KR20010108025A - 2,3,4,4a-Tetrahydro-1H-pyrazino(1,2-a)quinoxalin-5(6H)one derivatives being 5HT2C agonists - Google Patents

Abstract

The present invention is a compound of formula (I), which is a 5HT _2C receptor agonist useful in the treatment of central nervous system related disorders such as obsessive compulsive disorder, depression, anxiety, schizophrenia, migraine, sleep disorder, eating disorder, obesity, type II diabetes and epilepsy To enantiomers or pharmaceutically acceptable salts thereof.

Formula I

In the above formula,

R is hydrogen or alkyl of 1 to 6 carbon atoms,

R 'is hydrogen, alkyl of 1 to 6 carbon atoms, acyl or aroyl of 2 to 7 carbon atoms,

R ₁ , R ₂ , R ₃ and R ₄ are each independently hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, trifluoroalkyl, -CN, alkyl sulfonamide of 1 to 6 carbon atoms, Alkyl amides having 1 to 6 carbon atoms, amino, alkylamino having 1 to 6 carbon atoms, dialkylamino having 1 to 6 carbon atoms per alkyl residue, trifluoroalkoxy having 1 to 6 carbon atoms, acyl or aroyl having 2 to 7 carbon atoms, ,

X is CR ₅ R ₆ [wherein R ₅ and R ₆ are each independently hydrogen or alkyl having 1 to 6 carbon atoms] or a carbonyl group,

Provided that at least one of R ₁ , R ₂ , R ₃ or R ₄ is not hydrogen.

Description

2,3,4,4a-tetrahydro-1H-pyrazino (1,2-a) quinoxalin-5 (6H) one derivative, which is a 5HT2C agonist {2,3,4,4a-Tetrahydro-1H-pyrazino (1 , 2-a) quinoxalin-5 (6H) one derivatives being 5HT2C agonists}

The invention OCD (obsessive-compulsive disorder), depression, anxiety, schizophrenia, migraine, sleep disorders, eating disorders, obesity, treatment useful serotonin 5-hydroxy-trip in disorders such as type II diabetes, and epilepsy glutamate 2 _C 2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a] quinoxalin-5 (6H) one, which is a (5HT _2C ) receptor agonist.

Obesity is a medical disorder characterized by excess body fat or adipose tissue. Obesity-related diseases include type II diabetes, cardiovascular disease, hypertension, hyperlipidemia, seizures, osteoarthritis, sleep apnea, gallbladder disease, gout, some cancers, some infertility, and infant deaths. Obesity is expected to be a major health risk for the 21st century as the proportion of obese population continues to increase both in the United States and around the world. Serotonin 5-hydroxytryptamine (5-HT) receptors are G-protein coupled receptors that appear in many neurons of the human central nervous system. Wilkinson, LO and Dourish, CT in Serotonin Receptor Subtypes: Basic and Clinical Aspects (ed. Peroutka, SJ) 147-210 (Wiley-Liss, New York, 1991). The 5HT _2C receptor (formerly the 5HT _1C receptor) is the major subtype of the cetoronin receptor found in the central nervous system of both rats and humans. It is widely seen in the cortex and subcortex (Julius, D. MacDermott, AB, Axel, R, Jessell, TM Science 241: 558-564 (1988)). Studies on several animal species and humans have shown that non-selective 5HT _2C receptor agonist meta-chlorophenylpiperazine (MCPP) reduces food intake. Cowen, PJ, Clifford, EM, Williams, C., Walsh , AES, Fairburn, CG Nature 376: 557 (1995)]. Tecott et al. Described that transgenic mice deficient in 5HT _2C receptors eat more and are heavier than wild-type mice. Tecott, LH, Sun, LM, Akana, SF, Strack, AM, Lowenstein, DH, Dallman, MF, Jullus, D. Nature 374: 542-546 (1995). Compounds of the invention are 5HT _2C receptor subtype selective agonists that are selective over other monoamine receptors, reduce food intake, and reduce weight. Other therapeutic applications for 5HT _2C agonists include obsessive compulsive disorder, depression, panic disorder, schizophrenia, sleep disorders, eating disorders and epilepsy.

U.S. Pat.Nos. 4,032,639, 4,089,958 and 4,203,987 disclose 2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a] quinoxalin-5 (6) -one as an antihypertensive agent and its Derivatives are described. In contrast, the compounds of the present invention are useful in the treatment of CNS disorders because they bind to and activate the 5HT _2C receptor of the CNS.

See Indian J. Chem. 17B, 244-245 (1979), discloses 3-substituted 2,3,4,4a, 5,6-hexahydro-1 (H) that exhibits no appetite or excitatory activity at an intraperitoneal dose of 60 mg / kg. Pyrazino [1,2-a] quinoxaline is described. Weak CNS sedative activity and significant hypotension activity were observed in anesthetized animals. Over tolerance was observed.

The present invention is a 5HT _2C receptor agonist useful in the treatment of central nervous system related disorders such as obsessive compulsive disorder, depression, anxiety, panic disorder, schizophrenia, migraine, sleep disorder, eating disorder, obesity, type II diabetes and epilepsy Provided are the compounds of or pharmaceutically acceptable salts thereof.

In the above formula,

R is hydrogen or alkyl of 1 to 6 carbon atoms,

R 'is hydrogen, alkyl of 1 to 6 carbon atoms, acyl or aroyl of 2 to 7 carbon atoms,

R ₁ , R ₂ , R ₃ and R ₄ are each independently hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, trifluoroalkyl, -CN, alkyl sulfonamide of 1 to 6 carbon atoms, Alkyl amides having 1 to 6 carbon atoms, amino, alkylamino having 1 to 6 carbon atoms, dialkylamino having 1 to 6 carbon atoms per alkyl residue, trifluoroalkoxy having 1 to 6 carbon atoms, acyl or aroyl having 2 to 7 carbon atoms, ,

X is CR ₅ R ₆ [wherein R ₅ and R ₆ are each independently hydrogen or alkyl having 1 to 6 carbon atoms] or a carbonyl group,

Provided that at least one of R ₁ , R ₂ , R ₃ or R ₄ is not hydrogen.

The compounds of the present invention may contain asymmetric carbon atoms, and some of the compounds of the present invention may contain one or more asymmetric centers, thus generating optical isomers, enantiomers and diastereomers. Although not shown for stereochemistry in Formula (I), the present invention not only includes such optical isomers and diastereomers, but also racemates and resolved enantiomerically pure R and S stereoisomers, and R and S stereoisomers. Other mixtures thereof and pharmaceutically acceptable salts thereof.

The term "alkyl" includes straight and branched chain saturated aliphatic hydrocarbon groups. Preferred alkyl groups are methyl, ethyl, propyl or butyl, most preferably methyl. The term “aroyl” is defined as aryl ether, where aryl is defined as an aromatic system having 6 to 14 carbon atoms, which is a single condensed or bonded together to form an aromatic system in which at least a portion of the condensed or bonded ring is conjugated. It may be a ring or a poly aromatic ring. Preferred aryl groups include phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, phenanthryl groups. Halogen is defined as Cl, Br, F and I, preferably chlorine or fluorine.

Pharmaceutically acceptable salts include organic and inorganic acids such as acetic acid, propionic acid, lactic acid, citric acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malonic acid, mandelic acid, malic acid, phthalic acid, hydrochloric acid, bromic acid, phosphoric acid, Nitric acid, sulfuric acid, methanesulfonic acid, naphthalenesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, camphorsulfonic acid and similarly known acceptable acids.

Preferred compounds of the invention are those wherein at least one of R ₁ , R ₂ , R ₃ or R ₄ is not hydrogen and the substituents other than hydrogen in R ₁ , R ₂ , R ₃ and R ₄ are halogen or trifluoromethyl .

Preferred enantiomerically pure compounds of formulas (IA) and (IB) are as follows.

In the above formula,

R, R ₁ , R ₂ , R ₃ and R ₄ are as defined above.

Compounds of the present invention can be prepared from commercially available starting materials or starting materials which can be prepared using the processes of the literature according to the following scheme. This scheme represents the preparation of representative compounds of the present invention.

In the above formula,

Symbol Cbz represents a carbobenzyloxy group,

Y represents chlorine, fluorine or bromine.

4-Carbobenzyloxypiperazine-2-carboxylic acid (1) solution was reacted with substituted ortho-nitrohalobenzene (2) to 4-carbozenzyloxy-1- (o-nitro substituted phenyl) -piperazine- 2-carboxylic acid (3) is obtained. The reaction is carried out in an inert organic solvent such as dimethylsulfoxide in the presence of a base such as triethylamine at temperatures above ambient (eg 50 to 150 ° C.).

The intermediate (3) is preferably reduced by nitro group to an amino group by reaction of a metal (eg iron) in an acid (eg acetic acid) and then heated at an elevated temperature (eg 50-100 ° C.) (4) It is closed by a method including ring closure. Boron tribromide, catalytic reduction or a base (eg potassium hydroxide) is used to remove the Cbz protecting group to afford the product 4a of the present invention. Otherwise (4) is treated with a base (eg sodium hydroxide) followed by an alkyl halide (eg methyl iodide) to give intermediate (5). The Cbz group is removed with boron tribromide or potassium hydroxide to give compound (6) of the invention wherein R 'is lower alkyl.

Compound (6) can also be alkylated a second time with a base (such as sodium hydroxide) and an alkyl halide (such as methyl iodide) to give compound (8) of the invention. Alternatively, the compound (6) can be reduced to the compound (7) of the present invention by reducing it with a reducing agent (eg borane in THF). Compound (8) can also be reduced with borane in THF to afford (9) which is a compound of the present invention.

It is also possible to reduce the amide compound (5) to amine (7) at 0 to 50 ° C. using a reducing agent (eg borane in tetrahydrofuran). Compound (7) is also a compound of the present invention.

Similarly, the amide compound 6 can be reduced to the amine 8 which is the compound of the present invention. In compound (6) in which R 'is acyl, this group is added after reduction of amide (6) in which R' is hydrogen, as already described.

In Scheme 2, the carboxylic acid of the intermediate (10) and the corresponding acid (10) at a temperature of 0-50 ° C. in a base (e.g. pyridine) and a coupling agent (e.g. dicyclohex) in an organic solvent (e.g. methylene chloride) Reaction with N, O-dimethylhydroxyamine hydrochloride in the presence of silk carbodiimide (DCC)) converts to the corresponding N-methoxy-N-methyl amide (11). Intermediate 11 is treated with a Grignard reagent or an organolithium reagent such as methyl lithium to give ketone 12. Reduction of the nitro group of intermediate 12 with a reducing agent (eg iron in acetic acid) yields the corresponding amine 13, which is inert organic solvent (eg benzene) in the presence of an acid (eg p-toluenesulfonic acid). ) Is closed at an elevated temperature (eg, 50-150 ° C.) to afford the compound (14) of the present invention. (14) is alkylated with an alkyl halide (e.g. methyl iodide) or an acyl halide (e.g. acetyl chloride) to afford compound 15 of the present invention. Intermediate 12 is treated with Grignard reagent (eg methylmagnesium chloride) to give tertiary alcohol (16). The nitro group of intermediate 16 is reduced to a metal (eg iron) in an acid (eg acetic acid) and then heated at a temperature of 50-150 ° C. to give compound 17 of the invention. Compound (17) is reacted with alkyl halide (e.g. methyl iodide) or acyl halide (e.g. acetyl chloride) to afford compound (18) of the present invention.

