CA2155355A1 - Heterocyclic compounds and their preparation and use - Google Patents

Abstract

Novel 9H-indeno[1,2-b]pyrazin-3(4H)ones and 9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-diones or tautomeric forms thereof which are useful in the treatment of neurological and psychiatric diseases.

Description

~ WO 94/18175 215 5 3 ~ ~ PCT/DK94/00050 Heterocyclic Compounds and Their Preparation and Use The present invention relates to therapeutically active 9H-indeno[1,2-b]-pyrazin-3(4H)-one and 9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione deriva-tives or tautomeric forms thereof, a method of preparing the same, pharma-ceutical compositions comprising the compollnds, and a method of treating therewith.

Interaction with glutamic acid mediated neurotransmission is considered a useful approach in the treatment of neurological and psychiatric diseases.
Thus, known antagonists of excitatory amino acids have shown potent anti-epileptic and muscle relaxant properties (A. Jones et al., Neurosci. Lett. 53, 321 (1985)) as well as anxiolytic activity (D.A. Bennett et al., Life Sci. 39, 2355 (1986)).

It has been suggested that accumulation of extracellular excitatory and neurotoxic amino acids, followed by hyperstirnulation of neurons, may explain the neuronal degenerations seen in neurological diseases as 25 Huntingtons chorea, Parkinsonism, epilepsy, senile dementia, and defi-ciencies of mental and motoric performance seen after conditions of brain ischemia, anoxia and hypoglycemia (E.G. Mc~eer et al., Nature, 263, 517 (1976) and R. Simon et al., Science, 226, 850 (1984)).

30 Excitatory amino acids exert their actions via specific receptors located postsynaptically or presynaptically. Such receptors are at present conveni-ently subdivided into four groups based on electrophysiological and neuro-WO 94/18175 ~Çj53'j~ PCT/DK94/00050 ~

chemical evidence: AMPA, metabotropic, kainate and NMDA receptors. L-glutamic acid and aspartic acid probably activate all the above types of excitatory amino acid receptors and possibly other types as well.

5 It was recently found that glycine was essential for NMDA receptor agonist induced responses in cultured neurons (J.W. Johnson et al., Nature 325, 529 (1987)). In contrast to glycine activated chloride conductance in spinal cord neurons, this response was insensitive to strychnine (D.W. Bonhaus et al., European J. Pharmacol. 142, 489 (1987)).
Glycine is believed to potentiate NMDA action through a modulatory siteallosterically coupled to the NMDA ionophore complex (T. Honoré et al., European J. Pharmacol. 172, 239 (1989)). D-serine and D-alanine exert a strong agonist activity on this site (J.B. Monahan et al., J. Neurochem. 53, 370 (1989)), whereas 1 -amino-cyclopropanecarboxylate (P. Skolnick et al., Life Sci. 45, 1647 (1989), V. Nadler et al., European J. Pharmacol. 157, 115 (1988), R. Trullas et al., Pharmacol. Biochem. Behav., 34, 313 (1989)) and D-cycloserine (W.F. Hood et al., Neurosci. Lett. 98, 91 (1989)) act as partial agonists.
1-amino-cyclobutanecarboxylate (W.F. Hood et al., European J. Pharmacol.
161, 281 (1989)), 1-amino-cyclopentanecarboxylate (L.D. Snell et al., Euro-pean J. Pharmacol. 151, 165 (1988)), 3-amino-1-hydroxy-2-pyrrolidone (HA-966) (E.J. Fletcher et al., European J. Pharmacol. 151, 161 (1988)), 5-chloro-indole-2-carboxylate (J.E. Huettner, Science 243, 1611 (1989)) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (R.A.J. Lester et al., Mol. Phar-macol. 35, 565 (1989)) are all weak antagonists, whereas 7-chloro-kynurenic acid (7-CI-Kyn) (R. Sircar et al., Brain Res. 504, 325 t1989)) and 6,7-di-chloro-3-hydroxy-quinoxaline-2-carboxylate (M. Kessler et al., Brain Res.
489, 377 (1989)) are quite strong antagonists of glycine at the glycine site.
However, all of the above reported compounds act nonselectively at this ~ wo 94/18175 2 I 5 ~ PCT/DK94/000~0 site in so far as they have higher or equal affinity for other targets.

We have now discovered novel 9H-indeno[1,2-b]pyrazin-3(4H)-one and 9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione deri~/atives which are potent and 5 selective antagonists at the glycine binding site on the NMDA receptor complex.

The present invention accordingly provides compounds of formula (I) or tautomeric forms thereof selected from the group consisting of or ~5 R7 (1) wherein R1, R2, R3 and R4 independently represent hydrogen, halogen, C, 6-alkyl or C1 6-alkoxy; and R5 represents hydrogen, hydroxy, halogen, cyano, C, 6-alkyl optionally 20 substituted with hydroxy, Cl 6-alkoxy optionally substituted with one or two phenyl group(s) which phenyl group(s) is/are optionally substituted with halogen, C, 6-(alkoxyalkoxy), C, 6-thioalkyl optionally substituted with an amino group which amino group is optionally mono or disubstituted with C, 6-alkyl, C, 6-acyloxy, phosphono, C, 6-alkoxy disubstituted phosphonyl or 25 a 5 or 6 membered heterocyclic group containing one or two N or O
atom(s) or a combination thereof which heterocyclic group is optionally substituted with C, 6-alkyl which alkyl group is optionally substituted by hydroxy or which heterocyclic group is optionally substituted with one or two phenyl group(s) which phenyl group(s) is/are optionally substituted with 30 methoxy; and R6 represents hydrogen, C, 6-alkyl or phenyl, or WO 94118175 ', i2 ~ ~ 5 ~ 5 ~ PCT/DK94/00050 ~

R5 and R6 together represent a carbonyl group, a hydroxyimino group or a benzyloxyimino group, or R5 and R6 together form a 5 or 6 membered heterocyclic group containing one or two N, O, S or S(O)z atom(s) or a combination thereof, wherein z is 5 1 or 2, which heterocyclic group is optionally substituted with one or two methyl group(s), hydroxymethyl, piperidinomethyl or (4-methyl-1-piperazi-nyl)methyl; and R7 represents hydrogen, phenyl or -CH2OR8 wherein R3 is hydrogen or benzyl, or a pharmaceutically acceptable salt thereof.
These salts include pharmaceutically acceptable acid addition salts, phar-maceutically acceptable metal salts or optionally alkylated ammonium salts, such as hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, triflu-oroacetic, trichloroacetic, oxalic, maleic, pyruvic, malonic, succinic, citric, 15 mandelic, benzoic, cinnamic, methanesulfonic, ethane sulfonic, picric and the like, and include acids related to the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977) and incorporated herein by reference, or lithium, sodium, potassium, magnesium and the like.

20 The invention also relates to methods of preparing the novel 9H-indeno[1,2-b]pyrazin-3(4H)-one and 9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione derivatives. These methods involves reacting commercially available inter-mediates or intermediates prepared by standard procedures of formula (Il) ~<OH (Il) R
wherein R~, R2, R3 and R4 have the meanings as defined for formula (I) with 30 a compound of formula (Ill) ~Wo 94/18175 21 ~ ~3$~ PCT/DK94/00050 2 ~ (111) wherein R7 has the meaning as defined for formula (I), to form a compound of formula (IV) 0 "~_ N/>--R 7 ( IV) wherein R1, R2, R3, R4 and R7 have the meanings as defined for formula (I).

15 Oxidizing a compound of formula (IV) wherein R', R2, R3 and R4 have the meanings as defined for formula (I) and R7 is hydrogen with, e.g. hydrogen peroxide, in a mixture of acetic acid and acetic anhydride to form a com-pound of formula (V) 3,~ NH - (V) 25 wherein R', R2, R3 and R4 have the meanings set forth above.

Reacting a compound of formula (V) with hydroxylamine or O-benzyl-hydroxylamine to form a compound of formula (Vl) R2~\~ 0 3J~ NH (Vl) R

WO 94/18175 2155355 PCT/DK94/00050 ~

wherein R', R2, R3 and R4 have the meanings set forth above and R9 represents hydrogen or benzyl.
Reducing a compound of formula (V) with, e.g. sodium borohydride, to form a compound of formula (Vll) 3,~= (Vll) R OH
wherein R1, R2, R3 and R4 have the meanings set forth above.

15 Reacting a compound of formula (Vll) with a halogenating agent, e.g.
thionyl chloride or thionyl bromide, to form a compound of formula (Vlll) ~ (Vlll) wherein R1, R2, R3 and R4 have the meanings set forth above and Y is halogen.

25 Reacting a compound of formula (Vlll) with R10-COOH, wherein R10 is alkyl, to form a compound of formula (IX) R3~ N~= (IX) R o a~

~ WO 94/~8~75 ~ ~S PCT/D1~94/OnOSO

wherein R', R2, R3, R4 and R~ have the meanings set forth above.

Reacting a compound of formula (Vlll) or a compound of formula (Vll) with an alcohol R11-OH, wherein R11 represents alkyl optionally substituted with 5 one or two phenyl group(s) which phenyl group(s) is/are optionally substi-tuted with halogen or alkoxyalkyl, e.g. ethyl, 3,3-diphenylpropyl, 2,2-(4-chlorophenyl)ethyl or 2-methoxyethyl, to form a compound of formula (X) 3~ N~= (X) R4 O~Rll wherein R', R2, R3, R4 and R" have the meanings set forth above.

15 Reacting a compound of formula (IV) with 1,3 or 1 ,2-diols, which may be substituted with one or two lower alkyl groupl's) in an inert solvent such as benzene or toluene in the presence of an acicl catalyst to form a compound of formula (Xl) or (Xll) ~R7 R4 ~R13 R4 ~R13 (Xl) R (Xll) wherein R', R2, R3, R4 and R7 have the meanings as defined for formula (I) and R12 and R'3 represent an alkyl group, e.g. methyl.

Oxidizing a compound of formula (Xll) wherein R7 is hydrogen with, e.g.
30 hydrogen peroxide, in a mixture of acetic acicl and acetic anhydride to form a compound of formula (Xlll) WO 94/18175 ' 21SS35 PCT/DK94/000~0 ~

~0 (Xlll) R ~,~R13 ,R12 wherein R' R2 R3 R4 R12 and R13 have the meanings as defined for formula (Xll).

