TW387890B - [1,2,4]triazolo[4,3-a]quinoxalinone derivatives, their preparation and use - Google Patents

Description

V. Description of the invention (#) ψK, R7, R8 and R3 have the same definitions as above, and Q is bromine, gas or iodine. The compound is reacted with hydrazine to form a compound of formula v.

2 wherein R7, R8 and R9 have the same definitions as above, and the compound R 1-C 0 C 1 (VI) is halogenated with a fluorenyl chloride compound containing formula VI (VI) where R1 has the same definition as that of X 'and X * in the compound of formula I above (C, a C6) alkoxy group to form a compound of formula VI I ------------- (-pack --------- (Please read the precautions on the back first (Fill in this page again) Order --- Γ --- Printed by Shellfish Consumer Cooperative, Bureau of Intellectual Property, Ministry of Economic Affairs

Among them, R 1, R β, R 7 · R a and R 9 have the same definitions as above, and decompose the compound to form the compound of formula VIII-17-. This paper size applies the Chinese National Standard (CNS) A4 specification (210 * 297mm *) ·, * J-1 ·-·, pin 1¾¾ A7 B7__ 5. Description of the invention (/) The present invention relates to a therapeutically active fluorene ring compound. The preparation method includes a pharmaceutical composition of the compound, M and K Methods of treatment. More specifically, the present invention is based on [1,2,4] triazolo [4,3-a] quinazolinone derivatives, which can be used to treat any caused by the reaction of amidine amino acids. Cricket-like. Various related compounds are well known in the art. Therefore * EP — 004040 1 nature of the triazolyl ring is substituted by, for example, alkyl, ethenyl or carboxy, triazoquinoxaline-4-one. Some of these compounds are claimed to have useful antihypertensive activity. U.S. Patent No. 5,153,196 shows some stimulating amino acid receptor antagonists and methods of using the same. This compound conforms to a triazolium oxaline with a triazole ring substituted with a hydrogen, alkyl, aromatic or CF3. Furthermore, the application of Wondershare WO 93/200077 discloses a fused oxaxazinone derivative in which the triazole ring is selectively substituted with a lower alkyl group which may be substituted with a mono or di (lower alkyl) amino group. Printed by the Consumers' Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs --------- η Pack-(Please read the precautions on the back before filling out this page) L-glutamic acid * L-aspartic acid and many others All closely related amino acids can activate the neural units of the central nervous system (CNS). Biochemical, gardenia physiology, and pharmacology studies have confirmed what was described in K, and acid amino acids have also been shown to be the most agonistic neurotransmitter in mammalian CNS. Interaction with neurotransmitting glutamic acid is considered a useful solution for treating neurological and psychiatric disorders. Therefore * known antagonists of stimulating amino acids have shown potential potholes (Stephens et al., This paper size applies to China National Standards (CNS) A4 specifications (210X297 mm)

V. Description of the invention (7

Where Rs, R7, R8 and R9 have the same definitions as above, and V 'and V " are M or methoxy, respectively, and the compound is reacted with ethyl grass atmosphere to form a compound of formula X I V It_

(XIV) where RS, R7, R8 * R9 have the same definitions as above, and V 'and V * are hydrogen or methoxy, respectively, and then undergo a hydrogenation reaction to form a middle part of a cyclized N-hydroxy compound, followed by a deoxygenation or KSS reaction Cyclization, formation XV Compound Printed by the Intellectual Property Bureau of the Ministry of Economy

R R I

(XV) wherein R6, R7, R8 and RI have the same meanings as above; V / and V " respectively, are fi or methoxy, and are combined by the chemical formula XV, so that the compound thus prepared is reacted with hydrazine, then The compound is defined by the general formula Vi 鼸 group i as described above, and then compounded to form a compound of formula XVI. 20 This paper is in accordance with China National Standard (CNS) A4 (210 X 297 mm).

Printed A7 _B7_ 'by the Central Standards Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperative' V. Description of the invention (1) P sych 〇phar in ac ο 1 〇gy 9 0, 14 3-14 7, 1 9 8 5), soft and thin friction (Croucher et al., Science 216, 8 9-9 0 1, 1, 982) and muscle relaxation properties (Turski et a 1., Neurosci. Lett. 5.3, 3 2 1 -326, 1 985) ° Someone once It is suggested that the accumulation of extracellular excitatory amino acids and the encroachment of the incoming neuron army units can explain the neuronal degeneration observed in neurological diseases, such as muscular atrophy Lateral sclerosis (aeiyotrophic lateral sclerosis) * Parkinson's disease, Alzheimer's disease, Huntington's disease, Caesarean disease, K and after cerebral ischemia * Hypoxia and hypoglycemia, or the head and spine Psychological and motor functions observed after trauma (McGeer et al., Nature 263, 517-519, 1976; Simon et al., Science 226, 850-852, 1984; Wieloch, Science 230, 681-683, 1985 ; Faden et a 1., Science 2 4 4, 7 9 8- 8 0 0, 1 98 9; Turski et a 1.,

Nature 3 4 9, 4 1 4-4 1 8, 1 9 9 1). Other possible symptoms are psychosis, hard muscles, vomiting and painlessness. Stimulating amino acids perform their function through specific receptors that are located either postynaptically or presynaaptically. These receptors are currently conveniently sub-categorized into three groups based on electrophysiological and neurochemical evidence: 1) NMDA (N-methyl-aspartate) receptors, 2) AMPA receptors, And 3) Caine salt receptors ° L-glutamic acid and L-aspartic acid substantially activate the aforementioned types of stimulating amino acids, and may also activate other types. This paper size is applicable to China National Standard (CNS) A4 (210X297mm) --------------- 1T ------ C (Please read the precautions on the back before (Fill in this page) Printed by A7 B7, Shellfish Consumer Cooperatives, Central Bureau of Standards, Ministry of Economic Affairs 5. Description of the invention (3) The above-mentioned K classifies amino acid receptors as NMDA · AM PA and caine salt. The body is mainly based on the electrophysiology and neurochemical hair regulation under K. 1) N-methyl-D-aspartate (NMDA) receptors are highly selective for NMDA. Ibotenic acid and L-co-sulfoalanine, D-glutamic acid and trans-2,3-piperidinedicarboxylic acid (trans-2,3-PDA) show strong performance on these receptors To moderate agonist activity. The most potential and selective antagonists are the D-isomers of 2-amino-5-phosphonocarboxylic acids, such as 2-amino-5phosphono-pentanoic acid (D-APV) and 3 — [(±) —2—Carboxypyrazine-4-yl] -propyl-1 monophosphonic acid (CPP), while the medium antagonist activity consists of a long-bonded 2-aminodicarboxylic acid (such as D_2-amine As shown in the D-isomers of diamine diacid (e.g. diamine adipic acid) and fluorene. NMDA-induced synaptic junctions have been extensively studied in the mid-sacral nervous system of lactating animals, especially in the spinal cord (J. Davies et al., J. Physiol. 2 9 7, 6 2 1-6 3 5, 1 9 7 9), and its response has been shown to be strongly inhibited by magnesium ions (Mg + 2). 2) AMPA receptor is selectively activated by AMPA (2-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid), other potential agents are quisquaiie acid * L _ quite sour. Glycolic acid (GDEE) is a selective antagonist at this position, but its antagonistic power is weak. AMPA receptors are relatively insensitive to magnesium ions. For a long time, the release of glutamate has been regarded as cerebral ischemia and the god -6- This paper size applies to China National Standard (CNS) 6 4 * 1 grid (210X297 mm) ------ ---- / sk-- (Please read the notes on the back before filling this page)

