SK119699A3 - Crystalline hydrated sodium salt of (e)-4,6-dichloro-3-(2-oxo- -1-phenylpyrrolidin-3-ylidene methyl)-1h-indole-2-carboxylic acid - Google Patents

Abstract

A crystalline hydrated form of the sodium salt of the compound of formula (I), processes for its preparation and its use in therapy.

Description

Technical field

The present invention relates to the sodium salt of an excitatory amino acid antagonist (E) -4,6-dichloro-3- (2-oxo-1-phenylpyrrolidin-3-ylidenemethyl) -1H-indole-2-carboxylic acid, a process for its production, isolation and use in therapy.

BACKGROUND OF THE INVENTION

WO 95/1057 discloses, inter alia, a compound of formula I

and physiologically acceptable salts thereof, as a potent antagonist at the strychnine-insensitive glycine binding site associated with the N-methyl-D-aspartate (NMDA) receptor complex. A compound of formula I and salts thereof, e.g. sodium salt, are useful for treating or preventing neurotoxic damage or neurodegenerative diseases. Therefore, these compounds are useful in the treatment of neurotoxic damage resulting from stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxiation, cardiac arrest. The compounds are useful in the treatment of chronic neurodegenerative diseases such as: Huntington's disease, Alzheimer's dementia, amyotrophic lateral sclerosis, a kind of glutaric acidemia, multi-infarct dementia. They are also useful in the treatment or prevention of status epilepticus, contusive damage (e.g. spinal cord damage or head injury), induction of neurodegeneration by viral infections (e.g. AIDS,

-2encephalopathy), Down's syndrome, epilepsy, schizophrenia, depression, fear, pain, migraine, neurogenic disorders of the bladder, irritable bladder, drug addiction, including symptoms related to alcohol withdrawal, cocaine, opioids, nicotine, benzodiazepine and vomiting.

The sodium salt of the compound of formula I is of particular importance since it can be readily adapted for administration to patients. Accordingly, it is desirable to prepare the sodium salt of a compound of formula I in a purity and crystalline degree as far as possible in order to meet the exact standards required in the pharmaceutical composition.

The process for preparing the sodium salt of the compound of formula I must be such that it can be carried out under industrial conditions and that the product can be isolated directly.

The sodium salt of the compound of formula I was prepared and isolated in solid form by lyophilizing an aqueous solution of the sodium salt of the compound of formula I as described in WO 95/1057. This process is not particularly suitable for industrial scale use and the product thus obtained does not have the desired degree of crystallization of the product.

It has now been found that the sodium salt of the compound of formula I can advantageously be prepared and isolated in crystalline hydrated form, the hydrated form being directly obtainable with the desired degree of purity and good stability, and therefore fulfills the exact requirements set for the pharmaceutical composition.

SUMMARY OF THE INVENTION

The present invention provides a crystalline hydrated form of the sodium salt of a compound of Formula I, i. j. (E) -4,6-dichloro-3- (2-oxo-1-phenylpyrrolidin-3-ylidenemethyl) -1H-indole-2-carboxylic acid sodium salt.

More specifically, the invention provides a crystalline hydrate which, according to analysis, contains from 2.5 to 3.1 wt. % water and preferably 2.6 to 2.9 wt. water, e.g.

2.6 to 2.8%.

The water content referred to above for the new crystalline hydrated form is that found in the product which is effectively dried to constant weight; e.g. vacuum dried (1 to 5 mm Hg) at 40 to 45 ° C for up to 4 days.

The crystalline hydrated form of the sodium salt of the compound of formula I can be characterized by its infrared spectrum as a suspension in mineral oil or by the X-ray diffraction characteristics of the powder.

Thus, the invention provides a crystalline hydrated form of the sodium salt of a compound of formula I characterized by an infrared spectrum as a suspension in mineral oil and with KBr disks having the following peaks:

(cm- ¹ ) 3308 1539 1349 3280 1500 1331 1668 1480 1305 1655 1482 1284 1639 1449 1244 1587 1435 834 1550 1407 814 690

The invention also provides a crystalline hydrated form of the sodium salt of a compound of formula I characterized by the following powder X-ray diffraction pattern expressed as 2 theta (1Θ) values obtained on Phillips X ¹ Part MPD Theta-2 Theta diffractometer using CuKα radiation (1.541 angstroms). ° / second and with a counting time of 1 second.