10 Reacting a compound of formula (Vlll) with an amine HN~x wherein X is oxygen or N-R14, wherein R14 represents hydrogen or an alkyl group, e.g.
methyl, or a substituted alkyl group, e.g. 2-hydroxyethyl, diphenylmethyl or a phenyl group which is optionally substituted with methoxy, e.g. 2-methoxyphenyl, in a suitable solvent such as tetrahydrofuran to form a 15 compound of formula (XIV) 0 ~ (XIV) ~x wherein R1, R2, R3 and R4 have the meanings as defined for formula (I) and X and N-R14 have the meanings defined above.

Reacting a compound of formula (Vlll) with an alkylphosphite to form a 25 compound of formula (XV) ~ (XV) R15 0 ~R15 wherein R1, R2, R3 and R4 have the meanings set forth above and R15 is ~ WO 94/18175 ,~ PCT/oK94/~oo50 methyl or ethyl.

Reacting a compound of formula (X\/) with bromotrimethylsilane in acetonitrile to form a compound of formula (XVI) - R~_ N~O (XVI) 4 p-O
R HO' ~
OH

wherein R1, R2, R3 and R4 have the meanings set forth above.

Reacting a compound of formula (V) with 1,3 or 1,2-dithiols which may be substituted with one or two lower alkyl grou,:)(s) in an inert solvent such as 15 toluene in the presence of boron trifluoride etherate to form a compound of formula (XVII) or (XVIII) ~ ~3 (XVII) (XVIII) wherein R', R2, R3, R4, R12 and R'3 have the meanings set forth above.

Oxidizing a compound of formula (XVII) with, e.g. hydrogen peroxide, in a mixture of acetic acid and acetic anhydride to form a compound of formula (XIX) 5 ~,~ PCT/DK94/00050 '~$~ (XIX) R ~,S ~ Rl 3 ()a 12 wherein R1, R2, R3, R4, R12 and R'3 have the meanings set forth above and a and b independentiy are 0, 1 or 2, provided that a and b are not 0 at the same time.

10 Reacting a compound of formula (Vll) with alkylthiol or 2-aminoalkylthiol optionally substituted in the amino group with lower alkyl in acetic acid in the presence of boron trifluoride etherate to form a compound of formula ~NH (Xx) R4 S ~R16 wherein R1, R2, R3 and R4 have the meanings set forth above and R16 is thioalkyl optionally substituted with an amino group which amino group is 20 optionally mono or disubstituted with alkyl.

Silylating a compound of formula (IV) with, e.g. trimethylsilyl chloride and triethylamine, in a suitable solvent such as tetrahydrofuran and thereafter, reacting with alkyl or phenylmagnesium bromide and subsequent hydrolysis 25 to form a compound of formula (X)(l) R 4 HO (XXl) 30 wherein R', R2, R3, R4 and R7 have the meanings as defined for formula (I) and R'7 is alkyl or phenyl.

WO 94/18175 45~ PCT/DK94/00050 Reacting a compound of formula (XXI) with a mixture of R'-COOH, (R10-CO)20 and hydrogen peroxide to form a compound of formula (XXII) 3~R ~ R (XXll) 0//~R 1 0 wherein Rl, R2, R3, R4 and R7 have the meanings as defined for formula (I) 10 and R10 and R~7 have the meanings set forth above.

Silylating a compound of formula (V) with, e.g. trimethylsilyl chloride and triethylamine, in a suitable solvent such as tetrahydrofuran and thereafter reacting with alkyl or phenylmagnesium bromide and subsequent hydrolysis 15 to form a compound of formula (XXIII) 3~1N7~- (XXIII) L~
wherein R', R2, R3 and R4 have the meanings as defined for formula (I) and R17 has the meaning set forth above.

Reacting a compound of formula (XXIII) with an alcohol R'3-oH wherein R13 25 iS alkyl to form a compound of formula (XXIV) R3~=~NH~ (XXIV) ~--\ HN
R /\ 17 WO 94/18175 215 ~ ~ 5 5 PCTtDK94/00050 ~

wherein R', R2, R3 and R4 have the meanings as defined for formula (I) and R17 and R13 have the meanings set forth above.

The compounds according to the invention were tested as regards the 5 affinity for one or more of the different types of excitatory amino acid receptors and studied in simple radioligand binding experiments. In essence, the method involves incubation of a particular selected radio-labelled ligand and the particular specific substance to be investigated with brain homogenates which contain the receptor. Measurement of receptor 10 occupancy is made by determination of the specific radioactivity bound to the homogenate.

It has now been found that the heterocyclic compounds of the invention have affinity for the glycine site of the NMDA receptor complex and are 15 antagonists in connection with this type of receptors. This will make them useful in the treatment of any of the numerous indications caused by hyperactivity of excitatory amino acids.

The glycine site binding activity of these compounds of the present inven-20 tion can be illustrated by determining their capability for displacing radioac-tively labelled glycine from the glycine site.

The displacement activity of the compounds may be shown by determining the IC50 value which represents the concentration (,uM) which causes a 25 displacement of 50% of the specific binding of [3H]-glycine.

In summary, the influence of glutamic acid analogues on secondary effects of glutamate receptor interactions, such as on ligand-gated channel open-ing and G-protein mediated signal transduction, may be studied in vitro 30 using brain slices, brain homogenates or clonal lines expressing glutamate receptor subtypes. Such experiments will provide information as to the ~ WO 94/18175 ,~ PCT/DK94/00050 ~S

efficacies (agonist/ antagonist) of the test substances.

The glycine antagonistic properties of the colmpounds are demonstrated by their capability to counteract convulsions induced by i.c.v. infusion of NMDA. The glycine antagonists are co-infused with NMDA and their anti-convulsive effect is measured by determiningl a) the TV50 value which represents the dose (,ug/kg) of the glycine antagonist that has to be infused per minute in order to increase time to onset of clonic seizures by 50%, b) the ED50 value which represents the dose (,ug/kg) of the glycine antagonist that has to be infused per minute in order to protect 50% of the animals against clonic seizures for 150 seconds after the start of i.c.v. infusion.

In vitro [3H]-Glycine Binding to Rat Brain Mernbranes (Test 1) The membrane preparation and assay of specific [3H]-glycine binding is based upon methodology described by Haring et al. (1991) J. Neurochem.
57, 323-332 and Yoneda et al. (1991) J. Neurochem. 55, 237-244.

All steps are performed at 4C. Buffers are prepared fresh each week from distilled, deionized water and filtered through sterile 0.2 ,~lm membranes to eliminate artifacts due to microbial contamination. Crude synaptic (P2) membranes are prepared from rat forebrains freshly dissected from male Wistar rats and washed 4 times with low ionic strength buffer. On the day of the assay these preparations are additionally washed with buffer containing a low concentration (0.08% 9/9) of Triton X-100, and then twice more in the absence of this detergent. The procedure is aimed at the disruption of synaptic membrane vesicles and removal of endogenous amino acids.

Specific radioligand binding is measured by incubating membranes (400-600 ,ug/ml of protein) with 50nM [3H]-glycine in the presence or absence of 1mM of unlabelled glycine at 4C for 30 min. Free and bound ligand are wo 94/l8175 5 - 14 - PCT/DK94/0005 separated by centrifugation. Each pellet is rinsed 2X and bound radioactiv-ity measured by liquid sc;, ILillaliGl ~ counting. Test substances are substituted for unlabelled glycine in the assay.
5 Convulsions induced by i.c.v. infusion of NMDA (Test 2 & 3) 58.84 ~g/ml (1 nmol in 2.5 ,~LI) of NMDA (Sigma) dissolved in 0.9% NaCI is - co-infused i.c.v. with a glycine antagonist at a speed of 5 ,LI/min. Infusion is performed through a cannula placed 1 mm posterior and 1 mm lateral to 10 the Bregma point. The cannula is injected 4.3 mm into the skull of male NMRI mice weighing 25 9 (range 23-27 9). Placement and length of the cannula into the skull is fixed by a plate positioned 4.3 mm from the point of the cannula. The infusion is stopped after the appearance of clonic seizures in all extremities or 150 seconds after the start time of the infusion. At least15 5 doses of each glycine antagonist are tested using 8 mice per dose.

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

Compound Test 1 Test 2 Test 3 of lCso IlM TV50 ED50 Example (~g/kg) (~lg/kg) 2 0.92 44 170 6 3.7 11 0.92 5.0 18 0.15 4.5 7.0 The compounds of the invention, together with a conventional adjuvant, ~WO 94/18175 ~ s PCT/DK94/00050 carrier, or diluent, and if desired in the form of a pharmaceutically accept-able salt thereof, may be placed into the form of pharmaceutical composi-tions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or lil~uids, such as solutions, 5 suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal admini~lraLiull; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without addi-10 tional active compounds or principles, and such unit dosage forms maycontain any suitable effective central nervous system ailment alleviating amount of the active ingredient commensurate with the intended daily dosage range to be employed. Tablets containing one (1) to two hundred (200) milligrams, per tablet, are accordingly suitable representative unit 15 dosage forms.

The compounds of this invention can thus be used for the formulation of pharmaceutical preparations, e.g. for oral and parenteral administration to mammals including humans, in accordance v~,ith conventional methods of 20 galenic pharmacy.

Conventional excipients are such pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral or oral application which do not deleteriously react with the active compound.
Examples of such carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatin, lactose, amylose, mag-nesium stearate, talc, silicic acid, fatty acid monoglycerides and diglyce-rides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinyl-30 pyrrolidone.

WO 94/18175 PCT/DK94/00050 ~
2~3~

The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or =
colouring substances and the like, which do not deleteriously react with the 5 active compound.

For parenteral ~prlic~tion, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
Ampoules are convenient unit dosage forms.

For oral application, particularly suitable are tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like, the carrier 15 preferably being lactose and/or corn starch and/or potato starch. A syrup, elixir or like can be used when a sweetened vehicle can be employed.
Generally, as to broader ranges, the compounds of the invention are dispensed in unit dosage form comprising 0.05-100 mg in a pharmaceuti-cally acceptable carrier per unit dosage.
A typical tablet which may be prepared by conventional tabletting tech-niques contains:

Active compound 2.0 mg Lactosum 67.8 mg Ph.Eur.
Avicel~ 31.4 mg Amberlite~ IRP 88 1.0 mg Magnesii stearas 0.25 mg Ph.Eur.