* 1T A7 __ B7_ Twenty-fifth, invention description (f) plays an important role in death (Benveniste, H. et al., J. N eurochem. 4 3, 1 3 6 9-1 3 7 4, 1 9 8 4). N M D A caused by calcium ion influx is very important in the control of ischemic nerve cell loss. * 埴 is also known. Non-NMDA receptors of ionophor are impermeable to calcium. However, the stimulus caused by the Scaffer collaterals in the CA 1 region is motivated by non-NMDA, a fact is quite important in the post-ischemic period. Recent studies have shown that selective AMPA antagonists protect neural response to global ischemia in gerbils, even after several hours of reperfusion (Sheardown et al., Science 247, 5 7 1-5 74, 199) AMPA antagonizes cocoons and can therefore be used to treat cerebral ischemia. 3) Du Yinye, a shellfish consumer cooperation agency of the Ministry of Economic Affairs of the Ministry of Economic Affairs, Cainate (please read the precautions on the back before filling in this section). And the antagonism caused by GDE E is quite insensitive. Caine acid derivatives have been suggested as the third class of amino acid receptors. Some lactone derivatives of caine acid are selective antagonists (0. Goldberg et al., Neurosci. Lett. 23, 187-191, 1981), and the dipeptide 3-glutamyl-glycine also shows some Selectivity to Cainate Receptors. Calcium is a strong inhibitor of binding to caine acid, magnesium is not. The affinity of the matrix of one or more different types of stimulating amino acid receptors can be studied by adding K to a simple binding assay. In essence, this method involves cultivating specially selected radiolabeled ligands, and the particular substrate being studied carries a homogeneous plutonium containing receptors. Equal mass can be measured to determine the occupation of the receptor. -7- This paper size applies to the Chinese national standard (CNS> A4 size (210X297mm) A7 B7 V. Description of the invention (-Γ) Ray binding, deducting non-specific binding Measured. AMPA was subjected to * binding to K3 H-AMPA as a radioligand plus K. The effect of glutamate analogs on the second effect of glutamate receptor interactions can be exploited in vitro using difficult retinal spreading depression Phenomenon to study. This kind of experiment will provide information on the efficacy of the test substance (acting agent / antagonist). 豳 Contrary to the binding study, this study only provides information on the affinity of the compound to the receptor. It has been found The compound of the present invention has the affinity of AMPA receptor. The compound is an antagonist with W type, and can be used to treat any sigma caused by irritating amino acid excessive reaction, especially for neurological diseases. Observed neuronal degeneration, such as anyotrophic lateral (anyotrophic lateral System --------- 0! (Please read the precautions on the back before filling in this page sclerosis), Huntington's disease, Parkinson's disease, Alzheimer's disease, epilepsy, M and brain Psychological and motor functions observed after symptoms such as ischemia, hypoxia, and hypoglycemia or after head and spinal cord trauma, other possible irritations are mental malnutrition • Hard muscles, vomiting, and acute and chronic inflammation Diseases and analgesics. The compounds of the present invention are represented by the following general formula I: -8-The paper size is in accordance with the Chinese National Standard (CNS) A4 specification (210 X 297 cm) A7 B7 V. Description of the invention (

E

E

A straight or branched (Ci-Ce) alkyl group, X 'and X "are a hydroxyl group or an alkoxy group, respectively, and R 6, R 7, R 8 and R 9 are hydrogen, respectively, (C!-C6)

Alkyl, halogen, NH2, No2 > CN > CF 3 * S 0 2 NY or COZ ', where Z' is NY 'Y "or (Ci-Cs) alkyl, Y' and Y" are Hydrogen or (Ci -C6) alkyl, triazolyl, oxazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, ring systems are optionally substituted with (Ci -C6) alkoxy , And its scientifically acceptable salt. The term " (Ci-Cs) alkyl refers to a straight or branched hafnium, a saturated hydrocarbon containing 1 to 6 carbon atoms, such as methyl, ethyl • n-propyl, isopropyl, N-butyl, 2-butyl, tertiary butyl, 3 ~ pentyl, neopentyl or n-hexyl. The term " (Ci-(: 6) alkoxy), alone or together, refers to a monovalent substituent containing an (Ci-c6) alkyl group bound by a free-valent bond containing its ether oxygen. , Such as methoxy, ethoxy, propoxy, isopropoxy • cyclopropylmethoxy, butoxy, phenoxy. The term “halogen” here means fluorine, chlorine, bromine And iodine. In a preferred embodiment of the present invention, R1 is COX '-9-this paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm)

