HRP940225A2 - The sulphate salt of a substituted triazole, pharmaceutical compositions thereof, and their use in therapy - Google Patents

Description

This invention relates to a special salt of a pharmaceutically active ingredient. In more detail, this invention relates to the sulfate salt of a substituted triazole derivative that acts on 5-hydroxytryptamine (5-HT) receptors, because it is a selective agonist of the so-called "5-HT1-like" receptors. This compound is therefore useful in the treatment of clinical conditions in which a selective agonist of these receptors is indicated.

5-HT1-like receptor agonists that exhibit selective vasoconstrictor activity have recently been described for use in the treatment of migraine (see, eg, A. Doenicke et.al., The Lancet. 1988, Vol. 1, 1309-11). The salt of this invention is due to the manifestation of selective action of 5-HT1-like receptor agonists of importance in the treatment of migraine and similar conditions, eg cluster headaches, chronic paroxysmal hemicrania, headaches associated with vascular disorders, tension headaches and pediatric migraines.

EP-A-0497512, published August 5, 1992, describes a class of substituted imidazole, triazole and tetrazole derivatives which are said to be selective 5-HT1-like receptor agonists and therefore of particular importance in the treatment of migraine and similar conditions.

This invention provides the sulfate salt of N,N-dimethyl-2-(5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl)ethylamine. Specifically, the invention provides N,N-dimethyl-2-(5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl/ethylamine sulfate salt (2:1) of structural formula I:

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and pharmaceutically acceptable solvates, including hydrates, especially its 0.7 hydrate.

Pharmaceutically acceptable salts of N,N-dimethyl-2-(5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl/ethylamine) are generically covered within the scope of EP-A-0497512. The oxalate hemihydrate, succinate and benzoate salts of this compound are particularly emphasized in EP-A-0497512. However, nowhere in EP-A-0497512 is a specific salt of the above structural formula 1 or pharmaceutically acceptable solvates thereof specifically mentioned.

It was established that the salt of structural formula I given above has favorable characteristics in several aspects, which make it particularly suitable for use as a pharmaceutical agent. For example unlike many drugs which have an unpleasant taste, the salt of formula I was found to be relatively tasteless. In another aspect, the present invention therefore provides a pharmaceutical composition comprising a sulfate salt of formula I above or a pharmaceutically acceptable solvate thereof together with one or more pharmaceutically acceptable excipients.

The ingredients according to the given invention are appropriate in individual doses such as tablets, pills, capsules, powders, granules, sterile solutions or suspensions, metered aerosol or liquid spray, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Formulation of the ingredients according to the invention provided herein can be carried out by methods known in the art, for example described in Remington's Pharmaceutical Sciences. 17th ed., 1985.

For example for the preparation of solid ingredients such as tablets, the active ingredient is mixed with a pharmaceutical base, eg standard tableting ingredients such as microcrystalline cellulose, corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to obtain a solid ingredient containing a homogeneous mixture of salts of formula I above. When the ingredients are stated as homogeneous, it means that the active substance is completely dispersed throughout the entire amount of the ingredient, so that the ingredient can be immediately divided into equally effective smaller unit doses such as tablets, pills and capsules. This solid ingredient is further divided into dosage units for administration as described above, containing from 0.1 to about 500 mg of the active ingredient of the invention provided herein.

Liquid forms in which a salt of the present invention may be incorporated, for oral, intranasal or injectable administration, include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and flavored suspensions with edible oils such as cottonseed oil, sesame, coconut or peanut oil , as well as elixirs and similar pharmaceuticals. Suitable dispersing or suspending agents for aqueous suspensions include artificial and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyridoline or gelatin.

In the treatment of migraine, the appropriate dose of the drug is about 0.01 to 250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, and especially 0.05 to 5 mg/kg per day. The ingredient can be given according to the regime from 1 to 4 times a day.

Together with the ingredient according to the given invention, a pharmaceutical ingredient in solid form, adapted for sublingual administration, including the salt of the formula I given above or its pharmaceutically acceptable solvates is provided; one or more pharmaceutically acceptable buffering agents capable of creating at least a pH of 7.5 in the oral cavity after administration of the drug; and one or more pharmaceutically acceptable excipients.

Although the area under the tongue of the oral cavity is small, it is rich in blood and lymphatic vessels. Therefore, the absorption of some molecules is fast and a systemic therapeutic effect can be achieved very quickly. An additional advantage of the sublingual route is that the medicine taken by the sublingual route can enter the bloodstream directly, avoiding the route through the liver where it could be metabolized differently. However, the vast majority of commercially available drugs are amines and therefore basic. In the physiological environment of the oral cavity, where the natural pH is between 6.2 and 7.4, the ionization degree of such basic drugs is unfavorable for an acceptable level of their absorption from the oral cavity.

It is known from the literature (see e.g. Rathbone and Hadgraft, Int. J. Pharmaceutics. 1991, 74. 9-24) that increasing the pH of oral ingredients can increase the absorption of basic drugs in the oral cavity. Due to this property, the sublingual preparation of the given invention contains a buffer that can create at least a pH of 7.5 in the oral cavity after the application of the medicine.

