N,n-dimethyl-2-[5-(1,2,4-triazole-1-ylmethyl)-1h-indol-3-yl] ethylamine sulphate salt (2:1) and its pharmaceutically acceptable hydrates, the means of its production, the pharmaceutical composition based on it, the way it is received and drug

 

(57) Abstract:

The invention relates to a new compound N,N-dimethyl-2-[5-(1,2,4-triazole-1-yl methyl)-1H-indol-3-yl] ethylamine sulphate salt (2:1) structural formula I and its pharmaceutically acceptable hydrate. The method of obtaining salt or its hydrate is in the interaction of N,N-dimethyl-2-[5-(1,2,4-triazole-1-ylmethyl)-1H-indol-3-yl] ethylamine of formula II with about 0.5 molar equivalent of sulfuric acid in a suitable solvent. Describes a pharmaceutical composition and a pharmaceutical agent for the treatment and/or prevention of clinical conditions for which illustrates the application of a selective agonist of 5-HT-like receptors. The sulfate salt of N, N-dimethyl-2-[5-(1,2,4-triazole-1-ylmethyl)-1R-indol-3-yl]ethylamine is a selective agonist of 5-HT1-like receptors and are therefore useful in the treatment of clinical conditions, especially migraine and associated disorders, for which illustrates the application of a selective agonist of these receptors. 6 C. and 11 C.p. f-crystals, 6 PL.

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The invention relates to certain salts of pharmaceutically active agent. More specifically, the invention relates to a sulfate substituted triazole, which loads the service" receptors. Therefore, this compound is useful in the treatment of clinical conditions for which illustrates the use of selective agonists of these receptors.

Agonists of 5-HT1-like receptors, that are selective vasoconstrictor activity, recently described as substances used in the treatment of migraine (see, for example, A. Doenicke et al., The Lancet, 1988, Vol. 1, 1309-11). Salt of the present invention, showing selective activity of the agonist 5-HT1-like receptors, is according to this invention are useful in the treatment of migraine and accompanying conditions, such as migranal" headache, headache due to vascular disorders or pressure, and pediatric migraine.

In EP 0313397 A1 disclosed a pharmaceutical composition having the property of agonist 5-HT1-like receptors.

In the application EP-A-0497512, published August 5, 1992, describes a class of substituted imidazole, triazole and derivatives tetrazole, which, allegedly, are selective agonists of 5-HT1-like receptors and, consequently, specifically used in the treatment of migraine and accompanying conditions.

The present invention proposes sulfate C2-[5-(1,2,4-triazole-1-ylmethyl)-1H-indol-3-yl]ethylamine sulphate salt (2:1) structural formula I

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and its pharmaceutically acceptable solvate, including hydrates, in particular 0.7 to hydrate.

Pharmaceutically acceptable salts of N,N-dimethyl-2-[5-(1,2,4-triazole-1-ylmethyl)-1H-indol-3-yl]ethylamine in General included in the scope of application EP-A-0497512. In fact disclosed providercomcast, succinate and benzoate. However, nowhere in the application EP-A-0497512 there is no description of a specific salt of the above structural formula I or its pharmaceutically acceptable solvate.

It was found that the salt of the above structural formula I possesses favorable properties in some respects, which makes it particularly suitable for use as pharmaceutical agents. For example, unlike many drugs that are known to have an unpleasant taste, salt of formula I is relatively tasteless.

Therefore, another aspect of the present invention is a pharmaceutical composition comprising a sulfate salt of formula I above, or its pharmaceutically acceptable MES in combination with one or more pharmaceutically acceptable carriers.

Composition, corresponding to this invention, are respectively of the form that contains a single dose, and or liquid sprayable solutions, drops, ampoules device for autodiscovery or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflate. The preparation of compositions of this invention can be carried out with known methods, for example, as described in Remington's Pharmaceutical Sciences, 17th Ed., 1985.

For example, for solid compositions such as tablets, the active ingredient is mixed with a pharmaceutical carrier, such conventional ingredients of the pills as microcrystalline cellulose, corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, secondary acidic calcium phosphate or resin, or other pharmaceutical excipients, such as water, to form a solid, pre-processed composition containing a homogeneous mixture of salt of the above formula I. When referring to these pre-processed homogeneous composition, this means that the active ingredient is dispersed evenly within the composition so the composition can be easily separated on the form that contains equal doses, such as tablets, pills and capsules. This Tue, containing from 0.1 to about 500 mg of the active ingredient of the present invention.

The liquid forms in which the salt of the present invention may be included for oral or intranasal injection include aqueous solutions, syrups with improved taste, aqueous or oil suspensions and emulsions improved taste with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical solvents. Conventional dispersing or suspendresume agents for aqueous suspensions include synthetic and natural resins, such as tragakant, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.

Suitable level of doses in the treatment of migraine is approximately from 0.01 to 250 mg/kg / day, preferably from about 0.05 to 100 mg/kg / day, and particularly preferably from about 0.05 to 5 mg/kg / day. The compositions may be administered from 1 to 4 times a day.

In one embodiment of the compositions in accordance with this invention presents a pharmaceutical composition in solid form, adapted for sublingual primariamente acceptable buffering agent, able to give the environment of oral cavity after application of the composition is pH of at least 7,5; and one or more pharmaceutically acceptable excipients.

