WO2011069944A1 - Crystalline {(3s)-3-[({1-[(2r)-2-carboxy-4-(1-naphthyl)butyl]cyclopentyl}-carbonyl)amino]-2-oxo-2,3,4,5-tetrahydro-1h-1benzazepin-1-yl}acetic acid, its preparation and use - Google Patents

Abstract

This invention relates to organic, analytical and pharmaceutical chemistry. In particular to crystalline (2R)-2-{[1-({[(3S)-1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]-amino}carbonyl)cyclopentyl]methyl}-4-(1-naphthyl)butanoicacid, its preparation and use. The compound was first disclosed in EP 0733 642, and isolated as an amorphous solid. Neither salts nor crystal forms have been described.

Description

CRYSTALLINE {(3S)-3-[({1 -[(2R)-2-CARBOXY-4-(1 -NAPHTHYL)BUTYL]CYCLOPENTYL}- CARBONYL)AMINO]-2-OXO-2,3,4,5-TETRAHYDRO-1 H-1 -BENZAZEPIN-1 -YL}ACETIC ACID, ITS PREPARATION AND USE This invention relates to organic, analytical and pharmaceutical chemistry. In particular to crystalline {(3S)-3-[({1 -[(2R)-2-carboxy-4-(1 -naphthyl)butyl]cyclopentyl}carbonyl)amino]-2-oxo- 2,3,4,5-tetrahydro-1 H-1 -benzazepin-1 -yl}acetic acid ('the compound of formula (1 )') its preparation and use. The compound (CAS number 182821-33-6) was first disclosed in EP 0733 642, and later also in DE 19638020, US 2005/0153936 and WO 2006/064016. Neither salts nor crystal forms have been described.

Its use in the treatment of traumatic brain injury was disclosed in EP 1 706 121 . Administration of medication to patients with traumatic brain injury nearly always is by intravenous injection. At the production of sterile solutions for intravenous injection, an unexpected problem was encountered: steam sterilization of solutions of the compound of formula (1 ), prepared as described in the original patent, invariable resulted in turbid solutions, unsuitable as intravenous formulation. A pragmatic solution to the problem was found in aseptic production, resulting in clear solutions of the compound. But aseptic production is a tedious, time-consuming, and expensive process, often frowned upon by Registrations Authorities, because between production and formulation, microbial infections cannot be excluded completely.

Although when synthesized and purified as described in the original patent, the compound of formula (1 ) fully met the high standard purity qualifications for human administration, apparently it retained a quantity of an impurity causing solutions of the compound to become turbid after steam sterilization. Obviously, obtaining the compound in an even higher purity would lead to a solution of the problem. Generally speaking, crystallization is preferred over any other method of purification. Some of the compounds disclosed in EP 0733642 were obtained in crystalline form, using dichloromethane or methyl-i-bytylether. But in most cases attempts to crystallize the compounds failed, and they were purified using chromatographic methods, resulting in descriptions like: "amorpher feststoff", "oliges product", "glasartiges product", Jester schaum" or— and this includes the compound of formula (1 )— "schaumharz". From this it was evident that straightforward crystallization processes were not likely to be successful. Indeed every obvious— and many less obvious— attempts to crystallize the compound failed. DISCLOSURE

This invention aims at the development of a pure form of the compound of formula (1 ) that can be dissolved and steam-sterilized without turning turbid.

Surprisingly, crystals of the compound could be obtained by an unconventional process using a solvent/anti-solvent mixture. Crystallization of the compound only occurred after heating solvent/anti-solvent mixture at a temperature well above room temperature, rather than after the usual cooling. This process resulted in the desired product in a very pure form. When dissolved in physiological fluids, after steam sterilization those solutions remained clear.

