Guanidinium heterocyclic compounds useful as agonists alpha-2 adrenergic receptors

 

(57) Abstract:

The invention relates to new guanidinium heterocyclic compounds of the formula (I), where R1denotes H, alkyl or is absent when R1missing link (a) is a double bond, D represents CR2, R2selected from H, alkyl, halogen, or, when is a CR3D can be N, denotes NR9, CR3=CR8, CR3, S, where R9denotes H, alkyl, alkenyl or quinil and where R3and R8selected from H, alkyl, alkenyl, quinil or cyano, R4, R5, R6each independently selected from H, alkyl, alkenyl, quinil, cyano, halogen or NH-C(= NR10)OTHER11(guanidine), R10and R11selected from H, methyl and ethyl, and where only one of R1, R5and R6is guanidines, R7selected from H, alkyl, alkenyl, quinil and halogen. These compounds possess agonistic activity against alpha-2 adrenergic receptors and therefore, together with a pharmaceutically acceptable carrier can form a pharmaceutical composition. The invention also covers a method of activation of alpha-2 adrenergic receptors for the prevention and treatment of diseases . the 4 C.p. f-crystals, 4 PL.

The technical field to which the invention relates

The invention relates to certain substituted guanidinium heterocyclic compounds. Discovered that these compounds are agonists alpha-2 adrenergic receptors and can be used in the treatment of diseases modulated by alpha-2 adrenergic receptors.

Prior art

In the literature discussed therapeutic indications agonists alpha-2 adrenergic receptors: Ruffolo, R. R., A. J. Nicols, J. M. Stadel & J. P. Heible, "Pharmacologic and Therapeutic Applications of Alpha-2 Adrenoreceptor Subtypes", Annual Review of Pharmacology & Toxicology, Vol.32 (1993), pp. 243-279.

Information on alpha adrenergic receptors, agonists and antagonists mainly and relatively compounds similar in structure to the described in the present invention, are described in the following references: Timmermans, P. B. M. W. M., A. T. Chiu & M. J. M. C. Thoolen, "12.1-Adrenergic Receptors", Comprehensive Medicinal Chemistry, Vol.3, Membranes &Receptors, P. G. Sammes & J. B. Taylor, eds., Pergamon Press (1990), pp.133-185; Timmermans, P. B. M. W. M. & P. A. van Zwierten "-Adrenoceptor Agonists and Antagonists", Drugs of the Future, Vol.9, No. 1 (January, 1984), pp.41-55; Megens, A. A. H. P., J. E. Leysen, F. H. L. Awouters & C. J. E. Niemegeers, "Further Validation of in vivo and in vitro Pharmacological Procedures for Assessing the1- and2-Selectivity values of Test Compounds: (2) -Adrenoceonships between-Adrenergic Activity and Binding Affinity of-Adrenoceptor Adonists and Antagonists", Journal of Medical Chemistry, Vol.27 (1984), pp.495-503; van the meel J. C. A., A. de Jonge, P. B. M. W. M. Timmermans & P. A. van Zwieten, "selectivity values of Some Alpha Adrenoceptor Agonists for Peripheral Alpha-1 and Alpha-2 Adrenoceptors in the Normotensive Rat", The Journal of Pharmacology and Experimental Therapeutics. Vol.219, No. 3 (1981), pp.760-767; Chapleo, S. C., J. C. Doxey, P. L. Myers, m. Myers, C. F. C. Smith & M. R. Stillings, "Effect of 1,4-Dioxanyl Substitution on the Adrenerdic Activity of Some Standard-Adrenoreceptor Agents", European Journal of Medicinal Chemistry, Vol.24 (1989), pp.619-622; Chapleo, S. C., R. C. M. Butler, D. C. England, P. L. Myers, A. G. Roach, C. F. C. Smith, M. R. Stillings & I. F. Tulloch, "Heteroaromatic Analogues of the2-Adrenoreceptor Partial Agonist Clonidine", Journal of Medicinal Chemistry, Vol.32 (1989), pp.1627-1630; Clare K. A., M. C. Scrutton & N. T. Thompson, "Effects of2-Adrenoceptor Agonists and of Related Compounds on Aggregation of, and on Adenylate Cyclase Activity in. Human Platelets", British Journal of Pharmacology, Vol.82 (1984), pp. 467-476; U.S. patent N 3890319 issued by Danielewicz, Snarey & Thomas June 17, 1975; and U.S. patent 5091528 issued Gluchowski 25 February 1992. However, many compounds similar in structure to the described in the present invention do not possess the desired activity and specificity in the treatment of diseases modulated by alpha-2 adrenergic receptors.

For example, found that many compounds which, as shown, is effective as a decongestant means for nasopharynx, often have undesirable side effects, such as induction of hypertension and insomnia, when used in d is Genie swelling of the nasopharynx, without causing unwanted side effects.

The purpose of the invention

The aim of the invention are compounds and compositions suitable for the treatment of diseases modulated by alpha-2 adrenergic receptors.

The aim of the invention are new compounds with significant activity in the prevention or treatment of edema of the nasopharynx, middle ear inflammation and sinusitis without unwanted side effects.

The aim of the invention are new compounds for the treatment of cough, chronic obstructive pulmonary disease (COPD) and/or asthma.

The aim of the invention are new compounds for treating diseases and disorders associated with the activity of the sympathetic nervous system, including benign prostatic hypertrophy, cardiovascular disorders, including myocardial ischemia, circulatory disorders of the heart, angina, cardiac arrhythmia, heart failure, and hypertension.

The aim of the invention are new compounds for the treatment of eye conditions, such as increased eye pressure, glaucoma, hyperemia, conjunctivitis and uveitis.

The aim of the invention are new compounds which and, hyperchlorhydria (increased acidity) and peptic ulcer (ulcer).

The aim of the invention are new compounds for the treatment of migraine.

The aim of the invention are new compounds for the treatment of pain, substance abuse and/or withdrawal syndrome.

An additional aim of the invention are such compounds that are highly active in oral, parenteral, intranasal, and/or local introduction.

The invention

The invention relates to compounds having the following formula:

< / BR>
where R1represents hydrogen or alkyl, or absent; when R1missing link (a) is a double bond;

D represents CR2and R2selected from hydrogen, unsubstituted C1-C3alkenyl, amino, hydroxy, mercapto, C1-C3alkylthio or alkoxy, C1-C3alkylamino or C1-C3dialkylamino and halogen, or, when is a CR3D may denote N;

In represents NR9, CR3=CR8, CR3=N, CR3, S, O, SO or SO2where R9selected from hydrogen, unsubstituted C1-C3alkenyl, alkenyl or quinil, the SUB>1-C3alkenyl, alkenyl or quinil, cycloalkenyl, cycloalkenyl, unsubstituted C1-C3alkylthio or alkoxy, hydroxy, thio, nitro, cyano, amino, C1-C3alkylamino or C1-C3dialkylamino and halogen;

R4, R5and R6each independently selected from hydrogen, unsubstituted C1-C3alkenyl, alkenyl or quinil, cycloalkenyl, cycloalkenyl, unsubstituted C1-C3alkylthio or alkoxy, hydroxy, thio, nitro, cyano, amino, C1-C3alkylamino or C1-C3dialkylamino, halogen and NH-C(= NR10)OTHER11(guanidine), where R10and R11independently selected from hydrogen, methyl and ethyl, and one and only one of R4, R5and R6is guanidines;

R7selected from hydrogen, unsubstituted C1-C3alkenyl, alkenyl or quinil, cycloalkenyl, cycloalkenyl, unsubstituted C1-C3alkylthio or alkoxy, hydroxy, thio, nitro, cyano, amino, C1-C3alkylamino or C1-C3dialkylamino and halogen;

and enantiomers, optical isomers, stereoisomers, diastereomers, tautomers, additive salts, biohydrology Amida and esters and is profilaktiki or treatment of diseases, associated with involvement of alpha-2 adrenergic receptors.

Detailed description of the invention

As used herein, the term "alkenyl" denotes a saturated hydrocarbon Deputy with a straight or branched chain, unsubstituted or substituted.

As used herein, the term "alkenyl" denotes a hydrocarbon Deputy with one double bond, straight or branched chain, unsubstituted or substituted.

As used herein, the term "alkylthio" means the Deputy, having the structure Q-S-, where Q is alkenyl or alkenyl.

As used herein, the term "alkoxy" refers to the Deputy, having the structure Q-O-, where Q is alkenyl or alkenyl.

As used herein, the term "alkylamino" means the Deputy, having the structure Q-NH-, where Q is alkenyl or alkenyl.

As used herein, the term "dialkylamino" means the Deputy, having the structure Q1-N(Q2)-, where each Q independently represents alkenyl or alkinyl.

"Guanidine" is defined as a moiety having the structure

< / BR>
When used in the examples of this radical, wherever he appeared in the schema, S="ptx2">

"Pharmaceutically acceptable salt" is a cationic salt formed with any acidic (e.g., carboxyl) group, or an anionic salt formed with any basic (e.g., amino) group. Many such salts are known to science, as described in World Patent Publication 87/05297, Johnston et al. publication dated September 11, 1987, the Preferred cationic salts include alkali metal salts (such as sodium and potassium), salts of alkaline-earth metals (such as magnesium and calcium), and salts of organic bases. Preferred anionic salts include the halides, sulfonates, carboxylates, phosphates, and the like. Such salts are additive salts, which may be optically active center in those cases when he was absent. For example, of the compounds according to the invention can be obtained chiral salt of tartaric acid, and in the determination of salts include chiral salt.

Compounds according to the invention are sufficiently basic to the education of additive salts with acids. Connections can be used both as free bases and in the form of additive salts with acids, and both forms are included in the scope of the present invention. Additive salts with acids in nekotachi application main form of active connections. The acid used to obtain the additive salts with acids, preferably include those which when combined with the free base give acceptable for medicine salt. These salts contain anions that when using these salts in medical doses are relatively safe for the animal organism such as a mammal, so that the beneficial properties inherent in the free base are not overlapping any adverse effects that could be attributed to acid anions.

Examples of the additive salts with acids include, but are not limited to, hydrochloride, giropay, hydroiodide, sulfate, bisulfate, acetate, triptorelin, nitrate, maleate, citrate, fumarate, formate, stearate, succinate, malate, malonate, adipate, glutarate, lactate, propionate, butyrate, tartrate, methanesulfonate, trifluromethanesulfonate, p-toluensulfonate, dodecylsulfonate, cyclohexanesulfamic and the like. However, within the scope of the invention other suitable, suitable from a medical point of view salts are those salts which are obtained from the use of other inorganic and organic acids. Additive salts of the basic compounds with acids get several methods. Example: the IC on evaporation of the solution. In another embodiment, they can be obtained by reaction of the free base with an acid in an organic solvent, resulting directly separated salt. In that case, when the selection of salt is difficult, it can be precipitated second organic solvent or can be obtained by concentrating the solution.

Although acceptable in medicine, the salts of the basic compounds are preferred, the scope of the present invention includes all additive salts with acids. All additive salts with acids can be used as sources of the free base form even if the particular salt itself is required only as an intermediate product. For example, when the salt is obtained only for purposes of purification or identification, or when it is used as an intermediate product in obtaining acceptable in medicine salts by ion-exchange procedures, it is quite obvious that these salts are part of the present invention.

"Biogerontology amide" refers to an amide compounds according to the invention, which can be easily transformed in vivo in the body of a mammal, forming an active compound of the invention.

"Gidrolizuemye in Biol who recapitalise active compound according to the invention.

Shown here "optical isomer", "stereoisomer, enantiomer, diastereoisomer" has the ordinary meaning known to specialists (compare Hawleys Condensed Chemical Dictionary, 11thEd.). Of course, the additive salt may be optically active center in the case when it was not. For example, chiral salt of tartaric acid can be obtained from the compounds of the invention, and in the designation of the latter included such chiral salt. For professionals it is obvious that only one indication of the racemic mixture indicates any of enantiomers that are included in its composition. Thus, using the same instructions you specify more than one connection.

Used here, the term "animal" includes mammals, including man."

Expert it is clear that for some compounds according to the invention include tautomeric forms. For example, when R2is hydroxyl, and the relationship (a) represents a double bond, it is clear that this includes ketoform this molecule, where R2is exography and communication (a) represents a simple bond, though it is not discussed specifically. Thus, in this description, the indication of one tautomeric form specifies each separately and all VMS shall otomari In this molecule, although it is not specifically described (see diagram 1 at the end of the description).

Illustration a particular protected forms and other derivatives of formula (I) are not intended to be limiting. Other possible protective groups, salt forms, etc. are available to professionals in this field.

As indicated above and as applied here, the group of substituents can themselves be substituted. Such substitution may be one or more substituents. Such substituents include those listed in C. Hansch and A. Leo, Substituent Constants for Correlation Analysis in Chemistry and Biology (1979). Preferred substituents include (for example) alkyl, alkenyl, alkoxy, hydroxy, oxo, nitro, amino, aminoalkyl (for example, aminomethyl and etc.), cyano, halogen, carboxy, alkoxyalkyl (for example, carboxymethoxy and so on ), thiol, aryl, cycloalkyl, heteroaryl, heteroseksualci (for example, piperidinyl, morpholinyl, pyrrolidinyl and so on), amino, thioxo, hydroxyalkyl, aryloxy, arylalkyl and combinations thereof. As shown in the following example, in terms of item position guanidinium radical is

< / BR>
It is clear that, when is a CR3=CR8and the like, this numbering is not in full compliance with the range is closer to the IUPAC nomenclature.

Connection

The invention includes compounds having the following structure:

< / BR>
as described in the section "summary of the invention".

In the above structure, when guanidine is in the 6th position, R7preferably selected from hydrogen; unsubstituted alkenyl or alkenyl having from 1 to about 3 carbon atoms; unsubstituted, alkylthio or alkoxy having from 1 to about 3 carbon atoms; hydroxy; thiol; cyano or halogen. R4preferably represents hydrogen, cyano, halogen or methyl. R7also preferably represents alkenyl, more preferably methyl or ethyl, most preferably methyl. R7that is alkylthio or alkoxy, preferably saturated, also preferably presents 1or2most preferably methylthio or methoxy. R7that is a halogen, preferably represents chlorine or bromine.

In the above structure, when guanidine is in the 5th position, R4preferably selected from hydrogen; unsubstituted alkenyl or alkenyl having from 1 to about 3 carbon atoms; unsubstituted, alkylthio or alkoxylated alkenyl or halogen. R4and R7most preferably represent methyl.