Although the sublingual region of the oral cavity is small, it is rich in blood vessels and lymph nodes. Therefore, the absorption of certain molecules occurs rapidly and systemic therapeutic effect can be achieved very quickly. An additional advantage of the sublingual method of application is that in this case, medicines can enter the systemic circulation directly, bypassing the liver, where they may be metabolized differently. However, most commercially available drugs are amines and, therefore, are basic. In the physiological environment of the intraoral cavity, where of course the pH will be from 6.2 to 7.4, dissolvine condition such essential drugs has an adverse effect on the acceptable rate of absorption of the intraoral cavity.

It is known from literature (see Rathbone and Hadgraft, Int, T. Pharmaceutices 1991, 74, 9-24) that increase the pH of the buccal compositions can enhance buccal absorption of basic learstar buffer agent, able to give the environment of oral cavity after application of the composition is pH of at least 7,5.

Examples of typical compositions in solid form, which can be adapted for sublingual administration, include tablets, especially freeze-dried tablets, such as the system Zidis(R)described in U.S. patent N 4371516; capsules, including hard capsules filling, soft gelatin capsules and hard gelatin capsules, liquid filling; powders and granules. The preferred composition of this invention for sublingual injection composition is in tablet form.

Complete composition of the present invention for sublingual application is the composition of any suitable size and shape that is acceptable for sublingual administration. In that case, when the composition is made in the form of tablets, the typical weight of the tablet will be from 50 to 500 mg. Preferred weight of the tablet weight is about 220 mg.

Composition for sublingual introduction in accordance with this invention includes one or more buffer agents, capable of giving the environment intraoral cavity after administration of the composition is pH of Menshevist, if the pH of the intraoral cavity is increased. The solid composition of the present invention for sublingual injection can, therefore, have the advantage that when it is injected into the intra-oral cavity, the pH of the intraoral environment increases and, consequently, may increase the absorption of drugs on the introduction of drugs made in the form of a corresponding nebuferizirovannoj composition.

To the nature of the buffer agent used in the composition for sublingual introduction in accordance with this invention, in General there are no restrictions, provided that it is pharmaceutically acceptable and is able to achieve a pH of oral cavity after administration of the composition to at least a 7.5. Qualified know a large number of buffer agents, which can conveniently be used in this case. Examples of appropriate buffer agents 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 the buffer agent, which must be entered into the composition for sublingual introduction of ACC is shown, it is important to ensure that the amount of the applied buffer agent, which maintains a higher pH environment of the intraoral cavity after administration of the composition in a physiologically acceptable limits. For example, it was found that when using a buffer solution containing sodium carbonate and sodium bicarbonate required to maintain pH of the composition of the present invention below approximately 9.6, since at pH values above this level there may be some irritation of the intraoral cavity, leading to burning sensation in the mouth. Thus, in those cases, when using a mixture of carbonate and bicarbonate of sodium, the amount of sodium carbonate in the final composition, calculated on the anhydrous sodium carbonate or an equivalent amount of aqueous sodium carbonate, accordingly, would be from 5 to 20%, preferably approximately 10% by weight; and the amount of sodium bicarbonate will accordingly be from 15 to 35%, preferably 30% by weight of the finished composition.

Pharmaceutically acceptable fillers, entered into the composition of the present invention for sublingual use, can be fillers, wide used for the compositions of padya the t linking agents, such as corn starch; lubricating agents such as magnesium stearate, sealing agents, such as cellulose, lactose and mannitol; and dezintegriruetsja agents, such as sodium starch glycolate and sodium carboxymethylcellulose.

Since the composition of the present invention sublingual application is adapted for insertion through the mouth, the taste of the finished composition is a factor that must be taken into account. Many of buffer agents have an unpleasant taste. For example, the buffer system containing a mixture of sodium carbonate and sodium bicarbonate, it has been found that imparts an unpleasant taste to the composition containing the system. Therefore, the introduction of agents, giving a sweet and/or pleasant taste in the composition of this invention can be very useful.

Suitable sweetening agents include water-soluble natural sweeteners such as monosaccharides, disaccharides and polysaccharides such as xylose, ribose, glucose, galactose, fructose, dextrose, sucrose, inert sugar, maltose, partially hydrolyzed starch or hard corn syrup solids and sugar alcohols such as sorbitol, xylitol, mannitol, dihydrochalcone, solid and stevia rebaudina (stevioside); odora is saccharin, cyclamate salt saccharin in the form of the free acid and synthetic sweeteners 3,4-dihydro-6-methyl-1,2,3-oxathiazin-4-one, 2,2-dioxide, particularly the potassium (Acesulfame-K), sodium and calcium salts, sweeteners based dipeptides, such as methyl ether, aspartyl--phenylalanine, and mixtures thereof. Preferred sweetening agent is saccharin sodium.

In General, the amount used sweetening agent will vary depending on the desired sweet taste to a single track and, if necessary, to disguise the unpleasant taste. As an example, when used as a sweetening agent, saccharin sodium, the amount of the composition of the present invention is from 0 to 10% by weight of the composition for sublingual use and preferably about 5% by weight.

