SI9400157A - Sulphate salt of a substituted triazole, its pharmaceutical compositions and their use as medicaments - Google Patents

Abstract

1. Sulphated N,N-dimethyl-2-[5-(1,2,4-triazole-1-methyl)-1H-indole-3-yl]ethylamine (2:1) with the structural formula 1 and its pharmaceutically acceptable solvates, preferably hydrates.

Description

SUBSTITUTED TRIAZOLE SULFATE SALT, THEIR PHARMACEUTICAL COMPOSITIONS AND THEIR USE IN TREATMENT

The present invention relates to a particular salt of a pharmaceutically active substance. More specifically, the invention relates to a sulfate salt of a substituted triazole derivative acting on 5-hydroxytryptamine (5-HT) receptors as a selective agonist of e.g. 5-HT1-like receptors. This compound is therefore useful in the treatment of clinical conditions for which a selective agonist of these receptors is indicated.

5-HT1-receptor receptor agonists that are active as selective vasoconstrictors have recently been described as useful in the treatment of migraine (see, for example, A. Doenicke et al., The Lancet, 1988, Vol. 1, 1309-11). Thus, the salt of the present invention, as a selective agonist of 5-HT1-like receptors, is particularly useful in the treatment of migraine and related conditions, for example, certain types of cluster headache, chronic paroxysmal hemicrania, headache coupled with vascular disorders, headache that it is caused by pressure and pediatric migraines.

EP-A-0497512, published August 5, 1992, describes a group of substituted imidazole, triazole and tetrazole derivatives, which are said to be selective agonists of 5-HT1-like receptors and therefore particularly useful in the treatment of migraine and related conditions.

The present invention provides a sulfate salt of N, N-dimethyl-2- [5- (1,2,4 triazol-1-ylmethyl) -1H-indol-3-ylethylamine. Specifically, the invention provides the sulfate salt of N, N-di-methyl-2- / 5- (1,2,4-triazol-1-ylmethyl) -1H-indol-3-yl / ethylamine (2: 1) of structural formula I :

H. 5 H ₂ S0 ₄ (i) and its pharmaceutically acceptable solvates, including hydrates, in particular 0.7 hydrates.

The pharmaceutically acceptable salts of N, N-dimethyl-2- [5- (1,2,4-triazol-1-ylmethyl) -1H-indol-3-yl] ethyl amine are generally covered by the framework EP-A0497512. In any case, its salts: oxalate hemihydrate, succinate and benzoate are specifically disclosed in EP-A-0497512. However, nowhere in EP-A-0497512 is there an explicit discovery of a particular salt of the above-mentioned structural formula I or its pharmaceutically acceptable solvates.

We have found that the salt of the above structural formula I has, in several respects, beneficial properties, making it particularly suitable for use as a pharmaceutical ingredient. For example, unlike many medicines known to have an unpleasant taste, in the case of salts of Formula I, they are found to be relatively tasteless.

Therefore, in another aspect, the present invention provides a pharmaceutical composition comprising a sulfate salt of the above Formula I, or a pharmaceutically acceptable solvate thereof, combined with one or more pharmaceutically acceptable carriers.

The compositions of the invention are suitably in the form of single dose preparations such as: tablets, pills, capsules, powders, granules, sterile solutions or suspensions, metered aerosol or liquid dispensers, droplets, ampoules, auto-injection devices or suppositories; for oral, parenteral, intranasal, under the tongue or rectal use, or for administration by inhalation or insufflation. The formulations of the compositions of the invention can be suitably carried out by methods known in the art, for example as described in Remington's Pharmaceutica! Sciences, 17th Ed., 1985.

For example, to prepare solid compositions such as tablets, the active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tabletting ingredients such as microcrystalline cellulose, corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or resins, and other pharmaceutical diluents, e.g. water to form a solid preformulation composition containing a homogeneous mixture of salts of Formula I above. When these preformulation compositions are referred to as homogeneous, we mean that the active ingredient is uniformly dispersed throughout the composition so that the composition can be easily divided into smaller equally effective single dose forms such as tablets, pills and capsules. This solid preformulation composition is then formulated into single dose formulations of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.

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

A suitable dose for migraine treatments is about 0.01 to 250 mg / kg per day, preferably about 0.05 to 100 mg / kg per day, and in particular about 0.05 to 5 mg / kg per day. The administration regimen of the compounds may be from 1 to 4 times daily.

One embodiment of the composition of the present invention provides a pharmaceutical composition in solid form adapted for use in a tongue containing a salt of formula I as defined above, or a pharmaceutically acceptable solvate thereof; then one or more pharmaceutically acceptable buffers capable of adjusting the oral cavity pH to at least 7.5; and one or more pharmaceutically acceptable excipients.

