SK78092A3 - Imidazoquinoxalines - Google Patents

Abstract

Imidazo(1,5-a)quinoxalin -1,3(2H,5H)dione derivs. of formula (I) are new. R1 and R4 = H, halogen, opt. branched 1-6C alkyl, or opt. branched 1-6C alkoxy; X = H, halogen, OH or NH2, or mono- or di-(1-6C alkyl)amino; W = Ph, thienyl or pyridyl, each of which may be mono- or di-substd. with halogen, OH, opt. branched 1-6C alkyl, NH2, mono- or di-(opt. branched 1-6C alkyl)amino or opt. branched 1-6C alkoxy; R2 and R3 = (a) H, (b) halogen, (c) OH, (d) NH2, (e) indanyl, 4-(thio)-chromanyl, 1-(1,2,3,4- tetrahydronaphthyl), each opt. monosubstd. with halogen, opt. branched 1-6C alkyl or opt. branched 1-6C alkoxy, (f) OR5, COR5, CO2R5, OCOR5 or R5; R5 = H, Ph, pyridyl, opt. branched 1-6C alkyl, Ph (opt. branched 1-6C alkyl) or pyridyl- (opt. branched 1-6C alkyl); (g) -CONR6R7 or -(CH2)nNR6R7; n = 0-2; R6 = H or opt. branched 1-6C alkyl; R7 = H, Ph, pyridyl, opt. branched 1-6C alkyl, Ph (opt. branched 1-6C alkyl) or pyridyl (opt. branched 1-6C alkyl), or NR6R7 forms a heterocyclic gp., e.g. morpholyl, piperidinyl, pyrrolidyl or N-alkyl; (h) -NR8CO2R9; R8 and R9 = H, Ph, pyridyl, opt. branched 1-6C alkyl, Ph (opt. branched 1-6C alkyl) or pyridyl (opt. branched 1-6C alkyl); or (i) C(OH)R10R11; R10 and R11 = opt. branched 1-6C alkyl, Ph or Ph (opt. branched 1-6C alkyl). 45 Cpds. are specifically claimed, including 2-phenyl-imidazol(1,5,a) quinoxaline-1,3(2H,5H)-dione (1), and 5-propionyl-2- (4-ethoxyphenyl)-imidazo (1,5,a)quinoxaline-1,3 (2H,5H)-dione.

Description

Technical field

The invention relates to certain imidazoquinoxaline compounds that selectively bind to GABAα receptors. The invention also relates to pharmaceutical compositions containing these compounds. The proportion of the compounds of the invention may be used in the treatment of ^T of anxiety, sleep and seizure. They can also be used in the treatment of a condition associated with an overdose of benzodiazepine-type drugs or as stimulants. Further, the present disclosure describes the interaction of imidazoquinoxaline of the invention with GABA binding sites and benzodiazepine (BDZ) receptors. This interaction results in different types of pharmacological activity of these compounds.

BACKGROUND OF THE INVENTION

? -Aminobutyric acid (GABA) is considered to be one of the major inhibitory amino acid-type transmitters in the mammalian brain. 30 years have elapsed since her presence in the brain was detected (Roberts and Frankel, J. Biol. Chem. 187, pp. 55-63, 1950; Udenfriend, J. Biol. Chem. 187, pp. 65-69, 1950) . Since then, immense efforts have been devoted to the role of GABA in the etiology of seizure, sleep disorders, anxiety disorders and cognitive disorders (Tallman and Gallager, Ann. Rev. Neuroscience 8, pp. 21-44, 1985). GABA, which is largely albeit unevenly distributed throughout the mammalian brain, is reported to be a transmitter at approximately 30% of brain synapses. In most areas of the brain, GABA is associated with local inhibitory neurons, and in only two areas, GABA is associated with longer projections. GABA mediates much of its action through a protein complex that is located on both the cell surface and the nerve endings; these sites are called GABAα receptors. Postsynaptic responses to GABA are mediated by changes in the conductivity of chloride ions, which usually, although not necessary, leads to hyperpolarization of cells. Recent studies have shown that the protein complex associated with postsynaptic responses to GABA is a major site of action for a number of structurally different compounds capable of modifying the postsynaptic response to GABA. Depending on the mode of interaction, these compounds are capable of providing a wide range of different second activities (either sedative, anxiolytic, and anticonvulsant, or stimulatory, anxiotic, and convulsive).

1,4-Benzodiazepines are among the drugs still widely used in the world. Among the most successful benzodiazepines, chlordiazepoxide, diazepam, flurazepam and triazolan are the most important. These compounds are widely used as anxiolytics, sedatives and hypnotics, muscle relaxants and anticonvulsants. Many of these compounds are very potent drugs; this potency indicates a site of action with high affinity and specificity for individual receptors. Early electrophysiological studies have shown that the major action of benzodiazepine is to stimulate GABAergic inhibition. Benzodiazepines are capable of stimulating presynaptic inhibition of the monosynaptic reflex of Radix ventralis, a GABA-mediated effect (Schmidt et al., 1967, Ar. Exp. Path. Pharmacol. 285, pp. 69-82). All other electrophysiological studies (reviewed by Tallmann et al., 1980, Science 207, pages 274-281; Haefley et al., 1981, Hand. Exptl. Pharmacol. 33, pages 95-102) generally confirm this finding and in the mid 70s. More or less, there has been a consensus among electrophysiologists that benzodiazepines can stimulate the effects of GABA.

When the benzodiazepine receptor was discovered and the nature of the interaction between GABA and benzodiazepines was defined, it appeared that the interactions of benzodiazepines with various neurotransmitter systems, which interactions are important from a behavioral perspective, are largely due to the increased ability of the

GABA to modify these systems. Furthermore, any modified system can be associated with the expression of behavior.

Studies of the mechanistic nature of these interactions depended on the demonstration of a high affinity binding site (receptor) for benzodiazepines. Such a receptor is present in the CNS of all vertebrates that are phylogenetic younger than bony fish (Squires and Braestrup 1977, Nature 166: 732-34, Mohler and Okada, 1977, Science 198; 854-51, Mohler and Okada, 1977, Br. J. Psychiatry 133: 261-68). Using tritiated diazepam and various other compounds, it has been demonstrated that these benzodiazepine binding sites meet many of the criteria of pharmacological receptors. Binding to these in vitro sites is rapid, reversible, stereospecific and saturable. More importantly, a highly significant correlation has been found between the ability of benzodiazepines to displace diazepam from its binding site and efficacy in many animal behavioral tests that can be used to predict the strength of benzodiazepine (Braestrup and Squires 1978, Br. J. Psychiatry 133: 249 - 60, Mohler and Okada, 1977, Science 198: 854-51, Mohler and Okada, 1977, Br. J. Psychiatry 133: 261-68). The average therapeutic doses of these drugs in human medicine also correlate with receptor potency. (Tallman et al., 1980, Science 207: 274-281).

