KR20000075907A - 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

The crystalline hydrated forms of the sodium salts of the compounds of formula (I) of the invention, methods for their preparation and their use in the treatment.

Description

(E) -4,6-dichloro-3- (2-oxo-1-phenylpyrrolidine-3-ylidene methyl) -1H-indole-2-carboxylic acid crystalline hydrated sodium salt of (E) -4,6-Dichloro-3- (2-Oxo-1-Phenylpyrrolidin-3-ylidene Methyl) -1H-Indole-2- Carboxylic Acid}

The present invention relates to sodium of (E) -4,6-dichloro-3- (2-oxo-1-phenylpyrrolidine-2-ylidene methyl) -1H-indole-2-carboxylic acid, which is an antagonist of excitatory amino acids. Salts, their preparation, separation and treatment.

International Patent Application Publication No. 95/1057 discloses compounds of formula (I) and their physiologically acceptable salts as potent antagonists, particularly at the strinineine-insensitive glycine binding site associated with the N-methyl-D-aspartate (NMDA) receptor complex It is described.

Compounds of formula (I) and salts thereof, such as sodium salts, are useful for the treatment or prevention of neurotoxic damage or neurodegenerative diseases. Therefore, these compounds are useful for the treatment of neurotoxic damage following stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, forgetfulness, hypoxia, oxygen deficiency, housework at delivery, and cardiac arrest. These compounds are useful for the treatment of chronic neurodegenerative diseases such as Huntingdon disease, Alzheimer's dementia, Amyotrophic lateral sclerosis, glutaric acid thrombosis, and multi-infarct dementia. They may also have seizure severity (eg, spinal cord injury and head injury), neurological degeneration (eg AIDS, brain disease) due to viral infections, Down syndrome, epilepsy, schizophrenia, depression, anxiety, pain, migraine headaches, neurological bladder It is used for the treatment or prevention of disorders, irritable bladder disorders, drug dependence, including withdrawal syndrome of alcohol, cocaine, opiates, nicotine, benzodiazepines, and vomiting.

Sodium salts of the compounds of formula (I) are particularly important because they can be conveniently formulated for administration to a patient. Therefore, in order to meet the stringent standards required for pharmaceutical products, the production of sodium salts of the compounds of formula (I) as pure and highly crystalline as possible is required.

In addition, the process for preparing the sodium salt of the compound of formula (I) is convenient to be carried out at plant scale and the separation of the product should be easy.

Sodium salts of compounds of formula (I) were prepared and separated in solid form by lyophilization of aqueous solution of sodium salt of compounds of formula (I) as described in WO 95/1057. Such a process is particularly inconvenient to use on a plant scale and the product obtained is not the desired high crystalline product.

In accordance with the present invention, the sodium salts of the compounds of formula (I) can be readily obtained in hydrated form with the high purity and good stability required, and thus can be advantageously prepared and separated into crystalline hydrated forms that meet the stringent criteria required for pharmaceutical products. It turns out that you can.

Accordingly, the present invention provides sodium salts of compounds of formula I in novel crystalline hydrated form. More particularly, the present invention provides crystalline hydrates which, as a result of analysis, contain 2.5 to 3.1% by weight, preferably 2.6 to 2.9% by weight (eg 2.6 to 2.8% by weight) of water.

The moisture content given above for the novel crystalline hydrated form is for products that are effectively dried to a constant weight, for example dried under vacuum (1 to 5 mmHg) for up to 4 days at 40 to 45 ° C.

The sodium salt of the compound of formula (I) in crystalline hydrated form can be characterized by the infrared spectrum in the mule state in mineral oil and / or by its X-ray powder diffraction pattern.

The present invention therefore provides sodium salts of the compounds of formula I in crystalline hydrated form having the properties of the following peaks in the mule state in mineral oil and by the infrared spectrum with KBr discs.

(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 utilizes a CuK _α line (1.541 μs), a 2-theta (2 θ), obtained with a Philips X ¹ part MPD Theta-2 Theta Diffractometer with a step size of 0.04 ° / sec and a counter time of 1 sec. The sodium salt of the compound of formula (I) in crystalline hydrated form, characterized by the following X-ray powder diffraction pattern expressed as a value of).

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 of the invention there is provided a process for preparing sodium of a compound of formula (I) in novel crystalline hydrated form by crystallizing from a mixture of alkanols (e.g., ethanol, IMS (ethanol / methanol 95/5) or isopropanol) and water do. The crystallization process is preferably carried out at 55 ° C. to reflux temperature, conveniently at 60 to 80 ° C.

