OA11154A

OA11154A - Crystalline hydrated sodium salt of (E)-4,6-dichloro-3-(2-oxo-1-phenylpyrrolidin-3-ylidene methyl)-1H-indole-2-carboxylic acid

Info

Publication number: OA11154A
Application number: OA9900201A
Authority: OA
Inventors: Zadeo Cimarosti; Paolo Maragni
Original assignee: Glaxo Wellcome Spa
Priority date: 1997-03-05
Filing date: 1999-09-02
Publication date: 2003-04-16
Also published as: KR20000075907A; CA2282851A1; GB9704498D0; AP9901637A0; HUP0002109A2; CO4940415A1; NO994303L; IS5166A; ZA981791B; PL335652A1; IL131489A0; AU6825198A; NO994303D0; HRP980114A2; NZ337315A; EA199900710A1; BG103779A; JP2001513796A; EP0966463A1; SK119699A3

Description

011154

CRYSTALLINE HYDRATED SODIUM SALT OF (E)-4,6-DICH0L0R0-3-(2-0X0-l-PHENYLPYRR0LIDIN-3-YLIDENE METHYL)-lH-IND0LE-2-CARB0XYLIC ACID

The présent invention is concerned with the sodium sait of the excitatory aminoacid antagonist (E) 4,6-dichloro-3-(2-oxo-1-phenylpyrrolidin-3-yledine methyl)-1 H-indole-2-carboxyiic acid, its production, isolation and use in therapy. WO 95/1057 describes inter alia the compound of formula (1).

(I) and physiologicaily acceptable salts thereof, as a potent antagonist at thestrychnine insensitive glycine binding site associated with the N-methyl-D-aspartate (NMDA) receptor complex. The compound of formula (I) and saltsthereof e.g. the sodium sait are useful in the treatment or prévention ofneurotoxic damage or neurodegenerative diseases. Thus the compounds areuseful for the treatment of neurotoxic injury which follows cérébral stroke,thromboembolie stroke, hémorrhagie stroke, cérébral ischemia, cérébralvasospam, hypoglycemia, amnesia, hypoxia, anoxia, périnatal asphyxiacardiac arrest. The compounds are useful in the treatment of chronicneurodegenerative diseases such as: Huntingdon's disease, Alzheimer'ssenile dementia, amyotrophie latéral sclerosis, Glutaric Acidaemia type, multi-infarct dementia. They hâve further uses in the treatment or prévention ofstatus epilecticus, contusive injuries (e.g. spinal cord injury and head injury),viral infection induced neurodengeration , (e.g. AIDS, encephalopaties),Down’s syndrome, epilepsy, schizophrénie, dépréssion, anxiety, pain,migraine, neurogenic bladder, irritative bladder disturbances, drugdependency, including withdrawal symptoms from alcohol, cocaïne, opiates,nicotine, benzodiazépine, and emesis. 2 011154

The sodium sait of the compound of formula (l) is of particular importance sinceit enables the compound to be conveniently formulated for administration' to thepatients. There is thus a need to produce the sodium sait of the compound offormula (I) in as pure and as highly crystalline a condition as possible in order tofulfil the exacting standards required for a pharmaceutical product.

The process by which the sodium sait of the compound of formula (I) also needsto be one which is convenient to carry out on a plant scale, and from which theproduct can be readily isolated.

The sodium sait of the compound of formula (I) has been prepared and isolatedin solid form by lyophilisation of an aqueous solution of the sodium sait of acompound of formula (I) as described in WO 95/1057. This process is notparticularly convenient for use on a plant scale and the product thus obtained isnot the highly crystalline product desired.

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

The présent invention thus provides a new crystalline hydrated form of thesodium sait 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 given above for the new crystalline hydrated form is that 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 sait of the compound of formula (I) may be characterised by its infra red spectrum as a mull in minerai oil, and or its X-ray powder diffraction pattern. 5 The invention thus provides a crystalline hydrated form of the sodium sait of thecompound of formula (1) characterised by an infra-red spectrum as a mull inminerai oil and with KBr dises showing 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 sait of the10 compound of formula I characterised by the following - X-ray powder diffractionpattern expressed as 2 Thêta (1Θ) values and obtained on a Philips X1 Part MPD Theta-2 Thêta diffractometer utilising CuKa radiation (1.541 angstroms)with a step size of 0.047sec 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 préparation of thenew crystalline hydrated form of the sodium of the compound of formula (I) bycrystallisation from a mixture of an alkanol (e.g. éthanol, IMS (ethanol/methanol95/5) or isopropanol) and water. Preferably the crystallisation process is carried 5 out at a température between 55° and reflux and conveniently 60-80°C.

Thus in one embodiment of the process the acid may be dissolved with heatingin the alkanol e.g. isopropanol or IMS containing aqueous sodium hydroxidesolution. If necessary, the hot solution may then diluted with water to effect 10 crystallisation and then cooled.