Y s / ^ nn · ml Half m · ^ H9 til ^ i ftvllv nft m ^ in Jr, Λ- (Please read the notes on the back before filling in this page) Order the Central Bureau of Standards of the Ministry of Economic Affairs W: Industry and Consumer Cooperation Du Print A7 B: 7 V. Description of the invention () or POX 'substituted (Ci -Cs) alkyl. In another preferred embodiment of the present invention * R6 · R 7. R 8 and R 9 are hydrogen, N 2, NO 2, CN, CF, piperidinyl, morpholinyl, thiomorpholinyl, * morphazinyl respectively. , Piperazinyl substituted by methyl, phenyl or methoxyphenyl, triazolyl substituted by methyl, oxazolyl substituted by methyl, ethyl, phenyl. In yet another embodiment of the present invention, R6 and R9 are hydrogen. The preferred compounds of the present invention are as follows: 1- (ethoxy-hydroxy-phosphoniummethyl)-8- (4-methyl-2-phenyl-1 1-pyrazole- 1-yl)-7-tris Fluoromethyl [1,2,4] triazolo [4,3- —a] quinoxaline-4 4- (5 Η) ketone; 8-(4-methyl-1 2-phenyl-1 Η-oxazole 1-yl) 1-phosphoniummethyl-7-trifluoromethyl [1,2,4] triazolo [4,3-a] quinoxaline-4 4- (5H) one; 1-( Ethoxy-Hydroxymonophosphinomethyl)-8— (2-Ethyl Ethyl Chlorine Consumers Cooperative Printing Bag of the Central Samples Bureau of the Ministry of Economic Affairs (Please read the notes on the back before filling this page) -4 1H-oxazolyl-l-yl) -7-trifluoromethyl [1,2,4] triazolo [4,3 -a] quinoxaline-4 4- (5 fluoren) ketone; 8-(2 — Ethyl-4, methyl-1, 1-oxazole-1, 1-yl), 1-phosphonmethyl-1, 7-trifluoromethyl [1,2,4] triazolo [4,3-a] quinoxaline Porphyrin-4 mono (5H) one; 8-morpholinyl-1 monophosphoranylmethyl-7-trifluoromethyl [1, -10- This paper is applicable to China Home Standard (CNS) A4 Specification (210 X 297 mm) A7 B7 V. Description of the Invention (Friends) 2, 4] Triazolo [4, 3 — a] Quinoxaline One 4 One (5 Η) 嗣 t 8 _Morpholinyl-1 (1-phosphoglysylethyl) -7-trifluoromethyl [1,2,4] triazolo [4,3_a] quinoxaline-4 4- (5Η) 醑; 8 — # pyridyl-1 monophosphosylmethyl-7-trifluoromethyl [1,2,4] triazolo [4,3-a] quinoxaline-4 ~ (5 Η) one-1- (2-ethoxycarbonylethyl) -8-morpholinyl-7-trifluoromethyl [1,2,4] triazolo [4,3-a] quinoxaline_4-(5 Η) Ketones; 1 ~ (2-postylethyl) -8-morpholinyl-7-trifluoromethyl [1,2,4] triazolo [4,3-a] quinoxaline-4-(5 Η) 嗣. Other preferred compounds of the present invention are: 8-(2,4-dimethyl-1,1-oxazolyl-l-yl), printed by Shelley Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs (please read the note on the back first) Please fill in this page again for matters) 1 monophosphoranylmethyl-7-trifluoromethyl [1,2,4] trifluoren [4,3-a] quinoxaline-4 4- (5H) one; 7 — Cyano-8- (2,4-dimethyl-1H-oxazole-1 1-yl) -1 1-phosphoniummethyl [1,2,4] triazolo [4,3-a] quinoxaline One 4 one (5H) ketone; 8-(2,4-dimethyl-1 11 ^ -oxazole-1 1-yl) -fluorene _nitro-1 1-phosphorylmethyl [1,2,4] three Zolo [4,3 -11- This paper size applies to the Chinese National Standard (CNS) A4 Regulation (210X297 mm) A7 B7 V. Description of the Invention (7) a] Quinoxaline 4 4 (5H) Meng; 7 —Cyano-8— (2-ethyl-4—methyl-1 1 hydrazine—weili—l-yl) —1 1 squamylmethyl [1,2,4] triazolo [4, 3-a ] Quinoxaline-4- (5H) one; 7-cyano-8-morpholinyl_1-phosphoniummethyl [1,2,4] triazolo [4,3 —a] fluoroxaline A 4 (5H) fluorene; 8-morpholinyl-7-nitro_1-phosphoniummethyl) [1,2,4] triazolo [4,3_a] quinoxaline-4 4- (5H) one; 7-cyano-1 monophosphinomethyl-8-thiomorpholinyl [1,2,4] triazolo [4,3-a] quinoxaline-4 · (5H) fluorene; 1 a Limonium methyl-8-thiomorpholinyl-7-trifluoromethyl [1,2,4] triazolo [4,3-a] quinoxaline-4- (5 fluoren) one; 7- Cyano-l-phosphonomethyl-8-meridinyl [1,2,4] triazolo [4,3 -a] quinoxaline-4 4- (5H) one; central sample bureau of the Ministry of Economic Affairs Printed by the Industrial and Consumer Cooperatives (please read the precautions on the back before filling out this page) 1 Monophosphorylmethyl-8 — (Merazinyl 1-yl) — 7 —Trifluoromethyl [1,2,4 ] Triazolo [4,3- —a] quinoxaline 4-(5 Η) fluorene; 7 —cyano-1 1-phosphoniummethyl-8 — (piperazinyl 1 — 1) [1, 2,4] triazolo [4,3-a] quinoxaline-4 4- (5 Η) germination; 8- (4-phenylphenylsulfonyl-1 1-yl) -1-phosphoniummethyl-7- Trifluoromethyl [1,2 ， 4] triazolo [4,3 — a] quinoxaline-12- This paper size is applicable to Chinese National Standard 隼 (CNS) M specifications (210X 297 mm) A7 B7 V. Description of the invention (π) -4- (5 Η) 嗣; 7-amino- 8- (4-phenylphenylsulfan-1-yl) -1 1-disc methyl [1,2,4] triazolo [4,3-a] quine Oxolinone 4-(5 fluoren) ketone; 8-(4 ((3-methoxyphenyl) pyrazine-1 1 -yl)-1 -phosphoniummethyl -7 -trifluoromethyl [1,2 , 4] triazolo [4,3-a] quinaline-4- (5-fluoren) one; 8- (4- (4-methoxyphenyl) piperazine-1, 1-yl), 1-phosphonium Methyl-7-trifluoromethyl [1,2,4] triazolo [4,3-a] quinoxaline-4 4 (5 Η) M > 8_ (2,4_dimethyl-1 11 ^ _. Oh _1-yl) _1 monophosphonium ethyl-7-trifluoromethyl [1,2,4] triazolo [4,3-a] quinoxaline-4 4- (5H) one ; 7-Chloro-8- (2,4-dimethyl-11 ^ _imidazole-1-yl) -1 1-phosphonomethyl [1,2,4] triazolo [4,3 -a] quine Abusive one 4 one (5H) ketone; 8-(3,5-dimethyl-1 2,4 Triazolyl 1-Printed by DuPont Consumer Cooperation of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page)-1_ Phosphonomethyl-7 — Trifluoromethyl [1,2,4] triazolo [4,3-a] quinoline-4 (5H) one; 8- (4-methylmorphazine-1yl) -1phosphoniummethyl -7-trifluoromethyl [1,2,4] triazolo [4,3-a] quinoxaline -4-(5 Η) 嗣; 1- (2 -Ethylethyl) -8- ( 2,4 -dimethyl-1 -13- This paper size is applicable to China National Standards (CNS> A4) (210 ×: 297 mm) Printed by A7 B7, Consumer Cooperatives, Central Procurement Bureau, Ministry of Economic Affairs Explanation (I 丨) Η —oxazole-1 1-yl) _7 —trifluoromethyl [1,2,4] triazolo [4,3-a] quinoxaline-4 4- (5H) one; 1 — (2-Sorylethyl) -8- (2-ethyl-4Methyl-1H-oxazole-1-1-yl) -7-trifluoromethyl [1,2,4] triazolo [4 , 3-a] quinoxaline-4 4- (5H) one; 1- (2-carboxyethyl) -7-cyano-8- (2,4-dimethyl-1H-imidazole-1 Yl)-[1,2,4] triazolo [4,3-a] quinoxaline-4- (5H) one; 1- (2-carboxyethyl) -8- (4-phenyl helpazine-1 1-yl) -7-trifluoromethyl [1,2,4] triazolo [4 * 3-a] quinoxaline-4- (5H) one; 1- (2-carboxyethyl) -8- (2,4-Dimethyl-1,1-oxazolyl-1,1-yl) -7-nitro [1,2,4] tripyrido [4,3-a] quinoxaline-4,5 (5)) one ; 1-(2-carboxyethyl) -7-cyano-8-morpholinyl [1,2,4] triazolo [4,3-a] quinoxaline-4- (5 fluoren) one; 1-(2-carboxyethyl)-8-morpholinyl-7-nitro [1,2,4] triazolo [4,3-a] quinoxaline-4 4- (5 Η) 嗣; 1 -(2-carboxyethyl) -8- (4-methylazinyl-1 1-yl) -7-trifluoromethyl [1,2,4] triazolo [4,3-a] quinoxaline —4 One (5H) 黼; -14- This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) ---- ^ ------- 0 ^ —----- 1T- ----- r > (Please read the notes on the back before filling this page) Printed by Bureau of Work Consumer Cooperatives A7 B7 V. Description of the invention (/ 1) 1-(2-carboxyethyl) -7-chloro_8 — (2,4-dimethyl-1H —oxazole-1 1 radical ) [1,2,4] triazolo [4,3-a] quinoxaline-4 4- (5H) pyrene; 1_ (2-carboxyethyl) -8- (4-methoxy4-benzene (Yl) pyrazine- 1-yl)-7-trifluoromethyl [1,2,4] triazolo [4,3-a] quinoxaline-4 4- (5H) fluorene; 1-(2-carboxy (Ethyl) -8-pyridinyl-7-trifluoromethyl [1,2,4] triazolo [4,3-a] quinoxaline-4 4- (5 Η) fluorene. The compounds of the invention may be in different tautomeric forms. Accordingly, the invention includes all such tautomeric forms. Another specific embodiment of the present invention is a pharmaceutically acceptable toilet of a [1,2,4] triazolo [4,3-a] quinoxaline derivative of formula I. This category includes those derived from lauric acid and organic acids * including hydrochloric acid, osmium bromide, 2 acid, sulfuric acid, nitric acid, oxalic acid * fumaric acid, tartaric acid and the like. Other salts include osmium salts such as sodium or potassium salts; alkaline earth osmium lithium, such as calcium or magnesium salts and ammonium salts. Furthermore, another aspect of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof as a medicine, preferably as a treatment for stimulatory neurotransmitters (especially AMAP receptors). Crickets caused by overreaction. The present invention is also limited to a method for preparing the above-mentioned compounds. The compound of formula I was prepared at -15- This paper size applies to China National Standard (CNS) A4 specification (210 × 297 mm) --------- 61- (Please read the precautions on the back before filling this page ) '1Τ A7 B7

2. E R

V. Description of the invention (β) a) Alkylation of the compound of formula II with benzyl halide II) wherein R6-R 7, R8 and R9 have the same definitions as above to form the compound of formula III m · Bmv nn -IV m ^ i ^ mv tin ^ 1 · ^ —— (Please read the notes on the back before filling this page)

R

III) Order Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economics where R6 · R 7, RS and R9 have the same definitions as above, and the compound is halogenated to form a compound of formula IV

-16 V) This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm)

V. Description of the invention (#) ψK, R7, R8 and R3 have the same definitions as above, and Q is bromine, gas or iodine. The compound is reacted with hydrazine to form a compound of formula v.

