JPH06228112A - @(3754/24)1h,4h)quinoxaline derivative - Google Patents

Abstract

PURPOSE:To obtain the subject new compound useful as a medicine for preventing Huntington's chorea, Parkinson's disease, erosion, senile dementia, cerebral ischemia, anoxia, etc., having glutamate receptor antagonism and protecting action on nerve cells. CONSTITUTION:A (1H,4H)quinoquixaline derivative of formula I (R<1> is H, nitro or trifluoromethyl; R<2> is H, OH, lower alkoxy, carboxyl, lower alkoxycarbonyl, amino, lower alkoxycarbonylamino) such as 6-(1-morpholino)quinoxaline 2,3(1H,4 H)-dione of formula IV. The compound of formula I, for example, is obtained by reacting a compound of formula II (X is halogen) with a nitrogen-containing heterocyclic compound of formula III while stirring.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention has a glutamate receptor antagonistic action and a neuronal cell protective action (1H, 4
H) relates to a quinoxaline derivative or a salt thereof.

[0002]

Amino acids such as L-glutamic acid and L-aspartic acid are known to be central nervous system transmitters. When these excitatory amino acids accumulate extracellularly and continue to stimulate nerves excessively, Huntington's disease, Parkinson's disease, epilepsy, senile dementia, and cerebral ischemia, hypoxia, and hypoglycemia It is said to lead to observed neurodegeneration or deficiency of mental and motor functions. Therefore, drugs capable of regulating the abnormal action of these excitatory amino acids have been considered to be useful for treating neurodegeneration and psychiatric disorders.

The action of excitatory amino acids is exerted through specific receptors located at the postsynaptic or presynaptic sites. Such receptors are currently subdivided into five groups based on electrophysiological and neurochemical evidence. 1) NMDA (N-methyl-D-aspartate) receptor 2) AMPA [2-amino-3- (3-hydroxy-5)
-Methyl-4-isoxazole) propionic acid] receptor 3) Kainate receptor 4) Metabotropic glutamate receptor 5) AP-4 (2-amino-4-phosphonobutanoic acid) receptor

L-glutamic acid and L-aspartic acid activate the above receptors and transmit excitement. NMD
When an excessive amount of A, AMPA or kainate is applied to the nerve, neuropathy occurs. 2-amino-5-phosphonovaleric acid or 2 which is a selective antagonist of NMDA receptor
-Amino-7-phosphonoheptanoic acid has been reported to be effective in neuropathy by NMDA action, and experimental animal model of epilepsy and cerebral ischemia (J. Pharmacology and Exper.
imental Therapeutics 250 , 100 (1989); J.Pharmacology
and Experimental Therapeutics, 240 , 737 (1987); Scienc
e, 226 , 850 (1984). The NMDA receptor is reported to act allosterically by the glycine receptor (EJP, 126 , 303 (1986)), and the HA-966, a glycine receptor antagonist, is also an experimental animal for cerebral ischemia. It has been reported to be effective in a model (American Society of Neuroscience 1989).

NBQX (6-nitro-7-sulfamoylbenzo [f] quinoxaline), a selective antagonist of AMPA receptor, was also reported to be effective in an experimental animal model of cerebral ischemia. (Science, 247 , 571
(1990)), on the other hand, no selective antagonist of kainate receptor, metabotropic glutamate receptor, AP-4 receptor has been reported so far.

[0006]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a compound having a diketoquinoxaline glutamate receptor antagonistic action. NMDA-
Examples of the diketoquinoxaline derivative having a glycine receptor antagonism and / or an AMPA receptor antagonism include:
Some reports have been made (JP-A-63-83074, JP-A-63-258466, JP-A-1-153680, JP-A-2-48578, JP-A-2-221263, JP-A-2-221264). Is a R ² -substituted nitrogen-containing heterocyclic group-substituted (1H, 4H) quinoxaline derivative which may contain a sulfur atom or an oxygen atom, and has the following substituent R ¹ other than the saturated heterocyclic group in terms of chemical structure. It is a novel compound that has characteristics and exhibits superior pharmacological activity.