In the above structure, when guanidine is in the 4th position, R7preferably selected from hydrogen; unsubstituted alkenyl or alkenyl having from 1 to about 3 carbon atoms; hydroxy; thiol; cyano and halogen. R7that is elkayam, preferably represents methyl or ethyl, more preferably methyl. R7that is a halogen, preferably represents chlorine or bromine. R6preferably represents hydrogen, alkenyl, cyano and halogen. R6that is alkanol, is preferably stands or ethyl, most preferably the stands. R5preferably is hydrogen, elkayam and halogen. 5that is elkayam, preferably represents methyl or ethyl, most preferably methyl.

Preferred compounds according to the invention have the following structure:

< / BR>
where R1no, (a) represents a double bond, and D,, R4, R5, R7and R10such as indicated in the table.1.

Methods of obtaining according to the invention

Solo connection but the person skilled in the art it is clear that in a similar way and get the 4 - and 5-guanidinium connection. R1-R7radicals are omitted for clarity, if they do not receive in accordance with this scheme. The person skilled in the art it is clear that missed radicals can be introduced by known science methods. The person skilled in the art it is clear that the described methods can be carried out with the participation of the protective groups and the like, if appropriate.

Guanidinium group conveniently be obtained from nitro and amino compounds in accordance with the sequence of the synthesis presented in figure 2 (see the end of the description).

These compounds are preferably derived from nitro and amino compounds. (Nitro - and amino compounds get by known methods.) Connections can be processed to obtain the appropriately substituted aminoheterocycles. This aminoheterocycles processed by known methods to obtain guanidinium derived. For example, aminosilane can interact with cyanamide (H2NCN) in acid, giving guanidinium connection. Alternative aminosidine can communicate with the predecessor of the uti or the like.

Above the original nitro and amino compounds are obtained by one or several stages, including alkylation, halogenoalkane (usually bromination) and substitution reactions of Halogens. These types of reactions are summarized in scheme 3 (see end of description).

The chlorination is preferably carried out using Cl2and iodination using ICl using the same reactions (see scheme 4, is provided at the end of the description).

The person skilled in the art it is clear that illustrated above reactions are well-known reactions. Moreover, the competence of a specialist to vary these reactions to produce compounds included in the formula of the present invention.

In the above schemes, where R is an alkoxy or alkylthio corresponding hydroxyl or thiol compounds obtained from the final compounds using the standard method of dialkylamide (Bhatt et al., "Cleavage of Esters", Synthesis, 1983, pp. 249-281).

Source products used to produce compounds according to the invention are known, they get known methods or are commercially available as the original product.

It is clear that the expert in the field of organic is th is completely contained within the objectives and practical abilities of the person skilled in the art. They include the reduction of carbonyl compounds to the corresponding alcohols, oxidation, acylation, aromatic substitutions, both electrophilic and nucleophilic, esterification, the ester esterification and saponification and the like. These methods are discussed in the usual guidelines, such as March, Advanced Organic Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemistry (2 vol.) and Trost and Fleming, Comprehensive Organic Synthesis (6 vol.). Expert it is clear that some reaction is best done when the other functional group in the molecule shielded or protected, thus avoiding any undesirable side reactions and/or can increase the yield of the reaction. Often the specialist uses a protective group to achieve high-yield, or in order to avoid unwanted reactions. These reactions are described in the literature and well known to the specialist. Examples of many of these methods are presented, for example, in T. Greene, Protecting Groups in Organic Synthesis.

Examples of compounds

The following not limiting the invention to the examples refer to the detailed description of the synthesis guanidinium heterocycles:

Example 1

(4-Methylbenzimidazole-5-yl)guanidine

A. 2,3-Diamino-6-nitrotoluene. To a solution of 30 g of 3-methyl-2,4-dinitroaniline in 750 ml is the end of the addition the mixture is heated under reflux for 30 minutes and then poured on ice (2000 g) and left to stand until the ice melts. The mixture was then extracted with methylene chloride and the organic layer is dried over magnesium sulfate and evaporated on a rotary evaporator. The residue is purified column flash chromatography on silica gel, elwira with methylene chloride to obtain 2,3-diamino-6-nitrotoluene in the form of an orange solid product.

Century 4-Methyl-5-nitrobenzimidazole. A mixture of 11.8 g of 2,3-diamino-6-nitrotoluene, 390 ml of 88% formic acid and 38 ml 12 N. hydrochloric acid is heated under reflux for 1 hour. The resulting mixture was cooled to room temperature and evaporated on a rotary evaporator. The residue is diluted with 200 ml of water, then alkalinized with ammonium hydroxide (28-30%). The suspension is extracted with ethyl acetate (CH ml). The combined extracts are dried over magnesium sulfate and evaporated on a rotary evaporator to obtain 4-methyl-5-nitrobenzimidazole in the form of an orange solid product.

C. 1-tert-Butoxycarbonyl-4-methyl-5-nitrobenzimidazole. A suspension of 11.2 g of 4-methyl-5-nitrobenzimidazole, 21,58 g of di-tert-BUTYLCARBAMATE, to 11.7 ml of triethylamine and 100 mg of 4-dimethylaminopyridine in methanol (800 ml) and ethyl acetate (400 ml) was stirred at room temperature overnight. The mixture is evaporated on a rotary evaporator and the residue purified kolonochnoi and evaporated on a rotary evaporator to obtain a white solid, dirty yellow oil. The solid is dissolved in methylene chloride and add sufficient to cause the formation of sludge, the amount of hexane. The solid is filtered and washed with 50% methylene chloride/hexane. The filtrate is evaporated on a rotary evaporator and the procedure is repeated until the termination precipitation transparent solid product. Combined fractions of the solid product dried in vacuum to obtain 1-tert-butoxycarbonyl-4-methyl-5-nitrobenzimidazole in the form of a white solid product.

D. 5-Amino-1-tert-Butoxycarbonyl-4-methylbenzimidazole. To a solution of 8 g of 1-tert-butoxycarbonyl-4-methyl-5-nitrobenzimidazole in 40 ml of methanol and 400 ml of ethyl acetate is added 500 mg of palladium-on-coal (10%) and 7,27 g of ammonium formate. The mixture was stirred at 50oC for 2 hours, then filtered on celite with washing the solid product with methanol. The filtrate is evaporated on a rotary evaporator and the residue partitioned between water and ethyl acetate. The organic layer was washed with saturated ammonium chloride, dried over magnesium sulfate, filtered and evaporated on a rotary evaporator to obtain pure 5-amino-1-tert-butoxycarbonyl-4-methylbenzimidazole as not quite white solid about benzimidazol. To a solution of 500 mg of 5-amino-1-(tert-butoxycarbonyl)-4-methylbenzimidazole in 20 ml of tetrahydrofuran, add 753 mg ethyl-N,N-bis(benzyloxycarbonyl)pseudodomain and 645 mg of the acetate of mercury and the mixture is stirred at room temperature for 1 hour. The resulting suspension is diluted with ethyl acetate and washed with water followed by washing with saturated saline solution. The aqueous layers are extracted with ethyl acetate; the combined organic layers are dried over magnesium sulfate, filtered and evaporated on a rotary evaporator. The residue is purified column flash chromatography on silica gel, elwira 50% ethyl acetate/hexane followed by recrystallization from hexane/methylene chloride to obtain 927 mg of 1-(tert-butyloxycarbonyl)-5-[N2N3bis(benzyloxycarbonyl) guanidino] -4-methylbenzimidazole in the form of a white solid product.

F. 5-[N2N3bis(benzyloxycarbonyl)guanidino] -4-methylbenzimidazole. To a cold (0oC) the solution 874 mg of 1-(tert-butyloxycarbonyl)-5-[N2N3bis(benzyloxycarbonyl)guanidino]-4-methylbenzimidazole in 20 ml of methylene chloride is added 2 ml triperoxonane acid. The resulting solution was stirred at room temperature for 30 minutes, then upazila/chloroform followed by recrystallization from hexane/methylene chloride to obtain 573 mg of 5-[N2N3bis(benzyloxycarbonyl)guanidino] -4-methylbenzimidazole in the form of a white solid product.

G. (4-Methylbenzimidazole-5-yl)guanidine, dihydrochloride acid salt. To a solution of 740 mg of 5-[N2N3bis(benzyloxycarbonyl)guanidino]-4-methylbenzimidazole in 20 ml of ethanol is added 240 mg of ammonium formate and palladium on coal in catalytic quantity. The resulting suspension is stirred at room temperature for 10 hours. The reaction mixture is filtered and the filtrate evaporated on a rotary evaporator. The residue is dissolved in 25 ml of methanol and treated with a weak stream of gaseous hydrogen chloride for about 5 minutes. The resulting solution was stirred at room temperature for 2 hours and evaporated on a rotary evaporator to obtain a pale yellow solid product. The solid product was then purified by recrystallization from methanol/ethyl acetate to obtain 361 mg (4-methylbenzimidazole-5-yl)guanidine, dihydrochloride salt in the form of a yellow solid product.

Example 2

(4,7-Dimethylbenzimidazole-5-yl)guanidine

A. 4,7-Dimethylbenzimidazole. A mixture of 5.1 g of 2,3-diamino-p-xylene, 200 ml of 88% formic acid and 20 ml 12 N. hydrochloric acid is heated with reverse Kholodilin the E. The residue is diluted with 100 ml of water, then alkalinized with ammonium hydroxide (28-30%). The suspension is extracted with ethyl acetate (CH ml). The combined extracts are dried over magnesium sulfate and evaporated on a rotary evaporator to obtain 4,7-dimethylbenzimidazole in the form of a yellow solid product.

Century 4,7-Dimethyl-5-nitrobenzimidazole. To a cold (ice bath) solution of 1 g of 4,7-dimethylbenzimidazole in 8 ml of concentrated sulfuric acid are added dropwise concentrated nitric acid (0,37 ml) for 50 minutes. The mixture is stirred for 30 minutes in an ice bath, then poured onto a mixture of crushed ice (30 ml) and ammonium hydroxide (30 ml). The resulting mixture was extracted with ethyl acetate. The extract is dried over magnesium sulfate and evaporated on a rotary evaporator to obtain 4,7-dimethyl-5-nitrobenzimidazole in the form of a dark reddish-brown solid product.

C. 5-Amino-4,7-dimethylbenzimidazole. To a solution of 1.17 g of 4,7-dimethyl-5-nitrobenzimidazole in 150 ml of methanol is added 160 mg of palladium-on-coal (10%) and 1.31 g of ammonium formate. The mixture is stirred at room temperature overnight, then filtered on celite with washing the solid product with methanol. The filtrate is evaporated on a rotary esprital, dried over magnesium sulfate, filtered and evaporated on a rotary evaporator to obtain 5-amino-4,7-dimethylbenzimidazole in the form of a foamy reddish solid product.

D. 5-[N2N3bis(benzyloxycarbonyl)guanidino]-4,7-dimethylbenzimidazole. To a solution of 430 mg of 5-amino-4,7-dimethylbenzimidazole in 100 ml of ethyl acetate and 10 ml of methanol was added 1 g of ethyl-N,N-bis(benzyloxycarbonyl)pseudodomain and 855 mg of the acetate of mercury and the mixture is stirred at room temperature for 15 hours. The mixture is evaporated on a rotary evaporator and the residue is purified column flash chromatography on silica gel, elwira 5% methanol/ethyl acetate to obtain 1.01 g of 5-[N2N3bis(benzyloxycarbonyl)guanidino]-4,7-dimethylbenzimidazole in the form of a glassy solid product.

E. (4,7-Dimethylbenzimidazole-5-yl)guanidine, dihydrobromide salt. To a solution of 1 g of 5-[N2N3bis(benzyloxycarbonyl)guanidino]-4,7-dimethylbenzimidazole in 100 ml of 1/1 ethyl acetate/methanol added palladium-on-coal in a catalytic quantity. The resulting suspension is stirred at room temperature in hydrogen atmosphere under atmospheric pressure for 15 hours. The reaction mixture is filtered on celite with flushing t is srabatyvayut of 0.85 ml of 30% Hydrobromic acid/acetic acid for 5 minutes. The resulting solution was evaporated on a rotary evaporator and the residue is purified by recrystallization from ethanol/ether to obtain 490 mg (4,7-dimethylbenzimidazole-5-yl)guanidine, debrominate salt in the form of a white solid product.

Example 3

(2,4-Dimethylbenzimidazole-5-yl)guanidine

A. 2,4-Dimethyl-5-nitrobenzimidazole. The mixture 668 mg of 2,3-diamino-6-nitrotoluene, 20 ml of glacial acetic acid and 2 ml of 12 N. hydrochloric acid is heated under reflux for 3 hours. The resulting mixture was cooled to room temperature and evaporated on a rotary evaporator. The residue is diluted with 20 ml of water and alkalinized with ammonium hydroxide (28-30%). The resulting suspension is extracted with ethyl acetate and the extracts dried over magnesium sulfate, filtered and evaporated on a rotary evaporator to obtain 720 mg of 2,4-dimethyl-5-nitrobenzimidazole in the form of a reddish-brown solid product.

Century 5-Amino-2,4-dimethylbenzimidazole. To a solution of 700 mg of 2,4-dimethyl-5-nitrobenzimidazole in 50 ml of methanol is added palladium-on-coal in a catalytic quantity. The resulting suspension is stirred at room temperature in hydrogen atmosphere under atmospheric pressure for 15 hours. The reaction mixture is filtered on celite with promyelocyte, elwira 5% methanol/ethyl acetate to obtain 565 mg of 5-amino-2,4-dimethylbenzimidazole in the form of a reddish-brown solid product.

C. (2,4-Dimethylbenzimidazole-5-yl)guanidine, dihydrochloride salt. To 565 mg of 5-amino-2,4-dimethylbenzimidazole add 0.75 ml of concentrated hydrochloric acid and 0.38 ml of water. The resulting mixture was stirred at room temperature for 5 minutes to provide a homogeneous mass. To this mixture add 589 mg of cyanamide and the mixture was stirred at 70oC for 3 hours. The reaction mixture was cooled to 0oWith and add 1 ml of water and 0.5 ml of concentrated hydrochloric acid. The mixture was stirred at 0oC for 30 minutes and evaporated on a rotary evaporator. The residue is dissolved in 10 ml of methanol and precipitated with ether, giving 594 mg (2,4-dimethylbenzimidazole-5-yl)guanidine, dihydrochloride salt in the form of a white solid product.