2 wherein R7, R8 and R9 have the same definitions as above, and the compound R 1-C 0 C 1 (VI) is halogenated with a fluorenyl chloride compound containing formula VI (VI) where R1 has the same definition as that of X 'and X * in the compound of formula I above (C, a C6) alkoxy group to form a compound of formula VI I ------------- (-pack --------- (Please read the precautions on the back first (Fill in this page again) Order --- Γ --- Printed by Shellfish Consumer Cooperative, Bureau of Intellectual Property, Ministry of Economic Affairs

Among them, R 1, R β, R 7 · R a and R 9 have the same definitions as above, and decompose the compound to form the compound of formula VIII-17-. This paper size applies the Chinese National Standard (CNS) A4 specification (210 * 297mm *) ·, * J-1 ·-·, pin 1¾¾ A7 B7 V. Description of the invention (/ 5)

(VIII), RS and R9 have the same definitions as above, followed by thermal cyclization and simultaneous deoxygenation to form a compound of formula I, wherein X ′ and (Ct) alkoxy, or b) combine formula IX

Where R

R

R thing

(IX) ---------_ 〇 ------ ΐτ ------ η] (Please read the notes on the back before filling out this page) Central Bureau of Standards, Ministry of Economic Affairs, Shellfish Consumption Cooperatives where R6 · R 7, R8 and R9 have the same definitions as above, q is bromine, chlorine, iodine, and react with the compound of formula VI R 1-C 0 C 1 (VI) where R1 has the same definition as X in the compound of formula I above 'And X " are (Ci-C6) alkoxy groups to form the compound of Formula XI 18- This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 5. Description of the invention (4

R R

N. ^ NH R A7 B7 (XI) where R1, RS, R7, R8 and R9 have the same definitions as above, Q is bromine, chlorine or iodine, and then cyclized and then hydrolyzed, or cyclized and hydrolyzed simultaneously to form the compound I compounds, where X 'and hydroxy are respectively, (C! -C6) alkoxy, or c) K monomethoxy, dimethoxy or trimethoxy substituted fluorenyl benzylamine substituted compounds of formula XII

R R

R (XII) (Please read the notes on the back before filling this page), 6., 1T c Printed by Shelley Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs where R6, R7, R8 and R3 are defined as above, Z is halogen or ( Ci_C6) alkoxy group to form a compound of formula XI II

R. P

(XIII This paper size is applicable to China National Standard (CNS) A4 (210X297 mm)

V. Description of the invention (7

Where Rs, R7, R8 and R9 have the same definitions as above, and V 'and V " are M or methoxy, respectively, and the compound is reacted with ethyl grass atmosphere to form a compound of formula X I V It_

(XIV) where RS, R7, R8 * R9 have the same definitions as above, and V 'and V * are hydrogen or methoxy, respectively, and then undergo a hydrogenation reaction to form a middle part of a cyclized N-hydroxy compound, followed by a deoxygenation or KSS reaction Cyclization, formation XV Compound Printed by the Intellectual Property Bureau of the Ministry of Economy

R R I

(XV) wherein R6, R7, R8 and RI have the same meanings as above; V / and V " respectively, are fi or methoxy, and are combined by the chemical formula XV, so that the compound thus prepared is reacted with hydrazine, then The compound is defined by the general formula Vi 鼸 group i as described above, and then compounded to form a compound of formula XVI. 20 This paper is in accordance with China National Standard (CNS) A4 (210 X 297 mm).

A7 B7 Printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards and Quarantine of the Ministry of Economic Affairs 5. Description of Invention (Λ?)

Where R1, R6, R7, R8 and R9 have the same definitions as above, and V 'and VV are hydrogen or methoxy respectively, and are hydrolyzed to form a compound of formula I, wherein X' and χΛ are hydrogen or (Ci -cs) alkoxy Or d) MH aqueous alkaline hydrolysis of a compound of formula I where X 'and X' are (Ci —) alkoxy groups to form a compound of formula I, where X 'is a hydroxyl group, and 乂 # is (C, -C6) alkoxy , Or e) K halotrimethylsiliconium reacts with formula I, where X 'is a hydroxyl group or (C ^ -C6) alkoxy, and X〃 is (Cjl -Cs) alkoxy to form a compound of formula I, Where X and X 〃 are hydroxyl. Pharmaceutically acceptable hydrazones can be prepared according to standard procedures and are treated with an acid or sickle compound of formula I. The starting material of the preparation method is a conventional compound (for example, from the international application PCT DK94 / 00170) or can be prepared by a similar method to the conventional compound plus M or a similar conventional method, and will not be repeated here. The pharmacological properties of the compounds of the present invention can be increased by measuring the ability of the AMAP-type to be replaced by 2-amino-3-hydroxy-5-methyl-4 4-isoxazolepropionic acid (AMPA), which is marked by radiation. Instructions. Antagonistic properties of the compound The ability of the chicken retina to stimulate diffusion and depression via quinic acid-2 1- This paper size is applicable to China's family standard (CNS) A4 specification (210 × 297 mm) II ------ ό- ---- IT —----- η (Please read the notes on the back before filling out this page) A7 __B7 _ V. Description of the invention (/?) The compound substitution activity can be displayed by measuring the ICs0 value, which represents the concentration (wM) that will replace 50¾ specific binding 3 H-AMPA. The measurement of antagonisticity is obtained by measuring the I Cs 0 value, which represents a maximum of 5 0% inhibits the degree to which quinica acid causes the diffuse diffusion depression of the mesopic membrane. 3 h-AMPA binding (Experiment 1) 500w formed in thawed rat cerebral cortical membrane in Tris-HCl (30 m Μ) • C a C 1 2 (2.5 mM) and KSCN (100 m M) 1Homogeneous (pH 7 * 1) at OX) was incubated with 25wl of 3 H-AMPA (the final degree of 5nM), and the test compound and buffer were incubated for 30 minutes. Nonspecific binding was determined by incubation with L_glutamic acid (600 wM final concentration) plus K. Combined with the reaction, 5 ml of ice-cold buffer solution K was added and printed by Whatman GF / Central Labor Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperative (read the precautions on the back before filling this page) , And terminate with 2 x 5 亳 liters of ice-cold 鑀 rinse. Binding radioactivity is measured by a scintillation counter. IC50 is obtained by measuring at least 4 concentrations of test compounds by Hi 1 1 analysis. 0 Expanded depression (Test 2). The head of a chicken (3 to 10 days after birth) is chopped, and the eye is taken out and cut along the MDF. Remove the anterior chamber and vitreous body. The posterior chamber of each eye is placed on a petri dish containing a physiological saline solution (P · S * S). The composition of the physiological saline solution (mM) is NaCl (100) and KC1 (- 22- The size of this paper is applicable to China National Standards (CNS) 8.4 (21〇X 297 mm) A7 B7 V. Invention Description (f) 6 〇), CaCl2 (1 * 0) »M g S 0 4 ( 1.0) * Na HC 0 3 (3 0) * Na H 2 P 0 4 (1.0), glucose (2 0). The solution was saturated with 100% oxygen and maintained at 26.0. The eyes are initially incubated in a normal physiological saline solution for 15 to 30 minutes • Then transferred to a physiological saline solution containing quicaric acid (iμg / mL). In this alkaline solution, depressions are usually scattered spontaneously from the edge of the retina, visible to the naked eye. Hold 1 time for each eye to start to sag. After culturing for 15 minutes in a normal physiological saline solution, the eyes were transferred to an aqueous physiological food solution containing a test compound and cultured for another 15 minutes. After that, the eyes were transferred to an irritating solution # containing the phase test compound. Then measure the time at which each eye begins to diffuse. Then put the eyes back into the normal physiological food "water solution", and after 15 minutes, measure the time to start the spread of the sag again. K assess the degree of recovery due to any drug effect. ---------- Q-- (Please read the notes on the back before filling out this page) Printed by the Central Laboratories of the Ministry of Economic Affairs Tong most display clock agent ¾ display seconds to ο. Result ο Test 5K 3K Health Table to test out this property} The group of test multi-factor KM should be able to reach the effective value, and the test result shall be compared with the concentration of the test substance. . Concavity display of the materialization 1 when the quality is confirmed. The test of the sag rate will be based on the divergence of the divergence. 百 The response should be 0% from the beginning. ο Most +1 1 1 to ί The paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7