In 1978, it became apparent that GABA and similar analogs could act on the low affinity (1 µM) GABA binding site while stimulating benzodiazepine binding to a clonazepan-sensitive site (Tallman et al., 1978, Nature 274: 383-385) ). This stimulation is due to an increase in the affinity of the benzodiazepine binding site due to the occupancy of the GABA site. The data obtained was interpreted as meaning that the GABA site and the benzodiazepine site are allosterically linked in the membrane as part of the protein complex. For numerous GABA analogs, the ability to stimulate diazepam binding and 50% of the maximal value and the ability to inhibit GABA binding to brain membranes by 50% could be directly correlated. GABA agonist enhancement of benzodiazepine binding is blocked by the antagonist

GABA receptor (+) bicucullin. The stereoisomer (-) bicucullin is much less effective (Tallman et al., 1978, Nature 274: 383-385).

Soon after the discovery of high affinity binding sites for benzodiazepines, it was found that triazolopyridazine can act on benzodiazepine receptors in numerous brain regions in a manner consistent with receptor heterogeneity or negative cooperativity. In these studies they were numerous. Hill coefficients with significantly lower values than 1, such as in the cortex, hippocampus and striatum, were found in brain regions. In the cerebellum, thioazolopyridazine acts with Hill coefficient I benzodiazepine sites (Squires et al., 1979, Pharma. Biochem. Behav. 10: 825-830; Klepner et al., 1979, Pharmacol. Biochem. Behav. 11: 457-462). Thus, numerous benzodiazepine receptors have been predicted in the cortex, hippocampus, striatum, but not in the cerebellum.

Based on these studies, extensive autoradiographic receptor localization studies were performed at the light microscope level. Although receptor heterogeneity has been demonstrated (Young and 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), but these early studies did not show a simple correlation between the location of the receptor subtypes and the behavior associated with this region. In addition, in the cerebellum, where one receptor was predicted based on binding studies, autoradiography showed receptor heterogeneity ((Niehoff et al., 1982, J. Pharmacal. Exp. Ther. 221: 670-675)).

The physical basis of the difference in drug specificity for the two apparent subtypes of benzodiazepine sites has been shown by Sieghart and Karobath, 1980, Nature 286: 285-287.

Receptors have been identified by covalent incorporation of radioactive flunitrazepam, a benzodiazepine that can covalently label all types of receptors. Major labeled bands have molecular weights of 50,000 to 53,000, 55,000 and 57,000, and triazolopyridazines inhibit labeling of slightly higher molecular weight forms (53,000, 55,000, and 57,000) (Seighart et al., 1983, Eur. J. Pharmacol. 88: 291-299).

At that time, it was considered that many forms of the receptor may represent! isoreceptors or numerous allelic forms of the receptor (Tallman and Gallager, 1985, Ann. Rev. Neurosci. 8: 21-44). Although common to enzymes, genetically distinct forms of the receptor have not generally been described. Based on the study of the receptor already initiated using specific radioactive probes and electrophoretic techniques, it is almost certain that isoreceptors will prove important in research into the etiology of psychiatric disorders in humans.

GABA A receptor subunits have been cloned from a bovine and human cDNA library (Schoenfield et al., 1988; Duman et al., 1989). A variety of cDNAs have been identified as subunits of the GABAα receptor complex by cloning and expression. These various cDNAs are categorized as 0c,, S and provide a molecular basis for GABAa receptor heterogeneity and distinctive regional pharmacology (Shivvers et al., 1980, Levitan et al., 1989). The subunit j * appears to allow drugs such as benzodiazepines to modify GABA responses (Pritchett et al., 1989). The presence of low Hill coefficients in ligand binding to the GABAa receptor shows unique profiles of subtype-specific pharmacological activity.

Drugs that can act on the GABA receptor may exhibit a spectrum of pharmacological activities depending on their ability to modify the action of GABA. For example, beta-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). The biological activity of these compounds cannot be completely predicted by a receptor binding assay. Agents, partial agonists, inverse agonists and antagonists may inhibit binding. Having determined the structure of beta-carboline, numerous analogs could be synthesized and tested for how these compounds affect behavior. It has been immediately recognized that beta-carbolines can antagonize the action of diazepam on behavior (Tenen and Hirsch, 1980, Nature 288: 609-610). In addition to this antagonism, beta-carbolines have their own intrinsic activity, which is opposite to that of benzodiazepine. These agents are known as inverse agonists.

In addition, numerous other specific benzodiazepine receptor antagonists have been developed based on the ability to inhibit benzodiazepine binding. The best studied compound of this type is imidazodiazepine (Hunkeler et al., 1981, Nature 290: 514-516). This compound is a competitive inhibitor of the binding of benzodiazepine and beta-carboline, which is characterized by high affinity so that it is able to block the pharmacological action of both classes of these compounds. It itself has little intrinsic pharmacological activity in animals and humans (Hunkeler et al., 1981, Nature 290: 514-516; Darragh et al., 1983, Eur. J. Clin. Pharmacol. 14: 569-570). When the radiolabelled form of this compound has been studied (Mohler and Richards, 1981, Nature 294: 763-765), it has been found to act at the same number of sites as benzodiazepines and beta-carbolines and that the interactions of these compounds are purely competitive. This compound is a preferred ligand for binding to GABAα receptors since it does not exhibit specificity for the receptor subtype and measures each receptor state.

Interaction studies of a large number of similar compounds lead to their categorization. Currently, those compounds that exhibit! similar activity to benzodiazepines, referred to as agonists. Compounds showing opposite activity to benzodiazepines are termed inverse agonists, and compounds blocking both types of activity are termed antagonists. This categorization was developed to underline the fact that a number of different compounds exhibit a spectrum of pharmacological effects, to show that compounds can act on the same receptors to produce opposite effects and to show that beta-carbolines and antagonists with intrinsic anxiogenic effects are not synonyms. The biochemical assay of pharmacological and behavioral properties of compounds that act on the benzodiazepine receptor further emphasizes the interaction with the GABAergic system. In contrast to benzodiazepines that have an increased 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 shift due to GABA (i.e., a change in receptor affinity due to GABA) (Mohler and Richards, 1981, Nature, 294: 763-765) and inverse agonists show a decrease in affinity due to GABA (Braestrup and Nielson 1981, Nature, 294: 472-474). Thus, the shift due to GABA can generally serve to predict the expected behavioral properties of these compounds.

Various compounds have been prepared as benzodiazepine agonists and antagonists. For example, U.S. Pat. Nos. 4,312,870 and 4,713,383; EP 181 282 discloses various compounds which are useful in the treatment of anxiety disorders

depression. U.S. Pat. 4 713 383 are described compounds of the formula ri ✓ her Q I r ₂ where

r is optionally substituted phenyl, (dihydro) furanyl, tetrahydrofuranyl, (dihydro) thienyl, tetrahydrothienyl, pyranyl or ribofuranosyl, all of which are bonded via a carbon atom;

I <2 is hydrogen or alkyl;

X is O, S or R3N, wherein R3 is H, alkenyl, alkynyl, cycloalkyl of 3 to 20 carbon atoms, optionally substituted alkyl, aryl or aralkyl, wherein aryl is phenyl, pyridyl, thienyl or furyl; and ring A is optionally substituted with alkyl, alkoxy, halogen, amino, alkylthio, and the like.

