RU2092487C1 - Imideazoquinoxalines - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: product: imideazoquinoxalines of the formula (I)

where: R - H, CH₃; R₁ and R₄ - H; W - phenyl or phenyl substituted with halogen, acetoxy, hydroxy, lower -C₁-C₄-alkyl group, amino or lower -C₁-C₄-alkoxy group, or phenyl disubstituted with halogen and lower -C₁-C₄-alkyl, or phenyl disubstituted with halogen and lower -C₁-C₄-alkoxy group; R₂ and R₃ are similar or different and mean H, halogen, -C₁-C₄-alkyl,

Description

 The invention relates to certain imidazoquinoxalines that selectively bind to GABA receptors. The compounds of the present invention can be used in the treatment of anxiety or fear, sleep disturbances, epileptic seizures, the effects of an overdose of benzodiazepine drugs and high anxiety conditions. The interaction of the imidazoquinoxaline of the present invention with the GABA binding site, a benzodiazepine receptor, is described. This interaction leads to the pharmacological activity of these compounds.

 γ-Aminobutyric acid (GABA) is considered one of the main inhibitory amino acid transporters 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: 55-63, 1950; Udenfriend, J. Biol. 187: 65-69, 1950). Since then, a lot of work has been devoted to studies on the involvement of GABA in the etiology of epileptic seizures, sleep disorders, anxiety disorders, and cognitive disorders (Tallman and Gallager, Ann. Rev. Neuroscience 8: 21-44, 1985). It is believed that GABA, which is widespread, although not uniformly, throughout the mammalian brain, is a carrier of approximately 30% of brain synapses. In most areas of the brain, GABA is associated with local inhibitory neurons, and only in two areas of the GABA is associated with longer processes. GABA mediates many of its actions with the help of a complex of proteins localized both on the cell bodies and on the nerve endings, they are called GABA receptors. The postsynaptic responses to GABA are mediated through a change in chloride conductivity, which usually, although not always, leads to hyperpolarization of the cell. Recent studies have shown that the complex of proteins associated with postsynaptic GABA responses is the main site of action for many structurally different compounds capable of modifying postsynaptic GABA responses. Depending on the type of interaction, these compounds are capable of producing a wide range of activities (either sedative, tranquilizing and anticonvulsant, or stimulating and stimulating anxiety states and epileptic seizures activity).

 1,4-Benzodiazepines are still one of the most widely used drugs in the world. Among them, the most well-known medications are chlordiazepoxide, diazepam, flurazepam and triazolam. These compounds are widely used as tranquilizers, sedatives, hypnotics, muscle relaxants and anticonvulsants. A number of these compounds are extremely potent drugs; and such activity indicates the presence of a site of high affinity and specific action for individual receptors. Early electrophysiological studies showed that the main activity of benzodiazepines is aimed at increasing GABA ergic inhibition. Benzodiazepines have the ability to increase the presynaptic inhibition of the monosynaptic reflex of the abdominal roots, which is mediated by GABA (Schmidt et al. 1967, Arch. Exp. Path. Pharmacol. 258: 69-82). All subsequent electrophysiological studies (Tallman et al. 1980, Science 207: 274-281, Haefley et al. 1981, Handb. Exp. Pharmacol. 33: 95-102) confirmed these observations, and in the mid-1970s, electrophysiologists came to general agreement that benzodiazepines may enhance the effects of GABA.

 With the discovery of the “receptor” for benzodiazepines and the subsequent determination of the nature of the interaction between GABA and benzodiazepines, it became apparent that the functionally important interactions of benzodiazepines with various neurotransmitter systems are largely due to the increased ability of GABA itself to modify these systems. Each modified system, in turn, can be associated with the expression of behavioral function.

 Studies of the nature of the mechanism of these interactions depend on the detection of a high affinity benzodiazepine (receptor) binding site. Such a receptor is present in the central nervous system of all vertebrates, which phylogenetically are later 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). Using tritium-labeled diazepam and many other compounds, it has been shown that these benzodiazepine binding sites satisfy many criteria for pharmacological receptors; and binding to these sites in vitro is fast, reversible, stereospecific and saturable. And more importantly, a particularly close relationship has been illustrated between the ability of benzodiazepines to displace diazepam from its binding site and the activity of a number of animals in behavioral tests for 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 doses of these drugs for humans also correlate with receptor activity (Tallman et al. 1980, Science, 207: 274-281).

 In 1978, it was found that GABA and its analogues can interact in the low affinity binding site (1 μM) of GABA with increased binding of benzodiazepine to the clonazepam-sensitive site (Tallman et al. 1978, Nature, 274: 383-385). This increase may be due to an increase in the affinity of the benzodiazepine binding site, which is due to the occupation of the GABA site. These data were interpreted as evidence that the GABA and benzodiazepine sites are allosterically linked in the membrane as part of the protein complex. For a number of GABA analogues, the ability to increase the binding of diazepam by a maximum of 50% can directly correlate with the ability to inhibit GABA in the membranes of the brain by 50%. An increase in the binding of benzodiazepine to GABA agonists is blocked by a GABA receptor antagonist, (+) bicucullin; the stereoisomer of (-) bicucullin is significantly less active (Tallman et al. 1978, Nature 274: 383-385).

 Shortly after the discovery of high affinity binding sites for benzodiazepines, it was found that in a number of brain regions, triazolopyridazine can interact with benzodiazepine receptors in a manner consistent with receptor variability or negative cooperativity. In these studies, Hill ratios were significantly lower than unity in a number of parts of the brain, including the cerebral cortex, hippocampus, and striatum. In the cerebellum, triazolopyridazine interacted with benzodiazepine sites with a Hill coefficient of 1 (Squires et al. 1979, Pharmacol. Biochem. Behav. 10: 825-830, Klepner et al. 1979, Pharmacol. Biochem. Behav. 11: 457-462). Thus, many benzodiazepine receptors were predicted for the hippocampus and striatum, but not for the cerebellum.

 Based on these studies, autoradiographic studies of receptor localization using an optical microscope were performed. Although the presence of multiple receptors has been illustrated (Young Kuhar, 1980, J. Pharmacol. Exp. Ther. 212: 337-346, Young et al. 1981, J. Pharmacol. Exp. Ther. 216: 425-430, Niehoff et al. 1982, J. Pharmacol. Exp. Ther. 221: 670-675), however, in early studies, there was no direct correlation between the localization of receptor subtypes and the behavior associated with this region. In addition, in the cerebellum, where a single receptor was predicted in binding studies, a variety of receptors was detected autoradiographically (Niehoff et al. 1982, J. Pharmacol. Exp. Ther. 221: 670-675).

 Sieghart Karobath (1980, Nature, 286: 285-287) demonstrated the physical justification for the difference in drug specificity for these two explicit subtypes of benzodiazepine sites. Using gel electrophoresis with sodium dodecyl sulfate, the presence of several molecular weight receptors for benzodiazepines was established. These receptors have been identified by covalent administration of radioactive flunitrazepam, benzodiazepine, which can covalently label all types of receptors. Most of the labeled bands had a molecular weight of 50,000 to 53,000, 55,000 and 57,000, and triazolopyridazines inhibited the labeling of forms with slightly higher molecular weights of 53,000, 55,000, 57,000 (Sieghart et al. 1983, Eur. J. Pharmacol. 88: 291-299) .

 At the same time, it has been suggested that many forms of receptors are “isoreceptors” or numerous allelic forms of the receptor (Tallman Gallager, 1985, Ann. Rev. Neurosci. 8, 21-44). Although generally for genes, mainly genetically distinct forms of receptors have not been described. Even at the beginning of receptor studies undertaken by the authors of the present invention using specific radioactive probes and electrophoresis techniques, it became almost obvious that the study of isoreceptors would be a critical phase on the path to understanding the etiology of psychiatric disorders in humans.

 GABA receptor subunits were cloned into bovine and human cDNA libraries (Schoenfield et al. 1988; Duman et al. 1989). By cloning and expression, a number of different cDNAs have been identified as subunits of the GABA receptor complex. These subunits are divided into the categories α, β, γ, δ, ε and provide the molecular basis for the heterogeneity of GABA receptors and characteristic regional pharmacology (Shivvers et al. 1980; Levitan et al. 1989). The g-subunit appears to allow the drug, like benzodiazepine, to modify the GABA responses (Putchett et al. 1989). The presence of low Hill coefficients in the binding of ligands to the GABA receptor indicates unique profiles of the specific pharmacological action of the subtype.