Printed by the Consumers Cooperative of the Central Bureau of the Ministry of Economic Affairs of the People's Republic of China SL 5. Invention Description (7 丨) Test 1 Test 2 Example compound IC 5 0 IC 5 (u Μ u Μ 2 0 · 3 9 0 * 4 Including the compound of the compound of the present invention The pharmaceutical preparation of the product can be administered orally, enterally or parenterally to humans or animals. The active compound of the active agent ft or a pharmaceutically acceptable agent can depend on common factors, such as the nature and severity of the condition and the treatment to be performed It depends on M in mammals. Traditional excipients are pharmaceutically acceptable organic or non-impregnated carrier matrices that are intended for parenteral or oral use without reaction with the active compound. An example of such a carrier is water , Salt solution, yeast, polyethylene glycol * polyhydroxyethoxy ramie oil, gelatin * lactose, pectin, magnesium stearate, talc, silicic acid, stearic acid, fatty acid monoglyceride and diglyceride, Pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidine tincture. Pharmaceutical preparations can be sterilized • with additives such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, Salt that affects osmotic pressure, The buffer solution and / or coloring substances and the like will not react with the active compounds. For non-administrative administration, especially injectable solutions or floating liquids are preferred * The active compounds are preferably soluble Aqueous solution of polyhydroxylated ramie oil. Ampoule is a traditional unit dosage form. For oral application, it is especially suitable for tablets, sugar-coated nine or containing slip -24- This paper: Standards apply to China National Standards (CNS) Α4 Specifications (210 × 2? 7 mm) ------------- ο ------ II ------ ((Please read the precautions on the back before filling this page) 5 、 Explanation of the invention (Shihe / Sugar and / Dangke grams live disease mg / Pharmacologically activated colloidal di-microcrystalline male modified fiber A7 B7 or carbohydrate carrier or binder capsule or the like, the carrier is preferably milk or starch And / or potato starch. When using a sweetening vehicle, syrups, tinctures, or the like can be used. The unit dose of the compound of the present invention is 10 to sexual ingredients, and can also contain a pharmaceutically acceptable carrier ». In the case of humans, the dosage of the compound of the present invention is 1 to 500 days | 100 mg / day, for example. Typical tablet tablets (free-state compounds or their salts) for operation include oxidized sand (Aerros®), vitamins (A vice 1 ®), vitamins (Ac-Di-Sol®) 10 7 analogs. 2 0 0 (Please read the precautions on the back before filling this page) 0 7 Magnesium stearate printed by the Central Government Bureau of Standards, Ministry of Economic Affairs, Real Consumer Cooperative, PMC Mywace tt®9—40T As a plasticizer for the coating film, about 0 mg, 5 g, 0 g, 5 mg, 1 mg, 9 g, and 9 g. The form is used. This kind of gold tincture or salty gold tincture salt is generally formed in the M equivalent of 1 or an excess of the selected gold tincture or soil gold tincture is a hydroxide and a compound, which is often and suitably mixed in neutral In the solvent, -25- This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) Order A7 _____B7_ V. Description of the invention (V)) Use other traditional methods to precipitate or recover salts * For example, by evaporation method . The compound of the present invention to be administered is usually preferably K. Its scientifically acceptable water-soluble Siamium sibiricum salt or soil test A. saccharum salt, K. and orally, parenterally or K. It is pharmaceutically acceptable for administration. , Which is associated with a pharmaceutically acceptable liquid "or a solid carrier or diluent. The compounds of the present invention can be formulated into traditionally acceptable adjuvants, carriers, or diluents in the form of pharmaceutically acceptable products and unit dosage forms, which can be solid, such as tablets or tincture capsules, or liquids « , Such as solutions, suspensions, emulsions, excipients, or capsules filled with the above substances * for oral bile use; M suppositories for Teng administration; or sterile injectable solutions for parenteral administration ( Including subcutaneous administration). Such pharmaceutical compositions and unit dosage forms may include traditional ingredients in traditional proportions, with or without the addition of additional active compounds or medicaments. This unit dosage form may contain any of the synergistically effective AMPA antagonistic agents and the required agent per day Active ingredients. Tablets contain 1-500 mg of active ingredient or, more specifically, 10-200 mg, and are representative unit dosage forms. Printed by the Central Government Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperative (please read the precautions on the back before filling out this page). Because of the high AMPA antagonistic activity and its low toxicity both represent the best therapeutic index, the compounds of this invention can be effective. Agents are most needed for this type of treatment, such as sclerosis, Parkinson's disease, and Alzheimer's disease, in subjects who are sensitive to changes in AMPA receptor status (such as living animals). Huntington's disease, paralysis, M and in ischemia, hypoxia and hypoglycemia, head and spinal trauma • Psychopathy, muscle stiffness, vomiting, and painlessness are usually better for their tests靥 Toilet or soil test metal-26- This paper size is applicable to China National Standards (CNS> Α4 size (210 × 297 mm)) Central Government Bureau of Economic Affairs, Ministry of Economic Affairs, Shellfish Consumption Cooperation Du printed A7 B7 V. Description of invention (乂) Salt The form, together with a pharmaceutically acceptable carrier or diluent, is particularly preferably a medically acceptable composition, whereby the oral, parenteral or parenteral (including subcutaneous) route is appropriate. A suitable dosage range is 1- 500 * g / day , Preferably 10-200 mg / day, particularly preferably 50- 100 mg / day, usually in the correct manner and form of administration, the target number of administration, the target and weight * M and B or It depends on the preference of animal B. This treatment can be described as the treatment of irritations caused by or associated with irritable neurotransmitter overreactions, or in particular AMPA caused by » Contingent irritability • The method includes the following step: administering to the subject a neurologically effective number of ft of the AMAPA resistant compound of the present invention, or a pharmaceutically acceptable salt thereof. Furthermore, the present invention relates to a compound of the present invention In preparation for the treatment of condyles caused by irritable neurotransmitter overreaction, especially those caused by AMPA receptors of the subject to be treated. Examples of the present invention under K will be further developed. Description. Example 1 1- (ethoxy-hydroxy-phosphonomethyl)-8_ (4-methyl- 2-phenyl-1H-oxazole-1 1-yl) -7-trifluoromethyl [1, 2 · 4] triazolo [4,3-a] quinoxaline-4-(5 Η) 嗣 Step 1 a-benzyloxy A 3 —Amo 6 — (4 Methyl 2 —Phenyl 1H —Imidazole 1 1 A) —7_trifluoromethylquinoxaline_2 -27- This paper is in accordance with the national standard of China ( CNS) A4 size (210X297mm) (Please read the notes on the back before filling in this f)

Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (rr) _ (1 Η) Ketone, hydrochloride 20% phosgene solution in toluene (18 · 2 liters, 35 milliliter Mol) was added dropwise to 8.8 g (17. 5 mils) of 1-benzyloxy-6- (4-methyl-1, 2-phenyl-1, 1-oxazole) 1 1 1 radical) 7-trifluoromethyl [1,2,4] triazolo [4,3-a] quinoxaline-2,3- — (1Η, 4Η) -dione at 100 奄 L Anhydrous N, N-dimethylformamide formed solution. Mixture # 25 · 0 was stirred overnight. The precipitated solid was separated by centrifugation and K ether was rinsed with K to obtain 8.0 g (84%) of the title compound. ^ -NMR (DMS0-de): ^ 2.42 (s, 3H), 5.35 (s, 2H), 7.30-7.61 (m, 10 H), 7.62 (s, 1H), 7.75 (s, 1H), 8.48 ( s, 1H). 'Step b 1-benzyloxy- 3 -xylyl-6-(4-methyl-2 -phenyl-1 -oxazole-1 -yl) -7-trifluoromethyl Quinoxaline 2 (1 Η) -one 1-benzyloxy-3-amine-6-(4-methyl-2-phenyl-1 Η-hoe fluorene-1-1) trimethylol Linyi 2 (1 Η)-a mixture of ketone hydrochloride (2 ♦ 0 g, 3 '6 mol) and hydrazine hydrate (0.74 liters, 15 mils) in 40 ml of dichloromethane It was stirred for 1 hour at 〇〇. The mixture was evaporated to dryness in vacuo and the residue was triturated with water to give 1.59 g (87%) of the title compound with a melting point of 1 17-13010. I ------------- ίτ ------ C (Please read the notes on the back before filling this page) 1 28- This paper size is applicable to China National Standards (CNS) Α4 Specifications (210 × 2? 7 mm)> Printed by the Ministry of Economic Affairs, China Standards Bureau Industrial Cooperative Consumer Cooperative A7 B7 _ V. Description of Invention (/) 'H-NMR (DMS0-d6): ^ 2.21 (s, 1H). 5.34 ( s, 2H), 7.01 (s, 1H), 7.18 (s, 1H) (7.27 (s, 5H), 7.37 * 7.45 (m, 3H), 7.48 (s, TH), 7.51-7.60 (m, 2H) Step c 1 monobenzyloxy-3 [2-[(diethoxyphosphino) ethenylhydrazino] -6- (4-methyl-1 2-phenyl-1H-oxazole-1 1 base) a 7-trifluoromethylquinoxaline-2 (1H) -one (diethoxyphosphonium) ethyl fluorenyl gaseous (0.67 g, 3 · 1 奄 ear) at 20 奄The solution formed in one liter of anhydrous tetrahydrofuran was added dropwise to the mixture of 1-benzyloxy-3-fluorenyl-6- (4-methyl-2-2-phenyl-1fluorene-imidazole-1 1-yl)- 7-trifluoromethylquinoline-2 (1Η) -one (1.52 g, 3.0 mol) and anhydrous triethylamine (0.43 draft, 3.1 mol) at 50 In anhydrous tetrahydrofuran The solution was formed. The mixture was stirred overnight at room temperature and evaporated to dryness. The residue was absorbed in 500 ml of water, and the residue was triturated with water to obtain 1.8 g (88%) of orange title. Compound * Melting point ST9 0 C (decomposition). 1H-NMR (DMSO-de): d 1.10-1.21 (m, 6H), 2.20 (s, 3H), 2.99 (d, 2H), 々.OUquint., 4H ), 5.4Ό (s, 2H), 7.04 (s, 1H), 7.24 < s, 7.37-7Λ6 (m, 3H), 7.50-7.62 < m, 3H), 10.26 (s, 1H), 10.38 < s, 1H). Step d 3-[2-[(diethoxyphosphoranyl) ethynyl] hydrazino]-1 -hydroxyl 6-(4 -methyl-2 -phenyl_1H- Imidazole-1, 1-yl), 7-trifluoromethylquinoxaline-2 (1H) — Meng1, 1-benzyloxy-1, 3— [2 -— ((diethoxyphosphoryl) ethenylhydrazine) 〕 —6— （4-Methyl-2—Phenyl-1 1—Imidazole—-29- This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling (This page)

• Consumption cooperation between employees of the Central Bureau of Prospecting and Quarantine of the Ministry of IT and Economics Du printed A7 B7 V. Description of the invention (M) 1-based) 7-Trifluoromethylquinoxaline-2 (1H) —Meng (1 * 8 grams, 2 · 6 奄 ears) and 50 gram of 5¾ h of palladium suspended in 50 ml of acetic acid suspension for 9 hours. The catalyst was removed by filtration and rinsed with ethyl acetate. The mixed mash was evaporated to dryness in a vacuum, and the residue was triturated with ether to obtain 1.51 g (97 炻) of the title compound with a melting point greater than 1 7 7 (decomposed). ^ -NMR (DMSO-de): δ 1.10-1.22 (m, 6H), 2.23 (s, 3H), 2.98 (d, 2H), 4.00 (quint., 4H), 7.12 (s, 1H), 7.18- 7.30 (m, 5H), 7.31 (s, 1H), 7.92 (s, 1H), 10.24 (s, 2H), 12.52 (br. S, 1H). Step e 1— (ethoxy monohydroxy monophosphate) (Methyl)-8- (4-methyl- 2 -phenyl- 1H-Panyl- 1-yl)-7-triset methyl [1,2,4] triazolo [4 * 3-a] Quinoxaline-4 4 (5 Η) m 3-i 2-[(di-Z-aminophosphino) ethenyl] hydrazino] 1 1 triphenyl group 6 — (4_methyl-1 2 —benzyl —1H —Miles — 1 mono) — 7 —trifluoromethylquinoxaline — 2 (1H) -one (1.5 g, 2.5 mmol) and triphenylphosphine (1.3 g (5 mmol) in 50 ml of glacial acetic acid was stirred overnight at 120D. After the mixture was cooled, it was washed with ether, and the separated product was washed with ether to obtain 0.64 g (48%) of the title compound. Melting point: 303-3 0 8 * C ° -30- This paper size is applicable to Chinese National Standard (CNS) Α4 size (210X297 mm) (Please read the precautions on the back before filling this page)

