CN1249750A - 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

(E)-4,6-Dichloro-3-(2-oxo-1-phenylpyrrolidine-3-ylidenemethyl)-1H-indole-2-carboxylic acid, crystalline hydrated sodium salt

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

该化合物在对马钱子碱不敏感的与N-甲基-D-天冬氨酸(NMDA)受体复合物有关的甘氨酸结合位点上是有效的拮抗剂。式(I)化合物及其盐如钠盐可用于治疗或预防神经毒性损伤或神经变性疾病。因此，该化合物可用于治疗大脑中风、血栓栓塞性中风、出血性中风、大脑局部缺血、大脑血管痉挛、低血糖、记忆缺失、低氧症、缺氧症、产期窒息心脏停跳后的神经毒性损伤。该化合物可用于治疗慢性神经变性疾病，例如杭廷顿氏舞蹈病、早老性痴呆、肌萎缩性脊髓侧索硬化、戊二酸酸血症、多梗塞性痴呆。它们还可用于治疗或预防癫痫持续状态、挫伤性损伤(例如脊髓损伤和头部损伤)、病毒感染引起的神经变性(例如AIDS、脑病)、Down’s综合征、癫痫、精神分裂症、抑郁、焦虑、疼痛、偏头痛、神经原性膀胱障碍、刺激性膀胱障碍、药物依赖，包括乙醇、可卡因、鸦片制剂、尼古丁、苯并二氮的戒断症状、呕吐。WO95/1057 describes compounds of formula (1) and their physiologically acceptable salts,

The compound is a potent antagonist at the strychnine-insensitive glycine binding site associated with the N-methyl-D-aspartate (NMDA) receptor complex. Compounds of formula (I) and their salts, such as sodium salt, are useful in the treatment or prevention of neurotoxic injuries or neurodegenerative diseases. Therefore, the compound can be used in the treatment of cerebral apoplexy, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, hypoxia, perinatal asphyxia after cardiac arrest neurotoxic injury. The compounds are useful in the treatment of chronic neurodegenerative diseases such as Huntington's chorea, Alzheimer's disease, amyotrophic lateral sclerosis, glutaric acidemia, multi-infarct dementia. They may also be used to treat or prevent status epilepticus, contusive injuries (such as spinal cord injuries and head injuries), neurodegeneration caused by viral infections (such as AIDS, encephalopathy), Down's syndrome, epilepsy, schizophrenia, depression, anxiety , pain, migraine, neurogenic bladder disorder, irritative bladder disorder, drug dependence, including withdrawal symptoms from alcohol, cocaine, opiates, nicotine, benzodiazepines, and vomiting.

The sodium salt of the compound of formula (I) is of great importance since it allows the compound to be conveniently formulated for administration to the patient. It is therefore desirable to produce the sodium salt of the compound of formula (I) as pure as possible and as highly crystalline as possible in order to meet the stringent standards required for pharmaceuticals.

A process for the production of the sodium salt of the compound of formula (I) also needs to be easily carried out on a plant scale and the product can be easily isolated from the process.

WO 95/1057 describes the preparation and isolation of the sodium salt of the compound of formula (I) in solid form from an aqueous solution of the sodium salt of the compound of formula (I) by freeze-drying. This process is inconvenient to use on a plant scale and the product thus obtained is not the desired highly crystalline product.

It has now been found that the sodium salt of the compound of formula (I) can be prepared and isolated in the form of a crystalline hydrate which is conveniently obtained in the required high purity and has good stability, thus meeting the requirements of pharmaceuticals. demanding standards.

Accordingly, the present invention provides a novel crystalline hydrate form of the sodium salt of the compound of formula (I). More specifically, the present invention provides a crystalline hydrate which, upon analysis, contains 2.5-3.1% by weight water, preferably 2.6-2.9% by weight water, eg 2.6-2.8%.

The water content of the new crystalline hydrate form given above is that of the product which has been dried effectively to constant weight; for example under vacuum (1-5 mmHg) at 40-45°C for up to 4 days.

The crystalline hydrate of the sodium salt of the compound of formula (I) can be characterized by its infrared spectrum measured in powder form in mineral oil, or by its X-ray powder diffraction pattern.

Therefore, the present invention provides the following crystalline hydrate form of the sodium salt of the compound of formula (I), characterized in that the infrared spectrum measured in powder form in mineral oil and measured with KBr discs shows the following peaks:

(cm ^-1 )

3308 1539 1349

328 1500 1331

1668 1480 1305

1655 1482 1284

1639 1449 1244

1587 1435 834

1550 1407 814

690

The present invention also provides a crystalline hydrate form of the sodium salt of the compound of formula (I) characterized by having the following X-ray powder diffraction pattern expressed in terms of 2θ values in a Philips Measured on an X ¹ Part MPD Theta-2θ diffractometer with a step size of 0.04°/sec and a 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

In another aspect, the present invention provides a process for the preparation of a novel crystalline hydrated form of the sodium salt of the compound of formula (I), which process comprises, from an alkanol such as ethanol, IMS (ethanol/methanol 95/5) or isopropanol) and Crystallizes in water mixtures. Preferably the crystallization process is carried out at a temperature from 55°C to reflux, suitably at 60-80°C.