The invention relates to a process for the preparation of crystalline compound of formula (1 ), comprising the steps of: taking up the oily compound of formula (1 ), obtainable as described in EP 0733 642, in an organic solvent miscible with water, preferably MEK or n-butyl acetate, and heating to a temperature between approximately 50°C and 80°C, preferably to around 50°C, until everything is dissolved. The solution is cooled to a temperature between approximately 10°C and 30°C, preferably to around 20°C, and filtered. This filtrate then is warmed to a temperature between approximately 40°C and 60°C, preferably to around 50°C, whereafter an alkane, prefably hexane(s) or heptane(s), most preferably heptane (Aldrich, distillation range 98°-99°C), is added. This solution is then stirred, preferably between about 1 to 10 hours during which spontaneous crystallization occurs. Crystallization is slow: up to a certain limit prolonging the stirring results in a higher yield. The mixture is then slowly cooled within about 1 to 10 hours to a temperature between approximately 10°C and 30°C, preferably to around 20°C, and stirred for an additional 1 to 5 hours at that temperature. The mixture is then filtered and the residue is washed on the filter with a mixture of an organic solvent miscible with water, and an alkane, preferably a mixture of MEK and heptane, more preferably a mixture of about 70% MEK and about 30% (v/v) heptane, and subsequently washed with an alkane, preferably heptane. After isolation the product is dried, preferably at elevated temperature and lowered pressure, yielding the compound of formula (1 ) in crystalline form. The preferred drying temperature is between 20°C and 60°C. The most preferred drying temperature is 50°C. The preferred pressure during drying is between approximately 1 ,000 and approximately 30 mbar. The most preferred pressure during drying is approximately 100 mbar. Alternatively, seed crystals can be used to start the crystallization process.

Optionally, in particular when there is a possibility that the starting material: oily compound of formula (1 ), obtainable as described in EP 0733 642, contains sodium or other ions, in other words when there is a possibility that the starting material partly consists of a salt rather than the free acid, the crystallization can be preceded by the following washing procedure: dissolving oily compound of formula (1 ), obtained as described in EP 0733 642, in a sufficient amount of an organic solvent. Suitable solvents are for instance methyl ethyl ketone (MEK) and dichloromethane. The most preferred solvent is MEK. Thereafter a base is added, until pH is between approximately 4 and approximately 6, preferably about 4.8. Then the organic layer is isolated and subsequently washed with water, an acid, preferably HCI, more preferably 1 M HCI, and again water. Next the organic layer was separated and evaporated to dryness at a temperature between about 40 and 60°C, preferably around 60°C, yielding purified compound of formula (1 ), again as oil.

The base used in the steps described above is selected from alkaline compounds, such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, alkaline hydroxides such as sodium hydroxide, potassium hydroxide or magnesium hydroxide, alkaline phosphates such as dipotassium hydrogen phosphate. Also mixtures of these alkaline compounds can be used. Preferred alkaline compounds are sodium hydroxide, potassium hydroxide or magnesium hydroxide. Even more preferred is 20% (m/m) NaOH. Crystalline {(3S)-3-[({1 -[(2R)-2-carboxy-4-(1 -naphthyl)butyl]cyclopentyl}carbonyl)amino]-2- oxo-2,3,4,5-tetrahydro-1 H-1 -benzazepin-1 -yl}acetic acid {the compound of formula (1)) is defined by the following physicochemical characteristics:

(i) An X-ray powder diffraction (=XRPD) pattern having characteristic reflexes (expressed in degrees of diffraction angle 2Θ) at about: 4.20, 8.37, 10.95, 12.77, 13.50, 14.63, 16.32,

17.05, 20.38, 21.99, 23.90, 24.60 ± 0.1 degrees. Diffraction angles are indicated as mean values (± 0.1 °) of two independent measurements. The complete XRPD pattern of crystalline compound of formula (1 ) is shown in Figure 2. Most distinguishing peaks are those about: 16.32, 17.05 and 20.38 degrees.

(ii) An infrared (=IR) spectrum recorded in attenuated total reflectance (=ATR) having characteristic absorption bands expressed in reciprocal centimeters at about: 3426, 3267, 3060, 2936, 2876, 2598, 2456, 1736, 1639, 1597, 1512, 1487, 1459, 1441 , 1424, 1391 , 1315, 1232, 1 191 , 1 137, 781 , 773, 735, 713, 670 cm^"1. Absorption bands are indicated as mean values of twoindependent measurements. The complete IR spectrum of crystalline compound of formula (1 ) is shown in Figure 3. Most distinguishing bands are those about 1736, 1597, and 781 cm^"1. (iii) A DSC thermogram showing a characteristic sharp melting point expressed as endotherm of the extrapolated peak at 187°C. The thermogram of crystalline compound of formula (1 ) is shown in Figure 4.