In European patent application no. EP 181 282 discloses compounds of the general formula

wherein is optionally substituted phenyl or heterocyclic;

is hydrogen, alkyl, alkenyl, hydroxyalkyl, aralkyl, aralkenyl or aryl;

R ^ is hydrogen, alkyl, alkoxy, hydroxy, halogen, trifluoromethyl, O ON, amino, alkylthio, alkylsulfinyl, alkylsulfonyl or aralkoxy;

X is O or S or NR NR, wherein H, alkyl, aralkyl, cycloalkyl, alkenyl, alkynyl, aryl, optionally substituted aminoalkyl or hydroxyalkyl.

U.S. Pat. No. 4,312,870 discloses compounds of general interest of formula i and ii ^R 1X, ^R NN R N - N ^Z jl < Λλ _Ph AA ° J ⁰ N == ^ N N r ₂ r / r ₂ (I) (Ii)

where

Ph is 1,2-phenylene optionally substituted with up to 3 identical or different substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio, hydroxy, halogen, trifluoromethyl, nitro, amino, mono- and di-lower alkylamino, cyano , carbamoyl and carboxy;

R is an optionally substituted phenyl having the formula H-Ph, wherein Ph is as defined above, pyridyl, lower alkylpyridyl or halopyridyl;

R ^ is hydrogen, lower alkyl optionally substituted with hydroxy, dialkylamino or H-Ph; and

is hydrogen or lower alkyl;

their three hydroxytautomers and the lower alkanoyl-, carbamoyl-, mono- or di-lower alkylcarbamoyl derivatives of these (hydroxy or amino) (phenyl or phenylene) compounds; and formula iii (iii)

Η where

R is hydrogen, alkyl or alkoxy, each containing up to 4 carbon atoms, hydroxy, fluoro, chloro, bromo or trifluoromethyl; and

R 1 represents hydrogen, o- or m-fluoro; or represents p-fluoro when R is chlorine.

The compounds of this invention differ from the above known compounds. These known compounds are not imidazoquinoxalines and do not contain the various ring substituents characteristic of the compounds of the invention.

SUMMARY OF THE INVENTION

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

The present invention also provides pharmaceutical compositions comprising compounds of Formula I. In addition, the present invention provides compounds useful as stimulants for the treatment of seizure, anxiety and sleep disorders, and for the treatment of benzodiazepine overdose. In a broadest embodiment, the present invention provides compounds of formula I

W _R1 VN The r ^N T ° (I) R4 1 H

and the pharmaceutically acceptable nontoxic salts thereof, wherein, and R ^ which are the same or different, each represents a hydrogen atom, a halogen atom, a straight or branched lower alkyl group having 1 to 6 carbon atoms or a straight or branched lower alkoxy group having 1 to 6 carbon atoms. 6 carbon atoms;

X represents a hydrogen atom, a halogen atom, a hydroxy group, an amino group or a mono- or dialkylamino group in which each alkyl radical is lower and contains 1 to 6 carbon atoms;

W is phenyl, thienyl or pyridyl, each of which is optionally mono- or disubstituted with halogen, hydroxy, straight or branched chain alkyl of 1 to 6 carbon atoms, amino, mono- or dialkyl amino, each of which is lower alkyl a straight or branched chain of 1 to 6 carbon atoms or a lower alkoxy group of a straight or branched chain of 1 to 6 carbon atoms;

and R 3, which are the same or different, each represents a hydrogen atom, a halogen atom, a hydroxy group, an amino group, a 1-indanyl group, a 4- (thio) chromanyl group or a 1- (1,2,3,4-tetrahydronaphthyl) group;

1-indanyl, 4- (thio) chromanyl, 1- (1,2,3,4-tetrahydronaphthyl), each monosubstituted with halogen, straight or branched lower alkyl of 1 to 6 carbon atoms, or lower alkoxy a straight or branched chain containing from 1 to 6 carbon atoms;

ORg, CORg, ^{CO2 R5} 'OCORg or Rg, wherein Rg is hydrogen, phenyl, pyridyl, straight or branched lower alkyl of 1 to 6 carbon atoms, or phenylalkyl or pyridylalkyl, each alkyl group being a straight or branched chain lower alkyl group having from 1 to 6 carbon atoms;

a group of the formula -CONR 8 R 6 or - (CH ₂ ) _n NR 8 R 6 wherein n is 0, 1 or 2;

R 8 represents a hydrogen atom or a straight or branched lower alkyl group having 1 to 6 carbon atoms;

R ^ is hydrogen, phenyl, pyridyl, straight or branched lower alkyl of 1 to 6 carbon atoms or phenylalkyl or pyridylalkyl, each alkyl group being lower alkyl of straight or branched chains of 1 to 6 carbon atoms; the sky

NRgR.? is a heterocyclic group selected from morpholyl, piperidyl, pyrrolidyl or N-alkylpiperazyl;

-NR ₈ CO ₂ R ₉ where

R _a and R _Q are the same or different, are each a hydrogen atom OJ, phenyl, pyridyl, lower alkyl straight or branched chain of 1 to 6 carbon atoms or phenylalkyl or pyridylalkyl where each alkyl is lower alkyl of a straight or branched chain containing from 1 to 6 carbon atoms; the sky

C (OH) R ₁₀ R ₁₁ wherein ^R 10 ^and R _11, which are the same or different, each represent a straight or branched lower alkyl group having 1 to 6 carbon atoms, a phenyl group or a phenylalkyl group in which the alkyl group is lower, straight or branched; branched chain and contains 1 to 6 carbon atoms.

These compounds are highly selective agonists, antagonists or inverse agonists of GABAα receptors in the brain or prodrugs thereof, and are useful in the diagnosis and treatment of anxiety, sleep disorders, seizures, benzodiazepine drug overdoses, and as memory enhancers.

The present invention also relates to compounds of formula II

FU H wherein and R ₄ , which are the same or different, each represent a hydrogen atom, a halogen atom or a straight or branched chain alkyl group having 1 to 6 carbon atoms;

X is hydrogen, halogen, hydroxy, amino or mono- or dialkylamino, each of which is lower, straight or branched and contains 1 to 6 carbon atoms;

W is phenyl or phenyl which is mono- or disubstituted by halogen, hydroxy, amino, lower alkyl of straight or branched chain of 1 to 6 carbon atoms or lower alkoxy of straight or branched chain of 1 to 6 carbon atoms.

The present invention further provides compounds of formula III wherein:

H (III)

W is phenyl or phenyl which is mono- or disubstituted by halogen, hydroxy, amino, lower alkyl of straight or branched chain of 1 to 6 carbon atoms or lower alkoxy of straight or branched chain of 1 to 6 carbon atoms.