Examples of typical solid form ingredients that can be adapted for sublingual administration include tablets, especially lyophilized tablets such as the Zydis(R) system described in US Patent No. 4,371,516; capsules, including capsules with dry filling, soft and hard gelatin capsules with liquid filling; powders and granules. Preferably, the sublingual ingredient of the present invention is in tablet form.

The final sublingual ingredient of the present invention will be of any suitable shape or size suitable for sublingual administration. When the ingredient is in tablet form, the tablets will typically weigh from 50 to 500 mg. Preferably, the weight of the tablet is in the range of 220 mg. The sublingual ingredient according to the invention contains one or more pharmaceutically acceptable buffering agents that can create a pH of at least 7.5 in the oral cavity after the application of the drug. As mentioned above, it is known that the absorption of basic drugs in the oral cavity can be enhanced if the pH of the oral cavity is increased. The solid sublingual preparation of the given invention can therefore have advantages, because when used in the oral cavity, it raises the pH in the mouth and therefore the absorption of the drug can be accelerated compared to the absorption that would be achieved with the corresponding preparation without a buffer agent.

There are generally no restrictions on the type of buffering agents used in the sublingual ingredients according to the invention, except that they are pharmaceutically acceptable and capable of creating at least a pH of 7.5 after administration of the drug in the oral cavity. The skilled artisan will be aware of the existence of a large number of buffering agents that can be successfully used in this case.

Examples of suitable buffering agents include glycine/sodium hydroxide, sodium carbonate, sodium bicarbonate and mixtures thereof. Preferred buffer systems include a mixture of sodium carbonate and sodium bicarbonate.

The amount of buffering agent to be incorporated into the sublingual ingredient according to the invention will depend significantly on the desired pH of the final ingredient. It is important to ensure that the amount of buffering agent used maintains the upper pH level of the oral cavity within physiologically acceptable limits. For example when using a buffer system made of a mixture of sodium carbonate and sodium bicarbonate, it has been found that it is desirable to maintain the pH of the ingredient of the present invention below 9.6, because above this pH level irritation of the oral cavity occurs, resulting in a burning sensation in the mouth. Therefore, where a mixture of sodium carbonate and sodium bicarbonate is used, the amount of sodium carbonate in the final ingredient, calculated as anhydrous sodium carbonate or an equal amount of hydrated sodium carbonate, will be from 5 to 20%, optimally about 10% by weight; and the amount of sodium bicarbonate will be appropriate from 15 to 35%, optimally 30% of the weight of the final ingredient.

Pharmaceutically acceptable excipients incorporated in the sublingual ingredients according to the present invention can be those that are standardly used in sublingual preparations. Typical excipients are described in, eg, Remington's Pharmaceutical Sciences. supra, and include binders such as corn starch, lubricants such as magnesium stearate, compressing agents such as cellulose, lactose and mannitol; and disintegrants such as sodium starch glycolate and sodium carboxymethylcellulose.

As the sublingual ingredient according to the given invention is adapted for oral administration, the taste of the final ingredient is an important factor to be taken into account. Many buffering agents have an unpleasant taste. For example a buffer system containing a mixture of sodium carbonate and sodium bicarbonate has been found to impart an unpleasant taste to agents containing it. Therefore, it may be useful to incorporate a sweetening and/or flavoring agent into the sublingual ingredient of the present invention.

Suitable sweetening agents include water-soluble natural sweeteners such as monosaccharides, disaccharides, and polysaccharides, e.g., xylose, ribose, glucose, mannose, galactose, fructose, dextrose, sucrose, invert sugar, maltose, partially hydrolyzed starch, or corn syrup and sugar products. alcohols such as sorbitol, xylitol, mannitol, dihydrochalcone, glycyrrhizin and stevia rebaudiana (steviosides); water-soluble artificial sweeteners such as soluble salts of saccharin, e.g. sodium or calcium salts of saccharin, cyclamate salts, free acid forms of saccharin, synthetic sweeteners 3,4-dihydro-6-methyl-1,2,3-oxathiazin-4-one 2 ,2-dioxide, especially its potassium (acesulfame-K), sodium and calcium salts; dipeptide-based sweeteners such as L-aspartyl-L-phenylalanine methyl ester; and their mixtures.

The preferred sweetener is sodium saccharin.

In general, the amount of sweetener used will depend on the desired sweetness of the individual ingredient and, if necessary, the lingering unpleasant taste to be masked. By way of example, when the saccharin-sodium sweetener is used, its incorporated amount is from 0 to 10% by weight of the final sublingual ingredient, optimally about 5% by weight.

Examples of flavoring agents useful for use in sublingual compositions of the present invention include synthetic flavoring oils, fruit essences, and natural flavoring oils derived from plants, leaves, and flowers, as well as mixtures of these agents. Typical examples include spearmint oil, peppermint oil, cinnamon oil, and wintergreen oil (methyl salicylate); citrus oils derived from lemon, orange, grapefruit, lime and grape; fruit essences derived from apple, strawberry, cherry and pineapple; and extracts such as kola extract. A special flavoring agent is Peppermint NAEFCO/P05.51.