* 1T

C A7 B7 V. Description of the invention (4) Ή-NMR (DMSO-d6): δ 1.10 (t, 3H), 2.25 (s, 3H), 3.87 (quint., 2H), 3.97 (d, 2H), 7.12 (s, 1H), 7.14-7.45 (m, 5H), 7.72 (s, 1H), 8.62 (s, 1H), 12.4 (s, 1H). Example 2 8-(4-methyl-2-phenyl 1H-imidazol-1-yl) 1-Phosphinomethyl-7-trifluoromethyl [1,2,4] triazolo [4,3 -a] quinoxaline-4-(5 Η) Bromotrimethylsilane (1 liter, 7 mol) was added dropwise to the stirred 1- (ethoxy-hydroxy-phosphonium-methyl)-8- (4-methyl-2-phenyl-1 1 hydrazone — sialyl 1-yl) -7-trifluoromethyl [1,2,4] triazolo [4,3-a] quinoxaline-4 4- (5Η) one (500 mg · .0 · 94 奄 ears) in a solution of 20 奄 of anhydrous N, N-dimethylformamide. The solution was stirred at room temperature overnight and evaporated to dryness in vacuo. The oily residue was triturated with 10 ml of water, and the resulting precipitate was filtered and divided into males, washed with a small amount of ice water and ethanol to obtain 0.45 g (95%) of the title compound, melting point: 321-325 =. 'H-NMR (DMS0-d6): d 2.35 < s, 3H), 3.93 (d, 2H), 7.22-7.52 (m, 6H), 7.74 (s, 1H), 8.79 (s, 1H), 12.4 (s, 1H). Printed by the Consumers' Cooperative of the Central Bureau of Standards and Assistance of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page). Example 3 -(2-ethyl-4-methyl-1H-imidazole_1-yl) -7-trifluoromethyl [1'2,4] triazolo [4,3_a] quinoxaline-4 4- (5 )) 醑 -31- This paper size is applicable to China National Standards of Standards (CNS) A4 (210X297 mm) Consumer Cooperation of the Central Standards and Standards Bureau of the Ministry of Economic Affairs of the People's Republic of China Du printed A7 B7 V. Description of the invention (β) Prepared in a manner similar to that described in Example 1 from 1-benzyloxy-6- (2-ethyl-4, methyl-1H-oxazole-1 1-yl) -7-trifluoromethylquinoxaline_2 , 3 (1H * 4H) —dione, the only difference is that the final product (theoretical value is 10 · 8 奄 mol) is performed in the following manner. To the cooled solution was added 100 liters of diazamethane and 100 liters of ether. The precipitated solid was separated by filtration and extracted with boiling water (2 × 100 liters), and cooled in an ice bath. The resulting precipitate was separated and dried to obtain 0 * 90 g (17%) of the title compound. ^ -NMR (CF3COOD): 6 1.38 (t, 3H), 1.45 (ΐ, 3Η), 2.51 (s, 3H), 2.72-3.10 (m, 2H), 4.31 (quint., 2H), 4.58 (dd, 2H (partially exchanged)), 7.22 (s, 1H), 8.32 (s, 1H), 9.00 (s, 1H). Example 4 8-(2 -ethyl-4 4-methyl-1H-oxazole_1-1 A) 1 1-phosphoniummethyl-7-trifluoromethyl [1,2,4] triazolo [4,3-a] quinoxaline-4-(5H) ketone fluorene compounds are similar examples The method described in 2 is prepared from 1-(ethoxy monohydroxy monophosphorylmethyl) _8_ (2-ethyl_4_methyl-1 1 fluorene-oxazole-1 1-yl)-7-trifluoromethyl Pyridoxine-2,3 (1Η * 4Η)-醑, the yield is 710 奄 g (86%), and the melting point is greater than 300 ° C. -32- This paper size is applicable to China National Standard (CNS) A4 (210X297mm) (Please read the notes on the back before filling this page) Order C- A7 B7 V. Description of the Invention (Production) ^ -NMR ( DMSO-de): tf 1.10 (t, 3H), 2.20 (s, 3H), 2.27-2.77 (m, 2H), 3.62-3,95 (m, 2H), 7.07 (s, 1H), 7.85 (s , 1H), 8.55 (s, 1H); MS (FAB): m / e 457 {MH +} · (Ci 7 Hi 6 N 6 F 3 0 4 P · 0 · 5 H 2 0) Theoretical value: C43.88 H3.6 8 N18.06 Actual value: C44.07 H3.56 N18.02 Example 5 8-morpholinyl-1 monofluorenylmethyl-7-trifluoromethyl [1,2,4] triazole And [4,3-a] quinoxaline-4 4- (5H) 嗣 a · 1 -— (ethoxymonohydroxy-phosphonomethyl) _8_morpholinyl_7—trifluoromethyl [1, 2,4] triazolo [4,3-a] quinoxaline-4 ((5H)) one title compound was prepared in a similar manner as described in Example 1 to 1-benzyloxy-6-morpholinyl- 7 —Trifluoromethylquinoxaline-2 · 3 (1 印 Printed by the Consumers' Cooperative of the Central Government Bureau of the Ministry of Economic Affairs --------- C 袈-(Please read the notes on the back before filling This page), 4Η) _ dione, the only The same is that the final product is separated as described below. The mixture is dried in vacuum, and the residue is taken up in 200 ml of dichloromethane and 50 liters of chloroform. The resulting solution is extracted with water (6 x 100 liters), and the pressure is reduced. Azeotropy with 1-propionase · The aqueous solution is evaporated to dryness to obtain the crude product, which must be purified separately and used directly in the next step. B · 8-morpholinyl-1_phosphoramidylmethyl-7-7 The fluoromethyl [1,2,4] triazolo [4,3-a] quinoxaline-4 (5H) one title compound was prepared on a crude 1-33-sheet in the same manner as described in Example 2. Standards are applicable to China National Standards (CNS > A4 (210X297 mm). Printed by the Consumer Cooperative of the Central Bureau of the Ministry of Economic Affairs, Consumer Cooperatives. A7, B7. 5. Description of the invention (3)) A) 8-morpholinyl-7-three set of methyl # [1,2,4] triazolo [4 * 3-a] quinoxaline-4-(5H) melting point is greater than 30oC (decomposition) ( Acetic acid). 'H-NMR (DMSO-d6): δ 2.9-3.03 (m, 4H), 3.66-3.78 (m, 4H) f 3.98 (d, 2H), 7.68 (s, 1H), 8.39 (s , 1H), 12.18 (s, 1H). Example 6 8- Morpholinyl-l- (l-phosphoramidylethyl) -7-trifluoromethyl [1,2,4] triazolo [4,3 -a] quinoxaline-4 mono (5 fluorene) ketone A · (1- (ethoxy-hydroxy-phosphono-methyl) -8-morpholinyl-7-trifluoromethyl [1,2,4] triazolo [4,3-a] quine Benzoline-4 (5H) ketone title compound was prepared from crude 1-benzyloxy-6-morpholinyl-7-trimethylquinoxaline-2,3 in a manner similar to that described in Example 5. (1H, 4H) -dione, the only difference is the replacement of (diethoxyphosphonium) acetamidine chloride with 2- (diethoxyphosphonium) propanium gas. The next step was to use the crude product directly without further purification. b 8 —morpholinyl-1 (1-phosphoramidylethyl) -7-trifluoromethyl [1,2,4] triazolo [4,3-a] quinoline-4 4 (5 Η) The title compound was prepared from crude 1- (1- (ethoxy-hydroxy-phosphorylmethyl) -8-morpholinyl-. Applicable to China® Standard (CNS) Α4 specification (2 丨 0 × 297mm) --------- 04 ------ 1T ------ C (Please read the precautions on the back first (Fill in this page again.) Printed on A7 _______ B7_ by the Central Procurement Bureau of the Ministry of Economic Affairs. V. Description of the invention 7-Trifluoromethyl [1,2,4] triazolo [4,3 — a] quinoxaline One 4 one (5H) ketone * The only difference is that the final product is purified by chromatography * melt viscosity is greater than 3 00Ό (decomposition). 1H-NMR {DMSO-de >: < 5 1.73 {dd, 3H), 2.87-3.02 m, 4H), 3.68-3.78 (m, 4H), 4.11-4.38 (m, 1H) f 7.68 (s, 1H), 8.38 (s, 1H), 12.18 (s, 1H). Example 7 8 — 锨Pyridinyl-1 monophosphinomethyl-7-trifluoromethyl [1,2,4] triazolo [4,3_a] oxoxaline-4 4 ((5H)) M a · 1 — (ethoxy Keiichi Hydroxymonophosphorylmethyl) -8-piperidinyl-7-trifluoromethyl [1,2,4] triazolo [4,3-a] quinoline-4 4- (5H) 醑The compound was prepared in a similar manner to that described in Example 3 from the crude 1-benzyloxy-6-piperidinyl-7-trifluoromethylquinoxaline-2,3 (1 Η · 4H) -dione. The difference is that the crude product is used directly in the next step without additional purification. b 8 —Pyridinyl-1—phosphonoethyl—7-trifluoromethyl [1,2,4] triazolo [4,3-a] quinoxaline-4 4- (5H) one The compound instrument was prepared in a similar manner to that described in Example 2 on the crude 1- (ethoxy-hydroxy-phosphoramidylmethyl) -8-pyridinyl-7-trifluoromethyl [1,2,4] triazolo [4,3- —a] Quinoxaline 4- (5 fluoren) ketone. -3 5 _ This paper size applies to China National Standard (CNS) Α4 size (210 X 297 mm) --------- ρ—I (Please read the precautions on the back before filling this page) Order A7 B7_ V. Description of the invention (3 >) 1H-NMR (DMSO-d6): δ 1.48Ί.72 (m, 6H), 2.83-2.98 (m, 4H), 3.90 (d, 2H), 7.65 (s, 1H), 8.32 (s (1H), 12.12 (s, 1H). Example 8 1 Mono (2-ethoxycarbonylethyl) -8-morpholinyl-7-trifluoromethyl [1,2,4 ] Triazolo [4,3-a] quinoxaline 4- (5 fluoren) one. The title compound is 1-benzyloxy-6-? 7 —Trimethylquinolin — 2 '3 (1 Η, 4Η) —Diketone and succinic acid chloride * The only difference is that the final product is reacted in the following manner. The cooled mixture is in the sky It was evaporated to dryness and subjected to flash chromatography with dichloromethane and ethyl acetate ore to purify the 'K ether, and obtained a blunt product, melting point 204-210C. 1H-NMR (DMS0-d6): ί 1.22 (t , 3Η), 2.88-3.00 (m, 4H), 3.02 (t, 2H), 3.61-3.82 (m, 6H), 4.12 (q, 2H), 7.71 (s, 1H), 7.99 (s, 1H), 12.2 (br. S, 1H). Example 9 1 Mono (2-carboxyethyl) -8-morpholinyl-7-trifluoromethyl [1,2,4] triazolo [4 * 3 —a] Quinoxaline-4 4- (5) ketone printed by the Consumer Cooperative of the Central Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) 1- (2—ethoxycarbonylethyl) _8 — Suspension of morpholinyl-7-trifluoromethyl [1,2,4] triazolo [4,3-a] quinoxaline-4 (5H) in 10 ml of 2N potassium hydroxide The mixture was stirred at room temperature for 3 hours. After the solution obtained, the solution was acidified with 4M hydrogen acid to obtain a precipitate. The product was separated by filtration, washed with water, and dried to obtain the title compound. -36- Applicable to China National Standard (CNS) A4 (210X297 cm) 5. Description of the invention (outside) Melting point is 170-176C. A7 B7 W-NMR (DMS0-de): ί 2.88-3.02 < m, 6H), 3.67 (t, 2H), 3.68-3.80 (m, 4H), 7.71 (s, 1H), 7.99 (S / 1H), 12.26 (br. S, 1H). (锖 Please read the precautions on the back before filling in this page)

