Imidazopyridine

 

(57) Abstract:

Usage: in the pharmaceutical industry. The inventive compounds: imidazopyridine formula I, in which R is H, CH3; R1and R4Is H; X is H; W is phenyl or phenyl substituted by halogen, acetoxy, hydroxy, lower alkyl group, a C1- C4, amino, or lower alkoxygroup C1- C4or phenyl, disubstituted by halogen and lower alkyl (C1- C4or phenyl, disubstituted by halogen and lower alkoxygroup C1- C4; R2and R3the same or different and are H, halogen, alkyl (C1- C4. The compounds have activity binding to GABA receptors. The structure of the compounds of formula I

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39 C.p. f-crystals, 2 Il.

The invention relates to certain imidazoquinolines that selectively bind to the GABA-a receptors. Compounds according to the present invention can be used in the treatment of anxiety or fear, sleep disorders, epileptic seizures, the effects of overdose with benzodiazepine drugs and States of increased anxiety. Describes the interaction of imidazoquinolines of the present invention with logicheskoi activity of these compounds.

-Aminobutyric acid (GABA) is one of the major inhibitory amino acid vectors in the mammalian brain. The presence of these mediators in the brain was already established over 30 years ago (Roberts Frankel, J. Biol. Chem. 187: 55 To 63, 1950; Udenfriend, J. Biol. 187: 65-69, 1950). Since that time, many works were devoted to investigation of the involvement of GABA to the etiology of epileptic seizures, sleep disorders, anxiety and disorders of cognitive abilities (Tallman and Gallager, Ann. Rev. Neuroscience 8: 21-44, 1985). It is believed that widespread, though it varies across the brain of the mammal GABA is a carrier of approximately 30% of the synapses in the brain. In most areas of brain GABA is associated with local inhibitory neurons, and only in two areas GABA is associated with longer shoots. GABA Mediaset many of their actions with the help of complex proteins localized on the bodies cells, and nerve endings, they are called GABA receptors. Postsynaptic responses to GABA mediasource through changes in chloride conductance, which is usually, though not always, leads to hyperpolarization of the cell. Conducted long and, is the main site of action for many structurally different compounds able to modification of postsynaptic responses to GABA. Depending on the type of interaction between these compounds capable of producing a wide range of activities (or sedative, anxiolytic and anticonvulsant or exciting and stimulating anxiety and seizure activity).

1,4-Benzodiazepines still remain one of the most widely used medicines in the world. Among them the most well-known drugs are chlordiazepoxide, diazepam, flurazepam, and triazolam. These compounds are widely used as anxiolytics, sedative-hypnotics, muscle relaxants and anticonvulsants. A number of these compounds is extremely strong drugs; and such activity indicates the presence of a site of high affinity and specific actions for individual receptors. Early electrophysiological studies have shown that the main activity of benzodiazepines is aimed at increasing GABA ergicheskoe inhibition. Benzodiazepines have the ability to raise other presynaptic 1967, Arch. Exp. Path. Pharmacol. 258: 69-82). All subsequent electrophysiological studies (Tallman and others 1980, Science 207: 274-281, Haefley and others 1981, Handb. Exp. Pharmacol. 33: 95-102) confirmed these observations, and in the middle of the 1970-ies electrophysiology came to a General agreement that benzodiazepines may potentiate the action of GABA.

With the opening of the "receptor" for benzodiazepines and subsequent determination of the nature of interaction between GABA and benzodiazepines, it became apparent that functionally important interaction of benzodiazepines with different neurotransmitter systems largely due to the increased ability of the GABA to the modification of these systems. Each modified system, in turn, can be associated with the expression of behavioral functions.

Studies of the nature of the mechanism of these interactions depend on the discovery site of high affinity benzodiazepine binding (receptor). This receptor is present in the CNS of all vertebrates, which are phylogenetically more recent species than fish Squieres Braestrup 1977, Nature 166: 732-734, Mohler Okada, 1977, Science, 198: 854-861, Mohler Okada, 1977, Br. J. Psychiatry 133: 261-268). Through the use of diazepam, labeled with tritium, and many other compounds was showing the Directors; and linking to these sites in vitro is rapid, reversible, stereospecific and is able to saturation. And more importantly, was illustrated particularly close relationship between the ability of benzodiazepines to displace diazepam from its binding site and the activity of a number of animals in behavioural tests on the effectiveness of benzodiazepine (Braestrupe Squires, 1978, Br. J. Psychiatry, 133: 249-260, Mohler Okada, 1977, Science 198: 854-5, Mohler Okada, 1977, Br. J. Psychiatry, 133: 261-268). The average therapeutic dose of the medicines for human also correlate with receptor activity (Tallman and others 1980, Science 207: 274-281).

In 1978 it was found that GABA and its analogues can interact in the website low-affinity binding (1 μm) GABA by increasing the binding of benzodiazepine with clonazepam-sensitive site (Tallman and others, 1978, Nature, 274: 383-385). This increase could be caused by an increase in the affinity of the binding site of the benzodiazepine, which is determined by the occupation of the site GABA. These data were interpreted as evidence that the sites of GABA and benzodiazepines are allosteric bound to the membrane as part of a protein complex. For a number of GABA-a unique ability to enhance the binding of diazepam to a maximum of 50% may nepos binding of the benzodiazepine GABA-agonists is blocked by an antagonist of the GABA-a receptor, (+) bicucullin; stereoisomer (-) bicucullin is much less active (Tallman and others, 1978, Nature 274: 383-385).

Soon after the discovery of high-affinity sites linking to benzodiazepines, it was found that in some areas of the brain triazolopyridine can interact with benzodiazepine receptors in a way that is consistent with the variability of receptors or negative cooperatively. In these studies, the hill coefficients are significantly smaller than the unit, was observed in some parts of the brain, including the cerebral cortex, hippocampus, and striatum. In the cerebellum, triazolopyridine interacted with sites benzodiazepine with a hill coefficient of 1 (Squires and others, 1979, Pharmacol. Biochem. Behav. 10: 825-830, Klepner and others 1979, Pharmacol. Biochem. Behav. 11: 457-462). Thus, many benzodiazepine receptors were predicted to cortex, hippocampus and striatum, but not the cerebellum.

