OA11154A - 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

011154

CRYSTALLINE HYDRATED SODIUM SALT OF (E) -4,6-DICHOLORO-3- (2-OX-1-PHENYLPYRROLIDIN-3-YLIDENE METHYL) -1H-INDOLE-2-CARBOXYLIC ACID

The present invention is concerned with the sodium of the excitatory amino acid antagonist (E) 4,6-dichloro-3- (2-oxo-1-phenylpyrrolidin-3-yledin-methyl) -1H-indole-2-carboxylic acid, its production, isolation and use in therapy. WO 95/1057 discloses inter alia the compound of formula (1).

(I) and physiologically acceptable salts thereof, as a potent antagonist at thestrychnine insensitive glycine binding site associated with N-methyl-D-aspartate (NMDA) receptor complex. The compound of formula (I) and salts of e.g. sodium are useful in the treatment or prevention of neurotoxic damage or neurodegenerative diseases. Thus the compounds areuseful for the treatment of neurotoxic injury which follows cerebral stroke, thromboembolism stroke, stroke hemorrhage, cerebral ischemia, cerebralvasospam, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxiacardiac arrest. The compounds are useful in the treatment of chronicneurodegenerative diseases such as: Huntingdon's disease, Alzheimer's dementia, lateral amyotrophy sclerosis, Glutaric Acidaemia type, multi-infarction dementia. They havea greater care in the treatment or prevention of epilecticus disease, contusive injuries (eg spinal cord injury and head injury), viral infection induced neurodengeration, (eg AIDS, encephalopaties), Down syndrome, epilepsy, schizophrenia, depression, anxiety, bread, migraine neurogenic bladder, irritative bladder disturbances, drugdependency, including symptoms of alcohol, cocaine, opiates, nicotine, benzodiazepine, and emesis. 2 011154

The sodium knows of the compound of formula (I) is of particular importance since it allows the compound to be conveniently formulated for administration to the patients. It is thus necessary to produce the sodium compound of the compound of formula (I) in a pure and highly crystalline form.

The process by which sodium is known to contain the compound of formula (I) also requires that it be carried out on a plant scale, and from which the product can be readily isolated.

The sodium of the compound of formula (I) has been prepared and isolated in solid form by the freeze-drying of an aqueous solution of sodium in acompound of formula (I) as described in WO 95/1057. This process is not necessarily very convenient for the production of the product and is therefore highly crystalline product desired.

It has been found that the sodium compound of the compound of formula (I) canbe advantageously prepared and isolated in a crystalline hydrated form whichhydrated form can be obtained with the requred high degree of purity andgood stability and thus fulfillment a pharmaceuticalproduct.

The present invention thus provides a novel crystalline hydrated form of the sodium of the compound of formula (I). More particularly the inventionprovides a crystalline hydrate which by analysis contains from .2.5 to 3.1% waterby weight, and preferably 2.6 to 2.9% water by weight e.g. 2.6 to 2.8%.

The water content is higher for the new crystalline hydrated form for the product which has been effectively dried to constant weight; for example dried under vacuum (1 to 5 mm Hg) at 40-45 ° C for up to 4 days. 3 011154

The crystalline hydrated form of the sodium is known from the compound of formula (I), and its X-ray powder diffraction pattern. The invention thus provides a crystalline form of sodium in the form of a compound of formula (1), characterized by an infra-red spectrum and a high molecular weight, with the following peaks: (cm1) 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 compound of the compound of formula I - X-ray powder diffraction patents of the 2 Theta (1) values and obtained on a Philips X1 MPT Theta-2 Theta diffractometer using CuKa radiation (1.541 angstroms) with a step size of 0.047 sec and count time of 1 sec.

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 4 011154 A further aspect of the invention provides a process for the preparation of thenew crystalline hydrated form of sodium the compound of formula (I) bycrystallization from a mixture of an alkanol (eg ethanol, IMS (ethanol / methanol95 / 5) or isopropanol) and water. The process is carried out at a temperature between 55 ° and reflux and conveniently 60-80 ° C.

Thus, in one embodiment of the process the alkanol may be dissolved with alkanol and isopropanol or IMS containing aqueous sodium hydroxide solution. Crystallization and then cooled.

In a further embodiment of the process, the novel crystalline hydrated form of the compound of formula (I) may be prepared and isolated directly from the hydrolysis of an alkyl ester eg C1-4 alkyl ester such as the methyl or ethyl ester of the compound of formula (I) by heating with aqueous sodium hydroxide and an alkanol eg ethanol, IMS (ethanol / methanol 95/5) orisopropanol, followed by the addition of water.