The invention furthermore relates to compounds of the general formula

IV

where

W is phenyl or phenyl which is mono- or di-substituted with halogen, hydroxy, amino, straight or branched lower alkyl of 1 to 6 carbon atoms or lower alkoxy of straight or branched chain of 1 to 6 carbon atoms; and

R @ 1 and R @ 2, which may be the same or different, each represent a hydrogen atom, a halogen atom, a hydroxy group, an amino group, a 1-indanyl group, a 4- (thio) chromanyl group or a 1- (1,2,3,4-tetrahydronaphthyl) group. ;

1-indanyl, 4- (thio) chromanyl, 1- (1,2,3,4-tetrahydronaphthyl), each monosubstituted with halogen, straight or branched lower alkyl of 1 to 6 carbon atoms, or lower alkoxy a straight or branched chain containing from 1 to 6 carbon atoms;

OR, COR, CC ORRg, OCOR ^ or R ^, wherein R ^ is hydrogen, phenyl, pyridyl, straight or branched lower alkyl having 1 to 6 carbon atoms, or phenylalkyl or pyridylalkyl, wherein each alkyl is a straight or branched lower alkyl group having from 1 to 6 carbon atoms;

a group of the formula -CONR, R-, or - (CH_) NR, R-.

b / z n b / wherein n is 0, 1 or 2;

R 8 is a hydrogen atom or a straight or branched chain alkyl group having 1 to 6 carbon atoms;

R1 represents a hydrogen atom, a phenyl group, a pyridyl group, a straight or branched chain lower alkyl group having 1 to 6 carbon atoms or a phenylalkyl or pyridylalkyl group, each alkyl group having a straight or branched chain alkyl group having 1 to 6 carbon atoms; the sky

NRgR? is a heterocyclic group selected from morpholyl, piperidyl, pyrrolidyl or N-alkylpiperazyl;

-nr ₈ what ₂ r ₉ where

R and R _t are the same or different are each a hydrogen atom, a phenyl, pyridyl, lower alkyl straight or branched chain of 1 to 6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkyl is lower alkyl of straight or branched a chain of 1 to 6 carbon atoms; or c (oh) r ₁₀ r _1; where ^R 10 ^{and R} 11 ' ^, which are the same or different, are in each case a straight or branched lower alkyl group having 1 to 6 carbon atoms, a phenyl group or a phenylalkyl group in which the alkyl group is lower, it has a straight or branched chain and contains 1 to 6 carbon atoms.

The term "non-toxic pharmaceutically acceptable salts" refers to: acid salts such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, hydroiodic, acetic and the like. A wide range of non-toxic pharmaceutically acceptable acid addition salts are well known to those skilled in the art.

Representative compounds of the present invention that fall within the scope of the present invention include: Formula I includes compounds of the following formulas and pharmaceutically acceptable salts thereof

Η Η

Compound 1

Compound 4

OCH ₂ CH ₃

H

'N

H

Compound 5

Compound 3

Η

Compound 33

However, the compounds of formula I are not limited to the specific compounds listed above. Also included within the scope of the present invention are acylated prodrugs derived from compounds of Formula I. Various synthetic methods are apparent to those skilled in the art and may be used to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs derived from compounds of Formula I.

The term lower alkyl as used herein refers to straight or branched chain alkyl groups having 1 to 6 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-methylpentyl.

The term lower alkoxy as used herein means! straight or branched chain alkoxy groups having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentoxy, isopentoxy, neopentoxy, hexoxy, 2- hexoxy, 3-hexoxy and 3-methylpentoxy.

The term halogen as used herein refers to fluorine, bromine, chlorine and iodine.

As used herein, N-alkylpiperazyl means groups of the general formula

N - R wherein R is a straight or branched chain lower alkyl group as defined above.

The term 4- (thio) chromanyl group refers to a group of the formula

The pharmaceutical utility of the compounds of the invention can be illustrated by the following assay for GABAα-receptor activity.

The assays were performed as described by Thomas and Tallman (J. Bio. Chem. 156: 9838-9842, J. Neurosci. 3: 433-440, 1983). Rat cortical tissue is dissected and homogenized in 25 volumes (w / v) of 0.05 M Tris HCl buffer (pH 7.4 at 4 ° C). The tissue homogenate is centrifuged cold (4 ° C) (20,000 g for 20 minutes). The supernatant was decanted and the pellet re-homogenized in the same volume of buffer. The mixture is centrifuged again at 20,000 g, the supernatant is decanted and the pellet is frozen at -20 ° C overnight. The pellet is then thawed and re-homogenized in 25 volumes (original weight / volume) of buffer. This procedure is performed twice in total. Finally, the pellet is resuspended in 50 volumes (w / v)

0.05M Tris HCl buffer, pH 7.4, 40 ° C).

Incubation mixtures include 100 µl tissue homogeneity, 100 µl 3'3 'radioligand, 0.5 nM (H-RO 15-1788 (H-Flumazenil / specific activity 80 Ci / mmol), drug or blocker and buffer to total volume. 500 / ul. Incubation is performed for 30 minutes at 4 ° C and then the mixture is rapidly filtered through a GFB filter to separate the free and bound ligand. The filter was washed 2X with fresh 0.05 M Tris HCl buffer (pH 7.4, 4 ° C) and counted in a liquid scintillation chamber. 1.0 µM diazepam was added to some tubes to determine non-specific binding. All assays are reproduced 3 times, the values are averaged and the percent inhibition of specific binding total is calculated. Specific binding is quite common! difference in total binding and non-specific binding. In some cases, the amount of unlabeled drug varies and total binding displacement curves are constructed. The data is converted into a form suitable for calculating the _IC50 and Hill coefficient (nH).

The values determined for the compounds of this invention are shown in Table I.

Table I

Compound number

IC ₅₀ (/ UM)

0.0095

0,015

0.0095

0,016

0.0024

Compounds No. 1, 3 and 4 introduce! preferred embodiments of the invention.

The compounds of formula (I) may be administered orally, topically, parenterally, by inhalation or spray, or rectally in unit dosage form containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. As used herein, parenteral administration means administration by subcutaneous, intravenous, intramuscular or intrasternal injection or by infusion. The present invention also provides pharmaceutical compositions comprising a compound of Formula I and a pharmaceutically acceptable carrier. One or more compounds of formula (I) may be included in one preparation in association with one or more non-toxic pharmaceutical carriers and / or diluents and / or adjuvants and optionally other active ingredients. Pharmaceutical compositions containing the compounds of Formula I may be in a form suitable for oral administration such as tablets, pills, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups and exillers.

Formulations for oral administration may be prepared by any of the known methods of making pharmaceutical compositions of this type. These formulations may contain one or more substances selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives, in order to obtain pharmaceutically acceptable formulations which are easy to ingest. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are commonly used in the manufacture of tablets. These excipients include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate and sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders, for example starch, gelatin or acacia;

and lubricants such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay their disintegration and absorption in the gastrointestinal tract to provide a prolonged duration of action. Glyceryl monostearate or glyceryl distearate are, for example, suitable for achieving such deferred activity.

Oral formulations may also take the form of hard gelatin capsules comprising a mixture of the active ingredient with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin, or soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active ingredients in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth and acacia; dispersing or wetting agents, such as naturally occurring phosphatides, for example lecithin or alkylene oxide condensation products with fatty acids, for example polyoxyethylene stearate, or long chain aliphatic alcohols, e.g. is polyoxyethylene sorbitol monooleate or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides such as polyoxyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, such as 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 a mineral oil such as liquid paraffin. The oily suspensions may contain thickeners such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those mentioned above and flavor enhancers may be added to make these oral preparations pleasant to taste. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension comprise the active ingredient in admixture with a dispersing or wetting agent, suspending agent and at least one preservative. Suitable dispersing and wetting agents as well as suspending agents are mentioned above. Sweetening, flavoring and coloring agents may also be present as additional excipients.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may consist of a vegetable oil, for example olive oil or arachis oil or a mineral oil, for example paraffin or a mixture thereof. Suitable emulsifiers include naturally occurring resins such as acacia or tragacanth, naturally occurring phosphatides such as soya lecithin and esters or partial esters derived from fatty acids and hexitol anhydride such as sorbitan monooleate and condensation products of these partial ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be prepared using sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. These preparations may also contain irritants, preservatives, flavors and coloring agents.