Examples of flavoring agents used for the introduction into the composition of the present invention for sublingual use, include synthetic fragrant oil, fruit essences, natural aromatic oils, obtained from sources such as plants, leaves and flowers, as well as mixtures of the above components. Specific examples include peppermint oil, eucalyptus oil, capelin, grapes, citrus pomerancevoyi and grapefruit; fruit essences obtained from sources such as Apple, strawberry, cherry, and pineapple; extracts such as extract of Cola. Special flavoring agent is Pippermint NAFCO/P05.51.

As the amount of sweetening agent, the amount used flavoring agent is determined individually, but will, in particular, depend on the extent unpleasant taste that you want to mask. In the General case, an appropriate amount of flavoring agent in the final composition for sublingual use in accordance with this invention is from 0 to 10%, preferably about 3% by weight.

If necessary, the composition for sublingual injection according to this invention can be incorporated pharmaceutically acceptable dye. Typical dye used in international practice, is blue aluminium painted Blue FDLCN2.

The dye can be included in the final composition in an amount of from 0 to 1.0%, preferably approximately 0.25% by weight.

Reasonable selection of the proportions of the individual components constituting the composition of this invention for sublingual vnutrirodovoe cavity, equal at least to 7.5, preferably at least 9,0, over a long period.

Composition for sublingual introduction in accordance with this invention can be easily manufactured by a variety of standard methods known to the skilled technician. Typical well-known methods include a method of direct pressing method and wet granulation.

Compositions for oral administration can have some drawbacks in the treatment of conditions such as migraine, because these conditions are often accompanied by nausea, which makes it difficult for the patient oral administration of the composition. Parenteral administration usually has the advantage of rapid absorption of the drug, but this route of administration may be unacceptable to some patients, especially if the composition is made in the form, adapted for use without medical supervision.

It is established that the salt of formula I has an unexpectedly high solubility in water, which makes it convenient for preparation of compositions, especially compositions for the intranasal route, which requires a relatively concentrated aqueous solutions of the active ingredient is approximately 170 mg/ml For comparison, for example, the solubility of salts of benzoic acid 4,4-dimethyl-2-/5-(1,2,4-triazole-1-ylmethyl)-1H-indol-3-yl/ - ethylamine (example 18 application EP-A-0497512) in comparable conditions is, it has been found that approximately 40 mg/ml

In addition, the sulfate in accordance with this invention, as installed, has an unexpectedly low onicescu. Theoretically, sonicnet (fonicity) of this solution in the form of its osmolarity in milliosmoles can be calculated using the following equation:

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where T is theoretical toychest;

C is the solution concentration, mg/ml;

N is the number of ions per molecule of salt;

M - molecular weight salt.

Applying the above equation to the salt of formula I above theoretical toychest its aqueous solution with a concentration of 189 mg/ml (equivalent to 160 mg/ml free base) can be calculated as follows:

, mosml

or T = 891 mosml.

However, the actual measurement of the availability of practical ways (for example, using osmometry using well-known technique based on the reduction of the freezing point) toychest aqueous solution of the salt of formula I with a concentration of 189 mg/ml (equivalent is>This unexpected low toychest aqueous solutions of sulfate compounds of this invention can be ratsionalisticheskie explained with the help of one or a number of mechanistic interpretations. One possible explanation could be the fact that ions of the free base are connected to micelli in the process of dissociation of the salt, resulting in the number of "particles" in the solution will decrease, thus decreasing the value of the parameter N in equation theoretical toychest presented above. Are equiprobable however, other explanations, but it is clear that none of these explanations will not be construed as limiting the scope of the present invention in any way.

Almost a consequence of low toychest solutions of salts in accordance with this invention relative to the calculated values is implemented in sequential decrease local irritation in those areas of the body where these solutions are applied. This action is particularly noticeable in areas with particularly sensitive membranes, such as intranasal cavity. Thus, due to this property, in combination with high solubility, as described above, the sulfate of the formula I is ideal the particular irritant effect on ionic solutions can be proillyustrirovano for example, aqueous solutions of sodium chloride of different concentrations. In fact, an aqueous solution of sodium chloride with onicescu 900 mosml (compare theoretical toychest equal 891 mosml to form salts of formula I, above, at a concentration of 189 mg/ml (equivalent to a concentration of 160 mg/ml free base) by intra cause a noticeable feeling of pinching. This solution is very hypertonic. On the other hand, the portability of an aqueous solution of sodium chloride with onicescu 305 mosmol (compare the observed actual toychest equal to 340 salt of formula I above at a concentration of 189 mg/ml (equivalent to a concentration of 160 mg/ml free base)) if natalina the introduction is completely acceptable. If toychest 305 mosmol aqueous sodium chloride solution is isotonic. Thus, as observed the actual amount of toychest sulfate of this invention at a concentration of 160 mg/ml (expressed in terms of free base) is 340 mosmol, it means that for a given concentration of its aqueous solution is only very weakly hypertonic.

For the above reasons, we can conclude that the salt of this invention is especially valuable for intranasal eticeskaja composition, adapted for intranasal use, which contains sulfate (salt) of formula I, above, or its pharmaceutically acceptable MES in combination with one or more pharmaceutically acceptable carriers.