Thus, in one embodiment of this process, the acid can be dissolved while heating in an aqueous solution of sodium hydroxide containing alkanol (eg, isopropanol or IMS). If necessary, this hot solution may then be diluted with water to effect crystallization and then cooled.

In another embodiment of this process, the sodium salt of the compound of formula I in a novel crystalline hydrated form is heated with an aqueous sodium hydroxide solution and alkanol (e.g., ethanol, IMS (ethanol / methanol 95/5) or isopropanol) Then, if necessary, water can be added to prepare and separate directly by hydrolysis of alkyl esters of the compound of formula (I), for example C _1-4 alkyl esters such as methyl or ethyl esters.

Alkyl esters of compounds of formula I are tributyl bromide (2) in the presence of a base (eg 1,8-diazabicyclo [5.4.0] undec-7-ene) in a solvent such as an alkanol (eg isopropanol) It can be conveniently prepared by the reaction of oxo-1-phenylpyrrolin-1-yl) phosphonium with the corresponding alkyl ester of 3-formyl-4,6-dichloroindole-2-carboxylic acid.

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

According to another aspect of the invention, the invention also provides excitability to the NMDA receptor complex, comprising administering to a patient in need thereof an amount capable of antagonizing the sodium salt of the compound of formula I in a novel crystalline hydrated form. Provided are methods for antagonizing the action of amino acids. Thus, for example, the present invention provides a method for treating or preventing pain, comprising administering to a patient in need thereof an effective amount of a compound of formula I in a novel crystalline hydrated form.

Those skilled in the art will appreciate that the term treatment herein extends to the prevention as well as the treatment of the disease or syndrome that has occurred.

In addition, the required amount of the compound of the present invention in the treatment will vary depending on the nature of the condition to be treated, the route of administration and the age and condition of the patient, and ultimately, the judgment of the attending physician. In general, however, dosages used for adult treatment will typically range from 2 to 800 mg per day, depending on the route of administration.

Thus, for parenteral administration, the daily dosage will typically be in the range of 20 to 100 mg, preferably 60 to 80 mg per day. For oral administration, the daily dosage will typically be in the range of 100 to 800 mg, for example 200 to 600 mg per day.

Preferred administrations will be convenient for single or divided doses administered at appropriate intervals, for example twice, three, four or more times per day.

It is also possible to administer the original drug for use in the treatment of the compounds of the invention, but it is preferred to provide the active ingredient in the form of a pharmaceutical formulation.

Accordingly, the present invention also provides pharmaceutical formulations comprising sodium salts of the compounds of formula (I) in novel crystalline hydrated form with one or more pharmaceutically acceptable carriers, and optionally other therapeutic and / or prophylactic agents. . This carrier must be "acceptable" in that it must be compatible with the other ingredients in the formulation and harmless to the recipient.

Compositions of the present invention include formulations specifically formulated for oral, oral, parenteral, infusion or aeration, transplantation or rectal administration.

Tablets and capsules for oral administration include binders such as syrup, acacia, gelatin, sorbitol, tragacanth, starch mucus or polyvinylpyrrolidone; Fillers such as lactose, sugars, microcrystalline cellulose, corn starch, calcium phosphate or sorbitol; Lubricants such as magnesium stearate, stearic acid, talc, polyethylene glycol or silica; Disintegrants such as potato starch or sodium starch glycolate; Or conventional excipients such as wetting agents, such as sodium lauryl sulfate. Tablets may be coated by methods known in the art. Oral liquid preparations may be, for example, in the form of aqueous solutions or oily suspensions, solutions, emulsions, syrups or elixirs, or as dry products which reconstitute with water or other suitable vehicle before use. have. Such liquid preparations include antisettling agents such as sorbitol syrup, methyl cellulose, glucose / sugar syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats; Emulsifiers such as lecithin, sorbitan mono-oleate or acacia; Water-insoluble vehicles (which may include edible oils) such as almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; Solubilizers such as surfactants such as other agents such as polysorbates or cyclodextrins; And conventional additives such as preservatives such as methyl or propyl p-hydroxybenzoate or ascorbic acid. These compositions may also be formulated in suppositories containing conventional suppository bases such as, for example, cocoa butter or other glycerides.

For oral administration, the compositions may be in the form of tablets or lozenges formulated in conventional manner.

The composition according to the invention may be formulated for parenteral administration by injection or continuous infusion. Formulations for infusion may be provided in a single dosage form in ampoules or in multidose container dosage forms with a preservative added. These compositions may be in the form of antisettling agents, solutions or emulsions in oily or aqueous phase vehicles, and may contain formulations such as antisettling agents, stabilizers and / or dispersants. The active ingredient may also be in powder form which reconstitutes with a suitable vehicle, eg, sterile pyrogen-free water, before use.