Thus, in one embodiment of the method, the acid can be dissolved with heating in an alkanol such as isopropanol or IMS containing aqueous sodium hydroxide. If necessary, the hot solution can be diluted with water to induce crystallization and then cooled.

In another embodiment of this method, the novel crystalline hydrated form of the sodium salt of the compound of formula (I) can be prepared and isolated by directly reacting an alkyl ester of the compound of formula (I), such as a C ₁ -C ₄ alkyl Esters such as methyl or ethyl esters are hydrolyzed by heating with aqueous sodium hydroxide and alkanols such as ethanol, IMS (ethanol/methanol 95/5) or isopropanol, followed by the addition of water as required.

Generally, the alkyl ester of the compound of formula (I) can be prepared by combining the corresponding alkyl ester of 3-formyl-4,6-dichloroindole-2-carboxylic acid with tributyl (2-oxo-1-benzene ylpyrrolidin-1-yl)phosphonium bromide in the presence of a base such as 1,8-diazabicyclo[5.4.0]undec-7-ene in a solvent such as an alkanol such as isopropanol be made of.

The present invention also provides the use of the novel crystalline hydrate form of the sodium salt of the compound of formula (I) in therapy, in particular as a medicament for antagonizing the action of excitatory amino acids on the NMDA receptor complex.

The present invention also provides the use of the novel crystalline hydrate form of the sodium salt of the compound of formula (I) in the preparation of a medicament for antagonizing the action of excitatory amino acids on the NMDA receptor complex.

In another aspect, the present invention provides a method of antagonizing the action of an excitatory amino acid on an NMDA receptor complex comprising administering to a patient in need thereof an antagonistic amount of a novel crystalline hydrate form of the sodium salt of a compound of formula (I). Accordingly, the present invention provides a method of treating or preventing pain comprising administering to a patient in need thereof an effective amount of a novel crystalline hydrate form of the sodium salt of the compound of formula (I).

Those skilled in the art will understand that the treatment referred to herein includes prevention as well as treatment of established diseases or symptoms.

It is also understood that the amount of a compound of the invention required for treatment will vary with the nature of the condition being treated, the route of administration, and the age and condition of the patient, and will ultimately be at the discretion of the attending physician. However, in the treatment of adults, the dosage used is usually in the range of 2-800 mg/day, depending on the route of administration.

Thus, for parenteral administration, the daily dosage will generally be in the range of 20-100 mg/day, preferably 60-80 mg/day. For oral administration, the daily dosage will generally be in the range of 100-800 mg/day, eg 200-600 mg/day.

The desired dose will generally be presented in a single dose, or in divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day.

Although it is possible for the compounds of the invention to be administered in the form of the raw compound in therapy, it is preferred to be the active ingredient in a pharmaceutical formulation.

Accordingly, the present invention also provides pharmaceutical formulations comprising the novel crystalline hydrate form of the sodium salt of the compound of formula (I) together with one or more pharmaceutically acceptable carriers and optionally other therapeutic and/or prophylactic ingredients. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the user who uses it.

Compositions of the present invention include forms formulated for oral, buccal, parenteral, inhalation or insufflation, implant or rectal administration.

Tablets and capsules for oral administration may contain customary excipients such as binders, for example syrup, acacia, gelatin, sorbitol, tragacanth, starch mucilage or polyvinylpyrrolidone; fillers, such as lactose, sugar, microcrystalline cellulose, corn starch, calcium phosphate, or sorbitol; lubricants such as magnesium stearate, stearic acid, talc, polyethylene glycol, or silicon dioxide; disintegrants such as potato starch or sodium starch glycolate; or a humectant such as sodium lauryl sulfate. Tablets may be coated by methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. The liquid preparations may contain conventional additives such as suspending agents, for example sorbitol syrup, methylcellulose, glucose/sucrose syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or Hydrogenated edible fats; emulsifiers such as lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (including edible oils) such as almond oil, fractionated coconut oil, oily esters, propylene glycol, or ethanol; solubilizers such as surface active agents such as polysorbates or other agents such as cyclodextrins; preservatives such as methyl or propyl parabens or ascorbic acid. The compositions may also be formulated in the form of suppositories, eg, containing conventional suppository bases such as cocoa butter or other glycerides.

For buccal administration, the compositions of the invention may be in the form of tablets or lozenges prepared in conventional manner.