The pharmaceutical preparations of the invention may also take the form of sterile injectable suspensions in water or oils. These suspensions may be prepared by known methods using suitable dispersing or wetting agents and suspending agents as hereinbefore described. The sterile injectable preparation may also take the form of a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Suitable vehicles and solvents include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any non-irritating, fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectables.

The compounds of formula (I) may also be administered in the form of a suppository for rectal administration of the drug. The suppositories may be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but which is liquid at the rectal temperature and which will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols.

The compounds of formula I may be administered parenterally in a sterile medium. The drug may be present in the form of a suspension or solution, depending on the type of vehicle and concentration used. Advantageously, various adjuvants, such as local anesthetics, preservatives and buffers, can also be dissolved in the vehicle.

The dosage level of the compounds of Formula I is in the order of from about 0.1 to about 140 mg / kg body weight per day (about 0.5 mg to 7 g per patient per day). This dose is useful in the treatment of the above conditions. The amount of active ingredient to be mixed with the carrier in the manufacture of unit dosage forms will depend on the patient being treated and the particular mode of administration selected. Unit dosage forms usually contain from about 1 mg to about 500 mg of the active ingredient.

However, the specific dosage level for each particular patient will depend on a number of factors including the efficacy of the compound specifically employed, the subject, body weight, general health, sex and diet of the patient, time of administration, route of administration, elimination rate, combination of drugs and the severity of the disease being treated.

The preparation of the compounds of the present invention is illustrated in Scheme I below. It will be apparent to those skilled in the art that starting materials can be varied and additional production steps can be added to produce the compounds of the present invention, as shown in the Examples below.

Scheme I

N0 ₂

Scheme II

wherein and R 4, which are the same or different, each represents a hydrogen atom, a halogen atom, a straight or branched lower alkyl group having 1 to 6 carbon atoms or a straight or branched lower alkoxy group having 1 to 6 carbon atoms;

X represents a hydrogen atom, a halogen atom, a hydroxy group, an amino group or a mono- or dialkylamino group in which each alkyl radical is lower and contains 1 to 6 carbon atoms;

W is phenyl, thienyl or pyridyl, each optionally mono- or disubstituted with halogen, hydroxy, straight or branched chain alkyl of 1 to 6 carbon atoms, amino, mono- or dialkyl amino, each of which is lower alkyl; a straight or branched chain having from 1 to 6 carbon atoms or a lower alkoxy group having a straight or branched chain having from 1 to 6 carbon atoms;

R 6a, which are the same or different, each represents a hydrogen atom, a halogen atom, a hydroxy group, an amino group, a 1-indanyl group, a 4- (thio) chromanyl group or a 1- (1,2,3,4-tetrahydronaphthyl) group;

1-indanyl, 4- (thio) chromanyl, 1- (1,2,3,4-tetrahydronaphthyl), each monosubstituted with halogen, a straight or branched lower alkyl group having 1 to 6 atoms, a carbon or a lower alkoxy group a straight or branched chain containing from 1 to 6 carbon atoms;

a group of the formula OR4, COR4, CC4R-, OCOR4 or R8, wherein R8 is hydrogen, phenyl, pyridyl, straight or branched lower alkyl of 1 to 6 carbon atoms or phenylalkyl or pyridyl lobes Wherein each alkyl group is a straight or branched lower alkyl group having 1 to 6 carbon atoms;

a group of the formula -CONR, R_ or - (CH_) NR, R 4.

wherein the number is 0, 1 or 2;

n

represents a hydrogen atom or a straight or branched chain lower alkyl group having 1 to 6 carbon atoms;

represents a hydrogen atom, a phenyl group, a pyridyl group, a straight or branched chain lower alkyl group having 1 to 6 carbon atoms or a phenylalkyl or pyridylalkyl group, each alkyl group being a lower alkyl group having a straight or branched chain having 1 to 6 carbon atoms; the sky

NR 8 R 6 is a heterocyclic group selected from morpholyl, piperidyl, pyrrolidyl or N-alkylpiperazyl;

NR _g CO ₂ R ₉ wherein

R 8 and R 8, which are the same or different, each represent a hydrogen atom, a phenyl group, a pyridyl group, a straight or branched lower alkyl group having 1 to 6 carbon atoms or a phenylalkyl or pyridylalkyl group, each alkyl group being a straight or branched lower alkyl group. a chain of 1 to 6 carbon atoms; the sky

C (OH) R ₁₀ R ₁₁ wherein * R _{1 q,} which are identical or different, are each a lower alkyl of straight or branched chain of 1 to 6 carbon atoms, phenyl or phenylalkyl in which the alkyl group is lower, a linear or branched, and contains 1 to 6 carbon atoms.

In some cases, certain reactive functional groups may need to be protected to carry out any of the above transformations. The need for such protecting groups and the conditions necessary for their attachment and cleavage are apparent to those skilled in the art.

The invention is illustrated by the following examples. These examples are illustrative only and in no way limit the scope of the invention.

EXAMPLES Example 1

H

To a solution of 2-nitrophenylisocyanate (3.34 g) in 100 mL toluene was added aniline (2 g). The mixture was stirred at 20 ° C for 30 minutes. Hexane (300 mL) was then added and the resulting solid was filtered and dried. N- (2-nitrophenyl) -N'-phenylurea was obtained as a light yellow solid.

Example 2

To a solution of diethylnitroterephthalate (17.9 g) in 300 mL of ethanol was added 1 N sodium hydroxide (70 mL) and the mixture was stirred overnight. 1N hydrochloric acid (70 ml) was added and the reaction mixture was partitioned between methylene chloride (200 ml) and water (200 ml). The aqueous layer was extracted three more times. The combined organic extracts were dried and the solvent was removed by vacuum distillation. Ethyl 3-nitro-4-carboxybenzoate was obtained as a white solid.

To a diphenylphosphoryl azide (5.75 g) in anhydrous toluene (50 mL) at 100 ° C under nitrogen 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 hour and then aniline (5 mL) was added. The resulting reaction mixture was allowed to cool to room temperature over 40 minutes. Ethyl acetate (300 ml) was then added and the solution was washed successively with 1N hydrochloric acid solution (300 ml), water (300 ml), 1N sodium hydroxide solution (300 ml) and water (300 ml). The organic layer was dried and the solvent was evaporated under vacuum. Diethyl ether (50 mL) was added to the resulting oil, and the resulting solid was collected and dried. N- (2-nitro-5-methylphenyl) -N'-phenylurea was obtained as a white solid.