Compositions for intranasal in the General case can be represented in the form of liquid or dry powder. Good composition for intranasal must be sufficiently stable chemically and physically, to be evenly distributed in precisely measured doses even after long-term storage with possible fluctuations of temperatures in the range from 0 to 40oC., Respectively, the active ingredient must be compatible with the excipients used in the composition and should not be subject to aggregation, which would have resulted in the loss of opportunities in the delivery of precise doses, for example the planting of the liquid composition or the sintering of the powder. To maximise the retention of the composition for intranasal inside the nasal cavity of the patient after applying, especially liquid compositions it is necessary to ensure the delivery of a single dose of the active ingredient in a relatively small carrying amount, for example 50 to 200 μl, preferably the major ingredients with high solubility are preferred. Obviously, the active ingredient must be made in a form that is readily absorbed through the mucous membrane of the nose, but which does not have any side effects, such as irritation.

As shown above, it was found that intranasal salt of this invention can be successfully applied in the form of a solution.

In the General case, the solutions will be water: they can be prepared using one of water (for example, pyrogenic sterile water or with water and a pharmaceutically acceptable co-solvent (e.g. ethanol, propylene glycol and polyethylene glycol, such as PEG 400).

Such solutions can additionally contain other excipients, such as preservatives (e.g. benzalkonium chloride and phenethyl alcohol), buffer agents, agents to achieve a desired toychest (e.g., sodium chloride), agents for increasing the viscosity of the agents to increase the absorption, flavoring agents (e.g., aromatic flavoring agents such as menthol, eucalyptol, camphor and methyl salicylate in amounts from about 0.001 to about 0.5 wt%./weight.) and sweetening agents (e.g. saccharin or saccharin sodium is edocfile, the solutions corresponding to the present invention will be sterile and will not contain preservatives. Sterile compositions can be prepared using well known methods, such as aseptic processing or sterilization of components.

Mortars are used directly in the nasal cavity by conventional means, such as a dropper, pipette or spray. The composition can be offered in form, containing single or multiple dose. In the latter case, it is necessary to ensure by means of dosing. In the case of a dropper or pipette, this can be achieved by the introduction of the patient corresponding to a predetermined volume of the solution. In the case of aerosol this is achieved, for example, through separate metering discharge.

Intranasal administration can be accomplished via the aerosol composition, in which the connection is in the tank under pressure with a suitable spray substance, such as a chlorofluorocarbon (CFC), for example DICHLORODIFLUOROMETHANE, Trichlorofluoromethane or dichlorotetrafluoroethane; HFC (HFC), such as 1,1,1,2-Tetrafluoroethane or 1,1,1,2,3,3,3-Heptafluoropropane; hydrochlorofluorocarbons (HCFCs), such as an; carbon dioxide; or other appropriate gases. Control dose may be a metering valve. Alternative to obtain the necessary aerosol can be used with a piezoelectric device.

Preferred pharmaceutical composition adapted for intranasal and containing a salt of this invention is to provide an aqueous solution.

Thus, this invention provides essentially isotonic aqueous solution of the salt of formula I, above; and the use of this solution for the preparation of pharmaceutical compositions adapted for intranasal administration.

Aqueous solutions of salts of the present invention, adapted for intranasal will have a pH essentially contained in the region from 4 to 8. The preferred pH of aqueous solutions of salts of the present invention for intranasal will be between 5 and 7. At a concentration of 160 mg/ml (in terms of free base) pH of an aqueous solution of sulfate of formula I, above, are equal, it has been found that approximately 5,8. It is a special advantage, since such solutions do not require reguliruemoi region, will need in the regulation of pH by the use of other fillers, in particular buffer agents, and this, in turn, will adversely affect the pharmaceutical properties of the resulting solution due to the increase of toychest.

However, if you want the regulation of pH of aqueous solutions of salts of the formula, it can be implemented by using common methods, such as metered addition of pharmaceutically acceptable acid or base.

It is shown that aqueous solutions of sulfate according to the invention can be easily obtained by dissolving the salt in water. In accordance with another method such solutions can be obtained by blending 1 molar equivalent of N,N-dimethyl-2-[5-(1,2,4-triazole-1-ylmethyl)-1H-indol-3-yl] ethylamine from 0.5 to 0.7 molar equivalents of concentrated sulfuric acid, preferably from 0.5 molar equivalent of sulfuric acid in water.

Salt aqueous solutions for intranasal according to this invention in the ideal case will contain salt in a concentration from 1 mg/ml to 200 mg/ml, preferably from 10 mg/ml to 190 mg/ml

Salt of the present invention for intranasal can be easily represent what keeps the active ingredient in an amount of from 0.1 mg to 100 mg, acceptable range is from 1 to 60 mg, preferably from 2 to 40 mg, which can be entered in either one or both nostrils. Ideally introduction from 1 to 35 mg of the active ingredient with one dose in one nostril.

A typical composition is a unit dose may be in the form of a single dose, placed in a sealed (closed) volume, for example a bubble made of glass or plastic, which may be filled and sealed using available technological methods. In another case, a sealed bubble of plastic can be produced by technology: form - fill - sealing. In the ideal case, the bubble and the components of the pharmaceutical compositions are resistant to heat. Sealed air bubble can be sterilized, for example by curing in an autoclave at a temperature of 121oC for at least 15 minutes, or irradiation container gamma radiation followed by sterile filtering the solution and then placed at a convenient means of introduction before use. The preferred amount of the unit dose ranges from 50 to 200 μl, for example 100 μl.