Although the surface area of the oral cavity under the tongue is small, it has many blood vessels and lymph glands. Therefore, absorption of some molecules is rapid and systemic therapeutic effects can be achieved very quickly. An added benefit of the tongue application is that the drugs taken in this way can enter the bloodstream directly, avoiding passage through the liver where they may be otherwise metabolized. But, the vast majority of commercially available drugs are amines and are therefore basic. In the physiological environment of the oral cavity, where the pH will be in the range of 6.2 to 7.4, the ionization state of such basic drugs is detrimental to the acceptable rate of absorption from the oral cavity.

It is known from the literature (see, for example, Rathbone and Hadgraft, Int. J. Pharmaceutics, 1991, 74, 9-24) that by increasing the pH of oral formulations, oral absorption of the basic medicaments contained therein can be increased. Therefore, the formulation of the present invention for use in the tongue includes a buffer capable of adjusting the pH of the oral cavity after use to at least 7.5.

Examples of typical solid form compositions that can be customized for tongue application include tablets, in particular frozen-dried tablets, such as the Zydis ^ system described in U.S. Pat. No. 4,371,516, capsules, including capsules filled with dry matter, soft gelatin capsules filled with liquid, and solid gelatin capsules, powders and granules. Preferably, the composition of the invention is for tablet-shaped tongue application.

The final composition of the invention for the tongue application will have any suitable size and shape compatible with the tongue application. If the composition is in tablet form, the tablet will typically weigh 50 to 500 mg. A tablet weight of 220 mg is recommended.

The composition of the invention for tongue application includes one or more suitable buffers capable of adjusting the oral cavity pH to at least 7.5 after administration. As mentioned above, it is known that oral absorption of basic medicines can be increased by increasing the pH of the oral cavity. The solid formulation of the present invention may therefore have the advantage that when placed in the oral cavity, the pH of the mouth is increased and therefore the absorption of the drug is increased, relative to that which would be achieved with a suitably non-buffered formulation.

In principle, there is no limit to the nature of the buffer used in the composition of the invention for tongue application, provided that it is pharmaceutically acceptable and is capable of ensuring that the oral cavity pH is at least 7.5 after use. The skilled person will be aware of the variety of buffers that can be properly used in this connection. Examples of suitable buffers include glycine / sodium hydroxide, sodium carbonate, sodium bicarbonate and mixtures thereof. The preferred buffer system comprises a mixture of sodium carbonate and sodium bicarbonate.

The amount of buffer to be mixed into the application composition under the tongue of the invention will largely depend on the desired pH of the final composition. As will be appreciated, it is important to ensure that the amount of buffer is such that, after use, it maintains the upper pH of the oral cavity within physiologically acceptable limits. For example, we have found that in the case of using a buffer system containing a mixture of sodium carbonate and sodium bicarbonate, it is desirable to adjust the pH of the composition of the invention below about 9.6 because a certain amount of oral inflammation is encountered above this pH level, resulting in a burning sensation in the mouth. Thus, if a mixture of sodium carbonate and sodium bicarbonate is used, the amount of sodium carbonate in the final composition will be calculated as anhydrous sodium carbonate or an equivalent amount of hydrated sodium carbonate of about 5 to 20% by weight, preferably about 10% by weight; accordingly, the amount of sodium bicarbonate will be from 15 to 35% by weight, recommending 30% by weight of the final composition.

The pharmaceutically acceptable excipients included in the composition for the tongue application of the invention may suitably be those commonly used in the formulations intended for such an application. Typical fillers have been described, for example, in the aforementioned Remington's Pharmaceutical Sciences, and typically include binders such as cornstarch, glidants such as magnesium stearate, thickening aids such as cellulose, lactose and mannitol, these breakers such as are sodium starch glycolate and sodium carboxymethylcellulose.

Because the composition for the tongue application according to the invention has been adapted to oral administration, the taste of the final composition is a factor to be considered. Many buffers have an unpleasant taste. For example, a buffer system consisting of a mixture of sodium carbonate and sodium bicarbonate has been shown to give an unpleasant taste to formulations containing this system. For this reason, it may be advantageous to mix a sweetener and / or fragrance in the application composition under the tongue of the invention.

Suitable sweeteners include water-soluble natural sweeteners, such as monosaccharides, disaccharides and polysaccharides, for example xylose, ribose, glucose, mannose, galactose, fructose, dextrose, sucrose, invert sugar, maltose, partially hydrolysed starch, or corn syrup solids and sugars alcohols such as sorbitol, xylitol, mannitol, dihydroalkone, glycyrrhizin and stevia rebaudiana (stevioside); water-soluble artificial sweeteners such as soluble saccharinate salts, e.g. sodium or calcium saccharinate salts, cyclamate salts and saccharin in the free acid line, and the synthetic sweetener 3,4-dihydro-6-methyl-1,2,2-oxathiazin-4-one 2,2-dioxide, in particular potassium ( acesulfam-K), sodium and calcium salts; sweeteners based on dipeptides, such as L-aspartyl-L-phenylalanine methyl ester, and mixtures thereof. The preferred sweetener is sodium saccharinate.