Example 4

(1,4-Dimethylbenzimidazole-5-yl)guanidine

A. 2,4-Dinitro-3-methyl-formanilide. To a solution of 2 g of 2,4-dinitro-3-methylaniline in 10 ml of 99% formic acid, heated to 55oWith that added dropwise 2.5 ml of acetic anhydride for 15 minutes. The mixture is stirred for 1 hour at 55oC, then cooled to room temp the first sodium bicarbonate solution, dried over magnesium sulfate and evaporated on a rotary evaporator. The residue is purified column flash chromatography on silica gel, elwira chloroform, obtaining 2,4-dinitro-3-methyl-formanilide in the form of a white solid product.

C. N, 3-Dimethyl-2,4-dinitroaniline. To a solution of 1.15 g of 2,4-dinitro-3-methyl-formanilide in 40 ml of anhydrous Tetra-hydrofuran add to 1.21 ml complex brandibelle. The mixture is heated under reflux for 2 hours, then cooled in an ice bath, add 30 ml of methanol and stirred for 1 hour at 0oC. the Mixture is acidified to pH 2 with concentrated hydrochloric acid and heated under reflux for 1 hour, diluted with 70 ml of methanol and evaporated on a rotary evaporator. The solid residue is suspended in 150 ml of water and alkalinized to pH 12 with concentrated sodium hydroxide. The mixture is extracted with chloroform and the organic layer is dried over potassium carbonate and evaporated on a rotary evaporator. The residue is purified column flash chromatography on silica gel, elwira 25% ethyl acetate/hexane to obtain N,3-dimethyl-2,4-dinitroaniline in the form of an orange solid product.

D. N, 3-Dimethyl-2,4-dinitrophenyl. To a solution of 450 mg of N,3-dimethy the ml acetic anhydride in two portions with an interval of 1 hour. The mixture is stirred for 5 hours at 55oC, then cooled to room temperature, poured to 50 ml of 1 n sodium hydroxide and alkalinized to pH 12 with concentrated sodium hydroxide. The mixture is extracted with methylene chloride and the organic layer is dried over magnesium sulfate and evaporated on a rotary evaporator. The residue is purified column flash chromatography on silica gel, elwira chloroform to obtain N,3-dimethyl-2,4-dinitrophenolate in the form of a white solid product.

That is, 2,4-Diamino-N, 3-dimethylformamide. To a solution of 440 mg of N,3-dimethyl-2,4-dinitrophenolate in 40 ml of a 3/1 methanol/ethyl acetate added 95 mg of palladium-on-coal (10%) and 930 mg of ammonium formate and the mixture is stirred for 2 hours at room temperature. The mixture is filtered on celite with washing the solid product with methanol and the filtrate evaporated on a rotary evaporator. The residue is distributed between methylene chloride and water. The aqueous layer was exteriour 4 times with methylene chloride. The combined organic layers are dried over magnesium sulfate and evaporated on a rotary evaporator to obtain 2,4-diamino-N,3-dimethylformamide in the form of a brown solid product.

F. 5-Amino-1,4-dimethylbenzimidazole. A suspension of 240 mg of 2,4-diamino-N,3-dimethyl is water (50 ml), alkalinized 1 N. sodium hydroxide and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and evaporated on a rotary evaporator to obtain 5-amino-1,4-dimethylbenzimidazole.

G. 5-[N2N3bis(benzyloxycarbonyl)guanidino]-1,4-dimethylbenzimidazole. To a solution of 250 mg of 5-amino-1,4-dimethylbenzimidazole in 75 ml ethyl acetate and 10 ml of methanol add 789 mg ethyl-N,N-bis(benzyloxycarbonyl)pseudodomain and 665 mg of the acetate of mercury and the mixture is stirred at room temperature for 15 hours. The mixture is filtered on celite and evaporated on a rotary evaporator. The residue is purified column flash chromatography on silica gel, elwira 5% methanol/ethyl acetate to obtain 590 mg of 5-[N2N3bis (benzyloxycarbonyl)guanidino] -1,4-dimethylbenzimidazole in the form of a white solid product.

N. (1,4-Dimethylbenzimidazole-5-yl)guanidine, dihydrobromide salt. To a solution of 530 mg of 5-[N2N3bis(benzyloxycarbonyl)guanidino]-1,4-dimethylbenzimidazole in 60 ml of 1/1 ethyl acetate/methanol added palladium-on-coal in a catalytic quantity. The resulting suspension is stirred at room temperature in hydrogen atmosphere under atmospheric pressure for 15 hours. The reaction is barely. The residue is dissolved in 10 ml of methanol and treated with 0.2 ml of 30% Hydrobromic acid/acetic acid for 5 minutes. The resulting solution was evaporated on a rotary evaporator and the residue is purified by recrystallization from ethanol/ether to obtain 30 mg (1,4-dimethylbenzimidazole-5-yl)guanidine, dihydrobromide salt in the form of a white solid product.

Example 5

(4-Bromobenzimidazole-5-yl)guanidine

A. 5-Amino-4-bromobenzimidazole. To a solution of 1.08 g of 5-aminobenzimidazole in 20 ml of glacial acetic acid add 2,68 g of sodium acetate. To this solution is added dropwise 0.4 ml of bromine. The obtained brown residue was stirred at room temperature for 2 hours. The reaction mixture is evaporated on a rotary evaporator and the residue diluted with water and ethyl acetate. The mixture is alkalinized 1 N. sodium hydroxide and decanted. The organic layer is washed with water, then with saturated salt solution. The aqueous layers are extracted with ethyl acetate; the combined organic layers are dried over magnesium sulfate, filtered and evaporated on a rotary evaporator. The residue is purified column flash chromatography on silica gel, elwira from 12.5 to 16.5% methanol/methylene chloride followed by recrystallization from hexane/this is

Century 4-Bromobenzimidazole-5-yl)guanidine, dihydrochloride salt. To 637 mg of 5-amino-4-bromobenzimidazole add 0.5 ml

of concentrated hydrochloric acid and 0.25 ml of water. The resulting mixture was stirred at room temperature for 5 minutes to provide a homogeneous mass. To this mixture add 531 mg of cyanamide and the mixture was stirred at 80oC for 1 hour. The reaction mixture was cooled to 0oWith and add 0.5 ml water and 1 ml of concentrated hydrochloric acid. The mixture was stirred at 0oC for 30 minutes and evaporated on a rotary evaporator. The residue is dissolved in hot methanol and precipitated with ethyl acetate, giving 766 mg (4-bromobenzimidazole-5-yl)guanidine, dihydrochloride salt in the form of not quite white solid product.

Example 6

N1N-methyl-N2-(4-methylbenzimidazole-5-yl)guanidine

A. 1-(tert-Butyloxycarbonyl)-5- [N2N3bis(benzyloxycarbonyl)-N2-methylguanine] -4-methylbenzimidazole. To a solution of 600 mg of 5-amino-1-(tert-butoxycarbonyl)-4-methylbenzimidazole in 20 ml of tetrahydrofuran, add 938 mg ethyl-N,N - bis(benzyloxycarbonyl)-N-methylpseudoephedrine and 773 mg of the acetate of mercury and the mixture is stirred at room temperature for 1 hour. Suspensie extracted with ethyl acetate; the combined organic layers are dried over magnesium sulfate, filtered and evaporated on a rotary evaporator. The residue is purified column flash chromatography on silica gel, elwira 50% ethyl acetate/hexane followed by recrystallization from hexane/methylene chloride to obtain 927 mg of 1-(tert-butyloxycarbonyl)-5-[N2N3bis(benzyloxycarbonyl)-N2-methylguanine] -4-methylbenzimidazole in the form of a white solid product.

Century N1N-methyl-N2-(4-methylbenzimidazole-5-yl)guanidine, dihydrochloride salt. To a solution of 339 mg of 5-[N2N3bis(benzyloxycarbonyl)-N2-methylguanine] -4-methylbenzimidazole in 10 ml of ethanol is added 160 mg of ammonium formate and palladium on coal in catalytic quantity. The resulting suspension is heated under reflux for 5 hours. The reaction mixture is filtered on celite and the filtrate evaporated on a rotary evaporator. The residue is dissolved in 2 ml of methanol and add 0.5 ml of concentrated hydrochloric acid. After 5 minutes the mixture was evaporated on a rotary evaporator and dried in vacuum. The residue is purified by recrystallization using methanol/ethyl acetate, to obtain 211 mg, N1N-methyl-N2-(4-methylbenzimidazole-5-yl)guanidine, digital-7-nitroquinoline. To a suspension of 2 g of 2-methyl-3-nitroaniline and of 1.02 g of the hydrate of oxide of arsenic (V) add 2,88 ml of glycerin and then 1,09 ml of concentrated sulfuric acid. Received the black suspension is stirred at a temperature of approximately 150oC for 4 hours. Black oil is cooled to room temperature, diluted with water and poured into a mixture of 25% aqueous ammonium hydroxide and ethyl acetate. The organic layer is washed with water, followed by washing with saturated saline solution. The aqueous layers are extracted with ethyl acetate; the combined organic layers are dried over magnesium sulfate, filtered and evaporated on a rotary evaporator. The residue is purified column flash chromatography on silica gel, elwira 50% ethyl acetate/hexane followed by recrystallization from hexane/methylene chloride to obtain 1.45 g of 8-methyl-7-nitroquinoline in the form of a light brown solid product.

Century 7-Amino-8-methylinosine. To a solution of 1.45 g of 8-methyl-7-nitroquinoline in 20 ml of ethanol is added 1.45 g of ammonium formate and palladium on coal in catalytic quantity. The resulting suspension is stirred at room temperature for 3 hours. The reaction mixture is filtered on celite and the filtrate evaporated on a rotary evaporator. The residue is purified column is Aksana/methylene chloride to obtain 1.10 g of 7-amino-8-methylinosine in the form of a light yellow solid product.

C. 7-[N2N3bis(benzyloxycarbonyl)guanidino]-8 - methylinosine. To the light yellow solution of 500 mg of 7-amino-8-methylinosine in 20 ml of tetrahydrofuran added 1.18 g of ethyl-N,N-bis(benzyloxycarbonyl)pseudodomain and 1.01 g of the acetate of mercury and the mixture is stirred at room temperature for 1 hour. The suspension is diluted with ethyl acetate and the organic layer washed with water followed by washing with saturated saline solution. The aqueous layers are extracted with ethyl acetate; the combined organic layers are dried over magnesium sulfate, filtered and evaporated on a rotary evaporator. The residue is purified column flash chromatography on silica gel, elwira 50% ethyl acetate/hexane and recrystallization from hexane/methylene chloride to obtain 1,257 g of 7-[N2N3bis(benzyloxycarbonyl)guanidino] -8-methylinosine in the form of a white solid product.

D. 8-(Medicinalis-7-yl)guanidine, dihydrochloride salt. To a solution of 1.25 g of 7-[N2N3bis(benzyloxycarbonyl)guanidino]-8-methylinosine in 40 ml ethanol add 672 mg of ammonium formate and palladium on coal in catalytic quantity. The resulting suspension is stirred at room temperature for 10 hours. The reaction mixture is filtered n the th stream of gaseous hydrogen chloride for 5 minutes. The resulting solution was stirred at room temperature for 2 hours and evaporated on a rotary evaporator to obtain a light-yellow solid product, which is purified by recrystallization from methanol/ethyl acetate to obtain 313 mg, 8-(medicinalis-7-yl)guanidine, dihydrochloride salt in the form of a yellow solid product.

Example 8

(8-Bronchioles-7-yl)guanidine

A. 7-Amino-8-bronchioles. To a solution of 401 mg of 7-aminoquinoline in 15 ml of glacial acetic acid add 913 mg of sodium acetate and then of 0.14 ml of bromine in 5 ml of glacial acetic acid. The obtained yellow suspension was stirred at room temperature for 2 hours. The brown mixture was evaporated on a rotary evaporator and the residue diluted with water and ethyl acetate. The mixture is alkalinized 1 N. sodium hydroxide and decanted. The organic layer is washed with water and then saturated saline solution, the combined aqueous layers are extracted with ethyl acetate; the combined organic layers are dried over magnesium sulfate and evaporated on a rotary evaporator. The residue is purified column chromatography on silica gel, elwira from 20 to 50% ethyl acetate/hexane followed by recrystallization from hexane/methylene chloride to obtain 521 mg of 7-amino-8-br is of IMT guanidino]-8 - bromoquinoline. To the light yellow solution of 0.40 g of 7-amino-8-bromoquinoline in 10 ml of tetrahydrofuran, add a 1.11 g of ethyl-N,N-bis(tert-butoxycarbonyl)pseudodomain and of 1.16 g of the acetate of mercury and the mixture is stirred at room temperature for 26 hours. The suspension is diluted with ethyl acetate and washed with water followed by washing with saturated saline solution. The aqueous layers are extracted with ethyl acetate; the combined organic layers are dried over magnesium sulfate and evaporated on a rotary evaporator. The residue is purified column flash chromatography on silica gel, elwira 15% ethyl acetate/hexane to obtain 0,78 g of 7-[N2N3bis(tert-butoxycarbonyl)guanidino]-8-bromoquinoline in the form of a white solid product.

C. (8-Bronchioles-7-yl)guanidine, cleaners containing hydrochloride salt. To a cold (0oC) the solution 0,735 g of 7-[N2N3bis(tert-butoxycarbonyl)guanidino]-8-brainline in 2 ml of methylene chloride is added 2 ml triperoxonane acid. The resulting solution was stirred at room temperature for 3 hours and evaporated on a rotary evaporator until the consistency of a viscous oil. The oil is dissolved in 10 ml of methanol and add 0.5 ml of concentrated hydrochloric acid. After 5 minutes the solution is evaporated on a rotary IP is 0,41 g of the hydrochloride of 8-(bronchioles-7-yl)guanidine in the form of a yellow solid product.

Example 9

(6-Methylbenzothiazol-5-yl)guanidine

A. 6-Methyl-5-nitrobenzothiazole. A mixture of 1.6 g of 5-chloro-2,4-dinitrotoluene and 20 ml of N,N-dimethylthioformamide heated to 120oC for 16 hours. After cooling to room temperature the mixture was purified column flash chromatography on silica gel, elwira from 3% to 10% ethyl acetate/hexane to obtain 0,78 g of 6-methyl-5-nitrobenzothiazole in the form of a yellow solid product.