Example 4

A solution containing N- (2-nitrophenyl) -N'-phenyl urea (5.76 g) and chloroacetyl chloride (40 mL) was refluxed for 30 minutes under a nitrogen atmosphere. The excess chloroacetyl chloride was then removed in vacuo, diethyl ether (50 mL) was added, and the resulting solid was filtered and dried. There was thus obtained N '- (2-chloroacetyl) -N- (2-nitrophenyl) -N'-phenylurea as a white solid.

A solution of N '- (2-chloroacetyl) -N- (2-nitrophenyl) -N'-phenylurea (3.7 g), di-methylformamide (15 mL) and diisopropylethylamine (15 mL) was refluxed for 5 minutes. The hot mixture was allowed to cool to room temperature and precipitated by addition to 200 ml of water. The precipitate was collected and dried. 1- (2-Nitrophenyl) -3-phenylimidazoline-2,4- (1H, 3H) -dione was obtained.

Η (Compound 1)

To a solution of 1- (2-nitrophenyl) -3-phenylimidazoline-2,4 (1H, 3H) dione (2.7 g) in anhydrous dimethylformide (2 mL) was added N, N-dimethylformamide dimethylacetal (2.7) under nitrogen. g). The reaction mixture is stirred at 80 ° C for 2 hours and then the solvent is evaporated off under vacuum. To the resulting oil was added iron powder (5 g) and acetic acid (250 mL). The resulting mixture was gently heated to reflux for 3 minutes and then stirred for an additional 30 minutes. The resulting heterogeneous mixture was diluted with 10% methanol in dichloromethane (200 mL) and filtered through silica gel using 10% methanol in dichloromethane as eluent. The solvent was evaporated in vacuo and hot ethanol (200 mL) was added to the residue. Water (200 mL) was added to the resulting mixture, and the resulting solid was filtered, washed successively with ethanol, ethyl acetate, diethyl ether, and dried. There was obtained 2-phenylimidazo [1,5-a] quinoxaline-1,3 (2H, 5H) dione as a yellow solid (compound).

no. 1) mp 231-234 ° C.

Η (Compound 2)

To a solution of 1- (2-nitrophenyl) -3- (2-fluorophenyl) imidazoline-2,4 (1H, 3H) dione (1.18 g) in anhydrous dichloromethane (5 mL) was added tris (dimethylamino) under nitrogen. methane (1 mL ·). The reaction mixture was stirred for 20 minutes at room temperature and then the solvent was distilled off in vacuo. The remaining solid was dissolved in dimethylformamide (100 mL) and a slurry of Raney nickel (50% in water, 1 mL) was added. The mixture is hydrogenated for 45 minutes at 50 psi. The resulting reaction mixture was filtered through celite, the filtrate was concentrated to 30 ml by evaporation of the solvent in vacuo and water (50 ml) was added to the concentrate. The precipitated solid was collected and washed successively with ethanol, ethyl acetate and diethyl ether. After drying in air, 2- (2-fluorophenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione is obtained as a yellow solid (Compound No. 2), m.p. 261-264. ° C) clad 8

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

Example 9

OEt

H (Compound 3)

To 1- (2-aminophenyl) -3- (4-ethoxyphenyl) imidazoline-2,4 (1H, 3H) dione (2 g) was added dimethylformamide (5 mL), acetic acid (5 mL) and N, N dimethylacetal. -dimethylformamide (5 mL). The reaction mixture was heated at 60 ° C for 16 hours, then cooled and filtered. The resulting orange solid was washed with isopropyl alcohol and recrystallized from acetic acid. There was thus obtained 2- (4-ethoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione, m.p. 268-269 [deg.] C (Compound No. 3).

Example 10

The following compounds were prepared essentially as described in Examples 6, 7 and 9:

2- (4-methoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione (compound 4), m.p. 240-242 ° C.

2. 2- (4-Methylphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione (compound 5), m.p. 305 DEG-308 DEG.

3. 2- (4-Fluorophenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione (compound 5), m.p. 235-238 ° C.

. 2- (2-aminophenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione (compound 7), m.p. 247-249 ° C.

5. 2- (3-Fluorophenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione (Compound 8), m.p. 265-266 ° C.

6. 2- (4-Chlorophenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione (Compound 9), m.p. 235-238 ° C.

7. 2- (3-methylphenyl) imidazo [1,5-a] quinoxaline-1,3- (2H, 5H) -dione (compound 10), m.p. 263-265 ° C.

8. 2- (2-fluoro-4-ethoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) dione (compound 11), m.p. 264-267 ° C.

9. 2- (3-Chlorophenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione (Compound 12), m.p. 235-239 ° C.

10. 2- (2-methoxyphenyl) imidazo [1,5-a] quinoxaline-1,3- (2H, 5H) -dione (compound 13), m.p. 270-272 ° C.

11. 2- (4-ethylphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione (compound 14), m.p. 215-216 ° C.

12. 2- (2-fluoro-4-methoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) dione (compound 15), m.p. 280-284 ° C.

13. 2- (3-methoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione (compound 16), m.p. 212-214 ° C.

14. 2- (3-methoxyphenyl) imidazo [1,5-a] quinoxaline-1,3- (2H, 5H) -dione (compound 17), m.p. 197-200 ° C.

15. 2- (4-n-Propoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione (Compound 18), m.p. 182-185 ° C.

. 2- (4-n-butoxyphenyl) imidazo [1,5-a] quinoxaline-1,3- (2H, 5H) -dione (compound 19), m.p. 155-156 ° C.

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

18. 7-Chloro-2- (4-methylphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) dione (compound 21), m.p. 200-204 ° C.

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

20. 8-Methyl-2-phenylimidazo [1,5-a] quinoxaline-1,3- (2H, 5H) -dione (compound 23), m.p. 240-244 ° C.

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

. 7-ethoxycarbonyl-2- (4-ethoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (3H, 5H) -dione, m.p. 152-155 ° C.

23. 8-Bromo-2- (4-ethoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione (Compound 26), m.p. 152-155 ° C.

. 2- (4-propylphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione (compound 27), m.p. 185-186 ° C.

5. 7-methyl-2- (4-ethoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione (compound 28), m.p. 200-203 ° C.

2- (3-Bromo-4-ethoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione (compound 29), m.p. 147-150 ° 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).

. 2- (4-acetoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione (Compound 32), m.p. 210-211 ° C.

H (compound 33)

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 at 20 ° C for 15 min and then poured directly into boiling acetic acid (50 mL) containing zinc dust (500 mg). The reaction mixture was refluxed for 5 minutes and then allowed to cool to room temperature. The mixture was then diluted with 10% methanol in dichloromethane (100 mL), filtered through silica gel, and the solvent was removed in vacuo. To the resulting solid was added boiling ethanol (25 mL) and the mixture was diluted with water (100 mL). The resulting mixture was cooled to 0 ° C and the solid was filtered and dried. There was thus obtained 8-bromo-2- (4-methoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione (compound 33) as a yellow solid, m.p. dec).

Example 12

The following compound was obtained essentially as described in Example 11:

8-Bromo-2- (3-bromo-4-ethoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione (Compound 34), m.p. 146-149 ° C.