Conveniently the alkyl ester of the compound of formula (I) prepared by the corresponding alkyl ester of 3-methyl-4,6-dichloroindole-2-carboxylic acid with tributyl (2-oxo-1-phenylpyrrolin) -yl) phosphonium bromide ina solvent such as an alkanol eg isopropanol and in the presence of a base eg1,8-diazabicyclo [5.4.0] undec-7-ene. The invention also provides for the use of the novel crystalline hydrated form of the compound of formula (I) for use in therapy and for particularizing the antagonism of the effects of excitatory amino acids on the NMDA receptor complex. The invention also provides for the use of the novel crystalline hydrated form of the compound compound of formula (I) for the manufacture of a drug for antagonizing the effects of excitatory amino acids upon the NMDA receptor complex. 5 011154

The present invention also provides a method for antagonizing the effects of excitatory amino acids on the NMDA receptor complex, which comprises administering to a patient in an antagonistic fashion of the novel crystalline hydrated form of sodium compound of the formula compound (I ). Thus, for example, the invention provides a method for the treatment or prevention of an effective treatment of a new patient in an effective amount of the new crystalline hydrated form of the compound of formula (I).

It will be appreciated by those skilled in the art that reference herein to treatmentextends to prophylaxis as well as the treatment of established diseases orsymptoms.

It will be further appreciated that the amount of the invention will be dependent on the availability of the patient and the patient. . In general however doses are usually used in the range of 2 to 800mg per day, depend upon the route of administration.

Thus for parenteral administration a daily dose will typically be in the range 20-100mg preferably 60-80mg per day. For oral administration a daily dose will be 100-800mg e.g. 200-600mg per day.

The desired dose may be conveniently presented in a single dose or as divided doses at appropriate intervals, for two or three times, orrhore sub-doses per day.

While it is possible that, for use in therapy, the compound of the present invention has the advantage that it is preferable to present the active ingredient as a pharmaceutical formulation.

The invention thus further provides a pharmaceutical formulation comprising a novel crystalline hydrated form of the sodium, which may be used for the preparation of pharmaceutically acceptable ingredients and / or other therapeutic agents. The carrier (s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the container thereof.

The compositions of the invention include those in the form of oral, oral, parenteral, inhalation or insufflation, implant, or rectal administration. 011154

Tablets and capsules for oral administration may may be used as excipients, binders, syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone; fillers, for example, lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate orsorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch or sodium glycollate, or wetting agents such as sodium lauryl sulphate. The tabletsmay be coated according to the methods of the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, emulsion solutions, gold syrups or elixirs, or may be presented as a dry product. Such liquid preparations may be used for such purposes as suspending agents, forexample, sorbitol syrup, methyl cellulose, glucose / sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminum stearate gel orhydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitanmono-oleate or acacia; non-aqueous vehicles, for example, almond oil, fractionated coconut oil, oily esters, propylene glycol orethyl alcohol; solubilizers such as surfactants for exampie polysorbates or otheragents such as cyclodextrins; and preservatives, for example, methyl or propylp-hydroxybenzoates or ascorbic acid. The compositions may also be formulated as suppositories, e.g.

For oral administration the composition may take the form of tablets orlozenges formulated in the manner. 7 011154

The composition according to the invention may be formulated for parenteraladministration by injection or continuous infusion. Formulations for injectionmay be presented in unit dose form in ampoules, or in multi-dose containerswith an additional preservative. The compositions may take such forms assuspensions, solutions, gold emulsions in oily or aqueous vehicles, and maycontain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be sterile, pyrogen-free water, before use.

Aerosol spray formulation frompressurised packs, with the use of a suitable propellant, such asdichlorodifluoromethane, tirchlorofluoromethane, dichloro-tetrafluoroethane, carbon dioxide or other suitable propellant, such as dichlorodifluoromethane , trichlorofluoromethane, dichloro-tetrafluoroethane, carbon dioxide or othersuitable gas, or from a nebuliser. In the case of a pressurized aerosol can be determined by providing a valve to deliver a meteredamount.

Alternatively, the invention may be used for the formulation of a dry powder composition, forexample a powder mix of the compound and a suitable carrier such as lactoseor starch. The powder composition can be presented in unit dosage form forexample capsules or cartridges of e.g. gelatin, or blister packs from which the powder may be administered with the aid of an inhaler or insufflator.