As with sweeteners, the amount of flavoring agent used will depend on individual preferences, but will especially depend on the lingering unpleasant taste to be masked. In general, appropriate amounts of flavoring agents in sublingual ingredients are from 0 to 10% by weight of the final ingredient, optimally about 3% by weight.

If desired, a suitable pharmaceutically acceptable coloring agent can be added to the sublingual ingredient according to the invention. A typical coloring agent is the internationally accepted blue aluminum lake Blue FD&C No.2.

The coloring agent may be suitably incorporated into the final ingredient in an amount of 0 to 1.0%, preferably about 0.25% by weight.

According to the optimal choice of the proportion of individual ingredients that make up the sublingual ingredient of the given invention, it is possible to obtain a final preparation that shows good characteristics of maintaining the pH of the oral cavity at least 7.5, preferably at least 9.0, over a longer period.

The sublingual ingredient according to the given invention can in practice be produced by various standard procedures that are known from work. Typical known methods include the direct compression process and the wet granulation process.

Oral ingredients can also have some disadvantages in the treatment of conditions such as migraine, since such conditions are often accompanied by nausea, which makes it difficult for the patient to tolerate the use of the oral agent. Parenteral administration generally has the advantage of rapid drug absorption, but this route of administration may be unacceptable to some patients, especially if the ingredient is prepared in a form for self-administration.

It was found that the salt of formula I has a surprisingly high water solubility, which makes it particularly suitable for the preparation of formulations, especially intranasal ones, which require relatively concentrated aqueous solutions of the active ingredient. The water solubility of the salt of formula I, expressed in the form of free bases, was determined to be about 170 mg/ml. This can be compared with, for example, the solubility of the benzoate salt N,N-dimethyl-2-(5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl/ethylamine (Example 18 EP- A- 04975120), whose solubility in comparative conditions was determined to be around 40 mg/ml.

In addition, sulfate salts according to the present invention have been found to exhibit extremely low tonicity. From theoretical considerations, the tonicity of a given solution, expressed as its osmolarity in milliOsmoles, can be derived using the following equation:

[image]

where:

T is the theoretical tonicity in mOsml;

C is the concentration of the solution in mg/ml

N is the number of ions per salt molecule; and

M is the molecular weight of the salt.

According to the above equation for the salt of formula I above, the theoretical tonicity of its aqueous solution at a concentration of 189 mg/ml (equivalent to 160 mg/ml free base) can be calculated as follows:

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However, when actually measured by standard practical procedures (e.g., with an osmometer, using a known freezing point lowering procedure), the tonicity of an aqueous solution of a salt of formula I at a concentration of 189 mg/ml (equivalent to 160 mg/ml free base) was found to be only about 340 mOsml .

This unexpectedly low tonicity of the aqueous sulfate salt solution according to the present invention can be rationally interpreted with one or more mechanistic interpretations. One of the possible explanations can be that free base ions aggregate into micelles above salt decomposition where the number of "particles" in the solution will be reduced, thus effectively lowering the value of the parameter N in the above theoretical tonicity equation. Other mechanistic interpretations may, however, be equally plausible, and it is to be understood that none of these explanations shall be construed as limiting the scope of the present invention.

The practical consequence of the low tonicity of the salt solution according to the given invention, in relation to the predicted value, is seen as a consequence of lowering the local irritation of the part of the body where the drug is administered. This effect is particularly noticeable in areas containing particularly sensitive membranes, such as the intranasal cavity. Therefore, from the point of view of this property in combination with the high solubility indicated above, the sulfate salt of formula I is ideally formed for the preparation of aqueous intranasal preparations.

The influence of the tonicity of the ionic solution on the irritation effect can be illustrated with an aqueous solution of sodium chloride of varying concentration. Thus, aqueous sodium chloride solution at a tonicity of 900 mOsml/cp. a theoretical tonicity of 891 mOsml for the salt of formula I above at a concentration of 189 mg/ml (equivalent to 160 mg/ml free base)/ when administered intranasally causes a significant stinging sensation. Such a solution is very hypertonic. On the other hand, the tolerance of aqueous sodium chloride solution at a tonicity of 305 mOsml/cp. the measured actual tonicity of 340 mOsml for the salt of formula I above at a concentration of 189 mg/ml (equivalent to 160 mg/ml free base)/ when administered intranasally is completely acceptable. At a tonicity of 305 mOsml, the aqueous sodium chloride solution is isotonic. Therefore, since the value of the measured actual tonicity for the sulfate salt according to the present invention at a concentration of 160 mg/ml (expressed as free base) is 340 mOsml, this means that at this concentration its aqueous solution is only very slightly hypertonic.

For the above reasons, it can be noted that the salt of the present invention is particularly advantageous for intranasal administration. In the preferred composition of the ingredient according to the present invention, therefore, a pharmaceutical ingredient suitable for intranasal administration is provided, which includes a sulfate salt of formula I or a pharmaceutically acceptable solvate thereof together with one or more pharmaceutically acceptable carriers.