Example 13

A solution of 1- (2-nitrophenyl) -3- (4-ethoxyphenyl) imidazoline-2,4 (1H, 3H) -dione (5 g) in anhydrous tetrahydrofuran (50 mL) was added dropwise over 30 minutes to solution 0, 5M 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 over 30 minutes and then quenched by the addition of saturated ammonium chloride solution. The reaction mixture was partitioned between ethyl acetate and water, and the organic layer was dried. The solvent was removed in vacuo. Column chromatography on silica gel using 50% ethyl acetate in hexane as eluent gave 5-ethoxycarbonyl-1- (2-nitrophenyl) -3- (4-ethoxyphenyl) imidazoline-2,4 (1H, 3H) -dione.

Example 14

H (compound 35)

To a suspension containing zinc dust (6 g) in acetic acid (250 mL) was added 5-ethoxycarbonyl-1- (2-nitrophenyl) -3- (4-ethoxyphenyl) imidazoline-2,4 (1H, 3H) -dione ( The mixture was refluxed for 15 minutes, cooled to room temperature and filtered, the solvent was evaporated in vacuo and the resulting solid was slurried in ethanol (50 mL), then filtered from the 4-hydroxy- 2- (4-ethoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione (compound 35).

Example 15

(Compound 36)

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 boiled under reflux for 16 hours. reflux condenser. Then the solvent was evaporated in vacuo and water (15 ml) was added. The pH of the mixture was adjusted to 7.0 with ammonium hydroxide and the resulting solid was filtered off and dried. There was thus obtained 4-chloro-2- (4-ethoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione (compound 36).

Example 16

(Compound 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 added after heat for 4 hours in a sealed tube at 100 ° C. After cooling to room temperature, the solvent was removed from the reaction mixture in vacuo. The solid was suspended in a 50% solution of ethanol in water and filtered. There was thus obtained 4-amino-2- (4-ethoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione (compound 37).

Example 17

The following compounds were prepared essentially as described in Example 16:

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-methoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione (compound 40).

Example 18

H

OH

2- (4-acetoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) dione (250 mg) was added to ethanol (50 mL) saturated with hydrogen chloride. The solution is stirred for 2 hours and then the solvent is evaporated off under vacuum. 2- (4-Hydroxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione (Compound 41), m.p. 318 DEG-322 DEG C. was obtained.

Example 19

(compound 42)

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) in dimethylformamide (5 mL). The reaction mixture was heated at 100 ° C for 4 h and the solution was cooled to room temperature and poured into water (200 mL). The resulting precipitate was collected and dried. There was obtained 5-N-methyl-2- (4-ethoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione (compound 42), m.p. 263 DEG-266 DEG.

Example 20

2- (4-Ethoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione was added to a solution of anhydrous dimethylformamide (5 mL) and tert.

potassium butoxide (125 mg) at 50 ° C. After 5 minutes trimethylacetyl chloride (150 mg) was added. The reaction mixture was stirred for 15 minutes and then poured into water (25 mL). The resulting precipitate was collected, washed with ethanol and dried. There was thus obtained 3-trimethylacetoxy-2- (4-ethoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione (compound 43).

Example 21

The following compounds were prepared essentially as described in Example 20:

3-n-Propoxy-2- (4-ethoxyphenyl) imidazo [1,5-a] quinoxalin-1 (2H, 5H) -one (Compound 44).

2. 5-Propionyl-2- (4-ethoxyphenyl) imiadzo [1,5-a] quinoxaline-1,3 (2H, 5H) dione (Compound 45).

In the above description, the invention is described in its particularly preferred specific embodiments. The present invention is not limited to these specific embodiments and is intended to include various modifications and modifications that one of ordinary skill in the art can do without departing from the spirit of the invention. Only the claims that follow are critical to the scope of the invention.

- i 'iiyd

Claims (55)