The preferred means of delivery for introduction composition intranasal according to this invention include Ostrovnoy dose Valois "Monaspray", described, for example, in the application WO-A-3/00172.

According to another aspect, the invention provides a method of obtaining a sulfate salt of formula I above, or MES, including the interaction of N, N-dimethyl-2-[5-(1,2,4-triazole-1-ylmethyl)-1H-indol-3-yl]-ethylamine structural formulas II

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

The process takes place mainly when moving reagents at room temperature in aqueous medium, usually in the presence of a lower alcohol, such as ethanol or isopropanol.

Salt of formula I above, or its MES can also be obtained salt exchange, which includes the processing of salts of compounds of formula II, above, other than sulphate salt (2:1) of formula I, the corresponding sulfate salt.

Examples of the corresponding sulfates that can be used in the above-mentioned salt metabolism include sulfates of metals, such as sodium sulfate or sulfate of silver, and sulfonated ionoobmennye resin. The reaction can be easily carried out in the aquatic environment.

The compound of formula II above can be obtained by one mneo indole, a convenient method for obtaining a well-known synthesis of indole Fisher, which is realized by the interaction of hydrazine of formula III

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with the compound of the formula IV

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or carbonization form.

Suitable carbonization forms of the compounds of formula include dimethyl - and diethylacetal.

The reaction conveniently takes place at the mixing of reagents in the presence of 4% sulfuric acid at an elevated temperature, usually around 90oC.

Hydrazinopyridazine formula III can be obtained from the corresponding aniline of formula V

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the diazotization and subsequent recovery. Diazotization easily flows when using sodium nitrite/conc. HCl, and the resulting dataproducts restore immediately when using, for example, tin chloride (II)/conc. HCl, sodium sulfite/conc. HCl or sodium sulfite/conc. H2SO4.

Anisindione formula V can be obtained by reduction of the corresponding nitro compounds of formula VI

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usually carrying out hydrogenation using a hydrogenation catalyst such as palladium on charcoal, in the presence of a hydrogen donor such as ammonium formate, or friend is the Association of the formula VI can be obtained by the interaction of the sodium salt of 1,2,4-triazole with nitrobenzylamine, for example, 4-nitrobenzylamine, N,N-dimethylformamide at room temperature. Another method of obtaining compounds VI lies in the interaction of nitrobenzaldehyde, for example 4-nitrobenzylamine, 4-amino-1,2,4-triazole, followed by diaminononane formed salt of triazole in the processing of nitric acid and subsequent neutralization. This transformation, which can be done in two different phases or predominantly in a single reactor by combining both stages, flows easily under conditions similar to those described in the publication: J.Org. Chem. 1989, 54, 731.

In another aspect, the invention provides a method of treatment and/or prevention of clinical conditions, which shows the use of selective agonists of 5-HT1-like receptors; the method comprises the administration to a patient in need of such treatment an effective amount of the salt of formula I, above, or its pharmaceutically acceptable MES. In a separate embodiment of the method according to the invention the salt of formula I or its pharmaceutically acceptable MES is introduced in the form of a solution, preferably in the form of an aqueous solution adapted for intranasal administration.

D is acceptable MES for production of medicines, acceptable solution and preferably an aqueous solution adapted for intranasal administration, for the treatment and/or prevention of clinical conditions, which shows the use of a selective agonist of 5-HT1-like receptors.

For illustration of this invention, the following examples do not limit the scope of this invention.

Receiving 1.

Stage (i): Bromide 1-(4-nitrobenzyl)-4-amino-4H-1,2,4-triazole.

A mixture of 4-amino-1,2,4-triazole (250 g) and 4-nitrobenzylamine (Tanssen, 99%, 617,5 g, and 2.83 mol) in isopropyl alcohol (5,66 l) is brought to a boil while stirring. The mixture becomes transparent, and then almost immediately the desired salt of a triazole crystallizes during boiling. The mixture is stirred at boiling 7.5 hours, and then allow it to cool to room temperature overnight. The next day the mixture is cooled to 0-5oC, allowed to stand for 1 hour, the product filtered, washed with a small amount of isopropyl alcohol, then dried under vacuum at a temperature of 50oC, the result of which are salt of the triazole specified in the title (808 g, 95%) as a solid white color, so pl. 199oC (decomp.).

Stage (ii): 1-(4-Nitrobenzene obtained in the previous phase salt of triazole (beneath the surface) (808 g, 2,69 mol) in water (5,61 l) and concentrated hydrochloric acid (505 ml) at a temperature of 0-5oC. the Light yellow suspension is stirred at a temperature of less than 5oC for 15 minutes and then allow it to heat up to a temperature of 25oC for 1 hour. the pH of the resulting colorless solution was adjusted to 9 by addition of aqueous ammonium hydroxide (380 ml, 18N), keeping the temperature less than 30oC. the Mixture is cooled to 0 to 5oC and stirred for 1 hour. The solids are filtered, washed with water (400 ml) containing aqueous ammonium hydroxide (20 ml, 18N) and dried under vacuum at a temperature of 50oC, resulting in a gain 535 g (97% yield) of nitro compounds specified in the title, so pl. 102-103oC.

Stage (iii): 1-(4-Aminobenzyl)-1,2,4-triazole.