Enantiomerically pure compounds of the invention can be prepared from commercially available starting materials or starting materials which can be prepared using the processes of the literature according to Scheme 3 below. This scheme represents a process for preparing representative (R) -compounds of formula (IA) of the present invention starting with the known 2- (R) -piperazinecarboxylic acid (see below). Known 2- (S) -piperazine Starting from the carboxylic acid yields the (S) -compound of formula (IB) of the present invention.

In the above formula,

The symbol Cbz represents a carbobenzyloxy group.

In Scheme 3, (R) -2-piperazinecarboxylic acid (prepared according to the reference below) is converted to N protected amino acid 19 by standard methods. (R) -4-carbobenzoyloxypiperazin-2-carboxylic acid (19) solution was reacted with substituted ortho-nitrofluorobenzene to 4-carbobenzoyloxy-1- (o-nitro substituted phenyl)-(R ) -Piperazine-2-carboxylic acid (20) is obtained. The reaction is carried out in an inert organic solvent such as dimethylformamide at a temperature above ambient (eg 50 to 70 ° C.) in the presence of a base such as triethylamine.

The intermediate 20 is preferably reduced to an amino group by reaction of a metal (eg iron) in an acid (eg acetic acid) and then heated at an elevated temperature (eg 50-70 ° C.) The ring closure to (21) is performed by ring closing by the containing method. The chiral product (IA) of the invention is obtained by removing the Cbz protecting group using 30% HBr, boron tribromide or catalytic reduction in acetic acid.

Processes for the preparation of compounds of Formulas (I), (IA) and (IB) form a further aspect of the invention.

The ability of the compounds of the present invention to act as 5HT _2C agonists is achieved in several standard pharmacological test processes, providing the process used and the results obtained below.

Test process

5HT _2C Receptor binding test process

To assess high affinity for the 5HT _2C receptor, CHO (Chinese hamster ovary) cell lines transfected with cDNA expressing the human 5-hydroxytrytamine _2C (h5HT _2C ) receptor were calf fetal serum, glutamine and markers. It is maintained in DMEM (Dulbecco's Modified Eagle Media) supplied with marker guanine phospholibosyl transferase (GTP) and hypoxanthine thymidine (HT). Cells are grown to confluence in large culture dishes with medium replacement and splitting medium. When confluence is reached, the cells are scraped and recovered. The recovered cells are suspended in ½ volume of fresh physiological phosphate buffered saline (PBS) solution and centrifuged at low speed (900 x g). Repeat this one more time. The collected cells are then set to # 7 and homogenized with polytron for 15 seconds in 10 volumes of 50 mM Tris HCl and 0.5 mM EDTA at pH 7.4. Discard the pellet and centrifuge the supernatant at 40,000 x g for 30 minutes. The resulting pellets are resuspended in a small amount of Tris HCl buffer and the tissue protein content is measured in 10-25 microliter (μL) volumetric aliquots. Protein measurement by Lowry et al. [J. Biol. Chem., 193: 265 (1951) use bovine serum albumin (BSA) as a standard. The volume of the suspended cell membrane is adjusted with 50 mM Tris HCl buffer containing 0.1% ascorbic acid, 10 mM paragiline and 4 mM CaCl ₂ to obtain a concentration of 1-2 mg tissue protein per ml suspension. The preparation membrane suspension (concentrated several times) is divided into 1 ml volumes and stored at −70 ° C. until used in subsequent binding experiments.

The binding test is performed in 96-well microtiter plate format with a total volume of 200 μl. Each well was prepared in 50 mM Tris HCl buffer at pH 7.4 and 4 mM CaCl ₂ ; Culture buffer containing 20 [mu] l of [ ¹²⁵ I] DOI (SA, 2200 Ci / mmol, NEN life Science) is added.

KD, the dissociation constant of [ ¹²⁵ I] DOI at the human serotonin 5HT _2C receptor, is 0.4 nM by saturation binding due to an increase in the concentration of [ ¹²⁵ I] DOI. The reaction is initiated by the final addition of 100.0 μl of tissue suspension containing 50 μg of receptor protein. Nonspecific binding is measured in the presence of 1 μM of unlabeled DOI added in 20.0 μl of volume. Add test compound to 20.0 ml. The mixture is incubated at room temperature for 60 minutes. The culture is stopped by rapid filtration. Packed Ligand-Receptor Complexes Bound Filtermate 196 Harvester (Packard) Filtermate 196 Harvester) in a 96 well single filter. The combined complex trapped on the filter disc was dried in a vacuum oven, heated to 60 ° C. and packed with a top counterpack with six photomultiplier detectors. (Packard TopCount ) Is measured by liquid scintillation with 40 μl Microcint-20 scintillation.

Specific binding is defined as bound total radioactivity that is less than the amount bound in the presence of 1 μM of unlabeled DOI. Binding in the presence of various concentrations of the test agent is shown as the percentage of specific binding in the presence of the agent. These results are then plotted as log (log%) versus concentration (log) of test agent. Nonlinear regression of the data points yields both IC ₅₀ and Ki values of the test compound with a 95% confidence range. Alternatively, you can plot a linear regression line for the decay of the data points, read the IC ₅₀ value from this curve, and measure the Ki value by solving the following equation:

{Where L is the concentration of the radioligand, KD is the dissociation constant of the ligand for the receptor, both expressed in nM}

The following KIs are provided for various reference compounds.

Ki value and 95% confidence interval Ritanserin 2.0 (1.3-3.1) nM Ketanserin 94.8 (70.7-127.0) nM Sorry serine 2.7 (1.9-3.8) nM Clozapine 23.2 (16.0-34.0) nM Methiotepine 4.6 (4.0-6.0) nM Methisergid 6.3 (4.6-8.6) nM Roxapin 33.0 (24.0-47.0) nM mCPP 6.5 (4.8-9.0) nM DOI 6.2 (4.9-8.0) nM

5HT _2C By agonist [ ³ H] Stimulation of inositol monophosphate production

CHO cells transfected with cDNA expressing the human 5-HT _2C receptor are cultured in DMEM with the addition of 10% calf fetal serum and non-essential amino acids. Upon reaching confluence, cells are recovered using PBS / EDTA and plated in 24-well plates at an initial cell density of 2.5 × 10 ⁵ per well. 1 ml of preservation medium containing 1 μCi / ml Myo- [ ³ H] inositol is added to each well. After labeling for 48 hours, cells are washed once with 0.5 ml of DMEM containing 25 mM HEPES and 10 mM LiCl and then preincubated with medium for 30 minutes (include agonists in this period if tested). At the end of the preculture, the medium is removed and the cells are then incubated with the test compound for 30 minutes (in the presence of agonist if necessary). The reaction is terminated by removing the culture solution and adding 0.5 ml of ice-cold 5% PCA and incubating on ice for 15-30 minutes. 200 μl of 0.5 MTes / 1.5MK ₂ CO ₃ is added to each well to neutralize to pH 7, and the plate is left on ice for an additional 15-30 minutes to precipitate all salts. The liquid and solid phases are separated by centrifugation.

A portion of the upper aqueous phase (350 μl) is added to a Dowex AG-IX8 (formate form, 100-200 mesh) column. The column is then washed sequentially with 10 ml of water and 10 ml of 25 mM ammonium formate to remove free myo- [ ³ H] inositol and deacylated phosphinositol, respectively. Finally, 10 ml of 0.2 M ammonium formate solution is added to the column to elute [ ³ H] inositol monophosphate ([ ³ H] IP ₁ ) directly into the scintillation vial. In this eluate, 1 ml is used to measure radioactivity by scintillation coefficient.

Agonist stimulation of [ ³ H] inositol monophosphate (IP ₁ ) is expressed as percent response observed at the maximum effective concentration of 5-HT (10 μM). EC ₅₀ / IC ₅₀ is estimated using a 3-parameter logistic function. Agonists are tested in the presence of 10 μM 5-HT.

The following data is provided for various reference compounds:

5-HT 15.1nM EC ₅₀ mCPP 46.8 nM EC ₅₀ 60% E _MAX (about 5HT) SB200646 286 nM IC ₅₀ (10 μM 5-HT as agonist)

Effect of Compounds on Dietary Behavior in Rats

Eight male Sprague-Dowley rats, weighing 150-180 g, are separated into individual cages and acclimated to powdered food for two weeks. During this period and throughout the course of the test, the weights of food cups and animals are measured daily. After the acclimation period, animals are fasted for 24 hours and then injected with either 4 doses of vehicle or test compound. Food intake is assayed 2 to 24 hours after compound administration. The compound to be evaluated is injected 1-2 × per week until all animals receive the full dose of test compound. Dose order is selected using a modified Latin Square design. Further studies can be performed with satiety rats at the start of the cancer cycle. Compounds are injected intraperitoneally, subcutaneously or orally. The effect of the test compound on food intake at the end of the study is assessed using repeated measures ANOVA. Collect data for 2 hour food intake (g). The data is applied to unilateral ANOVA with subsequent t-tests to test for group differences. If appropriate, the ED ₅₀ value is measured. The ED ₅₀ value is the dose that reduces the food intake by 50% during the test period.

result

Results from in vitro test process

compound 5HT _2C Affinity DOI / Agonist Binding (Ki, nM) 5HT _2C % Emax (5HT, 100%) Stimulation of IP3 (EC ₅₀ , nM) Example 1 4.33 107.50 12.00 Example 2 4.18 112.50 7.92 Example 3 66.40 89.00 289.50 Example 4 1.00 99.00 7.32 Example 5 7.00 100.00 33.80 Example 6 8.00 77.00 23.20 Example 7 8.00 100.00 97.30 Example 8 516.00 85.00 2607.00 Example 9 25.00 100.00 18.80 Example 10 1036.00 ND ^* ND Example 11 19.79 73% @ 1μM ND Example 12 9.00 95.00 30.00 Example 13 91.00 ND ND ^* ND = not measured

Results from in vivo 5HT _2C food intake of rats (fasted for 24 hours)

compound Route of administration ED ₅₀ (mg / kg) Example 1 Subcutaneous oral cavity 1.919.73 Example 2 Subcutaneous 1.99 Example 11 Subcutaneous 9.99

The results obtained in standard pharmacological test processes indicate that the compounds of the present invention are compulsive disorder, depression, anxiety, panic disorder, schizophrenia, migraine, sleep disorders such as sleep apnea, eating disorders such as binge eating, obesity, type II diabetes and It is shown to be useful for the treatment of central nervous system related disorders such as epilepsy. The compound is for treating a disease of a mammal, preferably a human.