In a further embodiment of the process the new crystalline hydrated form of thesodium sait of the compound formula (I) may be prepared and isolated directlyby the hydrolysis of an alkyl ester e.g. Ci_4alkyl ester such as the methyl or 15 ethyl ester of the compound of formula (I) by heating with aqueous sodiumhydroxide and an alkanol e.g. éthanol, IMS (ethanol/methanol 95/5) orisopropanol, followed if necessary by addition of water.

Conveniently the alkyl ester of the compound of formula (I) may be prepared by 20 reaction of the corresponding alkyl ester of 3-fomnyl-4,6-dichloroindole-2-carboxylic acid with tributyl (2-oxo-1-phenylpyrrolin-1-yl)phosphonium bromide ina solvent such as an alkanol e.g. ispropanol and in the presence of a base e.g.1,8-diazabicyclo[5.4.0]undec-7-ene. 25 The invention also provides for the use of the new crystalline hydrated form of' the sodium sait of compound of formula (I) for use in therapy and in particularuse as medicine for antagonising the effects of excitatory amino acids upon the NMDA receptor complex. 30 The invention also provides for the use of the new crystalline hydrated form ofthe sodium sait of compound of formula (I) for the manufacture of a médicamentfor antagonising the effects of excitatory amino acids upon the NMDA receptorcomplex. 5 011154

According to a further aspect the invention also provides for a method forantagonising the effects of excitatory amino acids upon the NMDA receptorcomplex, comprising administering to a patient in need thereof an antagonisticamount of the new crystalline hydrated form of the sodium sait of the compoundof formula (I). Thus for example the inventon provides a method for thetreatment or prévention of pain which comprises administering to a patient inneed thereof an effective amount of the new crystalline hydrated form of thesodium sait 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 further be appreciated that the amount of the compound of the inventionrequired for use in treatment will vary with the nature of the condition beingtreated the route of administration and the âge and the condition of the patientand will be ultimately at the discrétion of the attendant physician. In generalhowever doses employed for adult human treatment will typically be in the rangeof 2 to 800mg per day, dépendent upon the route of administration.

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

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

While it is possible that, for use in therapy, the compound of the invention màybe administered as the raw Chemical it is préférable to présent the activeingrédient as a pharmaceutical formulation.

The invention thus further provides a pharmaceutical formulation comprising thenew crystalline hydrated form of the sodium sait of the compound of formula (I)together with one or more pharmaceutically acceptable carriers therefor and, optionally, other therapeutic and/or prophylactic ingrédients. The carrier(s) must be 'acceptable' in the sense of being compatible with the other ingrédients of the formulation and not deleterious to the récipient thereof.

The compositions of the invention include those in a form especially formulatedfor oral, buccal, parentéral, inhalation or insufflation, implant, or rectaladministration. 011154

Tablets and capsules for oral administration may contain conventional excipientssuch as binding agents, for example, syrup, accacia, gelatin, sorbitol,tragacanth, mucilage of starch or polyvinylpyrrolidone; fillers, for example,lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate orsorbitol; lubricants, for example, magnésium stéarate, stearic acid, talc,polyethylene glycol or silica; disintegrants, for example, potato starch or sodiumstarch glycollate, or wetting agents such as sodium lauryl sulphate. The tabletsmay be coated according to methods well known in the art. Oral liquidpréparations may be in the form of, for example, aqueous or oily suspensions,solutions émulsions, syrups or élixirs, or may be presented as a dry product forconstitution with water or other suitable vehicle before use. Such liquidpréparations may contain conventional additives such as suspending agents, forexample, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin,hydroxyethylcellulose, carboxymethyl cellulose, aluminium stéarate gel orhydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitanmono-oleate or acacia; non-aqueous vehicles (which may include edible oils),for example, almond oil, fractionated coconut oil, oily esters, propylene glycol orethyl aîcohol; 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 beformulated as suppositories, e.g. containing conventional suppository basessuch as cocoa butter or other glycerides.

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

The composition according to the invention may be formulated for parentéraladministration by injection or continuous infusion. Formulations for injectionmay be presented in unit dose form in ampoules, or in multi-dose containerswith an added preservative. The compositions may take such forms assuspensions, solutions, or émulsions in oily or aqueous vehicles, and maycontain formulatory agents such as suspending, stabilising and/or dispersingagents. Alternatively the active ingrédient may be in powder form forconstitution with a suitable vehicle, e.g. stérile, pyrogen-free water, before use.

For administration by inhalation the compound according to the invention isconvenientiy delivered in the form of an aérosol spray présentation frompressurised packs, with the use of a suitable propellant, such asdichlorodifluoromethane, tirchlorofiuoromethane, 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 pressurised aérosol thedosage unit may be determined by providing a valve to deliver a meteredamount.

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

The composition according to the invention may also be formulated as a depotpréparation. 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 hydrophobie materials (for example as an émulsion in anacceptable oil) or ion exchange resins, or as sparingly soluble dérivatives, forexample, as a sparingly soluble sait. 011154

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

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

In order that the invention may be more fully understood the following examplesare given by way of illustration only.