[0007]

That is, the present invention is based on the general formula

[0008]

[Chemical 3] (The symbols in the formulas have the following meanings: R ¹ : hydrogen atom, nitro group or trifluoromethyl group

[0009]

[Chemical 4]

R ² is a (1H, 4H) quinoxaline derivative represented by hydrogen atom, hydroxyl group, lower alkoxy group, carboxyl group, lower alkoxycarbonyl group, amino group, lower alkoxycarbonylamino group) or a salt thereof. Hereinafter, the compound represented by the general formula (I) will be described in detail.

[0011]

[Chemical 5]

Examples of the nitrogen-containing saturated heterocyclic group which may contain an oxygen atom or a sulfur atom represented by are 4- to 8-membered rings, and specific examples thereof include azetidinyl group, pyrrolidinyl group, piperidinyl group and hexaso. Examples thereof include a droazepinyl group, an isoxazolidinyl group, an oxazolidinyl group, a morpholino group and a thiomorpholino group, and a pyrrolidinyl group, a piperidinyl group, a morpholino group and a thiomorpholino group are preferable. As the lower alkoxy group in R ² , a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a pentyloxy (amyloxy) group, an isopentyloxy group, straight or branched alkoxy having 1 to 6 carbon atoms such as tert-pentyloxy group, neopentyloxy group, 2-methylbutoxy, 1,2-dimethylpropoxy group, 1-ethylpropoxy group, hexyloxy group. A group, preferably a linear or branched alkoxy group having 1 to 4 carbon atoms.

The lower alkoxycarbonyl group for R ² is methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group. , Pentyloxy (amyloxy) carbonyl group, isopentyloxycarbonyl group, tert
A linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms such as a pentyloxycarbonyl group and a neopentyloxycarbonyl group, preferably 1 carbon atom
To 4 alkoxycarbonyl groups, specifically, a methoxycarbonyl group and an ethoxycarbonyl group.

The lower alkoxycarbonylamino group for R ² means a group in which a hydrogen atom of an amino group is substituted with the above lower alkoxycarbonyl group, and preferably a methoxycarbonylamino group, an ethoxycarbonylamino group, or a tert- It is a butoxycarbonylamino group. The (1H, 4H) quinoxaline derivative of the present invention is specifically shown in the table below, but the present invention is not limited thereto. In the table, "Mo" is a morpholino group and "P"
“Y” is a pyrrolidinyl group, “Pi” is a piperidinyl group,
"Th" means thiomorpholino group.

[0015]

[Chemical 6]

[0016]

[Table 1]

Among the above compounds, particularly preferable compounds are 1, 2, 27, 55, 56, 58, 65, 76 and 78 compounds. These compounds can be synthesized by a method similar to the synthetic route described in the following process chart and examples.

The compound (I) of the present invention has stereoisomers, optically active compounds and tautomers depending on the kind of the substituents.
The object compound of the present invention includes a separated product or a mixture of these isomers. The compound (I) of the present invention forms a salt with an acid or a base. Hydrochloric acid as the salt with acid,
Mineral acids such as hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid , An acid addition salt with an organic acid such as tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid and glutamic acid. Examples of salts with bases include inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum, organic bases such as methylamine, ethylamine, and ethanolamine, or salts with basic amino acids such as lysine, arginine, ornithine, and ammonium salts. To be In addition, hydrates and solvates can be formed. (Production Method) The compound of the present invention can be produced by the method represented by the following reaction scheme. First manufacturing method

[0019]

[Chemical 7]

(In the formula, X means a halogen atom. R
¹ and R ² have the above-mentioned meanings. ) To carry out the above reaction, a halogen compound (II) in an amount corresponding to the reaction is used.
And the nitrogen-containing heterocyclic compound (III) are reacted with stirring. The reaction is usually carried out by heating in a solvent such as dimethylformamide, dimethylsulfoxide, acetonitrile, acetone, tetrahydrofuran. To promote the reaction, a base such as caustic soda, caustic potash, sodium hydride or a copper salt may be added. Second manufacturing method

[0021]

[Chemical 8]

(The symbols in the formulas have the above-mentioned meanings.) To carry out this production method, the diamino compound (IV) and an equivalent or excess amount of oxalic acid or its reactive derivative (V) are added. React at room temperature or under heating. Examples of the reactive derivative of oxalic acid include salts, esters, hydrates, anhydrides and acid chlorides. This reaction is usually performed in an aqueous or alcohol solvent. An acid such as hydrochloric acid is preferably added to accelerate the reaction. Third method