Intranasal preparations can generally be given in liquid form or as a dry powder. Satisfactory intranasal preparations must be sufficiently stable, chemically and physically, to be consistently administered in precisely measured doses, even after prolonged storage with potential temperature fluctuations between 0 and 40°C. Therefore, the active ingredient must be compatible with the excipients used in the preparation and must not aggregate in a way that would result in the loss of the correct amount of the dose, eg precipitation from liquid preparations or caking of powder preparations. In order to maximize the retention of the intranasal preparation after application inside the nasal passages of patients, especially liquid preparations, it is preferable to give a unit dose of the active substance within a relatively small volume, for example 50-200 ul, preferably around 100 ul. This may require the use of higher concentrations of the drug, and in the advantages are active vats with high solubility.

Of course, the active substance must also be given in a form that is immediately absorbed through the nasal mucosa, but which does not cause any side effects such as irritation.

As stated above, it has been found that for intranasal administration, the salt according to the present invention has an advantage when administered in the form of a solution.

Solutions will generally be aqueous; they can be prepared with only water (eg, sterile, non-pyrogenic water), or with water and a pharmaceutically acceptable solvent (eg, ethanol, propylene glycol, and polyethylene glycols such as PEG 400).

Such solutions may additionally contain other excipients such as preservatives (e.g. benzalkonium chloride and phenylethyl alcohol), buffering agents, agents for regulating tonicity (e.g. sodium chloride), agents for increasing viscosity, agents for increasing absorption, agents for aromatization (e.g. aromatic agents such as menthol, eucalyptol, camphor and methyl salicylate in amounts from about 0.001 to about 0.5% by weight) and sweeteners (e.g. saccharin or saccharin-sodium in amounts from about 0.01% by weight to about 10% by weight, optimally in range from 0.01 to 2% v.t).

Optimally, the solutions according to the given invention will be sterile and preservative-free. Sterile preparations can be prepared by methods known from practice, for example by aseptic production and sterilization of the entire amount of the product.

Solutions are applied directly into the nasal cavity by standard means, eg with a dropper, pipette III as a spray. Formulations can be prepared in the form of a single dose or as a multidose. In the latter case, it is desirable to provide means for dosing. With a dropper or a pipette, the patient can take the correct, predetermined amount of the solution himself. In the case of sprays, this is achieved by means such as a measuring dosing atomizing spray pump.

Intranasal administration can also be achieved with an aerosol preparation in which the ingredient is given in a pressurized charge with a suitable propellant such as a chlorofluorocarbon (CFC), eg dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane; hydrofluorocarbon (HFC), eg 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane; hydrochlorofluorocarbon (HCFC), eg chlorodifluoromethane, 1,1,1-chlorodifluoroethane, 1,1-dichloro-2,2,2-trifluoroethane, 1-chloro-1,2,2,2-tetrafluoroethane or 1, 1,1-dichlorofluoroethane; carbon dioxide; or other suitable gas. The dose of the drug can be controlled with a metering valve. Alternatively, a piezoelectric device can be used to produce the required spray.

Optimally, the pharmaceutical ingredient suitable for intranasal administration containing a salt according to the present invention will be in the form of an aqueous solution.

Furthermore, the given invention also provides an important isotonic aqueous solution of the salt of the formula I defined above; as well as the use of such a solution in the preparation of pharmaceutical ingredients suitable for intranasal administration.

Aqueous solutions of salts of the present invention adapted for intranasal administration will have a suitable pH in the range of 4 to 8. Preferably, the pH of an aqueous solution of salts of the present invention for intranasal administration will be between 5 and 7. At a concentration of 160 mg/ml (expressed as free bases), the pH of the aqueous solution of the sulfate salt of formula I given above was found to be around 5.8. This is a particular advantage, because such a solution does not require pH adjustment before use. Solutions of more acidic salts, whose pH value is outside the acceptable range, will need pH adjustment by adding further excipients, especially buffers, and this will have an adverse effect on the pharmaceutical properties of the final solution and a simultaneous increase in tonicity. However, if adjustment of the pH of the aqueous salt solution of formula I is required, this can be accomplished by standard means, such as the controlled addition of a pharmaceutically acceptable acid or base.

It will be appreciated that the aqueous solution of the sulfate salt according to the present invention can be practically prepared by dissolving the salt in water. Alternatively, such solutions can be obtained by mixing 1 molar equivalent of N,N-dimethyl-2-(5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl)ethylamine with 0.5 to 0.7 molar equivalents of concentrated sulfuric acid, preferably 0.5 molar equivalents of sulfuric acid, in water.

For intranasal administration, aqueous salt solutions according to the present invention will ideally contain salt concentrations of from 1 mg/ml to 200 mg/ml, correspondingly from 10 mg/ml to 190 mg/ml.

For intranasal administration, the salt of the present invention may conveniently be administered in single dose vials. A practical single dose of the preparation for intranasal administration contains the active substance in an amount from 0.1 mg to 100 mg, correspondingly in the range from 1 to 60 mg, preferably from 2 to 40 mg, which can be applied in one or both nostrils. Ideally, 1 mg to 35 mg of the active ingredient is administered in a single dose into one nostril.

A typical unit dose of the composition may be obtained as a single dose in a closed unit, eg, an ampoule of glass or plastic material which can be filled and sealed by standard manufacturing methods. Alternatively, a closed ampoule made of plastic material can be produced by "form-fill-seal" technology. Ideally, the ampoule and the ingredients of the pharmaceutical preparation with which the ampoule is filled must be temperature stable. The sealed ampoule can be sterilized, eg by autoclaving at 121°C for not less than 15 minutes, or alternatively by gamma irradiation of the container followed by sterile filtration of the solution, to provide sterile single dose ampoules that can be fitted into practical dosing devices that precede the actual application. A preferred unit dose volume is from 50 to 200 μl, eg 100 ul. Preferred devices for administering the intranasal compositions of the present invention include the Bespak multidose device, available from Bespak, Kings Lynn, Great Britain; and in particular the Valois "Monospray" single dose spray device as described, eg, in WO-A-93/00172.

From a further point of view, the present invention provides a process for the preparation of the sulfate salt of the above-defined formula 1 or its solvate, the production of which includes the reaction N,N-dimethyl-2-[5-(1,2,4-triazol-1-ylmethyl)-1H -indol-3-yl/ethylamine of structural formula II:

[image]

with approximately 0.5 molar equivalents of sulfuric acid and a suitable solvent.

This process takes place by mixing the reactants at room temperature in an aqueous environment, typically in the presence of a lower alcohol such as ethanol or isopropyl alcohol.

A salt of formula I above or a solvate thereof may also be prepared by salt exchange, which involves treating a salt of a compound of formula II above, other than the sulfate salt (2:1) of formula I, with the appropriate sulfate salt.

Examples of suitable sulfate salts that can be used in the above salt exchange process include metal sulfates, such as sodium sulfate or silver sulfate, and sulfated ion exchange resins. The reaction is practically carried out in an aqueous environment.

The compound of formula II above can be prepared in any manner known to the skilled person from work. Since the compound of formula II contains an indole nucleus, the appropriate method for its preparation is the well-known Fischer synthesis of indole. This can be carried out in practice by reacting the hydrazine derivative of formula III:

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with a compound of formula IV:

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or its carbonyl-protected form.

Suitable carbonyl-protected forms of the compound of formula IV include the dimethyl and diethyl acetal derivatives.

The reaction practically takes place by mixing the reactants in the presence of 4% sulfuric acid at an elevated temperature, typically around 90°C.

The hydrazine derivative of formula III can be prepared from the corresponding aniline of formula V;

[image]

diazotization followed by reduction. Diazotization is practically carried out using sodium nitrite/conc. HCl and the resulting diazo product is reduced in situ using, for example, tin(II) chloride/conc. HCl, sodium sulfite/conc. HCl or sodium sulfite/conc H2SO4.

The aniline derivative of formula V can be prepared by reducing the corresponding nitro compound of formula VI:

[image]

typically with transfer hydrogenation using a hydrogenation catalyst such as palladium on charcoal in the presence of a hydrogen donor such as ammonium formate, or alternatively by standard catalytic hydrogenation or using stannous chloride.

The nitro compound of formula VI can be practically prepared by reacting the sodium salt of 1,2,4-triazole with a nitrobenzyl halide, eg 4-nitrobenzyl bromide, appropriately in N,N-dimethylformamide at room temperature. Alternatively, compound VI can be prepared by reacting a nitrobenzyl halide, eg 4-nitrobenzyl bromide, with 4-amino-1,2,4-triazole, followed by deamination of the resulting triazole salt by treatment with nitric acid and subsequent neutralization. This last transformation, which can take place in two separate stages or more simply as a "one-pot" process with both stages combined, is practically carried out under the reaction conditions described in J. Org. Chem,, 1989, 54, 731.

From a further point of view, the present invention provides a method for the treatment and/or prevention of clinical conditions in which selective 5-HT1-like receptor agonists are indicated, and the method comprises administering to a patient in need of such treatment an effective dose of a salt of the formula I defined above, or the method comprises to the patient in need of such treatment by administration of a pharmaceutically acceptable solvate thereof. In a special embodiment of the process according to the present invention, the salt of formula I or a pharmaceutically acceptable solvate thereof is administered in the form of a solution, preferably an aqueous solution adapted for intranasal administration.

The present invention also provides the use of a salt of the above-defined formula I or a pharmaceutically acceptable solvate thereof for the production of a drug, a suitable solution and preferably an aqueous solution adapted for intranasal administration, for the treatment and/or prevention of clinical conditions in which a selective 5-HT1-like receptor agonist is indicated .

The following non-limiting Examples illustrate the invention provided herein.

Preparation 1

Step (i): 1-(4-nitrobenzyl-4-amino-4H-1,2,4-triazolium bromide

A mixture of 4-amino-1,2,4-triazole (250 g, 2.976 mol) and 4-nitrobenzyl bromide (ex Janssen, 99%, 617.5 g, 2.83 mol) in isopropyl alcohol was stirred to reflux. The mixture becomes a solution and then, almost instantaneously, the desired triazole salt crystallizes at reflux. The mixture is stirred and heated under reflux for 7.5 hours and allowed to cool to room temperature overnight. The next day, the mixture is cooled to 0-5°C, kept like this for 1 hour and the product is filtered, washed with a little isopropyl alcohol and then dried in vacuo at 50°C to obtain the title triazole salt (808 g) in 95% of the obtained substance as a white solid, m.p. 199°C (dec.).

Step (ii): 1-(4-nitrobenzyl)-1,2,4-triazole

A solution of sodium nitrite (206 g, 222.98 mol) in water (840 ml) is added over 70 minutes under the surface of the suspension of the previously obtained triazole salt (808 g, 2.69 mol) in water (5.6 L) and conc. hydrochloric acid (505 ml) at 0-5°C. The pale yellow slurry is stirred at <5°C for 15 minutes and then allowed to warm up to 25°C for 1 hour. The colorless solution was brought to pH 9 by adding aqueous ammonia solution (380 ml, 18N) maintaining the temperature <30°C. The mixture is cooled to 0-5°C and stirred for 1 hour. The solid was collected by filtration, washed with water (400 ml) containing aqueous ammonium hydroxide (20 ml, 18 N) and dried under reduced pressure at 50°C to give 535 g (97% yield) of the title nitro compound, mp 102- 103°C.

Step (iii): 1-(4-aminobenzyl-1,2,4-triazole).

The resulting nitro compound (803 g, 3.9 mol), ammonium formate (1.16 kg, 18.4 mmol) and 10% Pd/C (28 g) in methanol (8 L) were mixed under a nitrogen atmosphere and heated to 30°C. Heating is discontinued and cooling is applied to control the exothermic reaction, maintaining the temperature at 35-45°C for 2 hours. The reaction mixture was cooled to 20°C and the catalyst was removed by filtration through a Hyflo filter aid. The filter cloth is washed with methanol (2 L). The filtrate was concentrated and the residue was diluted with ethyl acetate (12 L) and water (1.57 L). The lower aqueous layer is treated with aqueous ammonium hydroxide solution (10 ml, 18N) to pH 9. The aqueous layer is separated and extracted with ethyl acetate (2 x 6 L and 3 L). The combined extracts were washed with saturated aqueous sodium hydrogen carbonate solution (1.57 L), dried and evaporated under reduced pressure to give 679 g (99% yield) of the title amine, m.p. 127-128°C.

Step (iv): N,N-dimethyl-2-(5-(1,2,4-triazol-1-yl-methyl-1H-indol-3-yl-ethylamine)

A solution of sodium nitrite (16.7 g, 0.24 mol) in water is added below the surface to a solution of the previously obtained amine (40 g, 0.23 mol) in hydrochloric acid (65.3 ml) and water (162 ml) maintaining the temperature <5°C. The solution is stirred at 0-5°C for 1 hour. The solution was added to a suspension of sodium sulfite (72.4 g, 0.57 mol) in water (227 ml) cooled to 5-10°C under a nitrogen atmosphere. The red solution is stirred at 5-10°C for 10 minutes, allowed to warm to 20°C over 20 minutes and then heated to 70°C over 45 minutes. The solution is stirred at 70°C for 2.5 hours and cooled to 65°C. Concentrated sulfuric acid (56.8 ml) was added to the solution over 15 minutes, maintaining the temperature at 70-80°C.

The solution is stirred at 70°C under a nitrogen atmosphere for 2 hours and allowed to cool to 20°C overnight. The resulting hydrazine solution was heated to 25°C and 4-(N,N-dimethylamino)-1,1-dimethoxybutane (44.3 g, 0.28 mol) was added over 15 minutes, maintaining the temperature <35°C. The solution is stirred at 30-35°C for 30 minutes. The mixture is heated to 90°C for 30 minutes and maintained at 90-93°C for 15 minutes. The mixture was cooled to 15°C and Hyflo filter aid (68 g) was added followed by aqueous ammonium hydroxide (200 ml, 18N) to adjust the pH to 11-12. The mixture was filtered and the filtrate and Hyflo were extracted with ethyl acetate (5 x 300 ml). The extract is dried (Na2SO4) and evaporated under reduced pressure. The residue is chromatographed on silica (500 g) with ethyl acetate:methanol (80:20) changing to ethyl acetate:methanol (50:50). Fractions containing the product were evaporated under reduced pressure to give 27.8 g (45% yield) of the title compound as the free base.

Example 1

N,N-dimethyl-2-(5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl/ethylamine). 0.5 sulfate. 0.7 hydrate

Sulfuric acid (1N, 1.17 ml) was added to a stirred solution of N,N-dimethyl-2-(5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl/ethylamine (0.63 g , 2.34 mmol) in water (0.73 ml) and isopropyl alcohol (15.9 ml). The mixture is thickened and then cooled to 0°C. The reaction mixture was filtered and the resulting solid was washed with diethyl ether (100 ml) and then dried at 60°C in vacuo to give the title 0.5 sulfate salt (0.68 g), m.p. 233-234°C (Found: C, 54.45; H, 6.35; N, 21.23; S, 4.66%. C15H19N5 . 0.5 H2SO4. 0.7 H2O req. C, 54.43; H, 6.52; N, 21.16; S, 4.84%) .

Example 2

The sublingual tablet is buffered. which contains 50 μg (expressed as free base) of active substance

N,N-dimethyl-2-(5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl/ethylamine)

0.5 sulfate. 0.7 hydrate 0.056 mg

Avicel PH 200 91,194 mg

Starch 1500 22.0 mg

Sodium bicarbonate 67.5 mg

Anhydrous sodium carbonate 0.0 mg

Blue FD&C No.2 Aluminum Lake 0.55 mg

Saccharin-sodium 11.0 mg

Peppermint NAEFCO/P05.51 6.6 mg

Magnesium stearate 1.1 mg

Total weight 220.0 mg

All ingredients except magnesium stearate are mixed together in a suitable blender. The lubricant magnesium stearate was added to the obtained mixture and the mixture was compressed on a tableting press.

Example 3

Sublingual tablet with a buffer agent. which contains 20 mg (expressed as free base) of active substance

N,N-dimethyl-2-(5-(1,2,4-triazol-1-ylmethyl)-1H-indole

-3-yl/ethylamine

0.5 sulfate. 0.7 hydrate 22.34 mg

Avicel PH 200 68.91 mg

Starch 1500 22.0 mg

Sodium bicarbonate 67.5 mg

Anhydrous sodium carbonate 20.0 mg

Blue FD&C No.2 Aluminum Lake 0.55 mg

Saccharin-sodium 11.0 mg

Peppermint NAEFCO/P05.51 6.6 mg

Magnesium stearate 1.1 mg

Total weight 220.0 mg

All ingredients except magnesium stearate are mixed together in a suitable blender. The lubricant magnesium stearate was added to the obtained mixture and the mixture was compressed on a tableting press.

Examples 4 and 5

Sterile intranasal preparation

Example 4 Example 5

Compound of formula (II) 0.85 mg 170 mg

Sulfuric acid

(concentrated) BP 0.155 mg 30.9 mg

Water for refilling the injection

Ph. Eur. up to 1 ml up to 1 ml

The compound of formula (II) is dissolved in sulfuric acid previously diluted with water. The solution is prepared to the required volume.

The solution can be packaged for intranasal administration, eg by filling into ampoules, sealing and sterilizing the ampoules in an autoclave at 121°C for no less than 15 minutes, or by sterilizing by filtration and aseptically transferring them to sterile "containers".

Examples 6 and 7

Canned intranasal preparation

Example 6 Example 7

Compound of formula (11) 0.85 mg 170 mg

Sulfuric acid (concentrated) BP 0.155 mg 30.9 mg

Phenethyl alcohol USP 4.0 mg 4.0 mg

Benzalkonium chloride USNF 0.2 mg 0.2 mg

Distilled water B.P. up to 1 ml up to 1 ml

The compound of formula (II) is dissolved in sulfuric acid previously diluted with water. Add phenethyl alcohol and benzalkonium chloride and prepare the solution to the required volume. Other canned solutions containing 1, 5, 10, 50, 80, 100 and 150 mg/ml of the compound of formula (II) are prepared in a similar way.

The compositions can be administered in unit doses of a volume of 100 μl into one or both nostrils of patients suffering from occasional or frequent migraine attacks to achieve a dose of 0.1, 1, 5, 10 or 17 mg of the compound of formula (II).

Examples 8 and 9

Sterile intranasal preparation

Example 8 Example 9

Compound of formula (II) 1 mg 200 mg

Water for filling injections Ph. Eur. up to 1 ml up to 1 ml

The compound of formula (II) is dissolved in water and the solution is prepared to the required volume.

The solution can be packaged for intranasal use, eg by filling into ampoules, sealing and sterilizing the ampoules in an autoclave at 121°C for no less than 15 minutes, or by sterilizing by filtration and aseptically transferring to sterile containers.

Examples 10 and 11

Other preserved intranasal preparations

Example 10 Example 11

Compound of formula (II) 1 mg 200 mg

Benzethonium chloride 0.2 mg 0.2 mg

Distilled water B.P. up to 1 ml up to 1 ml

The compound of formula (I) dissolves in water. Benzethonium chloride is added and the solution is prepared to the required volume.

Examples 12 to 15

Sterile intranasal preparations

Example 12 Example 13 Example 14 Example 15

Compound of formula (II) 5 mg 50 mg 100 mg 160 mg

Benzethonium chloride 0.91 mg 9.1 mg 18.2 mg 29.1 mg

Distilled water B.P. up to 1 ml up to 1 ml up to 1 ml up to 1 ml

The compound of formula (II) is dissolved in sulfuric acid previously diluted with water. The solution is prepared to the required volume.

The preparations are filled in 100 μl ampoules, the ampoules are closed and sterilized in an autoclave at 121°C for no less than 15 minutes. Alternatively, the solution can be sterilized by filtration and aseptically filled into sterile ampoules.

The compositions can be administered in unit doses of a volume of 100 μl into one nostril of patients suffering from occasional or frequent migraine attacks to achieve a dose of 0.5, 5, 10 or 16 mg of the compound of formula (II).

Examples 16 and 17

Sterile intranasal preparations

Example 16 Example 17

Compound of formula (II) 160 mg 160 mg

Sulfuric acid (conc,+.) BP 29.1 mg 29.1 mg

Saccharin sodium BP 10 mg 20 mg

Water for filling injections Ph. Eur. up to 1 ml up to 1 ml

The compound of formula (II) is dissolved in sulfuric acid previously diluted with water. The solution is prepared to approximately 90% volume, saccharin is dissolved in it and finally the solution is prepared to the required volume. The preparations are filled in 100 μl ampoules, the ampoules are closed and sterilized in an autoclave at 121°C for no less than 15 minutes. Alternatively, the solution can be sterilized by filtration and aseptically filled into sterile ampoules.

The compositions can be administered in unit doses of a volume of 100 μl into one nostril of patients suffering from occasional or frequent migraine attacks to achieve a dose of 16 mg of the compound of formula (II).

Claims (19)

1. A salt characterized in that it is N,N-dimethyl-2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]ethylamine sulfate salt. 2. N,N-dimethyl-2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]ethylamine sulfate salt (2:1), indicated by the fact that the structural formula I: [image] and pharmaceutically acceptable solvates thereof. 3. Hydrate salt as claimed in claim 2. 4. 0.7 salt hydrate, indicated as claimed in claim 2. 5. A pharmaceutical composition comprising the salt claimed in claim 1 or 2 or its pharmaceutically acceptable solvate together with one or more pharmaceutically acceptable carriers. 6. A pharmaceutical composition in solid form, adapted for sublingual administration, comprising a salt as claimed in claim 1 or 2 or a pharmaceutically acceptable solvate thereof; one or more pharmaceutically acceptable buffering agents having the ability to achieve a pH of at least 7.5 after application in the oral cavity; and one or more pharmaceutically acceptable excipients. 7. A pharmaceutical composition adapted for intranasal administration comprising a salt as claimed in claim 1 or 2 or a pharmaceutically acceptable solvate thereof together with one or more pharmaceutically acceptable carriers. 8. The composition as claimed in claim 7, characterized in that it is in the form of an aqueous solution. 9. The composition as claimed in claim 8, characterized in that it is in the form of a solution in sterile, pyrogen-free water. 10. The composition as claimed in claim 8 or claim 9, characterized in that it contains a salt in a concentration of 1 mg/ml to 200 mg/ml. 11. The composition as claimed in claim 10, characterized in that it contains a salt in a concentration of 10 mg/ml to 190 mg/ml. 12. The composition as claimed in claim 11, characterized in that it contains the salt at a concentration of about 189 mg/ml. 13. A composition as claimed in any of claims 7 to 12, characterized in that it is provided in the form of a single dose and contains the active substance in an amount of 0.1 mg to 100 mg. 14. The composition as claimed in claim 13, characterized in that the volume of the single dose is from 50 to 200 μl. 15. Process for the preparation of the salt as requested in claim 1 or claim 2 or its solvate, characterized in that it contains: (A) reaction of N,N-dimethyl-2-[5-(1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]ethylamine of structural formula II: [image] with approximately 0.5 molar equivalents of sulfuric acid in a suitable solvent; or (B) treating a salt of the compound of formula II above, different from the sulfate salt (2:1) of formula 1 as defined in claim 2, with the corresponding sulfate salt. 16. A process for the preparation of a pharmaceutical composition as claimed in any one of claims 5 to 14, characterized in that it includes mixing a salt as claimed in claim 1 or claim 2 or a pharmaceutically acceptable solvate thereof with a pharmaceutically acceptable carrier. 17. A process for the preparation of a pharmaceutical composition as claimed in any one of claims 8 to 14, characterized in that it includes: (A) dissolving the salt as claimed in claim 1 or claim 2 or a pharmaceutically acceptable solvate thereof in water; or (B) mixing one molar equivalent of a compound of formula II as defined in claim 15, with 0.5 to 0.7 molar equivalents of concentrated sulfuric acid in water. 18. A salt as claimed in claim 1 or claim 2 or a solvate thereof, characterized in that it is for therapeutic use. 19. Use as claimed in claim 1 or claim 2 or a pharmaceutically acceptable solvate thereof, characterized in that a drug is produced for the treatment and/or prevention of clinical conditions in which a selective agonist of 5-HT1-like receptors is indicated.