Century 5-Amino-6-methylbenzothiazole. The mixture 0,78 g of 6-methyl-5-nitrobenzothiazole and 3,62 g of the dihydrochloride dihydrate tin in 25 ml of ethanol is heated to 65oC for 4 hours. The cooled reaction mixture is poured to 10 ml of 50% sodium hydroxide solution and 45 ml of saturated saline and extracted with ether (CH ml). The combined organic layers washed with saturated saline solution, dried over sodium sulfate and evaporated on a rotary evaporator. The residue is purified column flash chromatography on silica gel, elwira 15% ethyl acetate/hexane to obtain 0.45 g of 5-amino-6-methylbenzothiazole in the form of a yellow solid product.

C. 5-[N2N3bis(benzyloxycarbonyl)guanidino] -6 - methylbenzothiazol. To a solution of 230 mg of 5-amino-6-methylbenzothiazole in 10 ml of 1/1 ethyl acetate/methanol domantay temperature for 24 hours. The mixture is filtered on celite and evaporated on a rotary evaporator. The residue is purified column flash chromatography on silica gel, elwira 20% ethyl acetate/hexane to obtain 598 mg of 5-[N2N3bis(benzyloxycarbonyl)guanidino] -6-methylbenzothiazole in the form of a yellow solid product.

D. (6-Methylbenzothiazol-5-yl)guanidine, tribromsalan salt. To a solution of 0.58 g of 5-[N2N3bis(benzyloxycarbonyl)guanidino]-6-methylbenzothiazole in 25 ml of a 1/1 methanol/ethyl acetate was added 1 g of 10% palladium-on-charcoal grill. The mixture is stirred in hydrogen atmosphere at atmospheric pressure for 3 days. The mixture is filtered on celite and evaporated on a rotary evaporator. The residue is dissolved in a minimal amount of methanol and treated with 0.6 ml of 30% Hydrobromic acid/acetic acid. Added dropwise ethyl acetate until the turbidity and the mixture was kept in the refrigerator until the onset of crystallization. The solid is filtered and dried under vacuum to obtain 96 mg (6-methylbenzothiazol-5-yl)guanidine, tribromoethanol salt in the form of a white solid product.

Example 10

(4-Bromobenzoate-5-yl)guanidine

A. 5-Nitrobenzothiazole. A mixture of 10 g of 1-chloro-2,4-dinitrobenzene and 20,26 ml of N,N-dimethylthiophene is heated under reflux for 4 hours. Mixture is allowed to cool to room temperature and add 15 ml of ethanol. The resulting suspension is filtered and the brown solid was washed with a minimal amount of ethanol. The solid is dissolved in 120 ml of ethanol, heated to boiling and filtered to remove trace quantities of solids. After reducing the volume to approximately 100 ml of the solution is kept overnight at room temperature. The obtained solid is filtered and washed to obtain 4.68 g of 5-nitrobenzothiazole in the form of reddish-brown needles.

Century 5-Aminobenzothiazole. A mixture of 3.46 g of 5-nitrobenzothiazole and 15.7 g of the dihydrochloride dihydrate tin in 55 ml of 2-propanol is heated under reflux for 3 hours. The cooled reaction mixture is poured to 150 ml of ice/water and neutralized to pH 7 with solid sodium hydroxide. The mixture is extracted with ethyl acetate (CH ml). The combined organic layers dried over sodium sulfate, filtered through a small layer of silica gel and evaporated on a rotary evaporator to obtain a 2.45 g of 5-aminobenzothiazole in the form of a yellow-brown solid product.

C. 5-Amino-4-bromobenzoate. To a chilled (5oC) the solution 2,04 g 5-aminobenzothiazole in 60 ml of chloroform d the th mixture is stirred for 30 minutes at room temperature, then diluted with 14 ml of concentrated ammonium hydroxide and 16 ml of methylene chloride. The aqueous layer was washed with methylene chloride (2 x 16 ml) and the combined organic layers evaporated on a rotary evaporator. The residue is purified by filtration through silica gel with vacuum suction, elwira from 15% to 30% ethyl acetate in hexane to obtain 2,44 g of 5-amino-4-bromobenzoate in the form of a reddish solid product.

D. (4-Bromobenzoate-5-yl)guanidine, cleaners containing hydrochloride salt. A mixture of 100 mg of 5-amino-4-bromobenzoate, 0.05 ml of water and 0,097 ml of concentrated hydrochloric acid is stirred at room temperature for 5 minutes. To this mixture is added 74 mg of cyanamide and the new mixture is stirred for 90 minutes at 70oC. the Reaction mixture was cooled to 0oWith and add 0,194 ml of water and 0,098 ml of concentrated hydrochloric acid. The mixture is stirred for 30 minutes atoWith and evaporated on a rotary evaporator. The residue is diluted with 1 ml of methanol and precipitated with ether, giving 41 mg hydrochloride (4-bromobenzoate-5-yl)guanidine in the form of a white solid product.

Example 11

N, N-Dimethyl-(8-methylinosine-7-yl)guanidine (see figure 5 at the end of the description).

A. Methyl-N,N'-dimethyltitanocene. N,N'-diethylthiourea. actionnow the mixture is heated to 30-35oC for 45 minutes. This solution was directly used in the subsequent reaction.

Century Methyl-N-carbomethoxy-N,N'-dimethyltitanocene. Specified in (A) mixture is added potassium carbonate (10.1 g) and then with stirring, add methylchloroform (4,2 ml). After about 45 minutes the reaction mixture is heated to 55oWith and insoluble salts are filtered off. These salts are washed with 10 ml of absolute ethanol. The filtrate (and ethanol rinse) is cooled to -20oAnd the recrystallized product emit a Buechner funnel. The product is washed with 10 ml of cold (-20o(C) absolute ethanol. The product is dried overnight under vacuum at room temperature to obtain methyl-N-carbomethoxy-N,N'-dimethyltitanocene.

C. N, N'-Dimethyl-(8-methylinosine-7-yl)guanidine. Methyl-N-carbomethoxy-N, N'-dimethyltitanocene combine with 8-methyl-7-nitroquinoline, obtained as described in example 7B, 10% acetic acid in ethanol and heated under reflux. After spending the initial amine mixture discolor coal. The mixture is cooled, filtered and evaporated on a rotary evaporator. After recrystallization and drying obtain N,N'-dimetyl, the examples above, we obtained the following compounds. In these examples, if R1no, (a) represents a double bond and guanidine designated as GNDNL:

< / BR>
In table.2 R10=R11- hydrogen.

In table.3 R10- Me and R11- H.

In table.4 R10- Et and R11- H.

Songs

In another aspect the invention relates to compositions that comprise a safe and effective amount of a compound of the invention or pharmaceutically acceptable salts or its pharmaceutically acceptable carrier.

Used herein, the term "safe and effective amount" means an amount of compound according to the invention, sufficient for a significant induction of positive change condition being treated, but low enough to avoid serious side effects (at a reasonable ratio of favorable actions and risk) within the legal framework of medical practice. Safe and effective amount of the compounds according to the invention generally depends on the age and physical condition of the patient being treated, the severity of the condition, the duration of treatment, the nature of concomitant ternary and experience of the treating physician.

Getting the dosage form is within the competence of the specialist in this field. The examples are for specialists, but are not limiting, and it is assumed that the expert can obtain the variants of the compositions included in the invention.

The composition of the invention preferably contain from about 0,0001% to about 99% by weight of compounds according to the invention, more preferably from about 0.01% to about 90% of compounds according to the invention. Depending on the schemes and the corresponding biological availability, characteristics solubility or dissolution of the dosage form dosage form preferably contains from about 10% to about 50%, also preferably from about 5% to about 10%, also preferably from about 1% to about 5% and preferably from about 0.01% to about 1% of the compounds according to the invention. The frequency of the dose of the compounds according to the invention depends on the pharmacokinetic properties of each specific agent (e.g., period of biologic half-life) and can be determined by a specialist in this field.

In addition to the compounds according to the invention the compositions of this invention contain a pharmaceutically acceptable carrier. Applied here, those fillers/diluents or encapsulating substances, which are suitable for administration to a mammal. Used herein, the term "compatible" means that the components of the composition is able to be mixed with the compound according to the invention and with each other so that no interaction occurs which substantially reduce the pharmaceutical efficacy of the composition under commonly used conditions. When using liquid dosage forms preferably, compounds of the invention were soluble components of the composition. Pharmaceutically acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity, which makes them acceptable for administration to the mammal being treated.

Some examples of substances which can serve as pharmaceutically acceptable carriers or components thereof are sugars, such as lactose, glucose and sucrose; starches, such as corn and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethylcellulose and methyl cellulose; powdered tragakant; malt; gelatin; talc; solid lubricating agents, such as stearic acid and magnesium stearate; calcium sulfate; rustichello Theobroma; polyols, such as propylene glycol, glycerin, sorbitol, mannitol and polyethylene glycol; alginic acid; emulsifiers, such as Twins; moisturizing agents, such as sodium lauryl sulfate; coloring agents; perfumes; tabletiruemye agents, stabilizers; antioxidants; preservatives; water, free from pyrogens; isotonic salt solution and phosphate buffered solutions. The choice of pharmaceutically acceptable carrier, which will be applied together with the connection according to the invention is determined primarily by the introduction of this connection. If the connection according to the invention should be injected, the preferred pharmaceutically acceptable carrier is sterile physiological solution containing compatible with blood suspendisse agent, the pH was increased to approximately 7,4.

If the preferred route of administration of the compounds according to the invention is oral, the preferred standard dosage form are, therefore, tablets, capsules, pads, tablets, grinding and the like. Such a standard dosage forms contain a safe and effective amount of the compounds according to the invention, it is preferable from the eye of rmaceuticals acceptable carrier, suitable for preparation of unit dosage forms for oral administration, is well known to science. As inert diluents tablets usually contain conventional pharmaceutically compatible adjuvants such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; loosening agents, such as starch, alginic acid and crosscarmellose; lubricating agents such as magnesium stearate, stearic acid and talc. To improve the characteristics of the passage of the powder mixture can be applied agents that facilitate the sliding, such as silicon dioxide. To improve the appearance can be added coloring agents such as dyes, FD&C tablets grinding good adjuvants are sweeteners and flavouring agents, such as aspartame, saccharin, menthol, peppermint and fruit fragrances. Capsules typically include one or more solid diluents described above. The selection of carrier components depends on secondary factors such as taste, price, and stability during storage, which are not fundamental for the purposes of the present invention, and can be easily done by a specialist.

RC-591, tragakant and sodium alginate; a typical moisturizing agents include lecithin and Polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate. Oral liquid compositions may also contain one or more components such as sweeteners, perfumes and dyes described above.

Other compositions used for systemic delivery according to the invention include sublingual and cheek dosage forms. Such compositions typically include one or more soluble substances, fillers, such as sucrose, sorbitol and mannitol, and a binding agent such as gum, microcrystalline cellulose, carboxymethylcellulose and hydroxyprolin, tinted agents, antioxidants and fragrances.

The composition can also be used to deliver compounds to the site of his desired action: intranasal dosing for anti-edematous action on the nasopharynx, dosage for inhalation for the treatment of asthma and eye drops, gels and ointments for the treatment of eye diseases.

Preferred compositions according to the invention contain a solution or emulsion, preferably aqueous solutions or emulsions, comprising a safe and effective amount of the compounds according to the invention, intended for local intranasal. Such compositions preferably contain from about 0,001% to about 25% of the compounds according to the invention, more preferably from about 0.01% to about 10%. Similar compositions are preferred for systemic delivery of the compounds according to the invention intranasal way. Compositions intended for systemic delivery of compounds intranasal method, preferably contain a number of compounds according to the invention, similar to the quantities that are defined as safe and effective for oral and parenteral administration. Such compositions used for intranasal dosing, also usually is such; chelating agents, such as sodium salt of ethylenediaminetetraacetic acid and others; buffers such as phosphate, citrate and acetate; agents that support isotonicity, such as sodium chloride, potassium chloride, glycerin, mannitol and others; antioxidants such as ascorbic acid, acetylcysteine, metabisulfite sodium and others; aromatic agents; agents that regulate the viscosity, such as polymers, including cellulose and its derivatives and polyvinyl alcohols, and acids and bases to bring the pH of these aqueous compositions to the required level. The composition may also include local anesthetics and other active compounds. These compositions can be applied as sprays, sprinklers, drops and the like.

Other preferred compositions according to the invention include aqueous solutions, suspensions and dry powders comprising a safe and effective amount of the compounds according to the invention, intended for spraying and introduction via inhalation. Such compositions preferably contain from about 0.1% to about 50% of the compounds according to the invention, more preferably from about 1% to about 20%; of course, the number may be changed based on the status of the patient and t is osili usually also include dispersing agents, such as chloropropiophenone 12/11 and 12/114 and more acceptable to the environment ftoruglevodorodnyh or other non-toxic sprays; solvents such as water, glycerol and ethanol, which necessarily involve a cosolvent for solvation or suspension of the active compounds; stabilizers such as ascorbic acid, sodium metabisulfite; preservatives, such as cetylpyridinium chloride and benzalkonium chloride; agents that support isotonicity, such as sodium chloride; buffers and perfumes, such as sodium salt of saccharin. Such compositions suitable for the treatment of respiratory diseases such as asthma and the like.

Other preferred compositions according to the invention include aqueous solutions comprising a safe and effective amount of the compounds according to the invention, intended for local injection into the area of the eyeball. Such compositions preferably contain from about 0,0001% to about 5% of the compounds according to the invention, more preferably from about 0.01% to about 0.5%. Such compositions also typically include one or more preservatives, such as benzalkonium chloride, thimerosal, ACET phenyl mercury; binding agents, such as poloxamer, modified the, mannitol and glycerol; buffers such as acetate, citrate and borate; antioxidants, such as metabisulfite sodium, bottled hydroxytoluene and acetylcysteine; to establish the pH of these compositions, if necessary, can be applied to acids and bases.