 Medicines that interact with the GABA receptor may have a certain spectrum of pharmacological activities, depending on their ability to modify the actions of GABA. For example, β-carbolines were first isolated based on their ability to competitively inhibit the binding of diazepam to its binding site (Nielsen et al. 1979, Life Sci. 25: 679-686). A receptor binding assay is unpredictable with respect to the biological activity of such compounds; agonists, partial agonists, inverse agonists and antagonists can inhibit binding. When the structure of β-carboline was determined, it was possible to synthesize a number of analogues and conduct behavioral tests of these compounds. As a result, it was immediately established that β-carbolines can be antagonists of the behavioral activity of diazepam (Tenen Hirsh 1980, Nature, 288: 609-610). In addition to this antagonism, β-carbolines have an activity opposite to that of benzodiazepines, and they have become known as inverse agonists.

 In addition, based on the ability to inhibit the binding of benzodiazepines, other specific antagonists of benzodiazepine receptors have been developed. Of these compounds, imidazodiazepine is best studied (Hunkeler et al. 1981, Nature, 290: 514-516). This compound is a highly affective competitive inhibitor of the binding of benzodiazepine and beta-carboline and has the ability to block the pharmacological effect of compounds of these classes. By itself, this compound has little inherent pharmacological activity in humans and animals (Hunkeler et al. 1981, Nature, 290: 514-516; Darragh et al. 1983, Eur. J. Clin. Pharmacol. 14: 569-570 ) A study of the radiolabeled form of this compound (Mohler and Richards, 1981, Nature, 294: 763-765) showed that this compound interacts with the same number of sites as benzodiazepines and beta-carbolines and that the interactions of these compounds are purely competitive. The compound of interest is the optimal ligand for binding to GABA receptors, since it does not have the receptor specificity of the subtype and determines each state of the receptor.

 The study of the interaction of a wide range of compounds similar to those described above allowed us to divide these compounds into categories. Currently, compounds having activity similar to that of benzodiazepines are called agonists. Compounds with activity opposite to that of benzodiazepines are called inverse agonists, and compounds that inhibit both types of activity are called antagonists. The above categorization was done to emphasize the fact that a wide range of compounds can exhibit a wide range of pharmacological effects, as well as to show that the compounds can interact with the same receptor, giving opposite effects, and that beta-carbolines and antagonists with their inherent psychomotor action are not synonymous. A biochemical test for the pharmacological and psychoreactive properties of compounds interacting with the benzodiazepine receptor has once again demonstrated their connection with the GABA ergic system. In contrast to benzodiazepines, which show an increase in their affinity due to GABA (Tallman et al. 1978, Nature, 274: 383-385, Tallman et al. 1980, Science, 207: 274-281), compounds with antagonistic properties show little GABA- a shift (i.e., a change in receptor affinity due to GABA) (Mohler and Richard, 1981, Nature, 294: 763-765), and inverse agonists actually show a decrease in affinity due to GABA (Braestrup and Nielson, 1981, Nature, 294: 472-474). Thus, the GABA shift mainly indicates the alleged psychoreactive properties of these compounds.

где R₁ (не)замещенный Ph, (дигидро)фуранил, тетрагидрофуранил, (дигидро)тиенил, тетрагидротиенил, пиранил, рибофуранозил, все С связанные;
R₂ H, алкил;
X O, S, R₃N; R₃ H, алкенил, алкинил, C₃-C₂₀-циклоалкил, (не)замещенный алкил; арил; аралкил, где арилом является Ph, пиридинил, тиенил, фуранил;
кольцо А может быть замещено алкилом, алкокси, галоидом, амино, алкилтио и т.п.Various compounds have been obtained as agonists and antagonists of benzodiazepine. For example, U.S. Patent Nos. 4,312,870 and 4,713,383, and EP 181,282, discloses certain compounds used in the treatment of anxiety or depression. US Pat. No. 4,713,383 discloses compounds of the formula

where R ₁ (un) substituted Ph, (dihydro) furanyl, tetrahydrofuranyl, (dihydro) thienyl, tetrahydrothienyl, pyranyl, ribofuranosyl, all C bound;
R ₂ H, alkyl;
XO, S, R ₃ N; R ₃ H, alkenyl, alkynyl, C ₃ -C ₂₀ cycloalkyl, (un) substituted alkyl; aryl; aralkyl, where aryl is Ph, pyridinyl, thienyl, furanyl;
ring A may be substituted by alkyl, alkoxy, halogen, amino, alkylthio and the like.

где R₁ (замещенный) Ph или гетероцикл;
R₂ H, алкил, алкенил, гидроксиалкил, аралкил, аралкенил, арил;
R₃ H, алкил, алкокси, HO, галоид, F₃C, O₃N, H₂N, алкилтио, алкилсульфинил, алкилсульфонил, аралкокси;
X O, S, NR₄; а R₄ H, алкил, аралкил, циклоалкил, алкенил, алкинил, арил, (замещенный)аминоалкил, гидроксиалкил.European Patent Application EP 181282 discloses compounds of the formula

where R ₁ (substituted) Ph or heterocycle;
R ₂ H, alkyl, alkenyl, hydroxyalkyl, aralkyl, aralkenyl, aryl;
R ₃ H, alkyl, alkoxy, HO, halogen, F ₃ C, O ₃ N, H ₂ N, alkylthio, alkylsulfinyl, alkylsulfonyl, aralkoxy;
XO, S, NR ₄ ; and R ₄ H, alkyl, aralkyl, cycloalkyl, alkenyl, alkynyl, aryl, (substituted) aminoalkyl, hydroxyalkyl.

где Ph 1,2-фенилен, незамещенный или замещенный от 1 до 3-х одинаковыми или различными членами, выбранными из группы, включающей низший алкил, низший алкокси, низший алкилтио, гидрокси, галогено, трифторметил, нитро, амино, моно- или ди-низший алкиламино, циано, карбамоил и карбокси;
R незамещенный или замещенный фенил, обозначаемый H-Ph, пиридил, низший алкилпиридил или галогенпиридил;
R₁ водород, низший алкил или низший (гидрокси, диалкиламино или H-Ph)-алкил;
R₂ водород или низший алкил-алкил; их 3-гидрокситаутомеры; низший алканоил, карбамоил, моно- или ди-низший алкил-карбамоил-производные указанных (гидрокси или амино)-(фенил или фенилен) соединений,
и соединения формулы

где R'' водород, алкил или алкокси, каждый из которых содержит до 4 атомов углерода, гидрокси, фторо, хлоро, бромо, или трифторметил;
R' водород, о- или м-фторо; или если R'' является хлоро, то R' является п-фторо.US Pat. No. 4,312,870 describes compounds of the formula

where Ph 1,2-phenylene unsubstituted or substituted by 1 to 3 identical or different members selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio, hydroxy, halo, trifluoromethyl, nitro, amino, mono- or di -lower alkylamino, cyano, carbamoyl and carboxy;
R is unsubstituted or substituted phenyl, denoted by H-Ph, pyridyl, lower alkylpyridyl or halogenopyridyl;
R _{1 is} hydrogen, lower alkyl or lower (hydroxy, dialkylamino or H-Ph) -alkyl;
R _{2 is} hydrogen or lower alkyl-alkyl; their 3-hydroxy tautomers; lower alkanoyl, carbamoyl, mono- or di-lower alkyl-carbamoyl derivatives of the indicated (hydroxy or amino) - (phenyl or phenylene) compounds,
and compounds of the formula

where R ″ is hydrogen, alkyl or alkoxy, each of which contains up to 4 carbon atoms, hydroxy, fluoro, chloro, bromo, or trifluoromethyl;
R 'is hydrogen, o- or m-fluoro; or if R ″ is chloro, then R ′ is p-fluoro.

 The compounds of the present invention differ from the compounds described above. These compounds are not imidazoquinoxalines and do not have various ring substituents of the compounds of the present invention.