[0023]

[Chemical 9] (The symbols in the formulas have the above-mentioned meanings.) This production method is an alternative to the second production method and comprises the tert-butylamine compound (VI) and an equivalent or excess amount of oxalic acid or its reactive derivative. It can be carried out by reacting in an aqueous or alcoholic solvent under acidic condition with stirring at room temperature or under heating. The reactive derivative of oxalic acid is as described above. Fourth manufacturing method

[0024]

[Chemical 10]

(In the formula, R ³ represents a lower alkyl group. The other symbols are as described above.) This reaction is a reductive cyclization of the lower alcoxaryl amino compound (VII). , Pd-carbon and the like can be carried out by a conventional catalytic reduction method. The compound of the present invention thus produced is isolated or purified as a free salt or a salt thereof. Isolation / purification includes extraction, concentration, evaporation,
It is carried out by applying usual chemical operations such as crystallization, filtration, recrystallization and various kinds of chromatography.

[0026]

The compound of the present invention has an affinity for the AMPA receptor. Moreover, it showed a strong neuroprotective effect on the hippocampus of sand rats. It also showed an inhibitory effect on audiogenic convulsions in DBA / 2 mice. Therefore, the compound of the present invention is particularly useful for preventing Huntington's disease, Parkinson's disease, epilepsy, senile dementia, and cerebral ischemia, hypoxia, hypoglycemia and post-convulsive neurodegeneration or mental and motor dysfunction. It is a useful drug.

The [ ³ H] AMPA binding inhibitory activity, neuronal cell protective activity and audiogenic convulsive suppressive activity of the compound of the present invention were confirmed as follows. 1) Measurement of [ ³ H] AMPA binding activity: about 45 nM [
³ H] AMPA {2-amino-3- (3-hydroxy-
5-methyl-4-isoxazole) propionic acid}, about 300 mg of rat cerebral membrane preparation, and a test compound in a total amount of 0.5 ml of a reaction solution in ice water 45
Let react for minutes. Bound to quisqualate receptor [ ³ H]
The amount of AMPA was measured by the filtration method. The specific binding amount was the portion replaced by 10 μM quisqualic acid in the total binding amount. The test compounds were evaluated by determining the binding inhibition rate on the specific binding.

2) Neuronal Protective Action in Hippocampus The protective action of neuronal necrosis caused by cerebral ischemia was tested using a sand rat bilateral common carotid artery occlusion model. Procedure The animals were allowed to recover from anesthesia by occluding the bilateral common carotid arteries under halothane anesthesia for 5 minutes while keeping the sand rats warm to avoid a decrease in body temperature. Four days later, the brain was removed and a section was prepared, and the extent of nerve cell damage in the hippocampal CAI was examined histologically.

Administration Method The test drug was suspended in 0.5% methylcellulose solution or dissolved in physiological saline and administered intraperitoneally. 60 minutes, 70 minutes, and 85 minutes after the recanalization, 30 mg / kg was administered once.

Evaluation Method Histological examination was performed under an optical microscope. The degree of nerve cell damage in the hippocampal CAI part was evaluated on a four-point scale: no damage, mild necrosis, moderate necrosis and complete necrosis.

3) Measurement of audiogenic convulsive suppressive action in DBA / 2 mice: 10 male mice aged 21-28 days were placed in a soundproof box, and a sound stimulus of 12 kHz, 120 dB was applied for 1 minute or the mice were rigid. I had a load until I got sexual convulsions. The test compound was suspended in 0.5% methylcellulose solution and intraperitoneally administered 15 minutes before the sound stimulation. The drug efficacy was evaluated by the presence or absence of convulsions, and the minimum effective dose (MED) was determined. A preparation containing one or more kinds of the compound of the present invention or a salt thereof as an active ingredient is prepared by using a carrier, an excipient and other additives usually used for preparation. The carrier or excipient for the formulation may be solid or liquid,
For example, lactose, magnesium stearate, starch,
Examples include talc, gelatin, agar, pectin, acacia, olive oil, sesame oil, cocoa butter, ethylene glycol, and other commonly used substances.