Angle (° 2 Θ) 5,170 18,325 25,395 5,435 18,775 26,535 9,585 19,225 26,920 11,745 20,820 27,630 14,635 21,195 28,230 15,590 22,925 30,370 16,365 23,970 30,870

The invention further provides a process for producing a novel crystalline hydrated form of the sodium salt of a compound of formula I by crystallization from a mixture of alkanol (e.g. ethanol, IMS (ethanol / methanol 95/5) or isopropanol) and water. Preferably, the crystallization process is carried out at a temperature between 55 ° C and reflux and preferably at a temperature of 60 to 80 ° C.

Therefore, in one embodiment of the invention, the acid can be dissolved by heating in an alkanol, e.g. isopropanol or IMS containing aqueous sodium hydroxide solution. If necessary, the hot solution can then be diluted with water to make crystallization more efficient and then the solution can be cooled.

In another embodiment of the process, a novel crystalline hydrated form of the sodium salt of a compound of Formula I can be produced and isolated directly by hydrolysis of an alkyl ester, e.g. C 1-4 alkyl ester such as e.g. the methyl or ethyl ester of a compound of formula I by heating an aqueous solution of sodium hydroxide and an alkanol, e.g. ethanol, IMS (ethanol / methanol 95/5) or isopropanol, followed by the addition of water, if necessary.

The alkyl ester of the compound of formula I can be prepared without difficulty by reacting the corresponding 3-formyl-4,6-dichloroindole-2-carboxylic acid alkyl ester with tributyl (2-oxo-1-phenylpyrolin-1-yl) phosphonium bromide in a solvent such as an alkanol, e.g. . isopropanol and in the presence of a base, e.g. 1,8-diazabicyclo [5.4.0] undec-7-ene.

The invention also provides the use of a novel crystalline hydrated form of the sodium salt of a compound of formula I for use in therapy, and in particular as medicaments with antagonizing effects of excitatory amino acids on the NMDA receptor complex.

The invention also provides the use of a novel crystalline hydrated form of the sodium salt of a compound of formula I in the manufacture of a medicament that antagonizes the effects of excitatory amino acids on the NMDA receptor complex.

The invention further provides a method of antagonizing the effects of excitatory amino acids on the NMDA receptor complex, which comprises administering an antagonist amount of a novel crystalline hydrated form of the sodium salt of a compound of formula I to a patient in need of indication. Therefore, eg. The invention provides a method of treating or preventing pain comprising administering to a patient in need thereof an effective amount of a novel crystalline hydrated form of the sodium salt of a compound of Formula I.

Those skilled in the art will appreciate that the treatment mentioned herein will be extended to include the prophylaxis and treatment of indicated diseases or symptoms.

It is further appreciated that the amount of compound of the invention required for treatment will vary depending upon the nature of the disease to be treated by the particular route of administration and the age and condition of the patient, and this will be ultimately within the purview of the attending physician. Generally, doses used in an adult patient will normally be in the range of 2 to 800 mg / day, depending on the route of administration.

For parenteral administration, the usual daily dose will range from 20 to 100 mg, preferably 60 to 80 mg / day. For oral administration, the daily dose will normally be in the range of 100 to 800 mg, e.g. 200 to 600 mg / day.

The desired dose may be presented as a single dose or may be divided into doses administered at appropriate intervals, e.g. as two, three, four or more sub-doses per day.

Since it is possible for the compound of the invention to be administered as a raw chemical in therapy, it is preferred that the active ingredient be presented as a pharmaceutical composition.