Other preferred compositions according to the invention is convenient for oral administration include solid preparations such as tablets and capsules, and liquids, such as solutions, suspensions and emulsions (preferably in soft gelatin capsules), comprising a safe and effective amount of the compounds according to the invention. Such compositions preferably contain from about 0.01 mg to about 350 mg per dose, more preferably from about 0.1 mg to about 35 mg per dose. Such compositions can be coated by conventional methods, typically by coating, the dissolution of which depends on pH or time, so the connection according to the invention is released into the gastrointestinal tract at different times to extend the desired action. Such dosage forms typically include, but are not limited to, one or more of the following chemicals: phthalate cellulose acetate, polyvinyl acetate phthalate, hydroxypropyl phthalate is th according to the invention may optionally include other active drugs. Limitiruyuschie examples of active drugs that can be included in these compositions include:

Antihistamines, including:

hydroxyzine is preferably in the range of doses from about 25 to about 400 mg; doxylamine preferably in the range of doses from about 3 to about 75 mg; pyrilamine preferably in the range of doses from about 6,25 to about 200 mg; chlorpheniramine preferably in the range of doses from about 1 to about 24 mg; phenindamine preferably in the range of doses from about 6,25 to about 150 mg; dexchlorpheniramine preferably in the range of doses from about 0.5 to about 12 mg; dexbrompheniramine preferably in the range of doses from about 0.5 to about 12 mg; clemastin preferably in the range of doses from about 1 to about 9 mg; diphenhydramine preferably in the range of doses from about 6,25 to about 300 mg; azelastin preferably in the range of doses from about 140 to about 1680 mcg (dosage intranasal) ; from 1 to about 8 mg (dosage for oral administration); acrivastine preferably in the range of d is I intranasal or medicines for eye diseases) is preferably in the range of doses from about 100 to about 800 mg; mahaasin preferably in the range of doses from about 5 to about 20 mg; astemizole preferably in the range of doses from about 5 to about 20 mg; Bastin preferably in the range of doses from about 5 to about 20 mg; loratadine preferably in the range of doses from about 5 to about 40 mg; cetirizine preferably in the range of doses from about 5 to about 20 mg; terfenadine preferably in the range of doses from about 30 to about 480 mg; metabolite of terfenadine; promethazine preferably in the range of doses from about 6,25 to about 50 mg; dimenhydrinate is preferably in the range of doses from about 12.5 to about 400 mg; meclizine preferably in the range of doses from about 6,25 to about 50 mg; tripelennamine preferably in the range of doses from about 6,25 to about 300 mg; carbinoxamine preferably in the range of doses from about 0.5 to about 16 mg; cyproheptadin preferably in the range of doses from about 2 to about 20 mg; azatadine preferably in the range of doses from about 0.25 to about 2 mg; brompheniramine predpochtitel about 0.25 to about 10 mg; cyclizine preferably in the range of doses from about 12.5 to about 200 mg; thonzylamine preferably in the range of doses from about 12.5 to about 600 mg; feniramin preferably in the range of doses from about 3 to about 75 mg; cyclizine preferably in the range of doses from about 12.5 to about 200 mg, and others;

Antitussive agents, including:

codeine is preferably in the range of doses from about 2.5 to about 120 mg; hydrocodone preferably in the range of doses from about 2.5 to about 40 mg; dextromethorphan is preferably in the range of doses from about 2.5 to about 120 mg; noscapine preferably in the range of doses from about 3 to about 180 mg; benzonatate preferably in the range of doses from about 100 to about 600 mg; diphenhydramine preferably in the range of doses from about 12.5 to about 150 mg; chlophedianol preferably in the range of doses from about 12.5 to about 100 mg; clobutinol preferably in the range of doses from about 20 to about 240 mg; Foinaven preferably in the range of doses from about 80 to about redoctane in doses ranging from about 75 to about 300 mg; hydromorphone is preferably in the range of doses from about 0.5 to about 8 mg; carbetapentane preferably in the range of doses from about 15 to about 240 mg; caramiphen preferably in the range of doses from about 10 to about 100 mg; levopropoxyphene preferably in the range of doses from about 25 to about 200 mg, and others;

Anti-inflammatory agents, preferably non-steroidal anti-inflammatory agents (NSAIDS), including:

ibuprofen preferably in the range of doses from about 50 to about 3200 mg; naproxen preferably in the range of doses from about 62,5 to about 1500 mg of naproxen sodium salt is preferably in the range of doses from about 110 to about 1650 mg; Ketoprofen preferably in the range of doses from about 25 to about 300 mg; indoprofen preferably in the range of doses from about 25 to about 200 mg; indomethacin preferably in the range of doses from about 25 to about 200 mg; sulindac preferably in the range of doses from about 75 to about 400 mg; diflunisal preferably in the range of doses from about 125 to priblizim preferably in the range of doses from about 10 to about 40 mg; aspirin is preferably in the range of doses from about 80 to about 4000 mg; meclofenamate preferably in the range of doses from about 25 to about 400 mg; benzydamine preferably in the range of doses from about 25 to about 200 mg; cuprofen preferably in the range of doses from about 75 to about 300 mg; diclofenac preferably in the range of doses from about 6,25 to about 300 mg, preferably in the range of doses from about 25 to about 200 mg; etodolac preferably in the range of doses from about 200 to about 1,200 mg; fenbufen preferably in the range of doses from about 300 to about 900 mg; fenoprofen preferably in the range of doses from about 200 to about 3200 mg; flurbiprofen preferably in the range of doses from about 50 to about 300 mg; marennikova acid is preferably in the range of doses from about 250 to about 1500 mg; nabumeton preferably in the range of doses from about 6,25 to about 300 mg, preferably in the range of doses from about 250 to about 2000 mg; phenylbutazone preferably in the range of doses from priblizitel is but 800 mg; tolmetin preferably in the range of doses from about 200 to about 1800 mg, and others;

Analgesics, including:

acetaminophen is preferably in the range of doses from about 80 to about 4000 mg, and others;

Expectorants/mucolytics, including:

guaifenesin preferably in the range of doses from about 50 to about 2400 mg; N-acetylcysteine preferably in the range of doses from about 100 to about 600 mg; Ambroxol preferably in the range of doses from about 15 to about 120 mg; Bromhexine preferably in the range of doses from about 4 to about 64 mg; terpyridyl preferably in the range of doses from about 100 to about 1,200 mg; potassium iodide is preferably in the range of doses from about 50 to about 250 mg, and others;

Anticholinergics (eg, atropine), preferably injected intranasally or oral anticholinergics, including:

ipratropium (preferably intranasally) is preferably in the range of doses from about 42 to about 252 mcg; atropine sulfate (preferably oral), preferably in the range bottom at doses from about 15 to about 45 mg-equivalents; scopolamine is preferably in the range of doses from about 400 to about 3200 mcg; scopolamine methobromide preferably in the range of doses from about 2.5 to about 20 mg; gomatropina methobromide preferably in the range of doses from about 2.5 to about 40 mg; giostsiamin (preferably oral), preferably in doses ranging from about 125 to about 1000 μg; isopropamide (preferably oral), preferably in doses ranging from about 5 to about 20 mg; orphenadrine (preferably oral), preferably in doses ranging from about 50 to about 400 mg; benzalkonium chloride (preferably intranasally) preferably in doses ranging from approximately 0.005 to approximately 0.1% solution, and others;

The stabilizers of the fat cells, preferably injected intranasally or orally stabilizers fat cells, including:

Cromalin preferably in the range of doses from about 10 to about 60 mg; nedocromil preferably in the range of doses from about 10 to about 60 mg; oxatomide preferably in the range of doses from about 15 to about 120 mg; ketotifenum doses of from about 100 to about 3000 μg, and others;

The leukotriene antagonists, including zileuton and others;

Methylxanthines, including:

caffeine is preferably in the range of doses from about 65 to about 600 mg; theophylline is preferably in the range of doses from about 25 to about 1,200 mg; enprofylline; pentoxifylline is preferably in the range of doses from about 400 to about 3600 mg; aminophylline preferably in the range of doses from about 50 to about 800 mg; Tefillin preferably in the range of doses from about 200 to about 1600 mg, and others;

Antioxidants or inhibitors of radicals, including:

ascorbic acid is preferably in the range of doses from about 50 to about 10,000 mg; tocopherol is preferably in the range of doses from about 50 to about 2000 mg, preferably ethanol in doses ranging from about 500 to about 10,000 mg, and others;

Steroids, preferably intranasally administered steroids, including:

balconette preferably in the range of doses from about 84 to about 336 mcg; fluticasone preferably in the range of doses from about 50 to about 400 mcg; budesonide preferably in intervals in which Ino 50 to about 300 mg; triamcinolone preferably in the range of doses from about 110 to about 440 μg; dexamethasone preferably in the range of doses from about 168 to about 1008 mcg; flunisolide preferably in the range of doses from about 50 to about 300 mg; prednisone (preferably oral), preferably in doses ranging from about 5 to about 60 mg; hydrocortisone (preferably oral), preferably in doses ranging from about 20 to about 300 mg, and others;

Bronchodilators preferably for inhalation, including:

albuterol preferably in the range of doses from about 90 to about 1080 μg, about 2 to about 16 mg (if dosed for oral administration); epinephrine is preferably in the range of doses from about 220 to about 1320 μg; ephedrine preferably in the range of doses from about 15 to about 240 mg (if dosed for oral administration); from 250 to about 1000 mg (if dosed for intranasal); metaproterenol preferably in the range of doses from about 65 to about 780 μg or from about 10 to about 80 mg (if dosed for prorat 2.5 to about 20 mg (if dosed for oral administration); isoetharine preferably in the range of doses from about 340 to about 1360 mcg; pirbuterol preferably in the range of doses from about 200 to about 2400 ug; bitolterol preferably in the range of doses from about 370 to about 2220 mcg; fenoterol preferably in the range of doses from about 100 to about 1200 μg; 2.5 to about 20 mg (if dosed for oral administration); rimiterol preferably in the range of doses from about 200 to about 1600 mcg; ipratroprium preferably in the range of doses from about 18 to about 216 mcg (inhalation), and others; and

Anti-virus tools, including:

amantadine preferably in the range of doses from about 50 to about 200 mg; rimantadine preferably in the range of doses from about 50 to about 200 mg; enviroxime; nonoxinol preferably in the range of doses from about 2 to about 20 mg (preferably intranasal form); acyclovir preferably in the range of doses from about 200 to about 2000 mg (oral); from 1 to about 10 mg (preferably intranasal form); alpha-interferon and preferably in the C from about 3 to about 36 MIU (million ME), and others;

Drugs active against eye diseases: acetylcholinesterase inhibitors, such as echothiophate from about 0.03% to about 0.25% in the solution for local administration and others; and

Drugs acting on gastrointestinal tract:

protivodiareynoe drugs, such as loperamide from about 0.1 mg to about 1.0 mg per dose and basically salicylsalicylic bismuth, from about 25 mg to about 300 mg per dose, and others.

Of course, it is clear that considered and included in the above description of acidic or basic additive salts, esters, metabolites, stereoisomers and enantiomers of these preferred combinations of active substances and their analogues with this activity that are safe and effective. It should also be understood that the active compound may be useful when more than one of the above applications, and these applications also specifically considered. This overlap is known in the science and delivery of dosages and the like, and also the fitting instructions are in the competence of the practitioner.

Applications

Without going into theory, it can be assumed that the primary mechanism that provides applewine violation (s) and/or its (their) symptoms (manifestations). The situation may be such that there is insufficient activity of alpha-2 adrenergic receptors: this activity may be normal. However, the introduction of the alpha-2 agonist can be

convenient way for the correction of the disease, condition or symptoms.

Thus, the terms "disease", "violation" and "condition" are used interchangeably to refer to diseases related to alpha-2 adrenergic receptors or modulated using them.

The disease is described using the terms "modulated by alpha-2 adrenergic receptors" or "modulated using the activity of alpha-2 adrenergic receptors", here refers to the violation, condition or disease in which activity of alpha-2 adrenergic receptors is an effective tool to facilitate disease or one or more of the biological manifestations of the disease or disturbance or interferes with one or more stages of biological metabolism, leading to the disease or underlying violations; or alleviates one or more symptoms of the disease. Thus, violations subjected to modulation, include those for which:

- The disease or disorder or observable (observable) manifestation or symptoms of diseases or disorders alleviated by alpha-2 activity. The absence of alpha-2 activity does not necessarily causally associated with the disease or disorder or their observable manifestations;

Alpha-2 activity interferes with the part of the biochemical or cellular metabolism, which leads or is related to the disease or disorder. In this sense, the alpha-2 activity alters the metabolism and, thus, controls the disease, condition or disorder.

Compounds according to the invention are particularly useful for the treatment of swelling of the nose caused by allergies, cold and other violations in the nasopharynx, as well as for the treatment of complications of edema of the mucous membranes (for example, sinusitis and inflammation of the middle ear). It was found that adverse side effects can be avoided through the use of effective doses.

If not limited to a particular mechanism of action, it is believed that the compounds according to the invention have advantages in the treatment of edema Osogbo detected, the compounds according to the invention are agonists alpha-2 adrenergic receptors, which cause the reduction of the peripheral vascular bed in the nasal cavity.

Alpha-2 adrenergic receptors are located both in the Central nervous system and beyond. So, although this is not essential for activity or efficiency, certain violations preferably treated with compounds that act on alpha-2 adrenergic receptors in only one of these areas. Compounds according to the invention differ in their ability to penetrate into the Central nervous system and, therefore, to provide an effect mediated Central alpha-2 adrenergic receptors. For example, a compound that exhibits a higher degree of activity in the Central nervous system, is preferred when the evidence for effects on the Central nervous system in comparison with other compounds, as described below. However, even for compounds which have a primary Periferico activity, increasing the dose of the compound can be triggered by effects on the Central nervous system. Additional specificity of action of these compounds can be achieved by the delivery agent in obladateley tract).

Compounds preferred for the treatment of certain cardiovascular diseases, pain, substance abuse and/or syndrome, ulcers, acidity, but not limited to, include those compounds that act centrally. Under the Central action is understood that they have a specific action on alpha-2 adrenergic receptors in the Central nervous system in addition to their action on peripheral alpha-2 adrenergic receptors.

Compounds preferred for the treatment of respiratory disorders, eye disorders, migraine, some cardiovascular diseases and other gastrointestinal diseases, but not limited to, are applicable perifericheskie. Under peripheral action is understood that these compounds are primarily act on the alpha-2 adrenergic receptors in the periphery as opposed to those that primarily act on the Central nervous system. In science known methods determine which of the compounds is primarily applicable at the periphery and what characterized the primary Central action.

Thus, the compounds of the subject invention can be used also for the treatment of HL is of injected or oral, or applied topically directly to the eye surface of a mammal in the form of drops, sprays, sprinklers, gels or ointments.