The compounds of the present invention can be formulated neat or with a carrier for pharmaceutical administration, the ratio of which is determined by the solubility and chemical properties of the compound, the route of administration chosen and standard pharmacological practice. Pharmaceutical carriers may be solid or liquid.

The solid carrier may comprise one or more substances that can also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet disintegrants, which may also be encapsulating agents. In powders, the carrier is a finely divided solid mixed with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary compression properties of the suitable properties in suitable proportions and compacted in the shape and size desired. Powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers are, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, low melting waxes and ion exchange resins It includes.

Liquid carriers are used to prepare solvents, suspensions, emulsions, syrups, elixirs and pressurized compositions. The active ingredient may be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of the two, or a pharmaceutically acceptable oil or fat. The liquid carrier may contain other suitable pharmaceutical additives, such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavors, suspending agents, thickeners, pigments, viscosity modifiers, solubilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (partially containing such additives, for example cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, eg For example, glycols and other derivatives, lecithin and oils such as fractionated coconut oil and arachis oil. For parenteral administration, the carrier may also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration. The liquid carrier for the pressurized composition may be a halogenated hydrocarbon or other pharmaceutically acceptable sandpaper.

Pharmaceutical liquid compositions, which are sterile solvents or suspensions, can be used, for example, by intramuscular, intraperitoneal or subcutaneous injection. Sterile solvents can also be administered intravenously. The compounds of the present invention may also be administered orally in the form of liquid or solid compositions.

The compositions of the present invention can be administered rectally or vaginally in the form of conventional suppositories. For administration by intranasal or bronchial inhalation or insufflation, the compositions of the present invention may be formulated in aqueous or partially aqueous solutions and then used in aerosol form. The compounds of the present invention may also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier which is inert to the active compound, nontoxic to the skin, and which carries the agent for systemic absorption through the skin into the bloodstream. have. The carrier can take any number of forms such as creams and ointments, pastes, gels and closure devices. Creams and ointments may be viscous liquids or semisolid emulsions in oil-in-water or water-in-oil form. Pastes made of absorbent powder dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable. Various closure devices can be used to release the active ingredient into the bloodstream, such as a semipermeable membrane or matrix containing the active ingredient, covering the reservoir containing the active ingredient with or without the carrier. Other closure devices are known in the literature.

Dosing requirements vary depending on the particular composition used, the route of administration, the severity of the symptoms present and the particular subject being treated. Based on the results obtained in standard pharmacological test processes, the daily injection dose of the active compound is from 0.02 to 750 μg / kg. Treatment generally begins with small doses below the optimal dose of the compound. The dose is then increased until optimal effect is achieved under the circumstances, and the exact dose for oral, parenteral, intranasal or bronchial administration is determined by the administering physician based on the experience of the individual treated subject. Preferably, the pharmaceutical composition is in unit dosage form, eg, in the form of a tablet or capsule. In this form, the composition is subdivided into unit doses containing suitable amounts of the active ingredient, wherein the unit dose form is a packaged composition, eg, packaged powders, vials, ampoules, prefilled syringes or liquid containing sachets. Can be. The unit dosage form may be, for example, the capsule or tablet itself or any such composition in the form of a suitable number of packages.

Next, the manufacturing method of the typical compound of this invention is provided.

Example 1

8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a] quinoxaline-5 (6H) -one

A. 4-Carbenzyloxypiperazin-2-carboxylic acid, copper chelate

To a 10 g solution of piperazine-2-carboxylic acid in 40 ml of H ₂ O was added 39 ml of 2.5N NaOH. Subsequently, a 6.5 g solution of CuSO ₄ · 5H ₂ O in 80 mL of H ₂ O is introduced and the resulting dark blue solution is cooled to 0 ° C. To this cooling solution was added 5 g of solid NaHCO _{3 in portions} , and then a solution of 7.7 mL of benzylchloroformate in 40 mL of dioxane was added dropwise over 10 minutes. The pH is monitored and NaHCO ₃ is added as necessary to maintain the basic solution. The ice bath is then removed and the reaction mixture is stirred at ambient temperature overnight. The blue precipitate is filtered and the solid is washed with cold H ₂ O (20 mL), EtOH (20 mL) and EtOAc (20 mL) to give 10.4 g of a pale blue solid.

B. 4-Carbobenzyloxy-1- (4,5-dichloro-2-nitrophenyl) piperazine-2-carboxylic acid

A mixture of 4-carbobenzyloxypiperazin-2-carboxylic acid, 10.4 g of copper chelate and 7.9 g of ethylenediaminetetraacetic acid, disodium salt in 800 ml of H ₂ O is heated to 80 ° C. for 3 hours. After cooling to room temperature, the mixture is concentrated to dryness. A mixture of this solid, 7.3 g of 1,2-dichloro-4-fluoro-5-nitrobenzene and 20 mL of triethylamine in 100 mL of dimethylsulfoxide is heated to 60 ° C. for 12 h. After cooling to ambient temperature, the resulting mixture is treated with HCl to pH 3. The mixture is then diluted with H ₂ O and extracted with ethyl acetate. The combined extracts are dried over MgSO ₄ and concentrated to give 16 g of crude product.

C. 3-Carbenzyloxy-8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a] quinoxalin-5 (6H) -one

A rapidly stirred solution of 16 g of 4-carbobenzyloxy-1- (4,5-dichloro-2-nitrophenyl) piperazine-2-carboxylic acid in 200 ml of acetic acid was heated to 60 ° C., followed by 16 g of iron powder. Little by little The reaction mixture is stirred at 60 ° C. for 3 hours and then cooled to room temperature. The mixture is diluted with 1N HCl and the resulting precipitate is collected. The solid is washed with water and ether to give 11 g of product. Crude ¹ H NMR is inconsistent. A small amount of product (1 g) is purified by flash column chromatography (gradient elution with 25% ethyl acetate-hexane to 100% ethyl acetate) to give an analytically pure sample.

¹ H NMR (400 MHz, d ₆ -DMSO) δ 10.8 (s, 1H); 7.39-7. 31 (m, 5 H); 7.04 (s, 1 H); 6.96 (s, 1 H); 5.12 (s, 2 H); 4.38 (d, 1 H, J = 13.0 Hz); 4.06 (d, 1 H, J = 13.1 Hz); 3.71 (d, 1 H, J = 11.5 Hz); 3.63 (dd, 1H, J = 11.2, 3.7 Hz); 2.99 (brs, 2 H); 2.68 (dt, 1 H, J = 12.1, 3.6 Hz).

IR (KBr) 3400, 3250, 2800, 1690, 1500, 1370, 1240, 1130, 860, 770, 730 cm ^-1 .

MS (ESI, m / e (%)) 406 (100, [M + H] ⁺ ), 408 (65, [M + H] ⁺ ).

Anal for C ₁₉ H ₁₇ Cl ₂ N ₃ O ₃ : C, 56.17; H, 4. 22; N, 10.34.

Found: C, 55.95; H, 3.88; N, 10.29

D. 8,9-Dichloro-2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a] quinoxaline-5 (6H) -one

A solution of 20 g KOH in 50 mL H ₂ O was added to 3-carbobenzyloxy-8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a] quinox in 50 mL methanol. To 4.2 g solution of saline-5 (6H) -one. The resulting reaction mixture is heated to reflux for 3 hours and then cooled to ambient temperature. The solution is concentrated and the crude solid is separated into water and ethyl acetate. The phases are separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are concentrated. The crude solid is dissolved in a minimum amount of hot ethanol and then HCl solution in ethanol is added to pH 3. The solid is collected and dried in a vacuum oven at 80 ° C. to yield 2.4 g of product as its hydrochloride salt.

¹ H NMR (400 MHz, d ₆ -DMSO) δ 11.0 (s, 1H); 9.51 (br s, 2 H); 7.12 (s, 1 H); 7.02 (s, 1 H); 4.02 (dd, 1H, J = 11.5, 3.4 Hz); 3.88 (d, 1 H, J = 11.0 Hz); 3.61 (m, 1 H); 3.41 (d, 1 H, J = 9.8 Hz); 3.15-2.98 (m, 3 H).

IR (KBr) 3420, 3200, 3020, 2970, 2800, 1695, 1500, 1460, 1430, 1395, 1375, 1290, 1140 cm ^-1 .

MS (APCI, m / e (%)) 272 (100, [M + H] ⁺ ), 274 (65, [M + H] ⁺ ).

Anal for C ₁₁ H ₁₂ Cl ₃ N ₃ O: C, 42.81; H, 3.92; N, 13.62.

Found: C. 42.66; H, 3.75; N, 13.33.

Example 2

(R) -8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a] quinoxaline-5 (6H) -one

Method A (Disassembly Method)

The enantiomers of the compound of Example 1 are separated by HPLC using a Chiracel AD column with 100% ethanol at a flow rate of 0.5 ml / min to provide the compounds of Examples 2 and 3. The first enantiomer (Example 2) elutes at 10.4 minutes ([α] ²⁵ _D +27.8) and the second enantiomer (Example 3) elutes at 13.7 minutes ([α] ²⁵ _D -25.5) .

Method B (chiral synthesis)

A, (R) -4-carbenzyloxypiperazine-2-carboxylic acid

H in a 5.0 g solution of (R) -piperazine-2-carboxylic acid (E. Felder, S. Maffei, S. Pietra.D. Pitre, Hely, Chim. Acta, 1960, 888-896) in 30 ml of water exerts a CuSO ₄ · 5H ₂ O 5.0g, dissolved in ₂ O 60㎖. The solution is cooled to 0-5 [deg.] C. and 10.0 g of NaHCO ₃ are added followed by 5.3 g of benzylchloroformate in 40 ml of acetone over 90 minutes. The mixture is warmed to ambient temperature and stirred for 24 hours. The blue precipitate is filtered off and the solid is washed with cold water. The solid is slurried in 100 ml of a methanol: water 1: 1 mixture and the pH is adjusted to less than 4 by adding 2.5N HCl. The solution is added to a column of 400 g of AG 500W-8X resin, previously washed with a pyridine: methanol: water 1:16:16 mixture. The product is eluted with the same solvent mixture and the combined product fractions are concentrated under reduced pressure (<50 ° C.) to give a semisolid residue. This material is slurried with 50 ml of ethanol to give a crystalline solid. The solids are collected and dried to yield 6.0 g (59.5%) of a white solid having a melting point of 246 to 8 ° C. (decomposition).