Generally, the amount of sweetener used will vary with the desired sweetness of each composition and, if necessary, the degree of unpleasant fragrance that we want to mask. As an example, when saccharinate sodium is used as a sweetener, its incorporated amount will be correspondingly from 0 to 10% by weight of the final composition for application under the tongue, and preferably about 5% by weight.

Examples of fragrances useful for incorporation into a tongue composition according to the invention include synthetic fragrant oils, fruit essences and natural fragrant oils from sources such as plants, leaves and flowers, as well as mixtures thereof. Specific examples include green mint oil, peppermint oil, cinnamon oil and green oil (methyl salicylate); citrus oils obtained from sources such as: lemon, orange, grapes, citron and grapefruit; fruit essences obtained from sources such as apples, strawberries, cherries and pineapples; and extracts such as choline extract. The special scent is NAEFCO / PO5.51 peppermint.

As with sweeteners, the amount of fragrance used is usually a matter of the individual's choice, but it will be particularly affected by the degree of unpleasant fragrance that we wish to conceal if necessary. In general, suitable amounts of fragrances from 0 to 10% by weight of the final composition for the sublingual application are preferred, with an amount of about 3% by weight being preferred.

if desired, a pharmaceutically acceptable colorant may be suitably mixed into the application composition under the tongue of the invention. The typical colorant is the internationally accepted blue aluminum lipstick red Blue FD&C No. 2. The colorant may be suitably mixed into the final composition in an amount of 0 to 1.0% by weight, preferably about 0.25% by weight.

By cleverly selecting the proportions of the individual constituents that make up the tongue composition according to the invention, it is possible to obtain a final formulation capable of exhibiting the beneficial property of long-term oral cavity maintenance at at least 7.5, preferably at least 9.0.

The composition for the tongue application of the present invention can conveniently be prepared by various standard procedures known to the person skilled in the art. Typical well known methods include the direct compression method and the wet granulation method.

Oral compositions may be subject to certain losses in the treatment of conditions such as migraine because such conditions are often accompanied by gastric weakness, which makes it difficult for the patient to tolerate the oral composition. Parenteral administration usually has the advantage of rapid absorption of the drug, but this route of administration may be unacceptable for some patients, especially if the drug is in a form that is adapted to self-administration.

In fact, we have found that the salt of formula I is unexpectedly well soluble in water, making it particularly accessible for the preparation of formulations, especially intranasal formulations, which require relatively concentrated aqueous solutions of the active ingredient. The solubility of the salt of formula I in water, expressed as the free base, was found to be about 170 mg / ml. This can be compared to, for example, the solubility of the benzoate salt of N, N-dimethyl-2- [5- (1,2,4 triazol-1-ylmethyl) -1H-indol-3-ylJethylamine (Example 18 in EP-A-0497512). which was found to be about 40 mg / ml under comparable conditions.

Moreover, it has been found that the sulfate salt of the present invention has unexpected nicotine tonicity. Based on theoretical considerations, the tonicity of a given solution, expressed as its osmolarity in milliosmoles, (osmolarity = mole of osmotically effective particles per kg of solvent, mOsmol can be converted to g / L in a manner known to those skilled in the art) using the following equation:

T = C x 1000 x N M in which

T is the theoretical tonicity in mOsml;

C is the concentration of the solution in mg / ml;

N is the number of ions per molecule of salt;

M is the molar mass of the salt.

If the above equation is applied to a salt of the formula I previously given, the tonicity of its aqueous solution at a concentration of 189 mg / ml (160 mg / ml free base equivalents) can be calculated as follows:

T = 189 x 1000 x 3 mOsml

636.76 or

T = 891 mOsml, or 141.07 g / L, respectively

However, if 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) is actually measured by conventional practical methods (for example, an osmometer using a well-known freezing procedure), we will actually find that only about 53.89 g / L (340 mOsml).

This unexpected nicotine tonicity of an aqueous solution of the sulfate salt of the invention can be rationalized by one or more different mechanistic interpretations. One possible explanation is that the free base ions aggregate into the micelles after dissolution of the salt, thereby reducing the number of particles in the solution, thus effectively reducing the N value in the above theoretical equation for tonicity. However, other mechanistic interpretations may be equally likely, and it is understood that none of these interpretations should be construed as limiting the scope of the invention in any way.