(iv) A solid state ¹³C-NMR spectrum with characteristic shifts (expressed in ppm relative to glycine (5_C =176.03 for the C=0 resonance) at about: 177.0, 176.0, 174.7, 172.2, 169.7, 138.9, 136.4, 133.6, 131 .5, 130.2, 127.8, 126.5, 125.3, 124.2, 123.2, 121.9, 55.1 , 51.0, 41.9, 40.8, 38.5, 37.1 , 28.4, 25.9, 23.1 , 21 .1 ± 0.1 ppm. The complete solid state ¹³C-NMR spectrum of crystalline compound of formula (1 ) is shown in Figure 5.

Crystalline compound of formula (1 ) can be used for the preparation of pharmaceutical compositions for the treatment of traumatic brain injury, acute disseminated encephalo-myelitis, epilepsy related brain damage, spinal cord injury, bacterial or viral meningitis and meningoencephalitis, prion diseases, poisonings with neurotoxic compounds, and radiation-induced brain damage, and of ischemic stroke.

Other embodiments of the invention include:

pharmaceutical compositions for treating a disorder or condition chosen from traumatic brain injury, acute disseminated encephalo-myelitis, epilepsy related brain damage, spinal cord injury, bacterial or viral meningitis and meningo-encephalitis, prion diseases, poisonings with neurotoxic compounds, and radiation-induced brain damage, ischemic ;

pharmaceutical compositions for treating a disorder or condition chosen from the disorders listed herein, the compositions comprising a compound of the invention, and a pharmaceutically acceptable carrier;

pharmaceutical compositions for treating a disorder or condition chosen from the disorders listed herein, the compositions comprising a compound of the invention, a pharmaceutically acceptable carrier and additionally comprising one or more other pharmacologically active ingredients.

DEFINITIONS

General terms used in the description of compounds herein disclosed bear their usual meanings. The term alkane denotes a univalent saturated, branched or straight, hydrocarbon chain. Unless otherwise stated, such chains can contain from 1 to 18 carbon atoms, indicated as C1-C1₈. Representative of such alkanes group are methane, ethane, n-propane, isopropane, n-butane, isobutane, sec-butane, ie f-butane, n-pentane, isopentane, neopentane, n-hexane, isohexane, n-heptane, n-octane, n-nonane, decane, undecane, dodecane, tridecane, tetradecane, pentadecane, hexadecane, heptadecane, octadecane, etc. The heptane used in the crystallisation experiments had a distillation range of 98°-99°C (Aldrich), but also heptane with a distillation range of 94°-100°C can be used.

'Amorphous forms' are non-crystalline materials with no long range order, and generally do not give a distinctive powder X-ray diffraction pattern. Crystal forms in general have been described by Byrn et al., (Pharmaceutical Research, 12(7), 945-954, 1995. (1995)) and Martin 'Remington: The Science and Practice of Pharmacy", Mack Publishing Company, 19^th Edition, Easton, Pa, Vol 2., Chapter 83, 1447-1462, 1995).

To give a more concise description, some of the quantitative expressions given herein are not qualified with either "about" or "approximately". It is understood that whether either of these terms is used explicitly or not, every quantity given is meant to refer to the actual value, and also to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to experimental or measurement conditions for such given value. Here, the word "comprise" and its variations, such as "comprising" and "comprises", is not intended to exclude other additives, components, integers or steps.

While the compound of formula (1 ) can be administered as the raw chemical, it is preferable to present it as a 'pharmaceutical composition'. According to a further aspect, the present invention provides a pharmaceutical composition comprising the compound of formula (1 ), together with one or more pharmaceutically acceptable carriers thereof, and with or without one or more other therapeutic ingredients. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The term "composition" encompasses a product comprising specified ingredients in predetermined amounts or proportions, as well as any product that results, directly or indirectly, from combining specified ingredients in specified amounts. In relation to pharmaceutical compositions, this term encompasses a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product that results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. In general, pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. The pharmaceutical composition includes enough of the active object compound to produce the desired effect upon the progress or condition of diseases. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier. Here, the term 'combination preparation' comprises both true combinations, that is a crystalline compound of formula (1 ), and other medicaments physically combined in one preparation, as well as 'kit-of-parts', comprising a crystalline compound of formula (1 ) and another medicament in separate dosage forms, together with instructions for use, with or without further means for facilitating compliance with the administration of the component compounds, e.g. label or drawings. With true combinations, the pharmacotherapy by definition is simultaneous. The contents of 'kit-of-parts', can be administered either simultaneously or at different time intervals. Therapy being either concomitant or sequential will be dependant on the characteristics of the other medicaments used, such as onset and duration of action, plasma levels, clearance, etc., as well as on the disease, its stage, and characteristics of the individual patient.