H ¹ NMR (400 Hz, d ₆ -DMSO) δ 7.37-7.30 (m, 5H); 5.08 (s, 2 H); 4.19 (d, 1 H, J = 12.1 Hz); 3.89 (d, 1 H, J = 13.8); 3.27 (dd, 1H, J = 11.0, 4.0 Hz); 3.08 (m, 3 H); 2.82 (dt, 1 H, J = 12.2, 3.6 Hz).

IR (KBr) 3050, 1700, 1620, 1430, 1400, 1235, 1150 cm ^-1 .

MS (ESI (+), m / e (%)) 265 (100, [M + H] ⁺ )

Anal for C ₁₃ H ₁₆ N ₂ O ₄ : C, 59.08; H, 6. 10; N, 10.60.

Found: C, 59.04; H, 6.09; N, 10.40.

Chiral purity = 99.99% (HPLC: Chiralcel WH, 4.6 x 25 mm).

[a] _D = -38.77 ° (c = 1, H ₂ O).

B. (R) -4-carbenzyloxy-1- (4,5-dichloro-2-nitrophenyl) -piperazine-2-carboxylic acid

Trier to a slurry containing 5.0 g of (R) -4-carbenzyloxypiperazin-2-carboxylic acid, 4.2 g of 1,2-dichloro-fluoro-5-nitrobenzene, 85 ml of water and 170 ml of dimethylformamide 5.3 ml of thiamin is slowly added. The solution is heated to 50 ° C. for 5 hours and then left at ambient temperature overnight. The dark orange solution is concentrated under reduced pressure (1-2 mm, <50 ° C.) to give an orange oily residue. The oil is dissolved in 400 mL ethyl acetate and washed with 100 mL (2 ×) 1N HCl, 150 mL (2 ×) water and 100 mL brine. The organic layer is dried over MgSO ₄ , filtered and concentrated to give 8.1 g (94.2%) of the title compound as an orange solid.

MS (ESI (+), m / e (%)) 454 (40, [M + H] ⁺ ), 456 (35, [M + H] ⁺ ), 471 (100, [M + NH ₄ ] ⁺ ) And 473 (100, [M + NH ₄ ] ⁺ ).

Chiral purity = 99.99% (HPLC: Whelk-O, 4.6 x 250 mm).

C. (R) -Carbenzyloxy-8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino [1,2a] quinoxaline-5 (6H) -one

6.0 g of iron powder is added to a 8.0 g solution of (R) -4-carbobenzyloxy-1- (4,5-dichloro-2-nitrophenyl) -piperazine-2-carboxylic acid in 200 ml of acetic acid. With good stirring, the mixture is heated at 60 ° C. for 2 hours and then concentrated under reduced pressure (1-2 mm, <40 ° C.) to give a black gray residue. This material is slurried with 400 ml of ethyl acetate and filtered. Repeat this process. The combined ethyl acetate filtrates are washed with 150 mL 1N HCl, 200 mL water (2 ×), 200 mL brine and dried over MgSO ₄ . The solvent is filtered and concentrated to give a semisolid material which is crystallized from ethyl acetate-hexane to give 5.44 g (76.1%) of the title compound as a white solid having a melting point of 136 to 138 ° C.

H ¹ NMR (400 Hz, d ₆ -DMSO) δ 10.81 (s, 1H); 7.38-7. 31 (m, 5 H); 7.04 (s, 1 H); 6.95 (s, 1 H); 5.11 (s, 2 H); 4.37 (d, 1 H, J = 12.5 Hz); 4.05 (d, 1 H, J = 13.4 Hz); 3.70 (d, 1 H, J = 11.2 Hz); 3.63 (dd, 1H, J = 3.6, 10.8 Hz); 3.00 (bs, 2 H); 2.66 (dt, 1 H, J = 3.6, 12.2 Hz).

IR (KBr) 3240, 1710, 1675, 1500, 1300, 1245, 1130 cm ^-1 .

MS (APCI, m / e (%)) 406 (100, [M + H] ⁺ ) and 408 (90, [M + H] ⁺ ).

Anal for C ₁₉ H ₁₇ Cl ₂ N ₃ O ₃ : C, 56.17; H, 4. 27; N, 10.34.

Found: C, 55.97; H, 4.33; N, 9.90.

Chiral Purity = 99.99% (HPLC: Chiralcel AD, 4.6 × 250mm)

[a] _D = + 23.89 ° (c = 1, CHCl ₃ ).

D. (R) -8,9-Dichloro-2,3,4,4a-tetrahydro-1H-pyrazino [1,2a] quinoxaline-5 (6H) -one

5.0 g of (R) -carbenzyloxy-8,9-dichloro-2,3,3,4a-tetrahydro-1H-pyrazino- [1,2a] quinoxaline-5 (6H) -one in 100 ml of acetic acid To the solution is added dropwise 15 ml of 30% HBr in acetic acid. The solution is stirred at ambient temperature for 5 hours and concentrated under reduced pressure (1 mm, <40 ° C.) to give a solid residue. The residue is dissolved in 300 ml of ethyl acetate, washed with 100 ml of 1N NaOH, washed with 200 ml of water (2 ×) and 300 ml of brine and dried over MgSO ₄ . Filter and concentrate the solvent to afford 3.59 g (99%) of crude free base. Purification by column chromatography (265 g of silica gel, 9: 1 ethyl acetate: 2N NH _{3 in} methanol) affords 1.8 g (54.9%) as a yellow solid having a melting point of 203 ° C. (decomposition). The solid (1.6 g) is dissolved in 50 ml of methanol and treated with 1M HCl in excess ether to yield 1.6 g (88.2%) of a hydrochloride salt as an off-white solid with a melting point above 290 ° C.

H ¹ NMR (400 Hz, d ₆ -DMSO) δ 11.00 (s, 1H); 9.58 (s, 2 H); 7.12 (s, 1 H); 7.02 (s, 1 H); 4.03 (dd, 1H, J = 11.6, 3.6 Hz); 3.87 (d, 1 H, J = 10.7 Hz); 3.61 (dd, 1H, J = 12.9, 2.0 Hz); 3.41 (d, 1 H, J = 9.5 Hz); 3.42-2.99 (m, 3 H).

IR (KBr) 2950, 2700, 1700, 1590, 1500 cm ^-1 .

MS (APCI, m / e (%)) 272 (100, [M + H] ⁺ ) and 274 (65, [M + H] ⁺ ).

Anal for C ₁₁ H ₁₁ Cl ₂ N ₃ O.HCl: C, 42.81; H, 3.92; N, 13.62.

Found: C, 42.45; H, 3.78; N, 13.43.

Chiral purity = 99.99% (HPLC: chiralcel AD, 4.6 × 250 mm).

[a] _D = + 27.72 ° (c = 1, DMSO).

Example 3

(S) -8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a] quinoxaline-5 (6H) -one

Method A (Disassembly Method)

The enantiomers of the compounds of Example 1 were separated by HPLC at a flow rate of 0.5 ml / min using a Chilasel AD column with 100% ethanol to provide the compounds of Examples 2 and 3. The first enantiomer (Example 2) elutes at 10.4 minutes ([α] ²⁵ _D +27.8) and the second enantiomer (Example 3) elutes at 13.7 minutes ([α] ²⁵ _D -25.5 ).

Method B (chiral synthesis)

A. (S) -4-carbenzyloxypiperazin-2-carboxylic acid

To a solution of 4.0 g of (S) -piperazine-2-carboxylic acid in 70 ml of water, 4.2 g of CuCl _{2 was} added. The pH of the blue solution is adjusted to 10 by adding 2.6N NaOH and 70 ml of acetone are added. The solution is cooled to 0-5 [deg.] C. and 5.3 g of benzylchloroformate in 40 ml of acetone are added over 90 minutes. Monitor pH and maintain by addition of 1N NaOH. Warm the mixture to ambient temperature and stir overnight. The blue precipitate is filtered off and the solid is washed with cold water. The solid is slurried in 100 mL of a methanol: water 1: 1 mixture and the pH is adjusted to less than 4 with 2.5N HCl. The solution is added to a column of 400 g of AG 50W-8X resin, prewashed with a pyridine: methanol: water 1:16:16 mixture. The product is eluted with the same solvent mixture and the combined product fractions are concentrated under reduced pressure (<50 ° C.) to give a semisolid residue. This material is slurried with 50 ml of methanol to give a crystalline solid. The solid was collected and dried to yield 4.0 g (50%) of a white solid with a melting point of 247 ° C. (decomposition).

H ¹ NMR (400 Hz, d ₆ -DMSO) δ 7.37-7.30 (m, 5H); 5.08 (s, 1 H); 4.19 (d, 1 H, J = 12.1 Hz); 3.89 (d, 1 H, J = 13.8); 3.27 (dd, 1H, J = 11.0, 4.0 Hz); 3.08 (m, 3 H); 2.82 (dt, 1 H, J = 12.2, 3.6 Hz).

IR (KBr) 3200, 1700, 1620, 1430, 1400, 1235, 1150 cm ^-1 .

MS (APCI, m / e (%)) 263 (100, [M ⁻ H] ⁻ ).

Anal for C ₁₃ H ₁₆ N ₂ O ₄ : C, 59.08; H, 6. 10; N, 10.60.

Found: C, 58.90; H, 6. 20; N, 10.58.

Chiral purity = 99.88% (HPLC: Chiralcel WH, 4.6 x 25 mm).

B. (S) -4-carbenzyloxy-1- (4,5-dichloro-2-nitrophenyl) -piperazine-2-carboxylic acid

Triethylamine in a slurry containing 1.5 g of (S) -4-carbenzyloxypiperazine-2-carboxylic acid, 1.25 g of 1,2-dichlorofluoro-5-nitrobenzene, 25 ml of water and 50 ml of dimethylformamide 1.6 ml is added slowly. The solution is heated to 50 ° C. for 5 hours and then left at ambient temperature overnight. The dark orange solution is concentrated under reduced pressure (1-2 mm, <50 ° C.) to give an orange oily residue. The oil is dissolved in 100 ml of ethyl acetate and washed with 20 ml (2 ×) 1N HCl, 100 ml (2 ×) water and 100 ml brine. The orange layer is dried over MgSO ₄ , filtered and concentrated to yield 2.5 g (99%) of an orange solid foam.

MS (APCI, m / e (%)) 452 (100, [MH] ⁻ ) and 454 (75, [MH] ⁻ ).

Anal for C ₁₉ H ₁₇ Cl ₂ N ₃ O ₆ .0.5H ₂ O: C, 49.26; H, 3.92; N, 9.07.