Practical consequence of nic tonicity! The saline solutions of the invention according to the intended value are realized in a significant reduction of local inflammation in those parts of the body in which such solutions were used. This effect is particularly noticeable in those parts that have particularly sensitive membranes, such as the intranasal cavity. Hence the sulfate salt of the formula

In view of this property, combined with its high solubility mentioned above, it is ideally suited for the preparation of aqueous intranasal formulations.

The effect of tonicity on the irritant effect of ionic solutions can be illustrated by aqueous solutions of sodium chloride of different concentrations. Thus an aqueous solution of sodium chloride with a tonicity of 142.65 g / L (900 mOsml) / compare the theoretical tonicity of 141.07 g / L of the salt of the formula I given above at a concentration of 189 ml / mg (equivalent to 160 mg / ml free base) /, when administered intranasally, it causes considerable scalding sensation, the lacquer solution is very hypertonic. On the other hand, the tolerability of an aqueous solution with a tonicity of 48.34 g / L (305 mOsml) / compare the observed actual tonicity of 53.89 g / L of the salt of formula (1) above at a concentration of 189 mg / ml (equivalent to 160 mg / ml free base) ) / when used intranasally, is perfectly acceptable. The aqueous sodium chloride solution with a tonicity of 48.34 g / L is isotonic. Since the observed true tonicity value of the sulfate salt of the invention at a concentration of 160 mg / ml (expressed as free base) is 53.89 g / L, this means that at this concentration its aqueous solution is only very slightly hypertonic.

For the reasons discussed above, it may be appreciated that the salt of the invention is practically available for intranasal administration. In a preferred embodiment of the composition of the present invention, therefore, a pharmaceutical composition adapted for intranasal administration containing a sulfate salt of the above formula I or a pharmaceutically acceptable solvate thereof, together with one or more pharmaceutically acceptable carriers is provided.

Intranasal formulations can generally be provided in the form of a liquid or a dry powder. Satisfactory intranasal formulations must be sufficiently stable, chemically and physically, to allow them to be coherently divided into precise dosed doses, even after long-term storage with potential temperature fluctuations between 0 and 40 ° C. Accordingly, the active ingredient must be compatible with the fillers used in the formulations and must not be aggregated in such a way as to cause loss in terms of accurate dose release, for example by sedimentation from a liquid formulation or solidification of a powder formulation. In order to maximize the retention of the intranasal formulation in the nasal passages of the patient after administration of a particularly liquid formulation, it is desirable to release the dosage unit of the active ingredient in a relatively small volume, for example 50-200µl, preferably about 100µl. This may require the use of high concentrations of the drug and therefore very well soluble active ingredients are useful. Clearly, the active ingredient must also be present in a form that is easily absorbed through the nasal mucosa, but is not associated with any adverse effects such as inflammation.

As indicated above, we have found that for the intranasal administration of the salts of the invention, it can be advantageously used in solution form.

The solutions will usually be aqueous; they can be prepared only with water (for example sterile, depyrogenized water) or with water together with another pharmaceutically acceptable solvent (for example ethanol, propylene glycol and polyethylene glycols such as PEG 400).

Such solutions may additionally contain other fillers, such as preservatives (for example benzalkonium chloride and phenethyl alcohol), buffers, tonicity adjusters (eg sodium chloride), viscosity enhancers, absorption enhancers, fragrances (eg aromatic fragrances such as menthol, eucalyptol, camphor and methyl salicylate in amounts from about 0.001 to about 0.5% w / w) and sweeteners (for example saccharin or saccharin sodium in amounts from about 0.01% w / w to about 10% w / w w, recommended in the range of 0.01 to 2% w / w).

Preferably, the solutions of the invention will be sterile and preservative free. Sterile formulations can be prepared by methods known in the art, for example by aseptically making or sterilizing a large amount of products.

The solutions should be applied directly to the nasal cavity in the usual manner, for example with a dropper, pipette or spray. The formulations can be provided in single or multi-dose form. In the latter case, it is desirable to provide the dosage given. In the case of a dropper or pipette, this may be achieved by the patient taking a suitable, predetermined volume of solution. In the case of a sprayer this can be achieved, for example, by means of a spray metering pump of the sprayer.

Intranasal administration may also be accomplished by an aerosol formulation in which the compound is provided in a pressure jacket together with a suitable propellant such as chlorofluorocarbons (CFCs), for example dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane; hydrofluorocarbon (HCFC), for example 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 by supplying the dosing valve. Alternatively, a piezoelectric device can be used to achieve the required atomizer.

Preferably, a pharmaceutical composition adapted for intranasal administration containing the salt of the invention will be in the form of an aqueous solution.

Thus, the present invention also provides a true isotonic aqueous solution of a salt of formula I as defined above, as well as the use of such a solution in the preparation of pharmaceutical compositions adapted for intranasal administration.