The typical daily dose of the active ingredients varies within a wide range and will depend on various factors such as the relevant indication, the route of administration, the age, weight and sex of the patient, and may be determined by a physician. In general, total daily dose administration to a patient in single or individual doses, may be in amounts, for example, from 0.001 to 20 mg/kg body weight daily, and more usually from 0.01 to 20,000 mg per day, of total active ingredients. Such dosages will be administered to a patient in need of treatment from one to three times each day, or as often as needed for efficacy, and for periods of at least two months, more typically for at least six months, or chronically.

The term "treatment" refers to any treatment of a condition or disease, and includes: (1 ) inhibiting the disease or condition, i.e., arresting its development, (2) relieving the disease or condition, i.e., causing the condition to regress, or (3) stopping the symptoms of the disease.

EXAMPLE 1 : ANALYTICAL METHODS

IR spectra were recorded on a Fourier transform IR spectrometer in attenuated total reflectance (diamond crystal) with a spectral resolution of 1 cm^"1 using a deuterated triglycine sulfate detector.

X-Ray powder diffraction (XRPD) spectra were measured on a Bruker D8 advance X-Ray powder difrractometer having a copper-Κα radiation and a primary monochromator eliminating CuK_a2 radiation (CuK_a1 radiation, λ=1.54056 A). Approximately 10 mg was gently flattened on a sample holder and scanned from 3 to 50 degrees two-theta, at 0.009 degrees two-theta per step and a step time of 532 seconds using a variable angle. The sample was simply placed on the sample holder. The sample was rotated at 15 rpm at a voltage of 40 kV and 40 mA. The sample displacement was corrected using corundum powder as internal standard. Differential Scanning Calorimetry (DSC) measurements were performed on a DSC822 (Mettler Toledo). About 3 mg of the powder was placed in an open aluminum pan, thereafter crimped with an aluminum lid. This was then placed in the DSC cell opposite to an empty aluminum pan (reference) and the sample was scanned at 10 °C/min from 25 °C to 250°C.

Solid state ¹³C NMR spectra were obtained using the cross-polarisation magic-angle spinning (CP/MAS) accessory on a Bruker AM300 instrument (contact time of 4 ms, recycle delay 3 s, spectral width 30kHz, ¹H 90° pulse of 6 s, spinning rate about 8.5kHz. A standard 4 mm Bruker CP/MAS probe was used. Chemical shifts are referred to glycine (δ _c=176.03 ppm for the C=0 resonance).

EXAMPLE 2: SYNTHESIS OF CRYSTALLINE COMPOUND OF FORMULA (1)

14 g of oily compound of formula (1 ), obtainable as described in EP 0733 642, was taken up in 59 ml methyl ethyl ketone (MEK), and thereafter 20% (m/m) NaOH was added until pH = 4.8. The organic layer was isolated and washed with water (12 ml). Next the organic layer was washed with 1 M HCI (12 ml) and with water (12 ml). The organic layer was separated and evaporated to dryness on a rotary evaporator affording 12 gram purified compound of formula (1 ), again as oil.

To 1 1 g of this oily product, 102 ml MEK was added. The mixture was heated to 70°C until everything was dissolved. The solution was cooled to 20°C and filtered (0.45 μηη filter). The filtrate was warmed to 50°C after which 44 ml heptane (Aldrich, distillation range 98°-99°C) was added. The solution was stirred for three hours during which spontaneous crystallization occurred. The mixture was slowly cooled within 3 hours to 20°C and stirred for 2 hours at 20°C. The mixture was filtered and the residue washed on the filter once with 10 ml of MEK heptane (7/3), and twice with 10 ml of heptane each. The product was dried under vacuum at 50°C, affording 8.4 g of crystalline compound of formula (1 ).

IR (ATR): 3426, 3267, 3060, 2936, 2876, 2598, 2456, 1736, 1639, 1597, 1512, 1487, 1459, 1441 , 1424, 1391 , 1315, 1232, 1 191 , 1 137, 781 , 773, 735, 713, 670 cm^"1.

XRPD pattern showed characteristic reflexes expressed as two-theta angle positions at about 4.20, 8.37, 10.95, 12.77, 13.50, 14.63, 16.32, 17.05, 20.38, 21 .99, 23.90, 24.60 ± 0.1 degrees. DSC thermogram showed a characteristic sharp endotherm of the extrapolated peak at 187 °C.