The invention further provides a pharmaceutical composition comprising a crystalline hydrated form of the sodium salt of a compound of formula I together with one or more pharmaceutically acceptable carriers and optionally other therapeutic and / or prophylactic ingredients. The carrier (s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The formulations of the invention include those formulations adapted for oral, buccal, parenteral, inhalation or insufflation, implantation or rectal administration.

Tablets and capsules for oral administration may contain conventional excipients such as binding agents, e.g. syrup, acacia, gelatin, sorbitol, tragacanth, mucilages of starch or polyvinylpyrrolidone; fillers, e.g. lactose, sugar, microcrystalline cellulose, corn starch, calcium phosphate or sorbitol; lubricants, e.g. magnesium stearate, stearic acid, talc, polyethylene glycol or silicon; disintegrants, e.g. potato starch or sodium starch glycolate, or humectants such as sodium lauryl sulfate. The tablets may be coated according to methods known in the art. Oral liquid preparations may be in the form of e.g. water

Or oil suspensions, solutions, syrups or infusions, or may be in the form of dry products for dilution with water or other suitable carrier before use. Such liquid preparations may contain conventional additives such as suspending agents, e.g. sorbitol, syrup, methylcellulose, glucose / sugar syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats; emulsifiers, e.g. Iecithin, sorbitan monooleate or acacia; anhydrous carriers (which may contain edible fats), e.g. almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; solubilizers such as surfactants, e.g. polysorbates or other agents, e.g. cyclodextrins; preservatives, e.g. methyl or propyl p-hydroxybenzoates or ascorbic acid. The formulations may also be in the form of suppositories, e.g. containing conventional suppository bases such as cocoa oil or other glycerides.

For buccal use, the preparation may take the form of tablets or lozenges formulated in conventional manner.

The composition of the invention may be adapted for parenteral administration by injection or continuous infusion. The injectable preparations may be presented in unit dosage form in ampoules or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as e.g. suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form for the further addition of a suitable carrier, before use, e.g. sterile, pyrogen-free water.

For inhalation administration, the compound of the invention is delivered in the form of an aerosol spray in a pressurized container, using a suitable propellant such as e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gases, or from a nebulizer. In the case of a pressurized aerosol, a single dose is determined by a valve that releases a metered amount of the substance.

Alternatively, the compound of the invention may be intended for inhalation or insufflation administration in the form of a dry powder formulation, e.g. a powder mix of the compound and a suitable carrier such as e.g. lactose or starch. The powder formulation may be in unit dosage form, e.g. in capsules or cartridges of

-7napr. gelatin or in blister packs from which the powder may be administered by means of an inhaler or insufflator.

The formulation of the invention may also be adapted to a depot formulation. Such long-acting formulations may be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the invention may be treated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g. as a sparingly soluble salt.

The compounds according to the invention may contain 0.1 to 99% of active ingredient, preferably 30 to 95% for tablets and capsules and 3 to 50% for liquid preparations.

A compound of formula I or an alkyl ester thereof can be prepared according to the procedures described in WO95 / 1057. Alternatively, the alkyl ester of the compound of formula I can be prepared by the process described in more detail in the examples.

For a more complete understanding of the invention, the following examples are given by way of illustration only.

In the examples, temperatures are given in ° C. The water content was determined by the Karl Fischer method.

DETAILED DESCRIPTION OF THE INVENTION

Intermediate 1

Tributyl- (2-oxo-1-phenylpyrrolidin-1-yl) phosphonium bromide

N, N, N ¹ N ¹ -tetramethylethylenediamine (23.3 mL) was added to a solution of N-phenylpyrrolidone (5 g) in dichloromethane (50 mL). The solution was cooled to 0-5 ° C and trimethylsilyl triflate (8.4 mL) was added over a period of about 20 minutes while maintaining the temperature in the range of 0-5 ° C. The resulting solution was stirred for 10 min and a solution of pyridinium bromide perbromide (13 g) in acetonitrile (20 mL) was added over 20 min maintaining the temperature in the range of 0 to 10 °. The resulting suspension was stirred at 0-5 ° C for about 60 min. Sodium bicarbonate solution (50 mL) was carefully added. The mixture was stirred for about 5 min and the layers were separated. The aqueous phase was diluted with water (20 mL) and back extracted with dichloromethane (20 mL). The combined organic phases were washed with another