Obtained in the previous phase of nitrosoaniline (803 g, 3.9 mol), ammonium formate (1,16 kg, 18.4 mol) and 10% Pd/C (28 g) in methanol (8 l) was stirred under a nitrogen atmosphere and heated to 30oC. Heating stop and use cooling to control the exothermic reaction by maintaining the temperature at 35 - 45oC for 2 hours. The reaction mixture is cooled to 20oC and remove the catalyst by filtration through Hyflo filter. The filter is washed the organisms in an aqueous solution of ammonium hydroxide (10 ml, 18 N) to obtain a solution with a pH of 9. The aqueous layer was separated and extracted with ethyl acetate (2 x 6 l and 3 l). The United extracts washed with a saturated solution of sodium bicarbonate (1,57 l), dried and evaporated under vacuum, resulting in a gain 679 g (99% yield) of the amine indicated in the title, so pl. 127-128oC.

Stage (iv): N,N-Dimethyl-2-[5-(1,2,4-triazole-1-ylmethyl)-1H - indol-3-yl] ethylamine.

A solution of sodium nitrate (16.7 g, 0.24 mol) in water (22.7 ml) is added beneath the surface in a solution of amine, obtained in the previous phase (40 g, 0.24 mol) in hydrochloric acid (65,3 ml) and water (162 ml), maintaining the temperature of the reaction mass is less than 5oC. the Solution is stirred at a temperature of 0-5oC for 1 hour. The solution is added to a suspension of sodium sulfate (72.4 g, of 0.57 mol) in water, cooled to 5-10oC under nitrogen atmosphere. Solution red color is stirred at a temperature of 5-10oC for 10 minutes, allow it to warm to 20oC for 20 minutes and then heated to 70oC for 45 minutes. The solution is stirred at a temperature of 70oC for 2.5 hours and cooled to 65oC. thereafter, to the solution is added dropwise within 15 minutes of concentrated sulfuric acid (56,8 ml), maintaining the temperature for 2 hours, and then allow it to cool until the 20oC and left overnight. The resulting solution of hydrazine is heated to 25oC, then add to it 4-(N,N-dimethylamino)-1,1-diethoxybutane (44,3 g, 0.28 mol) over 15 minutes, maintaining the temperature below 35oC. the Solution is stirred at a temperature of 30-35oC for 30 minutes. The mixture is heated to 90oC within 30 minutes and maintained at a temperature 90-93oC for 15 minutes. The mixture is cooled to 15oC add the accelerator Hyflo filter, and then ammonium hydroxide (200 ml, 18N) bring the pH to 11-12. The mixture is filtered, and the filtrate Hyflo and extracted with ethyl acetate (5 x 300 ml). The extract is dried with anhydrous sodium sulfate and evaporated under vacuum. The remainder chromatographic on silica (500 g) with a mixture of ethyl acetate:methanol (80:20), changing the composition of the mixture to ethyl acetate:methanol = 50:50. The fractions containing the product, evaporated under vacuum, resulting in a gain of 27.8 g (45% yield) of the compound indicated in the title, in free base form.

Example 1. N,N-Dimethyl-2-[5-(1,2,4-triazole-1-ylmethyl)-1H - indol-3-yl]ethylamine 0.5 sulfate 0.7 hydrate.

To a solution of N, N-dimethyl-2-[5-(1,2,4-triazole-1-ylmethyl)-1H - indol-3-yl] ethylamine (0,63 g of 2.34 mmole) in water (0,73 ml) and isopropyl is cooled to 0oC. the Reaction mixture is filtered and the solid product washed with diethyl ether (100 ml) and then dried at a temperature of 60oC under vacuum, resulting in a gain of 0.5 sulfate salt, specified in the title (0.68 g), so pl. 233-234oC.

Found: C 54,45; H 6,35; N 21,23; S 4,66.

C15H19N50.5 H2SO40,7 H2O.

Calculated: C 54,43; H Of 6.52; N 21,16; S 4,84).

Example 2. Buffer tablet for sublingual use, containing 50 g (in terms of free base) of the active ingredient.

N, N-Dimethyl-2-[5-(1,2,4-triazole-1-ylmethyl)-1H-indol-3-yl]- ethylamine 0.5 sulfate 0.7 hydrate, mg - 0,056

Avicel PH 200, mg - 91,194

Starch 1500, mg - 22,0

Sodium bicarbonate, mg - 67,5

Anhydrous sodium carbonate, mg - 20,0

Dye (Bluel FDLC No. 2 Aluminium Lake), mg - 0,55

Saccharin sodium, mg - 11,0

Flavoring agent (peppermint Peppermit NAEFCO/P05.51), mg - 6,6

Magnesium stearate, mg - 1,1

Total weight, mg - 220,0

All ingredients, except magnesium stearate are mixed in a suitable mixer. The resulting mixture was lubricated with magnesium stearate and pressed to press for tablets.

Example 3.

Buffer tablet for sublingual use, containing 20 g (in terms of the min 0.5 sulfate 0.7 hydrate, mg - 22,34

Avicel PH 200, mg - 68,91

Starch 1500, mg - 22,0

Sodium bicarbonate, mg - 67,5

Anhydrous sodium carbonate, mg - 20,0

Dye (Bluel FDLC No.2 Aluminium Lake), mg - 0,55

Saccharin sodium, mg - 11,0

Flavoring agent (peppermint NAEFCO/P05.51), mg - 6,6

Magnesium stearate, mg - 1,1

Total weight, mg - 220,0

All ingredients, except magnesium stearate are mixed in an amalgamator. The resulting mixture was lubricated with magnesium stearate and pressed to press for tablets.

