KR20000029564A - Pharmaceutical composition containing a 5ht2c antagonist and a d2 antagonist - Google Patents

Abstract

PURPOSE: A pharmaceutical composition for the treatment or prevention of CNS disorders which comprises a compound having SHT2C antagonist activity, a compound having D2 receptor antagonist activity, and a pharmaceutically acceptable carrier is provided. CONSTITUTION: A pharmaceutical composition comprises: a 5HT2C antagonist is N-(1-methyl-1H-indol-5-yl)-N'-(3-pyridyl)urea or 5-methyl-1-(3- pyridylcarbamoyl)-2,3-dihydropyrrollo£2,3-f|indole or a pharmaceutically acceptable salts thereof; a D2 antagonist is haloperidol, raclopride and sulpiride or pharmaceutically acceptable salts thereof; a pharmaceutically acceptable carrier.

Description

Pharmaceutical Composition Containing a 5HT2c Antagonist and a D2 Antagonist

The present invention relates to novel combinations of compounds, pharmaceutical compositions containing them and their use in therapy.

WO 92/05170, WO 93/18028, WO 94 // 04533, WO 94/18170, WO 94/22871, WO 95/21844, WO 95/29177, WO 96/02537 and WO 96/23783 (all with Smithkline miserable) PL) describes heterocyclic derivatives that have been evaluated to contain 5HT2c receptor antagonist activity. Such compounds are used in the treatment of various central nervous system diseases such as depression.

D2 positive antagonists such as haloperidol, lacloprid and sulfide are known in the art and are described, for example, in Seeman et al. Current Opinion in Neurology and Neurosurgery, (1993), 6, 602-608. See.

It is presently believed that a combination of 5HT2c antagonist and D2 antagonist is more effective than single administration of 5HT2c or D2 antagonist in the treatment of certain central nervous system diseases such as schizophrenia.

In a first aspect the present invention

Compounds having 5HT2c antagonist activity;

Compounds having D2 receptor antagonist activity; And

To provide a pharmaceutical composition for the treatment or prevention of central nervous system diseases, including a pharmaceutically acceptable carrier.

It will be appreciated that compounds having 5HT2c or D2 activity are typically isolated in the form of salts, and the present invention can be extended to compositions in which the compounds are in the form of salts. Preferred salts are pharmaceutically acceptable salts such as hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartarate, citrate, oxalate, methanesulfonate and p-toluenesulfonate Such as acid addition salts.

The present invention also extends to compositions wherein the compound is in stereoisomeric or tautomeric form.

Preferred 5HT2c antagonists include those described in WO 92/05170, in particular compound N- (1-methyl-1H-indol-5-yl) -N '-(3-pyridyl) urea (SB-200646). Other preferred compounds are the 5-methyl-1- (3-pyridylcarbamoyl) -2,3-dihydropyrrolo [2,3-f] indoles (SB-206553) described in Example 1 of WO 94/04533. ) And pharmaceutically acceptable salts thereof. Other preferred compounds are described in WO 96/23783, in particular 1- [3-fluoro-5- (3-pyridyl) phenylcarbamoyl] -5-methoxy-6-trifluoromethyl indolin ( Example 8, SB-228357). Particularly preferred 5HT2c antagonists are the 5-methyl-6-trifluoromethyl-1- [6- (2-methylpyridin-3-yloxy) pyridin-3-ylcar described in Example 1 of PCT / EP 97/03156. Bamoyl] indolin (SB-243213) (2,3-dihydro-5-methyl-N- [2- (2-methyl-3-pyridinyl) oxy] -5-pyridinyl] -6-trifluoro Romethyl) -1H-indole-1-carboxamide). Other preferred 5HT2c antagonists are described in WO 93/18028, WO 94/04533, WO 94/18170, WO 94/22871, WO 95/21844, WO 95/21844, WO 95/29177, WO 96/02537, WO 96/23783 It includes the described compounds.

Preferred D2 antagonists include haloperidol, lacloprid, sulfide, ziprasidone, olanzapine, sertindol and quetiapine, and pharmaceutically acceptable salts thereof.

Compounds with 5HT2c and D2 antagonist activity may be administered together or separately, ie simultaneously or not simultaneously, for the treatment of central nervous system disease.

As used herein, 'simultaneously' means that the two drugs are together or less than 24 hours with each other, preferably within about 12 hours from each other, more preferably within about 1 hour from each other and most preferably from about 5 minutes from each other. It is to be understood that it means to be administered at intervals within. Simultaneous administration involves administering separate dosage forms of the two drugs simultaneously or as a single dosage unit. 'Not simultaneous' is understood to mean that two drugs are to be administered at least 24 hours apart.

In another aspect, the present invention provides a kit comprising a compound having 5HT2c antagonist activity and a compound having D2 antagonist activity in separate dosage forms. In particular, such kits are used to provide a patient when administration of separate dosages of the two active ingredients is necessary. Such kits may also be provided where continuous administration of a 5HT2c antagonist and a D2 antagonist is required.

The present invention also provides a pharmaceutical composition comprising a compound having antagonist activity at both 5HT2c and D2 receptors, i.e. a single compound having dual activity, and a pharmaceutically acceptable carrier thereof for the treatment or prevention of central nervous system diseases such as schizophrenia. Is enlarged. The present invention therefore provides compounds having antagonist activity at both 5HT2c and D2 receptors for use in the treatment of central nervous system diseases such as schizophrenia.

Compositions of the invention include schizophrenia; Mood disorders including depression, seasonal effects disorders and emotional disorders; Anxiety disorders including systemic anxiety, panic disorder, horror fear, social phobia, obsessive compulsive disorder and post-traumatic stress disorder; Memory disorders including dementia, forgetfulness and age-related memory impairment; And eating disorders, including eating disorders including anorexia nervosa and anorexia nervosa. Other central nervous system diseases include Parkinson's disease, dementia in Parkinson's disease, neuroleptic-induced parkinsonism and general motor disorders as well as mental disorders.

Accordingly, in a further aspect the present invention provides a pharmaceutical composition for use in therapy comprising a compound having 5HT2c antagonist activity, a compound having D2 antagonist activity and a pharmaceutically acceptable carrier.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound having a 5HT2c antagonist activity, a compound having a D2 antagonist activity, and a pharmaceutically acceptable carrier for use in the manufacture of a medicament for the treatment of the aforementioned diseases.

In particular, the present invention provides a pharmaceutical composition comprising a compound having 5HT2c antagonist activity, a compound having D2 antagonist activity, and a pharmaceutically acceptable carrier for use in the treatment or prevention of depression.

Those skilled in the art will recognize that the compounds and compositions according to the invention can be used advantageously in admixture with one or more other therapeutic agents.

The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The compositions of the present invention can also be administered in admixture with other agents, for example conventional antidepressants or anxiolytics.

Pharmaceutical compositions of the present invention that can be prepared in admixture at ambient temperature and atmospheric pressure are applied for oral, parenteral or rectal administration, and are used in tablets, capsules, oral liquid formulations, powders, granules, lozenges, powders that can be reconstituted, It may be in the form of a solution or suspension or suppository for injection or infusion. Orally administrable compositions are generally preferred.

Tablets and capsules for oral administration may be in unit dosage form and may include conventional excipients such as binders, fillers, tableting lubricants, disintegrants and acceptable wetting agents. Tablets can usually be coated according to methods well known in the pharmaceutical practice.

Oral liquid preparations can be, for example, in the form of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or in the form of dry products which can be reconstituted with water or other suitable vehicle before use. Such liquid formulations may include conventional additives such as suspending agents, emulsifiers, non-aqueous vehicles (which may include edible oils), preservatives and, if desired, conventional flavoring or coloring agents.

Liquid unit dosage forms for parenteral administration are prepared using a compound of the present invention or a pharmaceutically acceptable salt and sterile vehicle thereof. Depending on the vehicle and the concentration used, the compound may be suspended or dissolved in the vehicle. In preparing the solution, the compound is dissolved for injection, sterile filtered and sealed before filling in a suitable vial or ampoule. Advantageously, additives such as local anesthetics, preservatives and buffering agents are dissolved in the vehicle. The composition may be filled into vials to increase stability, freed of water after removal of vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compounds are suspended in the vehicle instead of dissolving the compound and asepticization cannot be performed by filtration. Compounds of the invention can be sterilized by exposure to ethylene oxide prior to suspension in a sterile vehicle. Advantageously, surfactants or wetting agents are included in the composition to facilitate uniform distribution of the compound.

The composition of the present invention may contain 0.1% to 99% by weight, preferably 10 to 60% by weight of the active substance, depending on the method of administration.

Dosages of the compounds used in the treatment of the aforementioned diseases can vary in a similar manner depending on the severity of the disease, the weight of the patient and other similar factors. However, as a general guideline the unit dose is 0.05 to 1000 mg, more suitably 1.0 to 200 mg, and such unit dose may be administered more than once a day, for example twice or three times a day. . Such treatment can be extended for weeks or months.

Preferred compounds of the invention can be prepared according to the following examples.

<Production example 1>

(5-methoxy-2-nitro-4-trifluoromethylphenyl) acetonitrile (D1)

A mixture of 1-methoxy-4-nitro-2-trifluoromethylbenzene (93 g, 0.421 mol) and 4-chlorophenoxyacetonitrile (77.55 g, 0.463 mol) in anhydrous DMF (500 ml) was stirred at 10 ° C. To a stirred solution of KO ^t Bu (103.85 g, 0.927 mol) in anhydrous DMF (400 ml) was added dropwise over 0.75 hours. After the addition was completed, the resulting purple solution was kept at −10 ° C. for 1 hour and then poured into a mixture of ice / water (1.5 l) and 5 M aqueous HCl solution (1.5 l). The resulting mixture was extracted with dichloromethane (3 × 1 l). The combined extracts were washed with water (3 l), dried (sodium sulfate) and evaporated under reduced pressure. The residue was chromatographed on silica using 10-40% ethyl acetate / petroleum ether as eluent to afford the crude product, recrystallized from ethyl acrylate / petroleum ether to give the title compound (85.13 g, 78%) as a white solid. Obtained. Mp 103-104 ° C.

¹H NMR (CDCl 3) δ: 4.10 (3H, s), 4.37 (2H, s), 7.34 (1H, s), 8.53 (1H, s).

<Production example 2>

5-methoxy-6-trifluoromethylindole (D2)

(5-methoxy-2-nitro-4-trifluoromethylphenyl) acetonitrile (D1) (85 g, 0.327 mol) in ethanol / water (9: 1, 1.6 l) and glacial acetic acid (16 ml) was stirred at room temperature, Hydrogenated on 10% palladium on carbon (50 g) at 50 psi for 0.5 hour. The reaction mixture was filtered and evaporated in vacuo. The residue was partitioned between aqueous potassium carbonate solution (1 l) and dichloromethane (2 x 1 l) and the combined organic extracts were dried (sodium sulfate) and evaporated to give the title indole (67.63 g, 96%) as a gray solid.

¹ H NMR (CDCl 3) δ: 3.94 (3H, s), 6.53 (1H, m), 7.21 (1H, s), 7.32 (1H, m). 7.64 (1 H, s), 8.25 (1 H, br s).

<Production example 3>

5-methoxy-6-trifluoromethylindolin (D3)

Indole (D2) (67.63 g, 0.315 mol) in glacial acetic acid (500 ml) was treated with a portion of sodium cyanoborohydride (40 g, 0.637 mol) with stirring at room temperature. After 3 h at rt, the reaction mixture was diluted with water (500 ml) and basified with 40% aqueous NaOH solution while cooling. The mixture was then extracted with dichloromethane (3 x 500 ml) and the combined extracts were dried (sodium sulfate) and evaporated to yield the title compound (67.73 g, 99%) as an off-white solid.

¹H NMR (CDCl 3) δ: 3.07 (2H, t), 3.58 (2H, t), 3.67 (1H, br s), 3.83 (3H, s), 6.83 (1H, s), 6.88 (1H, s).

<Production example 4>

5-hydroxy-6-trifluoromethylindolin (D4)

A mixture of 5-methoxy-6-trifluoromethylindolin (D3, 7.5 g, 34.3 mmol) and iodotrimethylsilane (12.5 ml, 89.3 mmol) in anhydrous chloroform (70 ml) was heated to reflux for 65 hours. . Then methanol was added carefully to the cooled mixture with stirring and the solvent was removed in vacuo. The residue was treated with saturated sodium bicarbonate solution and water until basic and extracted with dichloromethane / methanol. The organic extract was washed with brine, dried and evaporated. The residue was extracted with ether in a Soxhlet apparatus and the resulting solution was concentrated to give the title compound three times (total 2.85 g, 41%), melting point> 180 ° C. (decomposition).

¹H NMR (CDCl₃ / CD ₃ OD) δ: 3.02 (2H, d, J = 8), 3.52 (2H, d, J = 8), 4.00 (3H, s), 6.77 (1H, s), 6.83 (1H , s).

<Production example 5>

1-acetyl-5-hydroxy-6-trifluoromethylindolin (D5)

A mixture of indolin (D4, 2.84 g, 14 mmol) and acetic anhydride (1.32 ml, 14 mmol) in anhydrous dichloromethane (50 ml) was stirred at room temperature for 3 hours and evaporated. The residue was treated carefully with saturated sodium bicarbonate solution and the solid product was filtered off, washed with water and dried to give the title compound (3.28 g, 96%), melting point 244-7 ° C.

¹H NMR (d ₆ -DMSO) δ: 2.10 (3H, s), 3.11 (2H, t, J = 8), 4.06 (2H, t, J = 8), 6.88 (1H, s), 8.18 (1H, s).

<Production example 6>

1-acetyl-6-trifluoromethyl-5-trifluoromethylsulfonyloxy-indolin (D6)

To a solution of acetylindolin (D5, 1.19 g, 4.9 mmol) in anhydrous pyridine (10 ml) at 0 ° C. was added trifluoromethanesulfonic anhydride (1.52 g, 5.4 mmol). The mixture was then stirred overnight while slowly warming to room temperature. The mixture was partially evaporated, the residual liquid diluted well with water and the precipitate was filtered off. The crude product was dissolved in dichloromethane and the solution was washed with 1N hydrochloric acid and brine, dried and evaporated to give the title compound (1.77 g, 96%).

¹H NMR (CDCl₃) δ: 2.28 (3H, s), 3.32 (2H, t, J = 8), 4.19 (2H, t, J = 8), 7.29 (1H, s), 8.60 (1H, s).

MS m / z = 378 (MH ⁺ )

<Production example 7>

5-methyl-6-trifluoromethylindolin (D7)

Trifluoromethylsulfonyloxyindolin (D6, 1.77 g, 4.69 mmol), lithium chloride (0.60 g, 14.1 mmol) and bis (triphenylphosphine) palladium (II) chloride in anhydrous dimethylformamide (15 ml) To a mixture of (0.10 g, 0.14 mmol) tetramethyltin (0.72 ml, 5.2 mmol) was added. The mixture was heated at 110 ° C. for 3.5 h, cooled and evaporated. The residue was partitioned between dichloromethane and water and the organic phase was washed with brine, dried and evaporated. The crude product was dissolved in ethanol (30 ml), 10% aqueous sodium hydroxide solution (7.5 ml) and solid sodium hydroxide (1 g) were added and the mixture was heated to reflux overnight. Ethanol was removed under vacuum and the residue was diluted with water and extracted with dichloromethane. The organic extract was washed with brine, dried and evaporated. The residue was chromatographed on silica gel with suction with 2: 1 ether / petroleum ether to afford the title compound (0.70 g, 74%), melting point 43-4 ° C.

¹H NMR (CDCl₃) δ: 2.34 (3H, s), 3.02 (2H, t, J = 8), 3.57 (2H, t, J = 8), 3.78 (1H, broad), 6.85 (1H, s), 7.00 (1 H, s).

<Example 1>

N- (1-methyl-1H-indol-5-yl) -N '-(3-pyridyl) urea

This compound can be prepared according to the method given in WO 92/05170.

<Example 2>

5-methyl-1- (3-pyridylcarbamoyl) -2,3-dihydropyrrolo [2,3-f] indole

This compound can be prepared according to the method given in example 1 of WO 94/04533.

<Example 3>

5-methyl-6-trifluoromethyl-1- [6- (2-methylpyridin-3-yloxy) -pyridin-3-ylcarbamoyl] indolin

A mixture of indoline (D7, 20 g, 99.5 mmol), phenylcarbamate (D10, 31.9 g, 99.5 mmol) and triethylamine (13.9 ml, 100 mmol) in anhydrous dimethylformamide (1 L) Heated at 105 ° C. for 1 hour, cooled and evaporated under vacuum. The residue was diluted with dichloromethane, washed with 10% aqueous sodium hydroxide solution, and methanol was added to keep the product in solution. The organic phase was washed with water and brine, dried and evaporated. The crude product was recrystallized from dichloromethane to give the title compound (32.5 g, 76%), melting point 112-4 ° C.

The solution of free base in hydrochloride methanol or propanol can be prepared by treatment with concentrated hydrochloric acid.

Activity was assessed by reversal of haloperidol-induced stiffness in rats (rod method).

A 10 cm high by 10 mm diameter metal rod is suspended between two erected columns, and the rod is divided into cards or Pulsepex dividers. Groups of rats are administered intraperitoneally in the dosage range of test compound or vehicle. Position the rat so that its hind legs touch the ground and the forelimbs rest on a horizontal bar. The determination of stiffness is the time it takes for the rat to withdraw its forefoot from the rod, with 120 seconds being the maximum measurement, and the test is repeated at 30, 60 and 90 minutes. Rats are administered vehicle or haloperidol (3 umol / kg ip) to assess the reversal of stiffness, and stiffness is tested by standard methods at 30 and 60 minutes; The rats are then injected with a dosage range of test compound and the scleroderma is tested 30 minutes later.

SB-228357 effectively reversed haloperidol-induced stiffness at doses of 0.32, 3.2 and 10 mg / kg oral administration. SB-243213 (0.1-10 mg / kg oral administration) effectively reversed haloperidol-induced stiffness. The 5HT2 'antagonist, SB-215505 (0.1-3.2 mg / kg oral administration) and the 5HT2A antagonist, MDL-100907 (0.003-3.2 mg / kg oral administration) did not reverse haloperidol-induced stiffness.

Claims (9)

Compounds having 5HT2c antagonist activity; Compounds having D2 antagonist activity; And Pharmaceutical composition for the treatment or prevention of central nervous system diseases comprising a pharmaceutically acceptable carrier. The method of claim 1, wherein the 5HT2c antagonist is N- (1-methyl-1H-indol-5-yl) -N '-(3-pyridyl) urea or 5-methyl-1- (3-pyridylcarbamoyl ) -2,3-dihydropyrrolo [2,3-f] indole or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of claim 1, wherein the 5HT2c antagonist is 5-methyl-6-trifluoromethyl-1- [6- (2-methylpyridin-3-yloxy) pyridin-3-ylcarbamoyl] indolin Composition. The pharmaceutical composition of any one of claims 1-3, wherein the D2 antagonist is haloperidol, lacloprid and sulfide or a pharmaceutically acceptable salt thereof. 4. The pharmaceutical composition of claim 1, wherein the D2 antagonist is ziprasidone, olanzapine, sertindol and quetiapine or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a compound having antagonist activity at both 5HT2c and D2 receptors and a pharmaceutically acceptable carrier. The pharmaceutical composition according to any one of claims 1 to 6, for use in the treatment or prevention of schizophrenia. Compounds having antagonist activity at both 5HT2c and D2 receptors for use in the treatment of central nervous system diseases such as schizophrenia. A dosage unit comprising a dosage unit containing a 5HT2c antagonist or a pharmaceutically acceptable salt thereof and a dosage unit containing a D2 antagonist or a pharmaceutically acceptable salt thereof.