Solid state ¹³C-NMR: characteristic shifts at about: 177.0, 176.0, 174.7, 172.2, 169.7, 138.9, 136.4, 133.6, 131 .5, 130.2, 127.8, 126.5, 125.3, 124.2, 123.2, 121 .9, 55.1 , 51 .0, 41 .9, 40.8, 38.5, 37.1 , 28.4, 25.9, 23.1 , 21 .1 ± 0.1 ppm.

EXAMPLE 3: PHARMACEUTICAL PREPARATIONS

For clinical use, the compound of formula (1 ) is formulated into pharmaceutical compositions, novel embodiments of the invention, because they contain the specific compound disclosed herein. Types of pharmaceutical compositions that may be used include: tablets, chewable tablets, capsules (including microcapsules), solutions, parenteral solutions, ointments (creams and gels), suppositories, suspensions, and other types disclosed herein, or are apparent to a skilled person from the specification and general knowledge. The compositions are used for oral, intravenous, subcutaneous, tracheal, bronchial, intranasal, pulmonary, transdermal, buccal, rectal, parenteral or other ways to administer. The pharmaceutical formulation contains the compound of formula (1 ) in admixture with at least one pharmaceutically acceptable adjuvant, diluent and/or carrier. In embodiments of the present invention, the total amount of active ingredients can be in the range of from about 0.1 % (w/w) to about 95% (w/w) of the formulation, such as from 0.5% to 50% (w/w) and preferably from 1 % to 25% (w/w). In some embodiments, the amount of active ingredient can be greater than about 95% (w/w) or less than about 0.1 % (w/w).

The compound of the invention can be brought into forms suitable for administration by usual processes using auxiliary substances such as liquid or solid, powdered ingredients, such as pharmaceutically customary liquid or solid fillers and extenders, solvents, emulsifiers, lubricants, flavorings, colorings and/or buffer substances. Frequently used auxiliary substances include magnesium carbonate, titanium dioxide, lactose, saccharose, sorbitol, mannitol and other sugars or sugar alcohols, talc, lactoprotein, gelatin, starch, amylopectin, cellulose and its derivatives, animal and vegetable oils such as fish liver oil, sunflower, groundnut or sesame oil, polyethylene glycol and solvents such as sterile water and mono- or polyhydric alcohols such as glycerol, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture may then be processed into granules or pressed into tablets. A tablet can be prepared using the ingredients below:

Ingredient Quantity (mg/tablet)

crystalline compound of formula (1 ) 10

Cellulose, microcrystalline 200 Silicon dioxide, fumed 10

Stearic acid 10

Total 230 The components are blended and compressed to form tablets each weighing 230 mg.

The active ingredient may be separately premixed with the other non-active ingredients, before being mixed to formulation.

Soft gelatin capsules may be prepared with capsules containing a mixture of the active ingredients, vegetable oil, fat, or other suitable vehicle for soft gelatin capsules. Hard gelatin capsules may contain granules of active ingredients. Hard gelatin capsules may also contain active ingredients together with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin.

Dosage units for rectal administration may be prepared (i) in the form of suppositories that contain the active substance mixed with a neutral fat base; (ii) in the form of a gelatin rectal capsule that contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for gelatin rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.

Liquid preparations may be prepared in the form of syrups, elixirs, concentrated drops or suspensions, e.g. solutions or suspensions containing the active ingredients and the remainder consisting, for example, of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. Such liquid preparations may contain coloring agents, flavoring agents, preservatives, saccharine and carboxymethyl cellulose or other thickening agents. Liquid preparations may also be prepared in the form of a dry powder, reconstituted with a suitable solvent prior to use. Solutions for parenteral administration may be prepared as a solution of a formulation of the invention in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients, preservatives and/or buffering ingredients. Solutions for parenteral administration may also be prepared as a dry preparation, reconstituted with a suitable solvent before use.

Also provided according to the present invention are formulations and 'kits of parts' comprising one or more containers filled with one or more of the ingredients of a pharmaceutical composition of the invention, for use in medical therapy. Associated with such container(s) can be various written materials such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals products, which notice reflects approval by the agency of manufacture, use, or sale for human administration. LEGENDS TO THE FIGURES 1 - 5

Figure 1 . XRPD pattern of amorphous compound of formula (1 ).

Figure 2. XRPD pattern of crystalline compound of formula (1 ).