The pH of the aqueous solutions of the salts of this invention adapted to intranasal administration will be appropriate in the range of 4 to 8. Preferably, the pH of the aqueous solutions of the salts of the invention for intranasal administration is between 5 and 7. It has been found that at a concentration of 160 mg / ml (expressed as free base), the pH of an aqueous solution of the sulfate salt, of Formula I above, about 5.8. This is especially useful because such solutions do not require pH adjustment before use. Solutions of more acidic salts, with pH values outside the acceptable range, will require a pH adjustment by the continued addition of auxiliaries, in particular buffers, which will have a detrimental effect on the pharmaceutical properties of the resulting solution, thanks to the accompanying increase in tonicity. However, if the pH of aqueous solutions of salts of formula I is required, it may conveniently be carried out in the usual manner, as with the controlled addition of a pharmaceutically acceptable acid or base.

It will be appreciated that the aqueous solutions of the sulfate salt of the invention can conveniently be prepared by dissolving the salt in water. Alternatively, such solutions may be obtained by mixing 1 molar equivalent of Ν, Ν-dimethyl-2- [5 (1,2,4-triazol-1-ylmethyl) -IH-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, the aqueous dissolved salts of the present invention will ideally contain a salt at a concentration of 1 mg / ml to 200 mg / ml, preferably from 10 mg / ml to 190 mg / ml.

For intranasal administration, the salt of the present invention may conveniently be in the form of a single dose preparation. A suitable single dose formulation for intranasal administration contains the active ingredient in an amount of 0.1 mg to 100 mg, suitably in the range of 1 to 60 mg, preferably 2 to 40 mg, which can be administered either in one or in both nostrils. Ideally, a single dose of 1 mg to 35 mg of the active ingredient is given in a single nostril.

A typical single dose formulation can be provided as a single dose in a submerged unit, for example, in a glass vial or plastic materials that can be filled and then submerged using conventional manufacturing techniques. Alternatively, we can produce a submerged vial of plastic material using mold-fill-to-submerge technology. Ideally, the vial and ingredients of the pharmaceutical formulation it is filled with are thermostable.

The warmed vial can be sterilized, for example, by autoclaving at 121 ° C for at least 15 minutes, or alternatively by gamma irradiation of the packaging and then sterile filtering of the solution to provide a sterile one-dose vial that can be mounted in a suitable release device before use. . The recommended volume of a single dose preparation is 50 to 200 ^ 1, for example 100 pl.

Preferred devices for administering the intranasal formulations of the invention include a Bespak multidose device which can be obtained from Bespak, Kings Lynn, United Kingdom; and in particular a single-dose Valois Monospray device as described in, for example, WO-A-93 / OO172.

According to a further aspect, the present invention provides a process for the preparation of a sulfate salt of formula I as defined above, or a solvate thereof, a process comprising the conversion of N, N-dimethyl-2- [5- (1,2,4triazole-1) 1-methyl-1H-indol-3-yl] 1 amine of structural formula II:

H with about 0.5 molar equivalents of sulfuric acid in a suitable solvent.

The process is advantageously carried out by stirring the reactants at room temperature in an aqueous medium, typically in the presence of a lower alkanol such as ethanol or isopropyl alcohol.

A salt of the above Formula I, or a solvate thereof, can also be prepared by exchanging a salt comprising treating a salt of a compound of the above Formula II, other than a sulfate salt (2: 1) of the Formula I, with a suitable sulfate salt.

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

The compound of the above Formula I can be prepared by any of a number of procedures that will be readily apparent to one skilled in the art. Since the compound of formula II contains an indole nucleus, the Fischer indole synthesis is an appropriate method for its preparation. It can conveniently be effected by converting a hydrazine derivative of formula III

(Ni) with a compound of formula IV:

⁰ (IV) or its carbonyl protected form.

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

The reaction is conveniently carried out by stirring the reactants in the presence

4% sulfuric acid at elevated temperature, typically at about 90 ° C.

Hydrazine derivatives of formula lil can be prepared from the corresponding aniline of formula V:

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

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

N

NO (VI) typically by displacement hydrogenation using a hydrogenation catalyst such as palladium or charcoal in the presence of a hydrogen donor such as ammonium formate, or alternatively by catalytic hydrogenation or using tin (II) chloride.

The nitro compound of formula VI can be conveniently prepared by metabolizing the 1,2,4-triazole sodium salt with nitrobenzyl halide, e.g. 4-nitrobenzyl bromide, respectively, in Ν, Ν-dimethylformamide at room temperature. Alternatively light compound VI is prepared by the conversion of nitrobenzyl halide, e.g. 4nitrobenzyl bromide, with 4-amino-1,2,4-triazole followed by deamination of the resulting triazole salt by treatment with nitric (III) acid and subsequent neutralization. This second transformation, which can be carried out in two separate steps or advantageously as a one-pot process with both stages in combination, is conveniently performed using reaction conditions analogous to those described in J. Org. Chem., 1989, 54, 731.