For administration by inhalation, the compounds according to the invention can be prepared in suitable preparations such as dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane, carbon dioxide, or dichlorodifluoromethane, trichlorofluoromethane. , Other suitable charges, such as dichloro-tetrafluoroethane, carbon dioxide, or other suitable gas, are conveniently delivered in pressurized packs or in aerosol spray form from the nebulizer. In the case of a pressurized aerosol, a single dose may be provided with a valve to deliver a predetermined amount.

In addition, for administration by inhalation or insufflation, the compounds of the present invention may be in the form of a dry powder composition, for example in the form of a powder mix of this compound and a suitable carrier such as lactose or starch. The powder composition may, for example, be in unit dosage form of a capsule or cartridge (eg gelatin), or an expansion pack in which the powder may be administered with the aid of an inhaler or blower.

The composition according to the invention may also be formulated in a depot preparation. Such prolonged active agents can be administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular infusion. Thus, for example, the compounds of the present invention may be formulated with suitable polymerizable or hydrophobic materials (eg as emulsions in acceptable oils) or ion exchange resins, or as slightly soluble derivatives, for example slightly soluble salts. Can be.

The composition according to the invention may contain 0.1 to 99% of the active ingredient, conveniently 30 to 95% of the tablets and capsules and 3 to 50% of the liquid formulation.

Compounds of formula (I) or alkyl esters thereof may be prepared according to the methods described in WO 95/1057. In addition, alkyl esters of compounds of formula (I) may be prepared by the methods described in more detail in the Examples.

In order to more fully understand the present invention, the following examples are given by way of illustration only.

In an embodiment, the temperature is given in ° C. Moisture content was determined by Karl Fischer method.

〈Intermediate 1〉

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

N, N, N ¹ , N ¹ -tetramethylethylene diamine (23.3 ml) was added to a solution of N-phenylpyrrolidinone (5 g) in dichloromethane (50 ml). The solution was cooled to 0-5 ° C and trimethylsilyl triflate (8.4 ml) was added over about 20 minutes while maintaining a temperature in the range of 0-5 ° C. The resulting solution was stirred for 10 minutes and a solution of pyrobromide pyridinium (13 g) in acetonitrile (20 ml) was added over about 20 minutes while maintaining a temperature in the range from 0 to 10 ° C. The resulting suspension was stirred at 0-5 ° C. for about 60 minutes. Aqueous sodium bicarbonate solution (50 ml) was added carefully. The mixture was stirred for about 5 minutes and the layers separated. The aqueous layer was diluted with water (20 ml) and back extracted with dichloromethane (20 ml). The combined organic layers were further extracted with sodium bicarbonate solution (50 ml), 2M hydrochloric acid (twice with 50 ml) and water (50 ml) and each was back extracted with dichloromethane (10 ml). The organic solution was dried (MgSO ₄ ) and concentrated on a rotary evaporator. The reddish brown solid was stirred with ethyl acetate (50 ml), the warmed solution was cooled and tributylphosphine (8.5 ml) was added. The solution was heated to reflux and held at reflux for 2.5 hours. The solution was cooled to room temperature and then cooled to 0-5 ° C. The resulting suspension was aged at 0-5 ° C. for about 60 minutes. The product was isolated by vacuum filtration, then washed with ethyl acetate: t-butylmethylether (1: 1, 40 ml) and dried in a vacuum oven at 45 ° C. to give the title compound (10.12 g) as a white crystalline solid. Obtained. mp 127 to 128 ° C.

〈Intermediate 2〉

Ethyl (E) -4,6-dichloro-3- (2-oxo-1-phenylpyrrolidine-3-ylidenemethyl) -1 H-indole 2-carboxylate

1,8-diazabicyclo [5.4.0] undec-7-ene (1.24 ml) was added to ethyl 3-formyl-4,6-dichloroindole-2-carboxylate (2 g) in isopropanol (20 ml). ) And tributyl brominated (2-oxo-1-phenylpyrroline-1-yl) phosphonium (3.7 g). The mixture was heated to reflux and refluxed for 8 hours before slowly cooling to room temperature. The reaction mixture was cooled to about 5 ° C. using an ice water bath and aged at 0-5 ° C. for 2 hours. This precipitate was filtered under vacuum and washed with isopropanol (7.5 ml). The product was dried in a vacuum oven at 4 ° C. to give the title compound (1.95 g) as a white crystalline solid.