The compositions of the present invention may also be formulated for parenteral administration by injection or continuous infusion. Formulations for injection may be presented in unit dose form in ampoules or in multi-dose containers with a preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, eg sterile, pyrogen-free water, before use.

For administration by inhalation, the compounds of the present invention are generally dispersed in the form of an aerosol delivered from a pressurized pack or from a nebulizer using a suitable propellant such as Dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable propellants. For pressurized aerosols, the unit dose can be determined by providing a valve to release a quantitative meter.

Alternatively, for administration by inhalation or insufflation, the compounds of the invention may be in the form of a dry powder composition, for example a powder mix of the compound and a suitable carrier such as lactose or starch. The powder composition may be in the form of, for example, gelatin capsules or cartridges, or in a blister unit dose package from which the powder may be administered by means of an inhaler or insufflator.

The compositions of the invention may also be formulated as depot preparations. Such long-acting formulations may be administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection. Thus, the compounds of the invention can be formulated with suitable polymeric or hydrophobic materials (eg, as emulsions in acceptable oils) or ion exchange resins, or as sparingly soluble derivatives, for example, as sparingly soluble salts.

The compositions of the present invention may contain 0.1-99% active ingredient, usually 30-95% for tablets and capsules and 3-50% for liquid formulations.

Compounds of formula (I) or their alkyl esters can be prepared as described in WO95/1057. Alternatively, alkyl esters of compounds of formula (I) may be prepared by the methods described in detail in the Examples below.

In order to illustrate the invention more clearly, the following examples are given by way of illustration only.

In the examples, temperatures are given in °C. Water content was determined by the Karl Fisher method. Intermediate 1 Tributyl(2-oxo-1-phenylpyrrolidin-1-yl)phosphonium bromide

N,N,N ¹ ,N ¹ -Tetramethylethylenediamine (23.3ml) was added to a solution of N-phenylpyrrolidone (5g) in dichloromethane (50ml). The solution was cooled to 0-5°C and trimethylsilyl triflate (8.4ml) was added over about 20 minutes keeping the temperature in the range 0-5°C. The resulting solution was stirred for 10 minutes, then a solution of pyridinium perbromide bromide (13 g) in acetonitrile (20 ml) was added over about 20 minutes, maintaining the temperature in the range 0-10°C. The resulting suspension was stirred at 0-5°C for about 60 minutes. Aqueous sodium bicarbonate solution (50ml) was added carefully. The mixture was stirred for about 5 minutes, then the layers were separated. The aqueous phase was diluted with water (20ml) and back-extracted with dichloromethane (20ml). The combined organic phases were extracted with sodium bicarbonate solution (50ml), 2M hydrochloric acid (2 x 50ml) and water (50ml) and the washes were back-extracted with dichloromethane (10ml). The organic solution was dried (magnesium sulfate) and concentrated on a rotary evaporator. The red/brown solid was stirred with ethyl acetate (50ml) and heated to give a solution which was cooled and tributylphosphine (8.5ml) added. The solution was heated to reflux and held at reflux for 2.5 hours. The solution was cooled to room temperature, then to 0-5 °C. The resulting suspension was aged at 0-5°C for about 60 minutes. The product was isolated by vacuum filtration, washed with ethyl acetate: tert-butyl methyl ether (1:1, 40ml) and dried in vacuo at 45°C to give the title compound (10.12g) as a white crystalline solid, Mp 127-128°C. Intermediate 2(E)-4,6-dichloro-3-(2-oxo-1-phenylpyrrolidin-3-ylidenemethyl)-1H-indole-2-carboxylic acid ethyl ester

1,8-Diazabicyclo[5.4.0]undec-7-ene (1.24ml) was added to ethyl 3-formyl-4,6-dichloroindole-2-carboxylate (2g) and A solution of a mixture of tributyl(2-oxo-1-phenylpyrrolidin-1-yl)phosphonium bromide (3.7 g) in isopropanol (20 ml). The mixture was heated to reflux for 8 hours, then cooled slowly to room temperature. The reaction mixture was cooled to about 5°C with an ice-water bath, then aged 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 under vacuum at 40°C to give the title compound (1.95g) as a white crystalline solid. Example 1 (E)-4,6-dichloro-3-(2-oxo-1-phenylpyrrolidin-3-ylidenemethyl)-1H-indole-2-carboxylic acid sodium salt, hydrate