The composition according to the invention may also be formulated as depotpreparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.Thus for example, the compounds of the invention may be formulated withsuitable polymeric or hydrophobic materials (for example as an emulsion in anacceptable oil) or ion exchange resins, or sparingly soluble derivatives, forexample, as sparingly soluble. 011154

The compositions according to the invention may contain between 0.1 - 99% of the active ingredient, conveniently from 30-95% for tablets and capsules and 3-50% for liquid preparations.

The compound of formula (I) or an alkyl ester thereof may be preparedaccording to the processes described in WO95 / 1057. Alternatively, an alkyl ester of the compound of formula (I) may be prepared by the process morespecifically described herein in the Examples.

In order for the invention, the invention may be more fully understood

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

Intermediate 1

Tributyl (2-oxo-1-phenylpyrrolidin-1-yl) phosphonium bromide N, N, N, N-N-tetramethylethylene diamine (23.3ml) was added to a solution of N-phenylpyrrolidinone (5g) in dichloromethane (50ml). The solution was cooled to0-5 ° and trimethylsilyI triflate (8.4ml) was added over ca 20 mins maintaining thetemperature in the range 0-5 °. The resulting solution was stirred for 10 minutes and a solution of pyridinium bromide perbromide (13g) in acetonitrile (20ml) wasadded over ca 20 mins maintaining the temperature in the range 0-10 ° .Theresulting suspension was stirred at 0-5 ° for ca 60 mins. Aqueous sodium bicarbonate solution (50ml) was added, cautiously. The mixture was diluted with water (20ml) and extracted with dichloromethane (20ml). The combinedorganic phases have been washed with further sodium bicarbonate solution (50ml), 2m hydrochloric acid (2x50ml) and water (50ml), back extracting each wash withdichloromethane (10ml). The organic solution was dried (MgSOzO andconcentrated on a rotavapor.The red / brown solid was stirred with ethyl acetate (50ml) and warmed to give a solution which was then cooled andtributylphosphine (8.5ml) was added. The resulting suspension was aged at 0-5 ° for ca 60 min.The product was isolated by vacuum filtration and thenwashed with ethyl acetate: t-butylmethylether (1: 1, 40ml) and dried in a vacuumoven at 45 ° to give the title compound to a white crystalline solid (10.12g), mp127-128 °.

Intermediate 2

Ethyl (E) -4,6-dichloro-3- (2-oxo-1-phenylpyrrolidin-3-ylidenemethyl) -1H-indole 2-carboxylate 1,8-Diazabicyclo [5.4.0] undec-7- ene (1.24ml) was added to a mixture of ethyl 3-formyl-4,6-dichloroindole-2-carboxylate (2g) and tributyl (2-oxo-1-phenylpyrrolin-1-yl) phosphonium bromide (3.7g) in isopropanol ( 20ml). The mixture was heated to reflux and reflux for 8 hours before cooling slowly to room temperature.

The reaction mixture was cooled to approx. 5 ° C using an ice / water bath at 0-5 ° C for 2 hr. The precipitate was filtered under vacuum and washed with isopropanol (7.5 ml). The product was dried in a vacuum oven at 40 ° C togive the title compound as a white crystalline solid (1.95g).

Example 1 (E) -4,6-dichloro-3- (2-oxo-1-phenyl-pyrrolidin-3-ylidenemethyl) -1H-indole-2-carboxylic acid sodium knows, hydrates

Ethyl (E) -4,6-dichloro-3- (2-oxo-1-phenyl-pyrrolidin-3-ylidenemethyl) -1H-indole-2-carboxylate (494g) was added slowly, without stirring, to a two phase Systemcomposed of isopropanol (3458ml) and NaOH 32% w / w (640ml). The reactionmixture was heated to reflux (in 1hr 20min) and stirred for 1.5hrs. Water (10374ml) was added dropwise in 24 minutes (final temperature 55 ° C). The reaction mixture was stirred for 30 minutes at 55 ° / 59 ° C., cooled to 15 ° C. in the course of 2 hours 15 minutes, then the mixture was stirred for 45 minutes, filtered (27 cm diameter teflon filter with polypropylene as support). And washed with a mixture of isopropanol / water1 / 3 (988ml) and water (5928ml). The resulting solid was dried under vacuum at 10 011154 40 ° C for 22hrs 15min to give the title compound (475g) Water content 2.66% by weight.

1H-NMR (400MHz) DMSO 2.78δ (m, 2H), 3.815 (m, 2H), 7.05δ (d, 1H), 7.13δ (m, 1H). 7.38 δ (m, 2H), 7.36δ (d, 1H), 7.78δ (d, 2H), 7.83δ (t.1H), 11.72δ (bs, 1H).

Exampie 2 (E) -4,6-dichloro-3- (2-oxo-1-phenyl-pyrrolidin-3-ylidenemethyl) -1H-indole-2-carboxylic acid sodium knows, hydrates

Ethyl (E) 4,6-dichloro-3- (2-oxo-1-phenyl-pyrrolidin-3-ylidenemethyl) -1H-indole-2-carboxylate (2g) was added to a 14ml of IMS (Ethanol / Methanol 95 / 5vol). ANaOH 32% w / w solution (2.58ml) was added to the suspension. Thereaction mixture was heated to reflux (in 50min) and stirred for 1.5hrs. Water (42ml) was added dropwise in 10 minutes. The reaction mixture was cooled to 15 ° and then stirred for 2hrs, filtered and washed with a mixture of IMS / water1 / 3 (4mll) and water (42ml). The result is a good solution for the first time. Sodium carboxylic acid knows (1.67g) .Water content 2.7% by weight

1H-NMR (500MHz) DMSO -2.78 δ (m, 2H), 3.81δ (m, 2H). 7.06δ (d, 1H), 7.14δ (m, 1H), 7.40δ (m, 2H), 7.40δ (d, 1H). 7.78δ (d, 2H), 7.83δ (t, 1H), 11.82δ (bs, 1H). 11 011154 5.27-105.5mg340.Omg214.1mg13.6mg6.8mg

Pharmacy Example

Tablets 5 Active ingredient *

Lactose

Microcrystalline CelluloseSodium Starch GlycolateMagnesium Sterate 10

The tablets can be manufactured using a standard dry blending and direct compression process followed by a conventional coating and optionally coated by an enteric coating. The active ingredient is the compound of Example 1 and the amount is equivalent to 5 to 100 mg of the parent free acid.

Appropriate film coats include Opadry white and suitable entericcoatings include Suretric opadry enteric white. 20

Claims (12)

Claims 1. (E) -4,6-Dichloro-3- (2-oxo-1-phenylpyrrolidin-3-ylidene methyl) -1H-indole 2-carboxylic acid, sodium, in a crystalline hydrated form. 5 2. A crystalline hydrated form as claimed by the water content between 2.5 to 3.1% by weight. 3. A crystalline hydrated form as claimed by water. 4. A crystalline hydrated form as claimed in any claim 1 to 3 characterized byan infra-red spectrum as a mineral in oil showing the following peaks: 3308 1539 1349 3280 1500 1331 1668 1480 1305 1655 1482 1284 1639 1449 1244 1587 1435 834 1550 1407 814 690 15 5. A crystalline hydrate as claimed in any claim 1 to 4 characterizedby the following - X-ray powder diffraction pattern expressed as 2-Thetavalues (2Θ) and obtained on a Philips X1 MPD Theta-2 Theta portion utilistingCuKa radiation (1.541 angstroms) with a step size of 0.04 ° / sec and counttime of 1 sec. 20 13 011154 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 preparation of the crystalline hydrated form as defined in which 1 to 4 is included which crystallizes the sodium from the solution of an aqueous alkanol. A process for the production of sodium hydroxide in the presence of an alkanol, addition of water. 8. A process as claimed by the alkyl ester of the corresponding alkyl ester of 3-formyl-4,6-dichloroindole-2-carboxylic acid with tributyl (2-oxo-1-phenylpyrrolin-1-yl) phosphoniumbromide. 9. A process as claimed by the alkyl ester is an ethyl ester. 10. A pharmaceutical composition comprising a compound as claimed in any one of the preceding claims. 11. A method of treatment of a mammal for the purpose of treating the effects of excitatory amino acids on the NMDA receptor complex of therapeutic benefit, including the administration of an effective application of a compound as claimed in any of claims 1 to 5. ) 12. A method de traitement ou de traitement ou de procede de l'administration de l'administering a patient dans une application d'application d'effective une application d'article d'application d'une demande d'application d'une demande de l'invention de la concurrence 1 à 5.