<Example 1>

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

Ethyl (E) -4,6-dichloro-3- (2-oxo-1-phenyl-pyrrolidine-3-ylidenemethyl) -1H-indole-2-carboxylate (494 g) is not stirred Was slowly added to a two-phase system comprising isopropanol (3458 ml) and NaOH 32% w / w (640 ml). The reaction mixture was heated to reflux (after 1 h 20 min) and stirred for 1.5 h. Water (10374 ml) was added after 24 minutes (final temperature 55 ° C). The reaction mixture was stirred at 55-59 ° C. for 30 minutes, cooled to 15 ° C. after 2 hours and 15 minutes, and then the reaction mixture was stirred for 45 minutes (in a 27 cm diameter Teflon filter with polypropylene as support). Filtered. It was then washed with a mixture of isopropanol / water 1/3 (988 ml) and water (5928 ml). The resulting solid was dried in vacuo at 40 ° C. for 22 h 15 min to afford the title compound (475 g). The moisture content is 2.66 wt%.

¹ H NMR (400 MHz) DMSO

2.78 δ (m, 2H), 3.81 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, 1 H), 11.72 δ (bs, 1 H).

<Example 2>

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

Ethyl (E) 4,6-dichloro-3- (2-oxo-1-phenyl-pyrrolidine-3-ylidenemethyl) -1H-indole-2-carboxylate (2 g) was added to IMS (ethanol / To 95 ml of methanol). A 32 wt% solution of NaOH (2.58 ml) was added to the resulting suspension. The reaction mixture was heated to reflux (after 50 minutes) and stirred for 1.5 hours. Water (42 ml) was added dropwise after 10 minutes. The reaction mixture was cooled to 15 ° C., then stirred for 2 hours, filtered and washed with a mixture of IMS / water 1/3 (4 ml) and water (42 ml). The resulting solid was dried under vacuum at 40 ° C. for 20 hours to afford the title compound (1.67 g) of the desired carboxylic acid sodium salt. Moisture content is 2.7% by weight.

¹ H-NMR (500 MHz) DMSO

2.78 δ (m, 2H), 3.81 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, 1 H), 11.82 δ (bs, 1 H).

<Preparation Example>

refine

Active ingredient ^* 5.27-105.5 mg

Lactose 340.0 mg

Microcrystalline Cellulose 214.1 mg

Sodium Starch Glycolate 13.6 mg

Magnesium Stearate 6.8 mg

Tablets may be prepared by standard dry mixing and direct compression processes followed by conventional film coating methods and optionally enteric coating methods.

The active ingredient is the compound of Example 1, the amount of which is 5 to 100 mg without parent acid.

Typical suitable film coats include Opadry White, and suitable enteric coatings include Sureteric Opadry Enteric White.

Claims (12)

Sodium salt of (E) -4,6-dichloro-3- (2-oxo-1-phenylpyrrolidine-2-ylidene methyl) -1H-indole-2-carboxylic acid in crystalline hydrated form. The crystalline hydrated form according to claim 1, wherein the water content is 2.5 to 3.1% by weight. The crystalline hydrated form according to claim 1 or 2, wherein the water content is 2.6 to 2.9% by weight. 4. The crystalline hydrate form according to any one of claims 1 to 3, wherein the infrared spectrum in the mule state in mineral oil exhibits 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 Philips X ¹ part MPD Theta-2 Theta diffraction according to any one of claims 1 to 4, having a step size of 0.04 ° / second and a counter time of 1 second using a CuK _α line (1.541 μs). Crystalline hydrated form characterized by the following X-ray powder diffraction pattern, expressed as a 2-theta (2θ) value, as measured by a meter. 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 A process for the preparation comprising crystallizing the sodium salt from an aqueous solution of alkanol in the crystalline hydrated form as defined in claim 1. 7. The process according to claim 6, wherein the corresponding alkyl ester is hydrolyzed in the presence of an alkanol by reaction with aqueous sodium hydroxide solution and then water is added if necessary or desired to produce the sodium salt of the compound of formula (I) in the reaction system. . 8. The compound of claim 7 wherein the corresponding alkyl ester of 3-formyl-4,6-dichloroindole-2-carboxylic acid is substituted with tributyl bromide (2-oxo-1-phenylpyrrolin-1-yl) phosphonium. Reaction to produce alkyl esters. The method of claim 8, wherein the alkyl ester is ethyl ester. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 together with one or more physiologically acceptable carriers or excipients. A method of treating mammals, including humans, with a therapeutically beneficial condition that antagonizing the action of excitatory amino acids on the NMDA receptor complex, comprising administering an effective amount of the compound of any one of claims 1 to 5. . A method of treating or preventing pain, comprising administering to a patient in need thereof an effective amount of a compound of any one of claims 1 to 5.