Figure 3. IR (ATR) spectrum of crystalline compound of formula (1 ).

Figure 4. DSC thermogram of crystalline compound of formula (1 ).

Figure 5. Solid state ¹³C NMR spectrum of crystalline compound of formula (1 ).

Claims

CLAIMS:

1 . Crystalline (3S)-3-[[[1 -[(2R)-2-carboxy-4-(1 -naphthalenyl)butyl]cyclopentyl]carbonyl]amino] -2,3,4,5-tetrahydro-2-oxo-1 H-1 -benzazepine-1 -acetic acid, the compound of formula (1 ):

The compound as claimed in claim 1 with an X-ray powder diffraction pattern having characteristic reflexes (expressed in degrees of diffraction angle 2 Θ) at: 16.32, 17.05, 20.38.

The compound as claimed in claim 2 with an X-ray powder diffraction pattern having characteristic reflexes (expressed in degrees of diffraction angle 2 Θ) at 4.20, 8.37, 10.95, 12.77, 13.50, 14.63, 16.32, 17.05, 20.38, 21 .99, 23.90, 24.60.

The compound as claimed in any of claims 1 to 3 having an infrared spectrum recorded in Attenuated Total Reflectance having characteristic absorption bands at 3426, 3267, 3060, 2936, 2876, 2598, 2456, 1736, 1639, 1597, 1512, 1487, 1459, 1441 , 1424, 1391 , 1315, 1232, 1 191 , 1 137, 781 , 773, 735, 713, 670 cm^"1.

The compound as claimed in any of claims 1 to 4 having a solid state ¹³C-NMR spectrum with characteristic shifts (expressed in ppm relative to glycine (5_C =176.03 for the C=0 resonance) at: 177.0, 176.0, 174.7, 172.2, 169.7, 138.9, 136.4, 133.6, 131.5, 130.2, 127.8, 126.5, 125.3, 124.2, 123.2, 121.9, 55.1 , 51 .0, 41 .9, 40.8, 38.5, 37.1 , 28.4, 25.9, 23.1 , 21.1 ± 0.1 ppm.

Crystalline compound of formula (1 ), as claimed any of claims 1 to 5, for use in medicine.

Crystalline compound of formula (1 ), as claimed any of claims 1 to 5, for use in the treatment of traumatic brain injury, acute disseminated encephalo-myelitis, epilepsy related brain damage, spinal cord injury, bacterial or viral meningitis and meningo- encephalitis, prion diseases, poisonings with neurotoxic compounds, radiation-induced brain damage, and ischemic stroke.

A pharmaceutical composition comprising, in addition to a pharmaceutically acceptable carrier and/or at least one pharmaceutically acceptable auxiliary substance, a pharmacologically active amount of crystalline compound of formula (1 ) as claimed in any of claims 1 to 5, as an active ingredient.

A pharmaceutical composition as claimed in claim 8 additionally comprising one or more other pharmacologically active ingredients.

Use of crystalline compound of formula (1 ) as claimed in any of claims 1 to 5, for the preparation of a pharmaceutical composition for treatment of traumatic brain injury, acute disseminated encephalo-myelitis, epilepsy related brain damage, spinal cord injury, bacterial or viral meningitis and meningo-encephalitis, prion diseases, poisonings with neurotoxic compounds, radiation-induced brain damage, and ischemic stroke.

Method for manufacturing a medicament intended for treatment of traumatic brain injury, acute disseminated encephalo-myelitis, epilepsy related brain damage, spinal cord injury, bacterial or viral meningitis and meningo-encephalitis, prion diseases, poisonings with neurotoxic compounds, radiation-induced brain damage, and ischemic stroke, characterized in that the crystalline compound of formula (1 ) as claimed in any of claims 1 to 5, is used as active ingredient.

Process for preparing the crystalline compound according to any of claims 1 to 5, wherein the crystallization step is performed in a mixture of a solvent that is miscible with water, and an alkane at a temperature of between 40°C and 60 °C, preferably at a temperature of 50 °C.

The process according to claim 12, wherein the solvent that is miscible with water, is chosen from methyl ethyl ketone and dichloromethane, and the alkane is a C₆-C₈ alkane.

The process according to claim 12 or claim 13, wherein the mixture is a mixture of methyl ethyl ketone and heptane.

The process according to claim 14, wherein the mixture is a mixture of 70% (v/v) MEK methyl ethyl ketone and about 30% (v/v) heptane.