For administration, tablets, pills, capsules, granules,
It may be in any form of oral administration such as powder or liquid, or parenteral administration such as injection such as intravenous injection or intramuscular injection, suppository, and transdermal. The dose is appropriately determined depending on the individual case in consideration of symptoms, age of administration subject, sex, etc., but is usually 1 to 1000 mg, preferably 50 to 200 mg per adult per day. Oral administration in divided doses from one to several times a day, or in the range of 1 mg to 500 mg per adult per day, in divided doses from once to several times daily, or 1 hour per day Intravenous continuous administration in the range of -24 hours. Of course, as described above, the dose varies depending on various conditions, so a dose smaller than the above dose range may be sufficient.

[0033]

EXAMPLES Next, the present invention will be described in more detail by way of examples, but the present invention is not limited to these examples. The production examples of the main raw material compounds used in the examples will be described as reference examples. Reference example 1

[0034]

[Chemical 11]

A) 2,4-dichloro-5-nitrobenzotrifluoride 25 g, isopropanol 130 ml
A mixture of 50 ml of tert-butylamine was refluxed overnight. Water was added to the reaction solution, and the resulting crystals were filtered and washed with water to give N-tert-butyl-3-chloro-6-nitro-.
28 g of 4-trifluoromethylaniline was obtained.

B) 2 g of the above N-tert-butyl-3-chloro-6-nitro-4-trifluoromethylaniline
And 3 ml of piperidylin were heated at 120 ° C. for 3 hours. After allowing to cool to room temperature, dilute hydrochloric acid was added and the resulting crystals were washed with water to obtain 2.15 g of N-tert-butyl-6-nitro-3- (1-piperidino) -4-trifluoromethylaniline.

Physicochemical properties ¹ H-NMR (DMSO-d ₆ , δ from TM
S): 1.52 (9H, s), 1.61 (2H, m),
1.72 (4H, m), 3.03 (4H, m), 6.5
6 (1H, s), 8.47 (1H, s), 8.59 (1
H, s) GC-MS: 345 (M ⁺ ) The following Reference Examples 2 to 3 can be obtained by treating in the same manner as in Reference Example 1. Reference example 2

[0038]

[Chemical 12]

Product compound: N-tert-butyl-3-
(3-Hydroxy-1-piperidino) -6-nitro-4
-Trifluoromethylaniline raw material compound: 3-hydroxypiperidine and N-ter
t-Butyl-3-chloro-6-nitro-4-trifluoromethylaniline Physicochemical properties ¹ H-NMR (DMSO-d ₆ , δ from TM
S): 1.30 (1H, m), 1.49 (9H, s),
1.77 (1H, m), 1.93 (1H, m), 2.6
2 (1H, t), 2.78 (1H, t), 3.18 (1
H, m), 3.33 (2H, m), 3.62 (1H,
m), 4.94 (1H, d), 6.63 (1H, s),
8.30 (1H, s), 8.45 (1H, s) GC-MS: 361 (M ⁺ ) Reference Example 3

[0040]

[Chemical 13]

Product compound: N-tert-butyl-3-
(3-Ethoxycarbonyl-1-piperidino) -6-nitro-4-trifluoromethylaniline Raw material compound: 3-ethoxycarbonylpiperidine and N
-Tert-butyl-3-chloro-6-nitro-4-trifluoromethylaniline

Physicochemical properties ¹ H-NMR (DMSO-d ₆ , δ from TM
S): 1.15 (3H, t), 1.49 (9H, s),
1.57 (2H, m), 1.82 (1H, m), 1.9
1 (1H, m), 2.66 (1H, m), 2.94 (1
H, m), 3.06 (1H, m), 3.29 (1H,
m), 3.42 (1H, m), 4.08 (2H, d
d), 6.67 (1H, s), 8.31 (1H, s),
8.46 (1H, s) EI-MS: 417 (M ⁺ ) Reference Example 4

[0043]

[Chemical 14]

From the reaction of 3-chloro-6-nitro-4-trifluoromethylaniline with 3-tert-butoxycarbonylaminopyrrolidine in the same manner as in Reference Example 1, 3-
(3-tert-Butoxycarbonylamino-1-pyrrolidino) -6-nitro-4-trifluoromethylaniline was obtained.