PATENT CLAIMS (λΛΉΓΘΟν • λΖ3Τ · 7Ν. ·. ·· ..... J r What is claimed is: 1. An imidazoquinoxaline of the formula I ' 3: ⁵ l '' y ^w; / \ íV ^! it Ύ -k rY * I! O -.,., I j J í C (i) - »............- R4 H and their pharmaceutically acceptable non-toxic salts, wherein and R R, which are the same or different, each represent a hydrogen atom, a halogen atom, a straight or branched chain lower alkyl group having 1 to 6 carbon atoms or a straight or branched chain lower alkoxy group 1 to 6 carbon atoms; X represents a hydrogen atom, a halogen atom, a hydroxy group, an amino group or a mono- or dialkylamino group in which each alkyl radical is lower and contains 1 to 6 carbon atoms; W is phenyl, thienyl or pyridyl, each optionally mono- or disubstituted with halogen, hydroxy, straight or branched chain alkyl of 1 to 6 carbon atoms, amino, mono- or dialkyl amino, each of which is lower alkyl a straight or branched chain alkyl group having from 1 to 6 carbon atoms or a lower alkoxy group with a straight or branched chain having from 1 to 6 carbon atoms; R ₂ and R 8, which are the same or different, each represent a hydrogen atom, a halogen atom, a hydroxy group, an amino group, a 1-indanyl group, a 4- (thio) chromanyl group or a 1- (1,2,3,4-tetrahydronaphthyl) group; II 1-indanyl, 4- (thio) chromanyl, 1- (1,2,3,4-tetrahydronaphthyl), each monosubstituted by halogen, a straight or branched lower alkyl group having 1 to 6 carbon atoms, or a lower alkoxy group having 1 to 6 carbon atoms; a straight or branched chain containing from 1 to 6 carbon atoms; a group OR, -, COR 4, CO 4 R 6, OCOR 4 or R 6, wherein hydrogen, phenyl, pyridyl, straight or branched lower alkyl having 1 to 6 carbon atoms or phenylalkyl or pyridylalkyl, wherein each alkyl is a straight or branched lower alkyl of 1 to 6 carbon atoms; a group of the formula -CONR 8 R 6 or - (CH ₂ ) _n ^NR g ^R 7 wherein n is 0, 1 or 2; R 8 represents a hydrogen atom or a straight or branched lower alkyl group having 1 to 6 carbon atoms; is hydrogen, phenyl, pyridyl, straight or branched lower alkyl of 1 to 6 carbon atoms or phenylalkyl or pyridylalkyl, each alkyl group being lower alkyl of straight or branched chains containing 1 to 6 carbon atoms; the sky NRgR.? is a heterocyclic group selected from morpholyl, piperidyl, pyrrolidyl or N-alkylpiperazyl; - ^NR 8 ^CO 2 ^R 9 where R_ and R _Q are the same or different are each a hydrogen atom oy, phenyl, pyridyl, lower alkylskupiIII not a straight or branched chain of 1 to 6 carbon atoms, or phenylalkyl or pyridylalkyl where each alkyl is lower alkyl of a straight or branched chain containing up to 6 carbon atoms; the sky C (OH) R ₁₀ R ₁₁ wherein ^R 10 ^{and R} LL 'of ^ter s are the same or different, are each a lower alkyl of straight or branched chain of 1 to 6 carbon atoms, phenyl or phenylalkyl in which the alkyl group is lower, the a straight or branched chain containing from 1 to 6 carbon atoms. Compounds according to claim 1 of the general formula II H (II) wherein a, which are the same or different, each represents a hydrogen atom, a halogen atom or a straight or branched chain alkyl group having from 1 to 6 carbon atoms; represents a hydrogen atom, a halogen atom, a hydroxy group, an amino group or a mono- or dialkylamino group, wherein each of the alkyl groups is lower, has a straight or branched chain and contains 1 to 6 carbon atoms; is phenyl or phenyl which is mono- or disubstituted by halogen, hydroxy, amino, lower alkyl with a straight or branched chain X IV having 1 to 6 carbon atoms or a lower straight or branched chain alkoxy group having 1 to 6 carbon atoms. Compounds according to claim 1 of the general formula III H (III) wherein W kde W is phenyl or phenyl which is mono- or disubstituted by halogen, hydroxy, amino, lower alkyl of straight or branched chain of 1 to 6 carbon atoms or lower alkoxy of straight or branched chain of 1 to 6 carbon atoms. Compounds according to claim 1 of the general formula IV H (IV) is phenyl or phenyl which is mono- or disubstituted by halogen, hydroxy, amino, lower alkyl of straight or branched chain of 1 to 6 carbon atoms or lower alkoxy of straight or branched chain of 1 to 6 carbon atoms; in 1 * 2 and Rg, which are the same or different, are each hydrogen, halogen, hydroxy, amino, 1-indanyl, 4- (thio) chromanyl or 1- (1,2,3,4-tetrahydronaphthyl); 1-indanyl, 4- (thio) chromanyl, 1- (1,2,3,4-tetrahydronaphthyl), each monosubstituted with halogen, a straight or branched lower alkyl group having 1 to 6 carbon atoms, or a lower alkoxy group having 1 to 6 carbon atoms; a straight or branched chain of 1 to 6 carbon atoms; OR, -, COR 6, CO 2 R 5, OCOR 4, or R 6, wherein R 8 is hydrogen, phenyl, pyridyl, straight or branched lower alkyl of 1 to 6 carbon atoms, or phenylalkyl or pyridylalkyl, each alkyl a straight or branched lower alkyl group having 1 to 6 carbon atoms; a group of the formula -CONR 8 R 8 or - (C 1 R 11 NR 8 R 9); wherein n is 0, 1 or 2; R 8 is a hydrogen atom or a straight or branched chain alkyl group having 1 to 6 carbon atoms; R ₇ is hydrogen, phenyl, pyridyl, straight or branched lower alkyl of 1 to 6 carbon, or phenylalkyl or pyridylalkyl, wherein each alkyl is lower alkyl of straight or branched chain of 1 to 6 carbon; the sky NRgR.? is a heterocyclic group selected from morpholyl, piperidyl, pyrrolidyl or N-alkylpiperazyl; VI -nr ₈ what ₂ r ₉ where Rθ and Rg, which are the same or different, each represent a hydrogen atom, a phenyl group, a pyridyl group, a straight or branched lower alkyl group having 1 to 6 carbon atoms or a phenylalkyl or pyridylalkyl group, each alkyl group being a straight or branched lower alkyl group a chain of 1 to 6 carbon atoms; or c (oh) r ₁₀ R _1; R ^{and R} LL 'are the same or different, are each a lower alkyl of straight or branched chain containing ICI 1 -C 6 alkyl, phenyl or phenylalkyl in which the alkyl group is lower, is straight or branched and has 1 to 6 carbon atoms, . Compounds according to claim 1, wherein W is phenyl. 6. A compound of claim 1, wherein R ₂ is bromo. Compounds according to claim 1, wherein W is 4-methoxyphenyl. Compounds according to claim 1, wherein W is 2-fluorophenyl. Compounds according to claim 1, wherein W is 4-ethoxyphenyl. VII Compounds according to claim 1, wherein W is 2-thienyl. The compound of claim 1 which is 2-phenylimidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. ® The compound of claim 1 which is 2- (2-fluorophenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. The compound of claim 1 which is 2- (4-ethoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. A compound according to claim 1 which is 2- (4-methoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. A compound according to claim 1 which is 2- (4-methylphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. The compound of claim 1 which is 2- (4-fluorophenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. • 17. The compound of claim 1 which is 2- (2-aminophenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. The compound of claim 1 which is 2- (3-fluorophenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. 19. The compound of claim 1 which is 2- (4-chlorophenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. The compound of claim 1 which is 2- (3-methylphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. The compound of claim 1 which is 2- (2-fluoro-4-ethoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. VIII 22nd The compound of claim 1 which is 2- (3-chlorophenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. The compound of claim 1 which is 2- (2-methoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. The compound of claim 1 which is 2- (4-ethylphenyl) imidazo [1,5-a] quinoxaline-1,3- (2H, 5H) -dione. The compound of claim 1 which is 2- (2-fluoro-4-methylphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. The compound of claim 1 which is 2- (3-methoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. The compound of claim 1 which is 2- (3-ethoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. The compound of claim 1 which is 2- (4-n-propoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. 29. The compound of claim 1 which is 2- (4-n-butoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. The compound of claim 1 which is 2- (4-isopropoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. The compound of claim 1 which is 7-chloro-2- (4-methylphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. 32. A compound according to claim 1 which is 7,8-dimethyl-2- (4-ethoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. 33. The compound of claim 1 which is 8-methyl-2-phenylimidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. IX 34. The compound of claim 1 which is 8-ethoxycarbonyl-2- (4-ethoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. 35. The compound of claim 1 which is 7-ethoxycarbonyl-2- (4-ethoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. » 36. The compound of claim 1 which is 8-bromo-2- (4-ethoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. The compound of claim 1 which is 2- (4-propylphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. The compound of claim 1 which is 7-methyl-2- (4-ethoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. The compound of claim 1 which is 2- (3-bromo-4-ethoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. The compound of claim 1 which is 2- (3-thienyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. » 41. The compound of claim 1 which is 2- (2-thienyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. B The compound of claim 1 which is 2- (4-acetoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. The compound of claim 1 which is 8-bromo-2- (4-methoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. The compound of claim 1 which is 8-bromo-2- (3-bromo-4-ethoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. 45. The compound of claim 1 which is 4-hydroxy-2- (4-ethoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. x 46. The compound of claim 1 which is 4-chloro-2- (4-ethoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. The compound of claim 1 which is 4-amino-2- (4-ethoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. » A compound according to claim 1 which is 4-dimethylamino-2- (4,7-ethoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. * 49. The compound of claim 1 which is 4-n-propylamino-2- (4-ethoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. The compound of claim 1 which is 4-methylamino-2- (4-ethoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. The compound of claim 1 which is 2- (4-hydroxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. The compound of claim 1 which is 5-methyl-2- (4-ethoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. and * The compound of claim 1 which is 3-trimethylacetoxy-2- (4-ethoxyphenyl) imidazo [1,5-a] quinoxalin-1 (2H, 5H) -one. in The compound of claim 1 which is 3-n-propoxy-2- (4-ethoxyphenyl) imidazo [1,5-a] quinoxalin-1 (2H, 5H) -one. 55. A compound according to claim 1 which is 5-propionyl-2- (4-ethoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione.