FI98370B - Process for preparing a therapeutically active 2-phenyl- substituted imidazo[1,5-a]quinoxaline-1,3(2H,5H)-dione derivative - Google Patents

Description

. 98370

FIELD OF THE INVENTION The present invention relates to a process for the preparation of novel imidazo-clinoxaline derivatives. These compounds bind selectively to the GABAA receptor and can be used to treat anxiety, sleep and seizure disorders, and benzothiazepine-type drug overdose and to increase alertness. According to the invention, the pharmacological activities of the inidazoquinoxaline derivatives are based on their interaction with the GABA binding site, the benzodlazepil (BD2) receptor.

These novel imidate-sinoquinoxaline derivatives of the invention prepared from 2-phenyl-substituted imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dlone derivatives of formula (I)

W

* γ ^ γΟ ** ° x I x

B

wherein X is hydrogen, hydroxy, chloro or amino; 30 N is phenyl which may be mono- or di-substituted by halogen, hydroxyl, lower alkyl, amino, lower alkoxy or acetoxy; and R 1 and R 2) are the same or different and are each hydrogen, halogen or lower alkyl, or a pharmaceutically acceptable non-essential salt thereof.

2 night / u Description of the Related Art γ-aminobutyric acid (GABA) is considered to be one of the major inhibitors of malic acid in the mammalian brain. It has been more than 30 years since its presence in the brain was demonstrated (Roberts 6 Fr ankel, J. Biol.

Chen. 1B7 (1950) pp. 55-63; Udenfriend, J. Biol. Chen.

1B7 (1950) pp. 65-69]. Since then, enormous work has been done in the bays to reconcile GABA with the etiology of seizure disorders, sleep, distress, and comprehension (Tallaan 6 10 Gallager, Ann. Rev. Neuroscience A (1985) pp. 21-44].

Because GABA is widely, albeit unevenly, Levin-ne in the whole brain of mammals, it is said to be the appellant to approximately 30% of brain synapses. In several regions of the algae, GABA is associated with local Inhibitory neurons and in only two regions is GABA associated with longer protrusions. GABA appeals to nonet for its effects through a protein complex present in both cells and nerve terminals; these are called GABAA receptors. Postsy-naptl responses to GABA are mediated through changes in chloride conductivity; these changes usually lead, though. not invariably, to cellular hyperpolarization. Recent studies have shown that the protein complex involved in postsynaptls 'GABA-: responses is the site of action for a number of compounds that are not null-25 in structure and are capable of modifying postsynaptls' responses to GABA. Depending on their mode of action, these compounds are able to induce a spectrum of activity (either edative, anxiolytic and anticonvulsant or anticonvulsant control, seizures and anxiety).

".f 30 1,4-Benzodiazepyls are still among the most widely used drugs in the world. The main markets -. * ·· These benzodiazepines are chlordiazepoxide,: * ·: diazase, fluorazepam and triazolam. These compounds, *, · you are widely used as anxiolytics, sedative hyp- • · ..35 notes, muscle relaxants and anticonvulsants.

• · ** Many of these compounds are very effective drugs- 3 yoo / u; such efficacy is indicative of a site of action with strong affinity and specificity for individual receptors. Early electrophysiological studies showed that the main effect of benzodlatsepllle was to potentiate the inhibition of 5 GABA. Benzodiazeptics were able to amplify the monosynaptic ventral root reflex, the GABA-mediated event from the presynaptic lnhl-bitlota [Schmidt et al., Arch. Exp. Path. Pharmakol. 258 (1967) pp. 69 - 82). Lime is followed by electrophyslolo-10 gleet studies [reviewed in Tallaan et al. Science 207 (1980) pp. 274-281; Haefley et al. (Handb. Exptl. Pharmacol. 33 (1981) pp. 95-102] have generally confirmed this finding, and by the mid-1970s, there was a general belief among electrophysiologists that benzodiazepyls could potentiate GÄBA or effects.

With the discovery of the "receptor" of benzodlatseplln and the subsequent determination of the nature of the interaction between GABA and benzodlatsepllnlen, it becomes apparent that 20 behaviorally important benzodlatsepllnlen interactions. the effects with various neurotransmitter systems are largely due to the improved ability of GABA itself to modify these systems. Each modified system, in turn, may be associated with the expression of behavior.

Investigations of the mechanistic nature of these interactions depended on the detection of a high affinity benzodiazepine binding site (receptor).

·. Such a receptor is present in the central nervous system of all vertebrates less than 30 genera of bone marrow [Squires & Braestrup, Nature 166 (1977) pp. 732-734; Moh ·; ler & Okada, Science 198 (1977) pp. 854-851; Mohler 6 *: Okada, Br. J. Psychiatry 133 (1977) pp. 261-268]. Using tritiated diazepam and numerous other compounds, these binding sites for benzodiazepines have been shown to meet many of the criteria for pharmacological receptors; 4

? 837Q

binding to these sites in vitro is rapid, reverses-Beli # stereospecific, and occurs until saturation. More importantly, it has been shown that the ability of benzothlazines to displace dazazepam from its binding site-5 correlates significantly with their activity in numerous behavioral animal studies predicting the efficacy of benzodlazepines [Braestrup 6 Squires, Br. J. Psychiatry 121 (1978) pp. 249-260; Mohler 8 Okada, Science 198 (1977) pp. 854-851; Mohler 6 Okada, 10 Br. J. Psychiatry Hl (1977) pp. 261-268]. The average therapeutic doses of these drugs in humans also correlate with receptor efficacy [Tallman et al. Science 207 (1980) pp. 274-281].

In 1978, it became clear that GABA and related analogs may interact with a low affinity (1 μΜ) GABA binding site, enhancing the binding of benzodlazepines to the clonazepan-sensitive site [Ta? san et al. Nature 274 (1978) s.

383-385] · This enhancement was due to an increase in the affinity of the benzo-20 dlatsepllnle binding site due to the filling of the GABA- "· site. The results were interpreted to indicate that both GABA- and ben t sodi a zepilni sites were allosteric to the membrane protein. For many GABA analogues, the ability to potentiate the binding of diazepe 25 sepam by 50% of the maximum value and the ability to inhibit the binding of GABA to the membrane of the brain by 50% Γ may be directly proportional to the benzodlazepine effect of GABA agonist. GABA receptor antagonist (♦) -bicuculline is inhibited by its stereoisomer (-) - bicuculline [Tallman et al., Nature 224 (1978) pp. 383 ->! 385].

Shortly after the discovery of high-affinity binding sites for benzodlazepines, it was discovered that triazolopyridazine could interact with benzodiazepine receptors in many brain cells.

Jen regions in a way that looks at ree «peter heterogeneity or negative interaction. These studies found Hill coefficients that were significantly less than one in a number of brain regions, including 5 cortex, edema, and lesion. In the cerebellum, trlatolopyrldatsllni interacted with benzodlatsepilni treatment at Hll1 multiplier 1 [Squires et al. Pharma. Biochem. Behav. 1Q (1979) pp. 825-830; Klepner et al., Pharmacol. Biochem. Behav. 11 (1979) a. 457-462]. Thus, 10 benzodiazepine multiplex receptors were assumed to be absent in the cortex, cerebral cortex, and striatum but not in the cerebellum.

On the basis of these studies, extensive autoradiography was performed on the recruitment of receptors at the level of the free-microscope. Although receptor heterogeneity has been demonstrated [Young & Kuhar, J. Pharmacol. Exp. Ther.

212 (1980) pp. 337-346; Young et al., J. Pharmacol. Exp.

Ther. 216 (1981) pp. 425-430; Nlehoff et al., J. Pharmacol. Exp. Ther. 221 (1982) pp. 670-675], no direct correlation of receptors was observed in the previous 20 studies. the location of subtypes and area-related behaviors! Between ImiOide. In addition, autoradiography showed heterogeneity of receptors in the cerebellum, which, based on binding studies, was expected to have a single receptor [Nlehoff et al., J. Pharmacol. Exp. Ther. 221 (1982) · {pp. 670 - 675].

· *: The physical basis for the two apparent subtypes of benzodiazepine treatment in terms of drug alleles has been shown by Sieghart 6 Karobath, Nature 286 30 (1980) pp. 285-287. Using gel electrophoresis in the presence of sodium, sodium dodecyl sulfate, many benzodiazepine receptors of different molecular weights ··; presence. Receptors were identified by covalent attachment of radioactive flunitrazepam, a benzodiazemine that can covalently label all types of receptors. The molecular weights of the major labeled bands 6 are 50,000-53,000, 55,000, and 57,000, and the triazolopyridatines inhibit the labeling of the slightly increasing molecular weight (53,000, 55,000, 57,000) of the oavave forms [Seighart et al., Eur. J. Pharmacol. M (1983) pp. 291 -5 299).

At that time, the possibility was raised that the various forms of the receptor represent "isoreceptors", i.e. many allelic forms of the receptor [Tallman & Gal lager, Ann. Rev. Neurosci., 8 (1985) pp. 21-44). Genetically different forms of Recepto-10 are not commonly described, although this is common for enzymes. When starting to study receptors using radioactive probe and electrophoresis techniques, it is almost certain that the receptor will prove important in studies on the etiology of human psychiatric disorders.

GABAA receptor subunits have been cloned from bovine and human cOHA libraries (Schoenfield et al., 1988; Duman et al., 1989). A number of distinct cONAs were identified as subunits of the GABAA receptor complex by cloning and expression. These are grouped into categories α, β, Y,. δ, ε and are the molecular basis for the heterogeneity of GABA receptors and different regional pharmacology (Shiv- 9 vers et al., 1980; Levitan et al., 1989). γ subunit | seems to allow drugs such as benzo: diazepines to modify GABA responses (Pritchett et al., 1989). The low Hill coefficients for ligand binding to the GABAA receptor are indicative of the unique pro- subtype-specific pharmacological effect. profiles of.

.30 Drugs that interact with the GABAA receptor may have a spectrum of pharmacological effects that depend on their ability to modify the effects of GABA. For example, 8-carbolines were first isolated on the basis that they could competitively inhibit. 35 binding of diazepam to its binding site e [Nielsen et al., Life Sci 25 (1979) pp. 679-686). receptors

^ VV * V

Whereas the market binding assay is not a complete preliminary assessment of the biological activity of such compounds; agonists, partial agonists, inverse agonists, and antagonists can inhibit the agonist. Once the structure of β-carboline was determined, it was possible to synthesize a number of analogs and study the effect of these compounds on behavioral alcohols. It was immediately noted that β-carbolines may act against dlazepam in terms of behavior (Tenen 6 Hirsch, Nature 288 (1980) pp. 609-610). In addition to this mammalian antago-10, β-carboline has its inherent activity, as opposed to that of benzodiazepine; they became known as inverse agonists.

In addition, a number of aula benzodlatsep11-nl receptor-specific antagonists have been developed based on their ability to inhibit benzodlat-15 epithelial activity. One of these compounds best studied is the imidazodlatse method (Hunkeler et al. Nature 290 (1981) pp. 514-516).

This compound is a high affinity competing inhibitor of benzodiateepine and β-carboline binding and is able to block the pharmacological effects of both of these classes of compounds. As such, it has little inherent pharmacological activity in animals and humans (Hunkeler et al. Nature 290 (1981) pp. 514-516; Darragh et al. Bur. J. Clin. Pharmacol. 14 (1983) p.

25 569 - 570). Examination of the radloactively labeled form of this compound [Mohler 6 Richards, Nature 294 (1981) pp. 763-765] showed that this compound interacts with as many sites as benzodiazepines and β-carbolines and that these compounds the interactions were purely competitive. This compound is the primary ligand for binding to GABAA receptors because it lacks receptor subtype specificity and serves each state of the receptor.

The study of the effects of a number of different compounds such as those mentioned above has led to the grouping of these compounds. Today, compounds.

8 yw / u having similar activity to benzodlazepines, is said to be agonlstelksl. Compounds having the opposite activity compared to Bent-zodiacephalin are said to be antagonists, and compounds that block even coma-type activity are termed antagonists. This grouping has been developed to emphasize the fact that! many different compounds can produce a spectrum of pharmacological effects, to indicate that the compounds cannot act on the same receptor 10 to produce opposite effects, and to indicate that fl-carholins and antagonists with intrinsic anxlogeneic effects are not synonymous. A biochemical experiment to elucidate the pharmacological properties of compounds interacting with the benthiaziazepine receptor further emphasizes the interaction with the GABA system. In contrast to benzodlazeplines, which are potentiated by GABA [Tallman et al., Nature 274 (1978) pp. 383-385; Tallman et al., Science 207 (1980) p.

20,274-281], compounds with antagonistic properties have a waxy GABA syndrome (i.e., a change in receptor affinity under the influence of GABA) [Mohler & Richards, Nature 294 (1981) pp. 763-765) and in fact the lid agonist has decrease in affinity by GABA 25 [Braestrup 6 Nielson, Nature 221 (1981) pp. 472-474].

Thus, the GABA status generally predicts the expected behavioral properties of compounds.

Many compounds have been prepared as benzodlazepine agonists and antagonists. For example, U.S. Patent Nos. 4,312,870 and 4,713,383 and EP 181,282 disclose compounds useful in the treatment of anxiety or depression. U.S. Patent No. 4,713,383 discloses compounds of the formula yoo / υ * wherein R 1 is substituted (unsubstituted) Ph, (dihydro) -furanyl, tetrahydrofuranyl, (dihydro) tlenyl, tetra-10-hydrothienyl, pyranyl, rlbofuranoyl, which all are C-lllttyn; R 1 is H or alkyl; X - O, S, R, N? R 1 is hydrogen, alkenyl, alkynyl, C 1-30 cycloalkyl, substituted (unsubstituted) alkyl, aryl or aralkyl, wherein aryl is phenyl, pyridyl, tlynyl or furanyl; and Ring A may be substituted with alkyl, alkoxy, halogen, substituent, alkyl, etc.

BP-A-181 282 describes compounds of the formula "wherein R 1 is (substituted) Ph or heterocyclyl; R 1 is hydrogen, alkyl, alkenyl, hydroxyalkyl, aralkyl, aralkenyl-11, aryl; R 1 is hydrogen , alkyl, alkoxy, HO, halogen, F, C, OjH, H | N, alkylthio, alkylsulfinyl, alkylsulfonyl, aralkoxy, X is S, NR *, and R * is hydrogen, alkyl, aralkyl, cycloalkyl, alkenyl , alkynyl, aryl, (substituted) alkoalkyl, hydroxylalkyl.

U.S. Patent 4,312,870 discloses compounds of formulas 98,370 10

R »v„ «, H

nn-n 'n-n' P „A> ^ 0 Ph / YN0 5 K Ma.

* "" · "* I ii wherein Ph is 1,2-phenylene which is unsubstituted by up to three of the same or different substituents selected from aleapl alkyl, lower alkoxy, aleepl alkylthio, hydroxy, halogen, trifluoroethyl, nitro, amino, eono - or alkylalkyl, cyano, carbaoyl-11 and carboxyl; R cm is a substituent free or substituted phenyl defined by ny-Ph, pyrldyl, (aleepl alkyl) pyrldyl or halogen pyrldyl; Rx is hydrogen, aleap alkyl or aleap1 (hydroxy, alkylalkyl or H-Ph) alkyl; and Ra is hydrogen or aleapl alkylalkyl; their 3-hydroxyl tautomers and aleap alkanoyl-11, carbaoyl, mono- or dl (alphaalkyl) carbaaoyl-11 derivatives of said (hydroxy or amino) phenyl (phenyl or phenylene) compounds; n-n 30 7

B

U 1 wherein R "is hydrogen, alkyl or alkoxy each having up to 4 carbon atoms, hydroxy, fluoro, chloro, bromo or trifluoroethyl; and R * is hydrogen or o- or m-fluoro, or it is p-fluoro when R * is chlorine.

98370 11 The compounds of formula I prepared according to the present invention differ from the known compounds described above which are not imidazoquinoxines and which also lack the various ring substituents of the compounds of formula I.

Finnish patent publications 82050, 90548 and 92931 also describe benzodiazepine lantagonically active imidazo [1,5-a] clinoxallin derivatives. Of these known compounds, those of structure 10 which are predominantly prepared according to the invention can be represented by the formulas while the compounds prepared according to the invention are imidazoquinoxaline dones having (alternative substituents and excluding) the basic structure phenyl V "! ' ay ~

The latter compounds have keto groups at the 1- and 3-positions. The compounds prepared according to the invention differ: thus also in structure substantially from these known> compounds.

: Detailed description of the invention

The novel compounds of formula I as defined above and their pharmaceutically acceptable non-toxic salts are prepared in accordance with this invention by:

70U / U

12 a) the ring is called a compound. Of formula (IX) Λ w 5 11 for N, N-dlaethylphoraldehydeacetylacetal and dleethylforeate and then with a mixture of iron powder and acetic acid to give the open compound of formula I. Wherein X is hydrogen, or b) cyclizing a compound of formula XX by treating it with tris (dylethylalino) ethane followed by hydrogenation in diaethyl formate to give a compound of formula X. Wherein X is hydrogen, or c) cyclically dissolving the compound. Of formula (III): N, N-diaethylphoraldehyde dimethyl compounds

and acetic acid in diaethylforate of formula I

* to obtain an open compound. Wherein X is hydrogen, or d) cyclizing a compound of formula (IV) ϊ w. 30 O / 1 "XX ^" * 35 * 13 y oo / u wherein X 'is ethoxycarbonyl, by treatment with zinc in acetic acid to give a compound of formula I wherein X is hydroquid and, if desired, one or more of the following operations: a compound of formula 1 wherein R 2 and are each hydrogen is reacted with bromine in the presence of acetic acid and zinc to give a compound of formula 1 wherein R * is bromine and R 1 is hydrogen, ii) a compound of formula X wherein X is hydroxy , 10 is converted to a compound of formula X wherein X is chlorine by treatment with a conventional chlorination reagent, lii) a compound of formula X wherein X is chlorine is reacted with ammonia to give a compound of formula X wherein X is amino; a compound of formula X wherein W is phenyl substituted with acetoxy is hydrolyzed with an acid to give a compound of formula X wherein W is hydroxy substituted phenyl.

Non-toxic pharmaceutical salts include e.g. salts with acids such as hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric, sulfinic, formic and toluenesulfonic acid, hydrogen iodide, acetic acid and the like. A wide variety of non-toxic pharmaceutically acceptable acid addition salts are known to those skilled in the art.

Various synthetic methods are known to those skilled in the art from which non-toxic pharmaceutically acceptable salts of the compounds of formula I may be used.

In the context of the present invention, lower alkyl means straight-chain and branched lower 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.

- * 00/14

In the context of the present invention, lower alkoxy means unbranched and branched lower alkoxy groups having 1 to 6 carbon atoms, such as groups such as net, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy-5-s, tert-butoxy, pentoxy, 2- pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy and 3-methylpentoxy.

Halogen in the context of this invention means fluorine, bromine, chlorine and iodine.

The pharmaceutical utility of the compounds of this invention is demonstrated in the following assay for GABAA receptor activity.

The experiments are performed as described in Thomas & Tallman, J. Bio. Chem. 156 (1983) 8. 9838-9842 15 and J. Neurosci. 3 (1983) pp. 433-440. Rat cortical tissue is sectioned and homogenized in 25 volumes (palno / volume) of 0.05 H Tris-HCl buffer (pH 7.4 at 4 ° C).

This tissue homogenate is centrifuged in the cold (4 ° C) at 20,000 x g for 20 minutes. The supernatant is decanted and the pellet is rehomogenized to the same volume of buffer and centrifuged again at 20,000 x g. The supernatant is decanted and the pellet is frozen:> 20 ° C overnight. The pellet is then thawed and rehomogenized to 25 volumes (initial weight / volume) of buffer and the procedure is repeated twice. Finally, the pellet is resuspended in 50 volumes (w / v) of 0.05 M Tris-HCl buffer (pH 7.4 at 40 ° C).

Incubation batches contain 100 μom tissue homogenate, 100 μoll radioligand 0.5 nH (3H-R015-1788 [3H-flumazenil], total activity 80 Cl / mmol), drug, or blocker and buffer to a total volume of 500 μak. - • ka. Incubations are performed for 30 minutes at 4 ° C, min. then rapidly filtered through a GFB filter to separate free ♦ · 35 and bound ligand. Wash the filters. * Twice with fresh 0.05 M Tris-HCl buffer (pH 7.4 982 at 4 ° C) and count on a liquid gauge. In some tubes, 1.0 μΜ of dlazepam was determined to determine the binding of el-speslflsen. Multiply the measurement results from the three replicates by averaging and percent inhibition for specific total binding. Specific full-length - non-specific - non-specific binding. In some cases, the size of the unlabeled drug is varied and a total binding assay is performed. The results of Tu-10 are converted to a form from which IC, 0 and

Hlll factor (nH).

The values obtained for the compounds according to the invention are shown in Table 1

15 Table X.

Compound ΙΟ, ο (pH) 1 0.0095 3 0.015 4 0.0095 20 5 0.016 33 0.0024 «··· • · T: vim said compounds have the following formulas: ···; ··: 25 OOH,, P v0 Γ C i> CO "r:» »

H H

····. . 35 Compound 1 Compound 4 • e s e 16

9837C

OCH2CH3 ch3 O 0 5 f \ *

V-n y-N

ay ay

10 I I

H H

Compound · 3 Compound 5 15 ΟΜβ v0 XCr

B

25 Compound 33

Compounds 1, 3 and 4 are particularly preferred embodiments of this invention.

The compounds of general formula I may be administered orally, topically, parenterally, by inhalation or spray, or rectally in unit dosage formulations containing conventional non-toxic pharmaceutically acceptable carriers, excipients and vehicles. Such pharmaceutical compositions for various modes of administration are prepared by methods well known in the art.

* »^ V 0 'W' 17

Dosage levels in the range of about 0.1 mg to about 140 mg per kilogram of body weight per day are useful (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms generally contain from about 1 mg to about 500 mg of active ingredient.

10 It will be appreciated, however, that the specific dosage level employed in a given patient will depend on a number of factors, including: the activity of the particular compound used, the age, weight, general health, sex, diet, time of administration, route of administration and rate of excretion of the patient, the drug combination and the severity of the disease being treated.

Some alternative methods of the invention for the preparation of compounds of formula I, as well as the preparation of starting materials for use in the methods, are illustrated in Scheme I and Scheme II. It will be apparent to one skilled in the art that the starting materials s "can be varied and additional steps used, as shown in the following examples.

• s •• e ·· »s • 9 m 'm t · i m • e» · • 9 • 9 »« · ·· • • 99 9 • 0 990 0 0 9 9 0 0 VS 3 φ

S

t *

V

gtoee te., ^ * ......

..XX - I X! ^ ‘-M ** ** - m *** r + \ * t V l · I W ~ '' Ν /, <^ ΝΓ x» *, ^ jg # * ^ I 1½. ^ * ° "» V% (Hnvx% ”·. '··« »*« 4 | η, M · *

..: 1 ^ V

• \ · * «· '* *** ·" ^ A *%>, m

i>. I X I

# ♦ * * f • 9 9 9 9 9 9 9 9 9 • s # 2 ^ .......

# ·· ♦ 9

Figure II

19 ✓ V w> <V ϊ

5 WNHj R2> Y ^ 1 ^ N ^ 1 (^ NSSW

RT'V '^ NOa. RT ^^ N1) 10 OCH2COa 1 ° _ w ¥ y <ο ϊ \ ^ a _b3n / dmf F ^ Nli ^ v ^ N ^ v ^ N ^ w

„XL, JU J

NaH2P02

5% Pd-carbon DMF-H 2 O.

20

. y / ° y-N / W

: (MeO ^ CHNMea ^ R * Cause ^ NV ^ °

: 25 AA * A'V

: H

R2, R3 and W in Schemes I and II have the same meanings as given above.

In some cases, it may be necessary to protect certain • functional groups in order to carry out some of the above reactions. In general, the need for such protecting groups, as well as the conditions for their attachment and removal, are evident in the organic ...

: 35 for a person skilled in the art of synthetic syntheses.

20

9837C

Example Z

CCfO

To a solution of 2-nitrophenyl isocyanate (3.34 g) in 100 ml of toluene was added aniline (2 g). Mixture 10 was stirred at 20 ° C for 30 minutes. Hexane (300 mL) was added and the resulting solid was filtered and dried to give N- (2-nitrophenyl) -N'-phenylurea as a pale yellow solid.

Example 11 15 1 OEt 20

To a solution of diethyl nitroterephthalate (17.9 g) ...; In 300 mL of ethanol was added 1 N NaOH (70 mL) and stirred. overnight. 1 N HCl (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. Yh- | The combined organic extracts were dried and the solvent removed in vacuo to give ethyl 3-nitro-4-carboxy-benzoate as a white solid.

Example III

: 30

h H

ä vocrt),:. = 35 δ ** · • · · • · • · 7 \ J \ S t 21

To diphenylphosphoryl azide (5.75 g) in anhydrous toluene (50 ml) under nitrogen was added dropwise at 100 ° C a solution of ethyl 3-nitro-4-carboxybenzoate (5 g) and triethylamine (4 ml) in anhydrous toluene (5 ml). 50 ml). The mixture was stirred for 1 hour, then aniline (5 ml) was added and the reaction mixture was allowed to cool to room temperature (40 minutes). Ethyl acetate (300 mL) was added and the solution was washed successively with 1 N HCl (300 mL), water (300 mL), 1N NaOH (300 mL), and water (300 mL). The organic layer was dried and the solvent was removed in vacuo. Diethyl ether (50 ml) was added to the resulting oil and the resulting solid was collected and dried to give N- (2-nitro-5-methylphenyl) -N'-phenylurea as a white solid.

Example IV

OTO

··· • · • · ** ·. A solution of N (2-nitrophenyl) -N'-phenyl-25: urea (5.76 g) and chloroacetyl chloride (40 ml) was refluxed. was refluxed under nitrogen for 30 minutes. After the excess chloroacetyl chloride was removed in vacuo, diethyl ether (50 ml) was added and the solid formed was filtered off and dried to give N * - (2-chloroacetyl) -N- (2 -nitrophenyl) -N'-phenylurea as a white solid.

• # ...

* · ·· * # ........

φ * * • »w m 22. 98371

Example V

K O

A solution of 10 N, - (2-chloroacetyl) -N- (2-nitrophenyl) -N, -phenylurea (3.7 g), dimethylformamide (15 ml) and diisopropylethylamine (15 ml) was refluxed. 5 minutes. The hot mixture was allowed to cool to room temperature and precipitated by adding the mixture to 200 ml of water. Precipitate 15 was collected and dried to give 1- (2-nitrophenyl) -3-phenylimidazoline-2,4 (1H, 3H) -dione.

Example VI

VP

'·: I V

OC j. * 25 Compound 1

*: I

. B

To a solution of 1- (2-nitrophenyl) -3-phenylimidazoline-2,4- (1H, 3H) -dione (2.7 g) in anhydrous dimethyl- * 30 formamide (2 ml) was added. in the nitrogen shielding gas N, N-di- *. methylformamide dimethyl acetal (2.7 g). The reaction mixture was stirred at 80 ° C for 2 hours and the solvent was removed in vacuo. To the obtained oil were added iron powder (5 g) and acetic acid (250 ml). This mixture was gently heated to reflux for 3 minutes, after which the reaction mixture was stirred for an additional 30 minutes. Heterogeneous. The reaction mixture was diluted with 10% methanol-1-methylene chloride (200 mL) and filtered through silica gel using 10% methanol-methylene chloride as eluent. The solvent was removed in vacuo and hot ethanol (200 mL) was added. To this mixture was added water (200 mL) and the resulting solid was filtered and washed successively with ethanol, ethyl acetate and diethyl ether and dried to give 2-phenylimidazo [1,5-a] quinoxaline-1,3 (2H, 5H ) -dione yellow-10 as a solid (Compound 1) melting at 231-234 ° C.

Example VIZ

J, Compound 2 co ^ 20 i

B

To a solution of 1- (2-nitrophenyl) -3- (2-fluorophenyl) iridazoline-2,4 (1H, 3H) -dione (1.18 g) in anhydrous methylene chloride (5 mL) under nitrogen was added tris- (dimethylamino) methane (1 mL). The reaction mixture was stirred at room temperature for 20 minutes and the solvent was removed in vacuo. The resulting solid was dissolved in dimethylformamide (100 mL) and Raney nickel slurry (50% solution in water, 1 mL) was added. The mixture was hydrated at 345 kPa (50 psi) for 45 minutes. The mixture was filtered through celite, the solution was concentrated in vacuo. To 30 ml and water (50 ml) was added. The resulting solid was washed successively with ethanol, ethyl acetate and diethyl ether and air dried to give 2-: 2-fluorophenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -: dione as a yellow solid. as a substance (compound 2), m.p. 261-264 ° C.

Example VIII

24-6 V w · OEt 5 Ο VS-cc 10 in DMF (100 ml), H 2 O (15 ml), 5% internal Pd carbon (1.25 g) and 1- (2-nitrophenyl) To a solution of -3- (4-ethoxyphenyl) imidazoline-2,4 (1H, 3H) -dione (25 g) maintained at 60 ° C was added dropwise a solution of sodium hypophosphite (15 g) in H 2 O. in (40 ml). After 3 hours, the mixture was cooled to room temperature and filtered through celite. The filtrate was poured into 500 mL of water, filtered and dried to give 1- (2-aminophenyl) -3- (4-ethoxyphenyl) imidazoline-2,4 (1H, 3H) -20 dione.

Example IX

• ϊ OEt, ^ Compound 3: oo ^: 30 |

: H

. 1- (2-aminophenyl) -3- (4-ethoxyphenyl) imidazole; To di-2,4 (1H, 3H) -dione (2 g) was added DMF (5 ml), acetic acid (5 ml) and N, N-dimethylformamide dimethylacetate (35 ml). The reaction mixture was heated to 60 ° C for 16 hours, cooled and filtered. The resulting orange solid was washed with isopropanol and recrystallized from acetic acid to give 2- (4-ethoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione (Compound 3). ), sp. 268 - 269 eC.

5 Example X

The following compounds were prepared essentially according to the procedures described in Examples VI, VII and IX.

1,2- (4-methoxy phenyl) 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. 305-308 ° C.

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

4. 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.

•• '25 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-1,3-2 (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-methylphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione (Compound 15), m.p. 280-284 ° C.

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

.: 35 14,2- (3-Ethoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione (Compound 17), m.p. 197-200 ° C.

* 7UO / Kj 26 15. 2- (4-n-propyloxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione (Compound 18), m.p. 182-185 ° C.

16. 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 eC.

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

20. 8-Methyl-2-phenylimidazo [1,5-a] quinoxaline-10β-1,3 (2H, 5H) -dione (Compound 23), m.p. 240-244 ° C.

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

24,2- (4-propylphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione (Compound 27), m.p. 185-186 ° C.

25,7-Methyl-2- (4-ethoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione (Compound 28), m.p. 200-203 ° C.

26. 2- (3-Bromo-4-ethoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione (Compound 29), m.p. 147-150 ° C.

29,2- (4-acetoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione (Compound 32), m.p. 210-211 ° C.

Example XI

: OMe

cS

; \ = s / Compound 33 * /

: η — N

BfS ^ Ny, MsX0: 30

B

. 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 mixture was stirred at 20 ° C for 15 minutes, then poured directly into boiling acetic acid (50 ml) containing zinc powder (500 mg). The reaction mixture was refluxed for 5 minutes and allowed to cool to room temperature. Dilute with 10% methanol / methylene chloride (100 mL), filter the mixture through silica gel, remove the solvent in vacuo, and treat the resulting solid with boiling ethanol (25 mL), then dilute 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] -10 quinoxaline-1,3 (2H, 5H) -dione ( compound 33) as a yellow solid, m.p. 154 ° C (dec.).

Example XIX

The following compound was prepared essentially according to the procedure described in Example XI.

1. 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 XIII

OEt 20, / 25 00 ° *

A solution of 1- (2-nitrophenyl) -3- (4-ethoxy-phenyl) imidazoline-2,4 (1H, 3H) -dione (5 g) in anhydrous THF (50 mL) was added dropwise. over 1 minute to a solution of 0.5 M LDA in THF (29 mL) at -78 ° C. After 20 minutes, ethyl chloroformate (1.2 mL) in THF (5 mL) was added in one portion. The reaction mixture was warmed to room-35 over 30 minutes and quenched with saturated anunonium chloride solution. The reaction mixture was partitioned between ethyl acetate and water, the organic layer dried and the solvent removed in vacuo. Column chromatography on silica gel using 50% ethyl acetate / hexane as eluent gave 5-ethoxycarbonyl-1- (2'-nitrophenyl) -3- (4-ethoxyphenyl) imidazoline-2/4 (1H, 3H) -dione.

Example XIV

° Et v0 VNv

Compound 35 ox

B

To a suspension of zinc dust (6 g) in acetic acid 20 (250 mL) was added 5-ethoxycarbonyl-1- (2-nitrophenyl) -3- (4-ethoxyphenyl) imidazoline-2,4 (1H, 3H) -dione; (2.5 g). The mixture was heated to reflux for 15 minutes, cooled to room temperature and filtered; the solvent was removed in vacuo and the resulting solid 25 was mixed with ethanol (50 ml) and filtered to give 4-hydroxy-2- (4-ethoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione (Compound 35).

Example XV

rf n Compound 36

Coit

B

98370 29 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 refluxed. 16 hours. The solvent was removed in vacuo and water (15 mL) was added. The pH was adjusted to 7.0 with 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

10 ^ _ ^^ 0Et \ —N Compound 37

B

20 THF (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 at 100 ° C in a sealed tube for 4 hours. After cooling to room temperature, the solvent was removed in vacuo. The solid was soaked in 50% EtOH-H 2 O and filtered to give 4-aramino-2- (4-ethoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione (compound 37).

Example XVII

30 OH

v0

35 ’V

co ^

B

98370 30 2- (4-Acetoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (211,511) -0101113 (250 mg) was added to an ethanol solution (50 ml) saturated with HCl. The solution was stirred for 2 hours and the solvent removed in vacuo to give 2- (4-hydroxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione (Compound 41), m.p. 318-322 ° C.

Example XVIZZ

rf O) = / Compound 42

OF

2- [4-Ethoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione (100 mg) was added to dimethylformamide dimethylacetal (10 ml) and DMF (5 ml) to form a solution and the reaction mixture was heated at 100 ° C for 4 hours. The solution was cooled to room temperature and poured into water (200 mL). The resulting precipitate was collected and dried to give 5-N-methyl-2- (4-ethoxyphenyl-2-imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -). dione (compound M 42), m.p. 263-266 ° C.

Γ: 9> β> · • e i · I * ► · ·· - «· ·· • '

Claims (31)

A process for the preparation of a therapeutically active 2-phenyl-substituted imidazo [1,5-a] quinoxaline-5,1,3 (2H, 5H) -dione derivative of Formin (I) W Vn / 11H and pharmaceutically acceptable non-toxic salts thereof, in which formula X is hydrogen, hydroxy, chloro or amino; W is phenyl which may be mono- or disubstituted with halogen, hydroxy, lower alkyl, amino, lower alkoxy or acetoxy; as well. R 2 and R 3 are the same or different and are each hydrogen, halogen or lower alkyl, characterized in that: a) a compound of formula (II) VV at 25 ° yN '30': is cyclized by treatment with N, N -dimethylformamide-dimethylacetal and dimethylformamide and then with a mixture of iron powder and acetic acid to give a compound of formula I, where X is hydrogen, or 98370 b) a compound of formula II is cyclized by treatment with tris (dimethylamino) methane and followed by hydrogenation in dimethylformamide to give a compound of formula I wherein X is hydrogen, or c) a compound of formula (III) is cyclized by treatment with N, N-dimethylformamide dimethyl acetal and acetic acid to give a compound of formula I, wherein X is hydrogen, or d) a compound of formula (IV), where: X is ethoxycarbonyl cyclized by treatment with 2inc in acetic acid to obtain a a compound of the formula · *: In which X is hydroxy, and, if desired, one or more of the following is carried out:. i) a compound of formula I wherein R2 and R are each hydrogen reacted with bromine in the presence of acetic acid and zinc to give a compound of formula I wherein R2 is · bromine and R 3 is hydrogen; Ii) a compound of formula I, wherein X is hydroxy, is converted to a compound of formula I, wherein X is chlorine. by treatment with a conventional chlorination reagent; Iii) a compound of formula I wherein X is chloro, reacted with ammonia to give a compound of formula I, wherein X is amino; iv) a compound of formula I wherein W is phenyl substituted with an acetoxy group, hydrolyzed with an acid to give a compound of formula I, wherein W is phenyl substituted with a hydroxy group. 2. A process according to claim 1, characterized in that 2-phenylimidazo-[1,5-a] quinoxaline-1,3 (2H, 5H) -dione is prepared. 3. A process according to claim 1, characterized in that 2- (2-fluorophenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione is prepared. 4. A process according to claim 1, characterized in that 2- (4-ethoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione is prepared. 5. A process according to claim 1, characterized in that 2- (4-methoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione is prepared. . 20 6. A process according to claim 1, characterized in that 2- (4-methylphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) is prepared. ) -dione. 9ΨΨ Process according to claim 1, characterized in that 2- (4-fluorophenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione is prepared. . A process according to claim 1, characterized in that 2- (2-amino-phenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) is prepared. -dione. ···, ···. 9. A process according to claim 1, characterized in that 2- (3-fluorophenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione is prepared. Process according to claim 1, characterized in that 2- (4-chlorophenyl) - imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione is prepared. · * · 98370 11. A process according to claim 1, characterized in that 2- (3-methylphenyl 1) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione is prepared. Process according to claim 1, characterized in that 2- (2-fluoro-4-ethoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione is prepared. Process according to claim 1, characterized in that 2- (3-chlorophenyl) -imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione is prepared. 10 A process according to claim 1, characterized in that 2- (2-methoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione is prepared. 15. A process according to claim 1, characterized in that 2- (4-ethylphenyl) -imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione is prepared. Process according to Claim 1, characterized in that 2- (2-fluoro-4-methylphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione is prepared. The method of claim 1, characterized in. 2 (3-methoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. » 18. A process according to claim 1, characterized in that 3-ethoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione is prepared. • 25 Process according to claim 1, characterized in that 2- (4-n-propyl-oxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione is prepared. Process according to claim 1, characterized in that 2- (4-n-butoxy-3-phenyl) in idazo (1,5-a] quinoxaline-1,3 (2H, 5H) -dione is prepared . Method according to claim 1, characterized in that 2- (4-isopropoxy-phenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione is prepared. ·. 22. Process according to claim 1, characterized in that 7-chloro-2- (4-methylphenyl) imidazofl, 5-a] quinoxaline-1,3 (2H, 5H) -dione is prepared. 98370 23. A process according to claim 1, characterized in that 8-methyl-2-phenyl-imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione is prepared. 24. A process according to claim 1, characterized in that 8-bromo-2- (4-ethoxyphenyl) imidazof1,5-a] quinoxaline-1,3 (2H, 5H) -dione is prepared. 25. A process according to claim 1, characterized in that 2- (4-propylphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione is prepared. 10 Process according to claim 1, characterized in that 7-methyl-2- (4-ethoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione is prepared. Process according to Claim 1, characterized in that 2- (3-bromo-4-ethoxyphenyl) imidazof 1,5-a] quinoxaline-1,3 (2H, 5H) -dione is prepared. 28. A process according to claim 1, characterized in that 2- (4-acetoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione is prepared. The method of claim 1, characterized in. 8-bromo-2- (4- ··· methoxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione. s; 30. A process according to claim 1, characterized in that 8-bromo-2- (3-bromo-4-ethoxyphenyl) imidazo [1,5-a] quinoxal in-1.3 (2H, 5H) -dione. \\ 25 31. A process according to claim 1, characterized in that 2- (4-hydroxyphenyl) imidazo [1,5-a] quinoxaline-1,3 (2H, 5H) -dione is prepared. e • · • · * ·· • tt • · • · t • t e · • 9 • 9 Vt 9 9 9999 9 9> 9 9 e i