On the basis of these studies were carried out autoradiographically study of localization of receptors using an optical microscope. Although it was illustrated by the presence of multiple receptors (Young Kuhar, 1980, J. Pharmacol. Exp. Ther. 212: 337-346, Young and others, 1981, J. Pharmacol. Exp. Ther. 216: 425-430, Niehoff and dray subtypes of receptors and behavior, associated with this region. In addition, in the cerebellum, where the study of binding was predicted by the presence of a single receptor, autoradiographically revealed a variety of receptors (Niehoff and others, 1982, J. Pharmacol. Exp. Ther. 221: 670-675).

Sieghart Karobath (1980, Nature, 286: 285-287) demonstrated the physical basis of the differences in specificity of medicines for these two explicit subtypes of benzodiazepine sites. Using gel electrophoresis with sodium dodecyl sulfate was established the presence of several molecular mass of the receptors to benzodiazepines. These receptors are identified by covalent injection of radioactive flunitrazepam, a benzodiazepine, which can covalently to mark all types of receptors. Most of the labeled bands had molecular weight of from 50,000 to 53000, the 55,000 and 57,000, and triazolopyridine inhibited tagging forms with a slightly higher molecular mass 53000, 55000, 57000 (Sieghart and others, 1983, Eur. J. Pharmacol. 88: 291-299).

At the same time, it has been suggested that many forms of receptors are "sorezore or multiple allelic forms of the receptor (Tallman Gallager, 1985, Ann. Rev. Neurosci. 8, 21-44). Although generally to enzymes, mainly, were not documented genetically from the Oia using specific radioactive probes and techniques of electrophoresis, became almost obvious that the study of sorezore would be a vital phase on the way to understanding the etiology of psychiatric disorders in humans.

Subunit of the GABA receptor cloned in bovine and human cDNA libraries (Schoenfield and others 1988; Duman and others 1989). By cloning and expression of a number of different cDNA were identified as a subunit of the GABA-receptor complex. These subunits are divided into categories,,,, and give the molecular basis of the heterogeneity of GABA-receptors and distinctive regional pharmacology (Shivvers and others 1980; Levitan and others 1989). Apparently, the g-subunit allows drug similar to benzodiazepine modify GABA responses (Putchett and others 1989). The presence of a low hill coefficients when the ligand binding to the GABA-a receptor indicates a unique profile specific pharmacological action subtype.

Drugs that interact with GABA-a receptor, can have a certain range of pharmacological activities, depending on their ability to modify the actions of GABA. For example, carboline were first selected based on their ability to competitively inhibit the binding of diazepam to his website his tie the practical activity of such compounds, to inhibit the binding can be agonists, partial agonists, inverse agonists and antagonists. When we determined the structure-carboline, it was possible to synthesize a number of counterparts and conduct behavioral tests of these compounds. As a result, it was immediately determined that-carboline can be antagonists of behavioral activity of diazepam (Tenen Hirsh 1980, Nature, 288: 609-610). In addition to this antagonism-carboline have activity, the opposite activity of benzodiazepines, and they became known as inverse agonists.

In addition, on the basis of ability to inhibition of binding of benzodiazepines were developed and other specific antagonist of benzodiazepine receptors. Of these compounds is best studied imidazothiazoles (Hunkeler and others, 1981, Nature, 290: 514-516). This connection is the high-affinity competitive inhibitor of the binding of benzodiazepine and beta-carboline and has the ability to block the pharmacological action of the compounds of these classes. By itself, this connection has a small inherent pharmacological activity in humans and animals (Hunkeler and others, 1981, Nature, 290: 514-516; Darragh and others, 1983, Eur. J. Clin. Pharmacol. 14: 569-570). The study radiolucency of positiv, as the benzodiazepines and beta-carboline and that the interaction of these compounds are purely competitive. Consider the connection represents the optimal ligand for binding to the GABA-a receptors, as it has no receptor subtype specificity and determines each state of the receptor.

Investigation of the interaction of a wide range of compounds similar to those described above, allowed us to separate these compounds by category. Currently, compounds with activity similar to the activity of benzodiazepines, are called agonists. Compounds with activity, the opposite activity of benzodiazepines, are called inverse agonists, compounds that inhibit both types of activity are called antagonists. The above categorization was done in order to emphasize the fact that a wide range of compounds can detect a wide range of pharmacological actions, and show that the compounds can interact with the same receptor, giving the opposite effects, and that beta-carboline and antagonists with intrinsic psychomotor effects are not synonyms. Biochemical test drugs were Irinovac their relationship with GABA ergicheskoi system. In contrast to the benzodiazepines, which show an increase in their affinity due to GABA (Tallman and others, 1978, Nature, 274: 383-385, Tallman and others 1980, Science 207: 274-281), compounds with antagonistic properties show a small GABA-shift (i.e., the change in the affinity of the receptor due to GABA) (Mohler and Richard, 1981, Nature, 294: 763-765), and inverse agonists actually show a decrease in the affinity due to GABA (Braestrup and Nielson, 1981, Nature, 294: 472-474). Thus, GABA-shift mainly indicates the estimated psychoreactive properties of these compounds.