Compounds according to the invention can also be used to control gastro-intestinal diseases, such as diarrhoea syndrome of painful sensitivity of the intestine, hyperchlorhydria (hyperacidity and peptic ulcer.

Compounds according to the invention can also be used for treating diseases and disorders associated with the activity of the sympathetic nervous system, including hypertension, myocardial ischemia, circulatory disorders of the heart, angina, cardiac arrhythmia, heart failure and benign prostatic hypertrophy. Thanks to their sympatholytic effects, the compounds of the invention are also useful for achieving anesthesia during surgical procedures.

Compounds according to the invention can also be used to reduce the pain associated with various disorders. Compounds administered orally, parenterally and/or by direct injection into the cerebrospinal fluid.

Compounds according to the invention can also be used for the prophylaxis or direct treatment of migraine. The connection is used for the treatment of substance abuse, in particular, the abuse of alcohol and opiates, and facilitate the syndrome arising from the termination of these substances.

Compounds according to the invention can also be used to treat other diseases and disorders, including septic or cardiogenic shock, increased intracranial pressure, hemorrhoids, venous insufficiency, varicose veins and hot flashes in menopause, in which vasoconstriction, especially veins, should create favorable conditions.

Compounds according to the invention can also be used to treat neurological diseases and disorders, including spasticity, epilepsy, hyperactivity, attention deficit, Tourette syndrome, and disorders of learning.

The pharmacological activity and selectivity of these compounds can be determined using published test procedures. Alpha-2 selectivity of the compounds is determined by measuring the affinity to the receptor and functional efficiency in vitro in many tissues, for which it is known the presence of alpha-2 and/or alpha-1 receptors. (See, for example. The Alpha-2 Adrenergic Receptors. L. E. Limbird, ed., Humana Press, Clifton, NJ.) The following tests in vivo are usually carried out at gr the motor activity as a measure of sedation. (See, for example, C. Spyraki & N. Fibiger, "Clonidine-induced Sedation in Rats: Evidence for Mediation by Postsynaptic Alpha-2 Adrenoreceptors", Journal of Neural Transmission, Vol.54 (1982), pp.153-163).

Antitumor activity of the nasopharynx is measured by rhinomanometry in the form of resistance to nasal airflow. (See, for example, Salem S. & E. Clemente, "A New Experimental Method for Evaluating Drugs in the Nasal Cavity", Archives of Otolaryngology, Vol.96 (1972), pp.524-529).

Protivoglaucomny activity is determined by measuring intraocular pressure. (See, for example, Potter D., "Adrenergic Pharmacology of Aqueous Human Dynamics", Pharmacological Reviews, Vol.13 (1981), pp.133-153).

Antidiarrhoeal activity is determined by measuring the ability of compounds to inhibit diarrhea induced by prostaglandins. (See, for example, Thollander M. , P. Hellstrom & T. Svensson, "Suppression of Castor Oil-Induced Diarrhea by Alpha-2 Adrenoceptor Agonists", Alimentary Pharmacology and Therapeutics, Vol.5 (1991), pp.255-262).

The effectiveness of the treatment of the syndrome of painful sensitivity of the intestine is determined by measuring the ability of compounds to reduce the increase in the output of faeces induced stress. (See, for example, Barone F., J. Deegan, W. Price, P. Fowler, J. Fondacaro & H. Ormsbee III, "a Cold-restraint stress increases rat fecal pellet output and colonic transit", American Journal of discrimination, Vol.258 (1990), pp. G329-G337).

Effectiveness against protivogaz the SIP acid stomach caused by these compounds. (See, for example, Tazi-Saad, K., J. Chariot M. Del Tacca & C. Roze, "Effect of2-adrenoceptor agonists on gastric pepsin and acid secretion in the rat", British of Pharmacology, Vol.106 (1992), pp.790-796).

Anti-asthma activity is determined by measuring the activity of a compound to reduce the bronchi associated with such a light load, as inhalation antigens. (See, for example, J. Chang , J. Musser & J. Hand, "Effects of a Novel Leukotriene D4Antagonist witn 5-Lipoxygenase and Cyclooxygenase Inhibitory Activity, Wy-45,911, on Leukotriene-D4- and Antigen-Induced Bronchoconstriction in Guinea Pig", International Archives of Allergy and Applied Immunology, Vol.66 (1988), pp.48-54; and Delehunt J., A. Perruchound, L. Yerder, B. Marchette, J. Stevenson & W. Abraham, "The Role of Slow-Reacting Substance of Anaphylaxis in the Late Bronchial Response After Antigen Challenge in Allergic Sheep", American Reviews of Respiratory Disease, Vol.130 (1984), pp.748-754).

Activity against cough determined by measuring the amount and latent period of the cough response to such respiratory load, as inhalation of citric acid. (See, for example, Callaway j & R. King, "Effects of Inhaled 2-Adrenoceptor and GABA Receptor Agonists on Citric Acid-Induced Cough and Tidal Volume Changes in Guinea Pigs", European Journal of Pharmacology, Vol.220 (1992), pp.187-195).

Sympatholytic activity of these compounds was determined by measuring the decrease in the concentration of catecholamines in the plasma (see, for example, R. Urban, B. Szabo 29-37) or decrease sympathetic activity of the nerves in the kidney (see, for example, Feng Q., S. Carlsson, P. Thoeren & T. Hedner, "Effect of clonidine on renal sympathetic nerve activity, natriuresis and diuresis in chronic congestive heart failure rats". Journal of Pharmacology and Experimental Therapeutics, Vol. 261 (1992), pp. 1129-1135) that provides the basis for their successful application in heart failure and benign prostatic hypertrophy.

Hypotensive action of these compounds is directly measured as a decline in average blood pressure (see, for example, R. Timmermans & P. Van Zwieten, "Central and peripheral a-adrenergic effects of some imidazolidines", European Journal of Pharmacology, Vol.45 (1977), pp.229-236).

Clinical studies have shown a positive effect of alpha-2 agonists in the prevention of myocardial ischemia during surgical intervention (see, for example, Talke, P., J. Li, U. Jain, J. Leung, K. Drasner, M. Hollenberg & D. Mangano, "Effects of Perioperative Dexmede-tomidine Infusion in Patients Undergoing Vascular Surgery, Anesthesiology, Vol.82 (1995), pp. 620-633) and prevent angina (see, for example, Wright R. A., R. Decroly, So Kharkevitch & M. Oliver, "Exercise Tolerance in Angina is Improved by Mivazerolan2-Adrenoreceptor Agonist", Cardiovascular Drugs and Therapy, Vol.7 (1993), pp.929-934).

The effectiveness of these compounds in relation to disturbance in the blood supply of the heart demonstrated by measuring the reduction of necrosis of the heart and infiltration by neutrophils (see, for example, Weyrich, A., X. MA, &asoedanoe as cardiac antiarrhythmic agents demonstrated by measuring the suppression of the arrhythmia, induced obanon (see, for example, Thomas G. & Stephen R., "Effects of Two Imidazolines (ST-91 and ST-93) jn the Cardias Arrhythmias and Lethality Induced by Ouabain in Guinea-Pig", Asia Pacific Journal of Pharmacology, Vol.8 (1993), pp. 109-113); and R. Samson, J. Cai, E. Shibata, J. Martins & H. Lee, "Electrophysiological effects of2-adrenergic stimulation in canine cardiac Purkinje fibers", American Journal of discrimination, Vol.268 (1995), pp. H2024-H2035).

Vasoconstrictor activity of these compounds is demonstrated by measuring the contractile properties of isolated arteries and veins in vitro (see, for example, Flavahan, N., T. Rimele, J. Cooke & M. Vanhoutte, "Characterization of Postjunctional Alpha-1 and Alpha-2 Adrenoreceptors Activated by Exogenous or Nerve-Released Norepinephrine in the Canine Saphenous Vein", Journal of Pharmacology and Experimental Therapeutics. Vol.230 (1984), pp.699-705).

The effectiveness of these compounds in reducing intracranial pressure demonstrated by measuring this property on the model of hemorrhage under the arachnoid membrane in dogs (see, for example, R. McCormick, J. Zabramski & R. Spetzler, "Intracranial pressure reduction by a central alpha-2 adrenoreceptor agonist after subarachnoid hemorrhage", Neurosurgery, Vol.32 (1993), pp.974-979).

Suppression of hot flashes during menopause demonstrated by measuring the decrease in blood flow in the skin of the muzzle rats (see, for example, Escott, K., D. Beattie, H. Connor & s Brain, "The modulation of the increace in rat facial skin blood flow observed after trigeminal ganglion ctimulation", European Journal of Pharmacology, Vol. 284 (1995), pp.69-76), The W. Redfern, M. MacLean, R. Clague & J. McGrath, "The role of alpha-2 adrenoceptors in the vasculature of the rat tail", Britich Journal of Pharmacology, Vol.114 (1995), pp.1724-1730).

Antinociceptive and overwhelming pain properties of these compounds demonstrated by measuring the increase in pain threshold method cramps in rodents and antinociceptive models using the hot plate (see, for example, Millan M., K. Bervoets, J. Rivet, R. Widdowson, A. Renouard, S. Le Maroille-Girardon & A. Gobert, "Multiple Alpha-2 Adrenergic Receptor Subtypes. II. Evidence for a Role of Rat Alpha-2 Adrenergic Receptor in the Control of Nociception, Motor Behavior and Hippocampal Synthesis of Noradrenaline", Journal of Pharmacology and Experimental Therapeutics, Vol.270 (1994), pp.958-972).

The action of these compounds against migraine demonstrated by measuring the decrease in neurogenic inflammation of the hard shell of the brain in response to stimulation of the ganglion FREQ in rats (see, for example, T. Matsubara, M. Moskowitz & Z. Huang, "UK-14,304, R(-)-alpha-methylhistamine and SMS 201-995 block plasma protein leakage within dura mater by prejunctional mechanisms", European Journal of Pharmacology, Vol. 224 (1992), pp.145-150).

The ability of these compounds to suppress the cancel effect of opiates is demonstrated by measuring the suppression of the increased activity of the sympathetic nervous system (see, for example, Franz D., D. Hare & K. McCloskey, "Spinal sympathetic neorons: possible sites of opiatewithdrawal suppression by clonidine", Science, Vol.215 (1982), pp.1643-16 is eacli excitation (see, for example, M. Shouse, M. Bier, J. Langer, O. Alcalde, M. Richkind & R. Szymusiak, "The2-agonist clonidine suppresses seizures, whereas the alpha-2 antagonist idazoxan promotes seizures-a microinfu-sion study in amygdala-kindled kittens". Brain Research, Vol.648 (1994), pp.352-356).

Demonstrated the effectiveness of other alpha-2 agonists in the management of neurological disorders, including disorders characterized by hyperactivity and attention deficit, and Tourette syndrome (see, for example, R. Chappell, M. Riddle, L. Scahill, K. Lynch, R. Schultz, A. Arnsten, J. Leckman & D. Cohen, "Guanfacine treatment of comorbid attention-deficit hyper-activity disorder and Tourette''s syndrome: preliminary clinical experience. Journal of American Academy of Child and Adolescent Psychiatry, Vol.34 (1995), pp. 1140-1146), cognitive impairment (see, for example, J. Coull, "Pharmacological manipulations of the2-noradrenergic system. Effects on cognition", Drugs and Aging, Vol. 5 (1994), pp.116-126) and spasticity (see, for example, Eyssette M., F. Rohmer, G. Serratrice, J. Warter & D. Now, "Multicenter, doubleblind trial of a novel antispastic agent, tizanidine, in spasticity associated with multiple sclerosis", Current Medical Research &Opinion, Vol.10 (1988), pp. 699-708).

In another aspect, the invention includes methods of preventing or treating by administering a safe and effective amount of the compounds according to the invention to a mammal suffering from or at risk of swelling of the nasopharynx. Such swelling of the nasopharynx can be associated in humans with diseases or destroy the top respiratory tract, rhinitis and vasomotor rhinitis. In addition, edema of mucous usually can be associated with other disorders (eg, otitis media and sinusitis). Each dose of the compounds of the invention preferably is injected dose, which is in the range from about of 0.0001 mg/kg to about 5 mg/kg of the compound, more preferably from about 0.001 mg/kg to about 0.5 mg/kg, Preferably oral administration of the dose. The preferred frequency of introduction of compounds in accordance with the invention is from about one to about six times daily, more preferably from about one to about 4 times a day. Such a dose and frequency of the preferred treatment of other respiratory disorders such as cough, chronic obstructive pulmonary disease (COPD) and asthma. Such doses and frequency are preferred for the treatment of disorders that are associated with swelling of the mucous membranes (for example, sinusitis and inflammation of the middle ear).

In another aspect, the invention includes methods of preventing or treating glaucoma by administering a safe and effective amount of the compounds according to the invention to a mammal suffering from or at risk of glaucoma. When systemic administration is E. from about 0,0001 mg/kg to about 5 mg/kg compound, more preferably from about 0.001 mg/kg to about 0.5 mg/kg At the dosage used for eye drops, preferably the usual amount is entered (for example, 1 or 2 drops) of liquid composition comprising from about 0,0001% to about 5% of the compound of the invention, more preferably from about 0.01% to about 0.5% of the compound. Determining the exact dosage and the administration scheme is the responsibility of the specialist. Preferably the introduction of such doses in the region of the eyeball. The frequency of introduction of a joint in accordance with the invention is preferably from about one to about six times daily, more preferably from about one to about 4 times a day.

In another aspect, the invention includes methods of prophylaxis or treatment of gastrointestinal diseases such as diarrhea syndrome painful sensitivity of the intestine and peptic ulcer, by administering a safe and effective amount of the compounds according to the invention to a mammal suffering from or at risk of gastro-intestinal disorders. Each dose of the compounds of the invention preferably is injected dose, which is in the range from about of 0.0001 mg/kg to about 5 mg/kg of the compound, more preferably from ecotuesday with the invention is preferably from about one to about six times a day, more preferably from about one to about 4 times a day.

In another aspect, the invention includes methods of prevention or treatment of migraine by administering a safe and effective amount of the compounds according to the invention to a mammal suffering from or at risk of migraine. Each dose of the compounds of the invention preferably is injected dose, which is in the range from about of 0.0001 mg/kg to about 5 mg/kg of the compound, more preferably from about 0.001 mg/kg to about 0.5 mg/kg, Preferably oral, parenteral or intranasal introduction of such doses. The frequency of oral administration of compounds according to the invention is preferably from about one to about six times daily, more preferably from about one to about 4 times a day. The frequency of parenteral administration of the compounds according to the invention is preferably from about one to about six times daily, more preferably from about one to about 4 times a day, or by using infusion to achieve the desired effect. Frequency intranasal connection in accordance with the invention is preferably from about one to about six times the before methods of prevention or treatment of diseases, related to the activity of the sympathetic nervous system, such as hypertension, myocardial ischemia, circulatory disorders of the heart, angina, cardiac arrhythmia and benign hypertrophy of the prostate, by administering a safe and effective amount of the compounds according to the invention to a mammal suffering from or at risk for these diseases or disorders. Each dose of the compounds of the invention preferably is injected dose, which is in the range from about of 0.0001 mg/kg to about 5 mg/kg of the compound, more preferably from about 0.001 mg/kg to about 0.5 mg/kg, Preferably oral and parenteral administration of such doses. The frequency of oral administration of compounds according to the invention is preferably from about one to about six times daily, more preferably from about one to about 4 times a day. The frequency of parenteral administration of the compounds according to the invention is preferably from about one to about six times daily, more preferably from about one to about 4 times a day, or by using infusion to achieve the desired effect.

In another aspect, the invention includes methods of preventing or LECG, suffering or at risk of pain. Each dose of the compounds of the invention preferably is injected dose, which is in the range from about of 0.0001 mg/kg to about 5 mg/kg of the compound, more preferably from about 0.001 mg/kg to about 0.5 mg/kg, Preferably oral or parenteral administration of such doses. The frequency of oral administration of compounds according to the invention is preferably from about one to about six times daily, more preferably from about one to about 4 times a day. The frequency of parenteral administration of the compounds according to the invention is preferably from about one to about six times daily, more preferably from about one to about 4 times a day, or by using infusion to achieve the desired effect.

In another aspect, the invention includes methods of prevention or treatment of substance abuse and withdrawal syndrome resulting from cancellation of substances such as alcohol and opiates, by administering a safe and effective amount of the compounds according to the invention to a mammal suffering from or at risk of substance abuse or withdrawal symptoms. Each dose of the compounds of the invention p is its preferably from about 0.001 mg/kg to about 0.5 mg/kg Preferably oral administration of the dose. The frequency of introduction of a joint in accordance with the invention is preferably from about one to about six times daily, more preferably from about one to about 4 times a day.

Examples of compositions and methods

The following non-limiting examples illustrate the compositions and methods of use of the invention.

An example of a

The composition of oral tablets

The ingredient Quantity per tablet (mg)

Compound 4 according to the invention to 20.0

Microcrystalline cellulose (Avicel PH 102) - 80,0

Dicalcium phosphate - 96,0

Fumed silica (Cab-O-Sil) - 1,0

Magnesium stearate - 3,0

Total - 200.0 mg

The patient with edema of the nasopharynx swallow one pill. Swelling is greatly reduced.

With almost the same results apply to other compounds having a structure corresponding to formula I.

The example IN

The composition of the tablets grinding

The ingredient Quantity per tablet (mg)

Connection 1 according to the invention to 15.0

Mannitol - 255,6

Microcrystalline cellulose (Avicel PH 101) - 100,8

Destinationa sucrose (Di-Pac
Magnesium stearate - 3,0

Lake, FD&C yellow 6 - 3,0

Fumed silica (Cab-O-Sil) - 2,7

Total - of 600.0 mg

The patient with edema of the nasopharynx Razgulyay and swallow one pill. Swelling is greatly reduced.

With almost the same results apply to other compounds having a structure corresponding to formula I.

Example WITH

The composition of the sublingual tablet

The ingredient Quantity per tablet (mg)

Compound 5 according to the invention is 2.00

Mannitol - 2,00

Microcrystalline cellulose (Avicel PH 101) - 29,00

Mint fragrances - 0,25

Sodium saccharin - 0,08

Total - 33,33 mg

The patient with edema of the nasopharynx puts one tablet under your tongue and letting it dissolve. Swelling rapidly and significantly reduced.

With almost the same results apply to other compounds having a structure corresponding to formula I.

Example D

The composition of intranasal solution

Ingredient Composition (% wt./about.)

Compound 3 according to the invention - 0,20

The benzalkonium chloride - 0.02

Thimerasol - 0,002

d-Sorbitol - 5,0

Glycine - 0,35

Flavors - 0,075

Purified water - the Required number

Ecocomposite in the amount of one tenth ml. Swelling is greatly reduced.

With almost the same results apply to other compounds having a structure corresponding to formula I.

Example E

The composition of intranasal solution

Ingredient Composition (% wt./about.)

Connection 1 according to the invention is 0,10

The benzalkonium chloride - 0.02

Thimerasol - 0,002

The hypromellose (Metolose 65SH4000) - 1,00

Flavors - 0,06

Sodium chloride (0.65%) are - Required number

Total - 100,00

In each nostril of the patient with edema of the nasopharynx contribute in the form of droplets through the bottle-dropper composition in the amount of one fifth part ml. Swelling is greatly reduced.

With almost the same results apply to other compounds having a structure corresponding to formula I.

Example F

The composition inhalation aerosol

Ingredient Composition (% wt./about.)

Compound 2 according to the invention - 5,0

Alcohol - 33,0

Ascorbic acid - 0,1

Menthol - 0,1

Sodium saccharin - 0,2

Forming an aerosol agent - Required number

Total - 100,00

A patient suffering from asthma, ingaliruut two portions of aerosol composition using the inhaler, atmaram the following other compounds, having a structure corresponding to formula I.

Example G

Local eye tools

Ingredient Composition (% wt./about.)

Compound 5 according to the invention is 0,10

The benzalkonium chloride is 0.01

EDTA - 0,05

Hydroxyethylcellulose (Natrosol M) - 0,50

Metabisulphite sodium - 0,10

Sodium chloride (0.9 per cent) - the Required number

Total - 100,00

The patient suffering from glaucoma, injected directly into each eye one-tenth ml of the composition. Intraocular pressure is greatly reduced.

With almost the same results apply to other compounds having a structure corresponding to formula I.

Example N

The composition of the oral fluid

The ingredient Quantity per 15 ml dose

Compound 4 according to the invention 15 mg

The chlorpheniramine maleate 4 mg

Propylene glycol and 1.8 grams

Ethanol (95%) - 1.5 ml

Methanol - 12.5 mg

Eucalyptus oil - 7.55 mg

Perfumes - 0.05 ml

Sucrose - of 7.65 g

Carboxymethylcellulose (CMC) - 7.5 mg

Microcrystalline cellulose and sodium CMC (Avicel RC 591) - 187.5 mg

Polysorbate 80 - 3.0 mg

Glycerin is 300 mg

Sorbitol 300 mg

Lake, FD&C red 40 3 mg

N the fair water The required number

Total - 15 ml

A patient with swelling of the nose and runny nose due to allergic rhinitis eaten 15 ml dose of liquid composition. Swelling and runny nose is effectively reduced.

With almost the same results apply to other compounds having a structure corresponding to formula I.

Example J

The composition of the oral fluid

Ingredient - Number/15 ml dose

Compound 2 according to the invention 30 mg

Sucrose - 8,16 g

Glycerin is 300 mg

Sorbitol 300 mg

Methylparaben - 19.5 mg

Propylparaben - 4.5 mg

Menthol - 22,5 mg

Eucalyptus oil - 7.5 mg

Odorants of 0.07 ml

Lake, FD&C red 40 - 3.0 mg

Sodium saccharin 30 mg

Purified water - the Required number

Total - 15 ml

A patient with swelling of the nasopharynx eaten 15-ml-inhibiting dose of non-alcoholic liquid medicines. Swelling and runny nose is effectively reduced.

With almost the same results apply to other compounds having a structure corresponding to formula I.

Example TO

The composition of oral tablets

The ingredient Quantity per tablet (mg)

Connection 1 according to the invention - 4

Microcrys is m, suffering from migraine, eaten one tablet. The pain and the specter of migraine is significantly reduced.

With almost the same results apply to other compounds having a structure corresponding to formula I.

Example L

The composition of the oral fluid

The ingredient Quantity per tablet (mg)

Compound 2 according to the invention - 12

The hypromellose, USP - 12

Magnesium stearate, USP - 2

Lactose anhydrous, USP - 200

Total - 226 mg

For pain relief of persons 12 years and older take one tablet every twelve hours.

With almost the same results apply to other compounds having a structure corresponding to formula I.

Example M

The composition of the encapsulated oral tablet

The ingredient Quantity per tablet (mg)

Naproxen sodium anhydrous, USP - 220

Compound 3 according to the invention - 6

The hypromellose, USP - 6

Magnesium stearate, USP - 2

Povidone K-30, USP - 10

Talc, USP - 12

Microcrystalline cellulose, NF - 44

Total 300 mg

To relieve symptoms that accompany the common cold, sinusitis or flu, including swelling of the nose, headache and the LASS="ptx2">

With almost the same results apply to other compounds having a structure corresponding to formula I.

Example N

The composition of oral tablets

The ingredient Quantity per tablet (mg)

Compound 4 according to the invention - 6

The hypromellose, USP - 6

The colloidal silicon dioxide, NF - 30

Pre gelatinizing starch, NF - 50

Magnesium stearate, USP - 4

Total - 96 mg

To facilitate benign prostatic hypertrophy take one tablet a day.

With almost the same results apply to other compounds having a structure corresponding to formula I.

Example OF

The oral composition of tabletki

The ingredient Quantity per tablet (mg)

Compound 5 according to the invention - 6

The hypromellose, USP - 6

Magnesium stearate, USP - 2

Povidone K-30, USP - 10

Talc, USP - 12

Microcrystalline cellulose, NF - 44

80 mg

Used in the treatment of alcoholism or opiate addiction. Persons 12 years and over take two encapsulated tablets every twelve hours.

With nearly the same result using other connection with the article is the Quantity per tablet (mg)

Connection 1 according to the invention - 6

The hypromellose, USP - 12

Magnesium stearate, USP - 2

Povidone K-30, USP - 10

Talc, USP - 12

Microcrystalline cellulose, NF - 44

Total - 86 mg

For the treatment of ulcers and acidity take two tablets on demand.

With almost the same results apply to other compounds having a structure corresponding to formula I.

Example Q

The composition of oral tablets

The ingredient Quantity per tablet (mg)

Compound 5 according to the invention is 10 mg/ml carrier

Carrier: sodium citrate buffer containing (mass percentage based on the media) lecithin 0.48 per cent.

Carboxymethylcellulose - 0,53

Povidone - 0,50

Methylparaben - 0,11

Propylparaben - 0,011

To reduce the destruction of the blood supply to the heart. With almost the same results apply to other compounds having a structure corresponding to formula I.

Example R

The composition of the liquid composition for oral administration

Ingredient: Amount per dose in one liquid ounce (mg)

Acetaminophen, USP - 1000

Doxylamine succinate, USP and 12.5

Of of dextromethorphan hydrobromide, USP - 30

Sedimentological, NF - 3000

Propylene glycol, USP - 3000

Alcohol, USP - 2500

The dihydrate of sodium citrate, USP - 150

Citric acid anhydrous, USP - 50

Sodium saccharin, USP - 20

Odorant - 3,5

Purified water, USP - 3500

Total - 29275 mg/fluid. oz

To facilitate weak dull aches, headache, muscle aches, sore throat pains and fever associated with colds or the flu. Facilitates nasopharynx edema, cough due to minor irritations of the throat and bronchi, runny nose associated with common cold sneezing. Persons 12 years and older take one fluid ounce every six hours.

With almost the same results apply to other compounds having a structure corresponding to formula I.

Example S

The composition of the liquid composition for oral administration

Ingredient: Amount per dose in one liquid ounce (mg)

Naproxen sodium anhydrous, USP - 220

Doxylamine succinate, USP and 12.5

Of of dextromethorphan hydrobromide, USP - 30

Connection 1 according to the invention - 6

Resin Dow XYS-40010.00 - 3

Corn syrup high-fructose - 16000

The polyethylene glycol, NF - 3000

Propylene glycol, USP - 3000

Alcohol, USP - 2500

The dihydrate of sodium citrate, USP - 150
Total - 28795 mg/fluid. oz

To facilitate weak dull aches, headache, muscle aches, sore throat pains and fever associated with colds or the flu. Facilitates nasopharynx edema, cough due to minor irritations of the throat and bronchi, runny nose associated with common cold sneezing. Persons 12 years and older take one fluid ounce every six hours.

With almost the same results apply to other compounds having a structure corresponding to formula I.

Example T

The composition for parenteral administration, prepared in accordance with the invention, includes:

Component Amount (mg)

Connection 1 according to the invention is 10 mg/ml carrier

Carrier: sodium citrate buffer containing (mass percentage based on the media) lecithin 0.48 per cent.

Carboxymethylcellulose - 0,53

Povidone - 0,50

Methylparaben - 0,11

Propylparaben - 0,011

The above ingredients are mixed to form a solution. The person suffering from sepsis or cardiogenic shock, intravenous approximately 2.0 ml of this solution. The symptoms are attenuated.

With nearly the same result using other compounds, imediently - Quantity per tablet (mg)

Compound 5 according to the invention - 10

The hypromellose, USP - 12

Magnesium stearate, USP - 2

Povidone K-30, USP - 10

Talc, USP - 12

Microcrystalline cellulose, NF - 44

Total - 90 mg

For the treatment of cardiac arrhythmias. Adopted by prescription.

With nearly the same result using other compounds having a structure corresponding to formula I.

Example V

The composition of oral tablets

The ingredient Quantity per tablet (mg)

Connection 1 according to the invention - 4

Microcrystalline cellulose, NF - 130

Starch 1500, NF - 100

Magnesium stearate, USP - 2

A total of 236 mg

For the treatment of heart failure with congestive phenomena. Adopted by prescription.

With nearly the same result using other compounds having a structure corresponding to formula I.

In light of the current state of science modification of the above embodiments of the invention in the preparation of drugs, as shown in the description of the method, understood by a person skilled in this field.

Other examples of combinations of active drugs. Examples of drugs kotiyeva, what have been described particular embodiments of the invention, for specialists in this field should be obvious that it can be made various changes and modifications of the invention without going beyond the spirit and substance of the invention. The accompanying claims are intended to cover all those modifications that are included in the scope of the invention.