Without stirring, (E)-4,6-dichloro-3-(2-oxo-1-phenylpyrrolidin-3-ylidenemethyl)-1H-indole-2-carboxylic acid Ethyl ester (494g) was added slowly to a biphasic system consisting of isopropanol (3458ml) and sodium hydroxide 32% w/w (640ml). The reaction mixture was heated to reflux (over 1 hour 20 minutes) and stirred for 1.5 hours. Water (10374ml) was added dropwise over 24 minutes (final temperature 55°C). The reaction mixture was stirred at 55/59°C for 30 minutes, cooled to 15°C within 2 hours and 15 minutes, then the reaction mixture was stirred for 45 minutes and filtered (filtered on Teflon filter paper with a diameter of 27 cm, using polypropylene as a support) . Wash with isopropanol/water 1/3 mixture (988ml) and water (5928ml). The obtained solid was vacuum dried at 40°C for 22 hours and 15 minutes to obtain the title compound (475 g). Water content 2.66% by weight. ¹ H-NMR (400MHz)DMSO2.78δ(m, 2H), 3.81δ(m, 2H), 7.05δ(d, 1H), 7.13δ(m, 1H), 7.38δ(m, 2H), 7.36δ (d, 1H), 7.78δ(d, 2H), 7.83δ(t, 1H), 11.72δ(bs, 1H). Embodiment 2(E)-4,6-dichloro-3-(2-oxo Substituent-1-phenylpyrrolidin-3-ylidenemethyl)-1H-indole-2-carboxylic acid sodium salt, hydrate

(E)-4,6-Dichloro-3-(2-oxo-1-phenylpyrrolidin-3-ylidenemethyl)-1H-indole-2-carboxylic acid ethyl ester (2 g) was added to in 14ml IMS (ethanol/methanol 95/5 v/v). To the resulting suspension was added 32% w/w sodium hydroxide solution (2.58ml). The reaction mixture was heated to reflux (within 50 minutes) and stirred for 1.5 hours. Water (42ml) was added dropwise over 10 minutes. The reaction mixture was cooled to 15°C and stirred for 2 hours, filtered and washed with a mixture of IMS/water 1/3 (4ml) and water (42ml). The obtained solid was dried under vacuum at 40°C for 20 hours to obtain the title compound (1.67 g). Water content 2.7% by weight. ¹ H-NMR (500MHz)DMSO2.78δ(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). Drug Examples Tablet Active ingredient* 5.27-105.5mg lactose 340.0mg microcrystalline cellulose 214.1 mg Sodium Starch Glycolate 13.6mg Magnesium Stearate 6.8mg

The tablets are produced by conventional dry blending and direct compression methods, followed by conventional film coating and optionally enteric coating.

The active ingredient is the compound of Example 1 in an amount relative to 5-100 mg of the parent free acid.

Suitable conventional film coatings include Opadry White and suitable enteric coatings include Sureteric Opadry Enteric White.

Claims (12)

1. (E)-4 of crystalline hydrate form, 6-two chloro-3-(2-oxo-1-Phenylpyrrolidine-3-ylidenylmethyl)-1H-indole-2-carboxylic acid sodium salt.

2. the crystalline hydrate form of claim 1, water-content wherein is between 2.5-3.1% (weight).

3. claim 1 or 2 crystalline hydrate form, water-content wherein is between 2.6-2.9 (weight).

4. any described crystalline hydrate form among the claim 1-3 is characterized in that showing below peak value with the infrared spectra that powder type records in mineral oil:

(cm ^-1)

3308 1539 1349

3280 1500 1331

1668 1480 1305

1655 1482 1284

1639 1449 1244

1587 1435 834

1550 1407 814

690

5. any described crystalline hydrate form among the claim 1-4 is characterized in that having following usefulness 2 θ value representation X-ray powder diffraction pattern types, and described value is at the Philips X that uses CuK α radiation (1.541 ) ¹Record with the gate time of 0.04 °/second step-length and 1 second on the Part MPD Theta-2 θ diffractometer:

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

6. the method for preparing any defined crystalline hydrate form among the claim 1-4, this method comprise, crystallization sodium salt from the solution of moisture alkanol.

7. the method for claim 6, wherein, the sodium salt of formula (I) compound is by hydrolysis reaction in the presence of alkanol makes on the spot with corresponding alkyl ester and aqueous sodium hydroxide solution, adds entry then with the need.

8. the method for claim 7, alkyl ester wherein are by with corresponding 3-formyl radical-4, and (2-oxo-1-Phenylpyrrolidine-1-base) phosphonium bromide reaction makes for the alkyl ester of 6-dichloro-indole-2-formic acid and tributyl.

9. the method for claim 8, alkyl ester wherein is an ethyl ester.

10. pharmaceutical composition contains the mixture of any described compound and one or more pharmaceutically acceptable carrier or vehicle among the claim 1-5.

11. comprise among the people that Mammals the antagonism excitatory amino acid has the method for the treatment disease of treatment beneficial effect to the effect of nmda receptor complex, this method comprises any described compound among the claim 1-5 that uses significant quantity.

12. comprising to required patient, the treatment or the method for prevent irritation, this method use any described compound among the claim 1-5 of significant quantity.