-8 with sodium bicarbonate solution (50 mL), 2M HCl (2x50 mL) and water (50 mL), each washed phase was back extracted with dichloromethane (10 mL). The organic solution was dried (MgSO 4) and concentrated on a rotary evaporator. The red-brown solid was mixed with ethyl acetate (50 mL) and heated to form a solution, which was then cooled and tributylphosphine (8.5 mL) was added. The solution was heated to reflux and maintained at reflux for 2.5 hours. The solution was allowed to cool to room temperature and then cooled to 0-5 ° C. The resulting suspension was allowed to stand at 0-5 ° C for about 60 min. The product was isolated by vacuum filtration and washed with ethyl acetate: t-butylmethylether (1: 1, 40 mL) and dried in a vacuum oven at 45 • C ^e to give the title compound as a white crystalline solid (10.12 g). 1.1. 127 to 128 ^e .

Intermediate 2

Ethyl (E) -4,6-dichloro-3- (2-oxo-1-phenylpyrrolidin-3-ylidene methyl) -1H-indole-2-carboxylate

1,8-diazobicyclo [5.4.0] undec-7-ene (1.24 mL) was added to a mixture of ethyl-3-formyl-

4,6-dichloroindole-2-carboxylate (2 g) and tributyl (2-oxo-1-phenylpyrolin-1-yl) phosphonium bromide (3.7 g) in isopropanol (20 mL). The mixture was heated to reflux and refluxed for 8 h before being slowly cooled to room temperature.

The reaction mixture was cooled to about 5 ° C using an ice / water bath and allowed to stand at 0-5 ° C for 2 hours. The precipitate was filtered off in vacuo and washed with isopropanol (7.5 mL). The product was dried in a vacuum oven at 40 ° C to give the title compound as a white crystalline solid (1.95 g).

Example 1

(E) -4,6-Dichloro-3- (2-oxo-1-phenylpyrrolidin-3-ylidene-methyl) -1H-indole-2-carboxylic acid, sodium salt hydrate

Ethyl (E) -4,6-dichloro-3- (2-oxo-1-phenylpyrrolidin-3-ylidenemethyl) -1H-indole-2-carboxylate (494 g) was added slowly, without stirring, to a two-phase system consisting of isopropanol (3458 mL) and 32% NaOH (640 mL). The reaction mixture was heated to reflux (1 h 20 min) and stirred for 1.5 h. It was added dropwise

-9 water (10374 mL) over 24 min (final temperature 55 ° C). The reaction mixture was stirred for 30 min at 55/59 ° C, cooled to 15 ° C for 5 h 15 min, then the reaction mixture was stirred for 45 min, filtered (on a Teflon filter with a polypropylene backing with a diameter of 27 cm) and washed isopropanol / water 1/3 (988 mL) and water (5928 mL). The resulting solid was dried under vacuum at 40 ° C for 22 h 15 min to give the title compound (475 g). The water content was 2.66% by weight.

¹ H-NMR (4000 MHz) DMSO: 2.78 δ (m, 2H), 3.8 δ (m, 2H), 7.05 δ (d, 1H), 7.13 δ (m, 1H), 7.38 δ (m, 2H), 7.36 δ (d, 1H), 7.78 δ (d, 2H), 7.83 δ (t, 1H), 11.72 δ (bs, 1H).

Example 2 (E) -4,6-Dichloro-3- (2-oxo-1-phenylpyrrolidin-3-ylidenemethyl) -1H-indole-2-carboxylic acid sodium salt hydrate

Ethyl (E) -4,6-dichloro-3- (2-oxo-1-phenylpyrrolidin-3-ylidenemethyl) -1H-indole-2-carboxylate (2 g) was added to 14 mL of IMS (ethanol / methanol 95). / 5 volume). To the resulting slurry was added NaOH 32 wt. (2.58 mL). The reaction mixture was heated to reflux (for 50 min) and stirred for 1.5 hours. Water (42 mL) was added dropwise over 10 min. The reaction mixture was cooled to 15 ° C and then stirred for 2 h, filtered and washed with IMS / water 1/3 (4 mL) and water (42 mL). The resulting solid was dried under vacuum at 40 ° C for 20 h to give the title compound of the desired carboxylic acid sodium salt (1.67 g). The water content was 2.7 wt%.

