DK161022B - Imidazoquinoxaline compounds, their preparation and pharmaceutical preparations which comprise the compounds. - Google Patents

Description

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DK 161022 B

The invention relates to novel therapeutically active imidazoquinoxaline compounds, a process for their preparation, and pharmaceutical compositions comprising the compounds. The new compounds are advantageous for psychopharmaceutical use e.g. in the treatment of central nervous system diseases, for example, as anticonvulsants or anxiolytics.

It is well known (Squires, R.F. and Braestrup, C. in Nature 10 (London) 266 (1977) 732-734) that specific regions of the central nervous system of vertebrates exhibit a strong specific affinity for 1,4- and 1,5-benzodiazepines. These areas are called benzodiazepine receptors.

15 of U.S. Patent No. 4,440,929 discloses imidazoquinoxaline compounds substituted at the 3-position with a carboxyl function. The compounds are reported to have cardiotonic activity. On the other hand, it is by no means evident or suggested that the known compounds have affinity for benzodiazepine receptors, so it is surprising that the compounds of this invention possess this affinity.

Danish Patent Specification No. 154142 discloses imidazo-quinoxaline compounds with affinity for benzodiazepine receptors, wherein the substituents at the 5- and / or 6-position are different from the 5-methyl / substituted methyl groups of the compounds of the present invention. From the data set out in the following Table 2, it is evident that the substituents mentioned in the compounds of the present invention have an unexpected, greater binding affinity in vitro than the corresponding substituents of the known compounds.

Danish Patent Specification No. 155007 describes imidazo-quinazoline compounds which, in addition to differences in the 4- / 6-position, also differ from the compounds in question by being derived from the imidazoquinazoline backbone. These known compounds also exhibit a far inferior 1

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2 bind affinity in vitro than chemically, most closely related compounds of the present invention, as evidenced by the data set forth in Table 2 below.

5

Danish Patent Specification No. 155524 also deals with condensed imidazo derivatives with affinity for benzodiazepine receptors. The pharmaceutically most suitable compounds of this specification are in contrast to the compounds 10 derived from pyridopyrazine, and as shown in Table 2, these compounds exhibit a much weaker binding affinity in vitro.

The imidazoquinoxaline compounds of the invention have the general formula I

tfr - 20 tf tf where R3 is - <χ · -α or CXXR R where R 'is Cgg-cycloalkyl; R is methyl optionally substituted with C 1-6 alkyl, alkoxycarbonyl, pyridyl, morpholino, C 1-7 cycloalkyl, C 2-7 alkenyl, phenalkyl, C 1-6 alkylacyl, alkoxyalkyl, alkoxy, phthalimidophenyl, benzyl or phenyl, all of which are unsubstituted or substituted by halogen, C 1-6 alkyl, amino, azido or C 1-6 alkoxy; and R 1 is H, C 1-6 alkyl, halogen or CF 2.

k DK 161022 3

The compounds of the invention may be prepared by a process comprising: a) reacting a compound of formula II 5 10 r lp 5 6

wherein R and R have the above meanings and where Y is a leaving group, with a compound of formula III

CN - CH2 - R3 (III) 3 wherein R is as defined above to form a compound of the invention, or

B) reacting a reactive derivative of a compound of general formula IV

25 IC / T T (IV) 5 6

wherein R and R have the above meanings, with a compound of the general formula V

R '- C (' NOH) NH 2 (V) wherein R 'is as defined above to form a compound of general formula I wherein R is

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4 -o * 5 where R 'has the above meaning.

The leaving group, Y, may be any suitable leaving group and, for example, those mentioned in US Patent Nos. 4,031,079 or 4,359,420, for example, halogen, alkylthio, ie, methylthio, aralkylthio, N-nitrosoalkylamino, alkoxy, mercapto, -0F (O) (OR) 2 where R is lower alkyl or -0P (O) (NR'R ") where R 'and R" each represent lower alkyl or phenyl, or together with the nitrogen atom to which they are attached , represents a heterocyclic radical such as, for example, morpholine, pyrrolidine, piperidine or methylpiperazine. The reaction is best performed under alkaline conditions, e.g. in the presence of a base, and among bases, alkali metal is preferred, for example, 20 potassium or sodium alkoxides or hydrides. The reaction is best carried out in an organic solvent which does not react with the reactants and products of the reaction under the reaction conditions, especially an anhydrous solvent and preferably an anhydrous aprotic solvent such as dimethylformamide (DMF) or the like. The temperature range used may be within any range which allows the reaction to proceed at an appropriate rate and without undue delay or decomposition, and a range from -40 ° C to about room temperature is thus usually particularly suitable.

The starting materials can be prepared from commercially available organic compounds using well known synthetic methods.

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The pharmaceutical properties of the compounds of the invention can be illustrated by determining their ability to (displace radiolabeled flunitrazepam from benzodiazepine receptors.

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The displacement activity of the compounds of the invention is found by determining the ED The ED ^ value indicates the dose (mg / kg) of a test substance that causes the specific binding of flunitrazepam to benzodiazepine receptors in a living brain to be reduced to 50% of the control value.

Such an in vivo test is performed as follows: 3 Principle. Twenty minutes after the administration of a dose of H-3 flunitrazepam (H-FNM) (200 µCi / kg, i.v.), the specific binding of H-FNM to brain benzodiazepine receptors has reached its maximum value. This specific binding of 3 H-FNM can be partially or completely prevented by concomitant or prior administration of pharmacologically active benzodiazepines and some benzodiazepine-like substances (Chang and Snyder, Eur. J. Pharmacol. 48, 212-218 ( 1978)).

Test Procedure. Solutions of test substances (2 mg / ml) are prepared in 5% Duphasol-X (TM Duphar, castor oil-ethylene oxide derivative for emulsifying and dissolving oil and other water-insoluble substances) by ultrasound for 10 minutes using a Branson B15 microtip ultrasound (setting 7). Groups of three mice (females, NMR, 18-22 grams) 30 are injected intraperitoneally with 100 mg / kg of test substance. Fifteen minutes after administration of the test substance, 3 mice are injected 4 µCi intravenously by H-FNM (70-90 µCi / mol) in 200 µΐ physiological saline solution. Twenty minutes 3 after H-FNM administration, mice are sacrificed by cutting off the head; the foreskin is rapidly removed (within 30 sec) and homogenized in 12 ml of ice-cold 25 mM KH2PO4, pH 7.1, by means of an UltraTurrax homogenizer equipped 6

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with an N 10 shaft. Two 1 ml portions are immediately filtered through Whatman GF / C fiberglass filters and washed with 2x5 ml of the above buffer. The amounts of radioactivity on the filters are determined by conventional scintillation counting.

5 A group of untreated mice acts as a control. One to three mice are injected with 25 µg / kg clonazepam i.p. 30 minutes 3 hours before H-FNM to determine the amount of non-specific 3 H-FNM binding, which should be between 8-15% of the total binding. When doses of 100 mg / kg inhibit more than 50% of the specific H-flunitrazepam compound, test substances are administered at doses that are factors of 3.16 times lower than 100 mg / kg. ED 2Q for a test substance is defined as the dose which inhibits 50% of the specific 1 H-FNM bond. Specific binding is the amount of binding in control animals minus the amount of binding in clonazepam-treated mice.

Results. The ED ^ value is determined from dose-response curves. If only one dose of test substance is administered, the ED jQ value is calculated as follows, assuming that the inhibition of specific binding is in the range of 25-75%: EDqq = (administered dose) x - mg / kg r C η o 25 - - 1

L cx J

where C is specific binding in control animals and C is specific- U Λ 'got binding in mice treated with test substance.

'30

Test results obtained by testing some of the compounds of the invention will appear from the following Table 1.

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7 TABLE 1.

Compound ED 50 (mg / kg) 5--2 0.09 6 0.21 1 1.2 10 9 0.61 11 0.47 7 0.75 8 0.23 21 3.1 15 22 2.3 23 0 , 14 25 1.0 28 1.6 31 I 2.4 20

In order to compare the binding affinity of the compounds in vitro with the affinity of the known chemically related compounds, the following tests are performed: 3

In vitro inhibition of H-flunitrazepam binding 30 3

Principle: H-flunitrazepam binds specifically and with a high degree of finesse to brain membranes in all higher mammals. The ability of a substance to inhibit specific flunitrazepam binding is clearly related to its affinity for brain benzodiazepine receptors (Braestrup, C. and Squires, R.F., Eur.-J.Pharmacol. 48, 263-270 (1978)).

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Freeze-dried bovine cortex membranes have been found to have the same binding characteristics as healthy rat membranes (Lund, J., Scan.J.Clin.Lab.Invest., 41, 275-280 (1981)).

Test: Freeze-dried bovine benzodiazepine receptor preparations (Prep. 38912 or subsequent preparations) are suspended in 40 ml (10 mg / ml) 25 mM KI Add 25 μΐ of test preparation solution to 0.5 ml of receptor suspension - 3 equivalents, followed by 25 μΐ of H-flunitrazepam solution 10 (1 nM, final concentration); and the mixture is incubated for 60 min. in an ice bath (in duplicate). After incubation, the samples are filtered directly onto Whatman GF / C fiberglass filters under suction and washed immediately with 2 x 10 ml ice-cold buffer. The amount of radioactivity on the filters is determined by conventional liquid scintillation counting. Non-specific binding is determined in duplicate with clonazepam (100 ng / ml, final concentration) as test solution. Specific binding is total binding minus non-specific binding.

Method: Test substances are dissolved in 10 ml of water or 96% ethanol (acidified with 25 μΐ IN HCl if necessary and heated in a steam bath for a maximum of 5 minutes) at a concentration of 0.22 mg / ml. Three dilutions are made in water or 48% ethanol (220 ng / ml, 2.2 pg / ml and 22 pg / ml). Concentrations of 10, 100 and 1000 ng / ml (final concentration) are added for duplicate tests. 25-75% inhibition of specific binding must be achieved before calculating IC

Results: The test value will be given as ICj-q (concentration (ng / ml) of the test substance which inhibits specific 3 binding of H-flunitrazepam by 50%).

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9 10 = (applied test substance conc. X -— ng / ml 50 Γ co i - - 1 5 L cx - where CQ is specific binding in control experiment and is specific binding in test test.

TABLE 2

GOST

Compound R3 X - YR ^ Z - R ^ IQ-q (ng / ml) I Ov C'N 0 "™ 2 ^ 2) C'H 0.64 25 II C - N 0 -O C - H 1.5 30 2 C "N 0 ~ U 3 C" CF 3 ° 33 33 C "N 0 C_CF 3 0.54 35

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10

* N

IE, title - \ JL · C - NO -CHg C - H 11.0 5 * 2D, title C - N 0 - ° ¾ C - H 10 '° * 2D C_N ° “dc" H 19.4 10 ** 1F N - C -CHg 0 C - H 8.9 ** 2, title N - C -CHg 0 C_0C2H5 14.0 15, Ο'ν 10 "(I c - NO - ° ¾ N - H 9.6 20 *** 9D C - NO -CHg N - H 16.0 CH3 «X» 25 Danish Publication No. 154142

Danish Patent Specification No. 155007 Danish Patent Specification No. 155524 \ 1 30 As is clear from Table 2, these data indicate that methyl / substituted methyl at the 5-position and altered / unchanged substituents at the 6-position of the compounds of the present invention cause a pronounced binding affinity in vitro, compared with the methyl and isopropyl substitution of known compounds from the Danish publication 35.

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The compounds of the invention may, together with a conventional adjuvant, carrier or diluent, and, if desired, in the form of a pharmaceutically acceptable acid addition salt thereof, be formulated into pharmaceutical preparations and unit doses thereof, and may be used in this form in solid form. eg. as tablets or filled capsules, or as liquids, such as solutions, suspensions, emulsions, elixirs, or capsules filled with the compound, all for oral use, in the form of rectal 10 suppositories; or in the form of sterile injection solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional conditions, with or without additional active compounds or principles, and such unit dosage forms may comprise any suitably effective central nervous system disease-relieving amount of the active ingredient in accordance with the daily dosage which conceivably used. Thus, tablets containing 1-30 mg and more specifically 1 mg of active ingredient 20 per tablet are suitably representative unit dosage forms.

Thus, the compounds of this invention can be used to formulate pharmaceutical compositions, for example, for oral and parenteral administration to mammals, incl. humans, in accordance with conventional methods of galenic pharmacy.

Conventional excipients are pharmaceutically acceptable organic or inorganic carriers suitable for parenteral or oral administration and which do not adversely react with the active compound.

Examples of such carriers are water, saline, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides.

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12 pentaerythritol fatty acid esters, hydroxymethyl cellulose and polyvinylpyrrolidone.

The pharmaceutical compositions can, if desired, be sterilized and mixed with adjuvants, e.g. lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts which influence osmotic pressure, buffers and / or dyes or the like, which do not adversely react with the active compound.

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For parenteral administration, injectable solutions or suspensions are particularly suitable, preferably aqueous solutions, where the active compound is dissolved in polyhydroxylated castor oil.

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Ampoules are appropriate unit dosage forms.

For oral administration, tablets, dragees or capsules with talc and / or carbohydrate as carrier or binding agent or the like are most suitable. The carrier should be lactose and / or corn starch and / or potato starch.

A syrup, elixir or the like can be used when a sweetened carrier can be used. Generally, in a wider field of application, the compound of the invention is dispensed in unit dosage forms containing 0.05-100 mg in a pharmaceutically acceptable carrier per unit dose.

A typical tablet that can be prepared by conventional tablet manufacturing techniques contains: 30

Active compound 1.0 mg

Lactosum 67.8 mg Ph.Eur.

Avicel 31.4 mg

Amberlite® IRP 88 1.0 mg 35 Magnesii stearas 0.25 mg Ph.Eur.

Due to their high affinity for the benzodiazepine receptors, the compounds of the invention are extremely useful in the treatment of central nervous system disorders or disorders when administered in an amount that alleviates, ameliorates or removes them. The important CNS activity of the compounds of the invention encompasses both anti-convulsive and anxiolytic effects and low toxicity, which together provides an extremely favorable therapeutic index. Thus, the compounds of the invention may be administered to a subject, for example, a human or animal in need of treatment, relief, amelioration, or removal of a central nervous system disorder associated with the so-called benzodiazepine receptors which require such psychopharmaceutical treatment. i.e., especially cramping and / or anxiety states, if desired, in the form of a pharmaceutically acceptable acid addition salt thereof (such as hydrobromide, hydrochloride, or sulfate, as always prepared in the usual or conventional manner, e.g. dry substance of the free base in solution together with the acid), usually in association with, simultaneously with, or together with a pharmaceutically acceptable carrier or diluent, in particular and preferably in the form of a pharmaceutical composition thereof, either orally, rectally, or parenterally ( including subcutaneously), in a psychopharmaceutical central nervous system relieving effective dose, i.e. an anticonvulsant and / or anxiolytic amount, and in any case an amount effective for relieving such a central nervous system disease because of their benzodiazepine receptor affinity. Suitable dosage ranges are 30-1-200 milligrams daily, preferably 1-100 milligrams daily, and especially 1-30 milligrams daily, as always, depending on the actual manner in which it is administered, in which form it is administered, which symptom the treatment is directed to, the individual body and the individual's body weight involved, as well as the preference and experience of the responsible physician or animal.

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The invention will now be further described in detail with reference to the following Examples: EXAMPLE 1 a. N-phenethyl-2-nitroaniline 10 A stirred solution of 2-fluoronitrobenzene (14.1 g, 0.1 mole) and triethylamine (14 ml , 0.1 mole) in DMF (150 mL) was added phenethylamine (12.1 g, 0.1 mole). The mixture was then heated to 100 ° C and the reaction monitored on TLC. When the reaction was complete (2 hours), the solvent was removed by evaporation in vacuo. The residue is partitioned between 0.5 N aqueous HCl (100 ml) and ether (100 ml). The organic phase was washed with water, dried and evaporated to give the title compound as a yellow oil.

Similarly, the following compounds were prepared by reaction of 1-fluoro-2-nitrobenzene with the corresponding amines: 25 N- (2-morpholinoethyl) -2-nitroaniline. Mp. 42-44 ° C.

N- (2-chlorobenzyl) -2-nitroaniline. Mp. 106-107 ° C

N- (2-methoxybenzyl) -2-nitroaniline. Mp. 114-115 ° C.

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N- (2-methoxybenzyl) -2-nitroaniline. Mp. 92-93 ° C

N- (2-pyridylmethyl) -2-nitroaniline. Mp. 87-88 ° C.

N- (2-chlorobenzyl) -2-chloro-6-nitroaniline, m.p. 69-71 ° C

was prepared from 2,3-dichloronitrobenzene and 2-chlorobenzyl chloride. Purification on SiO 2 (pentane / ether 15: 1).

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15; b. N-Ethoxalyl-2-nitro-6-methylaniline

A stirred solution of 2-nitro-6-methylaniline (10 g, 65 mmol) and triethylamine (11 ml, 80 mmol) in THF (80 ml) was added dropwise to a solution of ethoxalyl chloride (9 ml, 80 mmol). When the addition was complete, the mixture was heated to reflux. After 3 hours, the mixture was cooled to room temperature and the precipitated triethylammonium chloride 10 was filtered off. The filtrate was evaporated to give the crude product as an oil. Purification (SiO 2 / ether: pentane, 1: 1) afforded the pure title compound as an oil.

Similarly, the following N-ethoxalyl anilines were prepared by reaction of ethoxalyl chloride with the corresponding anilines: N-ethoxalyl-N- (2-methoxybenzyl) -2-nitroaniline. Oil N-ethoxalyl-N- (4-methoxybenzyl) -2-nitroaniline. Oil N-ethoxalyl-N- (2-pyridylmethyl) -2-nitroaniline. Oil

N- (2-chlorobenzyl) -N-ethoxalyl-2-nitroaniline. Mp. 98-25 99 ° C

N-ethoxalyl-N- (2-morpholinoethyl) -2-nitroaniline. Mp. 75-76 ° C.

N-benzyl-N-ethoxalyl-2-nitroaniline. Mp. 170-175 ° C

N- (2-chlorobenzyl) -2-chloro-N-ethoxalyl-6-nitroaniline.

Mp. 101-102 ° C.

N-ethoxalyl-N-phenethyl-2-nitroaniline. Oil N-cyclopropylmethyl-N-ethoxalyl-2-nitroaniline. Oil

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16 C. N-ethoxalyl-N-methyl-2-nitro-6-methylaniline

NaH (1 g, 22 mmol) was added in portions to a stirred solution of N-ethoxalyl-2-nitro-6-methylaniline (5 g, 20 mmol) in DMF (50 ml). Then methyl iodide (2 ml, 22 mmol) was added. The mixture was allowed to stand overnight at room temperature, after which the solvent was removed by evaporation in vacuo. The evaporation residue is shared between ether and water.

The organic phase was washed with water, dried over Na 2 O 2 and evaporated to give the title compound as an oil.

Similarly, the following compound was prepared by alkylating the corresponding starting material: N-ethoxalyl-N-ethyl-2-nitro-6-methylaniline (oil) was prepared from N-ethoxalyl-2-nitro-6-methylaniline and ethyl iodide.

D. N-ethoxalyl-4-chloro-2-trifluorooroethylaniline

A mixture of 2-amino-5-chlorobenzotrifluoride (14.4 ml, 0.1 mol) and triethylamine (14.0 ml, 0.1 mol) was dissolved in dry tetrahydrofuran, THF (250 ml). This solution was added with stirring a solution of ethoxalyl chloride in THF (50 ml). When the addition was complete (30 minutes), the mixture was stirred at room temperature for 3 hours, then the precipitated triethylammonium chloride was filtered off and the filtrate was evaporated in vacuo. This gave the crude title compound (24 g) as pale crystals. Mp. 55-58 ° C.

e. N-Ethoxalyl-4-chloro-6-nitro-2-trifluoromethyl-aniline

A solution of N-ethoxalyl-4-chloro-2-trifluoromethylaniline in concentrated sulfuric acid (125 ml) was added to a stirred solution.

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17 mixture of 100% nitric acid (120 ml) and concentrated sulfuric acid (240 ml). The temperature was maintained between 8-10 ° C during the addition. After the addition was complete, the solution was stirred for an additional 20 min. without external cooling, after which it was poured into ice water. This precipitated the title compound as an oil which crystallized as pale yellow crystals on standing. The crystals were filtered off and washed thoroughly with water.

Mp. 100-101 ° C.

10 f. N-ethoxalyl-N-methyl-4-chloro-6-nitro-2-trifluoromethyl-aniline A stirred solution of N-ethoxalyl-4-chloro-6-nitro-2-trifluoromethylaniline (11 g, 32 3 mmol) and methyl iodide (3.0 ml, 48 mmol) in dry dimethylformamide (DMF, 50 ml) was added portionwise sodium hydride (total 1.7 g, 39 mmol).

External cooling was used to keep the reaction temperature below 25 ° C. Stirring was continued at room temperature for 3 hours, after which the solvent was removed by evaporation in vacuo. The residue is then divided between ether and water. The organic phase was washed twice with water, dried over Na2 SO4 and evaporated. This treatment gave the title compound as an oil which was continued without further purification.

g. 3,4-Dihydro-2-hydroxy-3-oxo-4-methyl-5-trifluoromethyl-quinoxaline-1-oxide

A solution of N-ethoxalyl-N-methyl-4-chloro-6-nitro-2-trifluoroaniline (12 g, 32 mmol) and triethylamine (5.6 mL, 32 mmol) in 96% ethanol (150 mL) was hydrogenated under standard conditions with 5% Pd / C (1 g) as catalyst.

After the reaction was complete, the catalyst was filtered off and the solvent was removed by evaporation.

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18 ning. Treatment of the residue with water / ethyl acetate (150 ml / 50 ml) gave the product as white crystals which were collected by filtration. Mp. 196-198 ° C.

Similarly, the following 1-oxide quinoxalines were prepared: 4-benzyl-3,4-dihydro-2-hydroxy-3-oxo-quinoxaline-1-oxide, m.p. 170-175 ° C by hydrogenation of N-ethoxalyl-N-benzyl-2-nitroaniline 3,4-dihydro-2-hydroxy-4- (2-morpholinoethyl) -3-oxo-quinox-aline-1-oxide. Mp. 170-172 ° C by hydrogenation of N-ethox-alyl-N- (2-morpholinoethyl) -2-nitroaniline 3,4-dihydro-2-hydroxy-3-oxo-4-phenethyl-quinoxaline-1-oxide, m.p. 200-201 ° C by hydrogenation of N-ethoxalyl-N-phenethyl-2-nitroaniline 4- (2-chlorobenzyl) -3,4-dihydro-2-hydroxy-3-oxo-quinoxaline-1-oxide, mp. 250-260 ° C (dec.) By hydrogenation of N-ethoxalyl-N- (2-chlorobenzyl) -2-nitroaniline.

RaNi was used as catalyst 3,4-dihydro-2-hydroxy-4- (4-methoxybenzyl) -3-oxo-quinoxaline-1-oxide, m.p. 193-194 ° C by hydrogenation of N-ethoxyl-N-N- (4-methoxybenzyl) -2-nitroaniline 3,4-dihydro-2-hydroxy-4- (2-pyridylmethyl) -3-oxo-quinoxaline lin 1-oxide, m.p. 220 ° C (dec.) By hydrogenation of N-ethoxalyl-N- (2-pyridylmethyl) -2-nitroaniline 3,4-dihydro-2-hydroxy-4- (2-methoxybenzyl) -3-oxo-quinoxa-lin-1- oxide, m.p. 243-244 ° C by hydrogenation of N-ethoxanol-N- (2-methoxybenzyl) -2-nitroaniline 19

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5-chloro-4- (2-chlorobenzyl) -3,4-dihydro-2-hydroxy-3-oxo-quinoxaline-1-oxide, m.p. 222-223 ° C by hydrogenation of 2-chloro-N- (2-chlorobenzyl) -N-ethoxalyl-6-nitroaniline. RaNi was used as catalyst 5 4-cyclopropylmethyl-3,4-dihydro-2-hydroxy-3-oxo-quinoxa-lin-1-oxide, m.p. 205-206 ° C.

10 In some cases, hydrogenation did not stop at the quinox-aline-1 oxide, but at the amino or quinoxaline oxidation state.

h. 4-Ethyl-1,2,3,4-tetrahydro-5-methyl-2,3-dioxo-quinoxalin

Hydrogenation of N-ethoxalyl-N-ethyl-6-methyl-2-nitroaniline under standard conditions gave N-ethoxalyl-N-ethyl-2-20 amino-6-methylaniline as an oil. Cycle to the title compound was made in ethanol / 1 N HCl (50 ml / 25 ml) by reflux for 10 min. The product was precipitated after cooling and collected by filtration. Mp. > 300 ° C.

4-Benzyl-1,2,3,4-tetrahydro-2,3-dioxo-quinoxaline

A solution of 4-benzyl-1,2,3,4-tetrahydro-2,3-dioxo-quinoxaline-1-oxide (14.6 g, 54 mmol) and triphenylphosphine (21 30 g, 80 mmol) in dimethylformamide (200 ml) was stirred at 110 ° C for 24 hours. The solution was evaporated in vacuo and the residue was stirred in methylene chloride (100 ml). This treatment gave the crude title compound as a crystalline precipitate.

The product was purified by recrystallization from ethanol, m.p. 273-274 ° C.

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Similarly, the following quinoxalins were prepared from their corresponding 1-oxides: 1.2.3.4-tetrahydro-2,3-dioxo-4-phenethyl quinoxaline, m.p.

Mp 105-106 ° C.

4- (2-chlorobenzyl) -1,2,3,4-tetrahydro-2,3-dioxo-quinoxaline, m.p. > 300 ° C.

1,2,3,4-tetrahydro-4- (4-methoxybenzyl) -2,3-dioxo-quinoxaline, m.p. 246-247 ° C.

5- chloro-4- (2-chlorobenzyl) -1,2,3,4-tetrahydro-2,3-dioxo-quinoxaline, m.p. 234-236 ° C.

1.2.3.4-tetrahydro-4- (2-methoxybenzyl) -2,3-dioxo-quinoxaline, m.p. 271-272 ° C.

1.2.3.4-tetrahydro-4- (2-morpholinoethyl) -2,3-dioxoquinonexaline, m.p. 233-236 ° C.

1.2.3.4-tetrahydro-4- (2-pyridylmethyl) -2,3-dioxo-quinoxaline, m.p. 295-297 ° C.

4-cyclopropylmethyl-1,2,3,4-tetrahydro-2,3-dioxo-quinoxa lin, m.p. 211-213 ° C.

j. 5-Benzyl-3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-4-oxo-imidazo [1,5-a] quinoxaline (Compound 1) ----

An ice-cold, stirred solution of 4-benzyl-1,2,3,4-tetrahydro-2,3-dioxo-quinoxaline (1 g, 4 mmol) in dry DMF (20 ml) was added potassium t-butylate (0 , 56 g, 5 mmol). Stirring was continued until all the potassium t-butylate was dissolved. In certain experiments, a strong precipitation of the potassium quinoxaline salt was observed.

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21

The mixture was then added with diethyl chlorophosphate (0.7 ml, 5 mmol) and stirring was continued at room temperature for 30 minutes, after which a pre-prepared -40 ° C cold solution of potassium t-butylate (0.56 g, 5 mmol) and 5-cyclopro 5-pyl-3-isocyanomethyl-1,2,4-oxadiazole (0.8 g, 5 mmol) in dry DMF (15 ml) was added.

The crude product was crystallized from the oily precipitate by treatment with a mixture of water (25 ml) and ethyl 10 acetate (10 ml). The crystals were collected by filtration and purified by column chromatography (SiO 2 / ethyl acetate), m.p.

250 DEG-255 DEG C.

Similarly, the following compounds were prepared from the corresponding guinoxalines and isonitriles: 3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-5-methyl-4-oxo- 6-trifluoromethyl-imidazo [1,5-a] quinoxaline, m.p. 231-234 ° C by reaction between 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole and 1,2,3,4-tetrahydro-4-methyl-2,3-dioxo-5 -trifluoromethyl quinoxaline (Compound 2) 3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-4-oxo-5-phenethyl-imidazo [1,5-a] quinoxaline, m.p. 200-201 ° C by reaction between 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxa-diazole and 1,2,3,4-tetrahydro-2,3-dioxo-5-phenethyl-quinoxaline ( Compound 3) 5- (2-Chlorobenzyl) -3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) 4,5-dihydro-4-oxo-imidazo [1,5-a] quinoxaline, m.p. 243-244 ° C by reaction between 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole and 4- (2-chlorobenzyl) -1,2,3,4-tetrahydro-2,3-dioxo-quinoxaline ( Compound 4) 3- (5-Cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-5- (4-methoxybenzyl) -4-oxo-imidazo [1,5-a] quinoxaline , m.p. 200- 35 22

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203 ° C by reaction between 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole and 1,2,3,4-tetrahydro-4- (4-methoxybenzyl) -2,3-dioxo-quinoxaline (Compound 5) (3-cyclopropyl-1,2,4-oxadiazol-5-yl) -4,5-dihydro-5-methyl-4-oxo-6-trifluoromethylimidazo [1,5-a] quinoxaline, m.p. 232-233 ° C by reaction between 3-cyclopropyl-5-isocyanomethyl-1,2,4-oxadiazole and 1,2,3,4-tetrahydro-4-methyl-2,3-dioxo-5-trifluoromethyl guinoxaline (Compound 6) 6- chloro-5- (2-chlorobenzyl) -3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-4-oxo-imidazo [1,5-a ] quinoxaline, m.p. 244-245 ° C by reaction between 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole and 5-chloro-4- (2-chlorobenzyl) -1,2,3,4-tetrahydro-2,3-dioxo -quinoxaline (Compound 7) 3- (5-Cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-4-oxo-5- (2-pyridylmethyl) imidazo [1,5- a] quinoxaline, m.p. 197-198 ° C by reaction between 5-cyclopropyl-3-isocyanomethyl-1,2,4-20 oxadiazole and 1,2,3,4-tetrahydro-4- (2-pyridylmethyl) -2,3-dioxo-quinoxaline (Compound 8) 3- (5-Cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-5- (2-methoxybenzyl) -4-oxo-imidazo [1,5-a] quinoxaline, m.p. 201-25 203 ° C by reaction between 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole and 1,2,3,4-tetrahydro-4- (2-methoxybenzyl) -2,3-dioxo-quinoxaline (Compound 9) 3- (5-Cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-5- (2-30 morpholinoethyl) -4-oxo-imidazo [1,5-a] quinoxaline, m.p. . 187-188 ° C by reaction between 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole and 1,2,3,4-tetrahydro-4- (2-morpholinoethyl) -2,3-dioxo-quinoxaline (Compound 10) 3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -5-cyclopropylmethyl-4,5-dihydro-4-oxo-imidazo [1,5-a] quinoxaline, m.p. 213-215 ° C by reaction between 4-cyclopropylmethyl-1,2,3,4-tetrahydro-23

DK 161022 B

2,3-dioxo-quinoxaline and 5-cyclopropyl-3-i-socyanomethyl-1,2,4-oxadiazole (Compound 11)

Ethyl 4,5-dihydro-5,6-dimethyl-4-oxo-imidazo [1,5-a] quinoxa-5-line 3-carboxylate, snip. 190-191 ° C by reaction between 1.2.3.4-tetrahydro-4,5-dimethyl-2,3-dioxo-quinoxaline and ethyl isocyanoacetate (Compound 12)

Ethyl 5-ethyl-4,5-dihydro-6-methyl-4-oxo-imidazo [1,5-a] quinoxaline-3-carboxylate, m.p. 159-160 ° C by reaction between 4-ethyl-1,2,3,4-tetrahydro-5-methyl-2,3-dioxo-quinoxaline and ethyl isocyanoacetate (Compound 13)

Ethyl 4,5-dihydro-5-phenethyl-imidazo [1,5-a] quinoxaline-3-carboxylate, m.p. 179-180 ° C by reaction between 1,2,3,4-tetrahydro-2,3-dioxo-4-phenethyl-quinoxaline and ethyl iso-cyanoacetate (Compound 14)

Ethyl 4,5-dihydro-5- (4-methoxybenzyl) -4-oxo-imidazo [1,5-a] -quinoxaline-3-carboxylate, m.p. 194-195 ° C by reaction between 1.2.3.4-tetrahydro-4- (4-methoxybenzyl) -2,3-dioxo-quinoxaline and ethyl isocyanoacetate (Compound 15)

Ethyl 5- (2-chlorobenzyl) -4,5-dihydro-4-oxo-imidazo [1,5-a] -quinoxaline-3-carboxylate, m.p. 203-209 ° C by reaction between 4- (2-chlorobenzyl) -1,2,3,4-tetrahydro-2,3-dioxo-quinoxaline and ethyl isocyanoacetate (Compound 16) EXAMPLE 2 3- (3-cyclopropyl) 1,2,4-Oxadiazol-5-yl) -4,5-dihydro-5,6-dimethyl-4-oxo-imidazo [1,5-a] quinoxaline (Compound 17) A mixture of ethyl-4, 5-dihydro-5,6-dimethyl-4-oxo-imidazo [1,5-a) quinoxaline-3-carboxylate (450 mg), cyclopropane-carboxamidoxime (500 mg) and crushed molecular sieve 4Å (5 g)

DK 161022B

in 24 treated with a solution of sodium (70 mg) in dry ethanol (50 ml). The stirred mixture was refluxed for 3 hours, cooled and filtered through a filter. The filtrate was concentrated to a volume of 10 ml by evaporation in 5 vacuo, whereby the title compound partially precipitated. Addition of water (50 ml) gave a further precipitation of the title compound. The crystals were collected by filtration and washed with water, m.p. 223-224 ° C.

Similarly, the following oxadiazoles were prepared by reaction of cyclopropane carboxamidoxime with the corresponding ethyl esters. The compound was purified by recrystallization from isopropanol.

3- (3-cyclopropyl-1,2,4-oxadiazol-5-yl) -4,5-dihydro-4-oxo-5-phenethyl-imidazo [1,5-a] quinoxaline, m.p. 235-236 ° C. (Compound 18) 5- (2-Chlorobenzyl) -3- (3-cyclopropyl-1,2,4-oxadiazol-5-yl) - 4,5-dihydro-4-oxo-imidazo [1,5-a ] quinoxaline, m.p. 276-277 ° C.

(Compound 19) 3- (3-Cyclopropyl-1,2,4-oxadiazol-5-yl) -4,5-dihydro-5- (2-methoxybenzyl) -4-oxo-imidazo [1,5-a] quinoxaline, m.p. 260-25 261 ° C. (Compound 20) 3- (3-Cyclopropyl-1,2,4-oxadiazol-5-yl) -5-ethyl-4,5-dihydro-6-methyl-4-oxo-imidazo [1,5-a] quinoxaline, m.p. 211-212 ° C. (Compound 21)

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EXAMPLE 3 3- (5-Cyclopropyl-1,2,4-oxadiazol-3-yl) -5-ethoxycarbonyl-methyl-4,5-dihydro-4-oxo-imidazo [1,5-a] quinoxaline (For -5 compound 22)

A stirred solution of 3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-4-oxo-imidazo [1,5-a] quinoxaline (200 mg) in DMF (10 ml) was added sodium hydride (50 mg) and after 10 minutes ethyl monochloroacetate (1 ml). The mixture was stirred for an additional 2 hours, after which the solvent was removed by evaporation in vacuo. The residue was partitioned between water (25 mL) and ether (20 mL) and the crystalline product was filtered off. Mp. 245-246 ° C.

With 3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-4-oxo-imidazo [1,5-a] quinoxaline and the appropriate halides as starting materials and DMF as solvent The following compounds are prepared: 3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-5- (3,3-dimethylallyl) -4-oxo-imidazo [1 , 5-a] quinoxaline, m.p. 133-134 ° C by alkylation with 3,3-dimethylallyl bromide. (Compound 23) 5-Allyl-3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-4-oxo-imidazo [1,5-a] quinoxaline , m.p. 188-189 ° C by alkylation with allyl bromide. (Compound 24) 3- (5-Cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-4-oxo-5-phenacyl-imidazo [1,5-a] quinoxaline, m.p. . 258-259 ° C by alkylation with phenacyl bromide (Compound 25) 5-Acetonyl-3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-4-oxo-imidazo [ 1,5-a] quinoxaline, m.p. 280-282 ° C by chloroacetone alkylation. Recrystallization from i

DK 161022 B

Methanol (Compound 26) 3- (5-Cyclopropyl-1,2,4-oxadiazol-3-yl) -5- (2-fluorobenzyl) 4,5-dihydro-4-oxo-imidazo [1,5-a] quinoxaline, m.p. 229-230 ° C by benzylation with 2-fluorobenzyl chloride. Recrystallization from toluene (Compound 27) 3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-5- (2-methylbenzyl) -4-oxo-imidazo [1,5 -a] quinoxaline, m.p. 235-10 237 ° C by benzylation with 2-methyl-benzyl chloride. Recrystallize from methanol (Compound 28) 5- (2-bromobenzyl) -3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) - 4,5-dihydro-4-oxo-imidazo [1,5- a] quinoxaline, m.p. 236-237 ° C by benzylation with 2-bromobenzyl bromide (Compound 29) 3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) - 4,5-dihydro-5- (3-methoxybenzyl) - 4-oxo-imidazo [1,5-a] quinoxaline, m.p. 188-190 ° C by benzylation with m-methoxybenzyl chloride. Recrystallization from toluene (Compound 30) 3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -5- (2-ethoxyethyl) 4,5-dihydro-4-oxo-imidazo [1,2] 5-a] quinoxaline, m.p. 161-162 ° C by alkylation with 2-bromoethylethyl ether. Recrystallization from ethanol (Compound 31) 3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-4-oxo-5- (4-phthalimidobenzyl) imidazo [1,2] 5-a] quinoxaline, m.p. 195-197 ° C, conversion to crystals with m.p. 280-282 ° C by benzylation with 4- (phthalimido) benzyl chloride. Recrystallization from dichloromethane acetone, 4: 1 (Compound 32) EXAMPLE 4 5- (4-Aminobenzyl) -3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -5,5 -dihydro-4-oxo-imidazo [1,5-a] quinoxaline (Compound 33)

A mixture of 3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-4-oxo-5- (4-phthalimidobenzyl) imidazo [1,5-a] qui -10 noxaline (0.46 g, 0.87 nunol) and hydrazine (2 ml) in ethanol (25 ml) were stirred at room temperature for 1.5 hours. The precipitate was collected by filtration, washed with ethanol and dried to give the title compound, m.p. 246-248 ° C.

EXAMPLE 5 5- (4-Azidobenzyl) -3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-4-oxo-imidazo [1,5-a] quinoxaline (Compound 34) 20 -

A stirred solution of 5- (4-aminobenzyl) -3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-4-oxo-imidazo [1,5-a] Quinoxaline (0.1 g, 0.25 mmol) in trifluoroacetic acid (3 ml) at 0 ° C was added sodium nitrite (0.1 g, 1.4 mmol). After 5 min. sodium azide (0.16 g, 2.5 mmol) was added. Stirring was continued for 1 hour. Then water (20 ml) was added and the mixture was extracted twice with dichloromethane (20 ml). The combined extracts were dried over sodium sulfate and evaporated to give the title compound as a pale yellow solid, m.p. 183-184 ° C (dec.). Chromatographic purification (SiO 2) / CH 2 Cl 2 acetone 4: 1) gave crystals with m.p. 194-197 ° C (dec.).

35

Claims (11)

1. Imidazoquinoxaline Compounds, CHARACTERISTICS OF THE GENERAL FORMULA I 5 OF X (I) 10 F® tf where R1 is or CO2R 'where R? is C3-7 cycloalkyl; E 20. is methyl optionally substituted with 4-alkyl / alkoxycarbonyl, pyridyl, morpholino, C 3-7 cycloalkyl, C 2-6 alkenyl, phenalkyl, C 1-6 alkylacyl, alkoxyalkyl, alkoxy, phthalimidophenyl, benzyl or phenyl unsubstituted or substituted by halogen, C 1-6 alkyl, amino, azido or C 1-6 alkoxy; and R is H, C ^gg alkyl, halogen or CFg. 2. A compound according to claim 1, characterized in that it is 5-benzyl-3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-4-oxo- imidazo [l, 5-a] quinoxaline. A compound according to claim 1, characterized in that it is 3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-5-methyl-4-oxo-6- trifluoromethyl-imidazo [1,5-a] quinoxaline. DK 161022 B 4. A compound according to claim 1, characterized in that it is 5-cyclopropylmethyl-3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-4-oxo-imidazo [1 , 5-a] quinoxaline. A compound according to claim 1, characterized in that it is 3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-5- (3,3-dimethylallyl) 4-oxoimidazo [1,5-a] quinoxaline. A compound according to claim 1, characterized in that it is 3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl) -4,5-dihydro-5- (4-methoxybenzyl) -4- oxoimidazo [1,5-a] quinoxaline. A pharmaceutical composition, characterized in that it contains an imidazoquinoxaline compound according to claims 1-6 and 15, a pharmaceutically acceptable carrier or diluent. Pharmaceutical composition according to claim 7, characterized in that it is in the form of an oral dosage unit containing 1-100 20 mg of the active compound. 9. A pharmaceutical composition suitable for use in the treatment of diseases of the central nervous system, characterized in that it contains an amount of a compound according to claims 25 to 6 which is effective for the relief of such a disease, together with a pharmaceutically acceptable carrier. or diluent. Use of an imidazoquinoxaline compound according to claims 1 to 6 for the preparation of a pharmaceutical composition for the treatment of diseases of the central nervous system. A process for preparing a compound according to claims 1-6, characterized in, a) reacting a compound of formula XI or tf V wherein R3 and R® have the meanings specified in claim 1, and wherein Y is a leaving group having a compound of formula III CN - CH 2 - R 3 (1 H) 3 wherein R is as defined in claim 1 to form a compound of the invention, or b) reacting a reactive derivative of a compound of the general formula IV (III) 1 (IV) wherein R 3 and R 3 have the meanings given in claim 1, with a compound of the general formula V R 1 - C (= NOH) NH 2 (V) where R 'has the as defined in claim 1, to form a compound of general formula I wherein R is -ζχ * wherein R 'is as defined above. DK 161022B Process according to claim 11, characterized in that the reaction according to step a) is carried out under alkaline conditions. 5 10 15 20 25 30 35