In the examples the températures are given in °C. The water content wasdetermined by the Karl Fischer method.

Intermediate 1

Tributyl (2-oxo-1-phenylpyrrolidin-1-yl) phosphonium bromide N,N,N1N1-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 thetempérature in the range 0-5°. The résultant solution was stirred for 10 minsand a solution of pyridinium bromide perbromide (13g) in acetonitrile (20ml) wasadded over ca 20 mins maintaining the température in the range 0-10°.Therésultant suspension was stirred at 0-5° for ca 60 mins. Aqueous sodiumbicarbonate solution (50ml) was added, cautiously. The mixture was stirred forca 5 mins and the layers are separated.The aqueous phase was diluted withwater (20ml) and back extracted with dichloromethane (20ml). The combinedorganic phases were 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 solution was heated to reflux and 9 011154 maintained at reflux for 2.5 hours. The solution was allowed to cool to roomtempérature and was then cooled to 0-5°. The resulting suspension was agedat 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 as a white crystalline solid (10.12g), mp127-128°.

Intermediate 2

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

The reaction mixture was cooled to approx. 5 °C using an ice/water bath andaged at 0-5°C for 2 hr. The precipitate was filtered under vacuum and washedwith 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 sait, hydrate

Ethyl (E)-4,6-dichloro-3-(2-oxo-1-phenyl-pyrrolidin-3-ylidenemethyl)-1H-indole-2-èarboxylate (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 temp. 55°C). The reactionmixture was stirred for 30min at 55/59°C, cooled to 15°C in 2hrs 15min then thereaction mixture was stirred for 45min, filtered (on a 27cm diameter teflon filterwith 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 2.78 δ (m, 2H), 3.815 (m, 2H), 7.05 δ (d, 1 H),7.13 δ (m, 1H). 7.38 δ (m, 2H), 7.36δ (d, 1H), 7.78 δ (d, 2H), 7.83 δ (t. 1H), 11.72 δ (bs, 1H).

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

Ethyi (E) 4,6-dichloro-3-(2-oxo-1-phenyl-pyrrolidin-3-yiidenemethyl)-1 H-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 obtained 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 to15° and then stirred for 2hrs, filtered and washed with a mixture of IMS/water1/3 (4mll) and water (42ml). The resulting solid was dried under vacuum at 40°for 20hrs to give the title compound desired carboxylic acid sodium sait (1.67g).Water content 2.7% by weight

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

Pharmacy Example

Tablets 5 Active ingrédient*

Lactose

Microcrystalline CelluloseSodium Starch GlycolateMagnésium Sterate 10

The tablets may be manufactured using a standard dry blending and directcompression process followed by a conventional film coating and optionallyfollowed by an enteric coating. 15 The active ingrédient is the compound of Example 1 and the amount iséquivalent to 5 to 100mg of the parent free acid.

Suitable conventional film coats include Opadry white and suitable entericcoatings include Sureteric Opadry enteric white. 20

Claims

12 011154 Claims 1. (E)-4,6-Dichloro-3-(2-oxo-1-phenylpyrrolidin-3-ylidene methyl)-1H-indole 2-carboxylic acid, sodium sait, in a crystalline hydrated form. 5

2. A crystalline hydrated form as claimed in claim 1 wherein the water contentis between 2.5 to 3.1% by weight.

3. A crystalline hydrated form as claimed in claim 1 or claim 2 wherein the 10 water content is between 2.6 to 2.9 by weight.

4. A crystalline hydrated form as claim in any of claims 1 to 3 characterised byan infra-red spectrum as a mull in minerai 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 hydrated form as claimed in any of claims 1 to 4 characterisedby the following - X-ray powder diffraction pattern expressed as 2-Thetavalues (2Θ) and obtained on a Philips X1 Part MPD Theta-2 Thêta 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 préparation of the crystalline hydrated form as defined inany of daims 1 to 4 which comprises crystallising the sodium sait from asolution of an aqueous alkanol.

7. A process as claimed in claim 6 wherein the sodium sait of the compound offormula (I) is generated in situ by hydrolysis of the corresponding alkyl esterby reaction with aqueous sodium hydroxide in the presence of an alkanol,followed if necessary or desired by the addition of water.

8. A process as claimed in claim 7 wherein the alkyl ester is prepared byreacting 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 in claim 8 wherein the alkyl ester is an ethyl ester.

10. A pharmaceutical composition comprising a compound as claimed in any ofdaims 1 to 5 in admixture with one or more physiologically acceptablecarriers or excipients.

11. A method of treatment of a mammal including man for conditions whereantagonising the effects of excitatory amino acids on the NMDA receptorcomplex is of therapeutic benefit, comprising administration of an effectiveamount of a compound as claimed in any of claims 1 to 5. 14 011154 » )

12. A method of treatment or prévention of pain which comprises administeringto a patient in need thereof an effective amount of a compound as claimedin any of ciaims 1 to 5.