 The present invention provides novel compounds of formula I that interact with a GABA binding site, a benzodiazepine receptor.

и к их фармацевтически приемлемым нетоксичным солям,
где R водород или метил;
R₁ и R₄ водород;
X водород;
W фенил; фенил, замещенный галогеном, ацетокси, гидрокси, низшей алкильной группой с прямой или разветвленной цепью, имеющей 1-4 атома углерода, амино, или низшей алкокси группой с прямой или разветвленной цепью, имеющей 1-4 атома углерода; фенил, дизамещенный галогеном и низшим алкилом с прямой или разветвленной цепью, имеющим 1-4 атома углерода; или фенил, дизамещенный галогеном и низшей алкокси группой с прямой или разветвленной цепью, имеющей 1-4 атома углерода; и
R₂ и R₃ одинаковые или различные и представляют водород, галоген, низший алкил с прямой или разветвленной цепью, имеющий 1-4 атома углерода.The present invention also provides compounds useful in the treatment of neurotic conditions associated with anxiety, sleep disturbance and fears, as well as in the treatment of epileptic seizures and the effects of benzodiazepine overdose. Accordingly, in a broad sense of the embodiment, the present invention relates to compounds of the formula

and their pharmaceutically acceptable non-toxic salts,
where R is hydrogen or methyl;
R ₁ and R _{4 are} hydrogen;
X is hydrogen;
W phenyl; phenyl substituted with halogen, acetoxy, hydroxy, a straight or branched chain lower alkyl group having 1-4 carbon atoms, amino, or a straight or branched chain lower alkoxy group having 1-4 carbon atoms; phenyl disubstituted with halogen and lower alkyl straight or branched chain having 1-4 carbon atoms; or phenyl disubstituted with halogen and a lower alkoxy group with a straight or branched chain having 1-4 carbon atoms; and
R ₂ and R _{3 are the} same or different and represent hydrogen, halogen, straight or branched chain lower alkyl having 1-4 carbon atoms.

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

 In FIG. 1 (a d), 2 are representative imidazoquinoxaline of the present invention.

а также их фармацевтически приемлемыми нетоксичными солями,
где R водород или метил;
R₁ и R₄ водород;
X водород;
W фенил; фенил, замещенный галогеном, ацетокси, гидрокси, низшей алкильной группой с прямой или разветвленной цепью, имеющей 1-4 атома углерода, амино, или низшей алкокси группой с прямой или разветвленной цепью, имеющей 1-4 атома углерода; фенил, дизамещенный галогеном и низшим алкилом с прямой или разветвленной цепью, имеющим 1-4 атома углерода; или фенил, дизамещенный галогеном и низшей алкокси группой с прямой или разветвленной цепью, имеющей 1-4 атома углерода; и
R₂ и R₃ одинаковые или различные и представляют водород, галоген, низший алкил с прямой или разветвленной цепью, имеющий 1-4 атома углерода.New compounds according to the present invention can be represented by the following General formula

as well as their pharmaceutically acceptable non-toxic salts,
where R is hydrogen or methyl;
R ₁ and R _{4 are} hydrogen;
X is hydrogen;
W phenyl; phenyl substituted with halogen, acetoxy, hydroxy, a straight or branched chain lower alkyl group having 1-4 carbon atoms, amino, or a straight or branched chain lower alkoxy group having 1-4 carbon atoms; phenyl disubstituted with halogen and lower alkyl straight or branched chain having 1-4 carbon atoms; or phenyl disubstituted with halogen and a lower alkoxy group with a straight or branched chain having 1-4 carbon atoms; and
R ₂ and R _{3 are the} same or different and represent hydrogen, halogen, straight or branched chain lower alkyl having 1-4 carbon atoms.

где R₁ и R₄ водород;
X водород;
W фенил; или фенил, замещенный галогеном, ацетоном, гидрокси, низшей алкильной группой с прямой или разветвленной цепью, имеющей 1-4 атома углерода, или низшей алкокси группой с прямой или разветвленной цепью, имеющей 1-4 атома углерода.The present invention also relates to compounds of the formula

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

где W фенил, дизамещенный галогеном и низшим алкилом с прямой или разветвленной цепью, имеющим 1-4 атома углерода; фенил, дизамещенный галогеном и низшей алкокси группой с прямой или разветвленной цепью, имеющей 1-4 атома углерода.In addition, the present invention relates to compounds of the formula

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

где W фенил, дизамещенный галогеном и низшей алкокси группой с прямой или разветвленной цепью, имеющей 1-4 атома углерода; и
R₂ и R₃ водород.The present invention also encompasses compounds of the formula

where W is phenyl disubstituted by halogen and a lower alkoxy group with a straight or branched chain having 1-4 carbon atoms; and
R ₂ and R _{3 are} hydrogen.

 The non-toxic pharmaceutically acceptable salts of the present invention can be salts formed with acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, sulfonic, hydroiodic, acetic acid and the like. Any specialist knows a wide range of non-toxic pharmaceutically acceptable additive salts.

 Representative compounds of the present invention that are encompassed by Formula I include, but are not limited to, the compounds of FIG. 1 and 2, and their pharmaceutically acceptable salts. The present invention also includes acylated precursors of the compounds of formula I. To prepare non-toxic pharmaceutically acceptable addition salts and acylated precursors of the compounds of formula I, various synthesis methods well known to those skilled in the art can be used.

 As used herein, the term “lower alkyl” means straight or branched chain alkyl groups having 1-4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl , 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methylenepentyl.

 As used herein, the term “lower alkoxy” means straight or branched chain alkoxy groups having 1-4 carbon atoms, for example, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy , 2-pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy and 3-methylpentoxy.

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

 The pharmaceutical usefulness of the compounds of the present invention is illustrated by the following analysis of GABA receptor activity.

Assays were performed as described by Thomas and Tallman J. Bio. Chem. 156: 9838-9842, J. Neurocsi. 3: 433-440, 1983. Brain tissue was excised from the rat and homogenized in 25 volumes (w / v) of 0.05 M Tris-HCl buffer (pH 7.4 at 4 ^° C). The resulting tissue homogenate was centrifuged for 20 min at 4 ^° C and at 20,000 g. The supernatant was decanted and the pellet was again homogenized in the same volume of buffer and centrifuged again at 20,000 g. After this, the supernatant was decanted, and the precipitate was left overnight at -20 ^o C. Then the precipitate was thawed and homogenized in 25 volumes (w / v) of buffer, and this procedure was repeated twice. Finally, the resulting precipitate was resuspended in 50 volumes of buffer (w / v. 0.05 M Tris-HCl, pH 7.4 at 40 ^° C.).

The incubation mixture contained 100 μl of tissue homogenate, 100 μl of radioactively labeled ligand (0.5 nM, ³ H-R015-1788 [ ³ H-Flumazenil] specific activity 80 Ku / mM), drug or inhibitor, and buffer to a total volume of 500 μl Incubation was carried out for 30 min at 4 ^° C, after which the mixture was quickly filtered through CFB filters to separate the free and bound ligand. The filters were washed twice with fresh Tris-HCl buffer (0.05 M, pH 7.4 at 4 ^° C.) and counted in a liquid scintillation counter. Then, 1.0 μM diazepam was added to the same tubes to evaluate non-specific binding. The data obtained in triplicate measurements were averaged and the inhibitions of total specific binding were calculated (total specific binding all binding nonspec. Binding). In some cases, the amounts of the intended drug varied, and according to this, complete binding substitution curves were constructed. The data obtained was converted to calculate the IC ₅₀ and Hill coefficient. The indicated data are presented below.

Compound N IC ₅₀ μm
1 0.0095
3 0.015
4 0.0095
5 0.016
33 0.0024
Compound numbers refer to the compounds shown in FIG. 12.