30 Due to their high degree of effect as glycine antagonists, the compounds of the invention are extremely useful in the treatment of central nervous system ~W094/18175 41~s E'CT/DK91/00050 ailments or disorders, when administered in an amount effective for the alleviation, amelioration, or elimination thereaf. The important CNS activity ofthe compounds of the invention includes bolh anticonvulsant, hypnotic, nootropic, anxiolytic and antipsychotic activities along with a low toxicity, 5 together presenting a most favourable therapeutic index. The compounds of the invention may accordingly be a-i",i"islered to a subject, e.g. a living mammal body, including a human, in need c,f the same for the treatment, alleviation, amelioration, or elimination of an indication, associated with the central nervous system and the so-called Nl\lDA receptors, which requires 10 such psychopharmaceutical treatment, e.g. especially convulsion, anxiety, epilepsy and ischemia, if desired in the form of a pharmaceutically accept-able salt thereof, ordinarily concurrently, simultaneously, or together with a pharmaceutically acceptable carrier or diluent, especially and preferably in the form of a pharmaceutical composition thereof, whether by oral, rectal, or 15 parenteral (including subcutaneous) route, in an effective psychopharma-ceutical central nervous system ailment alleviating amount, e.g. an anticonvulsant and/or anxiolytic amount, and in any event an amount which is effective for the alleviation of such a central nervous system ailment due to their NMDA receptor affinity. Suitable dosage ranges are 1-200 milligrams 20 daily, depending as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body vveight of the subject involved, and the preference and experience of the physician or veterinarian in charge.
The route of adminisll~lion may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral or parenteral e.g. rectal, transdermal, subcutaneous, intravenous, intramuscular or intranasal, the oral route being preferred.
The invention will now be described in further detail with reference to the --WO 94/18175 21$5- 3 5 ~ PCT/DK94/00050~

following examples.

WO 94/18175 ~ PCT/DK94tO0050 3Ss EXAMPLE l 9H-lndeno[1 ,2-b]pyrazine-3,9(4H)-dione A suspension of glycinamide, HCI (18.6 9, 168 mmol) in 500 ml of methanol was added to a solution of ninhydrin (30 g, 168 mmol) in 200 ml of meth-anol at -40C under stirring. After 20 min. a solution of sodium hydroxide (12 ml, 10 N) was added dropwise at -40C to -30C over 25 min. and the temperature was slowly raised to -10C while stirring. After 2 hours a solution of sodium hydroxide (4 ml, 10 N) was added dropwise and the mixture was stirred at -16C for 18 hours, then hydrochloric acid (360 ml, 1 N) was added over 1.5 hours at -15C and the temperature was raised gradually to room temperature and stirred for 4 hours. The yellow precipi-tate was filtered off, washed with water and dried to give 24 g (72%) of the title compound. M.p. >300C. ~H-NMR (DMSO-d6, ~): 7.5-7.61 (m, 2H), 7.65 (t, 1H), 7.78 (d, 1H), 7.87 (s, 1H), 13.8 (s, 1H).

Analysis: Calculated for C"H6N2O2:
C, 66.67; H, 3.05; N, 14.14%. Found:
C, 66.88; H, 3.07; N, 14.51%.

EXAMPLE .' 9H-lndeno [1 ,2-b] pyrazine-2,3,9(1 H,4H)-trione 9H-lndeno[1,2-b]pyrazine-3,9(4H)-dione (20 g, 100.9 mmol), recrystallized from acetic acid, was suspended in a mixture of 135 ml acetic acid and 135 ml acetic anhydride and hydrogen peroxide (9.8 ml, 35%) was added. After stirring overnight another portion (9.8 ml, 35%) of hydrogen peroxide was added. This was repeated five times over a week. The red precipitate was WO 94/18175 2 ~ 5 5 ~ ~ ~ PCT/DK94/00050~

filtered off, washed with acetic acid and water and dried to give 18.5 9 (79.6%) of the title compound. which could be further purified by dissolving in aqueous sodium hydroxide and precipitation by hydrochloric acid. M.p.
>300C.1H-NMR (DMSO-d6, ~): 7.15-7.45 (m, 4H), 12 (s, 1H), 12.8 (s, 1H).
Analysis: Calculated for C"H6N2O3. 0.9 H2O:
C, 57.35; H, 3.41; N, 12.16%. Found:
C, 57.40; H, 3.44; N, 12.20%.

9-Hydroxyimino-9H-indeno[1,2-b]pyrazin-3(4H)-one A mixture of 9H-indeno[1,2-b]pyrazine-3,9(4H)-dione (1.0 9, 5.0 mmol), pyridine (40 ml) and hydroxylamine hydrochloride (0.42 g, 6.0 mmol) was stirred at 80C for 18 hours. The reaction mixture was cooled to room tem-perature, and the precipitate was filtered off and washed with water, acetic acid and water and dried. The crude material (0.81 9) was recrystallized from DMF to afford 0.52 9 (49%) of the titie compound. M.p. >300C. 'H-NMR (DMSO-d6, ~): 7.49-7.62 (m, 2H), 7.88 (d, 1H), 7.95 (s, 1H), 8.36 (d, 1H), 12.5-13.2 (broad, 1H), 12.83 (s, 1H).

Analysis: Calculated for C1,H7N3O2:
C, 61.97; H, 3.31; N, 19.71%. Found:
C, 62.29; H, 3.26; N, 19.44%.

(E)- and (Z)-9-Hydroxyimino-9H-indeno[1,2-b]pyrazine-2,3(1 H,4H)-dione A mixture of 9H-indeno[1,2-b]pyrazine-2,3,9(1H,4H)-trione,1H2O (0.80 g, ~WO 94/18175 ~ PCT/DK94/00050 3S~

3.46 mmol), pyridine (20 ml)and hydroxylamine hydrochloride (0.39 g, 5.6 mmol) was stirred at 70C for 3 hours. The reaction mixture was cooled to room temperature, and the precipitate was filtered off and washed with pyridine, 50% acetic acid and water and dried to give 0.41 g (51.7%) of the (E)-isomer of the title compound. M.p. >300C. ~H-NMR (DMSO-d6, ~): 7.18 (t, 1H), 7.35 (t, 1H), 7.5 (d, 1H), 8.04 (d, 1H), 12.05 (s, 1H), 12.42 (s, 1H), 12.72 (s, 1H).

The mother liquor was evaporated in vacuo to dryness and 30 ml of 50%
acetic acid was added to give 0.344 g of a mixture of (E)- and (Z)-isomers.
From the filtrate it was possible by concentration to isolate 15 mg of the (Z)-isomer of the title compound. M.p. >300C. 1H-NMR (DMSO-d6, ~): 7.2 (t, 1H), 7.33 (t, 1H), 7.54 (d, 1H), 7.57 (d, 1H), 10.92 (s, 1H), 12.63 (s, 2H).

(E)- and (Z)-9-Benzyloxyimino-9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione A mixture of 9H-indeno[1,2-b]pyrazine-2,3,9(1H,4H)-trione.1H20 (1.0 g, 4.31 mmol), pyridine (30 ml) and O-benzylhydro:~ylamine hydrochloride (0.745 g, 4.67 mmol) was stirred at 80C for 18 hours. The reaction mixture was cooled to room temperature, and the precipitate was filtered off and washed with water, 50% acetic acid, water and dried to give 0.35 g (25.4%) as a mixture of (Z)- and (E)-isomers of the title compound containing (NMR) 67% of the (Z)-isomer and 33% of the (E)-isomer. M.p. >300C. 'H-NMR, (Z)-isomer, (DMSO-d6, ~): 5.33 (s, 2H), 7.2 (t, 1H), 7.29-7.58 (m, 8H), 11.32 (s, 1H), 12.69 (s, 1H).

Analysis: Calculated for C,8H,3N3O3:
C, 67.71; H, 4.10; N, 13.16%. Found:
C, 67.38; H, 4.04; N, 12.93%.

2~53~ --From the mother liquor another crop was filtered off. After suspension in 20 ml of 50% acetic acid the precipitate was filtered off, washed with water and dried to give 0.88 9 (64%) of the title comPound containing 7% of the (Z)-isomer and 93% of the (E)-isomer. M.p. ~ 300C. 'H-NMR, (E)-isomer, (DMSO-d6, ~):5.39 (S, 2H), 7.17 (t, 1H), 7.3 - 7.56 (m, 7H), 7.9 (d, 1H), 12.05 (s, 1H), 12.45 (s, lH).

9H-lndeno[1,2-b]pyrazine-3,9(4H)-dione 9-ethylene acetal A suspension of 9H-indeno[1,2-b]pyrazine-3,9(4H)-dione (1.0 9, 5.05 mmol) in ethylene glycol (10 ml), toluene (20 ml) and p-toluenesulfonic acid (20 mg) was refluxed with water separation for 18 hours. The reaction mixture was cooled to room temperature, ethanol (5 ml) was added and the precipi-tate was filtered off and washed with ethanol and dried to give 1.014 g (83%) of the titie compound. M.p. 296-298C.1H-NMR (DMSO-d6, ~): 4.3-4.42 (m, 4H), 7.43-7.6 (m, 3H), 7.75 (d, 1H), 7.88 (s, 1H), 12.7 (s, 1H).
Analysis: Calculated for C13H10N2O3:
C, 64.46; H, 4.16; N, 11.56%. Found:
C, 64.62; H, 4.09; N, 11.35%.

9H-lndeno[1,2-b]pyrazine-2,3,9(1H,4H)-trione 9-ethylene acetal A suspension of 9H-indeno[1,2-b]pyrazine-3,9(4H)-dione 9-ethylene acetal (4.0 g, 16.51 mmol) in a mixture of 30 ml of acetic acid and 30 ml of acetic anhydride and hydrogen peroxide (1.6 ml, 35%) was stirred overnight. Then another portion (1.6 ml, 35%) of hydrogen peroxide was added and stirring was continued overnight. That was repeated seven times over nine days.