Examples 4 and 5. Sterile composition intranasal (see tab. 1).

The compound of formula II is dissolved in sulphuric acid, previously diluted with water. The solution is brought to the desired volume.

The solution can be put up for intranasal, for example, an oil spill in the bubbles, sealing and sterilization keeping the bubbles in an autoclave at a temperature of 121oC for at least 15 minutes, or sterilized by filtration and aseptically transferred into a sterile container.

Examples 6 and 7. Composition for intranasal containing preservative (see tab. 2).

The compound of formula II is dissolved in sulphuric acid, previously diluted with water. Phenethyl alcohol ulichnym given composition, containing 1, 5, 10, 50, 80, 100 and 150 mg/ml of the compounds of formula II.

The composition may be injected in a volume of 100 µl, containing a single dose of 0.1, 1, 5, 10, or 17 mg of the compounds of formula II, in one or both nostrils of the patient suffering from mild or severe migraine.

Examples 8 and 9. Sterile intranasal (see tab. 3).

The compound of formula I is dissolved in water and the volume was adjusted to the required size.

The solution can be put up for intranasal, for example, by filling the bubbles with sealing and sterilization bubbles curing in an autoclave with a temperature of 121oC for at least 15 minutes or sterilized by filtration and aseptically transferred into a sterile container.

Examples 10 and 11. An alternative composition for intranasal (see tab. 4).

The compound of formula I is dissolved in water, add the chloride benzothia and bring the solution volume to the required size.

Examples 12 to 15. A sterile composition for intranasal (see tab. 5).

The compound of formula II is dissolved in sulphuric acid, previously diluted with water. The volume of solution was adjusted to the desired value.

Songs RA the 1oC for at least 15 minutes. Solutions can be sterilized by filtration and aseptically transferred into a sterile container.

The composition may be injected in a volume of 100 µl, containing a single dose of 0.5, 5, 10, or 16 mg of the compounds of formula II, in one nostril of the patient suffering from mild or severe migraine.

Examples 16 and 17. A sterile composition for intranasal (see tab. 6).

The compound of formula II is dissolved in sulphuric acid, previously diluted with water, bring the solution to about 90% of the required amount, dissolve in it saccharine and final volume was adjusted to the required size.

The composition is poured into the vials, 100 ál, the bubbles are sealed and sterilized in an autoclave with a temperature of 121oC for at least 15 minutes. Solutions can be sterilized by filtration and aseptically transferred into a sterile container.

The composition may be injected in a volume of 100 µl, containing a single dose of 16 mg of the compounds of formula II, in one nostril of the patient suffering from mild or severe migraine.

1. N, N-Dimethyl-2-[5-(1,2,4-triazole-1-ylmethyl)-1H-indol-3-yl] ethylamine sulphate salt (2 : 1) structural formula I

< / BR>1-like receptors, characterized in that it includes salt or its pharmaceutically acceptable hydrates on PP.1 and 2 in combination with one or more pharmaceutically acceptable carriers.

4. The composition according to p. 3 in solid form, adapted for sublingual administration, containing salt or its pharmaceutically acceptable hydrate on PP.1 and 2, one or more pharmaceutically acceptable superyoshi agents capable of imparting environment intraoral cavity after the introduction of a pH value of at least 7,5, and one or more pharmaceutically acceptable excipients.

5. The composition according to p. 3, adapted for intranasal containing salt or its pharmaceutically acceptable hydrate on PP.1 and 2 in combination with one or more pharmaceutically acceptable carriers.

6. Composition under item 5, which is made in the form of an aqueous solution.

7. The composition according to p. 6, which is made in the form of a solution in sterile pyrogen-free water.

8. The composition according to p. 6 or 7 containing salt at a concentration of 1 to 200 mg/ml

9. The composition according to p. 8 containing a salt at a concentration of 10 to 190 mg/ml

10. The composition according to p. 9 containing a salt at a concentration of 189 ingredient in an amount of 0.1 - 100,0 mg

12. The composition according to p. 11, in which the volume of a single dose is 50 - 200 ál.

13. The method of obtaining salt or its hydrate according to PP.1 and 2, characterized in that N,N-dimethyl-2-[5-(1,2,4-triazole-1-yl-methyl)-1H-indol-3-yl]ethylamine of formula II

< / BR>
subjected to interaction with about 0.5 molar equivalent of sulfuric acid in a suitable solvent.

14. The method of obtaining salt or its hydrate according to PP.1 and 2, characterized in that the salt of the compounds of formula II

< / BR>
other than sulphate salt (2 : 1) of formula I under item 1, is treated with a suitable sulfate salt.

15. The method according to any of paragraphs.3 to 12, characterized in that it comprises a mixture of salts or its pharmaceutically acceptable hydrate on PP.1 and 2 with a pharmaceutically acceptable carrier.