As agonists and antagonists of benzodiazepine were obtained for various compounds. For example, in U.S. patents NN 4312870 and 4713383, and in the application Europatent EP 181282 describes some of the compounds used in the treatment of anxiety or depression. In U.S. patent N 4713383 disclosed compounds of the formula

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where R1(UN)substituted Ph, (dihydro)furanyl, tetrahydrofuranyl, (dihydro)thienyl, tetrahydrofuryl, pyranyl, ribofuranosyl, all associated With;

R2H, alkyl;

X IS O, S, R3N; R3H, alkenyl, quinil, C3-C20-cycloalkyl, (UN)substituted alkyl; aryl; aralkyl, where the aryl is Ph, pyridinyl, thienyl, furanyl;
< / BR>
where R1(substituted) Ph, or heterocycle;

R2H, alkyl, alkenyl, hydroxyalkyl, aralkyl, aralkyl, aryl;

R3H, alkyl, alkoxy, HO, halogen, F3C, O3N, H2N, alkylthio, alkylsulfonyl, alkylsulfonyl, arakaki;

X IS O, S, NR4; and R4H, alkyl, aralkyl, cycloalkyl, alkenyl, quinil, aryl, (substituted)aminoalkyl, hydroxyalkyl.

In U.S. patent N 4312870 describes compounds of the formula

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where Ph is 1,2-phenylene, unsubstituted or substituted from 1 to 3 identical or different members selected from the group comprising lower alkyl, lower alkoxy, lower alkylthio, hydroxy, halogeno, trifluoromethyl, nitro, amino, mono - or di-lower alkylamino, cyano, carbarnoyl, and carboxy;

R is unsubstituted or substituted phenyl, denoted by H-Ph, pyridyl, lower alkylphenyl or haloperidol;

R1hydrogen, lower alkyl or lower (hydroxy, dialkylamino or H-Ph)-alkyl;

R2hydrogen or lower alkyl-alkyl; their 3-hydroxycoumarin; lower alkanoyl, carbarnoyl, mono - or di-lower alkyl-carbarnoyl-derivatives of these (hydroxy or amino)-(phenyl or phenylene) compounds

and the compounds of formula

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where R" is hydrogen, alkyl or alkoxy, each is - or m-fluorescent; or if R" is chloro, R' is p-fluorescent.

Compounds of the present invention differs from the above described compounds. These compounds are not imidazoquinolines and have various ring substituents of the compounds of the present invention.

The present invention provides new compounds of formula I, which interact with the binding site of the GABAA benzodiazepine receptor.

The present invention also provides compounds useful in the treatment of neurotic conditions associated with anxiety, sleep disorders and fears, as well as in the treatment of epileptic seizures and the effects of benzodiazepine overdose. Accordingly, in the broad sense of the embodiment of the present invention relates to compounds of the formula

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and their pharmaceutically acceptable non-toxic salts,

where R is hydrogen or methyl;

R1and R4hydrogen;

X is hydrogen;

W is phenyl; phenyl substituted by halogen, acetoxy, hydroxy, lower alkyl group with straight or branched chain having 1-4 carbon atoms, amino, or lower alkoxy group with a straight or branched chain having 1-4 carbon atoms; phenyl, disubstituted by halogenanion and a lower alkoxy group with a straight or branched chain, having 1-4 carbon atoms; and

R2and R3the same or different and represent hydrogen, halogen, lower alkyl straight or branched chain having 1-4 carbon atoms.

The described compounds are highly selective agonists, antagonists or inverse agonists of GABA receptors in the brain, or prodrugs of agonists. These compounds are useful in the diagnosis and treatment of anxiety States, sleep disorders, epileptic seizures, the effects of overdose with benzodiazepine drugs and for improving memory.

In Fig. 1 (a d), 2 presents typical imidazopyridine of the present invention.

The new compounds according to the present invention can be represented by the following General formula

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and their pharmaceutically acceptable non-toxic salts,

where R is hydrogen or methyl;

R1and R4hydrogen;

X is hydrogen;

W is phenyl; phenyl substituted by halogen, acetoxy, hydroxy, lower alkyl group with straight or branched chain having 1-4 carbon atoms, amino, or lower alkoxy group with a straight or branched chain having 1-4 carbon atoms; phenyl, disubstituted by halogenanion and a lower alkoxy group with a straight or branched chain, having 1-4 carbon atoms; and

R2and R3the same or different and represent hydrogen, halogen, lower alkyl straight or branched chain having 1-4 carbon atoms.

The present invention also relates to compounds of the formula

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where R1and R4hydrogen;

X is hydrogen;

W is phenyl; or phenyl substituted by halogen, acetone, hydroxy, lower alkyl group with straight or branched chain having 1-4 carbon atoms, or lower alkoxy group with a straight or branched chain having 1-4 carbon atoms.

In addition, the present invention relates to compounds of the formula

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where W is phenyl, disubstituted by halogen and lower alkyl straight or branched chain having 1-4 carbon atoms; phenyl, disubstituted by halogen and lower alkoxy group with a straight or branched chain having 1-4 carbon atoms.

The present invention also includes compounds of the formula

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where W is phenyl, disubstituted by halogen and lower alkoxy group with a straight or branched chain having 1-4 carbon atoms; and

R2and R3the hydrogen.

Non-toxic pharmaceutically acceptable salts of the present izobreteniya, formic, sulfonic, itestosterone, acetic acid, etc., Any specialist known for a wide range of non-toxic pharmaceutically acceptable additive salts.

Typical representatives of compounds of this invention encompassed by formula I, include, but are not limited to the compounds shown in Fig. 1 and 2, and their pharmaceutically acceptable salts. The present invention also encompasses the acylated precursor compounds of the formula I. To obtain non-toxic pharmaceutically acceptable additive salts and acylated precursor compounds of the formula I can be used by various synthesis methods well-known to experts.

Used in the present description, the term "lower alkyl" means alkyl groups of straight or branched chain having 1-4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylindenyl.

Used in the present description, the term "lower alkoxy" means alkoxy groups with straight or branched chain having 1-4 carbon atoms, such as methoxy, ethoxy, about the and, 2 hexose, 3 hexose and 3 methylpentane.

Used in the present description, the term "halogen" means fluorine, bromine, chlorine or iodine.

The pharmaceutical utility of compounds of the present invention is illustrated by the following analysis on the GABA-a receptor activity.

Analyses were carried out in accordance with the description given in the work of Thomas and Tallman J. Bio. Chem. 156: 9838-9842, J. Neurocsi. 3: 433-440, 1983. The rats cut the tissue of the cerebral cortex and homogenized in 25 volumes (wt. /about.) 0.05 M Tris-HCl buffer (pH of 7.4 at 4oC). The obtained tissue homogenate was centrifuged for 20 min at 4oC and at 20000 g. The supernatant decantation, and the residue is again homogenized in the same volume of buffer and again centrifuged at 20000 g. After that, the supernatant decantation, and the residue was left overnight at -20oC. Then the precipitate was thawed and homogenized in 25 volumes (wt./about.) buffer, and this procedure was repeated twice. Finally, the precipitate is re-suspended in 50 volumes of buffer (wt./about. 0.05 M Tris-HCl, pH 7,4 at 40oC).

The incubation mixture contained 100 μl of tissue homogenate, 100 μl of radioactively labelled ligand (0.5 nm,3H-R015-1788 [3H-Flumazenil] specifiesthe for 30 min at 4oC, after which the mixture was rapidly filtered through CFB filters to separate free and bound ligand. Filters were washed twice in fresh Tris-HCl buffer (0.05 M, pH of 7.4 at 4oC), and count in a liquid scintillation counter. Then in the same test tube was added to 1.0 μm diazepam to assess nonspecific binding. Data obtained from three measurements were averaged and calculated the complete inhibition of specific binding (total specific binding all linking nespec. binding). In some cases, the number of scheduled medicines varied, and in accordance with this build curves complete displacement of the binding. The obtained data were transformed to calculate the IC50and the hill coefficient. These data are presented below.

The compound N IC50μm

1 0,0095

3 0,015

4 0,0095

5 0,016

33 0,0024

Connections numbers relate to compounds shown in Fig. 1, 2.

Compounds 1, 3 and 4 are particularly preferred compounds of the present invention.

Compounds of General formula I can be administered orally, topically, parenterally, by inhalation or injection, or rectally fillers. Used in the present description, the term "parenteral" includes subcutaneous, intravenous, intramuscular or vnutrigrudne injection or infusion. Pharmaceutical compositions based on compounds of the present invention contain a compound of General formula I and a pharmaceutically acceptable carrier. While in the specified compositions may contain one or more compounds of General formula I in combination with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants, and if desired, in combination with other active ingredients. Pharmaceutical compositions containing compounds of General formula I, can be introduced in the form of appropriate forms for oral administration such as tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs.

Compositions for oral use can be obtained in accordance with a standard technique used in the pharmaceutical industry, and these compositions may contain one or more substances selected from the group comprising podlech qualities and aesthetic appearance. Tablets usually contain the active ingredient in a mixture with non-toxic pharmaceutically acceptable fillers, which are often used in the manufacture of tablets. Such fillers may be inert diluents, for example calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating or dezintegriruetsja agents, for example maize starch, or alginic acid; binding agents, for example starch, gelatin or the Arabian gum; sizing agents, for example magnesium stearate, stearic acid or talc. Tablets may be uncoated or they may be covered by the standard methods in order to slow down the disintegration and absorption of the active ingredient in the gastrointestinal tract, thereby informing the product of prolonged action. For this purpose, for example, can be used monostearate or distearate glycerin.

Preparations for oral administration can also be made in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin; or in the form of soft gelatin capsules in which the active inivalue oil.

The liquid suspension containing the active ingredients, usually in combination with fillers commonly used for the manufacture of aqueous suspensions. Such fillers can be suspendresume agents, for example sodium carbometalation, methylcellulose, gidropropilmetilzelluloza, sodium alginate, tragacanth gum and Arabic gum; and dispersing or wetting agents which may be natural phosphatides, for example lecithin, or condensation products of accelerated with fatty acids, for example polyoxyethylene, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecafluorooctane, or condensation products of ethylene oxide with a partial ester of a polyhydric alcohol, derived from fatty acids and exit, such as polyoxyethylenesorbitan, or condensation products of ethylene oxide with partial esters derived from fatty acids and mexicanvalium, such as polyethylenterephthalat. Aqueous suspensions may also contain one or more preservatives, for example ethyl-, or n-propyl-p-hydroxybenzoate; one or more coloring agents; one or more flavoring is spencie can be obtained by suspension of the active ingredients in a vegetable oil, such as peanut oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweeteners, such as were mentioned above, and flavoring agents may be added to the composition to impart a pleasant taste and aesthetic appearance. To protect the compositions from exposure to the environment can be added antioxidants, such as ascorbic acid.

Dispersible powders and granules, intended for the manufacture of aqueous suspensions by addition of water, are the active ingredient in combination with a dispersing or wetting agent, and one or more preservatives. Examples of suitable dispersing or wetting and suspendida agents listed above. The composition may also contain additional ingredients, for example sweetening, flavoring and coloring agents.

Pharmaceutical compositions can also be made in the form of emulsions of the type oil-in-water". The oil phase of such emulsions can be raising what they emulsifying agents are natural resins, such as the Arabian gum or tragacanth gum; natural phosphatides, such as soybean lecithin; and esters or partial esters derived from fatty acids and hexitol and anhydrides, such as servicemanual, and condensation products of these partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. These emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs can be prepared with the use of sweetening agents, such as glycerin, propylene glycol, sorbitol or sucrose. These preparations may also contain a means of reducing the irritation, preservative, flavoring agent and dye. The pharmaceutical compositions can be manufactured in the form of sterile injectable aqueous or oil suspensions. These suspensions can be obtained in accordance with standard techniques using suitable dispersing or wetting agents mentioned above. Such sterile injectable drugs may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, naptime and isotonic sodium chloride solution. In addition, as a solvent or suspendida environment can be used sterile fatty oil. For these purposes may be used any soft fatty oils, including synthetic mono - or diglycerides. In addition, injectable preparations may be used fatty acids, such as oleic acid.

Compounds of General formula I can also be introduced rectally as suppositories. These compositions can be obtained by mixing the active ingredient with a suitable not irritating filler, which at room temperature is solid, and getting into the rectum, melts and becomes liquid, thereby releasing the drug. For these purposes usually use cocoa butter and polyethylene glycols.

Compounds of General formula I may be introduced parenterally in a sterile environment. The drug depending on the fillers and concentration can be either suspended or dissolved in the vehicle. If you are using adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.

Used for LHA patient 0.5 mg to 7 g per day. The amount of the active ingredient, combined with the material of the carrier in the manufacture of a single dosage form may vary depending on the condition of the patient and the route of administration of the medicinal product. Standard single form usually contains 1 to 500 mg of active ingredient.

Obviously it is clear, however, that the specific dose for each particular patient depends on many factors, namely the activity of the specific tools used, age, weight, General health, and sex of the patient, as well as diet schemes, the method of administration, the rate of release of the medicinal product, its composition and the severity of the disease.

Obtaining the compounds of the present invention is illustrated in schemes I and II below. Specialists in this field clearly evident that in the present scheme of producing compounds of the present invention can be introduced an additional stage and used material may also vary, as shown in the examples below.

In schemes I and II below, marked: R1, R4and X represent hydrogen; and R2, R3and W have the meanings defined is necessary to hold the blocking of certain reactive functional groups. The need for such a block, as well as the conditions necessary for attachment and removal of such groups, and generally can be identified by experts in the field of organic synthesis.

Example I.

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To a mixture of isocyanate 2-nitrophenyl (3,34 g) in 100 ml of toluene was added aniline (2 g). The mixture was stirred for 30 min at 20oC. Then was added hexane (300 ml) and the resulting solid is filtered and dried, resulting in a received N-(2-nitrophenyl)-N'-phenyl-urea as a light yellow solid.

Example II.

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To a solution of diethyldithiocarbamate (17.9 g) in 300 ml of ethanol was added 1N. NaOH (70 ml) and stirred over night. Then was added 1N. HCl (70 ml) and the reaction was distributed between methylene chloride (200 ml) and water (200 ml). The aqueous layer was extracted 3 more times. The combined organic extracts were dried and the solvent was removed in vacuo, resulting in a received ethyl-3-nitro-4-carboxybenzoyl in the form of a white solid.

Example III.

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To diphenylphosphinite (5.75 g) in anhydrous toluene (50 ml) at 100oC in nitrogen atmosphere for one drop was added to a solution containing ethyl-3-nitro-4-carboxybenzoyl (5 g) and triethylamine (4 ml) in the Yu and the mixture was left to cool to room temperature (40 min). Then added ethyl acetate (300 ml) and the solution was washed successively with 1N. HCl (300 ml), water (300 ml), 1N. NaOH (300 ml) and water (300 ml). The organic layer was dried and the solvent was removed in vacuum. To the obtained oily substance was added diethyl ether (50 ml) and the resulting solid were combined and dried, resulting in a received N-(2-nitro-5-methyl-phenyl)-N'-phenyl-urea as a white solid.

Example IV.

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A solution containing N-(2-nitrophenyl)-N'-phenyl-urea (5,76 g) and chloroacetone (40 ml) was heated under reflux in nitrogen atmosphere for 30 minutes After removal of excess chloroacetanilide in vacuum was added diethyl ether and the resulting solid is filtered and dried, resulting in a received N'-(2-chloroacetyl)-N-(2-nitrophenyl)-N'-phenyl-urea as a white solid.

Example V.

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A solution of N'-(2-chloroacetyl)-N-(2-nitrophenyl)-N-phenyl-urea (3.7 g), dimethylformamide (15 ml) and diisopropylethylamine (15 ml) was heated under reflux for 5 minutes Heated the mixture was left to cool to room temperature and precipitated with a mixture of 200 ml of water. The precipitate was collected and dried in resultsare 1-(2-nitrophenyl)-3-phenyl-imidazoline-2,4(1H, 3H)-dione (2.7 g) in anhydrous dimethylformamide (2 ml) under nitrogen atmosphere was added N,N-dimethylformamidine (2.7 g). The reaction mixture was stirred 2 h at 80oC and the solvent was removed in vacuum. To the obtained oily substance was added iron powder (5 g) and acetic acid (250 ml). This mixture was carefully heated under reflux for 3 min, followed by stirring the reaction mixture an additional 30 minutes Heterogeneous mixture was diluted with 10% methanomicrobiales (200 ml) and filtered through silica gel, using as eluent a mixture of 10% methanol and methylene chloride. The solvent was removed in vacuum, and then added hot ethanol (200 ml). To this mixture was added water (200 ml) and the resulting solid was filtered and washed successively with ethanol, ethyl acetate, diethyl ether, and dried, resulting in a received 2-phenyl-imidazo [1,5-a] cinoxacin-1,3 (2H, 5H)-dione as a yellow solid with so pl. 231-234oC (compound 1).

Example VII.

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To a solution containing 1-(2-nitrophenyl)-3-(2-forefeel)-imidazolin-2,4 (1H, 3H)-dione (1.18 g) in anhydrous methylene chloride (5 ml) under nitrogen atmosphere was added Tris dimethylamino methane (1 ml). The reaction mixture was primaraly in DMF 100 ml) was added a suspension of Nickel catalyst for hydrogenation (50% solution in water, 1 ml). The mixture was hydrogenosomal at a pressure of 50 pounds per square inch (344,7 kPa) within 45 minutes After filtration through celite, the solvent was concentrated under vacuum in the amount of 30 ml, and then added water (50 ml). The obtained solid was collected and washed successively with ethanol, ethyl acetate and diethyl ether and aired, which was obtained 2-(2-forefeel)-imidazo[1,5-a]quinoxalin-1,3-(2H, 5H)-dione as a yellow solid matter (compound 2), so pl. 261-264oC.

Example VIII.

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To a solution containing DMF (100 ml), H2O (15 ml), 5%-Ro-charcoal (1.25 g) and 1-(2-nitrophenyl)-3-(4-ethoxyphenyl)-imidazolin-2,4 (1H,3H)-dione (25 g) at 60oC, one drop was added to the solution containing hypophosphite sodium (15 g) in H2O (40 ml). After 3 h the mixture was cooled to room temperature and filtered through celite. The mixture was poured into 500 ml of H2O, filtered and dried, resulting in the obtained 1-(2-AMINOPHENYL)-3-4-ethoxyphenyl-imidazolin-2,4(1H, 3H)-dione.

Example IX.

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To 1-(2-AMINOPHENYL)-3-(4-ethoxyphenyl)-imidazolin-2,4-(1H,3H)-dione (2 g) was added DMF (5 ml), acetic acid (5 ml) and dimethylformamidine (5 ml). The reaction mixture was heated at 60oC 16 h, then cooled and has shown what LOTOS, the result that was obtained 2-(4-ethoxyphenyl)-imidazo [1.5, and] cinoxacin-1.3 (2H,5H)-dione with so pl. 268-269oC (compound 3).

Example x Following basically the procedure described in examples VI, VII and IX received the following connections:

1. 2-(4-methoxyphenyl)-imidazo [1.5, and] cinoxacin-1.3 (2H, 5H)-dione (compound 4), so pl. 240-242oC.

2. 2-(4-were)-imidazo [1.5,and] cinoxacin-1.3(2H,5H)-dione (compound 5), so pl. 305-308oC.

3. 2-4-forefeel-imidazo[1.5, and]cinoxacin-1.3(2H,5H)-dione (compound 6), so pl. 235-238oC.

4. 2-(2-AMINOPHENYL)-imidazo[1.5,and]cinoxacin-1.3 (2H,5H)-dione (compound 7), so pl. 247-249oC.

5. 2-(3-forefeel)-imidazo[1,5,a]cinoxacin-1,3(2H,5H)-dione (compound 8), so pl. 265-266oC.

6. 2-(4-course)-imidazo[1.5,and]cinoxacin-1,3(2H,5H)-dione (compound 9), so pl. 235-238oC.

7. 2-(3-were)-imidazo[1,5,a]cinoxacin-1,3(2H,5H)-dione (compound 10), so pl. 263-265oC.

8. 2-(2-fluorescent-4-ethoxyphenyl)-imidazo [1,5,a] cinoxacin-1,3(2H,5H)-dione (compound 11), so square 264-267oC.

9. 2-(3-course)-imidazo[1,5,a]cinoxacin-1,3(2H,5H)-dione (compound 12), so pl. 235-239oC.

10. 2-(2-methoxyphenyl)-imidazo[1,5, a] cinoxacin-1,3(2H, 5H)-dione (compound 13), so pl. 270-272x2">

12. 2-(2-fluorescent-4-were)-imidazo [1,5,a] cinoxacin-1,3(2H,5H)-dione (compound 15), so pl. 280-284oC.

13. 2-(3-methoxyphenyl)-imidazo[1,5, a] cinoxacin-1,3(2H, 5H)-dione (compound 16), so pl. 212-214oC.

14. 2-(3-ethoxyphenyl)-imidazo[1,5,a]cinoxacin-1,3(2H,5H)-dione (compound 17), so pl. 197-200oC.

15. 2-(4-n-proproxyphene)-imidazo [1,5,a] cinoxacin-1,3(2H,5H)-dione (compound 18), so pl. 182-185oC.

16. 2-(4-n-butoxyphenyl)-imidazo [1,5, a] cinoxacin-1,3(2H, 5H)-dione (compound 19), so pl. 155-156oC.

17. 2-(4-isopropoxyphenyl)-imidazo [1,5, a] cinoxacin-1,3(2H,5H)-dione (compound 20), so pl. 164-167oC.

18. 7-chloro-2-(4-were)-imidazo [1,5,a] cinoxacin-1,3(2H,5H)-dione (compound 21), so pl. 200-204oC.

19. 7,8-dimethyl-2-(4-ethoxyphenyl)-imidazo [1,5, a] cinoxacin-1,3(2H, 5H)-dione (compound 22).

20. 8-methyl-2-phenyl-imidazo[1,5,a]cinoxacin-1,3(2H,5H)-dione (compound 23), so pl. 240-244oC.

21. 8 carboethoxy-2-(4-ethoxyphenyl)-imidazo [1,5,a] cinoxacin-1,3(2H, 5H)-dione (compound 24).

22. 7 carboethoxy-2-(4-ethoxyphenyl)-imidazo [1,5,a] cinoxacin-1,3(2H, 5H)-dione (compound 25).

23. 8-bromo-2-(4-ethoxyphenyl)-imidazo [1,5,a] cinoxacin-1,3(2H,5H)-dione (compound 26), so pl. 152-155="ptx2">

25. 7-methyl-2-(4-ethoxyphenyl)-imidazo [1,5,a] cinoxacin-1,3(2H,5H)-dione (compound 28), so pl. 200-203oC.

26. 2-(3-bromo-4-ethoxyphenyl)-imidazo [1,5,a] cinoxacin-1,3(2H,5H)-dione (compound 29), so pl. 147-150oC.

27. 2-(3-thienyl)-imidazo[1,5, a] cinoxacin-1,3(2H,5H)-dione (compound 30).

28. 2-(2-thienyl)-imidazo[1,5, a] cinoxacin-1,3(2H,5H)-dione (compound 31).

29. 2-(4-acetoxyphenyl)-imidazo [1,5, a] cinoxacin-1,3(2H, 5H)-dione (compound 32), so pl. 210-211oC.

Example XI.

< / BR>
To a suspension 2-4-methoxyphenyl-imidazo[1,5,a] cinoxacin-1,3(2H,5H)-dione (100 mg) in anhydrous dioxane (4 ml) was added bromine (200 mg). The reaction mixture was stirred 15 min at 20oC, and then poured directly in boiling acetic acid (50 ml) containing zinc powder (500 mg). The reaction mixture was heated under reflux for 5 min, and then cooled to room temperature. After dilution with 10% methanol and methylene chloride (100 ml) and the mixture was filtered through silica gel, the solvent was removed in vacuum and the resulting solid was treated with boiling ethanol (25 ml) followed by dilution with water (100 ml). The mixture was cooled to 0oC, and the solid is filtered and dried in financial p the solid substance so pl. 154oC.

Example XII. Following basically the procedure described in example XI, received the following connection:

8-bromo-2-(3-bromo-4-ethoxyphenyl)-imidazo [1,5, a] quinoxaline-1,3(2H, 5H)-dione (compound 34), so pl. 146-149oC.

Example XIII.

< / BR>
A solution containing 1-(2-nitrophenyl)-3-(4-ethoxyphenyl) imidazolin-2,4(1H,3H)-dione (5 g) in anhydrous tetrahydrofuran (50 ml) was added drop by drop over 30 minutes to a solution of 0.5 M LDA in tetrahydrofuran (29 ml) at -78oC. After 20 min was added to one portion of ethylchloride (1.2 ml) in tetrahydrofuran (5 ml). The reaction mixture was heated to room temperature for 30 min, and then extinguished with a saturated solution of ammonium chloride. The reaction mixture was distributed between ethyl acetate and water, the organic layer was dried and the solvent was removed in vacuum. Then spent column chromatography on silica gel, elwira a mixture of 50% ethyl acetate and hexane, resulting in received a 5-carboethoxy-1-(2-nitrophenyl)-3-(4-ethoxyphenyl)-imidazolin-2,4 (1H,3H)-dione.

Example XIV.

< / BR>
To a suspension containing zinc powder (6 g) in acetic acid (250 ml) was added 5-carboethoxy-1-(2-nitrophenyl)-3-(4-ethoxyphenyl)-imidazolin-2,4 (1H, 3H)-dione (2.5 g). The mixture was heated 1 is IU, and the resulting solid was stirred with ethanol (50 ml) and filtered, resulting in a received 4-hydroxy-2-(4-ethoxyphenyl)-imidazo [1,5,a] cinoxacin-1,3(2H,5H)-dione (compound 35).

Example XV.

< / BR>
A solution of 4-hydroxy-2-(4-ethoxyphenyl)-imidazo [1,5,a]-quinoxaline-1,3(2H, 5H)-dione (3.2 g) in phosphorus oxychloride (40 ml) was heated under reflux for 16 hours the Solvent was removed in vacuo and added 15 ml. water and Then the pH was brought to 7.0 using ammonium hydroxide and the resulting solid is filtered and dried, resulting in a received 4-chloro-2-(4-ethoxyphenyl)-imidazo[1,5,a]cinoxacin-1,3(2H,5H)-dione (compound 36).

Example XVI.

< / BR>
A solution of tetrahydrofuran (10 ml), ammonia (10 ml) and 4-chloro-2-(4-ethoxyphenyl)-imidazo[1,5, a]cinoxacin-1,3(2H,5H)-dione (100 mg) was heated for 4 h in a sealed tube at 100oC. After cooling to room temperature the solvent was removed in vacuum. The solid is suspended in 50% EtOH-H2O and filtered to obtain 4-amino-2-(4-ethoxyphenyl)-imidazo[1,5,a] cinoxacin-1,3(2H,5H)-dione (compound 37).

Example XVII. Following basically the procedure described in example XVI, received the following connections:

1. 4-di is 4-ethoxyphenyl)-imidazo [1,5,a] cinoxacin-1,3(2H, 5H)-dione (compound 39).

3. 4-N-methylamino-2-(4-ethoxyphenyl)-imidazo [1,5,a] cinoxacin-1,3 (2H, 5H)-dione (compound 40).

Example XVIII.

< / BR>
2-(4-acetoxyphenyl)-imidazo[1,5, a] cinoxacin-1,3(2H, 5H)-dione (250 mg) was added to a solution of ethanol (50 ml), saturated with HCl. The solution was stirred 2 h and the solvent was removed in vacuo, resulting in a received 2-(4-hydroxyphenyl)-imidazo [1,5, a] cinoxacin-1,3(2H,5H)-dione (compound 41), so pl. 318-322oC.

Example XIX.

< / BR>
2-(4-ethoxyphenyl)-imidazo[1,5, a] cinoxacin-1,3 (2H, 5H)-dione (100 mg) was added to a solution of dimethylformamidine (10 ml) and DMF (5 ml), then the reaction mixture was heated for 4 h at 100oC. the Solution was cooled to room temperature and poured into water (200 ml). The precipitate was collected and dried, resulting in a received 5-N-methyl-2-(4-ethoxyphenyl)-imidazo [1,5,a] cinoxacin-1,3 (2H,5H)-dione (compound 42), so pl. 263-266oC.

Example XX.

< / BR>
2-(4-ethoxyphenyl)-imidazo[1,5, a]cinoxacin-1,3 (2H,5H)-dione was added to a solution of anhydrous DMF (5 ml) and tert-butoxide potassium (125 mg) at 50oC. After 5 min was added trimethylacetylchloride (150 ml). The reaction mixture was stirred 15 min and poured into water (25 ml). Obtained insurance [1,5,a] cinoxacin-1,3 (2H,5H)-dione (compound 43).

Example XXI. Following basically the procedure described in example XX, received the following connections:

1. 3-n-propoxy-2-(4-ethoxyphenyl)-imidazo [1,5, a] cinoxacin-1 (2H, 5H)-on (compound 44).

2. 5-propionyl 2-(4-ethoxyphenyl)-imidazo [1,5, a] cinoxacin-1,3 (2H, 5H)-dione (compound 45).

Although illustrated and described above specific embodiments of the invention, specialists in the art of the obvious various modifications, and therefore assumes that the present invention is not limited to the described variants of its implementation or its separate parts, and that the possible deviations from them within the essence and scope of the present invention defined in the following claims.

1. Imidazopyridine General formula

< / BR>
where R is hydrogen or methyl;

R1and R4hydrogen;

X is hydrogen;

W is phenyl or phenyl substituted by halogen, acetoxy, hydroxy, lower alkyl group with straight or branched chain, having 1 to 4 carbon atoms, amino or lower alkoxygroup straight or branched chain, having 1 to 4 carbon atoms, or phenyl, disubstituted by halogen and lower alkyl straight or resetusersettings chain having 1 to 4 carbon atoms;

R2and R3the same or different, hydrogen, halogen, lower alkyl straight or branched chain, having 1 to 4 carbon atoms.

2. Connection on p. 1 of General formula

< / BR>
where R1and R4hydrogen;

X is hydrogen;

W is phenyl, phenyl substituted by halogen, acetoxy, hydroxy, lower alkyl straight or branched chain, having 1 to 4 carbon atoms, or lower alkoxygroup straight or branched chain, having 1 to 4 carbon atoms.

3. Connection on p. 1 of General formula

< / BR>
where W is phenyl, disubstituted by halogen and lower alkyl straight or branched chain, having 1 to 4 carbon atoms.

4. Connection on p. 1 of General formula

< / BR>
where W is phenyl, disubstituted by halogen and lower alkoxy, straight or branched chain, having 1 to 4 carbon atoms;

R2and R3the hydrogen.

5. Connection on p. 1, in which W is phenyl.

6. Connection on p. 1, in which R2bromine.

7. Connection on p. 1, in which W is 4-methoxyphenyl.

8. Connection on p. 1, in which W 2-forfinal.

9. Connection on p. 1, in which W 4-ethoxyphenyl.

10. Connection on p. 1, representing 2 fanmeet(1,5-a)cinoxacin-1,3(2H, 5H)-dione.

12. Connection on p. 1 representing 2-(4-ethoxyphenyl)-imidazo(1,5-a)cinoxacin-1,3(2H,5H)-dione.

13. Connection on p. 1 representing 2-(4-methoxyphenyl)-imidazo(1,5-a)cinoxacin-1,3(2H,5H)-dione.

14. Connection on p. 1 representing 2-(4-were)-imidazo(1,5-a)cinoxacin-1,3(2H,5H)-dione.

15. Connection on p. 1 representing 2-(4-forfinal)- imidazo(1,5-a)cinoxacin-1,3(2H,5H)-dione.

16. Connection on p. 1 representing 2-(2-AMINOPHENYL)-imidazo(1,5-a)cinoxacin-1,3(2H,5H)-dione.

17. Connection on p. 1 representing 2-(3-forfinal)- imidazo(1,5-a)cinoxacin-1,3(2H,5H)-dione.

18. Connection on p. 1 representing 2-(4-chlorophenyl)- imidazo(1,5-a)cinoxacin-1,3(2H,5H)-dione.

19. Connection on p. 1 representing 2-(3-were)-imidazo(1,5-a)cinoxacin-1,3(2H,5H)-dione.

20. Connection on p. 1 representing 2-(2-fluoro-4 - ethoxyphenyl)-imidazo(1,5-a)cinoxacin-1,3(2H,5H)-dione.

21. Connection on p. 1 representing 2-(3-chlorophenyl)- imidazo(1,5-a)cinoxacin-1,3(2H,5H)-dione.

22. Connection on p. 1 representing 2-(2-methoxyphenyl)-imidazo(1,5-a)hinckson-1,3(2H,5H)-dione.

23. Connection on p. dostavljaust a 2-(2-fluoro-4-were)imidazo(1,5-a)cinoxacin-1,3(2H,5H)-dione.

25. Connection on p. 1 representing 2-(3-methoxyphenyl)-imidazo(1,5-a)cinoxacin-1,3(2H,5H)-dione.

26. Connection on p. 1 representing 2-(3-ethoxyphenyl)-imidazo(1,5-a)cinoxacin-1,3(2H,5H)-dione.

27. Connection on p. 1 representing 2-(4-n-proproxyphene)-imidazo(1,5-a)cinoxacin-1,3(2H,5H)-dione.

28. Connection on p. 1 representing 2-(4-n-butoxyphenyl)-imidazo(1,5-a)cinoxacin-1,3(2H,5H)-dione.

29. Connection on p. 1 representing 2-(4-isopropoxyphenyl)-imidazo(1,5-a)cinoxacin-1,3(2H,5H)-dione.

30. Connection on p. 1, representing 7-chloro-2-(4 - were)-imidazo(1,5-a)cinoxacin-1,3(2H,5H)-dione.

31. Connection on p. 1, representing 8-methyl-2-phenylimidazo(1,5-a)cinoxacin-1,3(2H,5H)-dione.

32. Connection on p. 1, representing 8-bromo-2-(4 - ethoxyphenyl)-imidazo(1,5-a)cinoxacin-1,3(2H,5H)-dione.

33. Connection n. 1, which represents a 2-(4-propylphenyl)-imidazo(1,5-a)cinoxacin-1,3(2H,5H)-dione.

34. Connection on p. 1, representing 7-methyl-2-(4 - ethoxyphenyl)-imidazo(1,5-a)cinoxacin-1,3(2H,5H)-dione.

35. Connection on p. 1 representing 2-(3-bromo-4 - ethoxyphenyl)-imidazo(1,5-a)cinoxacin-1,3(2H,5H)-dione.

38. Connection on p. 1, representing 8-bromo-2-(3 - bromo-4-ethoxyphenyl)-imidazo(1,5-a)cinoxacin-1,3(2H,5H)-dione.

39. Connection on p. 1 representing 2-(4-hydroxyphenyl)-imidazo(1,5-a)cinoxacin-1,3(2H,5H)-dione.

40. Connection on p. 1, representing 5-methyl-2- (4-ethoxyphenyl)-imidazo(1,5-a)cinoxacin-1,3 (2H, 5H)-dione.

 

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