Found: C, 48.90; H, 3.80; N, 8.74.

Chiral purity = 99.99% (HPLC: Whelk-O, 4.6 x 250 mm).

[a] _D = -64.2 ° (c = 1, MeOH).

C. (S) -Carbobenzyloxy-8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino [1,2a] quinoxaline-5 (6H) -one

1.2 g of iron powder is added to a 1.5 g solution of (S) -4-carbobenzyloxy-1- (4,5-dichloro-2-nitrophenyl) -piperazine-2-carboxylic acid in 40 ml of acetic acid. With good stirring, the mixture is heated at 60 ° C. for 2 hours and then concentrated under reduced pressure (1-2 mm, <40 ° C.) to give a black gray residue. This material is slurried with 100 mL (2 ×) of ethyl acetate. The combined ethyl acetate filtrates are washed with 100 mL 1N HCl, 200 mL water (2 ×), brine 100 mL and dried over MgSO ₄ . The solvent is filtered and concentrated to give a semisolid material which is crystallized from hexane to give 1.08 g (80.6%) of the title compound as a white solid having a melting point of 174 to 6 ° C.

H ¹ NMR (400 Hz, d ₆ -DMSO) δ 10.93 (s, 1H); 7.41-7. 31 (m, 5 H); 7.04 (s, 1 H); 6.95 (s, 1 H); 5.11 (s, 1 H); 4.37 (d, 1 H, J = 12.5 Hz); 4.05 (d, 1 H, J = 13.4 Hz); 3.70 (d, 1 H, J = 11.2 Hz); 3.63 (dd, 1H, J = 3.6, 10.8 Hz); 3.00 (bs, 2 H); 2.66 (dt, 1 H, J = 3.6, 12.2 Hz).

IR (KBr) 3240, 1710, 1675, 1500, 1300, 1245, 1130 cm ^-1 .

MS (APCI, m / e (%)) 406 (70, [M + H] ⁺ and 408 (45, [M + H] ⁺ ).

Anal for C ₁₉ H ₁₇ Cl ₂ N ₃ O ₃ : C, 56.17; H, 4. 27; N, 10.34.

Found: C, 56,26; H, 4. 18; N, 10.37.

Chiral Purity = 99.9% (HPLC: Chiralcel AD, 4.6 × 250mm)

D. (S) -8,9-Dichloro-2,3,4,4a-tetrahydro-1H-pyrazino [1,2a] quinoxaline-5 (6H) -one

0.155 g of (S) -carbenzyloxy-8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino] [1,2a] quinoxaline-5 (6H) -one in 8 ml of acetic acid To the solution is added 1.5 ml 30% HBr in acetic acid dropwise. The solution is stirred at ambient temperature for 2.5 hours and concentrated under reduced pressure (1 mm, <40 ° C.) to give 0.18 g of a tan solid. The solid is dissolved in 50 ml of ethyl acetate, washed with 10 ml of 1N NaOH, 20 ml of water (2 ×) and brine 30 ml and dried over MgSO ₄ . Filtration and concentration of the solvent gave 0.056 g (53.8%) of the title compound as a white solid.

H ¹ NMR (400 Hz, d ₆ -DMSO) δ 10.63 (s, 1H); 6.96 (s, 1 H); 6.92 (s, 1 H); 3.49 (bd, 1 H, J = 10.0 Hz); 3.41 (dd, 1H, J = 10.5, 3.5 Hz); 3.29 (m, 1 H); 2.94 (bd, 1H, J = 9.9 Hz) 2.67-2.53 (m, 4H).

MS (APCI, m / e (%)) 272 (100, [M + H] ⁺ ) and 274 (55, [M + H] ⁺ ).

Chiral purity = 99.9% (HPLC: chiralcel AD, 4.6 × 250 mm).

[a] _D = -25.5 ° (c = 1, DMSO).

Example 4

8,9-dichloro-2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoxaline dihydrochloride

A 5 mL solution of 1 M BH ₃ · THF in THF was added to 8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a] quinoxaline-5 (6H) in 20 mL THF. Add to a 0.43 g cold solution (0 ° C.). The resulting solution is gradually warmed to room temperature overnight. The reaction is quenched with methanol and concentrated. The crude material is dissolved in methanol and concentrated again. The product was purified by flash column chromatography over silica gel (eluted with 40% ethyl acetate-hexanes) to yield 0.30 g (73%). The material is dissolved in ethanol and HCl in EtOH is added until the solution is acidic. Diethyl ether is then added until a precipitate forms. The solid is collected and dried in vacuo to give 68 mg of product as dihydrochloride salt.

¹ H NMR (400 MHz, d ₆ -DMSO) δ 9.44-9.35 (m, 2H); 6.86 (s, 1 H); 6.59 (s, 1 H); 3.78 (d, 1 H, J = 11.8 Hz); 3.37-3.24 (m, 4 H); 3.07-2.89 (m, 3 H); 2.69 (m, 1 H).

IR (KBr) 3380, 3190, 2970, 2810, 2750, 2400, 1600, 1500, 1450, 1380, 1270, 1140, 1110 cm ^-1 .

MS (APCI, m / e (%)) 258 (100, [M + H] ⁺ ), 260 (65, [M + H] ⁺ ).

Example 5

(R) -8,9-dichloro-2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoxaline dihydrochloride

In the same process as in Example 4, (R) -8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a] quinoxaline-5 (6H) 1.8 g of -one is reduced to give 0.77 g of product.

Enantiomers are separated by HPLC using a Kirapak AD column with 100% methanol at a flow rate of 0.8 ml / min. The first enantiomer elutes at 7.2 minutes and the second enantiomer elutes at 8.9 minutes.

HPLC analysis showed greater than 99% ee (hold time 7.2 min).

¹ H NMR (400 MHz, d ₆ -DMSO) δ 9.44-9.35 (m, 2H); 6.86 (s, 1 H); 6.59 (s, 1 H); 3.78 (d, 1 H, J = 11.8 Hz); 3.37-3.24 (m, 4 H); 3.07-2.89 (m, 3 H); 2.69 (m, 1 H).

IR (KBr) 3380, 3190, 2970, 2810, 2750, 2400, 1600, 1500, 1450, 1380, 1270, 1140, 1110 cm ^-1 .

MS (APCI, m / e (%)) 258 (100, [M + H] ⁺ ), 260 (65, [M + H] ⁺ ).

Example 6

(S) -8,9-dichloro-2,3,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoxaline, dihydrochloride

In the same process as described for Example 4, (S) -8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a] quinoxaline-5 (6H 0.80 g of) -one is reduced to yield 0.31 g of product.

Enantiomers are separated by HPLC using a Kirapak AD column with 100% methanol at a flow rate of 0.8 ml / min. The first enantiomer elutes at 7.2 minutes and the second enantiomer elutes at 8.9 minutes.

HPLC analysis showed greater than 99% ee (hold time 8.9 minutes).

[α] ²⁵ _D +4.35

¹ H NMR (400 MHz, d ₆ -DMSO) δ 9.44-9.35 (m, 2H); 6.86 (s, 1 H); 6.59 (s, 1 H); 3.78 (d, 1 H, J = 11.8 Hz); 3.37-3.24 (m, 4 H); 3.07-2.89 (m, 3 H); 2.69 (m, 1 H).

IR (KBr) 3380, 3190, 2970, 2810, 2750, 2400, 1600, 1500, 1450, 1380, 1270, 1140, 1110 cm ^-1 .

MS (APCI, m / e (%)) 258 (100, [M + H] ⁺ ), 260 (65, [M + H] ⁺ ).

Anal for C ₁₁ H ₁₄ Cl ₃ N ₃ : C, 44.85; H, 4.79, N, 14.26.

Found: C, 44.48; H, 4. 84; N, 13.71

Example 7

9-chloro-8-trifluoromethyl-2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a] quinoxalin-5 (6H) -one, hydrochloride

A. 4-Carbenzyloxy-1- (5-chloro-2-nitrophenyl-4-trifluoromethyl) piperazine-2-carboxylic acid

A mixture of 0.98 g of 4-carbobenzyloxypiperazin-2-carboxylic acid, 1.0 g of 2,4-dichloro-5-nitrobenzotrifluoride and 0.99 ml of diisopropylethylamine in 35 ml of dimethyl sulfoxide was heated to 60 ° C. Heat for hours. After cooling to ambient temperature, the resulting mixture is treated with HCl to pH 3. The mixture is then diluted with H ₂ O and extracted with ethyl acetate. The combined extracts are dried over MgSO ₄ and concentrated to give the crude product.

B. 3-Carbenzyloxy-9-chloro-8-trifluoromethyl-2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a] quinoxaline-5 (6H) -one

0.64 g of iron powder was added little by little to a rapidly stirred solution of 1.8 g of 4-carbobenzyloxy-1- (5-chloro2-nitrophenyl-4-trifluoromethyl) -piperazine-2-carboxylic acid in 35 ml of glacial acetic acid. Add. The resulting mixture is stirred at 50 ° C. overnight. After cooling to ambient temperature, the reaction mixture is poured into 20 ml of H ₂ O and filtered. The solid is washed with 1N HCl and diethyl ether to give 0.59 g of the desired product as a brown solid.

C. 9-Chloro-8-trifluoromethyl-2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a] quinoxaline-5 (6H) -one, hydrochloride

3-carbenzyloxy-9-chloro-8-trifluoromethyl-2,3,4,4a-tetrahydro-1H-pyrazino- [1,2-a] quinoxaline- in 12 ml of 50% aqueous methanol A mixture of 0.58 g of 5 (6H) -one and 2.3 g of potassium hydroxide is heated to reflux for 2 hours. The reaction mixture is concentrated under reduced pressure to about half of its original volume. The crude material is diluted with 100 ml of ethyl acetate and 100 ml of saturated aqueous sodium bicarbonate. The phases are separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over MgSO ₄ , filtered and concentrated. The crude material is dissolved in ethanol and the HCl solution in ethanol is added until it is acidic.

The resulting mixture is filtered and the solid is washed with ether. The solid is then dried in a vacuum oven to yield 0.21 g (48%) of the desired product as its hydrochloride salt.

¹ H NMR (400 MHz, d ₆ -DMSO) δ 11.0 (s, 1H); 9.47 (br s, 2 H); 7.22 (s, 1 H); 7.18 (s, 1 H); 4.19 (dd, 1H, J = 11.6, 3.2 Hz); 4.01 (d, 1 H, J = 11.8 Hz); 3.62 (d, 1 H, J = 11.7 Hz); 3.41 (d, 1 H, J = 10.1 Hz); 3.14-3.01 (m, 3 H).

IR (KBr) 3460, 3170, 3020, 2970, 2800, 1700, 1620, 1505, 1450, 1400, 1370, 1300, 1230, 1160, 1110 cm ^-1 .