1 g of 3- (3-tert-butoxycarbonylamino-1-pyrrolidino) -6-nitro-4-trifluoromethylaniline was dissolved in THF, and a solution of 0.44 ml of ethyl chlorooxalate in 2 ml of THF was cooled with ice. Was dripped. After slowly returning to room temperature and stirring overnight, under ice cooling,
A small amount of water was added. This was concentrated, made into a chloroform solution, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by column chromatography (eluting with chloroform) to give 3- (3-tert-butoxycarbonylamino-1-pyrrolidino) -6-nitro-
1 g of 4-trifluoromethyl-1-ethyloxalylanilide was obtained.

Physicochemical properties Mass spectrometric value (m / z): 491 (M + 1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δppm: 1.45 (12H), 2.01 (1H,
m), 2.29 (1H, m), 3.43 (1H, m),
3.64 (1H, m), 3.71 (1H, m), 3.8
5 (1H, m), 4.33 (1H, m), 4.46 (2
H, dd), 4.64 (1H, brs), 7.26 (1
H, s), 8.34 (1H, s), 8.64 (1H,
s), 12.35 (1H, s) Example 1

[0047]

[Chemical 15]

A) 5-chloro-2-nitroaniline 3 g
Morpholine (10 ml) was added to the mixture, and the mixture was stirred at 130 ° C overnight. Ether was added to the reaction solution, and the resulting crystals were recrystallized from isopropanol to give 5- (1-morpholino) -2.
-3.2 g of nitroaniline were obtained. Continue this 2
g, ethanol 40 ml, 10% Pd-carbon 100 mg
Was hydrogenated at room temperature under normal pressure. The reaction solution was filtered and washed with ethanol, and the mother liquor was concentrated to dryness.

B) Subsequently, a solution of 0.8 g of oxalic acid and 10 ml of 4N-hydrochloric acid was prepared and refluxed for 1.5 hours. The reaction solution was ice-cooled, the resulting crystals were collected by filtration, and recrystallized with 4N hydrochloric acid water to give 6- (1-morpholino) quinoxaline-2,3.
1.8 g of (1H, 4H) -dione.hydrochloride was obtained.

Physicochemical properties ¹ H-NMR (DMSO-d ₆ , δ from TM
S); 3.21 (4H, m), 3.84 (4H, m),
7.02 to 7.05 (3H), 7.40 (1H, b
r), 11.97 (2H, br) MS (EI); 247 (M ⁺ ) mp. > 300 ° C. EA; (as C ₁₂ H ₁₃ N ₃ O ₃ .1HCl.0.2H ₂ O) C H N Cl calculated value (%) 50.16 5.05 14.63 12.34 experimental value (% ) 50.09 5.03 14.66 12.32 Example 2 The following Example 2 can be obtained by treating in the same manner as in Example 1.

[0051]

[Chemical 16]

Product compound: 6- (1-pyrrolidino) quinoxaline-2,3 (1H, 4H) -dione Raw material compound: 5-chloro-2-nitroaniline and pyrrolidine

Physicochemical properties ¹ H-NMR (DMSO-d ₆ , δ from TM
S); 2.01 (4H, m), 3.37 (4H, m),
6.82 (2H), 7.10 (1H, d), 7.2 (1
H), 11.93 (2H) MS (EI); 231 (M
⁺ ) Mp. > 300 ° C. EA; (as C ₁₂ H ₁₃ N ₃ O ₂ .1HCl.0.5H ₂ O) C H N Cl calculated value (%) 52.09 5.46 15.19 12.81 experimental value (% ) 52.03 5.46 15.96 13.15 Example 3

[0054]

[Chemical 17]

6- (1-morpholino) quinoxaline-
1 g of 2,3 (1H, 4H) -dione was dissolved in 10 ml of sulfuric acid, and 0.16 ml of fuming nitric acid was added at -5 ° C. The temperature was gradually raised, and after 30 minutes, the reaction solution was poured into ice water. Alkaline water was added to the reaction solution, the resulting crystals were filtered, washed with water, and recrystallized from water to give 6- (1-morpholino) -7-
0.2 g of nitroquinoxaline-2,3 (1H, 4H) -dione was obtained.

Physicochemical properties ¹ H-NMR (DMSO-d ₆ , δ from TM
S); 2.91 (4H, m), 3.72 (4H, m),
6.94 (1H, s), 7.72 (1H, s), 11.
96, 12.09 (each 1H, br, s) MS (EI); 292 (M ⁺ ) mp. > 300 ° C. EA; (as C ₁₂ H ₁₂ N ₄ O ₅ ) C H N calculated value (%) 49.32 4.14 19.17 experimental value (%) 49.23 3.99 19.20 Example Four

[0057]

[Chemical 18]

N-tert-butyl-6-nitro-3-
1.86 g of (1-piperidino) -4-trifluoromethylaniline was added to 20 ml of ethanol, 5 ml of 1N hydrochloric acid water,
It was mixed with 250 mg of 10% Pd-carbon and hydrogenated under normal pressure and normal temperature. The reaction solution was filtered, insoluble matter was washed with 1N hydrochloric acid water, and concentrated. Oxalic acid 0.35g, 4N
10 ml of hydrochloric acid water was added and refluxed for 4 hours. The reaction solution was concentrated to dryness, and the crystals were washed with hot water to give 6- (1-piperidino) -7-trifluoromethylquinoxaline-2,3.
260 mg of (1H, 4H) -dione was obtained.

Physicochemical properties ¹ H-NMR (DMSO-d ₆ , δ from TM
S); 1.52 (2H, m), 1.61 (4H, m),
2.74 (4H, m), 7.16 (1H, s), 7.3
7 (1H, s), 11.96 (1H, s), 12.04
(1H, s) MS (FAB); 314 (M ⁺⁺ 1) mp. > 300 ° C. EA; (as C ₁₄ H ₁₄ N ₃ O ₂ F ₃ ) C H N calculated value (%) 53.68 4.50 13.41 experimental value (%) 53.65 4.54 13.21 Example 5

[0060]

[Chemical 19]

By treating in the same manner as in Example 4, the following compound can be obtained. Product compound: 6- (3-hydroxy-1-piperidino)
-7-Trifluoromethylquinoxaline-2,3 (1
H, 4H) -dione raw material compound; N-tert-butyl-6-nitro-3-
(3-Hydroxy-1-piperidino) -4-trifluoromethylaniline

Physicochemical properties ¹ H-NMR (DMSO-d ₆ , δ from TM
S); 1.18 (1H, m), 1.52 (1H, m),
1.70 (1H, m), 1.93 (1H, m), 2.3
5 (1H, t), 2.47 (1H, m), 2.80 (1
H, m), 3.00 (1H, m), 3.56 (1H,
m), 4.26 (1H), 7.25 (1H, s), 7.
38 (1H, s), 11.97 (1H, s), 12.0
4 (1H, s) MS (FAB); 330 (M ⁺⁺ 1) mp. > 300 ° C. EA; (as C ₁₄ H ₁₄ N ₃ O ₃ F ₃ .0.35H ₂ O) C H N calculated value (%) 50.11 4.42 12.52 experimental value (%) 50.60 4.45 12.07 Example 6

[0063]

[Chemical 20]

The following compounds can be obtained by treating in the same manner as in the examples. Product compound: 6- (3-carboxy-1-piperidino)
-7-Trifluoromethylquinoxaline-2,3 (1
H, 4H) -dione raw material compound; N-tert-butyl-6-nitro-3-
(3-Ethoxycarbonyl-1-piperidino) -4-trifluoromethylaniline

Physicochemical properties ¹ H-NMR (DMSO-d ₆ , δ from TM
S); 1.53 (2H, m), 1.77 (1H, m),
1.94 (1H, m), 2.56 (1H, m), 2.5
9 (1H, m), 2.72 (1H, t), 2.83 (1
H, m), 3.07 (1H, m), 7.24 (1H,
s), 7.43 (1H, s), 7.6 (1H, br),
12.05 (1H, s), 12.13 (1H, s) MS (FAB); 358 (M ⁺ +1) mp. 200-230 ° C. (dec.) EA; (as C ₁₅ H ₁₄ N ₃ O ₄ F ₃ .1HCl.1H ₂ O) C H N Cl calculated value (%) 43.75 4.16 10.20 8. 61 Experimental value (%) 43.52 4.37 10.07 8.44 Example 7

[0066]

[Chemical 21]

By treating in the same manner as in Example 4, the following compound can be obtained. Product compound: 6- (1-thiomorpholino) -7-trifluoromethylquinoxaline-2,3 (1H, 4H)-
Dione raw material compound; N-tert-butyl-6-nitro-3-
(3-Thiomorpholino) -4-trifluoromethylaniline

Physicochemical properties Melting point; 195 ° C. (decomposition) Elemental analysis value; (as C ₁₃ H ₁₂ N ₃ O ₂ SF ₃ .0.3HCl.0.5H ₂ O) CHNS Cl F theoretical value (%) 44.45 3.82 11.96 9.13 3.03 16.23 Experimental value (%) 44.73 3.79 11.10 9.95 2.97 15.96 Mass spectrum value (m / z): 332 (M + 1) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δppm: 2.71 (4H, 4H, m), 3.00 (4H,
m), 7.18 (1H, s), 7.39 (1H, s),
12.00 (1H, s), 12.07 (1H, s) Example 8

[0069]

[Chemical formula 22]

1 g of 3- (3-tert-butoxycarbonylamino-1-pyrrolidino) -6-nitro-4-trifluoromethyl-1-ethyloxalylanilide was added to DM.
F20ml, 10% palladium on carbon 300mg
Was added and hydrogenated at room temperature and pressure. The reaction solution is filtered,
It was concentrated under reduced pressure. Water was added to this, and the resulting crystals were washed with hot water to give 6- (3-tert-butoxycarbonylamino-1-pyrrolidino) -7-trifluoromethylquinoxaline-2,3 (1H, 4H) -dione. 700 mg
Obtained.

Physicochemical properties Melting point; 244 ° C. (decomposition) Elemental analysis value; (as C ₁₈ H ₂₁ N ₄ O ₄ F ₃ ) C H N F theoretical value (%) 52.17 5.11 13.52 13. 75 Experimental value (%) 51.93 5.00 13.28 13.63 Mass spectrum value (m / z): 415 (M + 1) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δppm: 1.39 (9H, s), 1.83 (1H,
m), 2.12 (1H, m), 3.00 (1H, m),
3.18 (1H, m), 3.24 (1H, m), 3.3
7 (1H, m), 4.05 (1H, m), 6.86 (1
H, s), 7.16 (1H, d), 7.34 (1H,
s), 11.82 (1H, s), 11.94 (1H,
s) Example 9

[0072]

[Chemical formula 23]

6- (3-Tert-butoxycarbonylamino-1-pyrrolidino) -7-trifluoromethylquinoxaline-2,3 (1H, 4H) -dione 300 mg
The 1N aqueous hydrochloric acid mixture of was heated for 10 minutes to remove a small amount of insoluble matter and then concentrated. Crystals were precipitated by adding ethanol to this, and the crystals were collected by filtration to give 6- (3-amino-1-pyrrolidino) -7-trifluoromethylquinoxaline-2,3.
200 mg of (1H, 4H) -dione was obtained.

Physicochemical properties Melting point;> 300 ° C. Elemental analysis value; (as C ₁₃ H ₁₃ N ₄ O ₂ F ₃ .HCl) CHN Cl F theoretical value (%) 44.52 4.02 15.97 10.11 16.25 Experimental value (%) 44.23 4.09 15.65 10.08 15.85 mass spectrometry value (m / z): 315 ( M + 1) nuclear magnetic resonance spectrum (DMSO-d _6, TMS internal standard) δppm: 2.02 (1H, m ), 2.30 (1H,
m), 3.22 (2H, m), 3.36 (1H, m),
3.47 (1H, m), 3.85 (1H, m), 7.0
4 (1H, s), 7.43 (1H, s), 8.49 (2
H, s), 11.99 (1H, s), 12.15 (1
H, s)

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Office reference number FI technical display location C07D 403/04 207 7602-4C 413/04 241 7602-4C 417/04 241 9051-4C // ( (C07D 401/04 211: 00 241: 00) (C07D 403/04 207: 00 241: 00) (C07D 413/04 241: 00 265: 00) (C07D 417/04 241: 00 8615-4C 279: 00) 9284-4C

Claims (1)

[Claims] 1. A general formula: (The symbols in the formulas have the following meanings: R ¹ ; hydrogen atom, nitro group or trifluoromethyl group R ² : hydrogen atom, hydroxyl group, lower alkoxy group, carboxyl group, lower alkoxycarbonyl group, amino group, lower alkoxycarbonylamino group) (1H, 4
H) Quinoxaline derivative or salt thereof