16. Salt or its hydrate according to PP.1 and 2 for use in therapy.

17. Medicinal product for the treatment and/or prevention of clinical conditions for which illustrates the application of a selective agonist of 5-HT1-like receptors containing salt or its pharmaceutically acceptable hydrate on PP.1 and 2.

Priority points:

05.06.92 - PP.3, 4, 16, and 17.

07.04.93 - PP.1, 2, 5 - 14.

 

Same patents:

The invention relates to new derivatives of 3(2H)-pyridazinone General formula I, where R1is hydrogen, phenyl, methyl, substituted CH3O or CH3SO2NH, C2-C4-alkyl, substituted R8R9N; C3-C5alkenyl, substituted phenyl, which is optionally substituted by halogen, one of A and B is hydrogen and the other a group of formula II, where R2and R3is independently hydrogen, C1-C4-alkyl or together with the adjacent group-N(CH2)nN - form pieperazinove or homopiperazine ring; R4is hydrogen or C1-C4-alkyl, R5, R6and R7is hydrogen, C1-C4-alkoxy, CH3SO2NH, X is a simple valence bond, an oxygen atom or the group-CH= CH-, m = 0-1, n = 2-3; R8and R9- independently C1-C4-alkyl, or together with the nitrogen atom to which they are attached, form morpholino - or 4-R10- piperazinone, where R10- C1-C4-alkyl, substituted phenoxypropane, or C3-C5alkenyl, substituted phenyl group, or an acid additive salts, which possess antiarrhythmic activity, pharmaceutical compositions containing an effective amount of the compounds in the mixture

The invention relates to a method for indole derivatives of General formula I, where F denotes a straight or branched C1-C4-alkylenes chain; R is a group of formula-CH2-CHR1-NR2R3where R1hydrogen; R2and R3the same and mean C1-C6-alkyl

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The invention relates to new derivatives of carbazole formula

< / BR>
where

A represents a group of the formula

-CH2-R (V)

where

R1denotes hydroxyl or 2-methyl-1H-imidazol-1-yl;

B represents a group of the formula

< / BR>
where

R1denotes hydrogen, methyl or ethyl group,

or

A and B form a group of the formula

< / BR>
where

R2denotes a methyl or ethyl group,

A and B form a group of the formula

< / BR>
The invention also provides a method of obtaining the above-mentioned compounds

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The invention relates to new biologically active compounds, namely isopropylamino 2-(4-chloroanilino)cinchoninic acid of the formula:

< / BR>
possessing anti-inflammatory and analgesic activity, suggesting the possibility of its use in medicine as a drug for the treatment of inflammatory processes

The invention relates to medicine and veterinary

The invention relates to a derived benzazepine with condensed nitrogen-containing aromatic 5-membered cycle, represented by formula I

The invention relates to pharmacy - suppositories with vasodilator and antispasmodic effect

The invention relates to new derivatives of Anthranilic acid of General formula (1) or their pharmacologically acceptable salts, where R1, R2, R3and R4- same or different and mean a hydrogen atom, halogen atom, optionally halogenated lower alkoxygroup, nitro, cyano, pyrazolidine group, a group of the formula (II), where R9and R10are the same or different and mean a hydrogen atom, a lower alkyl group and p is an integer from 0 to 6, a group of the formula (III), where R13represents a hydrogen atom, a lower alkyl group, q is an integer from 0 to 2; and R2may be 1,2,4-triazoline group; R5and R6are the same or different and represent a hydrogen atom, halogen atom, cyano, lower alkoxygroup, or R5and R6together with the carbon atoms to which they are attached, form oxolane ring, 1,3-dioxolane or 1,4-dioxane ring; W represents a group - N = or-CH=; R7and R8are the same or different and represent a hydrogen atom, a lower alkyl group, or R1and R7together with the carbon atoms and nitrogen, respectively, to which they are attached, form the second alkyl group or a group of the formula-X-(CH2)m-Z, where X represents-CO-, -CH2- or-S(O)2-; Z represents hydrogen, halogen, phenyl group which may be substituted by lower alkyl, lower alkoxygroup, carboxypropyl or lower alkoxycarbonyl group, pyridyloxy group, a group of the formula NR11R12where R11and R12together with the nitrogen atom to which they are attached, form piperidino or pyrolidine ring which may be substituted by a lower alkyl group, actigraphy, carboxypropyl, lower alkoxycarbonyl group, cycloalkyl group containing 3-8 carbon atoms which may be substituted by actigraphy, cyano, lower alkylcarboxylic, carboxypropyl or lower alkoxycarbonyl group, piperidino group, m is an integer from 0 to 6, Y is an oxygen atom; n is an integer from 0 to 6

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< / BR>
in which R1is phenyl, substituted cyclo(lower)alkyl, hydroxy(lower)alkyl, cyano, lower alkylenedioxy, carboxy, (lower alkoxy)carbonyl group, a lower alkanoyl, lower alkanoyloxy, lower alkoxy, phenoxy or carbamoyl, optionally substituted lower alkyl;

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or their pharmaceutically acceptable salts

The invention relates to a derived indole of General formula (I)

< / BR>
or its physiologically acceptable salt, or metabolically labile ether complex, where R is chlorine in positions 4 and 6 of the indole ring, R2represents phenyl, possibly substituted by one or two groups selected from fluorine, trifloromethyl, lower alkyl, alkoxy, hydroxy and nitro group, X represents NH
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