1. Guanidinium heterocyclic compounds of the formula

< / BR>
where R1represents hydrogen or alkyl, or absent; when R1missing link (a) is a double bond;

D represents CR2and R2selected from hydrogen, unsubstituted C1-C3of alkyl and halogen; or, when is a CR3D can represent N;

In represents NR9, CR3= CR8, CR3, S, where R9selected from hydrogen and unsubstituted C1-C3of alkyl, alkenyl or quinil; and where R3and R8each, independently, selected from hydrogen, nezameshchennogo1-C3of alkyl, alkenyl, quinil or cyano;

R4, R5and R6each, independently, selected from hydrogen, unsubstituted C1-C3of alkyl, alkenyl, quinil, cyano, halogen ilila, and where one and only one of R1, R5and R6is guanidines;

R7selected from hydrogen; unsubstituted C1-C3of alkyl, alkenyl, quinil and halogen.

2. Connection on p. 1, where In represents CR3= CR8D is CR2and R1is absent, or represents NR9and D is CR2or represents S and D is CR2and R1is missing.

3. The compound according to any one of the preceding paragraphs, where R4selected from hydrogen; unsubstituted C1-C3of alkyl, alkenyl, quinil, cyano, halogen, R5represents hydrogen; and R7selected from hydrogen; unsubstituted C1-C3of alkyl, alkenyl, quinil or halogen.

4. The compound according to any one of the preceding paragraphs, which is:

(4,7-dimethylbenzimidazole-5-yl)guanidine;

(2,4-dimethylbenzimidazole-5-yl)guanidine;

(1,4-dimethylbenzimidazole-5-yl)guanidine;

(4-bromobenzimidazole-5-yl)guanidine;

N1N-methyl-N2-(4-methylbenzimidazole-5-yl)guanidine;

(8-methylinosine-7-yl)guanidine;

(8-bronchioles-7-yl)guanidine;

(6-methylbenzothiazol-5-yl)guanidine;

(4-bromans is the prevention or treatment of diseases, when agonists alpha-2 adrenergic receptors are effective for the relief of disease, containing a safe and effective amount of a compound according to any one of the preceding paragraphs and a pharmaceutically acceptable carrier.

6. The pharmaceutical composition according to p. 5, characterized in that it additionally contains one or more active substances selected from the group including antihistamine, protivokashlevy agent, a stabilizer of mast cells, a leukotriene antagonist, expectorant mucolytic agent, an antioxidant or an inhibitor radicals, steroid, bronchodilator, anti-viral agent, analgesic agent, anti-inflammatory, gastrointestinal tool and ophthalmological tool.

7. Activation of alpha-2 adrenergic receptors for the prevention and treatment of diseases in which agonists alpha-2 adrenergic receptors are effective for the relief of disease, by introducing to a mammal in need of such treatment, a safe and effective amount of the compounds specified in paragraph 1.

 

Same patents:

The invention relates to novel benzimidazole compounds represented by the General formula I

< / BR>
where denotes the number 0, 1, 2 or 3; R1represents an alkyl group, phenyl group or a monocyclic heterocyclic group containing as the heteroatom N or O, and these groups may be substituted once or more than once, by substituents selected from alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy, cyano, amino and nitro; or R1represents cyano or a group of formula-alkyl-CO2R2alkenyl-CO2R2, -CO-R2, -CO2(CH2)mR2or-C(R3)=N-OR2where m denotes the number 0, 1, 2 or 3; R2represents hydrogen, alkyl, phenyl, benzyl, 5 - or 6-membered heterocyclic group, which 5 - or 6-membered heterocyclic group may be substituted once or more than once by alkyl or alkoxy; or R2may represent a group of the formula -(CH2)q-NR4R5, -(CH2)q-CON(R4R5), -(CH2)q-CO2R4or-alkyl-CO2R4where R4and R5independently представляюUP> represents a group of General formula-CO2-R9where R9represents an alkyl or R9can represent a 6-membered heterocyclic group, and this 6-membered heterocyclic group may be substituted once or more than once by alkyl or alkoxy; or R9represents a group of General formula-alkyl-N(R10R12), where R10and R12independently represent hydrogen or alkyl; or R11represents a group of General formula II

< / BR>
where n denotes the number 0, 1, 2 or 3; R' and R" together with the N atom to which they are attached, form a heterocyclic ring with the number of members from 5 to 7, and this heterocyclic ring can contain as a ring member, one oxygen atom and/or one additional nitrogen atom; and in this formula, a heterocyclic ring with the number of members from 5 to 7, formed by R' and R", may be substituted once or more than once by a group of the formula -(CH2)px, where p denotes the number 0, 1, 2 or 3; X represents hydrogen, hydroxyl, alkyl or alkenyl, and these alkyl and alkenyl can be possibly substituted by one or more the>R6or-CON-R6R7where R6and R7independently represent hydrogen or alkyl; or R11may represent a group of General formula III

< / BR>
where n denotes the number 1; R' represents hydrogen or alkyl; R'" and R" 'together with the atoms to which they are attached, form a heterocyclic ring with the number of members from 5 to 7, and this heterocyclic ring can contain as a ring member one chain-CH=CH-; and in this formula, a heterocyclic ring with the number of members from 5 to 7, formed R'" and R"", may be substituted once or more than once by a group of the formula -(CH2)pX, where p denotes the number 0, 1, 2 or 3; X represents hydrogen, alkyl; or its pharmaceutically acceptable salt; provided that if R11is morpholinyl, R1may not represent tert-butyl; pharmaceutical compositions having the properties of the modulator of the GABAANDreceptors and the treatment of disorders and diseases of the living organism, and it is a disorder or disease responsive to modulation of GABAAND-receptor complex of the Central nervous

The invention relates to new derivatives of benzimidazole of formula 1, where R1represents hydrogen or hydrocarbon group with a short chain, R2- CH2HE, COOH, СООR34,4-dimethyl-2-oxazoline

The invention relates to new halogensubstituted the benzimidazole of the formula I, in which R1, R2, R3and R4mean hydrogen, halogen, alkoxy with 1 to 4 carbon atoms, a group of the formula Z - R5where R5means unsubstituted phenyl, pyridinyl which can be substituted by trifluoromethyl, and Z denotes oxygen, sulfur; R2and R3together signify unsubstituted or substituted alkylenes chain with 3 or 4 links, in which two (non-adjacent) carbon atoms may be replaced by oxygen atom; A denotes a group of the formula: - SO2- R6or

,

where Y represents oxygen or sulfur; R6, R7, R8independently of one another denote alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, alkenyl with 1 to 4 carbon atoms, dialkylamino, phenyl which may be substituted by nitro, stands, trifluoromethyl; 1-pyrrolidinyl, 1-piperidinyl; or thienyl, pyrazolyl, isoxazolyl, each of these residues can be substituted by chlorine, amine, stands, methoxy, trifluoromethyl, methoxycarbonyl; X represents halogen, and their acid additive salt

The invention relates to analogs of purine nucleoside containing the balance of sugar carbocyclic ring, their pharmaceutically acceptable derivatives, and their use in medical therapy particularly for the treatment of certain viral infections

The invention relates to new derivatives of benzimidazole, method of production thereof and their use as medicines

The invention relates to previously unknown compounds, useful in medical and veterinary practice, to their pharmaceutically acceptable salts and biopremier derivatives, to methods for obtaining data of new compounds, to pharmaceutical compositions containing these new compounds, to a single dosage forms of these compositions and to methods of treating patients using these compositions and dosage forms

The invention relates to new chemical compounds having valuable properties, in particular derivatives of dihydropyridines of General formula (I)

< / BR>
where R1aryl with 6-10 carbon atoms, unsubstituted or once-three times substituted by identical or different substituents from the group comprising halogen atom, a nitro-group, cyano, trifluoromethyl, cryptometer and triptoreline,

or substituted unbranched or branched alkyl with 1-8 carbon atoms, which is not substituted or substituted aryl with 6-10 carbon atoms, or substituted unbranched or branched alkoxygroup or alkoxycarbonyl with 1-8 carbon atoms, carboxypropyl, an amino group or a group of the formula-NR4R5in which

R4and R5the same or different and mean a hydrogen atom, an unbranched or branched alkyl with 1-8 carbon atoms, phenyl or benzyl,

or thienyl,

R2a hydrogen atom or cycloalkyl with 5-8 carbon atoms or an unbranched or branched alkyl, alkenyl, alkadienes, or quinil with 1-10 carbon atoms, unsubstituted or once or twice substituted od the cyano and nitro-group, or unbranched or branched alkylthiol, alkoxygroup, alkoxycarbonyl, acyl or alloctype with 1-8 carbon atoms, or cycloalkyl with 3-8 carbon atoms, fenoxaprop or phenyl, the latter is not substituted or once or twice substituted by identical or different substituents from the group comprising halogen atom, an unbranched or branched alkyl and alkoxygroup with 1-6 carbon atoms, or substituted by the group-NR4R5in which R4and R5have the above values,

R3a hydrogen atom or an unbranched or branched alkyl with 1-8 carbon atoms,

mixtures of their isomers or their individual isomers and their salts, mainly their physiologically tolerable salts

The invention relates to organic synthesis and relates to new quinoline derivatives and method of production thereof

The invention relates to new derivatives cycloalkane-pyridine of General formula (I), where a is aryl with 6-10 carbon atoms, unsubstituted or monosubstituted with halogen, D-aryl with 6-10 carbon atoms, unsubstituted or substituted by phenyl, nitro, halogen, trifluoromethyl or triptoreline, or a residue of the formula presented in the claims, E-cycloalkyl with 3-8 carbon atoms, a linear or branched alkyl with 1-8 carbon atoms or phenyl, unsubstituted or substituted with halogen or trifluoromethyl, R1and R2together form a linear or branched alkylenes chain with 1-7 carbon atoms, which is substituted by a carbonyl group and/or a residue of the formula shown in the formula of the invention, mixtures of their isomers, or individual isomers, their salts and N-oxides, with the exception of 5(6N)-quinolone, 3-benzoyl-7,8-dihydro-2,7,7-trimethyl-4-phenyl

The invention relates to medicine, namely, neurology

The invention relates to medicine

The invention relates to phenylselenenyl guanidium alkenylboronic acid of the formula (I)

< / BR>
where T means

< / BR>
moreover, R(A) denotes hydrogen, fluorine, chlorine, bromine, iodine, CN, IT, OR(6), (C1-C4)-alkyl, Or(CH2)aCbF2b+l, (C3-C8-cycloalkyl or NR(7)R(8); where

r denotes zero or 1;

a represents zero, 1, 2, 3 or 4;

b means 1, 2, 3 or 4;

R(6) means (C1-C4)-alkyl, (C1-C4)-perfluoroalkyl, (C3-C6)-alkenyl, (C3-C8-cycloalkyl, phenyl or benzyl;

and the phenyl nucleus is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, metoxygroup and NR(9)R(10);

where

R(9) and R(10) mean hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;

R(7) and R(8) independently of one another are specified for R(6) the value, or

R(7) and R(8) together mean 4 or 5 methylene groups, of which one CH2group can be replaced by oxygen, sulfur, NH, N-CH3or N-benzyl;

R(B) R(C) and R(D) independently from each other are specified for R(A) mn is od CN, OR(12), (C1-C8)-alkyl, Op(CH2)fCgF2g+l, (C3-C8-cycloalkyl or (C1-C9)heteroaryl;

R denotes zero or 1;

f is zero, 1, 2, 3 or 4;

g means 1, 2, 3, 4, 5, 6, 7 or 8;

R(12) means (C1-C8)-alkyl, (C1-C4)-perfluoroalkyl, (C3-C8)-alkenyl, (C3-C8-cycloalkyl, phenyl or benzyl,

and the phenyl nucleus is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, metoxygroup and NR(13)R(14); where

R(13) and R(14) denote hydrogen, (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;

R(E) has independently specified for R(F) value;

R(1) independently has a specified T value; or

R(1) means hydrogen, -OkCmH2m+l, -On(CH2)pCqF2q+1, fluorine, chlorine, bromine, iodine, CN, -(C= O)-N=C(NH2)2, -SOrR(17), -SOr2NR(31)R(32), -Ou(CH2)vWITH6H5, -Ou2-(C1-C9-heteroaryl or-Su2-(C1-C9-heteroaryl;

k is zero or 1;

m means zero, 1, 2, 3, 4, 5, 6, 7 or 8;

n denotes zero or 1;

p denotes zero, 1, 2, 3 or 4;

q is 1, 2,with hydrogen, (C1-C8)-alkyl or (C1-C8)-perfluoroalkyl or

R(31) R(32) together form a 4 or 5 methylene groups, of which one CH2group can be replaced by oxygen, sulfur, NH, N-CH3or N-benzyl;

R(17) implies (C1-C8)-alkyl;

u means zero or 1;

u2 means zero or 1;

v means zero, 1, 2, 3 or 4;

and the phenyl nucleus is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, Cl, CF3, methyl, metoxygroup, -(CH2)wNR(21)R(22), NR(18)R(19) and (C1-C9)-heteroaryl;

where

R(18) R(19), R(21) R(22) independently of one another denote (C1-C4)-alkyl or (C1-C4)-perfluoroalkyl;

w is 1, 2, 3 or 4;

moreover, a heterocycle (C1-C9)-heteroaryl not substituted or is substituted by 1-3 substituents selected from the group consisting of F, C1, CF3, methyl or metoxygroup;

R(2), R(3), R(4) and R(5) independently of one another are specified for R(1); or

R(1) and R(2) or R(2) and R(3) together mean a group-CH-CH=CH-CH-, which is not substituted or is substituted by 1-3 substituents selected from the group consisting of F, C1, CF3, methyl, metoxygroup, -(CH2)w2NR(24)R(25) and NR(26)R(27);

where
is 1, 2, 3, or 4;

and the molecule contains at least two residue is T, at most three;

and their pharmaceutically acceptable salts

The invention relates to orthotamine benzoylpyridine formula (1), where R(1) denotes R(13)-SOmm denotes the number 2; R(13) denotes alkyl, one of the substituents R(2) and R(3) represents hydrogen; and the other CHR(30)R(31), R(30) represents-(CH2)g-(CHOH)h-(CH2)I-(CHOH)k-R(32), R(32) denotes hydrogen or methyl, g, h, I is equal to zero, k is 1, R(2) and R(3) represents-C(OH)R(33)R(34), R(31), R(33) R(34) denote hydrogen or alkyl, R(4) denotes alkyl, alkoxy, F, Cl, Br, I
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