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

 The compounds of general formula I can be administered orally, topically, parenterally, by inhalation or injection, or rectally in unit dosage forms containing standard pharmaceutically acceptable carriers, adjuvants and excipients. As used herein, the term “parenteral administration” includes subcutaneous, intravenous, intramuscular or intrathoracic injection or infusion. Pharmaceutical compositions based on the compounds of the present invention comprise a compound of general formula I and a pharmaceutically acceptable carrier. Moreover, one or more compounds of the general formula I may be present in said composition in combination with one or more non-toxic pharmaceutically acceptable carriers and / or diluents and / or adjuvants, and, if necessary, in combination with other active ingredients. Pharmaceutical compositions containing compounds of general formula I can be administered in suitable oral forms, for example, tablets, troches, 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 standard techniques used in the pharmaceutical industry, and these compositions may contain one or more substances selected from the group including sweetening agents, flavoring agents, coloring agents and preservatives, to give the preparation a pleasant taste qualities and aesthetic appearance. Tablets usually contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients, which are often used in the manufacture of tablets. Such excipients may be inert diluents, for example calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating or disintegrating agents, for example corn starch, or alginic acid; binders, for example starch, gelatin or gum arabic; sizing agents, for example magnesium stearate, stearic acid or talc. The tablets may be left uncovered, or they may be coated by standard methods in order to slow down the disintegration and absorption of the active ingredient in the gastrointestinal tract, thereby imparting a prolonged effect to the preparation. For this purpose, for example, glycerol monostearate or distearate can be used.

 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, for example, such as calcium carbonate, calcium phosphate or kaolin; or as soft gelatin capsules in which the active ingredient is mixed with water or an oil filler, such as peanut butter, liquid paraffin or olive oil.

 Liquid suspensions contain the active ingredients, usually in combination with excipients commonly used in the manufacture of aqueous suspensions. Such excipients may be suspending agents, for example sodium-containing carbomethyl cellulose, methyl cellulose, hydropropyl methyl cellulose, sodium alginate, tragacanth gum and Arabian gum; and dispersing or wetting agents, which may be natural phosphatides, for example lecithin, or products of condensation of alkylene oxide with fatty acids, for example polyoxyethylene stearate, or products of condensation of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethylene ethoxy ketanol, or products of condensation of ethylene oxide from fatty acids and hexite, for example polyoxyethylene sorbitan monooleate, or products of condensation of ethylene oxide with partial esters fatty acids and hexitanhydrides, for example polyethylene sorbitan monooleate. 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 agents; and one or more sweetening agents, such as sucrose or saccharin.

 Oily suspensions may be prepared by suspending the active ingredients in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil; or in mineral oil, for example liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweeteners, such as those mentioned above, and flavoring agents can be added to the composition to give them a pleasant taste and aesthetic appearance. To protect the compositions from environmental influences, antioxidants, such as ascorbic acid, can be added to them.

 Dispersible powders and granules intended for the manufacture of aqueous suspensions by adding 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 suspending agents are given above. Additional ingredients, for example, sweetening, flavoring and coloring agents, may also be present in the composition.

 The pharmaceutical compositions may also be formulated as oil-in-water emulsions. The oil phase in such an emulsion may be a vegetable oil, for example olive oil, or a mineral oil, for example liquid paraffin, or mixtures thereof. Suitable emulsifying agents are natural resins such as gum arabic or tragacanth gum; natural phosphatides such as soy and lecithin; and esters or partial esters derived from fatty acids and hexites and anhydrides, for example, such as sorbitan monooleate, as well as condensation products of said partial esters with ethylene oxide, for example, such as polyoxyethylene sorbitan monooleate. These emulsions may also contain sweetening and flavoring agents.

 Syrups and elixirs can be prepared using sweetening agents such as glycerin, propylene glycol, sorbitol, or sucrose. These preparations may also contain an irritant reducing agent, a preservative, a flavoring agent and a coloring agent. The pharmaceutical compositions may be formulated as sterile injectable aqueous or oily suspensions. These suspensions can be prepared according to standard techniques using suitable dispersing or wetting agents as described above. Such injectable sterile preparations may also be sterile injectable solutions or suspensions in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Examples of suitable excipients or solvents are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fatty oils may be used as a solvent or suspending medium. For this purpose any bland fixed oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids, for example, such as oleic acid, can be used in injectable preparations.

 The compounds of general formula I can also be administered rectally as suppositories. These compositions can be prepared by mixing the active ingredient with a suitable non-irritating excipient, which is solid and, when it enters the rectum, melts and becomes liquid, thereby releasing the drug. Cocoa butter and polyethylene glycols are commonly used for these purposes.

 The compounds of general formula I can be administered parenterally in a sterile medium. The drug, depending on the excipients used and the concentration, can either be suspended or dissolved in the excipient. If adjuvants such as local anesthetics, preservatives, and buffering agents are used, they can be dissolved in the vehicle.

 The doses used to treat the above disorders are ≈ 0.1 140 mg per 1 kg of the patient’s body per day, which is ≈ 0.5 mg 7 g per day for one patient. The amount of 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 method of administration of the drug. The unitary dosage form usually contains ≈ 1,500 mg of active ingredient.

 It is obviously clear, however, that the specific dose for each particular patient depends on many factors, namely the activity of the particular agent used, the age, weight, general health and gender of the patient, as well as the diet, administration schedule, route of administration, and drug release rate means, its composition and severity of the disease.

 The preparation of the compounds of the present invention is illustrated in Schemes I and II below. It will be apparent to those skilled in the art that additional steps may be introduced into the present compound preparation scheme of the present invention, and the starting materials used may also vary, as shown in the examples below.

In Schemes I and II below are indicated: R ₁ , R ₄ and X are hydrogen; and R ₂ , R ₃ and W have the meanings given for formula I.

 In some cases, for the implementation of the above transformations, it may be necessary to block certain reactive functional groups. The need for such blocking, as well as the conditions necessary for the addition and removal of such groups, can mainly be determined by specialists in the field of organic synthesis.

 Example I.

К смеси изоцианата 2-нитрофенила (3,34 г) в 100 мл толуола добавляли анилин (2 г). Смесь перемешивали 30 мин при 20^oC. Затем добавляли гексан (300 мл) и полученное твердое вещество фильтровали и высушивали, в результате чего получали N-(2-нитрофенил)-N'-фенил-мочевину в виде светло-желтого твердого вещества.

Aniline (2 g) was added to a mixture of 2-nitrophenyl isocyanate (3.34 g) in 100 ml of toluene. The mixture was stirred for 30 minutes at 20 ^° C. Hexane (300 ml) was then added and the resulting solid was filtered and dried, whereby N- (2-nitrophenyl) -N'-phenyl-urea was obtained as a light yellow solid.

 Example II

К раствору диэтилнитротерефталата (17,9 г) в 300 мл этанола добавляли 1н. NaOH (70 мл) и перемешивали в течение ночи. Затем добавляли 1н. HCl (70 мл) и реакцию распределяли между метиленхлоридом (200 мл) и водой (200 мл). Водный слой экстрагировали еще 3 раза. Объединенные органические экстракты высушивали, а растворитель удаляли в вакууме, в результате чего получали этил-3-нитро-4-карбоксибензоат в виде белого твердого вещества.

To a solution of diethyl nitroterephthalate (17.9 g) in 300 ml of ethanol was added 1N. NaOH (70 ml) and stirred overnight. Then added 1N. HCl (70 ml) and the reaction was partitioned 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 to give ethyl 3-nitro-4-carboxybenzoate as a white solid.

 Example III

К дифенилфосфорилазиду (5,75 г) в безводном толуоле (50 мл) при 100^oC в атмосфере азота по капле добавляли раствор, содержащий этил-3-нитро-4-карбоксибензоат (5 г) и триэтиламин (4 мл) в безводном толуоле (50 мл). Смесь перемешивали в течение 1 ч с последующим добавлением анилина (5 мл), и реакционную смесь оставляли для охлаждения до комнатной температуры (40 мин). Затем добавляли этилацетат (300 мл) и раствор промывали последовательно с 1н. HCl (300 мл) водой (300 мл), 1н. NaOH (300 мл) и водой (300 мл). Органический слой высушивали, а растворитель удаляли в вакууме. К полученному маслянистому веществу добавляли диэтиловый эфир (50 мл), и полученное твердое вещество соединяли и высушивали, в результате чего получали N-(2-нитро-5-метил-фенил)-N'-фенил-мочевину в виде белого твердого вещества.

To diphenylphosphoryl azide (5.75 g) in anhydrous toluene (50 ml) at 100 ^° C. under a nitrogen atmosphere was added dropwise a solution containing ethyl 3-nitro-4-carboxybenzoate (5 g) and triethylamine (4 ml) in anhydrous toluene (50 ml). The mixture was stirred for 1 h, followed by the addition of aniline (5 ml), and the reaction mixture was allowed to cool to room temperature (40 min). Ethyl acetate (300 ml) was then added and the solution was washed sequentially with 1N. HCl (300 ml) with water (300 ml), 1N. NaOH (300 ml) and water (300 ml). The organic layer was dried, and the solvent was removed in vacuo. Diethyl ether (50 ml) was added to the obtained oily substance, and the obtained solid was combined and dried, whereby N- (2-nitro-5-methyl-phenyl) -N'-phenyl-urea was obtained as a white solid.

 Example IV

Раствор, содержащий N-(2-нитрофенил)-N'-фенил-мочевину (5,76 г) и хлороацетилхлорид (40 мл) нагревали с обратным холодильником в атмосфере азота в течение 30 мин. После удаления избытка хлороацетилхлорида в вакууме добавляли диэтиловый эфир, а полученное твердое вещество фильтровали и высушивали, в результате чего получали N'-(2-хлороацетил)-N-(2-нитрофенил)-N'-фенил-мочевину в виде белого твердого вещества.

A solution containing N- (2-nitrophenyl) -N'-phenyl-urea (5.76 g) and chloroacetyl chloride (40 ml) was heated under reflux in a nitrogen atmosphere for 30 minutes. After removing the excess chloroacetyl chloride in vacuo, diethyl ether was added and the resulting solid was filtered and dried to give N '- (2-chloroacetyl) -N- (2-nitrophenyl) -N'-phenyl-urea as a white solid .

 Example V.

Раствор N'-(2-хлороацетил)-N-(2-нитрофенил)-N-фенил-мочевины (3,7 г), диметилформамида (15 мл) и диизопропилэтиламина (15 мл) нагревали с обратным холодильником в течение 5 мин. Нагретую смесь оставляли для охлаждения до комнатной температуры и осаждали с добавлением смеси в 200 мл воды. Осадок собирали и высушивали, в результате чего получали 1-(2-нитрофенил)-3-фенил-имидазолин-2,4 (1Н, 3Н)-дион.

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. The heated mixture was allowed to cool to room temperature and precipitated by adding the mixture to 200 ml of water. The precipitate was collected and dried, resulting in a received 1- (2-nitrophenyl) -3-phenyl-imidazoline-2,4 (1H, 3H) -dione.

 Example VI

К раствору 1-(2-нитрофенил)-3-фенил-имидазолин-2,4(1Н, 3Н)-диона (2,7 г) в безводном диметилформамиде (2 мл) в атмосфере азота добавляли N,N-диметилформамиддиметилацеталь (2,7 г). Реакционную смесь перемешивали 2 ч при 80^oC и растворитель удаляли в вакууме. К полученному маслянистому веществу добавляли железный порошок (5 г) и уксусную кислоту (250 мл). Эту смесь осторожно нагревали с обратным холодильником 3 мин, с последующим перемешиванием реакционной смеси дополнительно 30 мин. Гетерогенную смесь разбавляли 10% метанолметиленхлоридом (200 мл) и фильтровали через силикагель, используя в качестве элюента смесь 10% метанола и метиленхлорида. Растворитель удаляли в вакууме, а затем добавляли нагретый этанол (200 мл). К этой смеси добавляли воду (200 мл) и полученное твердое вещество фильтровали и промывали последовательно с этанолом, этилацетатом, диэтиловым эфиром и высушивали, в результате чего получали 2-фенил-имидазо [1,5-а] хиноксалин-1,3 (2Н, 5Н)-дион в виде желтого твердого вещества с т. пл. 231-234^oC (соединение 1).

To a solution of 1- (2-nitrophenyl) -3-phenyl-imidazoline-2,4 (1H, 3H) -dione (2.7 g) in anhydrous dimethylformamide (2 ml) in a nitrogen atmosphere was added N, N-dimethylformamide dimethylacetal (2 , 7 g). The reaction mixture was stirred for 2 hours at 80 ^° C. and the solvent was removed in vacuo. Iron powder (5 g) and acetic acid (250 ml) were added to the resulting oily substance. This mixture was carefully heated under reflux for 3 minutes, followed by stirring the reaction mixture for an additional 30 minutes. The heterogeneous mixture was diluted with 10% methanolmethylene chloride (200 ml) and filtered through silica gel using a mixture of 10% methanol and methylene chloride as eluent. The solvent was removed in vacuo, and then heated ethanol (200 ml) was added. Water (200 ml) was added to this mixture, and the resulting solid was filtered and washed sequentially with ethanol, ethyl acetate, diethyl ether and dried, resulting in 2-phenyl-imidazo [1,5-a] quinoxaline-1,3 (2H , 5H) -dione in the form of a yellow solid with a mp. 231-234 ^o C (compound 1).

 Example VII

К раствору, содержащему 1-(2-нитрофенил)-3-(2-фторофенил)-имидазолин-2,4 (1Н, 3Н)-дион (1,18 г) в безводном метиленхлориде (5 мл) в атмосфере азота добавляли трис диметиламино метан (1 мл). Реакционную смесь перемешивали 20 мин при комнатной температуре, а растворитель удаляли в вакууме. Полученное твердое вещество растворяли в ДМФ 100 мл и добавляли взвесь никелевого катализатора гидрирования (50% раствор в воде, 1 мл). Смесь гидрогенизировали при давлении 50 фунт/кв.дюйм (344,7 кПа) в течение 45 мин. После фильтрации через целит, растворитель концентрировали в вакууме в количестве 30 мл, а затем добавляли воду (50 мл). Полученное твердое вещество собирали и промывали последовательно с этанолом, этилацетатом и диэтиловым эфиром и проветривали, в результате чего получали 2-(2-фторофенил)-имидазо[1,5-а]квиноксалин-1,3-(2Н, 5Н)-дион в виде желтого твердого вещества (соединение 2), т. пл. 261-264^oC.

Tris was added to a solution containing 1- (2-nitrophenyl) -3- (2-fluorophenyl) -imidazolin-2,4 (1H, 3H) -dione (1.18 g) in anhydrous methylene chloride (5 ml) under nitrogen atmosphere dimethylamino methane (1 ml). The reaction mixture was stirred for 20 minutes at room temperature, and the solvent was removed in vacuo. The resulting solid was dissolved in DMF 100 ml and a suspension of a nickel hydrogenation catalyst was added (50% solution in water, 1 ml). The mixture was hydrogenated at a pressure of 50 psi (344.7 kPa) for 45 minutes. After filtering through celite, the solvent was concentrated in vacuo in an amount of 30 ml, and then water (50 ml) was added. The resulting solid was collected and washed sequentially with ethanol, ethyl acetate and diethyl ether and aerated to give 2- (2-fluorophenyl) imidazo [1,5-a] quinoxaline-1,3- (2H, 5H) dione in the form of a yellow solid (compound 2), so pl. 261-264 ^o C.

 Example VIII

К раствору, содержащему ДМФ (100 мл), H₂O (15 мл), 5%-Ро-уголь (1,25 г) и 1-(2-нитрофенил)-3-(4-этоксифенил)-имидазолин-2,4 (1Н,3Н)-дион (25 г) при 60^oC, по капле добавляли раствор, содержащий гипофосфит натрия (15 г) в H₂O (40 мл). Через 3 ч смесь охлаждали до комнатной температуры и фильтровали через целит. Смесь выливали в 500 мл H₂O, фильтровали и высушивали, в результате чего получали 1-(2-аминофенил)-3-4-этоксифенил-имидазолин-2,4(1Н, 3Н)-дион.

To a solution containing DMF (100 ml), H ₂ O (15 ml), 5% Ro-carbon (1.25 g) and 1- (2-nitrophenyl) -3- (4-ethoxyphenyl) imidazolin-2 , 4 (1H, 3H) -dione (25 g) at 60 ^° C. A solution containing sodium hypophosphite (15 g) in H ₂ O (40 ml) was added dropwise. After 3 hours, the mixture was cooled to room temperature and filtered through celite. The mixture was poured into 500 ml of H ₂ O, filtered and dried to give 1- (2-aminophenyl) -3-4-ethoxyphenyl-imidazoline-2,4 (1H, 3H) dione.

 Example IX

К 1-(2-аминофенил)-3-(4-этоксифенил)-имидазолин-2,4-(1Н,3Н)-диона (2 г) добавляли ДМФ (5 мл), уксусную кислоту (5 мл) и диметилформамиддиметилацеталь (5 мл). Реакционную смесь нагревали при 60^oC 16 ч, затем охлаждали и фильтровали. Полученное оранжевое твердое вещество промывали изопропанолом и перекристаллизировали уксусной кислотой, в результате чего получали 2-(4-этоксифенил)-имидазо [1.5, а] хиноксалин-1.3 (2Н,5Н)-дион с т. пл. 268-269^oC (соединение 3).

To 1- (2-aminophenyl) -3- (4-ethoxyphenyl) imidazoline-2,4- (1H, 3H) -dione (2 g) was added DMF (5 ml), acetic acid (5 ml) and dimethylformamide dimethylacetal ( 5 ml). The reaction mixture was heated at 60 ^° C. for 16 hours, then cooled and filtered. The resulting orange solid was washed with isopropanol and recrystallized with acetic acid to give 2- (4-ethoxyphenyl) imidazo [1.5, a] quinoxaline-1.3 (2H, 5H) -dione with mp 268-269 ^o C (compound 3).

Example X. Following the basic procedure described in examples VI, VII and IX, the following compounds were prepared:
1. 2- (4-methoxyphenyl) imidazo [1.5, a] quinoxaline-1.3 (2H, 5H) -dione (compound 4), so pl. 240-242 ^o C.

2.2- (4-methylphenyl) imidazo [1.5, a] quinoxaline-1.3 (2H, 5H) -dione (compound 5), mp 305-308 ^o C.

3. 2-4-fluorophenyl-imidazo [1.5, a] quinoxaline-1.3 (2H, 5H) -dione (compound 6), so pl. 235-238 ^o C.

4. 2- (2-aminophenyl) imidazo [1.5, a] quinoxaline-1.3 (2H, 5H) -dione (compound 7), so pl. 247-249 ^o C.

5. 2- (3-fluorophenyl) imidazo [1,5, a] quinoxaline-1,3 (2H, 5H) -dione (compound 8), so pl. 265-266 ^o C.

6. 2- (4-chlorophenyl) imidazo [1.5, a] quinoxaline-1,3 (2H, 5H) -dione (compound 9), mp 235-238 ^o C.

7. 2- (3-methylphenyl) imidazo [1,5, a] quinoxaline-1,3 (2H, 5H) -dione (compound 10), so pl. 263-265 ^o C.

8. 2- (2-Fluoro-4-ethoxyphenyl) imidazo [1,5, a] quinoxaline-1,3 (2H, 5H) -dione (compound 11), mp 264-267 ^o C.

9. 2- (3-chlorophenyl) -imidazo [1,5, a] quinoxaline-1,3 (2H, 5H) -dione (compound 12), so pl. 235-239 ^o C.

10. 2- (2-methoxyphenyl) imidazo [1,5, a] quinoxaline-1,3 (2H, 5H) -dione (compound 13), mp 270-272 ^o C.

11. 2- (4-ethylphenyl) -imidazo [1,5, a] quinoxaline-1,3 (2H, 5H) -dione (compound 14), so pl. 215-216 ^o C.

12. 2- (2-Fluoro-4-methylphenyl) imidazo [1,5, a] quinoxaline-1,3 (2H, 5H) -dione (compound 15), mp 280-284 ^o C.

13. 2- (3-methoxyphenyl) imidazo [1,5, a] quinoxaline-1,3 (2H, 5H) -dione, (compound 16), mp 212-214 ^o C.

14. 2- (3-ethoxyphenyl) imidazo [1,5, a] quinoxaline-1,3 (2H, 5H) -dione (compound 17), so pl. 197-200 ^o C.

15. 2- (4-n-propyloxyphenyl) imidazo [1,5, a] quinoxaline-1,3 (2H, 5H) -dione (compound 18), mp 182-185 ^o C.

16. 2- (4-n-butoxyphenyl) imidazo [1,5, a] quinoxaline-1,3 (2H, 5H) -dione (compound 19), mp 155-156 ^o C.

17. 2- (4-Isopropoxyphenyl) imidazo [1,5, a] quinoxaline-1,3 (2H, 5H) -dione (compound 20), mp 164-167 ^o C.

18. 7-chloro-2- (4-methylphenyl) imidazo [1,5, a] quinoxaline-1,3 (2H, 5H) -dione (compound 21), mp 200-204 ^o C.

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

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

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

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

23. 8-bromo-2- (4-ethoxyphenyl) -imidazo [1,5, a] quinoxaline-1,3 (2H, 5H) -dione (compound 26), so pl. 152-155 ^o C.

24. 2- (4-propylphenyl) imidazo [1,5, a] quinoxaline-1,3 (2H, 5H) -dione (compound 27), so pl. 185-186 ^o C.

25. 7-methyl-2- (4-ethoxyphenyl) imidazo [1,5, a] quinoxaline-1,3 (2H, 5H) -dione (compound 28), mp 200-203 ^o C.

26. 2- (3-bromo-4-ethoxyphenyl) imidazo [1,5, a] quinoxaline-1,3 (2H, 5H) -dione (compound 29), mp 147-150 ^o C.

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

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

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

 Example XI

К суспензии 2-4-метоксифенил-имидазо[1,5,а] хиноксалин-1,3(2Н,5Н)-диона (100 мг) в безводном диоксане (4 мл) добавляли бром (200 мг). Реакционную смесь перемешивали 15 мин при 20^oC, а затем выливали непосредственно в кипящую уксусную кислоту (50 мл), содержащую цинковый порошок (500 мг). Реакционную смесь нагревали с обратным холодильником в течение 5 мин, а затем охлаждали до комнатной температуры. После разбавления 10% метанолом и метиленхлоридом (100 мл) смесь фильтровали через силикагель, растворитель удаляли в вакууме, а полученное твердое вещество обрабатывали кипящим этанолом (25 мл) с последующим разбавлением водой (100 мл). Смесь охлаждали до 0^oC, а твердое вещество фильтровали и высушивали, в результате чего получали 8-бромо-2-(4-метоксифенил)-имидазо[1,5,а]хиноксалин-1,3(2Н,5Н)-дион (соединение 33) в виде желтого твердого вещества с т. пл. 154^oC.

To a suspension of 2-4-methoxyphenyl-imidazo [1,5, a] quinoxaline-1,3 (2H, 5H) -dione (100 mg) in anhydrous dioxane (4 ml) was added bromine (200 mg). The reaction mixture was stirred for 15 minutes at 20 ^° C. and then poured directly into boiling acetic acid (50 ml) containing zinc powder (500 mg). The reaction mixture was refluxed for 5 minutes and then cooled to room temperature. After dilution with 10% methanol and methylene chloride (100 ml), the mixture was filtered through silica gel, the solvent was removed in vacuo, and the resulting solid was treated with boiling ethanol (25 ml), followed by dilution with water (100 ml). The mixture was cooled to 0 ^° C. and the solid was filtered and dried to give 8-bromo-2- (4-methoxyphenyl) imidazo [1,5, a] quinoxaline-1,3 (2H, 5H) -dione (compound 33) in the form of a yellow solid with so pl. 154 ^o C.

Example XII. Following the basic procedure described in example XI, the following compound was obtained:
8-bromo-2- (3-bromo-4-ethoxyphenyl) -imidazo [1,5, a] quinoxaline-1,3 (2H, 5H) -dione (compound 34), so pl. 146-149 ^o C.

 Example XIII

Раствор, содержащий 1-(2-нитрофенил)-3-(4-этоксифенил) имидазолин-2,4(1Н,3Н)-дион (5 г) в безводном тетрагидрофуране (50 мл) добавляли по капле в течение 30 мин к раствору 0,5 М LDA в тетрагидрофуране (29 мл) при -78^oC. Через 20 мин добавляли одной порцией этилхлороформат (1,2 мл) в тетрагидрофуране (5 мл). Реакционную смесь нагревали до комнатной температуры 30 мин, а затем гасили насыщенным раствором хлорида аммония. Реакционную смесь распределяли между этилацетатом и водой, органический слой высушивали, а растворитель удаляли в вакууме. Затем проводили колоночную хроматографию на силикагеле, элюируя смесью 50% этил-ацетата и гексана, в результате чего получали 5-карбоэтокси-1-(2-нитрофенил)-3-(4-этоксифенил)-имидазолин-2,4 (1Н,3Н)-дион.

A solution containing 1- (2-nitrophenyl) -3- (4-ethoxyphenyl) imidazoline-2,4 (1H, 3H) -dione (5 g) in anhydrous tetrahydrofuran (50 ml) was added dropwise over 30 min to the solution 0.5 M LDA in tetrahydrofuran (29 ml) at -78 ^° C. After 20 minutes, ethyl chloroformate (1.2 ml) in tetrahydrofuran (5 ml) was added in one portion. The reaction mixture was warmed to room temperature for 30 minutes and then quenched with a saturated solution of ammonium chloride. The reaction mixture was partitioned between ethyl acetate and water, the organic layer was dried, and the solvent was removed in vacuo. Then, silica gel column chromatography was performed, eluting with a mixture of 50% ethyl acetate and hexane, whereby 5-carboethoxy-1- (2-nitrophenyl) -3- (4-ethoxyphenyl) imidazoline-2,4 (1H, 3H) was obtained ) -dion.

 Example XIV.

К суспензии, содержащей цинковый порошок (6 г) в уксусной кислоте (250 мл) добавляли 5-карбоэтокси-1-(2-нитрофенил)-3-(4-этоксифенил)-имидазолин-2,4 (1Н, 3Н)-дион (2,5 г). Смесь нагревали 15 мин с обратным холодильником, охлаждали до комнатной температуры, фильтровали, растворитель удаляли в вакууме, а полученное твердое вещество перемешивали с этанолом (50 мл) и фильтровали, в результате чего получали 4-гидрокси-2-(4-этоксифенил)-имидазо [1,5,а] хиноксалин-1,3(2Н,5Н)-дион (соединение 35).

To a suspension containing zinc powder (6 g) in acetic acid (250 ml) was added 5-carboethoxy-1- (2-nitrophenyl) -3- (4-ethoxyphenyl) -imidazoline-2,4 (1H, 3H) -dione (2.5 g). The mixture was heated under reflux for 15 minutes, cooled to room temperature, filtered, the solvent was removed in vacuo, and the resulting solid was stirred with ethanol (50 ml) and filtered, resulting in 4-hydroxy-2- (4-ethoxyphenyl) - imidazo [1,5, a] quinoxaline-1,3 (2H, 5H) -dione (compound 35).

 Example XV.

Раствор 4-гидрокси-2-(4-этоксифенил)-имидазо [1,5,а]-квиноксалин-1,3(2Н, 5Н)-дион (3,2 г) в оксихлориде фосфора (40 мл) нагревали с обратным холодильником в течение 16 ч. Растворитель удаляли в вакууме и добавляли воду 15 мл. Затем pH доводили до 7,0 с использованием гидроксида аммония и полученное твердое вещество фильтровали и высушивали, в результате чего получали 4-хлоро-2-(4-этоксифенил)-имидазо[1,5,а]хиноксалин-1,3(2Н,5Н)-дион (соединение 36).

A solution of 4-hydroxy-2- (4-ethoxyphenyl) -imidazo [1,5, a] -quinoxaline-1,3 (2Н, 5Н) -dione (3.2 g) in phosphorus oxychloride (40 ml) was heated under reflux refrigerator for 16 hours. The solvent was removed in vacuo and 15 ml of water was added. Then, the pH was adjusted to 7.0 using ammonium hydroxide and the resulting solid was filtered and dried to give 4-chloro-2- (4-ethoxyphenyl) imidazo [1,5, a] quinoxaline-1,3 (2H , 5H) -dione (compound 36).

 Example XVI.

Раствор тетрагидрофурана (10 мл), аммиака (10 мл) и 4-хлоро-2-(4-этоксифенил)-имидазо[1,5, а]хиноксалин-1,3(2Н,5Н)-диона (100 мг) нагревали 4 ч в герметично закрытой пробирке при 100^oC. После охлаждения до комнатной температуры растворитель удаляли в вакууме. Твердое вещество суспендировали в 50% EtOH-H₂O и фильтровали с получением 4-амино-2-(4-этоксифенил)-имидазо[1,5,а] хиноксалин-1,3(2Н,5Н)-диона (соединение 37).

A solution of tetrahydrofuran (10 ml), ammonia (10 ml) and 4-chloro-2- (4-ethoxyphenyl) imidazo [1,5, a] quinoxaline-1,3 (2H, 5H) -dione (100 mg) was heated 4 hours in a sealed tube at 100 ^o C. After cooling to room temperature, the solvent was removed in vacuo. The solid was suspended in 50% EtOH-H ₂ O and filtered to give 4-amino-2- (4-ethoxyphenyl) imidazo [1,5, a] quinoxaline-1,3 (2H, 5H) dione (compound 37 )

Example XVII. Following the basic procedure described in example XVI, the following compounds were prepared:
1. 4-dimethylamino-2- (4-ethoxyphenyl) imidazo [1,5, a] quinoxaline-1,3 (2H, 5H) -dione (compound 38).

 2. 4-n-propylamino-2- (4-ethoxyphenyl) imidazo [1,5, a] quinoxaline-1,3 (2H, 5H) -dione (compound 39).

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

 Example XVIII.

2-(4-ацетоксифенил)-имидазо[1,5, а] хиноксалин-1,3(2Н, 5Н)-дион (250 мг) добавляли к раствору этанола (50 мл), насыщенному HCl. Раствор перемешивали 2 ч, а растворитель удаляли в вакууме, в результате чего получали 2-(4-гидроксифенил)-имидазо [1,5, а] хиноксалин-1,3(2Н,5Н)-дион (соединение 41), т. пл. 318-322^oC.

2- (4-acetoxyphenyl) imidazo [1,5, a] quinoxaline-1,3 (2H, 5H) -dione (250 mg) was added to a solution of ethanol (50 ml) saturated with HCl. The solution was stirred for 2 hours, and the solvent was removed in vacuo to give 2- (4-hydroxyphenyl) imidazo [1,5, a] quinoxaline-1,3 (2H, 5H) -dione (compound 41), t. pl. 318-322 ^o C.

 Example XIX.

2-(4-этоксифенил)-имидазо[1,5, а] хиноксалин-1,3 (2Н, 5Н)-дион (100 мг) добавляли к раствору диметилформамиддиметилацеталя (10 мл) и ДМФ (5 мл), затем реакционную смесь нагревали 4 ч при 100^oC. Раствор охлаждали до комнатной температуры и выливали в воду (200 мл). Полученный осадок собирали и высушивали, в результате чего получали 5-N-метил-2-(4-этоксифенил)-имидазо [1,5,а] хиноксалин-1,3 (2Н,5Н)-дион (соединение 42), т. пл. 263-266^oC.

2- (4-ethoxyphenyl) imidazo [1,5, a] quinoxaline-1,3 (2H, 5H) -dione (100 mg) was added to a solution of dimethylformamide dimethyl acetal (10 ml) and DMF (5 ml), then the reaction mixture heated for 4 hours at 100 ^° C. The solution was cooled to room temperature and poured into water (200 ml). The resulting precipitate was collected and dried, resulting in a 5-N-methyl-2- (4-ethoxyphenyl) imidazo [1,5, a] quinoxaline-1,3 (2H, 5H) -dione (compound 42), t pl. 263-266 ^o C.

 Example XX.

2-(4-этоксифенил)-имидазо[1,5, а]хиноксалин-1,3 (2Н,5Н)-дион добавляли к раствору безводного ДМФ (5 мл) и трет-бутоксида калия (125 мг) при 50^oC. Через 5 мин добавляли триметилацетилхлорид (150 мл). Реакционную смесь перемешивали 15 мин и выливали в воду (25 мл). Полученный осадок собирали, промывали EtOH и высушивали, в результате чего получали 3-триметилецетокси-2-(4-этоксифенил)-имидазо [1,5,а] хиноксалин-1,3 (2Н,5Н)-дион (соединение 43).

2- (4-ethoxyphenyl) -imidazo [1,5, a] quinoxaline-1,3 (2H, 5H) -dione was added to a solution of anhydrous DMF (5 ml) and potassium tert-butoxide (125 mg) at 50 ^° C After 5 min, trimethylacetyl chloride (150 ml) was added. The reaction mixture was stirred for 15 minutes and poured into water (25 ml). The resulting precipitate was collected, washed with EtOH and dried, whereby 3-trimethyl-ketoxy-2- (4-ethoxyphenyl) -imidazo [1,5, a] quinoxaline-1,3 (2H, 5H) -dione (compound 43) was obtained.

Example XXI. Following the basic procedure described in Example XX, the following compounds were prepared:
1. 3-n-propoxy-2- (4-ethoxyphenyl) imidazo [1,5, a] quinoxaline-1 (2H, 5H) -one (compound 44).

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

 Despite the specific embodiments of the invention illustrated and described above, various modifications are apparent to those skilled in the art, and it is understood that the present invention is not limited to the stated embodiments or their individual details, and that deviations from them within the essence are possible. and the scope of the present invention defined in the following claims.

Claims (40)

1. Imidazoquinoxalines of the general formula

where R is hydrogen or methyl;
R ₁ and R _{4 are} hydrogen;
X is hydrogen;
W phenyl or phenyl substituted with halogen, acetoxy, hydroxy, a straight or branched chain lower alkyl group having 1 to 4 carbon atoms, a straight or branched chain amino or lower alkoxy group having 1 to 4 carbon atoms, or phenyl disubstituted with halogen and lower straight or branched chain alkyl having 1 to 4 carbon atoms, or phenyl disubstituted by halogen and lower alkoxy straight or branched chain having 1 to 4 carbon atoms;
R ₂ and R ₃ , the same or different, hydrogen, halogen, straight or branched chain lower alkyl having 1 4 carbon atoms. 2. The compound according to claim 1 of the General formula

where R ₁ and R ₄ hydrogen;
X is hydrogen;
W phenyl, phenyl substituted with halogen, acetoxy, hydroxy, lower or straight chain or branched chain alkyl having 1 to 4 carbon atoms, or lower or straight chain or branched chain alkoxy having 1 to 4 carbon atoms. 3. The compound according to claim 1 of the General formula

where W is phenyl disubstituted with halogen and lower alkyl straight or branched chain having 1 4 carbon atoms. 4. The compound according to claim 1 of the General formula

where W is phenyl disubstituted with halogen and lower alkoxy straight or branched chain having 1 4 carbon atoms;
R ₂ and R _{3 are} hydrogen.  5. The compound according to claim 1, in which W is phenyl. 6. The compound according to claim 1, in which R ₂ bromine.  7. The compound according to claim 1, in which W is 4-methoxyphenyl.  8. The compound according to claim 1, in which W 2-fluorophenyl.  9. The compound according to claim 1, in which W 4-ethoxyphenyl.  10. The compound according to claim 1, which is a 2-phenyl-imidazo (1,5-a) quinoxaline-1,3- (2H, 5H) -dione.  11. The compound according to claim 1, which is a 2- (2-fluorophenyl) - imidazo (1,5-a) quinoxaline-1,3 (2H, 5H) -dione.  12. The compound according to claim 1, which is a 2- (4-ethoxyphenyl) -imidazo (1,5-a) quinoxaline-1,3 (2H, 5H) -dione.  13. The compound according to claim 1, which is a 2- (4-methoxyphenyl) -imidazo (1,5-a) quinoxaline-1,3 (2H, 5H) -dione.  14. The compound according to claim 1, which is a 2- (4-methylphenyl) -imidazo (1,5-a) quinoxaline-1,3 (2H, 5H) -dione.  15. The compound according to claim 1, which is a 2- (4-fluorophenyl) - imidazo (1,5-a) quinoxaline-1,3 (2H, 5H) -dione.  16. The compound according to claim 1, which is a 2- (2-aminophenyl) -imidazo (1,5-a) quinoxaline-1,3 (2H, 5H) -dione.  17. The compound according to claim 1, which is a 2- (3-fluorophenyl) - imidazo (1,5-a) quinoxaline-1,3 (2H, 5H) -dione.  18. The compound according to claim 1, which is a 2- (4-chlorophenyl) - imidazo (1,5-a) quinoxaline-1,3 (2H, 5H) -dione.  19. The compound according to claim 1, which is a 2- (3-methylphenyl) -imidazo (1,5-a) quinoxaline-1,3 (2H, 5H) -dione.  20. The compound according to claim 1, which is a 2- (2-fluoro-4-ethoxyphenyl) imidazo (1,5-a) quinoxaline-1,3 (2H, 5H) -dione.  21. The compound according to claim 1, which is a 2- (3-chlorophenyl) -imidazo (1,5-a) quinoxaline-1,3 (2H, 5H) -dione.  22. The compound according to claim 1, which is a 2- (2-methoxyphenyl) -imidazo (1,5-a) hinsksalin-1,3 (2H, 5H) -dione.  23. The compound according to claim 1, which is a 2- (4-ethylphenyl) - imidazo (1,57a) quinoxaline-1,3 (2H, 5H) -dione.  24. The compound according to claim 1, which is a 2- (2-fluoro-4-methylphenyl) imidazo (1,5-a) quinoxaline-1,3 (2H, 5H) -dione.  25. The compound according to claim 1, which is a 2- (3-methoxyphenyl) -imidazo (1,5-a) quinoxaline-1,3 (2H, 5H) -dione.  26. The compound according to claim 1, which is a 2- (3-ethoxyphenyl) -imidazo (1,5-a) quinoxaline-1,3 (2H, 5H) -dione.  27. The compound according to claim 1, which is a 2- (4-n-propyloxyphenyl) -imidazo (1,5-a) quinoxaline-1,3 (2H, 5H) -dione.  28. The compound according to claim 1, which is a 2- (4-n-butoxyphenyl) -imidazo (1,5-a) quinoxaline-1,3 (2H, 5H) -dione.  29. The compound according to claim 1, which is a 2- (4-isopropoxyphenyl) -imidazo (1,5-a) quinoxaline-1,3 (2H, 5H) -dione.  30. The compound according to claim 1, which is a 7-chloro-2- (4-methylphenyl) -imidazo (1,5-a) quinoxaline-1,3 (2H, 5H) -dione.  31. The compound according to claim 1, which is an 8-methyl-2-phenylimidazo (1,5-a) quinoxaline-1,3 (2H, 5H) -dione.  32. The compound according to claim 1, which represents 8-bromo-2- (4-ethoxyphenyl) -imidazo (1,5-a) quinoxaline-1,3 (2H, 5H) -dione.  33. Connection n. 1, which is a 2- (4-propylphenyl) imidazo (1,5-a) quinoxaline-1,3 (2H, 5H) -dione.  34. The compound according to claim 1, which is 7-methyl-2- (4-ethoxyphenyl) imidazo (1,5-a) quinoxaline-1,3 (2H, 5H) -dione.  35. The compound according to claim 1, which is a 2- (3-bromo-4-ethoxyphenyl) imidazo (1,5-a) quinoxaline-1,3 (2H, 5H) -dione.  36. The compound according to claim 1, which is a 2- (4-acetoxyphenyl) -imidazo (1,5-a) quinoxaline-1,3 (2H, 5H) -dione.  37. The compound according to claim 1, which is 8-bromo-2- (4-methoxyphenyl) -imidazo (1,5-a) quinoxaline-1,3 (2H, 5H) -dione.  38. The compound according to claim 1, which is 8-bromo-2- (3-bromo-4-ethoxyphenyl) imidazo (1,5-a) quinoxaline-1,3 (2H, 5H) -dione.  39. The compound according to claim 1, which is a 2- (4-hydroxyphenyl) -imidazo (1,5-a) quinoxaline-1,3 (2H, 5H) -dione.  40. The compound according to claim 1, which is 5-methyl-2- (4-ethoxyphenyl) imidazo (1,5-a) quinoxaline-1,3 (2H, 5H) -dione.

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