¹ H-NMR (4000 MHz) DMSO: 2.78 δ (m, 2H), 3.8 δ (m, 2H), 7.06 δ (d, 1H), 7.14 δ (m, 1H), 7.40 δ (m, 2H), 7.40 δ (d, 1H), 7.78 δ (d, 2H), 7.83 δ (t, 1H), 11.82 δ (bs, 1H).

Pharmaceutical example

Tablets Active substance

5.27 to 105.5 mg

-10Laktóza

Microcrystalline cellulose

Sodium starch glycolate

Magnesium stearate

340.0 mg

214.1 mg

13.6 mg

6.8 mg

Tablets may be made by standard dry blending and direct compression techniques followed by conventional film coating and optionally enteric coating.

The active ingredient is the compound of Example 1 and the amount is equivalent to 5 to 100 mg of parent free acid.

Suitable conventional film forming coatings include Opadry white and suitable entero coatings include Sureteric Opadry entric white.

Claims (12)

PATENT CLAIMS A crystalline hydrated form of the sodium salt of (E) -4,6-dichloro-3- (2-oxo-1-phenylpyrrolidin-3-ylidene-methyl) -1H-indole-2-carboxylic acid of formula I. The crystalline hydrated form of claim 1, wherein the water content is between 2.5 to 3.1 wt. The crystalline hydrated form of claim 1 or 2, wherein the water content is between 2.6 to 2.9% by weight. A crystalline hydrated form according to any one of claims 1 to 3, characterized by an infrared spectrum as a suspension in a mineral oil which: shows the following peaks: (cm ’) 3308 1539 1349 3280 1500 1331 1668 1480 1305 1655 1482 1284 1639 1449 1244 1587 1435 834 1550 1407 814 690 The crystalline hydrated form of any one of claims 1 to 3, characterized by the following X-ray powder diffraction pattern expressed as 2 theta (1Θ), obtained on a Phillips X ¹ Part MPD Theta-2 Theta diffractometer using CuKα radiation (1.541 angstroms) , 04 ° / second and with a counting time of 1 second. Angle (° 2Θ) 5,170 18,325 25,395 5,435 18,775 26,535 9,585 19,225 26,920 11,745 20,820 27,630 14,635 21,195 28,230 15,590 22,925 30,370 16,365 23,970 30,870 6. A process for the production of a crystalline hydrated form according to claims 1 to 4 comprising crystallizing the sodium salt from an aqueous alkanol solution. Process according to claim 6, characterized in that the sodium salt of the compound of formula I is formed in situ by hydrolysis of the corresponding alkyl ester by reaction with an aqueous solution of sodium hydroxide in the presence of an alkanol, followed by the addition of water if necessary or desired. The process according to claim 7, wherein the alkyl ester is prepared by reacting the corresponding 3-formyl-4,6-dichloroindole-2-carboxylic acid alkyl ester with tributyl- (2-oxo-1-phenylpyrolin-1-yl) phosphonium bromide. The method of claim 8, wherein the alkyl ester is an ethyl ester. A pharmaceutical composition comprising the crystalline hydrated form of any one of claims 1 to 5 in admixture with one or more physiologically acceptable carriers or excipients. Use of the crystalline hydrated form of any one of claims 1 to 5 for the manufacture of a medicament for the treatment of diseases in a mammal including a human, wherein the therapeutic benefit is antagonizing the effects of excitatory amino acids on the NMDA receptor complex. The use of the crystalline hydrated form of any one of claims 1 to 5 for the manufacture of a medicament for treating or preventing pain in a mammal indicative of such treatment.