MS (APCI, m / e 306 (100, [M + H] ⁺ ), 308 (33, [M + H] ⁺ ).

Anal for C ₁₂ H ₁₂ ClF ₃ N ₃ O: C, 42.13; H, 3.54; N, 12.28.

Found: C, 41.88; H, 3.71; N, 11.81.

Enantiomers are separated by HPLC using a Kirapak AD column of methanol: water 85:15 (+ 0.1% diethylamine) at a flow rate of 0.5 ml / min. The first enantiomer (Example 9) is eluted at 17.5 minutes ([α] ²⁵ _D +43), and the second enantiomer is eluted at 22.0 minutes ([α] ²⁵ _D -40).

Example 8

(S) -9-Chloro-8-trifluoromethyl-2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a] quinoxaline-5 (6H) -one, hydrochloride

Enantiomers are separated by HPLC using a Kirapak AD column of methanol: water 85:15 (+ 0.1% diethylamine) at a flow rate of 0.5 ml / min. The first enantiomer (Example 9) elutes at 17.5 minutes ([α] ²⁵ _D +43) and the second enantiomer (Example 8) elutes at 22.0 minutes ([α] ²⁵ _D -40 ).

¹ H NMR (400 MHz, d ₆ -DMSO) δ 11.0 (s, 1H); 9.47 (br s, 2 H); 7.22 (s, 1 H); 7.18 (s, 1 H); 4.19 (dd, 1H, J = 11.6, 3.2 Hz); 4.01 (d, 1 H, J = 11.8 Hz); 3.62 (d, 1 H, J = 11.7 Hz); 3.41 (d, 1 H, J = 10.1 Hz); 3.14-3.01 (m, 3 H).

IR (KBr) 3460, 3170, 3020, 2970, 2800, 1700, 1620, 1505, 1450, 1400, 1370, 1300, 1230, 1160, 1110 cm ^-1 .

MS (APCI, m / e 306 (100, [M + H] ⁺ ), 308 (33, [M + H] ⁺ ).

[α] ²⁵ _D -40

Anal for C ₁₂ H ₁₂ ClF ₃ N ₃ O: C, 42.13; H, 3.54; N, 12.28.

Found: C, 41.59; H, 3.61; N, 12.07.

Example 9

(R) -9-Chloro-8-trifluoromethyl-2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a] quinoxaline-5 (6H) -one, hydrochloride

Enantiomers are separated by HPLC using a Kirapak AD column of methanol: water 85:15 (+ 0.1% diethylamine) at a flow rate of 0.5 ml / min. The first enantiomer (Example 9) elutes at 17.5 minutes ([α] ²⁵ _D +43) and the second enantiomer (Example 8) elutes at 22.0 minutes ([α] ²⁵ _D -40 ).

HPLC analysis showed 96% of ee (retention time 17.5 minutes).

[α] ²⁵ _D + 43

¹ H NMR (400 MHz, d ₆ -DMSO) δ 11.0 (s, 1H); 9.47 (br s, 2 H); 7.22 (s, 1 H); 7.18 (s, 1 H); 4.19 (dd, 1H, J = 11.6, 3.2 Hz); 4.01 (d, 1 H, J = 11.8 Hz); 3.62 (d, 1 H, J = 11.7 Hz); 3.41 (d, 1 H, J = 10.1 Hz); 3.14-3.01 (m, 3 H).

IR (KBr) 3460, 3170, 3020, 2970, 2800, 1700, 1620, 1505, 1450, 1400, 1370, 1300, 1230, 1160, 1110 cm ^-1 .

MS (APCI, m / e 306 (100, [M + H] ⁺ ), 308 (33, [M + H] ⁺ ).

Anal for C ₁₂ H ₁₂ ClF ₃ N ₃ O: C, 42.13; H, 3.54; N, 12.28.

Found: C, 41.83; H, 3. 49; N, 12.01.

Example 10

9,10-Dichloro-2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a] quinoxalin-5 (6H) -one, hydrochloride

A. 4-Carbenzyloxy-1- (5,6-dichloro-2-nitrophenyl) piperazine-2-carboxylic acid

In the same process as described in Example 7A, 0.75 g of the desired product is obtained as a brown oil from 0.86 g of 2,3,4-trichloronitrobenzene and 1.0 g of 4-carbobenzyloxypiperazine-2-carboxylic acid.

B. 3-Carbenzyloxy-9,10-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a] quinoxalin-5 (6H) -one

In the same process as described in Example 7B, the desired product was browned from 0.75 g of 4-carbobenzyloxy-1- (5,6-dichloro-2-nitrophenyl) piperazine-2-carboxylic acid and 0.28 g of iron powder. 0.34 g (49%) is obtained as a solid.

C. 9,10-Dichloro-2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a] quinoxalin-5 (6H) -one, hydrochloride

In the same process as described in Example 7, 18 mg of a separation product from 0.34 g of 4-carbobenzyloxy-1- (5,6-dichloro-2-nitrophenyl) piperazine-2-carboxylic acid and 1.5 g of potassium hydroxide thereof was obtained. Obtained as a hydrochloride salt.

¹ H NMR (400 MHz, d ₆ -DMSO) δ 11.1 (s, 1H); 9.05 (br s, 2 H); 7.45 (d, 1 H, J = 8.8 Hz); 6.97 (d, 1 H, J = 8.8 Hz); 4.06 (d, 1 H, J = 3.7 Hz); 3.84 (d, 1 H, J = 13.2 Hz); 3.29-3. 12 (m, 4 H); 2.77 (m, 1 H).

IR (KBr) 3440, 3160, 3020, 2970, 1695, 1570, 1470, 1390, 1280 cm ^-1 .

MS (EI, m / e (%)) 271 (55, M ⁺ ), 273 (35, M ⁺ ).

Anal for C ₁₁ H ₁₂ Cl ₃ N ₃ O: C, 42.81; H, 3.92; N, 13.62.

Found: C, 42.40; H, 3.98; N, 12.82.

Example 11

7,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a] quinoxalin-5 (6H) -one, hydrochloride

2,4-dichloro-6-fluoronitrobenzene [Clark, J. H .; Nightengale, D. J., J. Fluorine Chem. (1996) 78 (1), 91-93] by 1,2-dichloro-4-fluoro-5-nitrobenzene to synthesize the title compound according to the method of Example 1. The melting point of the title compound is from 308 to 311 ° C.

Example 12

(R) -9-Chloro-2,3,4,4a-tetrahydro-1H-pyrazino [1,2a] quinoxaline-5 (6H) -one

A, (R) -4-carbenzyloxy-1- (5-chloro-2-nitrophenyl) -piperazine-2-carboxylic acid

In the same process as described in Method 2B of Example 2, from 0.95 g of (R) -4-carbenzyloxypiperazine-2-carboxylic acid, 1.2 g (85.7%) of the title compound as an orange solid having a melting point of 145 to 155 ° C. ) To obtain.

MS (ESI, m / e (%)) 420 (100, [M + H] ⁺ ) and 422 (40, [M + H] ⁺ ).

[a] _D = + 196.0 ° (c = 1, MeOH).

B. (R) -Cabobenzyloxy-9-chloro-2,3,4,4a-tetrahydro-1H-pyrazino [1,2a] quinoxalin-5 (6H) -one

Melting point of the title compound from 1.12 g of (R) -4-carbenzyloxy-1- (5-chloro-2-nitrophenyl) -piperazine-2-carboxylic acid in the same process as described in Method 2C of Example 2 0.80 g (80.8%) is obtained as a white solid which is 139 to 141 ° C.

¹ H (NMR (400 Hz, d ₆ -DMSO) δ 10.73 (s, 1H); 7.38-7.30 (m, 5H) l 6.87-6.78 (m, 3H); 5.11 (s, 2H); 4.38 (d, 1H , J = 13.0 Hz); 4.06 (d, 1H, J = 13.0 Hz); 3.70 (d, 1H, J = 11.4 Hz); 3.57 (dd, 1H, J = 11.0, 3.7 Hz); 2.97 (bs, 2H 2.65 (dt, 1 H, J = 11.3, 3.5 Hz).

MS (APCI, m / e (%)) 372 (100, [M + H] ⁺ ) and 374 (40, [M + H] ⁺ ).

Anal for C ₁₉ H ₁₈ ClN ₃ O ₃ : C, 61.38; H, 4.88; N, 11.30.

Found: C, 61.46; H, 4.76; N, 11.27.

C. (R) -9-Chloro-2,3,4,4a-tetrahydro-1H-pyrazino [1,2a] quinoxaline-5 (6H) -one

(R) -Cabobenzyloxy-9-chloro-2,3,4,4a-tetrahydro-1H-pyrazino [1,2a] quinoxaline-5 in the same process as described in Method 2D of Example 2 From 0.50 g of (6H) -one, 0.27 g (87.1%) of the title compound is obtained as a white solid having a melting point of 146-149 ° C.

MS ((+) ESI, m / e (%)) 238 (85, [M + H] ⁺ ).

Anal for C ₁₁ H ₁₂ ClN ₃ O: C, 55.59; H, 5.09; N, 17.68.

Found: C, 55.59; H, 4.98; N, 17.40.

[a] ²⁵ _D = + 28.9 ° (c = 1, MeOH).

Chiral purity = 99.99% (Kirapak AD, 4.6 x 250 mm).

Hydrochloride salts are prepared from HCl and MeOH as pale green solids having a melting point of 270-280 ° C.

H ¹ NMR (400 Hz, d ₆ -DMSO) δ 10.90 (s, 1H); 9.53 (s, 2 H); 6.94 (bs, 1 H); 6.90-6.84 (m, 2 H); 3.96 (dd, 1H, J = 13.1, 3.4 Hz); 3.86 (d, 1 H, J = 11.0 Hz); 3.62 (bd, 1 H, J = 12.0 Hz); 3.42 (d, 1 H, J = 10.6 Hz); 3.10-2.97 (m, 3 H).

MS (APCI, m / e (%)) 238 (100, [M + H] ⁺ ) and 240 (40, [M + H] ⁺ ).

Anal for C ₁₁ H ₁₂ ClN ₃ OHCl: C, 48.19; H, 4.78; N, 15.33.

Found: C, 48.38; H, 5.06; N, 14.91.

Chiral purity = 99.99% (chiralpak AD, 4.6 × 250 mm).

[a] _D = + 7.0 ° (c = 1, MeOH).

Example 13

8,9-difluoro-2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a] quinoxaline-5 (6H) -one

A. 4-Carbenzyloxy-1- (4,5-difluoro-2-nitrophenyl) -piperazine-2-carboxylic acid

In the same process as described for method 2B of Example 2, the title compound was obtained from 1.5 g of racemic 4-carbenzyloxypiperazin-2-carboxylic acid and 1,2,4-trifluoro-5-nitrobenzene. 0.4 g (16.7%) is obtained as a red residue.