In a still further aspect, the present invention provides a method for treating and / or preventing clinical conditions for which a selective 5-HT1-receptor receptor agonist is indicated, comprising administering to a patient in need of such treatment an effective amount of a salt of formula I as defined above , or a pharmaceutically acceptable solvate thereof. In a particular embodiment of the method of the invention, a salt of formula I, or a pharmaceutically acceptable salt thereof, is administered in solution, preferably an aqueous solution adapted for intranasal administration.

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

The following non-limiting examples are intended to illustrate the present invention.

PREPARATION 1

Step (s): 1- (Nitrobenzyl) -4-amino-4H-1,2,4-triazole bromide

A mixture of 4-amino-1,2,4-triazole (250 g, 2,976 mol) and 4nitrobenzyl bromide (ex Janssen, 99%, 617.5 g, 2.83 mol) in isopropyl alcohol (5.66 l) the mixture was heated to reflux. The mixture became a solution and then, at reflux, almost immediately, the desired triazole salt crystallized. The mixture was stirred and refluxed for 7.5 hours and then allowed to cool to room temperature overnight. The next day, the mixture was cooled to 0-5 ° C, allowed to stand for 1 hour and the product filtered, washed with a little isopropyl alcohol and then dried in vacuo at 50 ° C to give the title triazole salt (808 g) in 95% yield. as a white solid, from the ground. 199 ° C (decomposition).

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

A solution of sodium nitrite (206 g, 2.98 mol) in water (840 ml) was added below the surface for 70 minutes to the previous triazole salts (808g 2.69 mol) in water (5.6 l) and conc. hydrochloric acid (505 ml) at 0-5 ° C. The pale yellow pulp was stirred at <5 ° C for 15 minutes and then allowed to warm to 25 ° C for 1 hour. The pH of the colorless solution was adjusted to 9 with the addition of aqueous ammonia solution (380 ml, 18M), and the temperature was maintained at <30 ° C. The mixture was 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, 18M) and dried under reduced pressure at 50 ° to give 535 g (97% yield) of the title nitro compound. from the ground. 102-103 C.

Step (iii): 1- (4-aminobenzyl) -J, 2,4-triazoyl

The previous nitro compound (803 g, 3.9 mol), ammonium formate (1.16 g, 18.4 mol) and 10% Pd / C (28 g) in metdnol (8 L) were stirred and heated under nitrogen atmosphere. 30 ° C. The heating was stopped and the mixture cooled to control the exothermic reaction by maintaining the temperature at 35-40 ° 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 residue was washed with methanol (2 L). The filtrate was concentrated and the residue was diluted with ethyl acetate (12 I) and water (1.57 l). The lower aqueous layer was treated with aqueous ammonium hydroxide solution (10 ml, 18M) to pH 9. The aqueous layer was separated and extracted with ethyl acetate (2 x 61 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. 127128 ° C.

Step (iv): N, N-dimethylH-2- (5- (1,2,4-triazol-1-ylmethyl) -1H-indol-3-ylmethylamine

A solution of sodium nitrite (16.7 g; 0.24 mol) in water (22.7 ml) was added below the surface to a solution of the previous amine (40 g; 0.23 mol) in hydrochloric acid (65.3 ml) and water ( 162 ml), maintaining the temperature at <5 ° C. The solution was 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 was stirred at 510 ° C for 10 minutes, allowed to warm to 20 ° C for 20 minutes and then heated to 70 ° C for 45 minutes. The solution was 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 was stirred at 70 ° C under nitrogen for 2 hours and then 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 moles) was maintained over 15 minutes, maintaining the temperature at <35 ° C. The solution was stirred at 30-35 ° C for 30 minutes. The mixture was heated to 90 ° C for 30 minutes and maintained at 90-93 ° C for 15 minutes. The mixture was cooled to 15 ° C and a Hyflo filter aid (68 g) was added followed by aqueous ammonium hydroxide solution (200 ml, 18M) to adjust the pH to 11-12. The mixture was filtered and the filtrate and Hyflo extracted with ethyl acetate (5 x 300 ml). The extract was dried (Na ₂ S0 ₄ ) and evaporated under reduced pressure. The residue was chromatographed on silica gel (550 g) with ethyl acetate / methanol (80:20), changing to ethyl acetate: methanol (50:50). The fractions containing the product were evaporated under reduced pressure to give 27.8 g (45% yield) of the title compound as a free base.