~ WO 94/18175 SS PCT/DK94/00050 ~S

After five days another portion (20 ml) of acetic anhydride was added. The precipitate was filtered off, washed with acetic acid and water and dried to give 1.57 g of the crude product, which was purified by suspension in a mixture of 1250 ml ethanol and 150 ml water, filtrated and dried to yield 0.728 g (17%) of the title comPound. M.p. 296-301C. 1H-NMR (DMSO-d6, ~): 4.25 (m, 2H), 4.32 (m, 2H), 7.12 (t, 1H), 7.28 (t, 1H), 7.33 (d, 1H), 7.41 (d, 1H), 12.0 (s, 1H), 12.3 (s, 1H).

Analysis: Calculated for: C~3H10N204:
C, 60.47; H, 3.90; N, 10.85%. Found:
C, 60.31; H, 3.89; N, 10.43%.

9H-lndeno[1,2-b]pyrazine-3,9(4H)-dione 9-(2,2-dimethylpropylene) acetal A suspension of 9H-indeno[1,2-b]pyrazine-3,9(4H)-dione (3.0 g, 15.14 mmol) in toluene (50 ml), 2,2-dimethyl-1,3-prcpanediol (10 g) and p-toluene-sulfonic acid (30 mg) was refluxed with water separation for 140 hours. The reaction mixture was cooled to ambient temperature and ethanol (50 ml) was added. The precipitate was filtered off and washed with ethanol to give 3.68 g of the crude product, which was recry;tallized from tetrahydrofuran to yield 2.34 g (54.4%) of the title compound. M.p. 281-283C. 'H-NMR
(DMSO-d6, ~): 0.9 (s, 3H), 1.39 (s, 3H), 3.58 ~d, 2H), 4.57 (d, 2H), 7.5 (m, 2H), 7.63 (m, 1H), 7.73 (m, 1H), 7.89 (s, 1H), 12.4 (broad s, 1H).

Analysis: Calculated for C16H,6N2O3:
C, 67.59; H, 5.67; N, 9.85%. Found:
C, 68.01; H, 5.74; N, 9.58%.

By concentration of the filtrate another crop 0.76 g (17.7%) of the title -WO 94/18175 2 ~ S S 3 ~ ~ PCT/DK94/00050~

compound was isolated.

9H-lndeno[1,2-b] pyrazine-3,9(4H)-dione 9-(1,2-dimethylethylene) acetal A suspension of 9H-indeno[1,2-b]pyrazine-3,9(4H)-dione (2.0 9, 10.09 mmol) in toluene (50 ml), 2,3-butanediol (20 ml) and p-toluenesulfonic acid (40 mg) was refluxed with water separation for 20 hours. The reaction mixture was evaporated In vacuo to dryness and another portion of toluene, 2,3-butanediol and p-toluenesulfonic acid was added and the mixture was refluxed again for 20 hours. After evaporation to dryness, the residue was suspended in ethanol (10 ml) and the precipitate was filtered off and washed with ethanol and dried to give 2.14 g (78.5%) of the title compound as a mixture of isomers. 'H-NMR (DMSO-d6, ~): 1.24-1.4 (m, 6H), 4.03-4.87 (m, 2H), 7.42-7.91 (m, 5H), 12.6 (s, 1H).

9H-lndeno[1,2-b]pyrazine-2,3,9(1H,4H)-trione 9-(1,2-dimethylethylene) acetal 9H-lndeno[1,2-b]pyrazine-3,9(4H)-dione 9-(1,2-dimethylethylene) acetal (1.0 g, 3.7 mmol) was suspended in a mixture of 5 ml of acetic acid and 5 ml of acetic anhydride and hydrogen peroxide (0.50 ml, 30%) was added. After stirring overnight, another portion of hydrogen peroxide (0.20 ml, 30%) was added and the mixture was stirred for 20 hours. The precipitate was filtered off and washed with acetic acid and water to give 0.236 9 of crude product, which was recrystallized from ethanol to yield 119 mg (11 %) of the titie compound, as a mixture of isomers.1H-NMR (DMS0-d6, ~): 1.2-1.4 (m, 6H), 4.3-4.8 (m, 2H), 7.12 (m, 1H), 7.27 (t, 1H), 7.34-7.48 (m, 2H), 11.83, 12.05 (2 x s, t H), 12.3 (s, 1 H).

9-Hydroxy-9H-indeno[1,2-b]pyrazine-2,3(1 H,~H)-dione To a stirred suspension of 9H-indeno[1,2-b]pyrazine-2,3,9(1 H,4H)-trione.-1 H2O (5.0 g, 21.5 mmol) in 200 ml of ethanol and 30 ml of water was added sodium borohydride (1.76 g, 46.5 mmol) in fl~ur portions over 2 hours, then 200 ml of water was added and the mixture ~lvas stirred for 18 hours at 10 room temperature. The reaction mixture was acidified with hydrochloric acid (70 ml, 1 N) to pH 1.5 and the precipitate was filtered off, washed with water and dried to give 4.59 g (91%) of the title compound. M.p. >300C. 1H-NMR
(DMSO-d6, ~): 5.1 (d, 1H), 5.72 (d, 1H), 7.15 (t, 1H), 7.28 (t, 1H), 7.41 (d, 1H), 7.48 (d, 1H), 12.0 (s, 1H), 12.25 (s, 1H).
Analysis: Caiculated for C1~H8N2O3 1 H2O
C, 56.41; H, 4.30; N, 11.96%. Found:
C, 56.43; H, 4.35; N, 11.91%.

9-Hydroxy-9H-indeno[1,2-b]pyrazin-3(4H)-on~s 9H-lndeno[1,2-b]pyrazine-3,9(4H)-dione (5.0 g, 25.23 mmol) was reduced with sodium borohydride (1.72 g, 45.5 mmol~ as described in example 11.
Yield 5.29 g (96%) of the title compound. M.p. 251-253C. 1H-NMR (DMSO-d6, ~): 5.32 (d, 1H), 5.92 (d, 1H), 7.47 (m, 2H), 7.64 (m, 1H), 7.8 (m, 1H), 7.9 (s, 1H), 12.5 (s, 1H).
Analysis: Calculated for C,~H8N2O2. 1 H2O:
C, 60.54; H, 4.62; N, 12.84%. Found:
C, 60.69; H, 4.70; N, 12.73%.

WO 94/18175 PCT/DK94/00050~
~3 S~

9-Chloro-9H-indeno [1,2-b] pyrazin-3(4H)-one 9-Hydroxy-9H-indeno[1,2-b]pyrazin-3(4H)-one. 1H2O (0.50 g, 2.29 mmol) was added to thionyl chloride (5 ml) under stirring. After 0.5 hours dichloro-methane (10 ml) was added and the stirring was continued for 10 min. The precipitate was isolated by filtration and washed with dichloromethane, 10 thereafter suspended in hydrochloric acid (10 ml, 0.5 N), filtrated and driedto give 0.359 g (72%) of the titie compound. M.p. >300C.1H-NMR (DMSO-d6, ~): 6.1 (s, 1H), 7.56 (m, 2H), 7.72 (m, 1H), 7.87 (m, 1H), 7.97 (s, 1H), 11.5 - 13.8 (broad s, 1 H).

Analysis: Calculated for C11 H7N20CI:
C, 60.43; H, 3.23; N, 12.81; Cl, 16.21%. Found:
C, 60.31; H, 3.26; N, 12.56; Cl, 16,07%.

9-Chloro-9H-indeno[1,2-b]pyrazine-2,3(1 H,4H)-dione 9-Hydroxy-9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione. 1H2O (3.0 g, 12.8 mmol) was suspended in 30 ml of dichloromethane under stirring. Thionyl chloride (6 ml) was added and after cooling on an ice bath, pyridine (0.6 ml) was added over 5 min. After 15 min. at 0 - 3C the temperature was elevated to room temperature and another 10 ml of dichloromethane was added. The mixture was stirred for 18 hours and the precipitate was filtered off and washed with dichloromethane to afford 2.91 g (97%) of the titie compound. M.p. >300C.1H-NMR (DMSO-d6, ~): 5.73 (s, 1H), 7.23 (t, 1H), 7.37 (t, 1H), 7.49 (d, 1H), 7.56 (d, 1H), 12.23 (s, 1H), 12.45 (s, 1H).

~'~S~

9-Acetoxy-9H-indeno[1,2-b]pyrazine-2,3(1 H,4H)-dione 9-Chloro-9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione (0.30 g, 1.28 mmol) was refluxed in 50 ml of acetic acid for 10 min. Activated carbon (100 mg) was added and the reaction mixture was filtered and evaporated in vacuo to about 3 ml, and 20 ml of water was added. The precipitate was filtered off and washed with water and dried to give 229 mg of the crude com-pound, which was recrystallized from acetic acid-water to yield 190 mg (57.5%) of the title compound. M.p. >300C. ~H-NMR (DMSO-d6, ~): 2.13 (s, 3H), 6.36 (s, 1H), 7.15 (t, 1H), 7.29 (d, 1H), 7.35 (t, 1H), 7.5 (d, 1H), 12.0 (s, 1H), 12.4 (s, 1H).
EXAMPLE 11~

9-Ethoxy-9H-indeno[1,2-b]pyrazine-2,3(1 H,4H)-dione 9-Chloro-9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione (0.50 g, 2.13 mmol) was refluxed in 25 ml dry ethanol for 7 hour;,. The mixture was evaporated to few ml and the precipitate was filtered off, washed with ethanol and dried to give 0.229 g of the crude compound, which was recrystallized from acetic acid-water to yield 0.131 g (25%) of the title compound. M.p. >300C.
'H-NMR (DMSO-d6, ~): 1.1 (t, 3H), 3.25 (dq, 1H), 3.43 (dq, 1H), 5.22 (s, 1H), 7.17 (t, 1H), 7.33 (t, 1H), 7.42 (d, 1H), f.51 (d, 1H), 12.1 (s, 1H), 12,31 (s, 1 H) .

EXAMPLE 1,' 9-Morpholino-9H-indeno[1,2-b]pyrazine-2,3(1 H,4H)-dione wos4/1sl7s ~ 2~ 5~3~ PCT/DK94/oOO~O~

9-Chloro-9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione (0.50 g, 2.13 mmol) was suspended in 5 ml of dry tetrahydrofuran, while cooling in an ice bath.
Morpholine(0.37 ml, 4.27 mmol) dissolved in 2 ml of dry tetrahydrofuran was added over 2 min. After 1 hour the ice bath was removed and stirring 5 was continued for 20 hours at room temperature. The precipitate was filtered off and washed with tetrahydrofuran, 10% acetic acid, water and dried to give 0.365 g of the crude product. Recrystallization from ethanol afforded 0.257 g (42%) of the title compound. M.p. 265-267C.1H-NMR
(DMSO-d6, ~): 2.47 (m, 2H), 2.61 (m, 2H), 3.56 (m, 4H), 4.54 (s, 1H), 7.13 (t, 1H), 7.3 (t, 1H), 7.47 (d, 1H), 7.53 (d, 1H), 11.8 (s, 1H), 12.25 (s, 1H).

9-(4-Methyl-1-piperazinyl)-9H-indeno[1,2-b]pyrazine-2,3(1 H,4H)-dione 9-Chloro-9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione (1.50 9, 6.39 mmol) was suspended in 15 ml of dry tetrahydrofuran, while cooling in an ice bath.
N-Methylpiperazine (1.42 ml, 12.78 mmol) dissolved in 3 ml of dry tetra-20 hydrofuran was added over 20 min, and the ice bath was removed andstirring was continued for 20 hours at room temperature. The precipitate was filtered off and washed with tetrahydrofuran and dried to give 2.42 g of a remanence, which was dissolved in 100 ml of boiling ethanol, and treated with 300 mg of activated carbon. The mixture was filtered and concentrated 25 to 10 ml. The precipitate was filtered off, washed with ethanol and dried to give 0.65 g of the crude product. From the filtrate another crop of 0.57 g could be isolated. Recrystallization from 6M HCI afforded 0.73 g (30%) of the titie compound as a dihydrochloride. M.p. 263-265C.1H-NMR (DMSO-d6, ~): 2.6 (m, 1H), 2.73 (s, 3H), 2.78-3.52 (m, 7H), 4.84 (s, 1H), 5.9-7.0 (broad, 2H), 7.2 (t, 1H), 7.35 (t, 1H), 7.48 (d, 1H), 7.58 (d, 1H), 10.92 (s, 1H), 11.76 (s, 1H), 12.34 (s, 1H).

WO 94/18175 ~ PCT/DK94/00050 Analysis: Calculated for: C~6H2oN4o2cl2 /2H20:
C, 50.53; H, 5.56; N, 14.73; Cl, 18.65%. Found:
C, 50.53; H, 5.51; N, 14.53; Cl, 18.34%.

9-Dimethoxyphosphonyl-9H-indeno[1,2-b]pyrazine-2,3(1 H,4H)-dione 9-Chloro-9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione (1.0 g, 4.26 mmol) and trimethyl phosphite (20 ml) were refluxed for 1 hour. The reaction mixture was evaporated in vacuo to dryness and triturated with 15 ml of methanol to give 0.355 g of the crude product. Recrys~allization twice from methanol yield 0.25 g (19%) of the title compound. M.p. 252-253C. 1H-NMR (DMSO-d6, ~): 3.46 (d, 3H), 3.7 (d, 3H), 4.6 (d, 1H), 7.23 (t, 1H), 7.4 (t, 1H), 7.56 (d, 1H), 7.66 (d, 1H), 11.6 (s, 1H), 12.48 (s, 1H).

Analysis: Calculated for C13H,3N2O5P:
C, 50.66; H, 4.25; N, 9.09%. Found:
C, 50.72; H, 4.41; N, 9.07%.

9-Diethoxyphosphonyl-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione 9-Chloro-9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione (1.0 g, 4.26 mmol) and triethyl phosphite (20 ml) was refluxed for 1 hour. The reaction mixture was evaporated in vacuo to dryness and triturated with 10 ml of ethanol to give 0.89 g of the crude product. Recrystallization from ethanol yield 0.62 g (43%) of the title compound. M.p. 248-249C ~H-NMR (DMSO-d6, ~): 1.02 (t, 3H), 1.15 (t, 3H), 3.8 (m, 1H), 3.9 (m, 1H), 4.0 (m, 2H), 4.5 (d, 1H), 7.22 (t, 1H), 7.38 (t, 1H), 7.55 (d, 1H), 7.65 (d, 1H~, 11.5 (s, 1H), 12.46 (s, 1H).

WO 94/18175 2 ~ 5 5 3 ~ ~ PCT/DK94/00050 ~

Analysis: Calculated for C,sH,7N2OsP:
C, 53.57; H, 5.10; N, 8.33%. Found:
C, 53.55; H, 5.29; N, 8.07%.

9-Phosphono-9H-indeno[1,2-b]pyrazine-2,3(1 H, 4H)-dione 9-Diethoxyphosphonyl-9H-indeno[1,2-b]pyræine-2,3(1 H, 4H)-dione (0.5 g, 1.49 mmol) was suspended in a mixture of acetonitril (30 ml) and bromo-trimethylsilane (3 ml) and stirred overnight at 40C. Then another portion of bromotrimethylsilane (3 ml) was added and stirring was continued at 50C
for seven days. The reaction mixture was evaporated in vacuo to dryness and triturated with 10 ml of ethanol to give 0.39 g of the crude product.
Purification was performed by dissolving in a mixture of 15 ml of water and 20 ml of saturated sodium hydrogen carbonate solution and precipitation with about 6 ml 6 M hydrochloric acid to pH 1Ø The yield was 0.28 g (60%) of the title compound as mono sodium salt. M.p. > 300C.1H-NMR
(D2O, ~): 4.2 (d, 1H), 7.35 (t, 1H), 7.45 (t, 1H), 7.5 (d, 1H), 7.72 (d, 1H).

Analysis: Calculated for C1,H8N2OsPNa.1/2H2O:
C, 42.46; H, 2.92; N, 9.00%. Found:
C, 42.18; H, 3.16; N, 8.72%.

2-Phenyl-9H-indeno [1,2-b] pyrazine-3,9(4H)-dione 2-Phenylglycinamide, HCI (5.22 g, 28 mmol) was reacted with ninhydrin (5.0 g, 28 mmol) following the procedure outlined in example 1. The crude product (4.73 9) was recrystallized from acetic acid to give 3.7 9 (48%) of WO 94/18175 ~ PCT/DK94/00050 the title compound. M.p. > 300C. lH-NMR ([)MSO-d6, ~): 7.45 - 7.68 (m, 6H), 7.81 (d, 1H), 8.25 (m, 2H), 14.0 (s, 1H).

Analysis: Calculated for C,7H~ON2O2:
C, 74.45; H, 3.67; N, 10.27%: Found:
C, 74.37; H, 3.73; N, 9.91%.

2-Phenyl-9H-indeno[1,2-b]pyrazine-3,9(4H)-dione 9-ethylene acetal 2-Phenyl-9H-indeno[1,2b]pyrazine-3,9(4H)-dione (0.90 g, 3.28 mmol) was reacted with ethylene glycol (9 ml) following the procedure outlined in 15 example 6. The crude product (0.93 g) was recrystallized from tetrahydro-furan/heptane to give 0.53 g (51%) of the title comPound. M.p. 296-296.5C.
'H-NMR (DMSO-d6, ~): 4.32 - 4.5 (m, 4H), 7.4 - 7.6 (m, 6H), 7.8 (d, 1H), 8.3 (m, 2H), 13.48 (s, 1H).

Analysis: Calculated for C19H,4N2O3:
C, 71.69; H, 4.43; N, 8.80%. Found:
C, 71,95; H, 4.41; N, 8.77%.

9-Hydroxy-9-phenyl-9H-indeno [1,2-b] pyrazin-3(4H)-one 9H-lndeno[1,2-b]pyrazine-3,9(4H)-dione (2 g) was dissolved in dry THF (50 ml). Triethylamine (1.6 ml) was added and trirnethylsilyl chloride (1.4 ml) dissolved in THF (10 ml) was added dropwis~ at room temperature. The mixture was stirred overnight and the precipitate filtered off. Phenylmag-nesium bromide (20 mmol) in THF (10 ml) was subsequently added drop-WO 94/1817~ PCT/DK94/00050 ` 21 ~5~SS ~

wise under nitrogen, and the resulting mixture stirred at room temperature for 3 days. Subsequent evaporation followed by addition of water and addition of HCI (1 N) to slightly acidic solution resulted in precipitation of yellow crystals (2.7 9). The precipitate was purified on silica gel column 5 using methylene chloride/methanol: (9/1) as eluent resulting in 1.2 9 pure title compound. M.p. >270C. The MS showed the molecular ion 276. ~H-NMR (DMSO-d6, ~): 6.39 (s, 1H), 7.15 - 7.5 (m, 8H), 7.82 (s+ m, 2H), 12.6 (s, 1 H).

9-Acetoxy-9-phenyl-9H-indeno[1,2-b]pyrazin-3(4H)-one 159-Hydroxy-9-phenyl-9H-indeno[1,2-b]pyrazin-3(4H)-one (0.24 g) was stirred with a mixture of acetic acid (3 ml), acetic anhydride (3 ml) and hydrogen peroxide (0.42 ml) at room temperature for 3 weeks. The resulting very complex mixture was evaporated and treated with water resulting in precipi-tation of 200 mg of a crystalline mixture. Purification on silica gel column 20 using methylene chloride/methanol: (9/1) as eluent resulted in 70 mg of a compound which was recrystallized from ethanol. Yield 40 mg of the title compound. M.p. 220-223C. MS showed the molecular ion 318 and a degradation pattern in accordance with the title compound. 'H-NMR
(CDCI3/CD30D: 9/1, ~): 2.4-2.5 (3H, s), 7.3-7.6 (9H, m), 7.9-8.0 (1H, m), 8.2 25 (1H, s).

9-(2-Methoxyethoxy)-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione A suspension of 9-hydroxy-9H-indeno[1,2-b]pyrazine-2,3(1 H, 4H)-dione.
1H2O (0.50 g, 2.13 mmol) in benzene (20 ml), 2-methoxyethanol (10 ml) and ~wo 94/18175 S~3,~3 p-toluensulfonic acid (20 mg) was refluxed with water separation for 20 hours. The reaction mixture was evaporated In vacuo to dryness, the residue was suspended in ethanol (10 ml) and the precipitate was filtered off and washed with ethanoi and dried to give 0.48 9 of the crude product, which was recrystallized from ethanol to yielcl 0.35 9 (60%) of the title compound. M.p. > 300C. ~H-NMR (DMSO-dlô, ~): 3.22 (s, 3H), 3.27 - 3.51 (m, 4H), 5.24 (s, 1H), 7.18 (t, 1H), 7.33 (t, 1H), 7.42 (d, 1H), 7.5 (d, 1H~, 12.06 (s, 1H), 12.29 (s, 1H).

9H-lndeno[1,2-b]pyrazine-3,9(4H)-dione 9-ethylene dithioacetal A suspension of 9H-indeno[1,2-b]pyrazine-3,9(4H)-dione (0.50 g, 2.52 mmol) in benzene (10 ml), 1,2-ethanedithiol (~.63 ml, 7.56 mmol) and boron trifluoride etherate (0.31 ml, 2.52 mmol) was r efluxed for 23 hours. The reaction mixture was cooled to room temperature, and the precipitate was filtered off and washed with benzene and water and dried. The crude material (0.64 g) was recrystallized twice from ethanol to give 0.44 g (64%) of the title compound. M.p. 284 - 290C. 'H-I\~MR (DMSO-d6, ~): 3.75 - 3.94 (m, 4H), 7.46 - 7.57 (m, 2H), 7.8 (m, 2H), 7.95 (s, 1H), 12.6 (s, 1H).

9H-indeno[1,2-b]pyrazine-2,3,9(1H, 4H)-trione 9-ethylene dithioacetal A suspension of 9H-indeno[1,2-b]pyrazine-2,;3,9(1H, 4H)-trione. 0.9 H2O (2.0 g, 8.68 mmol) in toluene (50 ml), 1,2-ethanedithiol (2.19 ml, 26.04 mmol) and boron trifluoride etherate (1.07 ml, 8.68 rnmol) was refluxed for 20 hours. The reaction mixture was cooled to room temperature, and the precipitate was filtered off and washed with toluene, ethanol-water (2:1) and WO 94/18175 2 15 5 ~ 5 ~ PCT/DK94/00050~

ethanol. The crude material (2.40 g) was recrystallized from DMF-water to give 2.09 g (83%) of the titie compound. M.p. ~ 300C.1H-NMR (DMSO-d6, ~): 3.68 (m, 2H), 3.91 (m, 2H), 7.2 (t, 1H), 7.3 (t, 1H), 7.51 (d, 1H), 7.59 (d,1H), 12.05 (s, 1H), 12.38 (s, 1H).
Analysis: Calculated for C~3H10N2O2S2:
C, 53.78; H, 3.47; N, 9.65; S, 22.08%. Found:
C, 53.43; H, 3.58; N, 9.55; S, 21.84%.

9-(3,3-Diphenylpropoxy)-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione A suspension of 9-hydroxy-9H-indeno [1,2-b] pyrazine-2,3(1 H, 4H)-dione.
1H2O (1.0 g, 4.26 mmol) in benzene (40 ml), 3,3-diphenyl-1-propanol (10 ml) and p-toluensulfonic acid (40 mg) was refluxed with water separation for 48 hours. The reaction mixture was evaporated in vacuo to dryness, the residue was suspended in ethanol (10 ml) and the precipitate was filtered off and washed with ethanol and dried to give 0.224 g (12.5%) of the title compound. M.p. 224-228C. 'H-NMR(DMSO-d6, ~): 2.14- 2.32 (m, 2H), 3.0 -3.22 (m, 2H), 4.13 (t, 1H), 5.22 (s, 1H), 7.0 - 7.5 (m, 14H), 12.12 (s, 1H), 12.26 (s, 1H).

Analysis: Calculated for C26HzN2O3.1/2H2O:
C, 74.45; H, 5.53; N, 6.68%. Found:
C, 74.37; H, 5.58; N, 6.28%.

WO 94/18175 S~5 PCT/DK94/00050 - 9-(2,2-Bis(4-chlorophenyl))ethoxy-9H-indeno[1,2-b]pyrazine-2,3(1 H, 4H)-dione A suspension of 9-hydroxy-9H-indeno[1,2-b]pyrazine-2,3(1 H, 4H)-dione.
1H2O (0.50 g, 2.13 mmol) in acetic acid (30 ml), 2,2-bis(4-chlorophenylj-ethanol (2.84 g, 10.65 mmol) and p-toluensulfonic acid (20 mg) was refluxed for 21 hours. The reaction mixture was evaporated in vacuo to dryness, the residue was suspended in ethanol (40 ml) and the precipitate was filtered off and washed with ethanol and ciried to give 0.39 g of the crude product, which was recrystallized from ethanol to yield 0.174 g (17.5%) of the title comPound. M.p. 234 - 237C. ~H-NMR (DMSO-d6, ~):
3.68 (t, 1H), 4.0 (t, 1H), 4.27 (t, 1H), 5.23 (s, 1H), 7.1 - 7.5 (m, 12H), 11.98(s, 1H), 12.25 (s, 1H).

Analysis: Calculated for C25H18N2O3CI2:
C, 64.53; H, 3.90; N, 6.02%. Found:
C, 64.30; H, 3.98; N, 5.95%.

9-(4-(2-Hydroxyethyl)-1-piperazinyl)-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-25 dione 9-Chloro-9H-indeno[1,2-b]pyrazine-2,3(1 H, 4H)-dione (3.0 g, 12.8 mmol) was reacted with N-(2-hydroxyethyl)piperazine (3.66 g, 28.2 mmol) as 30 described in example 18. The crude product ~as purified by dissolving in aqueous NaHCO3/NaOH and precipitated by adding to hydrochloric acid.
The procedure was repeated and the product was finally washed with ethanol and dried to give 1.53 g (28%) of the title compound as a dihydro-215535~ ~

chloride. M.p. 210C (destruction). 'H-NMR (DMSO-d6 + D2O, ~): 2.35 - 3.6 (m, 10H), 3.75 (m, 2H), 4.73 (s, 1H), 7.22 (t, 1H), 7.35 (t, 1H), 7.51 (d,1H), 7.57 (d, 1 H).

Analysis: Calculated for C1~H22N4O3CI2-1 1/4H2O:
C, 48.18; H, 5.83; N, 13.22; Cl, 16.73%. Found:
C, 48.18; H, 6.04; N, 12.98; Cl, 16.45%.

9-(4-(2-Methoxyphenyl)-1-piperazinyl)-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione 9-Chloro-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione (3.0 9, 12.8 mmol) was suspended in 50 ml of dry tetrahydrofuran, while cooling in an ice bath.
1-(2-Methoxyphenyl)piperazine. HCI (6.5 g, 28.2 mmol) was added and triethylamine (3.9 ml, 28.2 mmol) was added over 15 min., and the ice bath was removed and stirring was continued for 20 hours at room temperature.
The precipitate was filtered off, washed with tetrahydrofuran and dissolved in a mixture of 500 ml ethanol and 300 ml tetrahydrofuran by boiling and treated with 500 mg of activated carbon. The mixture was filtered, 10 ml of 6 M HCI was added and the mixture was concentrated to about 100 ml. The precipitate was filtered off, washed with ethanol and dried to give 3.79 9 of the crude product, which was purified by dissolving in 50 ml 1 M NaOH and precipitated by adding to 100 ml 1 M HCI. The product was filtered off and washed with 1 M HCI and dried to yield 1.86 g (31.7%) of the title compound as a hydrochloride. M.p. 235 - 238C. 'H-NMR (DMSO-d6 + D2O, ~): 3.0 -3.5 (m, 8H), 3.8 (s, 3H), 5.23 (s, 1H), 7.0 (t, 1H), 7.08 (d, 1H), 7.2 (m, 2H), 7.34 (t, 1 H), 7.48 (t, 1 H), 7.63 (d, 1 H), 7.75 (d, 1 H).

Analysis: Calculated for C22H23N4O3CI.13/4H2O:

~WO 94/18175 ~t~s PCT/DK94/00050 C, 57.64; H, 5.83; N, 12.22; Cl, 7.73%. Found:
C, 57.79; H, 5.56; N, 12.13; Cl, 8.05%.

9-(4-Diphenylmethyl-1-piperazinyl)-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione 9-Chloro-9H-indeno[1,2-b]pyrazine-2,3(1H, 4HI-dione (1.0 9, 4.26 mmol) was suspended in 10 ml of dry tetrahydrofuran, while cooling in an ice bath.
1-(Diphenylmethyl)piperazine (1.1 g, 4.26 mmol) dissolved in 10 ml of dry tetrahydrofuran was added over 10 min., thereafter triethylamine (0.59 ml, 4.26 mmol) in 3 ml tetrahydrofuran was added. The ice bath was removed 15 and stirring was continued for 20 hours at room temperature. The precipi-tate was filtered off and washed with tetrahydrofuran to give 1.36 g of the crude product which was recrystallized two times from acetic acid to yield 0.45 g (20%) of the title compound as a hydrochloride. M.p. 212-216C.1H-NMR (DMSO-d6, ~): 2.5 - 3.3 (m, 8H), 4.64 (s, 1H), 5.62 (d, 1H), 7.1 - 7.9 (m, 14H), 11.25 (s, 1H), 11.74 (s, 1H), 12.25 (s, 1H).

Analysis: Calculated for C28H27N4O2CI.2H2O:
C, 64.30; H, 5.97; N, 10.71; Cl, 6.78%. Found:
C, 64.36; H, 5.78; N, 10.24; Cl, 6.73%.

9-(1-Piperazinyl)-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione Piperazine (1.1 g, 12.8 mmol) was suspended in 15 ml of dry tetrahydro-furan at -20C. 9-Chloro-9H-indeno[1,2-b]pyrazine-2,3(1 H, 4H)-dione (1.5 9, 6.4 mmol) was added over 25 min. and the ternperature was slowly rised to 215~3~ --room temperature while stirring. After 20 hours another portion of piperazine (0.55 g, 6.4 mmol) was added and stirring was continued for 72 hours. The reaction mixture was evaporated in vacuo to dryness and the remanence was suspended in 10 ml 6M HCI. The product was filtered off and washed with 1 M HCI and dried to give 1.7 g of the crude product, which was purified by dissolving in aqueous sodium hydroxide and precipitated by adding to hydrochloric acid. The procedure was repeated and the product was finally washed with ethanol and dried to give 0.64 g (27%) of the title compound as a hydrochloride. M.p. 259 - 263C.1H-NMR (DMSO-d6, ~):
2.65 - 3.15 (m, 8H), 4.7 (s, 1H), 7.17 (t, 1H), 7.34 (t, 1H), 7.45 (d, 1H), 7.57(d, 1H), 8.93 (s, 2H), 11.8 (s, 1H), 12.3 (s, 1H).

9-(2-Aminoethylthio)-9H-indeno[1,2-b]pyrazine-2,3(1 H, 4H)-dione 9-Hydroxy-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione. 1H2O (0.5 g, 2.13 mmol), aminoethanethiol hydrochloride (0.48 9, 4.26 mmol) and boron trifluoride etherate (0.29 ml, 2.34 mmol) was refluxed in 10 ml of acetic acid for 24 hours. Another portion of aminoethanethiol hydrochloride (0.48 g, 4.26 mmol) was added and the reaction mixture was refluxed for 24 hours.
The reaction mixture was cooled to room temperature, and the precipitate was filtered off and washed with acetic acid and water and dried. The crude material (0.59 9) was purified by dissolving in aqueous sodium hydroxide and precipitated by adding to hydrochloric acid. The product was finally washed with ethanol containing a small amount of aqueous hydrochloric acid and dried to give 0.377 g (55%) of the title compound as a hydrochloride. M.p. 297 - 298C.1H-NMR (DMS0-d6, ~): 2.2 - 2.5 (m, 2H), 2.55 - 2.8 (m, 2H), 4.85 (s, 1 H), 7.22 (t, 1 H), 7.34 (t, 1 H), 7.52 (d, 1 H), 7.61 (d, 1H), 7.92 (s, 3H), 12.03 (s, 1H), 12.4 (s, 1H).

WO 94/18175 l~S~S PCT/DK94/00050 - 9-(2-Diethylaminoethylthio)-9H-indeno[1,2-b]pyrazine-2,3(1 H, 4H)-dione 9-Hydroxy-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione. 1H2O (1.0 g, 4.26 mmol), 2-diethylaminoethanethiol hydrochloridl3 (1.44 g, 8.~2 mmol) and boron trifluoride etherate (0.53 ml, 4.26 mmol) were refluxed in 20 ml of acetic acid for 3 hours. After stirring overnight at room temperature the 10 reaction mixture was evaporated in vacuo to dryness, the remanence was suspended in ethyl acetate, filtrated and washed with ethyl acetate and ethanol to give 0.96 g of crude product, which was recrystallized from acetic acid to yield 0.59 g (37%) of the title compound as a hydrochloride.
M.p. 221 - 225C. ~H-NMR (DMS0-d6, ~): 0.98 (m, 6H), 2.4 - 2.68 (m, 2H), 2.82 - 2.95 (m, 4H), 3.35 (s, 2H), 4.87 (s, 1 H), 7.22 (t, 1 H), 7.34 (t, 1 H), 7.53 (d, 1H), 7.59 (d, 1H), 10.18 (s, 1H), 12.06 (s, 1H), 12.36 (s, 1H).

Analysis: Calculated for Cl7H22N302SCI.1/4H20:
C, 54.83; H, 6.09; N, 11.28%. Found:
C, 54.83; H, 6.10; N, 11.20%.

9H-lndeno[1,2-b]pyrazine-2,3,9(1H, 4H)-trione 9-ethylene dithioacetal monosulfoxid 9H-lndeno[1,2-b]pyrazine-2,3,9(1H, 4H)-trione 9-ethylene dithioacetal (0.5 g, 1.72 mmol) was suspended in a mixture of 10 ml of acetic acid and 10 ml of acetic anhydride. Hydrogen peroxide 35% (0.18 ml, 1.89 mmol) was added and the mixture was stirred overnight at room temperature. The precipitate was filtered off and washed with acetic acid and dried to give 0.38 g of crude product, which was recrystallized from acetic acid to yield wo 94/18175 2 ~ ~ 5 3 5 j PCT/DK94/00050~

0.16 g (29%) of the title compound. ~H-NMR (DMSO-d6, ~): 3.58 - 3.72 (m, 1 H), 3.8 - 3.96 (m, 2H), 4.32 - 4.48 (m, 1 H), 7.25 (t, 1 H), 7.41 (t, 1 H), 7.5 (d, 1H), 7.64 (d, 1H), 11.86 (s, 1H), 12.55 (s, 1H).

9-Hydroxy-9-phenyl-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione 9H-lndeno[1,2-b]pyrazine-2,3,9(1 H, 4H)-trione. 1 H2O (2.31 g, 10.0 mmol) was suspended in a mixture of 100 ml of tetrahydrofuran and 100 ml of toluene and evaporated to dryness. Dry tetrahydrofuran (100 ml), trimethyl-silyl chloride (2.8 ml, 21 mmol) and triethylamine (3.1 ml, 21 mmol) were added and the mixture was refluxed overnight. After cooling to room temperature, the precipitate was filtered off and phenylmagnesium bromide (21.0 mmol) in ether (7 ml) was subsequently added dropwise, and the resulting mixture stirred at room temperature for 3 days. Subsequent evaporation to 50 ml followed by addition to 350 ml ice-cold 1 M HCI
resulted in precipitation of crystals (2.93 g). The precipitate was recrystallized from methanol/water to give 1.47 g (50%) of the titie com-pound. M.p. 243 - 253C. 'H-NMR (DMSO-d6, ~): 6.26 (s, 1H), 7.0 - 7.45 (m, 8H), 7.51 (d, 1H), 11.8 (s, 1H), 12.34 (s, 1H).

Analysis: Calculated for C1,H,2N203.l/2H20:
C, 67.77; H, 4.35; N, 9.30%. Found:
C, 67.84; H, 4.36; N, 8.98%.

9-Ethoxy-9-phenyl-9H-indeno[1,2-b]pyrazine-2,3(1 H, 4H)-dione 9-Hydroxy-9-phenyl-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione. l/2 H20 ~wo 94/1817~ 35~ PCT/DKg4/OOOSo (0.20 g, 0.66 mmol), benzene (10 ml), ethanol (10 ml) and p-toluensulfonic acid (20 mg) were refluxed with water separation overnight. The reaction mixture was evaporated in vacuo to dryness, the remanence was sus-pended in water (20 ml) and the precipitate was filtered off and dried to 5 give 0.20 9 of the crude product, which was l~urified by fractionated crystal-lization from acetic acid/water to yield 0.127 cl (60%) of the title compound.
M.p. 230C (destruction). 1H-NMR (DMSO-d6, ~): 1.12 (m, 3H), 2.98 - 3:35 (m, 2H), 7.0 - 7.6 (m, 9H), 11.9 (s, 1H), 12.4 ~s, 1H).

2-Hydroxymethyl-9H-indeno[1 ,2-b]pyrazine-3,9(4H)-dione Serinamide.HCI (3.0 g, 21.34 mmol) was reacted with ninhydrin (3.8 9, 21.34 mmol) following the procedure outlined in example 1. The crude product (1.86 g) was dissolved in aqueous NaHCO3 and added to hydro-gen chloride in 90% ethanol. The precipitate was filtered off and washed with ethanol and water and dried to yield 1.65 g (34%) of the title com-pound. M.p. > 300C. 'H-NMR (DMSO-d6, ~) 4.5 (s, 2H), 5.08 (broad, 1H), 7.45 - 7.8 (m, 4H), 13.8 (s, 1H).

Analysis: Calculated for C,2HBN2O3Ø1 H2O:
C, 62.66; H, 3.59; N, 12.18%. Found:
C, 62.52; H, 3.43; N, 12.24%.

Claims (10)

1. A compound of formula (I) or a tautomeric form thereof selected from the group consisting of or (I) wherein R1, R2, R3 and R4 independently represent hydrogen, halogen, C1-6-alkyl or C1-6-alkoxy; and R5 represents hydrogen, hydroxy, halogen, cyano, C1-6-alkyl optionally substituted with hydroxy, C1-6-alkoxy optionally substituted with one or two phenyl group(s) which phenyl group(s) is/are optionally substituted with halogen, C1-6-(alkoxyalkoxy), C1-6-thioalkyl optionally substituted with an amino group which amino group is optionally mono or disubstituted with C1-6-alkyl, C1-6-acyloxy, phosphono, C1-6-alkoxy disubstituted phosphonyl or a 5 or 6 membered heterocyclic group containing one or two N or O
atom(s) or a combination thereof which heterocyclic group is optionally substituted with C1-6-alkyl which alkyl group is optionally substituted by hydroxy or which heterocyclic group is optionally substituted with one or two phenyl group(s) which phenyl group(s) is/are optionally substituted with methoxy; and R6 represents hydrogen, C1-6-alkyl or phenyl, or R5 and R6 together represent a carbonyl group, a hydroxyimino group or a benzyloxyimino group, or R5 and R6 together form a 5 or 6 membered heterocyclic group containing one or two N, O, S or S(O)z atom(s) or a combination thereof, wherein z is 1 or 2, which heterocyclic group is optionally substituted with one or two methyl group(s), hydroxymethyl, piperidinomethyl or (4-methyl-1-piperazi-nyl)methyl; and R7 represents hydrogen, phenyl or -CH2OR8 wherein R8 is hydrogen or benzyl, or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 selected from the following:

9H-Indeno[1,2-b]pyrazine-3,9(4H)-dione, 9H-Indeno[1,2-b]pyrazine-2,3,9(1H,4H)-trione, 9-Hydroxyimino-9H-indeno[1,2-b]pyrazin-3(4H)-one, (E)-9-Hydroxyimino-9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione, (Z)-9-Hydroxyimino-9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione, (E)-9-Benzyloxyimino-9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione, (Z)-9-Benzyloxyimino-9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione, 9H-Indeno[1,2-b]pyrazine-3,9(4H)-dione 9-ethylene acetal, 9H-Indeno[1,2-b]pyrazine-2,3,9(1H,4H)-trione 9-ethylene acetal, 9H-Indeno[1,2-b]pyrazine-3,9(4H)-dione 9-(2,2-dimethylpropylene) acetal, 9H-Indeno[1,2-b]pyrazine-3,9(4H)-dione 9-(1,2-dimethylethylene) acetal, 9H-Indeno[1,2-b]pyrazine-2,3,9(1H,4H)-trione 9-(1,2-dimethylethylene) acetal, 9-Hydroxy-9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione, 9-Hydroxy-9H-indeno[1,2-b]pyrazin-3(4H)-one, 9-Chloro-9H-indeno[1,2-b]pyrazin-3(4H)-one, 9-Chloro-9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione, 9-Acetoxy-9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione, 9-Ethoxy-9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione, 9-Morpholino-9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione, 9-(4-Methyl-1-piperazinyl)-9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione, 9-Dimethoxyphosphonyl-9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione, 9-Diethoxyphosphonyl-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione, 9-Phosphono-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione, 2-Phenyl-9H-indeno[1,2-b]pyrazine-3,9(4H)-dione, 2-Phenyl-9H-indeno[1,2-b]pyrazine-3,9(4H)-dione 9-ethylene acetal, 9-Hydroxy-9-phenyl-9H-indeno[1,2-b]pyrazin-3(4H)-one, 9-Acetoxy-9-phenyl-9H-indeno[1,2-b]pyrazin-3(4H)-one, 9-(2-Methoxyethoxy)-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione, 9H-Indeno[1,2-b]pyrazine-3,9(4H)-dione 9-ethylene dithioacetal, 9H-Indeno[1,2-b]pyrazine-2,3,9(1H, 4H)-trione 9-ethylene dithioacetal, 9-(3,3-Diphenylpropoxy)-9H-indeno[1,2-]pyrazine-2,3(1H, 4H)-dione, 9-(2,2-Bis(4-chlorophenyl))ethoxy-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione, 9-(4-(2-Hydroxyethyl)-1-piperazinyl)-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione, 9-(4-(2-Methoxyphenyl)-1-piperazinyl)-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione, 9-(4-Diphenylmethyl-1-piperazinyl)-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione, 9-(1-Piperazinyl)-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione, 9-(2-Aminoethylthio)-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione, 9-(2-Diethylaminoethylthio)-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione, 9H-Indeno[1,2-b]pyrazine-2,3,9(1H, 4H)-trione 9-ethylene dithioacetal monosulfoxid, 9-Hydroxy-9-phenyl-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione, 9-Ethoxy-9-phenyl-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione, 2-Hydroxymethyl-9H-indeno[1,2-b]pyrazine-3,9(4H)-dione, or a pharmaceutically acceptable salt thereof.

3. A method of preparing a compound according to claim 1 CHARACTER-IZED IN

a) reacting a compound of formula (II) (II) wherein R1, R2, R3 and R4 have the meanings as defined for formula (I) with a compound of formula (III) (III) wherein R7 has the meaning as defined for formula (I), to form a compound of formula (IV) (IV) wherein R1, R2, R3, R4 and R7 have the meanings as defined for formula (I);
or b) oxidizing a compound of formula (IV) wherein R1, R2, R3 and R4 have the meanings as defined for formula (I) and R7 is hydrogen with, e.g. hydrogen peroxide, in a mixture of acetic acid and acetic anhydride to form a com-pound of formula (V) (V) wherein R1, R2, R3 and R4 have the meanings set forth above; or c) reacting a compound of formula (V) with hydroxylamine or O-benzyl-hydroxylamine to form a compound of formula (VI) (VI) wherein R1, R2, R3 and R4 have the meanings set forth above and R9 represents hydrogen or benzyl; or d) reducing a compound of formula (V) with, e.g. sodium borohydride, to form a compound of formula (VII) (VII) wherein R1, R2, R3 and R4 have the meanings set forth above; or e) reacting a compound of formula (VII) with a halogenating agent, e.g.
thionyl chloride or thionyl bromide, to form a compound of formula (VIII) (VIII) wherein R1, R2, R3 and R4 have the meanings set forth above and Y is halogen; or f) reacting a compound of formula (VIII) with R10-COOH, wherein R10 is alkyl, to form a compound of formula (IX) (IX) wherein R1, R2, R3, R4 and R10 have the meanings set forth above; or g) reacting a compound of formula (VIII) or a compound of formula (VII) with an alcohol R11-OH, wherein R11 represents alkyl optionally substituted with one or two phenyl group(s) which phenyl group(s) is/are optionally substituted with halogen or alkoxyalkyl, e.g. ethyl, 3,3-diphenylpropyl, 2,2-(4-chlorophenyl)ethyl or 2-methoxyethyl, to form a compound of formula (X) (X) wherein R1, R2, R3, R4 and R11 have the meanings set forth above; or h) reacting a compound of formula (IV) with 1,3 or 1,2-diols, which may be substituted with one or two lower alkyl group(s) in an inert solvent such as benzene or toluene in the presence of an acid catalyst to form a compound of formula (XI) or (XII) or (XI) (XII) wherein R1, R2, R3, R4 and R7 have the meanings as defined for formula (I) and R12 and R13 represent an alkyl group, e.g. methyl; or i) oxidizing a compound of formula (XII) wherein R7 is hydrogen with, e.g.
hydrogen peroxide, in a mixture of acetic acid and acetic anhydride to form a compound of formula (XIII) (XIII) wherein R1, R2, R3, R4, R12 and R13 have the meanings as defined for formula (XII); or j) reacting a compound of formula (VIII) with an amine wherein X is oxygen or N-R14, wherein R14 represents hydrogen or an alkyl group, e.g.
methyl, or a substituted alkyl group, e.g. 2-hydroxyethyl, diphenylmethyl or a phenyl group which is optionally substituted with methoxy, e.g. 2-methoxyphenyl, in a suitable solvent such as tetrahydrofuran to form a compound of formula (XIV) (XIV) wherein R1, R2, R3 and R4 have the meanings as defined for formula (I) and X and N-R14 have the meanings defined above; or k) reacting a compound of formula (VIII) with an alkylphosphite to form a compound of formula (XV) (XV) wherein R1, R2, R3 and R4 have the meanings set forth above and R15 is methyl or ethyl; or l) reacting a compound of formula (XV) with bromotrimethylsilane in acetonitrile to form a compound of formula (XVI) (XVI) wherein R1, R2, R3 and R4 have the meanings set forth above; or m) reacting a compound of formula (V) with 1,3 or 1,2-dithiols which may be substituted with one or two lower alkyl group(s) in an inert solvent such as toluene in the presence of boron trifluoride etherate to form a compound of formula (XVII) or (XVIII) or (XVII) (XVIII) wherein R1, R2, R3, R4, R12 and R13 have the meanings set forth above, or n) oxidizing a compound of formula (XVII) with, e.g. hydrogen peroxide, in a mixture of acetic acid and acetic anhydride to form a compound of formula (XIX) (XIX) wherein R1, R2, R3, R4, R12 and R13 have the meanings set forth above and a and b independently are 0, 1 or 2, provided that a and b are not 0 at the same time; or o) reacting a compound of formula (VII) with alkylthiol or 2-aminoalkylthiol optionally substituted in the amino group with lower alkyl in acetic acid in the presence of boron trifluoride etherate to form a compound of formula (XX) (XX) wherein R1, R2, R3 and R4 have the meanings set forth above and R16 is thioalkyl optionally substituted with an amino group which amino group is optionally mono or disubstituted with alkyl; or p) silylating a compound of formula (IV) with, e.g. trimethylsilyl chloride and triethylamine, in a suitable solvent such as tetrahydrofuran and thereafter, reacting with alkyl or phenylmagnesium bromide and subsequent hydrolysis to form a compound of formula (XXI) (XXI) wherein R1, R2, R3, R4 and R7 have the meanings as defined for formula (I) and R17 is alkyl or phenyl; or q) reacting a compound of formula (XXI) with a mixture of R10-COOH, (R10-CO)2O and hydrogen peroxide to form a compound of formula (XXII) (XXII) wherein R1, R2, R3, R4 and R7 have the meanings as defined for formula (I) and R10 and R17 have the meanings set forth above; or r) silylating a compound of formula (V) with, e.g. trimethylsilyl chloride and triethylamine, in a suitable solvent such as tetrahydrofuran and thereafter reacting with alkyl or phenylmagnesium bromide and subsequent hydrolysis to form a compound of formula (XXIII) (XXIII) wherein R1, R2, R3 and R4 have the meanings as defined for formula (I) and R17 has the meaning set forth above; or s) reacting a compound of formula (XXIII) with an alcohol R18-OH wherein R18 is alkyl to form a compound of formula (XXIV) (XXIV) wherein R1, R2, R3 and R4 have the meanings as defined for formula (I) and R17 and R18 have the meanings set forth above.

4. A pharmaceutical composition comprising a compound according to claim 1 together with a pharmaceutically acceptable carrier or diluent.

5. A pharmaceutical composition for use in treating a central nervous system ailment related to the glycine binding site on the NMDA receptor complex comprising an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof together with a pharmaceuti-cally acceptable carrier or diluent.

6. The pharmaceutical composition according to claim 4 or 5 in the form of an oral dosage unit or parenteral dosage unit.

7. The pharmaceutical composition according to claim 6 in the form of an oral dosage unit containing about 1-200 mg of the compound according to claim 1.

8. A method of treating a central nervous system ailment related to the glycine binding site on the NMDA receptor complex comprising administer-ing to a subject in need thereof an effective amount of a compound accord-ing to claim 1.

9. A method of treating a central nervous system ailment related to the glycine binding site on the NMDA receptor complex comprising administer-ing to a subject in need thereof a pharmaceutical composition according to claim 5.

10. The use of a compound according to claim 1 for the preparation of a medicament for treatment of a central nervous system ailment related to the glycine binding site on the NMDA receptor complex.