MS (APCI, m / e (%)) 422 (45, [M + H] ⁺ ).

B. 3-Carbenzyloxy-8,9-difluoro-2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a] quinoxalin-5 (6H) -one

Melting point of the title compound from 0.29 g of 4-carbobenzoyloxy-1- (4,5-difluoro-2-nitrophenyl) -piperazine-2-carboxylic acid in the same process as described in Method 2C of Example 2 0.17 g (66.0%) is obtained as a white solid which is 226 to 8 ° C.

H ¹ NMR (400 MHz, d ₆ -DMSO) δ 10.70 (s, 1H); 7.39-7. 30 (m, 5 H); 6.98-6.92 (m, 1 H); 6.82-6.77 (m, 1 H); 5.11 (s, 2 H); 4.38 (d, 1 H, J = 13.0 Hz); 4.06 (d, 1 H, J = 13.0 Hz); 3.62 (d, 1 H, J = 11.0 Hz); 3.52 (dd, 1H, J = 11.0, 4.0 Hz); 2.98 (bs, 2 H); 2.65 (dt, 1 H, J = 11.0, 4.0 Hz).

MS (APCI, m / e (%)) 374 (100, [M + H] ⁺ ).

Anal for C ₁₉ H ₁₇ F ₂ N ₃ O ₃ : C, 61.12; H, 4.59; N, 11.25.

Found: C, 60.79; H, 4.54; N, 10.95.

C. 8,9-Difluoro-2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a] quinoxaline-5 (6H) -one

3-Carbobenzyloxy-8,9-difluoro-2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a] in the same process as described in Method 2D of Example 2 From 0.28 g of quinoxaline-5 (6H) -one, 0.14 g (78.1%) of the title compound is obtained as white solid. The hydroclide salt of this material, prepared from excess hydrogen chloride in ethanol, is obtained as a white solid with a melting point above 280 ° C.

H ¹ NMR (400 MHz, d ₆ -DMSO) δ 10.89 (s, 1H); 9.57 (s, 2 H); 7.07-7.02 (m, 1 H); 6.90-6.86 (m, 1 H); 3.93 (dd, 1H, J = 11.0, 3.0 Hz); 3.77 (d, 1 H, J = 11.0 Hz); 3.62 (m, 1 H); 3.62 (m, 1 H); 3.42 (d, 1 H, J = 10.0 Hz); 3.00-2.95 (m, 3 H).

MS ((+) APCI, m / e (%)) 240 (75, [M + H] ⁺ ).

Anal for C ₁₁ H ₁₁ F ₂ N ₃ O: C, 47.92; H, 4. 39; N, 15.24.

Found: C, 47.96; H, 4. 37; N, 14.86.

Claims (17)

