodiments 19) to 24); Step (c) according to any one of aspects 12) to 18) [particularly any one of aspects 14) to 18] or one of steps (c)]; and Step (b) according to any one of aspects 7) to 11) [particularly any one of aspects 9) to 11] Step (b)]; Or, - step (d) according to any one of embodiments 19) to 24); Step (c) according to any one of Aspects 12) to 18) [in particular, step (c) according to any one of Aspects 14) to 18)]; ; Step (b) according to any one of Aspects 7) to 11) [in particular, step (b) according to any one of Aspects 9) to 11)]; and ; Step (a) according to any one of Aspects 1) to 6).

[0071] 31) Another aspect of the present invention is - Step (a) according to any one of Aspects 1) to 6); Step (b) according to any one of Aspects 7) to 11); Step (c) according to any one of Aspects 12) to 18) [in particular, step (c) according to any one of Aspects 14) to 18)]; ; Step (d) according to any one of Aspects 19) to 24); Step (e) according to any one of Aspects 25) to 28); Step (f) according to any one of Aspects 25) to 28); and Step (g) according to any one of Aspects 25) to 28); relates to a method for producing a compound of Formula 6 having

[0072] A sub-aspect of Aspect 31) is Step (a) according to any one of Aspects 1) to 6); Step (b) according to Aspect 7); Step (c) according to Aspect 12); Step (d) according to Aspect 19); Step (e) according to Aspect 25 ); relates to a method for producing a compound of Formula 6 having

[0073] A sub-aspect of Aspect 31) is Step (a) according to Aspect 1); Step (b) according to any one of Aspects 7) to 11) ; Step (c) according to Aspect 12); Step (d) according to Aspect 19); Step (e) according to Aspect 2 5); relates to a method for producing a compound of Formula 6 having

[0074] Sub-aspect of Aspect 31) is Step (a) according to Aspect 1); Step (b) according to Aspect 7); Aspect Step (c) according to any one of 12) to 18); Step (d) according to Aspect 19); Aspect 2 Step (e) according to 5); relates to a method for producing a compound of Formula 6 having.

[0075] Sub-aspect of Aspect 31) is Step (a) according to Aspect 1); Step (b) according to Aspect 7); Aspect Step (c) according to 12); Step (d) according to any one of Aspects 19) to 24); Aspect 2 Step (e) according to 5); relates to a method for producing a compound of Formula 6 having.

[0076] 32) Another aspect of the present invention relates to a method for producing a compound of Formula 6 according to Aspect 31), wherein Step (f) is optional. Compound.

[0077] 33) Another aspect of the present invention relates to a method for producing a compound of Formula 6 according to Aspect 31), wherein Step (g) is optional. Compound.

[0078] 34) Another aspect of the present invention relates to a method for producing a compound of Formula 6 according to Aspect 31), wherein Steps (f) and (g) are optional. Compound.

[0079] The individual manufacturing steps (a), (b), (c), etc. disclosed herein may be carried out in alphabetical order, i.e., manufacturing step (a) is carried out before manufacturing step (b); manufacturing step (b) is carried out before manufacturing step (c), etc. However, for the sole purpose of clarity, in the claims / aspects of the present application, the individual manufacturing steps may be described in an order different from the alphabetical order. For example, the following order of the steps may be possible and is intended: manufacturing step (b), manufacturing step (a), manufacturing step (c), etc.; or manufacturing step (b), manufacturing step (a), manufacturing step (c), etc.; or manufacturing step (b), manufacturing step (a), manufacturing step (c), etc.; or manufacturing step (b), manufacturing step (a), manufacturing step (c), etc.; or manufacturing Manufacturing process (c), manufacturing process (a), manufacturing process (b), etc. Step (f) is optional, and step (f1 ) and step (f2). If step (f1) is not present, step (f) is f2). If step (f1) is present, it is carried out prior to step (f2). .

[0080] The method disclosed in the present application, in particular the method according to any one of the embodiments 1) to 34), can be used on a large scale. For production, especially when more than 1 kg of product (intermediate or final product) is required, especially when more than 5 kg is required It should be understood that the present invention is suitable for the production of many products, especially products weighing more than 10 kg. In particular, manufacturing steps (e) and (f) are for processes involving more than 1 kg (in particular more than 3 kg; It is particularly suitable for the production of compounds of formula 6 (more than 5 kg; especially more than 10 kg). There will be.

[0081] 35) Another aspect relates to a compound of formula 2a or a hydrate thereof. A sub-aspect is any of aspects 1) to 6) or 7) of the formula 2a, which can be obtained by step (a) of the process according to any one of relates to the hydrate thereof.

[0082] 35a) A further embodiment is a compound having the following refraction angles 2θ in a powder X-ray diffractogram: Characterized by the presence of peaks at 8.3°, 9.1°, and 25.0°; A crystalline form of the compound; or a crystalline form obtained by step (a) of the process according to any one of embodiments 1) to 6). The crystalline form of the compound of formula 2 may be

[0083] 35b) A further embodiment is a powder X-ray diffractogram having the following refraction angles 2θ: Due to the presence of peaks at 8.3°, 9.1°, 20.2°, 25.0° and 27.1° a crystalline form of the compound of formula 2; or according to any one of embodiments 1) to 6); A crystalline form of the compound of formula 2 obtainable by step (a) of the process.

[0084] 35c) A further embodiment is a powder X-ray diffractogram having the following refraction angles 2θ: 8.3°, 9.1°, 12.3°, 16.7°, 18.1°, 20.2°, 20.5°, Characterized by the presence of peaks at 25.0°, 25.6°, and 27.1°; 2; or by step (a) of the method according to any one of embodiments 1) to 6). The present invention relates to a crystalline form of the compound of formula 2 which may be obtained by the method of the present invention.

[0085] 35d) Further aspects are - 8.3°, 9.1°, 12.3°, 16.7°, 18.1°, 20.2°, 20.5 at least one of the following: a refractive angle 2θ selected from 25.0°, 25.6°, and 27.1°; At least four peaks, or in particular at least six peaks, or especially at least eight peaks. by a powder X-ray diffractogram having peaks; or - by a powder X-ray diffractogram essentially showing the pattern shown in Figure 2; characterized in that the crystalline form of the compound of formula 2 is: It relates to a crystalline form of the compound of formula 2 obtainable by step (a) of the process.

[0086] 36) Another aspect relates to a compound of formula 3a or a hydrate thereof. Sub-aspects are those of aspects 7) to 11) or a compound of formula 3a obtainable by step (b) of the process according to any of This relates to hydrates of the formula:

[0087] 36a) A further embodiment is a compound having the following refraction angles 2θ in a powder X-ray diffractogram: Characterized by the presence of peaks at 9.8°, 18.2°, and 23.1°; 36) of the compound of formula 3a (or a hydrate thereof); or according to any of embodiments 7) to 11). Compounds of formula 3a according to embodiment 36) which can be obtained by step (b) of the process according to any This relates to the crystalline form of the compound (or its hydrate).

[0088] 36b) A further embodiment is a powder X-ray diffractogram having the following refraction angles 2θ: The presence of peaks at 9.8°, 18.2°, 23.1°, 26.2° and 29.0° a crystalline form of the compound of formula 3a (or a hydrate thereof) according to embodiment 36); or can be obtained by step (b) of the method according to any one of aspects 7) to 11). 6) of the compound of formula 3a (or a hydrate thereof).

[0089] 36c) A further embodiment is a compound having the following refraction angles 2θ in a powder X-ray diffractogram: 9.8°, 10.4°, 18.2°, 18.8°, 19.2°, 20.9°, 23.1° , characterized by the presence of peaks at 26.2°, 27.1° and 29.0°; A crystalline form of the compound of formula 3a (or a hydrate thereof) according to embodiment 36); or, embodiments 7) to 11). 36) according to the formula 3a, which can be obtained by step (b) of the process according to any one of This invention relates to the crystalline form of the compound (or its hydrate).

[0090] 36d) Further aspects are: - 9.8°, 10.4°, 18.2°, 18.8°, 19.2°, 20.9°, 23. At least one of the following has a refractive angle 2θ selected from: 1°, 26.2°, 27.1°, and 29.0° At least four peaks, or in particular at least six peaks, or especially at least eight peaks. or by a powder X-ray diffractogram having a peak of - by a powder X-ray diffractogram essentially showing the pattern shown in Figure 3; A crystalline form of the compound of formula 3a or a hydrate thereof according to embodiment 36); or According to embodiment 36), it can be obtained by step (b) of the method according to any one of 7) to 11). The present invention relates to a crystalline form of the compound of formula 3a (or a hydrate thereof).

[0091] 36e) A further embodiment is a powder X-ray diffractogram having the following refraction angles 2θ: Characterized by the presence of peaks at 7.0°, 13.8°, and 21.4°; Equation 4 or by step (c) of the method according to any of embodiments 12) to 18). It relates to the crystalline forms of the compound of formula 4 which can be obtained.

[0092] 36f) A further embodiment is a powder X-ray diffractogram having the following refraction angles 2θ: Due to the presence of peaks at 7.0°, 8.6°, 13.8°, 21.4° and 26.7° a crystalline form of the compound of formula 4; or according to any of embodiments 12) to 18). It relates to a crystalline form of the compound of formula 4 obtainable by step (c) of the process.

[0093] 36g) A further embodiment is a powder X-ray diffractogram having the following refraction angles 2θ: 7.0°, 8.6°, 11.6°, 12.6°, 13.8°, 18.2°, 21.4°, Characterized by the presence of peaks at 23.1°, 25.3° and 26.7°; 4; or by step (c) of the method according to any of embodiments 12) to 18). The present invention relates to a crystalline form of the compound of formula 4 which may be obtained.

[0094] 36h) Further aspects are - 7.0°, 8.6°, 11.6°, 12.6°, 13.8°, 18.2°, 21.4 at least one of the following: a refractive angle 2θ selected from 23.1°, 25.3°, and 26.7°; At least four peaks, or in particular at least six peaks, or especially at least eight peaks. by a powder X-ray diffractogram having peaks; or - by a powder X-ray diffractogram essentially showing the pattern shown in Figure 4; A crystalline form of a compound of formula 4; or a method according to any one of embodiments 12) to 18). It relates to a crystalline form of the compound of formula 4 obtainable by step (c) of the process.

[0095] 36i) A further embodiment is a compound having a differential scanning calorimetry thermogram (DSC2) of about 2 Characterized by an endothermic peak at 10°C (particularly 210±5°C; especially 210±2°C) [i.e., a melting point at about 210°C; in particular at 210±5°C; especially at 210±2°C] a crystalline form of the compound of formula 4, in particular any of embodiments 36e) to 36h); or a crystalline form of the compound of formula 4 according to any one of the embodiments 12) to 18); or Crystalline forms of the compound of formula 4 obtainable by step (c), in particular embodiments 36e) to 36h) The present invention relates to a crystalline form of the compound of formula 4 according to any one of the following:

[0096] For the avoidance of doubt, the crystalline form of embodiment 36i) exhibits a differential scanning calorimetry thermogram By its peak alone (i.e., by its melting point alone), or by the peak and the mode Refraction of the powder X-ray diffractogram specified in any one of 36e) to 36h) It may be characterized by the combination of angles.

[0097] 37) Another aspect is a tetrahydrofuran solvate of the compound of formula 5 (particularly a tetrahydrofuran solvate of the compound of formula 5). A subembodiment relates to step (d) of the process according to embodiment 19) or 24). The tetrahydrofuran solvates of the compounds of formula 5 (especially tetrahydrofuran solvates) can be obtained by Furan monosolvate).

[0098] 37a) A further embodiment is a compound having the following refraction angles 2θ in a powder X-ray diffractogram: Characterized by the presence of peaks at 9.0°, 24.2°, and 27.9°; 37) Tetrahydrofuran solvates (particularly tetrahydrofuran solvates) of the compounds of formula 5 according to or by step (d) of the method according to any of embodiments 19) to 24). A tetrahydrofuran solvate of the compound of formula 5 according to embodiment 37) (especially This relates to a crystalline form of tetrahydrofuran monosolvate.

[0099] 37b) A further embodiment is a compound having the following refraction angles 2θ in a powder X-ray diffractogram: The presence of peaks at 9.0°, 15.4°, 19.0°, 24.2° and 27.9° A tetrahydrofuran solvate of the compound of formula 5 according to embodiment 37 (particularly or a crystalline form according to any one of aspects 19) to 24). The tetrahydrofuran compound of formula 5 according to embodiment 37) can be obtained by step (d) of the process This relates to crystalline forms of tetrahydrofuran solvates (especially tetrahydrofuran monosolvates).

[0100] 37c) A further embodiment is a compound having the following refraction angles 2θ in a powder X-ray diffractogram: 9.0°, 15.4°, 17.2°, 19.0°, 21.7°, 23.6°, 24.2° , characterized by the presence of peaks at 24.4°, 25.8° and 27.9°; Tetrahydrofuran solvates of compounds of formula 5 according to embodiment 37 (especially tetrahydrofuran) or in step (d) of the process according to any of embodiments 19) to 24). A tetrahydrofuran solvate of the compound of formula 5 according to embodiment 37) ( In particular, it relates to a crystalline form of tetrahydrofuran monosolvate.

[0101] 37d) Further aspects are: - 9.0°, 15.4°, 17.2°, 19.0°, 21.7°, 23.6°, 24. At least one of the following has a refractive angle 2θ selected from 2°, 24.4°, 25.8°, and 27.9°: At least four peaks, or in particular at least six peaks, or especially at least eight peaks. or by a powder X-ray diffractogram having a peak of - by a powder X-ray diffractogram essentially showing the pattern shown in Figure 6; A tetrahydrofuran solvate (particularly tetrahydrofuran solvate) of the compound of formula 5 according to embodiment 37) tetrahydrofuran monosolvate); or according to any of the embodiments 19) to 24). The tetrahydrofuran of the compound of formula 5 according to embodiment 37) can be obtained by step (d) of the process This relates to crystalline forms of furan solvates (especially tetrahydrofuran monosolvates).

[0102] 37e) A further embodiment is a compound having the following refraction angles 2θ in a powder X-ray diffractogram: Characterized by the presence of peaks at 6.0°, 24.6°, and 25.8°; Equation 5 or by step (d) of the method according to any of embodiments 19) to 24). It relates to the crystalline forms of the compound of formula 5 which can be obtained.

[0103] 37f) A further embodiment is a compound having the following refraction angles 2θ in a powder X-ray diffractogram: Due to the presence of peaks at 6.0°, 9.0°, 18.0°, 24.6° and 25.8° a crystalline form of a compound of formula 5; or according to any of embodiments 19) to 24). It relates to a crystalline form of the compound of formula 5 obtainable by process step (d).

[0104] 37g) A further embodiment is a compound having the following refraction angles 2θ in a powder X-ray diffractogram: 6.0°, 9.0°, 12.7°, 17.7°, 18.0°, 20.7°, 23.0°, Characterized by the presence of peaks at 24.6°, 25.8° and 27.2°; 5; or by step (d) of the method according to any one of embodiments 19) to 24). The present invention relates to a crystalline form of the compound of formula 5 which may be obtained.

[0105] 37h) Further aspects are: - 6.0°, 9.0°, 12.7°, 17.7°, 18.0°, 20.7°, 23.0 at least one of the following: a refractive angle 2θ selected from 24.6°, 25.8°, and 27.2°; At least four peaks, or in particular at least six peaks, or especially at least eight peaks. by a powder X-ray diffractogram having peaks; or - by a powder X-ray diffractogram essentially showing the pattern shown in Figure 5; A crystalline form of a compound of formula 5; or a method according to any one of embodiments 19) to 24). It relates to a crystalline form of the compound of formula 5 obtainable by step (d) of the process.

[0106] 38) Another aspect relates to a compound of formula 5 adsorbed onto a filter aid, the filter aid being The subembodiment comprises diatomaceous earth, activated carbon or perlite; in particular diatomaceous earth. 23) to 24), which can be obtained by step (d) of the method according to any one of the above, For the compound of formula 5, the filter aid may be diatomaceous earth, activated carbon or perlite; It contains diatomaceous earth.

[0107] 39) Another aspect of the present invention relates to a method for producing a composition according to any one of aspects 25) to 34). The present invention relates to a compound of formula 6 (clazosentan disodium salt) which can be used as a base.

[0108] 40) Another embodiment is a compound of formula 6 (clazosentan disodium salt); or 9) Compounds according to the European Pharmacopoeia When measured according to Chapter 2.2.2 of OEIA 6.0, The 2.5% w / v test solution in water was ) having equivalent coloring to any one of Y3, BY3, GY3 or (optionally) B3 or less colored; the compound of formula 6 or a compound according to embodiment 39). 40) in accordance with Chapter 2.2.2 of the European Pharmacopoeia 6.0. When measured, the test solution has the same color as standard solution GY3 or Less coloring.

[0109] The degree of coloration of solutions of pharmaceutical active ingredients of solutions of pharmaceutical active in gredients) is a common method that is widely used and is described in European Pharmacopoeia 6. 0(Ph.Eur.), Chapter 2.2.2(01 / 2008:20202), Visual inspection as described in Method I or II (especially Method II) This may be done by visual color matching. cobalt(II) chloride (red), iron(III) chloride (yellow) and copper(II) sulfate (blue) From the three parent solutions and 1% hydrochloric acid, yellow (Y1-Y7), green-yellow (GY1-GY7), For brownish yellow (BY1-BY7), brown (B1-B9) and red (R1-R7) A total of 37 color reference solutions were prepared. The following steps for the measurement of the color of a solution are described in Ph.Eur.: A test solution of the substance of interest (in this application, clazosentan) was placed in a colorless glass vial. A predetermined amount of the compound is dissolved in a suitable solvent such as water to prepare a yellow compound (Y1- Y7), greenish yellow (GY1-GY7), brownish yellow (BY1-BY7), brown (B1 The color standard solutions for red (R1-R7) and red (B9-B9) were prepared according to Ph.Eur.6.0, Cha Prepare according to pter 2.2.2 or obtain ready-made standard solutions (e.g. Sig (from Ma-Aldrich or Merck). iii) Preparation of test and standard solutions. The colors were compared visually according to Method I or Method II to determine the color of the test material. The color of the solution is determined. Each standard solution is based on the International Commission on Illumination (ICI). For example, the Commission on Illumination requires that brightness ( A color space defined by saturation (lightness), hue and chroma (chrominance) The color space is defined in the CIELAB color space. The exact method to be used is described in Chapter 2.2.2(01 / 02) of the European Pharmacopoeia 6.0. 2008:20202), Method I or II (preferably Method II) The method is adequately described in, for example, US Pat. No. 6,393,363, which is incorporated herein by reference. Several different editions of the European Pharmacopoeia, such as European Pharmacopoeia 6.0 and 7.0, have been developed to measure color. It is understood that the terms used herein essentially describe the same method. "Y p , B.Y. Q , G.Y. R Or B s " (e.g., Y3, BY3, GY3 or B3) In the formula, the subscripts P, Q, and R independently represent integers from 1 to 7. The subscript S represents an integer For the avoidance of doubt, the color of the test solution is the same as that of the standard solution Y. p , B.Y. Q , G Y R Or B s It is described as having the same or less coloring as any one of the above. This means that the test solution is p , or standard solution BY Q , or standard solution GY R , or standard solution B s This means that the color is equal to or less than that of the original. The test solution is mixed with standard solutions Y1 to Y7, or with standard solutions GY1 to GY7, or with standard solutions The results are confirmed by comparing with the solutions BY1 to BY7 or with the standard solutions B1 to B9, as appropriate. Furthermore, the test solution should be mixed with only one of the above standard solutions (especially standard solutions GY1 to GY7). ) may be compared, and the series of standard solutions is selected based on the color of the test solution that best matches the color of the test solution. For example, the green-yellow test solution is compared with the standard solutions GY1 to GY7; The brownish yellow test solution is compared with the standard solutions BY1 to BY7, etc. If it is possible to match two or more of the standard solutions, a series of two or three standard solutions Comparisons may be made to the above.

[0110] 41) Another embodiment is a compound of formula 6 (clazosentan disodium salt); or embodiment 39 ) according to Chapter 2.2.2 of the European Pharmacopoeia 6.0. When the compound is measured using a 2.5% w / v test solution in water, the 4, GY4 or (optionally) B4, or The compound of formula 6 (clazosentan disodium salt); relates to a compound according to embodiment 39). In a subembodiment of embodiment 41), the compound according to the European Pharmacopoeia 6 When measured according to Chapter 2.2.2. of .0, the above test solutions are It has the same color or less color compared to GY4.

[0111] 42) Another embodiment is a compound of formula 6 (clazosentan disodium salt); or embodiment 39 ) according to Chapter 2.2.2 of the European Pharmacopoeia 6.0. When the compound was measured using a 2.5% w / v test solution in water, the standard solution Y5, BY 5, GY5 or (optionally) B5, or The compound of formula 6 (clazosentan disodium salt); relates to a compound according to embodiment 39). In a subembodiment of embodiment 42), the compound according to the European Pharmacopoeia 6 When measured according to Chapter 2.2.2. of .0, the above test solutions are Has similar or less color compared to GY5.

[0112] 43) Another embodiment is a compound of formula 6 (clazosentan disodium salt); or embodiment 39 ) according to Chapter 2.2.2 of the European Pharmacopoeia 6.0. When the compound was measured using a 2.5% w / v test solution in water, the 6, GY6 or (optionally) B6, or The compound of formula 6 (clazosentan disodium salt); relates to a compound according to embodiment 39). In a subembodiment of embodiment 43), the compound according to the European Pharmacopoeia 6 When measured according to Chapter 2.2.2. of .0, the above test solutions are It has the same color or less color compared to GY6.

[0113] 44) Another embodiment is a compound of formula 6 (clazosentan disodium salt); or embodiment 39 ) according to Chapter 2.2.2 of the European Pharmacopoeia 6.0. When the compound was measured using a 2.5% w / v test solution in water, the 7, GY7 or (optionally) B7, or The compound of formula 6 (clazosentan disodium salt); relates to a compound according to embodiment 39). In a subembodiment of embodiment 44), the compound according to the European Pharmacopoeia 6 When measured according to Chapter 2.2.2. of .0, the above test solutions are It has the same or less color compared to GY7.

[0114] 45) In another embodiment, the following refraction angle 2θ in a powder X-ray diffractogram is obtained: 6 is characterized by the presence of peaks at 12.0°, 12.0° and 21.9°; or any one of aspects 39) to 44). The present invention relates to a crystalline form of a compound according to the present invention.

[0115] 46) In another embodiment, the following refraction angle 2θ in a powder X-ray diffractogram is obtained: It is characterised by the presence of peaks at 12.0°, 18.4°, 21.2° and 21.9°. A crystalline form of the compound of formula 6 (clazosentan disodium salt); or, The present invention relates to a crystalline form of a compound according to any one of 9) to 44).

[0116] 47) In another embodiment, the following refraction angle 2θ in a powder X-ray diffractogram is obtained: °, 12.0°, 13.2°, 17.7°, 18.4°, 19.8°, 21.2°, 21 The compound of formula 6 (Cl) is characterized by the presence of peaks at 24.9° and 24.9°. Zosentan disodium salt); or according to any one of embodiments 39) to 44). This relates to the crystalline form of the compound.

[0117] 48) Another aspect is - 9.4°, 12.0°, 13.2°, 17.7°, 18.4°, 19.8°, 21. At least four peaks having refractive angles 2θ selected from 2°, 21.9° and 24.9° or in particular at least six peaks, or more particularly at least eight peaks. or by powder X-ray diffractograms; - by a powder X-ray diffractogram essentially showing the pattern shown in Figure 1; A crystalline form of the compound of formula 6 (clazosentan disodium salt) characterized in that: The present invention relates to a crystalline form of a compound according to any one of 39) to 44).

[0118] For the avoidance of any doubt, one of the above embodiments is "based on powder X-ray diffractograms." "At least one peak at the following refraction angle 2θ" or "at least one peak at the following refraction angle 2θ" Whenever a reference is made to a powder X-ray diffractogram having a peak of The diffractograms were obtained by combining Cu Kα1 and Kα2 radiation ( The results were obtained using combined Cu Kα1 and Kα2 radiation. and the accuracy of the 2θ values ​​provided herein is within the range of + / - 0.1 to 0.2°. It should be understood that, in particular, the refraction angle for the peak in the embodiments and claims of the present invention. When specifying 2 theta (2θ), the 2θ value stated ranges from -0.2° to between the value +0.2° (2θ+ / -0.2°); and in particular between the value -0.1° and the value +0 0.1° (2θ+ / -0.1°).

[0119] For example, the presence of a peak in a powder X-ray diffractogram is defined in the usual way. The trick is to do this in terms of the S / N ratio (S=signal, N=noise). This definition If you say that according to The peak in the powder X-ray diffractogram is greater than x (x is a number greater than 1). A signal-to-noise ratio (S=signal, N=noise) of typically greater than 2, and especially greater than 3. It is understood to be defined by having.

[0120] In the context of a crystalline compound essentially exhibiting the powder X-ray diffraction pattern shown in, for example, FIG. In the present specification, the term "essentially" means at least one of the diffractograms shown in the figure. Compared to the main peak, i.e. the most intense peak in the diffractogram, 20% This means that there must be peaks with a relative intensity greater than 10%, in particular with a relative intensity greater than 10%. However, those skilled in the art of powder X-ray diffraction will recognize the phase differences of powder X-ray diffractograms. Preferred orientations where the paired intensities may cause the disappearance of a peak or the intensity variation of a single peak It should be recognized that the optical fiber may be subject to strong intensity fluctuations due to effects.

[0121] 49) In another aspect, the present invention relates to a method for the determination of the methylation level of the At least 90% w / w as measured by HPLC method B described above or a similar HPLC method. / w, at least 91% w / w, at least 92% w / w; at least 93% w / w, at least 94% w / w, at least 95% w / w, at least 96% w / w, at least Assay of 97% w / w, at least 98% w / w or at least 99% w / w ay) (especially 99.1% assay); any of embodiments 40) to 48) or a compound of formula 6 (clazosentan disodium salt) according to embodiment 39); The present invention relates to a compound having the formula:

[0122] The term "assay" refers to a quantitative measurement, commonly used in the pharmaceutical industry, of the amount of an analyte in a sample. Specifically, as used herein, the term refers to a percentage of the total weight of a sample (% w / w Assay ("as is") refers to the amount of the compound of formula 6 in a sample. The standard assay “as is” is, in particular, performed by HPLC. by HPLC method B disclosed herein.

[0123] 50) In another aspect, the compound of formula 6 is present in an amount of 5% w / w or less, 4% w / w or less, in particular 3% w / w or less. / w or less, particularly 2% w / w or less of total impurities, and said impurities are by HPLC (by HPLC method B described herein or a similar HPLC method The compound of formula 6 according to any one of embodiments 40) to 49) is measured by LC method. lazosentan disodium salt); or a compound according to embodiment 39).

[0124] As used herein, the term "impurities" refers to those compounds that are, by HPLC, particularly those disclosed herein. Identified and unidentified impurities (identified and unidentified) detectable by HPLC method B The amount of impurities referred to in this specification is referred to as unspecified related substances. The total amount is detectable by HPLC, particularly by HPLC method B disclosed herein. "Specified" means the sum of essentially all impurities, both specified and unspecified.

[0125] 51) In another aspect, the compound of formula 6 is present in an amount of 5% w / w or less, 4% w / w or less, in particular 3% w / w or less. and having a total residual solvent content of less than 1% w / w, preferably less than 2% w / w, and especially less than 1% w / w, The solvent is ethylene glycol, ethanol, methanol, tetrahydrofuran and dimethyl (The total amount of the remaining solvent is determined by gas chromatography.) in particular by headspace gas chromatography (GC-HS) as described herein. (measured by) the compound of formula 6 (clazose) according to any one of embodiments 40) to 50). or a compound according to embodiment 39).

[0126] For the avoidance of doubt, the total amount of residual solvents is the total amount of ethylene glycol, ethylene glycol The sum of the individual amounts of ethanol, methanol, tetrahydrofuran, and dimethylformamide. means.

[0127] 52) In another aspect, the compound of formula 6 is (Measured by headspace gas chromatography (GC-HS) as described in the fine print) ethanol or the like. or a compound of formula 6 (clazosentan disodium salt) according to any one of the following embodiments: )

[0128] 53) In another aspect, the compound of formula 6 is (Measured by headspace gas chromatography (GC-HS) as described in the fine print) Aspects 40) to 52) having 0.3% w / w or less of a residual solvent selected from methanol. or a compound of formula 6 (clazosentan disodium salt) according to any one of the following embodiments: )

[0129] 54) In another aspect, the compound of formula 6 is (Measured by headspace gas chromatography (GC-HS) as described in the fine print) 40. The method of claim 40, further comprising administering to said patient a solution of the formula: 53) to 54); or , embodiment 39).

[0130] 55) In another aspect, the compound of formula 6 is (Measured by headspace gas chromatography (GC-HS) as described in the fine print) dimethylformamide. A compound of formula 6 (clazosentan disodium salt) according to any one of 0) to 54); or relates to compounds according to embodiment 39).

[0131] 56) In another aspect, the compound of formula 6 is (Measured by headspace gas chromatography (GC-HS) as described in the fine print) 5. The composition of claim 4, further comprising a residual solvent selected from the group consisting of ethylene glycol and ethylene glycol, and having 0.062% w / w or less. A compound of formula 6 (clazosentan disodium salt) according to any one of 0) to 55); or relates to compounds according to embodiment 39).

[0132] Any one of the embodiments 40) to 56) may be selected from two options, namely, the compound of formula 6 (Cla Zosentan disodium salt) itself, and according to embodiment 39) [or according to embodiments 39) to 44) and 49) to 56)], i.e. compounds of formula 6 which can be obtained by the corresponding methods each of the options independently determines the refraction angle, color, assay, impurity It shall be further characterized by each technical feature such as total amount, amount of residual solvent, etc.

[0133] 57) Another aspect relates to a pharmaceutical composition comprising a compound according to any one of aspects 39) to 56). With respect to compositions (especially for intravenous infusion; especially solutions for intravenous infusion), the compositions are At least one pharma- ceutically acceptable carrier (especially water) and optionally at least one pharma- ceutically acceptable In particular, such a pharmaceutical composition is any one of the embodiments 39) to 56). Compounds according to one of the following, and optionally a buffer (e.g., tris(hydroxymethyl)aminomethyl) (TRIS), optionally a chelating agent (e.g., edetate disodium), and optionally an isotonic agents (e.g., sodium chloride) and water.

[0134] 58) Another embodiment relates to a pharmaceutical composition according to embodiment 57) (especially for intravenous injection; especially Such a composition is a solution for intravenous infusion, - About 20 mg / mL to about 40 mg / mL according to any one of aspects 39) to 56). Compound; - water; Optionally, about 5 mg / mL to about 15 mg / mL of tris(hydroxymethyl)aminomethyl Tan; optionally, about 0.05 to about 0.15 mg / mL of disodium edetate; and optionally, about 2.0 to about 3.0 mg / mL sodium chloride; A pharmaceutical composition comprising:

[0135] 59) Another embodiment relates to a pharmaceutical composition according to embodiment 57) (especially for intravenous injection; especially Such a composition is a solution for intravenous infusion, - About 25.0 mg / mL to about 29.0 mg / mL (particularly about 27.0 mg / mL) A compound according to any one of 39) to 56); - water; Optionally, from about 8.0 mg / mL to about 12.0 mg / mL (particularly about 10.0 mg / mL) of tris(hydroxymethyl)aminomethane; Optionally, from about 0.08 mg / mL to about 0.12 mg / mL (particularly about 0.1 mg / mL) of edetate disodium; and Optionally, from about 2.0 mg / mL to about 3.0 mg / mL (particularly about 2.5 mg / mL) of the salt sodium chloride; A pharmaceutical composition comprising:

[0136] The amount of disodium salt of the compound of formula 6 in the pharmaceutical composition according to the present invention is The amount of the compound of formula 6 can be calculated based on the amount of the free acid of the compound of formula 6. The amount of free acid can be directly measured by analytical methods commonly used in the art, such as HPLC. For example, about 25.0 mg / mL to about 29.0 mg / mL (or about 27. The disodium salt of the compound of formula 6 at 0 mg / mL has a pH of about 23.2 to about 26.9 (or about 25.0 mg / mL) It is understood that this corresponds to a free acid of the compound of formula 6 (0.0 mg / mL), and the free acid of the compound of formula 6 The amount of released acid may be measured directly by HPLC. The term "free acid" refers to a compound of formula 5.

[0137] 60) Another embodiment relates to a pharmaceutical composition according to embodiment 57) (especially for intravenous injection; especially Such a composition is a solution for intravenous infusion, - About 23.5 mg / mL to about 26.5 mg / mL (particularly about 25 mg / mL) ) to 56) (the compound (listed in mg / mL) of the compound) The concentration relates to a compound according to any one of embodiments 39) to 56) in free acid form. - Tris of about 8.0 mg / mL to about 12.0 mg / mL (especially about 10.0 mg / mL) (Hydroxymethyl)aminomethane; - Edetate of about 0.08 mg / mL to about 0.12 mg / mL (especially about 0.1 mg / mL) disodium phosphate; and - Sodium chloride of about 2.0 mg / mL to about 3.0 mg / mL (especially about 2.5 mg / mL) Umm; A pharmaceutical composition comprising:

[0138] 61) Another embodiment is a pharmaceutical composition according to any one of embodiments 59) or 60), , when measured according to Chapter 2.2.2. of the European Pharmacopoeia 6.0. The composition is the same as that of any one of standard solutions Y3, BY3, GY3 or (optionally) B3. etc. or have little coloration; relating to pharmaceutical compositions.

[0139] 62) Another embodiment is a pharmaceutical composition according to any one of embodiments 59) or 60), , when measured according to Chapter 2.2.2. of the European Pharmacopoeia 6.0. The composition has equivalent or less coloring compared to standard solution GY3; pharmaceutical composition Regarding.

[0140] The pharmaceutical composition according to the present invention has a pH value of about 7.0 to about 9.0; particularly about 7. 5 to about 8.5; more preferably 8.0±0.1. do.

[0141] The preparation of pharmaceutical compositions can be carried out in a manner well known to any person skilled in the art (see, for example, Reming et al. ton, The Science and Practice of Pharmacy , 21st Edition (2005), Part 5, “Pharmaceutic 'Al Manufacturing' [Lippincott Williams & Wilkins, and the crystalline forms of the present invention may be optionally administered with other therapeutic agents. In combination with a therapeutically beneficial agent, a suitable non-toxic, inert, pharma- ceutically acceptable solid or liquid The pharmaceutical formulation is prepared by mixing the pharmaceutical composition with a suitable carrier material and, if necessary, with a conventional pharmaceutical adjuvant. Examples of pharma- ceutically acceptable excipients include, inter alia, cosolvents ( co-solvents), buffers, metal ion chelating agents, surfactants, osmolality adjusters Osmolarity regulators, preservatives, viscosity regulators and solubilizers It is a drug.

[0142] It is understood that the crystalline forms according to the present invention may contain non-coordinating and / or coordinating solvents. is used herein as a term for crystalline solvates (e.g., hydrates). Similarly, non-coordinating solvents are used herein in conjunction with the term physically adsorbed or physically trapped solvents. Used as a cal Industry(Ed.R.Hilfiker, VCH, 2006), Cha pter 8:UJGriesser:The Importance of So The crystalline form according to any one of the embodiments 45) to 49) can be prepared by the method according to the invention using a non-solvent. These correspond to non-hydrated, non-aqueous crystal forms, but may have non-coordinating water or another non-coordinating solvent.

[0143] The crystalline form according to the invention decomposes at about 250° C. as determined by DSC.

[0144] The sodium content in the compound of formula 6 disclosed herein is understood to be about 2 equivalents. The sodium content of the compound is within the normal technical limits accepted in the pharmaceutical industry. In particular, the sodium content of the compounds of formula 6 disclosed herein can be determined by potentiometric titration according to USP <541> / Ph.Eur.2.2.20. When measured by methods commonly used in the art, such as tric titration, About 6.4% w / w to about 8.4% w / w of the total weight; in particular about 7.2% w / w to about 7.7% w / w In particular, it may be about 7.4% w / w. The potentiometric titration method is described in this specification in Chapter 2.2.20 of the Palatinate Pharmacopoeia 6.0. This may be done by the method described.

[0145] 63) Another aspect relates to a pharmaceutical composition; in particular a pharmaceutical composition according to any one of the aspects 57) to 62). Use of a compound of formula 6 according to any one of embodiments 39) to 56) for the manufacture of a composition. Regarding.

[0146] 64) Another aspect is any one of aspects 39) to 56) for use as a medicament. or a composition according to any one of embodiments 57) to 62).

[0147] 65) Another embodiment is an endothelin receptor (particularly ET A Receptor-related diseases Any one of aspects 39) to 56) for use in the prevention or treatment of a disease or disorder. or a composition according to any one of embodiments 57) to 62).

[0148] 66) Another embodiment is aneurysmal subarachnoid hemorrhage surgery. Cerebral vasospasm after achnoid hemorrhage surgery and / or Vasospasm-related cerebral infarction farction and cerebral ischemic symptoms Any of the embodiments 39) to 56) for use in the prevention or treatment (particularly the prevention) of oms. or a composition according to any one of the embodiments 57) to 62). do.

[0149] 67) Another aspect is the use of vasospasm-related and Morbidity and mortality (from all causes) In particular, for the prevention or treatment (especially the prevention) of vasospasm-related morbidity and mortality from all causes A compound of formula 6 according to any one of embodiments 39) to 56) or embodiment 57) for use in 57) to 62).

[0150] The aneurysmal subarachnoid hemorrhage surgery (or aneurysm repair) described herein epair) is specifically a surgical clipping technique. or by endovascular coil embolization. The term "subarachnoid hemorrhage surgery" refers to the treatment of aneurysmal subarachnoid hemorrhage. barachnoid hemorrhage securing.

[0151] 68) Another embodiment is cerebral vasospasm and / or vasospasm after surgery for aneurysmal subarachnoid hemorrhage. For use in the prevention or treatment (especially prevention) of apoptosis-related cerebral infarction and cerebral ischemia conditions. Compounds of formula 6 according to any one of embodiments 39) to 56) or according to any one of embodiments 57) to 62). The composition according to claim 1, wherein the pharmaceutical composition having the compound is administered at a dose of about 5 mg / h, about 10 mg / h, / h or about 15 mg / h (particularly, about 10 mg / h or about 15 mg / h; especially about 10 mg / h g / h) to a patient as a continuous intravenous infusion, said dose being the amount of said compound in free acid form. The administration began after surgery for aneurysmal subarachnoid hemorrhage and was continued until the aneurysm rupture. and lasting for up to 15 days after urinary rupture], relating to the composition.

[0152] 69) Another aspect is the use of thrombolytic therapy in patients after aneurysmal subarachnoid hemorrhage (particularly in patients with thick aneurysmal subarachnoid hemorrhage). in patients with diffuse vascular endothelial cell carcinoma, Prevention of complications and / or permanent brain damage or for use in therapy (particularly prophylaxis) according to any one of the aspects 39) to 56). or a composition according to any one of embodiments 57) to 62).

[0153] 70) Another aspect is the use of thrombolytic therapy in patients after aneurysmal subarachnoid hemorrhage (especially in patients with thick and d) incidence and / or incidence of cerebral vasospasm in patients with diffuse or the formula according to any one of embodiments 39) to 56) for use in reducing the severity of 6 or a composition according to any one of embodiments 57) to 62).

[0154] 71) Another aspect is the use of thrombolytic therapy in patients after aneurysmal subarachnoid hemorrhage (especially in patients with thick and d in patients with diffuse A compound of formula 6 according to any one of embodiments 39) to 56) for use in reducing the severity of or a composition according to any one of embodiments 57) to 62).

[0155] 72) Another aspect is the use of thrombolytic therapy in patients after aneurysmal subarachnoid hemorrhage (especially in patients with thick and d) in patients with diffuse cerebral artery disease, vasospasm-related delayed cerebral ischemia Aspects 39) to 5) for use in the prevention or treatment (particularly prevention) of cerebral infarction caused by 6) or a compound of formula 6 according to any one of embodiments 57) to 62). Related to the composition.

[0156] 73) Another aspect is the use of thrombolytic therapy in patients after aneurysmal subarachnoid hemorrhage (especially in patients with thick and d) in patients with diffuse cerebral artery disease, vasospasm-related delayed cerebral ischemia Prevention or treatment of clinical deterioration caused by The compound of formula 6 according to any one of embodiments 39) to 56) for use in the treatment, especially prophylaxis, or a composition according to any one of embodiments 57) to 62).

[0157] 74) Another aspect is the use of thrombolytic therapy in patients after aneurysmal subarachnoid hemorrhage (especially in patients with thick and d) in patients with diffuse vascular disease, prevention or treatment of cerebral vasospasm of formula 6 according to any one of embodiments 39) to 56) for use in (especially prophylaxis) The compound or composition according to any one of the embodiments 57) to 62).

[0158] 75) Another aspect is the use of thrombolytic therapy in patients after aneurysmal subarachnoid hemorrhage (especially in patients with thick and d in patients with diffuse any cause; especially vasospasm-related) and / or In the prevention or treatment (especially the prevention) of death from any cause; especially death related to vasospasm A compound of formula 6 according to any one of embodiments 39) to 56) or embodiment 57 for use in ) to 62).

[0159] 76) Another embodiment is any of embodiments 39) to 56) for use in any of the following: or a composition according to any one of the embodiments 57) to 62). : Admission of patients (especially those with thick and diffuse cloth) Reduction of hospital stay / intensive care unit stay; patients after aneurysmal subarachnoid hemorrhage (especially thick reduction in time to return to work for patients with arterial and diffuse Patients after aneurysmal subarachnoid hemorrhage (especially those with thick and diffuse reduction in the need / amount of rehabilitation for patients after aneurysmal subarachnoid hemorrhage ( Long-term clinical outcomes, especially in patients with thick and diffuse and / or to improve outcomes in patients after aneurysmal subarachnoid hemorrhage (especially in patients with thick and Improvement of cognition, cognitive function, and quality of life in patients with fuse cloth good.

[0160] 77) Another embodiment is a pharmaceutical composition comprising the compound, the pharmaceutical composition being administered at a dose of about 5 mg / h, about 10 mg / h, h or about 15 mg / h (particularly, about 10 mg / h or about 15 mg / h; especially about 15 mg / h) as a continuous intravenous infusion to treat patients (especially those with thick and diffuse The dose is the amount of the compound in free acid form. The administration begins following the rupture of the aneurysm and continues for up to 14 days thereafter. A formula according to any one of embodiments 39) to 56) for use according to any one of embodiments 76). 6 or a composition according to any one of embodiments 57) to 62).

[0161] For the avoidance of doubt, the present invention relates to the prevention or treatment of any disease or disorder according to aspects 65) to 76). A compound of formula 6 according to any one of embodiments 39) to 56) for use in the treatment of When referring to a composition according to any one of aspects 57) to 62), the present invention relates to a method for treating a disease or disorder in question. A method for the prevention or treatment (in particular prevention), comprising the steps of: The method also includes administering (an effective amount of) the compound of formula 6 to a subject in need thereof. This is assumed to be the case.

[0162] For the avoidance of doubt, the present invention relates to the prevention or treatment of any disease or disorder according to aspects 65) to 76). A compound of formula 6 according to any one of embodiments 39) to 56) for use in the treatment of When referring to a composition according to any one of aspects 57) to 62), the present invention relates to a method for treating a disease or disorder in question. In the manufacture of a medicament for the prevention or treatment of The use of compound 6 is also disclosed.

[0163] For the avoidance of doubt, the present invention relates to the prevention or treatment of any disease or disorder according to aspects 65) to 76). A compound of formula 6 according to any one of embodiments 39) to 49) for use in the treatment of When referring to a composition according to any one of aspects 49) to 55), the composition is intended to be used for treating the disease or disorder in question. According to any one of the embodiments 39) to 56) for use in a method for prevention or treatment Compounds of formula 6 are also intended to be disclosed.

[0164] For the avoidance of doubt, the present invention is directed to the prevention or treatment of any disease or disorder according to aspects 65) to 76). A compound of formula 6 according to any one of embodiments 39) to 56) or embodiment 57) for use in When referring to a composition according to any one of 57) to 62), the prevention of the disease or disorder in question is mentioned. or a pharmaceutical for treatment (particularly prevention), according to any one of aspects 39) to 56). A medicament having a compound of formula 6 is also disclosed.

[0165] As used herein, the term "effective amount" refers to an amount administered to a subject for up to 15 days (particularly for Approximately 5 mg / day to approximately 20 mg / day (especially approximately 5 mg / day, approximately 10 mg / day) is administered for a maximum of 14 days. The effective amount is preferably administered intravenously. The therapeutic agent is administered intravenously, preferably as a continuous infusion.

[0166] The term "thick and diffuse cloth" as used in this specification The term refers to the presence of three or more basal cisterns as determined by computed tomography (CT). (basal cisterns) involved, thickened and confluent, >4 mm thick thick and confluent clot Patients diagnosed with diffuse idiopathic pulmonary disease are particularly in need of the compounds of the present invention. They may be classified as high-risk patients.

[0167] As used herein, the term "cerebral infarction" refers to a new or worsening stroke of any cause. Cerebral infarction (especially about 5 cm 3 (infarctions having a total volume exceeding 100 mm) The CT scan performed 16 days after the start of drug treatment was used to determine whether the stroke was a progressive stroke. Central radiology diagnostics compared with a previous CT scan This may be confirmed by institutional review.

[0168] As used herein, the term "clinical deterioration" refers to a condition in which the patient is on the mGCS or aNIHSS scale. At least 2 points higher than the reference score in the A worsening of the cerebral vasospasm that lasts for at least 2 hours and is completely attributable to a cause other than cerebral vasospasm Clinical deterioration due to delayed cerebral ischemia is difficult to predict without checking clinical data. Case studies, case narratives, angiograms and / or CT scans The term "mGCS" refers to Glasgow Coma The Consciousness Scale (SCI) is a reliable and objective means of recording the state of consciousness in humans. The term "aNIHSS" refers to a simple ( abbreviated)National Institutes of Health h Stroke Scale: This is a measure of the disability caused by a stroke. It is a tool used by health care providers to objectively quantify

[0169] The term "subject", also "patient", refers to a mammal, particularly a human. The term "subject" refers to the term "patient."

[0170] Therefore, based on the dependent relationships of the different aspects 1) to 6) disclosed above, the following aspects are possible: are contemplated and specifically disclosed herein as individual embodiments: 2+1, 3 +2+1, 4+1, 4+2+1, 4+3+2+1, 5+1, 5+2+1, 5+3+2+1 , 5+4+1, 5+4+2+1, 5+4+3+2+1, 6+1, 6+2+1, 6+3+2 +1, 6+4+1, 6+4+2+1, 6+4+3+2+1, 6+5+1, 6+5+2+1 , 6+5+3+2+1, 6+5+4+1, 6+5+4+2+1 or 6+5+4+3+2+ 1.

[0171] Therefore, based on the dependent relationship of the different aspects 7) to 11) disclosed above, the following aspects are possible: are contemplated and specifically disclosed herein as individual forms: 8+7, 9+7, 9+8+7, 10+7, 10+8+7, 10+9+7, 10+9+8+7, 11 +7, 11+8+7, 11+9+7, 11+9+8+7, 11+10+7, 11+10+ 8+7, 11+10+9+7 or 11+10+9+8+7.

[0172] Therefore, based on the dependency relationship of the different aspects 12) to 18) disclosed above, the following aspects are possible: It is possible, contemplated, and specifically disclosed herein as individual embodiments: 12, 14+12, 14+13+12, 15+12, 15+13+12, 15+14+1 2, 15+14+13+12, 16+12, 16+13+12, 16+14+12, 16 +14+13+12, 16+15+12, 16+15+13+12, 16+15+14+ 12, 16+15+14+13+12, 17+12, 17+13+12, 17+14+1 2, 17+14+13+12, 17+15+12, 17+15+13+12, 17+15 +14+12, 17+15+14+13+12, 17+16+12, 17+16+13+ 12, 17+16+14+12, 17+16+14+13+12, 17+16+15+1 2, 17+16+15+13+12, 17+16+15+14+12, 17+16+15 +14+13+12, 18+12, 18+13+12, 18+14+12, 18+14+ 13+12, 18+15+12, 18+15+13+12, 18+15+14+12, 1 8+15+14+13+12, 18+16+12, 18+16+13+12, 18+16 +14+12, 18+16+14+13+12, 18+16+15+12, 18+16+ 15+13+12, 18+16+15+14+12, 18+16+15+14+13+1 2, 18+17+12, 18+17+13+12, 18+17+14+12, 18+17 +14+13+12, 18+17+15+12, 18+17+15+13+12, 18+ 17+15+14+12, 18+17+15+14+13+12, 18+17+16+1 2, 18+17+16+13+12, 18+17+16+14+12, 18+17+16 +14+13+12, 18+17+16+15+12, 18+17+16+15+13+ 12 or 18+17+16+15+14+12, 18+17+16+15+14+13+ 12.

[0173] Therefore, based on the dependency relationship of the different aspects 19) to 24) disclosed above, the following aspects are possible: It is possible, contemplated, and specifically disclosed herein as individual embodiments: 20+ 19, 21+20+19, 22+19, 22+20+19, 22+21+20+19, 2 3+19, 23+20+19, 23+21+20+19, 23+22+19, 23+22 +20+19, 23+22+21+20+19, 24+19, 24+20+19, 24+ 21+20+19, 24+22+19, 24+22+20+19, 24+22+21+2 0+19, 24+23+19, 24+23+20+19, 24+23+21+20+19 , 24+23+22+19, 24+23+22+20+19 or 24+23+22+21 +20+19.

[0174] Therefore, based on the dependency relationship of the different aspects 25) to 28) disclosed above, the following aspects are possible: It is possible, contemplated, and specifically disclosed herein as individual embodiments: 25, 27+25, 27+26+25, 28+25, 28+26+25, 28+27+2 5 or 28+27+26+25.

[0175] Therefore, based on the dependency relationship of the different aspects 39) to 60) disclosed above, the following aspects are possible: It is possible, contemplated, and specifically disclosed herein as individual embodiments: 39, 45+40, 45+41, 45+42, 45+43, 45+44, 46+39, 4 6+40, 46+41, 46+42, 46+43, 46+44, 47+39, 47+40 , 47+41, 47+42, 47+43, 47+44, 48+39, 48+40, 48+ 41, 48+42, 48+43, 48+44, 49+39, 49+40, 49+41, 4 9+42, 49+43, 49+44, 49+45+39, 49+45+40, 49+45 +41, 49+45+42, 49+45+43, 49+45+44, 49+46+39, 49+46+40, 49+46+41, 49+46+42, 49+46+43, 49+4 6+44, 49+47+39, 49+47+40, 49+47+41, 49+47+42 , 49+47+43, 49+47+44, 49+48+39, 49+48+40, 49+ 48+41, 49+48+42, 49+48+43, 49+48+44, 50+39, 5 0+40, 50+41, 50+42, 50+43, 50+44, 50+45+39, 50 +45+40, 50+45+41, 50+45+42, 50+45+43, 50+45+ 44, 50+46+39, 50+46+40, 50+46+41, 50+46+42, 5 0+46+43, 50+46+44, 50+47+39, 50+47+40, 50+47 +41、50+47+42、50+47+43、50+47+44、50+48+39、 50+48+40、50+48+41、50+48+42、50+48+43、50+4 8+44、51+39、51+40、51+41、51+42、51+43、51+44 、51+45+39、51+45+40、51+45+41、51+45+42、51+ 45+43、51+45+44、51+46+39、51+46+40、51+46+4 1、51+46+42、51+46+43、51+46+44、51+47+39、51 +47+40、51+47+41、51+47+42、51+47+43、51+47+ 44、51+48+39、51+48+40、51+48+41、51+48+42、5 1+48+43、51+48+44、52+39、52+40、52+41、52+42 、52+43、52+44、52+45+39、52+45+40、52+45+41、 52+45+42、52+45+43、52+45+44、52+46+39、52+4 6+40、52+46+41、52+46+42、52+46+43、52+46+44 、52+47+39、52+47+40、52+47+41、52+47+42、52+ 47+43、52+47+44、52+48+39、52+48+40、52+48+4 1、52+48+42、52+48+43、52+48+44、53+39、53+40 、53+41、53+42、53+43、53+44、53+45+39、53+45+ 40、53+45+41、53+45+42、53+45+43、53+45+44、5 3+46+39、53+46+40、53+46+41、53+46+42、53+46 +43、53+46+44、53+47+39、53+47+40、53+47+41、 53+47+42、53+47+43、53+47+44、53+48+39、53+4 8+40、53+48+41、53+48+42、53+48+43、53+48+44 、54+39、54+40、54+41、54+42、54+43、54+44、54+ 45+39、54+45+40、54+45+41、54+45+42、54+45+4 3、54+45+44、54+46+39、54+46+40、54+46+41、54 +46+42、54+46+43、54+46+44、54+47+39、54+47+ 40、54+47+41、54+47+42、54+47+43、54+47+44、5 4+48+39、54+48+40、54+48+41、54+48+42、54+48 +43、54+48+44、 55+39、55+40、55+41、55+42、55+43、55+44、55+4 5+39、55+45+40、55+45+41、55+45+42、55+45+43 、55+45+44、55+46+39、55+46+40、55+46+41、55+ 46+42、55+46+43、55+46+44、55+47+39、55+47+4 0、55+47+41、55+47+42、55+47+43、55+47+44、55 +48+39、55+48+40、55+48+41、55+48+42、55+48+ 43、55+48+44、56+39、56+40、56+41、56+42、56+4 3、56+44、56+45+39、56+45+40、56+45+41、56+45 +42、56+45+43、56+45+44、56+46+39、56+46+40、 56+46+41, 56+46+42, 56+46+43, 56+46+44, 56+4 7+39, 56+47+40, 56+47+41, 56+47+42, 56+47+43 , 56+47+44, 56+48+39, 56+48+40, 56+48+41, 56+ 48+42, 56+48+43, 56+48+44, 59+39, 59+40, 59+4 1, 59+42, 59+43, 59+44, 59+45+39, 59+45+40, 59 +45+41, 59+45+42, 59+45+43, 59+45+44, 59+46+ 39, 59+46+40, 59+46+41, 59+46+42, 59+46+43, 5 9+46+44, 59+47+39, 59+47+40, 59+47+41, 59+47 +42, 59+47+43, 59+47+44, 59+48+39, 59+48+40, 59+48+41, 59+48+42, 59+48+43, 59+48+44, 60+3 9, 60+40, 60+41, 60+42, 60+43, 60+44, 60+45+39 , 60+45+40, 60+45+41, 60+45+42, 60+45+43, 60+ 45+44, 60+46+39, 60+46+40, 60+46+41, 60+46+4 2, 60+46+43, 60+46+44, 60+47+39, 60+47+40, 60 +47+41, 60+47+42, 60+47+43, 60+47+44, 60+48+ 39, 60+48+40, 60+48+41, 60+48+42, 60+48+43 or 60+48+44.

[0176] In the above list, the numbers represent the aspects according to the above numbers, and "+" represents the dependence from other aspects. It indicates a relationship between the various aspects. The various aspects are separated from one another by a comma. In other words, for example, "5 "+2+1" means embodiment 5) which is dependent on embodiment 2) which is dependent on embodiment 1), i.e. The embodiment "5+2+1" corresponds to embodiment 5) which is further characterized by the features of embodiments 2) and 1). Correct.

[0177] The definitions provided herein apply to the subject matter defined in any one of the embodiments disclosed herein. It is applied uniformly to all products, and may be given a broader or narrower definition depending on the specific definition. Unless otherwise noted herein, the present specification and claims apply mutatis mutandis. A definition or preferred definition of a term or expression may be used in any or all other applications defined herein. Any or preferred definitions of any term or expression may be defined separately (and together). It may be a replacement.

[0178] When the plural is used for a compound, solid, pharmaceutical composition, disease, etc., it refers to a singular compound. , solids, pharmaceutical compositions, diseases, and the like.

[0179] The word "about" before the numerical value "X" when not used in reference to temperature In this application, the range is between 10% of XX and 10% of X+X, preferably XX 5% to 5% of X+X, most preferably X. In this application, the term "about" before the temperature "Y" refers to the temperature Y-10°C. to Y+10°C; preferably, it means between Y-5°C and Y+5°C. Room temperature means a temperature of about 25°C.

[0180] Whenever the words "between" or "to" are used to describe a numerical range, the indication The endpoints of a range are explicitly included in the range. For example: If it is stated that the temperature is between 40oC and 80oC (or 40oC to (~) 80oC) means that the end points 40oC and 80oC are included in the range; or If the variable is defined as an integer between 1 and 7 (or 1 to 7), then This means that the variable value is the integer 1, 2, 3, 4, 5, 6, or 7.

[0181] The term "solvate" when used alone or in combination In the present invention, a compound as defined herein or a salt thereof and one or more solvents are used. Hydrate means a special form of aggregate. wherein one or more of the solvent molecules contained in the aggregate are water molecules.

[0182] The compound of formula 6 disclosed herein may, in its form, be a tetrazolium compound, as shown below: Different isomers / alternatives regarding the position of the sodium atom in the sulfonamide group and / or in the sulfonamide ring Variant forms may occur:

[0183] [ka] Thus, even though only one isomer / tautomer of the compound of formula 6 is represented herein, Nevertheless, all possible isomers / tautomers of the compounds of formula 6 in solid form are within the scope of the present invention. In solution, such compounds usually exist in different isomers / tautomers. In the solid state, one form typically predominates. The asterisk in the middle, * " and " ** " to the remainder of the molecule of the compound of formula 6 The points of attachment of the corresponding groups are indicated. Similarly, the compounds of formulae 2a and 3a for the sulfonamide group are All possible isomeric / tautomeric forms of are included within the scope of the present invention.

[0184] "w / w" (weight per weight), "w / v" (weight per volume), "v / v" (body The term volume per volume refers to the concentration measured in weight / volume per weight / volume, i.e. "%w / w", "%w / v" or "%v / v" means the percentage of a specific substance in a mixture. When expressed as a percentage, such as "%, " the term refers to the corresponding percentage concentration.

[0185] The term "vol." refers to the amount (e.g., in kg of reactant) per unit weight (e.g., For example, 1 vol. means kg (e.g. of reactant). means 1 liter (e.g. of solvent) per liter.

[0186] The term "wt." refers to the amount by weight (e.g., in grams) of compound B (e.g., reactant). The mass (e.g., in g) of a compound (e.g., reactant) A in a mixture. For example, 5 g of 1 wt. of compound A per compound B means 5 g of compound A; A mixture of 3 wt. of methanol and 3 wt. of ethanol is This means that the weight ratio is 1:3.

[0187] The term "equivalent," or its abbreviation "eq.", refers to the amount of another compound in a described chemical reaction. It means the number of moles of a compound that will react with (or is equivalent to) any number of moles of a compound.

[0188] ABBREVIATIONS (USED ABOVE OR BELOW) : a / a area / area ACN Acetonitrile aq. Water-based d day DABCO 1,4-diazabicyclo[2.2.2]octane DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DMF Dimethylformamide DMSO Dimethyl sulfoxide BHT 2,6-di-tert-butyl-4-methylphenol eq. equivalent weight EDTA Ethylenediaminetetraacetic acid EtOH Ethanol eq. equivalent weight h time 1 H-NMR nuclear magnetic resonance HPLC High Performance Liquid Chromatography IPC In-Process Control iPr2NEt N,N-Diisopropylethylamine KOtBu Potassium tert-butylate MeOH Methanol min ml or mL milliliter NaOMe Sodium methoxide NEt3 Triethylamine 2-PrOH Isopropyl alcohol rt room temperature THF Tetrahydrofuran TMS-Cl Chlorotrimethylsilane TMS-CN Trimethylsilyl cyanide UV ultraviolet light

[0189] Experimental section All temperatures are given in degrees Celsius.

[0190] HPLC Method A Equipment: Online degasser (e.g. G1322A), low pressure quaternary pump (quat ernary pump) (e.g. G1311A), autosampler (e.g. G132 9A), a temperature-controlled column compartment (e.g. G1316A) and a UV detector (e.g. Agilent 1100 Series system equipped with a DADG1315B or equivalent Solvent: ACN / H2O = 3 / 1 or ACN / H2O = 1 / 1 (Depending on the sample, DMS Addition of O may be required.) Column: Halo C18 4.6mm x 100mm , 2.7 μm. Mobile phase: A: 0.05% (v / v) HCOOH in water, B: 0 in ACN .05% (v / v) HCOOH. Column temperature: 40.0 ± 1.0 °C. Data collection time: 1 2min. Flow rate: 1.5mL / min. Gradient:

[0191] [Table 1] Method B Equipment: Online degasser (e.g. G1322A), low pressure quaternary pump (e.g. G 1311A), autosampler (e.g. G1329A), temperature controlled column compartment A thermocouple (e.g. G1316A) and a UV detector (e.g. DADG1315B) or equivalent. Agilent 1100 / 1200 / 1260 series system equipped with. Solvent: Mobile phase A. Column: Waters X-Bridge C18, 150mmx3.0mm, 3. 5 μm. Mobile phase: A: Buffer (3.7 mM sodium tetraborate decahydrate pH 9. 0) / ACN / Tetrabutylammonium hydroxide 70 / 30 / 0.35(v / v / v) and B: Buffer / ACN / Tetrabutylammonium hydroxide 40 / 60 / 0.35 (v / v / v). Column temperature: 50°C. Data collection time: 15 min. Rate: 1.0mL / min. Gradient:

[0192] [Table 2] The assay value ("as is standard" assay) may be calculated according to the following formula:

[0193]

number

[0194]

number

[0195] The assay values ​​described in this application are based on residual solvent and water that may be present in the analytical sample. The residual solvents are ethylene glycol, tetrahydrofuran, methyl The compounds are methanol, ethanol and N,N-dimethylformamide. The amount of solvent (by gas chromatography (method described herein) and the amount of water (by Fischer titration (as described herein) was first measured, and then the assay value (i.e., anhydrous and solvent-free assays) according to the following formula:

[0196]

number

[0197] The amount of each individual impurity (hereinafter also referred to as related substances) is calculated according to the following formula: You may:

[0198]

number

[0199] [Table 3] Photometric titration Apparatus: Titrino (e.g. Metrohm model 716). Electrode: Composite pH electrode. Combined pH-electrode (e.g. Metrohm6.023 2.100). Titration rate: Measurement drift rement drift):10mV / min, maximum waiting time (max.waitin g period)60s, measuring point density (measuring point density) ty): 4 min. Increment: 10.0 μL, Dosage rate ing rate): Max. mL / min. Solvent: Water. Reagent: Hydrochloric acid 0.1 mol / L. Standard (Standard): Trizma base. Sample concentration: approx. 1.9 mg / mL. Temperature: Ambient.

[0200] X-ray Powder Diffraction (XRPD) X-ray diffractograms were taken using a FlipStick® sample stage, Cu Kα Illumination (40 kV, 40 mA) and 1D-linear LynxEye® detection The measurements were performed on a Bruker D8 Advance diffractometer equipped with a 25 mm diameter Prepared on a silicon single crystal sample holder with a cavity of 0.5 mm and a depth of 0.5 mm. The powder was spread on a slide glass to create a flat surface, and the X-ray diffractogram shown in Figure 1 was obtained. In some cases, they were covered with Kapton foil to protect them from ambient humidity. The diffractograms show the reflection of bond theta / 2theta angles over the range 3 to 50° 2θ. Shooting mode, 0.02° increment and 0.4s accumulation time per step The divergence slit was a variable slit size. The anti-scatter slit was set to maximum opening (maximum o In the case of the X-ray diffractogram shown in Figure 1, the divergence and anti-scattering The stop slit may be set at 0.3°. During the measurement, the sample is rotated continuously at 30 rpm. Peak positions 2θ values ​​are provided with an accuracy of + / - 0.2°.

[0201] Differential Scanning Calorimetry 1 (DSC1) DSC data was obtained using a Mettler Toledo DSC unit (e.g., DSC82 The samples were collected using a DSC crucible (either DSC 3E or DSC 3+). Typically, a few milligrams of each sample were placed in a DSC crucible. The weight was weighed into a cible and heated at a heating ramp of 3-4K / min. Heating was from 20° C. to 400° C. Peak temperatures are reported for melting points.

[0202] Differential Scanning Calorimetry 2 (DSC2) DSC measurements were performed using a Mettler Toledo DSC 3+STARe system. 1-5 mg of compound was placed in an aluminum pan (Mettler T) under ambient conditions. Weighed in oledo (product numbers ME-51119870 and ME-51119873) The pan was closed with an aluminum cover and was then washed with the instrument's autosampler before being inserted into the instrument. The DSC oven was purged with a constant flow of nitrogen while the temperature was increased to 10°C / min. The temperature was scanned from -20°C to 250°C at a rate of .

[0203] 1 H-NMR Sample: 10 mg of material was dissolved in 0.8 mL of DMSO-d6. Instrument: 400 MHz Equipment; Number of scans: 16; Dwell time: 60.200μs ; FIDRES approx. 0.25Hz; Temperature 293K; Rotation 20 Hz; Acquisition time approximately 3.95s.

[0204] Karl Fischer titration Sample: 100 mg; Apparatus: KF-Coulometer without diaphragm Coulometer cell (e.g. Metrohm model 756); electrodes : Double Pt electrodes (e.g. Metrohm 6.0341.100); diaphragm-free Generator electrode (e.g. Metrohm 6.0345.100). Parameter: l(pol) : 10μA; Temperature: Ambient temperature; Generator current: ( without diaphragm) 400mA;Titration speed: Optimal (Control r ange:70.0mV, maximum speed: maximum μg / min, minute speed: 15.0μg / min) KF Reagent: Hydranal Coulomat AD. KF-Standard: H ydranal-Water Standard KF-Oven 140~160℃.

[0205] Headspace Gas Chromatography (GS-HS) Sample: 100 mg in 1.0 mL DMSO (methanol, ethanol, DMF and THF for ethylene glycol) or 500 mg in 1.0 mL of DMF. Column: DB-624, 30m x 0.32mm, 1.8μm (methanol, ethanol and and THF), DB-624, 30mx0.53mm, 3μm (DMF) and DB-WAX, 30mx0.32mm, 0.5μm (for ethylene glycol) Agilent GC with headspace sampler and FID detector equipped with System flow rate: 2-2.5mL / min helium.

[0206] [Table 4]

[0207] [Table 5]

[0208] [Table 6] Example 1 5-Methyl-pyridine-2-sulfonic acid 6-chloro-5-(2-methoxy -phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl A Synthesis of mido 4-(4,6-dichloro-5-(2-methoxy-phenoxy)-pyrimidin-2-yl) -pyridine-1-oxide (CAS RN 180385-16-4) and 5-methyl- Pyridine-2-sulfonamide (CAS RN 65938-77-4) is a commercially available substance. be.

[0209] 4-(4,6-dichloro-5-(2-methoxy-phenoxy)-pyrimidin-2-yl )-pyridine-1-oxide (1 eq.) and K2CO3 (2 eq.) in ACN (2.7 7 kg / kg pyridine-1-oxide) and heated to reflux. 5-Methyl-pyridine-2-sulfonamide (1.05e g / kg sulfonamide) q.) was added over 15-60 min and the reaction mixture was stirred until the conversion was >98.0%. The mixture was stirred at 4° C. for at least 6 h. The resulting suspension was cooled to 70° C. Aq.HCl (1M) was added until the pH was 2-4. Water (8 kg / kg pyridine-1-oxide) was added. The suspension was added dropwise over a period of about 20 min. The mixture was cooled to 0°C, stirred for at least 60 min, and filtered. After filtration, the remaining solid was washed with water. (8 kg / kg pyridine-1-oxide) at 5°C, followed by ACN (2.37 kg / kg g pyridine-1-oxide) at the same temperature. After drying, 5-methyl-pyridine- 2-Sulfonic acid 6-chloro-5-(2-methoxy-phenoxy)-2-(1-oxy- Pyridin-4-yl)-pyrimidin-4-yl amide free acid (90% yield) was It has a melting point of 100 °C (DSC1) and a purity of 99% (w / w, HPLC method A (Method A)). XRPD analysis by the methods disclosed herein revealed that the product was It was confirmed that the product was crystalline (see FIG. 2). DSC Measurement (DSC2) showed an exothermic event at about 260 °C, possibly due to decomposition. Batches (55-75 kg) were successfully produced using the above method. However, in this case, the reaction mixture may be kept at a pH of 2 to 4 as described above. and acidify (e.g. with acetic acid) to about pH 7.

[0210] Reference Example 1 5-Methyl-pyridine-2-sulfonic acid 6-chloro-5-(2-methyl (1-oxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl Synthesis of amides 2.4 eq. of base B (Table 1) and 4-(4,6-dichloro-5-(2-methoxy- (1 eq.) of (2-pyrimidinyl)-pyridine-1-oxide, 4 vol. 1. was suspended in solvent S (Table 1) and heated to 95°C (or reflux in the case of ACN). 5-Methyl-pyridine-2-sulfonamide (1 eq.) in solvent (4 vol.) Add dropwise under stirring 4-(4,6-dichloro-5-(2-methoxy-phenoxy The conversion of 2-pyrimidin-2-yl-pyridine-1-oxide was measured by HPLC (Method A). As soon as the conversion reached a satisfactory level, the reaction mixture was cooled to 85°C and ( Water (0.7 vol.) and then acetic acid (0.6 vol.) were added to adjust the pH to 6-6.5. Water (7 vol.) was added dropwise to the suspension. The suspension was cooled to 4°C and stirred for 90 min. After filtration, the solid was washed with dioxane / water (ratio = 1 / 10, 24 vol.) and dried. 5-Methyl-pyridine-2-sulfonic acid 6-chloro-5-(2-methoxy-phenoxy) oxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl amide tea A coloured solid was obtained.

[0211] [Table 7] Example 2 5-Methyl-pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy )-5-(2-Methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyridin Synthesis of rimidin-4-yl amide 5-Methyl-pyridine-2-sulfonic acid 6-chloro-5-(2-methoxy-phenoxy) )-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl amide (1eq .) and BHT (0.5eq.), ethylene glycol (6.66kg / kg pyridine -N-oxide) and toluene (3.48 kg / kg pyridine-N-oxide) The mixture was heated to 103-107°C. After initial distillation of about 3.0 vol. of the solvent at normal pressure (residue), Removal of residual water), NaOH (5.7eq.) of ethylene glycol (5.55kg / kg Lysine-N-oxide) in a hot (80-85°C) solution for at least 20 min. Add dropwise and stir the reaction mixture for 90-120 min until conversion is 98.0% or higher. The suspension was cooled to 70-75°C, and the toluene was removed by distillation under reduced pressure. Set the temperature of the reaction mixture to 50-60 °C and add methanol (3.16 kg / kg pyridine-N -oxide) is added over a period of at least 10 min, and the mixture is then stirred for at least 60 The suspension was cooled to 0-5°C over a period of 1 min and stirred for at least 60 min. The turbid liquid was filtered, and the solid residue was dissolved in THF (twice, 1.78 kg / kg pyridine-N-oxide ) and MeOH (2.37 kg / kg pyridine-N-oxide) at 0-5°C. The mother liquor was drained. The solid was dissolved in MeOH (3.56 kg / kg pyridine-N-oxide) and water (0.5 kg / kg pyridine-N-oxide) and heated to 80-90°C. After heating for at least 60 min, the mixture was cooled to 20° C. for at least 60 min. The suspension was further stirred for at least 30 min. Further filtration and addition of MeOH (2.37k g / kg pyridine-N-oxide), and after drying, the purity exceeded 99% ( 5-Methyl-pyridine-2-sulfonic acid 6-(2-hydroxyphenyl) 5-(2-methoxy-phenoxy)-2-(1-oxy-pyridyl) (4-phenyl-4-yl)-pyrimidin-4-yl amide sodium salt hydrate (80~85%) was obtained as an off-white solid material. XRPD analysis according to the methods disclosed herein showed that The product was confirmed to be crystalline (see FIG. 3). DSC measurements ( 2) showed an endotherm at around 220°C, which was probably due to melting and then quenching at over 230°C. This can be attributed to exothermic decomposition in the region. Several large batches (44-90 kg) was successfully prepared using the above method.

[0212] Reference Example 2 5-Methyl-pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy) oxy)-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl) Synthesis of -pyrimidin-4-yl amides 3g of 5-methyl-pyridine-2-sulfonic acid 6-chloro-5-(2-methoxy-phenyl (1-oxy-pyridin-4-yl)-pyrimidin-4-yl) The mixture was suspended in ethylene glycol (5-10 vol.) and heated to about 105°C. ) in the form of a warm solution (4-6 eq in 5 vol. of ethylene glycol) After stirring for a given period of time (see Table 2a), the mixture was cooled to room temperature and cooled to room temperature. The amount of converted starting material was determined by HPLC Method A described herein. If not, the solution was cooled to 90°C and aq. HCl was added to adjust the pH to 3. Water was then added dropwise, the suspension was cooled to 20° C., filtered, and washed with water and MeOH. 5-Methyl-pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5 -(2-Methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidinyl The reaction mixture was neutralized with acetic acid to give the benzoyl amide as an off-white solid. At a pH of about 5.5, 6-(2-hydroxy-ethoxy)-5-(2-methoxy) 1-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl The sodium salt hydrate of the amide was isolated.

[0213] The meaning of the term "base" in the above method is given in Table 2a / b / c.

[0214] [Table 8]

[0215] [Table 9]

[0216] [Table 10] Negative values ​​in Table 2c mean a depletion of the corresponding impurity, whereas positive values ​​mean its enrichment.

[0217] The impurities listed in Tables 2a / b / c have the following structures:

[0218] [ka] 5-Methyl-pyridine-2-sulfonic acid 6-chloro- 5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyridin The reaction of ethyl erythritol, ethylene glycol and metallic sodium is suitable for large-scale production. This is undesirable due to potential safety hazards (e.g. explosions) in the The use of ethanol can lead to increased by-products (e.g., Niphade et al.: Org. Pr Ocess Res.Dev. 2011, 15, 1382-1387.) Bases and The reduction of pyridine-N-oxide in the presence of alcohol was reported by Bjorsvik et al.:J .Org.Chem.2005 70(8), 3218~3224, DOI:10.10 This is discussed in 21 / jo047919b.

[0219] Example 3 5-Methyl-pyridine-2-sulfonic acid 2-(2-cyano-pyridine-4 -yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pi Synthesis of rimidin-4-yl amide 5-Methyl-pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2 -Methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidine-4 -yl amide sodium salt (1 eq.) was dissolved in ACN (4.71 kg / kg pyridine- Then, 2.4 vol. of ACN was distilled off at normal pressure (water). (azeotropic distillation for removal of benzene), ACN (1.90 kg / kg pyridine-N-oxide) was further added. The reaction mixture was then cooled to 20-25°C. NEt3 (per "acidic" H 1.4 eq.) was added and the mixture was cooled to 0-5°C. (1.15 eq. / mL) was added for at least 20 min. pyridine-N-oxide) for at least 20 min. The reactor was closed, the mixture was heated to 90-95°C, and pressurized with nitrogen (6 The reaction mixture was stirred at 55-60° C. for at least 16 hours at this temperature. The temperature was adjusted to 0°C, and acetic acid (1.96 kg / kg pyridine-N-oxide) was added for at least 30 min. Water (2 kg / kg pyridine-N-oxide) was added over a period of at least 15 min. After stirring at 60° C. for 30 minutes, 5.4 vol. of the solvent was distilled off. Water (8 kg / kg pyridine-N-oxide) was added over a period of at least 30 min. The resulting suspension is cooled to 20° C. over a period of at least 60 min and then further cooled at this temperature for a short period. The mixture was stirred for at least 60 min and filtered. The solid was washed as follows: first with ACN (1 0.1kg / kg pyridine-N-oxide) / water (0.86kg / kg pyridine-N-oxide) cid), then water (2 kg / kg pyridine-N-oxide), and finally ACN ( 2 kg / kg pyridine-N-oxide) twice. Drying results in a concentration of more than 98.5% w / w. 5-Methyl-pyridine-2-sulfonic acid 2-(2-cyano-pyridine-4 -yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pi Rimidin-4-yl amide (86-96%) was obtained as a beige solid. XRPD analysis by the method disclosed herein confirmed that the product was crystalline ( (See Figure 4.) DSC measurements (DSC2) show an endothermic event at 210 ± 2 °C. Several large batches (e.g., 27 kg) have been successfully produced using the above method. It was created.

[0220] Reference Example 3 5-Methyl-pyridine-2-sulfonic acid 2-(2-cyano-pyridine -4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy) Synthesis of -pyrimidin-4-yl amides a) In the absence of TMS-Cl As in Example 3, 5 g of 5-methyl-pyridine-2-sulfonic acid 6-(2-hydroxypropyl) C-ethoxy)-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridine-4 -yl)-pyrimidin-4-yl amide sodium salt was dissolved in ACN with triethylamine. It was reacted with TMS-CN (3.0 eq.) in the presence of amine (2.0 eq.) under reflux. After 16 hours no product was formed. Triethylamine (1.0 eq.) and TMS-CN (1.0 eq.) was further added and the reaction was continued for 39 h. LC analysis revealed approximately 14% 5-methyl-pyridine-2-sulfonic acid 2-(2-cyano-pyridinyl) Lysine-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-pheno The reaction mixture was found to be free of 85% starting material. It has been shown that it still exists.

[0221] b) In the absence of TMS-Cl and in the presence of dimethylcarbamoyl chloride As in Example 3, 5 g of 5-methyl-pyridine-2-sulfonic acid 6-(2-hydroxypropyl) C-ethoxy)-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridine-4 -yl)-pyrimidin-4-yl amide sodium salt was added to ACN(6 vol.), TMS-CN (2.0 eq.) and dimethylcarbamoyl chloride (1 .5 eq.) After 48 h, no conversion of the starting material was observed.

[0222] c) Increase in reaction pressure In the method of Example 3, increasing the pressure (e.g., 6 to 7 bar) significantly increases the reaction time. , preventing the formation of impurities such as Impurity 2 (structure shown in Reference Example 2). It was observed that:

[0223] Example 4 5-Methyl-pyridine-2-sulfonic acid {6-( 2-Hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-[2-(1H- Tetrazol-5-yl)-pyridin-4-yl]-pyrimidin-4-yl}-amide synthesis 5-Methyl-pyridine-2-sulfonic acid 2-(2-cyano-pyridin-4-yl)-6 -(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidine-4 1 eq. of 1-yl amide and 2.48 eq. of NH4Cl were dissolved in DMF (4.06 g / kg cyano-pyridine. A solution of 1000 g / kg cyano-pyridine was added within 15 min at 20-25°C. The mixture is heated to 95°C for at least 60 min and stirred at this temperature for 12-15 h. The mixture was stirred and cooled. At 20-25°C, NaNO2 (5.04 eq.) was dissolved in H2O (1.8 kPa). A solution of 100 g / kg cyano-pyridine was added over a period of at least 40 min. The reaction mixture was heated to 40-45°C for at least 20 min and diluted with aq. Cl (2M, ca. 3.9 kg / kg cyanopyridine) was administered for at least 60 min. The suspension was heated to 30° C. and the filter aid Hyflo S was added to the suspension to obtain a pH of about 3.3. super-Cel NF® (1.00 kg / kg cyano-pyridine; aqueous HC1 After filtration at 45°C, the solid was filtered using 100 ml of ethyl acetate and pre-washed with water. The mixture was then washed with H2O (3.30 kg / kg cyano-pyridine) at 4°C, and then filtered. The solid residue was further slurried with MeOH (3.86 kg / kg cyano-pyridine). - Wash, filter and then rinse with EtOH (3.86 kg / kg cyano-pyridine) The solids were dried and purified using Hyflo® Supe r 5-Methyl-pyridine-2-sulfonic acid {6- (2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-[2-(1H -tetrazol-5-yl)-pyridin-4-yl]-pyrimidin-4-yl}-amide (91-100%) as an off-white solid. Approximately 38-48 kg of final product was successfully produced using the above method.

[0224] 5-Methyl-pyridine-2-sulfonic acid {6-(2-hydroxy-ethoxy)-5- (2-Methoxy-phenoxy)-2-[2-(1H-tetrazol-5-yl)-pyridinyl] The 4-methyl-4-yl-pyrimidin-4-yl}-amide was obtained in Example 4, which was very Because it is obtained as fine particles, its direct filtration in large-scale production is nearly impossible. Addition of a filter aid such as Hyflo® Super Cel® NF At 20°C, 100% w / w Hyflo (registered trademark) was used to significantly improve the filtration rate. When the reaction mixture was filtered through a pad of Super Cel® NF, 5 It was observed that filtration took about 13 min at the 50 g scale. % reduction doubled the filtration time. Therefore, filtration without filter aid or with the amount of filter aid Filtration to reduce the amount of ethanol was not considered practical for large scale production.

[0225] Example 5 5-Methyl-pyridine-2-sulfonic acid {6-(2-hydroxy-ethoxy) 5-(2-methoxy-phenoxy)-2-[2-(1H-tetrazol-5-yl )-pyridin-4-yl]-pyrimidin-4-yl}-amide or its tetrahydrofuran Synthesis of amine solvates Obtained in Example 4 and adsorbed onto Hyflo Super-Cel NF (registered trademark) 5-Methyl-pyridine-2-sulfonic acid {6-(2-hydroxy-ethoxy)-5-( 2-Methoxy-phenoxy)-2-[2-(1H-tetrazol-5-yl)-pyridine

[0046] 1,2-dihydropyrimidin-4-yl}-amide was dissolved in THF (47.6 kg / kg cyano -pyridine) at reflux and incubated at this temperature for at least 90 min. The solid residue was dissolved again in THF (approximately 6 kg / kg cyano-pyridine) and filtered. The mixture was stirred at this temperature for at least 20 minutes and then filtered. The combined solution was concentrated by distillation of THF (53.5 vol.) at atmospheric pressure. Cool to 10-15°C over at least 60 min and stir for at least 60 min. The solid residue was dissolved in EtOH (3 kg / kg cyano-pyridine) and then in MeO H (3 kg / kg cyano-pyridine); Both were dried for 2 hours and 5-methyl-pyridine-2-sulfonic acid {6-(2-hydroxy -ethoxy)-5-(2-methoxy-phenoxy)-2-[2-(1H-tetrazole- 5-yl)-pyridin-4-yl]-pyrimidin-4-yl}-amide as a solid substance XRPD analysis by the methods disclosed herein confirmed that the product was crystalline. (See Figure 5.) DSC measurements (DSC2) showed that the temperature was approximately 245-250°C. The decomposition was endothermic and then exothermic. 1 / kg cyano-pyridine) is added to the solid material and the resulting suspension is refluxed for at least The product suspension was cooled to 20°C for at least 60 min. Cool, stir for at least 30 minutes, filter, and incubate the filter cake at 20-25°C. The mother liquor and washing solution were discarded, and the filter cake was washed with THF at 80°C. Pre-dried below 0°C and further dried at the same temperature under vacuum to obtain 5-methyl-pyridine -2-Sulfonic acid {6-(2-hydroxy-ethoxy)-5-(2-methoxy- 2-[2-(1H-tetrazol-5-yl)-pyridin-4-yl]-pyrimidinyl Diphenyl-4-yl}-amide tetrahydrofuran solvate (75-90%) white solid XRPD analysis by the methods disclosed herein showed that the product was crystalline. It was confirmed that the THF content was 100% (see FIG. 6). A broad endotherm at about 160°C attributable to the loss of benzene, and an endotherm at about 245°C, followed by It showed exothermic decomposition. Several large batches (14-19 kg for the THF solvate) , was successfully prepared using the method described above.

[0226] The previously disclosed embodiments 4 and 5 may be advantageously combined into a single step (compression step (tel escoped procedure) can be used. The product adsorbed on Super Cel® NF was not isolated but was analyzed in the laboratory. Direct treatment with THF under the conditions disclosed in Example 5 affords 5-methyl-pyridine-2-sulfate. Phenoxylic acid {6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2 -[2-(1H-tetrazol-5-yl)-pyridin-4-yl]-pyrimidine-4- This gives a tetrahydrofuran solvate thereof.

[0227] Example 6 5-Methyl-pyridine-2-sulfonic acid {6-(2-hydroxy-ethoxy) 5-(2-methoxy-phenoxy)-2-[2-(1H-tetrazol-5-yl )-Pyridin-4-yl]-pyrimidin-4-yl}-amide disodium salt (Crazo Synthesis of Sentan (disodium salt) A) Salt formation: 5-Methyl-pyridine-2-sulfonic acid {6-(2-hydroxy- 5-(2-methoxy-phenoxy)-2-[2-(1H-tetrazole-5- pyridin-4-yl]-pyrimidin-4-yl]-amide or its tetrahydro Furan solvate (crude material; 1 eq., corrected by HPLC-assay) was dissolved in MeOH ( The mixture was suspended in 100 ml of ethanol (4.34 kg / kg crude product) and stirred at 25-30° C. for at least 1 h. A 30% solution of NaOMe in MeOH (2.55 eq.) was added to this suspension at 25-42°C. The reaction mixture was heated to 35-42°C and stirred at this temperature for 60-120 min. The suspension is cooled to 20-25°C within 60-180 min and then heated to 240°C. The suspension was stirred for 120 to 240 min. The mixture was cooled to rt and stirred for at least 180 min. The product was filtered and the filter cake was , cooled (-15°C) MeOH (1 kg / kg crude), then cooled (-15°C) EtOH ( The raw product was dried under vacuum at T≦70° C. Solid 5-methyl-pyridine-2-sulfonic acid {6-(2-hydroxy-ethoxy)-5 -(2-Methoxy-phenoxy)-2-[2-(1H-tetrazol-5-yl)-pyridine pyrimidin-4-yl}-pyrimidin-4-yl}-amide disodium salt was obtained.

[0228] B) Recrystallization: 5-methyl-pyridine-2-sulfonic acid {6 -(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-[2-(1 H-Tetrazol-5-yl)-pyridin-4-yl]-pyrimidin-4-yl}-amine The disodium salt of 1,2-dichlorophenyl ether was suspended in water (2.8 kg / kg crude product) and the resulting suspension was Heat to 75-80°C for at least 30 minutes and keep at this temperature for at least 10 minutes. Then, a hot aqueous solution of NaOH (20%, 0.3 eq.) was added until a clear solution was obtained. The preheated filter was added at the same temperature under stirring until the mixture was heated (8-12 min). Immediately after filtration, the solution is cooled to about 40° C. over a period of 60 to 120 min. The mixture was stirred for 90 to 180 minutes until crystallization began. The resulting suspension was then The mixture was cooled to 0-5°C over 24 hours and stirred for 1-24 hours. The mother liquor was drained. The remaining solids were The body was stirred in MeOH (1 kg / kg crude) at 2° C. for at least 10 min. The solvent was then drained and the mixture was soaked in EtOH (1 kg / kg crude) at 2° C. for at least 10 min. Finally, the mother liquor was drained to obtain a solid product.

[0229] C) Grinding (Reslurry): The solid material from step B) is dissolved in hot (70° C.) MeOH / Et OH mixture (2 kg / kg crude / 6 kg / kg crude) and stirred for at least 20 The mixture was heated to reflux (90-95°C) for 1 min and stirred for at least 60 min. Partial distillation was carried out at atmospheric pressure (1.5 vol.). The remaining suspension was diluted with at least 180 ml The mixture was cooled to -15°C over a period of 120 min and stirred for at least 120 min to separate the solid material from the mother liquor. The solid product was separated by elution with MeOH / EtOH at -15 °C for at least 20 min. The mixture was further washed in a crude oil mixture (0.3 kg / kg crude / 0.8 kg / kg crude), and then Wash again in EtOH (1 kg / kg crude) at -15°C for at least 20 min. Finally, the mother liquor was drained to obtain a solid material.

[0230] D) Drying: The solid material from step C) is dried until condensation is observed. Pre-dry at 70°C or less under reduced pressure until no residue remains, then dry further at 75°C or less under vacuum. , 5-Methyl-pyridine-2-sulfonic acid {6-(2-hydroxy-ethoxy)-5- (2-Methoxy-phenoxy)-2-[2-(1H-tetrazol-5-yl)-pyridinyl] {4-methyl-4-yl}-pyrimidin-4-yl}-amide disodium salt (clazosentan dibasic Sodium salt) was obtained as a white to pale yellow crystalline powder. A total of ~20 kg of cellulose was successfully produced using the above method. Analytical data are shown in Table 3. To summarize:

[0231] [Table 11] Reference Example 4 Discoloration experiments In the manufacturing process without the purification step (f), the product has a noticeable color when dissolved in water. The disodium salt of clazosentan was obtained. Several attempts were made to decolorize the product: For example, 1) the reaction temperature in step (c) was reduced to a range suitable for large-scale production; The purity of 5-methyl-2-pyridine-sulfonamide in the synthesis step (a) is 95% w / 3) the sodium used in the salt formation step (e) was increased from 99% w / w to 99% w / w; Methoxide was replaced with sodium hydroxide or sodium hydride, and different amounts of Sodium methoxide, sodium hydroxide, and sodium hydride were tested; 4) charcoal Adsorbent materials such as silica gel and aluminum oxide may be added to the reaction mixture after completion of step (d). However, none of these measures adequately improved the undesirable coloration of the drug substance. This problem could only be solved by introducing the purification step (f). The results of the decolorization experiments are shown in Table 4 below.

[0232] [Table 12]

Claims

1. A method for producing a compound of Formula 6, comprising the following steps: (e) reacting a compound of Formula 5 or a solvate thereof with a sodium-containing base to obtain a compound of Formula 6; 【Chemical 1】 (f) subjecting the compound of Formula 6 to the following steps: (f1) recrystallizing the compound of Formula 6 in water with pH ≥ 7; and (f2) triturating the compound of Formula 6 in a solvent selected from methanol, ethanol, or a mixture thereof; to purify; (g) drying the compound of Formula 6; wherein the compound of Formula 6 has one or more of the following characteristics i), ii), iii) and vi): i) the compound has a sodium content of 7.2% w / w to 7.7% w / w; ii) When measured according to Chapter 2.2.

2. of the European Pharmacopoeia 6.0, the 2.5% w / v test solution of the compound in water has the same coloration or less coloration than any one of the standard solutions Y 5 , BY 5 , GY 5 or B 5 when compared to any one of them iii) the compound is crystalline; and vi) the compound has an assay of ≥ 98% w / w purity as measured by high performance liquid chromatography; The manufacturing method characterized by having one or more of them.

2. The compound of Formula 6 has the following characteristics iv), v), vii) and viii): iv) the compound is in an anhydrous form; v) the compound is in a non-solvated form; vii) the compound contains a total amount of impurities of ≤ 2% w / w as measured by high performance liquid chromatography; and viii) the compound contains a total amount of residual solvent of < 1% w / w as measured by gas chromatography, and the solvent is selected from the group consisting of ethanol, methanol, tetrahydrofuran, dimethylformamide and ethylene glycol The method according to claim 1, further characterized by having one or more of them.

3. The method according to claim 1, wherein the compound of Formula 6 is crystalline and is characterized by an X-ray powder diffraction pattern having at least four peaks with diffraction angles 2θ selected from 9.4°, 12.0°, 13.2°, 17.7°, 18.4°, 19.8°, 21.2°, 21.9° and 24.9°.

4. The method according to claim 1, wherein the compound of Formula 6 is crystalline and is characterized by the presence of peaks at the following diffraction angles 2θ in the X-ray powder diffraction pattern: 9.4°, 12.0° and 21.9°.

5. The production method according to claim 1, wherein the compound of formula 6 is crystalline and is characterized by the presence of peaks at the following diffraction angles 2θ in the X-ray powder diffraction pattern: 9.4°, 12.0°, 18.4°, 21.2° and 21.9°.

6. 4 The method according to claim 5, wherein the compound of formula 6 is crystalline and is characterized by the presence of peaks at the following diffraction angles 2θ in the X-ray powder diffraction pattern: 9.4°, 12.0°, 13.2°, 17.7°, 18.4°, 19.8°, 21.2°, 21.9° and 24.9°.

7. The method according to claim 1, wherein the compound of formula 6 is crystalline and is characterized in that the X-ray powder diffraction pattern essentially shows the pattern shown in FIG.

1.

8. One or more of the following features (a) to (c): (a) In step (e), the sodium-containing base is selected from sodium methoxide, sodium hydride, or sodium hydroxide; (b) pH ≧ 7 in step (f1) is achieved by the addition of sodium hydroxide; and (c) the solvent in step (f2) is a mixture of methanol and ethanol The method according to claim 1, having one or more of them.

9. The compound of formula 5 is as follows: (d) Reacting the compound of formula 4 with an alkali metal azide in the presence of ammonium chloride to form the compound of formula 5 or a solvate thereof: 【Chemical Formula 2】 The method according to claim 1, formed by.

10. The method according to claim 9, wherein the alkali metal azide in step (d) is sodium azide.

11. The compound of formula 4 is as follows: (c) reacting a compound of formula 3 or a salt thereof with trimethylsilyl cyanide in the presence of mono-, di-, or tri-C 1-4 -alkylamine to produce a compound of formula 4: [Chemical Formula 3] The method according to claim 9, formed by.

12. The compound of formula 3 or a salt thereof is a compound of formula 3a as follows: 【Chemical 4】 The method according to claim 11.

13. Tri-C in step (c) 1-4 The method according to claim 11, wherein the -alkylamine is triethylamine.

14. The compound of formula 3 or a salt thereof is as follows: (b) Reacting the compound of formula 2 or a salt thereof with ethylene glycol in the presence of an alkali metal hydroxide [Chemical Formula 5] The method according to claim 11, formed by.

15. The compound of formula 2 or a salt thereof is a compound of formula 2a: 【Chemical Formula 6】 The method according to claim 14.

16. The method according to claim 14, wherein the alkali metal hydroxide in step (b) is sodium hydroxide.

17. The compound of formula 2 or a salt thereof is as follows: Step of reacting a compound of formula 1 with 5-methylpyridine-2-sulfonamide or a salt thereof under basic conditions to produce a compound of formula 2 or a salt thereof 【Chemical Formula 7】 The method according to claim 14, formed thereby.

18. The method according to claim 17, wherein the salt of 5-methylpyridine-2-sulfonamide in step (a) is a potassium salt.

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