EXAMPLE 1

N, N-dimethyl 1-2 - [- (1,2,4-triazol-1-ylmethyl) -1H-indol -3-H] ethyl amine. 0,5 sulfate. 0.7 hydrate.

N, N-dimethyl-2- [5- (1,2,4-triazol-1-ylmethyl) -1H-indol-3-yl] ethylamine (0.63 g; 2.34 mol) in water (0, 73 ml) and isopropyl alcohol (15.9 ml) were added sulfuric acid (IN; 1.17 ml) while stirring. The mixture was initiated for crystallization and cooled to 0 ° C. The reaction mixture was filtered and the 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%. C ₁₅ H ₁₉ N _5. =, 5

H ₂ S0 ₄ . 0.7 H ₂ O requires C, 54.43; H, 6.52; N, 21.16; S, 4.84%).

EXAMPLE 2

Buffered Tablets for the sublingual application containing 50 ug (expressed as free base) of the active ingredient

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 20,0 mg Blue FD&C No. 2 Al umi ni mind Lake 0.55 mg Saccharinate sodium 11,0 mg Peppermint NAEFC0 / P05,51 6.6 mg Magnesium stearate 1.1 mg Total weight 220,0 mg

All ingredients except magnesium stearate were mixed together in a suitable blender. The resulting mixture was then oiled with magnesium stearate and pressed in a tablet press.

EXAMPLE 3

Buffered Tablets for sublingual administration containing 20 mg (expressed as free base) of the active ingredient

N, N-dimethyl-2- [5- (1,2,4-triazol-1-ylmethyl) -1H-indol-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 Al umi ni mind Lake 0.55 mg Saccharinate sodium 11,0 mg Peppermint NAEFC0 / P05,51 6.6 mg Magnesium stearate 1.1 mg

Total weight

220,0 mg

All ingredients except magnesium stearate were mixed together in a suitable blender. The resulting mixture was then oiled with magnesium stearate and pressed in a tablet press.

EXAMPLES 4 AND 5

Sterile intranasal formulation

Example 4 Example 5

Compound of Formula (II) 0.85 mg 170 mg Sulfuric acid (concentrated) BP 0,155 mg 30.9 mg Large amount of water for injections Ph. Eur. up to 1 ml to 1 ml

The compound of formula (II) is dissolved in sulfuric acid, previously diluted with water. Make up to volume with volume.

The solution can be packaged for intranasal use, for example by filling in vials, warming and sterilizing the vials by autoclaving at 121 ° C for at least 15 minutes, or sterilizing by filtration and aseptically transferred into sterile packaging.

EXAMPLES 6 AND 7

Conserved intranasal formulation

Example 6 Example 7

Compound of Formula (II) 0.85 mg 170 mg Sulfuric acid (concentrated) BP 0,155 mg 30.9 mg Phenylethyl alcohol USP 4.0 mg 4.0 mg Benzalkonium chloride USNF 0.2 mg 0.2 mg The purified water of B.P. to 1 ml to 1 ml

The compound of formula (II) is dissolved in sulfuric acid, previously diluted with water. Phenylethyl alcohol and benzalkonium chloride are added and the solution is made up to the desired volume.

Further preserved formulations containing 1, 5, 10, 50, 80, 100 and 150 mg / ml of the compound of formula (II) were prepared in a similar manner.

The formulations can be used in single dose volumes of 100 µL, either in one or both nostrils of patients suffering from moderate or severe migraine attacks to give a dose of 0.1, 1, 5, 10 or 17 mg of the compound of formula (II).

EXAMPLES 8 AND 9

Sterile intranasal formulation

Example 8 Example 9

Compound of Formula (I) 1 mg 200 mg

Large amount of water for injections Ph. Eur. up to 1 ml to 1 ml

The compound of formula (I) is dissolved in water and the solution is made up to the desired volume.

The solution can be packaged for intranasal use, for example by filling in vials, warming and sterilizing the vials by autoclaving at 121 ° C for at least 15 minutes, or sterilizing by filtration and aseptically transferred to sterile packaging.

EXAMPLES 10 AND 11

An alternative conserved intranasal formulation

Example 10

Example 11

Compound of Formula (I) mg

200 mg

Benzethonium Chloride Purified Water B.P.

0.2 mg ¹ to 1 ml

0.2 mg to 1 ml

The compound of formula (I) is dissolved in water. Benzethonium chloride was added and the solution was made up to the desired volume.

EXAMPLES 12 TO 15

Sterile intranasal formulation

Example 13

Example 12

Compound of Formula (II) 5 mg 50 mg Sulfuric acid (concentrated) BP 0.91 mg 9.1 mg Large amount of water for injections Ph. Eur. up to 1 ml to I ml

Example 15

Example 14

Compound of Formula (II) 100 mg 160 mg Sulfuric acid (concentrated) BP 18,2 mg 29.1 mg Large amount of water for injections Ph. Eur. to I ml to 1 ml

The compound of formula (II) is dissolved in sulfuric acid, previously diluted with water. Make up to volume with volume.

The formulations were filled into vials in 100 pl aliquots, the vials were warmed and sterilized by autoclaving at 121 ° C for at least 15 minutes. Alternatively, the solutions can be sterilized by filtration and aseptically filled with sterile bottles.

The formulations are used in single dose volumes of 100 pl in one nostril of patients suffering from moderate or severe migraine attacks to administer a dose of 0.5, 5, 10 or 16 mg of the compound of formula (II).

Ž1

EXAMPLES 16 AND 17

Sterile intranasal formulation

Example 16 Example 17

Compound of Formula (II) 160 mg 160 mg sulfuric acid (concentrated) BP 29.1 mg 29.1 mg Sodium saccharinate BP 10 mg 20 mg Large amount of water for injections Ph. Eur. to 1 ml to 1 ml

The compound of formula (II) is dissolved in sulfuric acid, previously diluted with water. Make up to 90% by volume of the solution and dissolve the saccharin therein, and then complete the solution to the desired volume.

The formulations were filled into vials in 100 pl aliquots, the vials were warmed and sterilized by autoclaving at 121 ° C for at least 15 minutes. Alternatively, the solutions can be sterilized by filtration and aseptically filled with sterile bottles.

The formulations are used in single dose volumes of 100 pl in one nostril of patients suffering from moderate or severe migraine attack to administer a dose of 16 mg of the compound of formula (II).

MERCK SHARP & DOHME LIMITED, Hertfordshire, England

Claims (15)

PATENT APPLICATIONS A sulfate salt of N, N-dimethyl-2- [5- (1,2,4-triazol-1-ylmethyl) 1H-indol-3-yl] ethyl amine (2: 1) of structural formula I: and pharmaceutically acceptable solvates thereof. A compound according to claim 1 wherein the hydrate is said salt. Compound according to claim 1, characterized in that 0.7 is the hydrate of said salt. A pharmaceutical composition comprising the salt of claim 1 or a pharmaceutically acceptable solvate thereof, together with one or more pharmaceutically acceptable carriers. 5. A pharmaceutical composition comprising a salt according to claim 1 or a pharmaceutically acceptable solvate thereof, together with one or more pharmaceutically acceptable carriers, for use in treatment with intranasal administration. 6. Composition after request 5, marked with so, Yes is in form aqueous solutions. 7. Composition after request 6, marked with so, Yes is in forms solutions in depirogenized sterile leads . 8. The composition of claim 6 or 7, characterized in that it contains a salt at a concentration of from 1 mg / ml to 200 mg / ml. Composition according to claim 8, characterized in that it contains a salt at a concentration of 10 mg / ml to 190 mg / ml. Composition according to claim 9, characterized in that it contains a salt at a concentration of about 189 mg / ml. Composition according to any one of claims 5 to 10, characterized in that it is in the form of a single dose preparation and contains the active ingredient in an amount of 0.1 mg to 100 mg. Composition according to claim 11, characterized in that the volume of the single-dose preparation is 50 to 200 µl. 13. A process for preparing a salt according to claim 1, or a solvate thereof, characterized in that it comprises: (A) conversion of N, N-dimethyl-2- [5- (1,2,4-triazol-1-ylmethyl) -1Hindol-3-yl] ethylamine of structural formula II: H (II) with about 0.5 molar equivalents of sulfuric acid in a suitable solvent; or i (B) treating a salt of a compound of Formula II above, other than a sulfate salt (2: 1) of Formula I as defined in claim 1, with a suitable sulfate salt. A process for the preparation of a pharmaceutical composition according to any of claims 4 to 12, characterized in that it comprises mixing the salt according to claim 1, or a pharmaceutically acceptable solvate thereof, with a pharmaceutically acceptable carrier. A method for preparing a pharmaceutical composition according to any one of claims 6 to 12, characterized in that it comprises: (A) dissolving the salt according to claim 1, or a pharmaceutically acceptable solvate thereof, in water; or (B) mixing one molar equivalent of a compound of formula II as defined in claim 13 with 0.5 to 0.7 molar equivalents of concentrated sulfuric acid in water. The salt of claim 1, or a solvate thereof, for use in treatment. 17. The salt of claim 1, or a pharmaceutically acceptable solvate thereof, for use in the treatment and / or prevention of clinical conditions for which a selective 5HT1-like receptor agonist is indicated. Use of a salt according to claim 1, or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment and / or prevention of clinical conditions for which a selective 5HT1-like receptor agonist is indicated.