A compound of formula (I) or a pharmaceutically acceptable salt thereof. Formula I In the above formula, R is hydrogen or alkyl of 1 to 6 carbon atoms, R 'is hydrogen, alkyl of 1 to 6 carbon atoms, acyl or aroyl of 2 to 7 carbon atoms, R ₁ , R ₂ , R ₃ and R ₄ are each independently hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, trifluoroalkyl, -CN, alkyl sulfonamide of 1 to 6 carbon atoms, Alkyl amides having 1 to 6 carbon atoms, amino, alkylamino having 1 to 6 carbon atoms, dialkylamino having 1 to 6 carbon atoms per alkyl residue, trifluoroalkoxy having 1 to 6 carbon atoms, acyl or aroyl having 2 to 7 carbon atoms, , X is CR ₅ R ₆ [wherein R ₅ and R ₆ are each independently hydrogen or alkyl having 1 to 6 carbon atoms] or a carbonyl group, Provided that at least two of R ₁ , R ₂ , R ₃ or R ₄ are not hydrogen. The compound of claim ₁ , wherein the non-hydrogen substituent of R ₁ , R ₂ , R ₃ or R ₄ is halogen or trifluoromethyl. The compound of formula IA or IB or a pharmaceutically acceptable salt thereof. Formula IA Formula IB The method of claim 1, (a) 8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a] quinoxalin-5 (6H) -one or a pharmaceutically acceptable salt thereof, (b) 8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a] quinoxaline-5 (6H) -onhydrochloride salt, (c) (R) -8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a] quinoxaline-5 (6H) -one or a pharmaceutically acceptable Salts thereof, (d) (R) -8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a] quinoxaline-5 (6H) -one hydrochloride salt, (e) (S) -8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a] quinoxaline-5 (6H) -one or pharmaceutically acceptable Salts thereof, (f) (S) -8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a] quinoxaline-5 (6H) -one hydrochloride salt, (g) 8,9-dichloro-2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoxaline or a pharmaceutically acceptable salt thereof, (h) 8,9-dichloro-2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoxaline hydrochloride salt, (i) (R) -8,9-dichloro-2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoxaline or a pharmaceutically acceptable salt thereof, (j) (R) -8,9-dichloro-2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoxaline dihydrochloride salt, (k) (R) -8,9-dichloro-2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoxaline or a pharmaceutically acceptable salt thereof, (l) (S) -8,9-dichloro-2,3,4,4a, 5,6-hexahydro-1H-pyrazino [1,2-a] quinoxaline dihydrochloride salt, (m) 9-chloro-8-trifluoromethyl-2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a] quinoxalin-5 (6H) -one or pharmaceutically acceptable Salts of lice, (n) 9-chloro-8-trifluoromethyl-2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a] quinoxaline-5 (6H) -one hydrochloride salt, (o) (S) -9-chloro-8-trifluoromethyl-2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a] quinoxalin-5 (6H) -one or Pharmaceutically acceptable salts thereof, (p) (S) -9-Chloro-8-trifluoromethyl-2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a] quinoxaline-5 (6H) -one hydro Chloride salts, (q) (R) -9-chloro-8-trifluoromethyl-2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a] quinoxalin-5 (6H) -one or Pharmaceutically acceptable salts thereof, (r) (R) -9-Chloro-8-trifluoromethyl-2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a] quinoxaline-5 (6H) -one hydro Chloride salts, (s) 9,10-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a] quinoxalin-5 (6H) -one or a pharmaceutically acceptable salt thereof, (t) 9,10-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a] quinoxalin-5 (6H) -one hydrochloride salt, (u) 7,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a] quinoxalin-5 (6H) -one or a pharmaceutically acceptable salt thereof, (v) 7,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a] quinoxaline-5 (6H) -onhydrochloride salt, (w) (R) -9-chloro-2,3,4,4a-tetrahydro-1H-pyrazino [1,2a] quinoxalin-5 (6H) -one or a pharmaceutically acceptable salt thereof, (x) (R) -9-chloro-2,3,4,4a-tetrahydro-1H-pyrazino [1,2a] quinoxalin-5 (6H) -one hydrochloride salt, (y) 8,9-difluoro-2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a] quinoxaline-5 (6H) -one or a pharmaceutically acceptable salt thereof or (z) 8,9-difluoro-2,3,4,4a-tetrahydro-1H-pyrazino [1,2-a] quinoxalin-5 (6H) -one hydrochloride salt. A method of treating obsessive compulsive disorder, depression, anxiety, panic disorder or schizophrenia in a mammal, comprising administering to the mammal a compound of formula (I) or a pharmaceutically acceptable salt thereof. Formula I In the above formula, R is hydrogen or alkyl of 1 to 6 carbon atoms, R 'is hydrogen, alkyl of 1 to 6 carbon atoms, acyl or aroyl of 2 to 7 carbon atoms, R ₁ , R ₂ , R ₃ and R ₄ are each independently hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, trifluoroalkyl, -CN, alkyl sulfonamide of 1 to 6 carbon atoms, Alkyl amides having 1 to 6 carbon atoms, amino, alkylamino having 1 to 6 carbon atoms, dialkylamino having 1 to 6 carbon atoms per alkyl residue, trifluoroalkoxy having 1 to 6 carbon atoms, acyl or aroyl having 2 to 7 carbon atoms, , X is CR ₅ R ₆ [wherein R ₅ and R ₆ are each independently hydrogen or alkyl having 1 to 6 carbon atoms] or a carbonyl group, Provided that at least one of R ₁ , R ₂ , R ₃ or R ₄ is not hydrogen. A method of treating a migraine in a mammal, comprising administering to the mammal a compound of formula (I) or a pharmaceutically acceptable salt thereof. Formula I In the above formula, R is hydrogen or alkyl of 1 to 6 carbon atoms, R 'is hydrogen, alkyl of 1 to 6 carbon atoms, acyl or aroyl of 2 to 7 carbon atoms, R ₁ , R ₂ , R ₃ and R ₄ are each independently hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, trifluoroalkyl, -CN, alkyl sulfonamide of 1 to 6 carbon atoms, Alkyl amides having 1 to 6 carbon atoms, amino, alkylamino having 1 to 6 carbon atoms, dialkylamino having 1 to 6 carbon atoms per alkyl residue, trifluoroalkoxy having 1 to 6 carbon atoms, acyl or aroyl having 2 to 7 carbon atoms, , X is CR ₅ R ₆ [wherein R ₅ and R ₆ are each independently hydrogen or alkyl having 1 to 6 carbon atoms] or a carbonyl group, Provided that at least one of R ₁ , R ₂ , R ₃ or R ₄ is not hydrogen. A method of treating a sleep disorder in a mammal, comprising administering to the mammal a compound of formula (I) or a pharmaceutically acceptable salt thereof. Formula I In the above formula, R is hydrogen or alkyl of 1 to 6 carbon atoms, R 'is hydrogen, alkyl of 1 to 6 carbon atoms, acyl or aroyl of 2 to 7 carbon atoms, R ₁ , R ₂ , R ₃ and R ₄ are each independently hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, trifluoroalkyl, -CN, alkyl sulfonamide of 1 to 6 carbon atoms, Alkyl amides having 1 to 6 carbon atoms, amino, alkylamino having 1 to 6 carbon atoms, dialkylamino having 1 to 6 carbon atoms per alkyl residue, trifluoroalkoxy having 1 to 6 carbon atoms, acyl or aroyl having 2 to 7 carbon atoms, , X is CR ₅ R ₆ [wherein R ₅ and R ₆ are each independently hydrogen or alkyl having 1 to 6 carbon atoms] or a carbonyl group, Provided that at least one of R ₁ , R ₂ , R ₃ or R ₄ is not hydrogen. A method of treating a mammalian eating disorder, comprising administering to a mammal a compound of formula (I) or a pharmaceutically acceptable salt thereof. Formula I In the above formula, R is hydrogen or alkyl of 1 to 6 carbon atoms, R 'is hydrogen, alkyl of 1 to 6 carbon atoms, acyl or aroyl of 2 to 7 carbon atoms, R ₁ , R ₂ , R ₃ and R ₄ are each independently hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, trifluoroalkyl, -CN, alkyl sulfonamide of 1 to 6 carbon atoms, Alkyl amides having 1 to 6 carbon atoms, amino, alkylamino having 1 to 6 carbon atoms, dialkylamino having 1 to 6 carbon atoms per alkyl residue, trifluoroalkoxy having 1 to 6 carbon atoms, acyl or aroyl having 2 to 7 carbon atoms, , X is CR ₅ R ₆ [wherein R ₅ and R ₆ are each independently hydrogen or alkyl having 1 to 6 carbon atoms] or a carbonyl group, Provided that at least one of R ₁ , R ₂ , R ₃ or R ₄ is not hydrogen. A method of treating obesity in a mammal, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to the mammal. Formula I In the above formula, R is hydrogen or alkyl of 1 to 6 carbon atoms, R 'is hydrogen, alkyl of 1 to 6 carbon atoms, acyl or aroyl of 2 to 7 carbon atoms, R ₁ , R ₂ , R ₃ and R ₄ are each independently hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, trifluoroalkyl, -CN, alkyl sulfonamide of 1 to 6 carbon atoms, Alkyl amides having 1 to 6 carbon atoms, amino, alkylamino having 1 to 6 carbon atoms, dialkylamino having 1 to 6 carbon atoms per alkyl residue, trifluoroalkoxy having 1 to 6 carbon atoms, acyl or aroyl having 2 to 7 carbon atoms, , X is CR ₅ R ₆ [wherein R ₅ and R ₆ are each independently hydrogen or alkyl having 1 to 6 carbon atoms] or a carbonyl group, Provided that at least one of R ₁ , R ₂ , R ₃ or R ₄ is not hydrogen. A method of treating type II diabetes in a mammal, comprising administering to the mammal a compound of formula (I) or a pharmaceutically acceptable salt thereof. Formula I In the above formula, R is hydrogen or alkyl of 1 to 6 carbon atoms, R 'is hydrogen, alkyl of 1 to 6 carbon atoms, acyl or aroyl of 2 to 7 carbon atoms, R ₁ , R ₂ , R ₃ and R ₄ are each independently hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, trifluoroalkyl, -CN, alkyl sulfonamide of 1 to 6 carbon atoms, Alkyl amides having 1 to 6 carbon atoms, amino, alkylamino having 1 to 6 carbon atoms, dialkylamino having 1 to 6 carbon atoms per alkyl residue, trifluoroalkoxy having 1 to 6 carbon atoms, acyl or aroyl having 2 to 7 carbon atoms, , X is CR ₅ R ₆ [wherein R ₅ and R ₆ are each independently hydrogen or alkyl having 1 to 6 carbon atoms] or a carbonyl group, Provided that at least one of R ₁ , R ₂ , R ₃ or R ₄ is not hydrogen. A method of treating epilepsy in a mammal, comprising administering to the mammal a compound of formula (I) or a pharmaceutically acceptable salt thereof. Formula I In the above formula, R is hydrogen or alkyl of 1 to 6 carbon atoms, R 'is hydrogen, alkyl of 1 to 6 carbon atoms, acyl or aroyl of 2 to 7 carbon atoms, R ₁ , R ₂ , R ₃ and R ₄ are each independently hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, trifluoroalkyl, -CN, alkyl sulfonamide of 1 to 6 carbon atoms, Alkyl amides having 1 to 6 carbon atoms, amino, alkylamino having 1 to 6 carbon atoms, dialkylamino having 1 to 6 carbon atoms per alkyl residue, trifluoroalkoxy having 1 to 6 carbon atoms, acyl or aroyl having 2 to 7 carbon atoms, , X is CR ₅ R ₆ [wherein R ₅ and R ₆ are each independently hydrogen or alkyl having 1 to 6 carbon atoms] or a carbonyl group, Provided that at least one of R ₁ , R ₂ , R ₃ or R ₄ is not hydrogen. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier. Formula I In the above formula, R is hydrogen or alkyl of 1 to 6 carbon atoms, R 'is hydrogen, alkyl of 1 to 6 carbon atoms, acyl or aroyl of 2 to 7 carbon atoms, R ₁ , R ₂ , R ₃ and R ₄ are each independently hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, trifluoroalkyl, -CN, alkyl sulfonamide of 1 to 6 carbon atoms, Alkyl amides having 1 to 6 carbon atoms, amino, alkylamino having 1 to 6 carbon atoms, dialkylamino having 1 to 6 carbon atoms per alkyl residue, trifluoroalkoxy having 1 to 6 carbon atoms, acyl or aroyl having 2 to 7 carbon atoms, , X is CR ₅ R ₆ [wherein R ₅ and R ₆ are each independently hydrogen or alkyl having 1 to 6 carbon atoms] or a carbonyl group, Provided that at least one of R ₁ , R ₂ , R ₃ or R ₄ is not hydrogen. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament. Formula I In the above formula, R is hydrogen or alkyl of 1 to 6 carbon atoms, R 'is hydrogen, alkyl of 1 to 6 carbon atoms, acyl or aroyl of 2 to 7 carbon atoms, R ₁ , R ₂ , R ₃ and R ₄ are each independently hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, trifluoroalkyl, -CN, alkyl sulfonamide of 1 to 6 carbon atoms, Alkyl amides having 1 to 6 carbon atoms, amino, alkylamino having 1 to 6 carbon atoms, dialkylamino having 1 to 6 carbon atoms per alkyl residue, trifluoroalkoxy having 1 to 6 carbon atoms, acyl or aroyl having 2 to 7 carbon atoms, , X is CR ₅ R ₆ [wherein R ₅ and R ₆ are each independently hydrogen or alkyl having 1 to 6 carbon atoms] or a carbonyl group, Provided that at least two of R ₁ , R ₂ , R ₃ or R ₄ are not hydrogen. 14. The treatment of a central nervous system related disease according to claim 13, for obsessive compulsive disorder, depression, anxiety, panic disorder, schizophrenia, migraine, sleep disorders such as sleep apnea, eating disorders such as binge eating, obesity, type II diabetes and epilepsy Compound for use as a medicament. The compound of formula 1 is reacted with a compound of formula 2 at a temperature exceeding ambient temperature in the presence of a base to form a compound of formula 3, which is reduced by the reduction of the NO ₂ group to an amino group, and then heated at an elevated temperature to After forming the compound of 4, the Cbz group is removed to give a compound of formula I wherein R 'is H, and optionally treated with a reducing agent to form a compound of formula I wherein X is CR ₅ R ₆ , or a base and an alkyl or Treatment with an acyl halide followed by removal of the Cbz group yields a compound of formula 6, optionally with a reducing agent to form a compound of formula I wherein X is CR ₅ R ₆ , or alkylation with a base and an alkyl halide to form R to yield the alkyl compound of formula (I) having 1 to 6 carbon atoms, and optionally by treatment with a reducing agent which comprises an X to form a compound of formula (I) CR ₅ R _6, formula (I) Salts thereof, process for producing the compound or a pharmaceutically acceptable. Formula I In the above formula, R is hydrogen or alkyl of 1 to 6 carbon atoms, R 'is hydrogen, alkyl of 1 to 6 carbon atoms, acyl or aroyl of 2 to 7 carbon atoms, R ₁ , R ₂ , R ₃ and R ₄ are each independently hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, trifluoroalkyl, -CN, alkyl sulfonamide of 1 to 6 carbon atoms, Alkyl amides having 1 to 6 carbon atoms, amino, alkylamino having 1 to 6 carbon atoms, dialkylamino having 1 to 6 carbon atoms per alkyl moiety, trifluoroalkoxy having 1 to 6 carbon atoms, acyl or aroyl having 2 to 7 carbon atoms, , X is CR ₅ R ₆ wherein R ₅ and R ₆ are each independently hydrogen or alkyl having 1 to 6 carbon atoms or a carbonyl group, Provided that at least two of R ₁ , R ₂ , R ₃ or R ₄ are not hydrogen, Cbz is a carbobenzyloxy group, Y is chlorine, fluorine or bromine. The compound of formula 10 is reacted with N, O-dimethylhydroxylamine hydrochloride in the presence of a base and a coupling agent to form a compound of formula 11, which is treated with a Grignard reagent or an organolithium reagent to The compound is obtained and then (a) reduced to the compound of formula 13 using a reducing agent and then ring-closed at elevated temperature in the presence of an acid to give a compound of formula I wherein R 'is hydrogen, or optionally the corresponding alkyl or acyl halide Alkylation or acylation with to give a compound of formula I wherein R 'is other than hydrogen, optionally forming a pharmaceutical salt thereof, or (b) treatment with a Grignard reagent to give a tertiary alcohol of formula 16 Reduced to metal in acid and then heated to elevated temperature to give a compound of formula I wherein R 'is hydrogen, optionally corresponding alkyl or acyl halide Alkylating or acylating to obtain a compound of formula (I), wherein R 'is other than hydrogen, and optionally forming a pharmaceutical salt thereof. 12. A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof. Formula I In the above formula, R is hydrogen or alkyl of 1 to 6 carbon atoms, R 'is hydrogen, alkyl of 1 to 6 carbon atoms, acyl or aroyl of 2 to 7 carbon atoms, R ₁ , R ₂ , R ₃ and R ₄ are each independently hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, trifluoroalkyl, -CN, alkyl sulfonamide of 1 to 6 carbon atoms, Alkyl amides having 1 to 6 carbon atoms, amino, alkylamino having 1 to 6 carbon atoms, dialkylamino having 1 to 6 carbon atoms per alkyl residue, trifluoroalkoxy having 1 to 6 carbon atoms, acyl or aroyl having 2 to 7 carbon atoms, , X is CR ₅ R ₆ wherein R ₅ and R ₆ are each independently hydrogen or alkyl having 1 to 6 carbon atoms or a carbonyl group, Provided that at least two of R ₁ , R ₂ , R ₃ or R ₄ are not hydrogen. Starting from the relevant (S) or (R) -piperazinecarboxylic acid, it is converted to the corresponding N protected compound of formula 19 ', followed by reaction with a substituted ortho-nitrofluorobenzene To yield the corresponding (S) or (R) compound, which is reduced by nitro group reduction to an amino group, heated to elevated temperature, and then the Cbz protecting group is removed to form a compound of formula (IA) or (IB), optionally A process for preparing a compound of formula (IA) or (IB) or a pharmaceutically acceptable salt thereof, comprising forming a pharmaceutical salt thereof. Formula IA Formula IB In the above formula, R, R ₁ , R ₂ , R ₃ and R ₄ are as defined in claim 1, Cbz is a carbobenzyloxy group.