Ordered by Ln for shellfish consumer cooperation with the Central Bureau of Standards of the Ministry of Economic Affairs. Printed by Du, 37 This paper size applies to China National Standard (CNS) A4 (210 × 297 mm)

Claims (1)

ABCD The following formula is a combination of a triazole and a ketoline oxoxaquine Take S separately, X s, XX and ο, Pl X or,, group X alkane and ο), C 6 group by C oxygen or monoalkane S 1 XC 6, (I ο chain 1 P branch C of CX is or { The 1 bond or the hydroxyl group in the R radical is replaced by (Please read the precautions on the back before filling out this page) The R 6 and R 9 printed by the 8th Industrial Cooperative Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs are hydrogen; R 7 is trifluoro Methyl; R8 is pyridinyl, #azinyl, morpholinyl; and its scientifically acceptable salt. 2 · The compound of item 1 of the patent application garden * which is selected from: 1-(ethoxy Monohydroxy-phosphorylmethyl) 8- (4-methyl-2-2-phenyl-1 1-imidazole-1 1-yl) -7-trifluoromethyl [1 • 2, 4] triazolo [4 , ≪ 3-a] quinoxaline-4 4- (5 Η)% ketone; 8- (4-methyl-1 2-phenyl-1 1 Η-imidazole-1 1-yl) 1 1-phosphonium methyl-1 7-trifluoromethyl [1,2,4] triazolo [4,3-ba] quinolinoline 4- (5Η) 鼷; This paper uses China National Standard (CNS) Λ4 size (210X297) Mm) ABCD The following formula is a combination of a triazole and a ketoline oxoxaquine Take S separately, X s, XX and ο, Pl X or,, group X alkane and ο), C 6 group by C oxygen or monoalkane S 1 XC 6, (I ο chain 1 P branch C of CX is or { The 1 bond or the hydroxyl group in the R radical is replaced by (Please read the precautions on the back before filling out this page) The R 6 and R 9 printed by the 8th Industrial Cooperative Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs are hydrogen; R 7 is trifluoro Methyl; R8 is pyridinyl, #azinyl, morpholinyl; and its scientifically acceptable salt. 2 · The compound of item 1 of the patent application garden * which is selected from: 1-(ethoxy Monohydroxy-phosphorylmethyl) 8- (4-methyl-2-2-phenyl-1 1-imidazole-1 1-yl) -7-trifluoromethyl [1 • 2, 4] triazolo [4 , ≪ 3-a] quinoxaline-4 4- (5 Η)% ketone; 8- (4-methyl-1 2-phenyl-1 1 Η-imidazole-1 1-yl) 1 1-phosphonium methyl-1 7-trifluoromethyl [1,2,4] triazolo [4,3-ba] quinolinoline 4- (5Η) 鼷; This paper uses China National Standard (CNS) Λ4 size (210X297) (Mm) 6. Scope of patent application 1-(ethoxy-hydroxyl Monophosphinomethyl) -8- (2-ethyl-4-methyl-1H-oxazole-1-yl) -7-trifluoromethyl [1,2,4] triazolo [4,3 -a] quinoline-4-(5 Η) 嗣; and 8 — (2-ethyl-4-methyl-1 1-pyridyl 1-yl) 1-phosphonium-methyl-7-trifluoro Methyl [1,2,4] triazolo [4,3 —a] quinoxaline-4 (5Η). 3 * As for the compound in the scope of the patent application *, which is selected from: 8? Phosphono-1-phosphorylmethyl-7-trifluoromethyl [1,2,4] triazolo [4,3-a] quinoxaline-4 4- (5Η) sugar f 8 -morpholinyl 1 1 (1 -phosphoranylethyl) -7 -trifluoromethyl [1,2,4] triazolo [4,3-a] quinoxaline-4 1 (5 Η) fluorene; Ministry of Economic Affairs Printed by the Consumer Property Cooperative of the Intellectual Property Bureau (please read the precautions on the back before filling out this page) 8 —N-Sialyl-1—Selling Glycosylmethyl-7'-Trifluoromethyl [1,2,4] Triazolo [4,3- —a] quinoxaline-4 4- (5Η) fluorene »1- (2-ethoxycarbonylethyl) -8-morpholinyl_7 —tri Fluoromethyl [1,2,4] trifluoro [4,3-a] quinoxaline-4 4- (5 Η) fluorene; and 1- (2-carboxyethyl) -8-morpholinyl-1 7-trifluoromethyl [1,2,4] triazolo [4 · 3 — a] oxoxaline-4 4 (5 -2- This paper size is applicable to China National Standards (CNS) A4 wash grid (210X297 Mm) Scope of patent application Η) Meng. 4. The compound according to any one of claims 1 to 3 of the patent application park or a pharmaceutically acceptable salt thereof, which is used for the preparation of a substance which is irritating to the excessive response of the stimulating neurotransmitter. 5-A pharmaceutical composition for treating stimuli in response to the stimulatory neurotransmitter encounter, which includes a compound such as ΪE-in the patent application No. 1 to 4 as an active ingredient or a medicament thereof Acceptable salts and technically acceptable carriers or diluents. 6 * A pharmaceutical composition according to item 5 of the scope of patent application, which is a unit dosage form containing 10 to 200 grams of active compound. 7 ♦ —Method for preparing a compound of formula I as described in item 1 of the patent application *, which includes I—I—I—I—1 ^! I—n I— ~ I nINI n I «I n 3J. I nϋ 111 ! 1. 2 .. in (Please read the notes on the back before filling out this page) This paper / ΙΑ 逋 is marked by Chinese house (c is called (210X297 mm) A8 B8 C8 D8 patent application scope where Re, R7, R8 and R9 are as defined in the first patent application park, forming a compound of formula I I I R (III) wherein R6, R7 and R9 are as defined in the first patent application range, and the compound is halogenated to form a compound of formula IV (Please read the note on the back before filling this page) (IV) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, R NH, Among them, R6, R7, R8 and R9 are as defined in item 1 of the patent application, and Q is bromine, chlorine or iodine; the compound is reacted with hydrazine to form a compound of formula V. The Chinese standard for this paper (CNS) Λ4 specification (210X297 mm) 8888 ABCD a. Patent application scope VR ' Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, among which RS, R7, R8 and R9 are used in the patent application 圔 item 1 · The fluorinated compound containing formula VI is used as the halogenated compound R 1-C 0 C 1 (VI) g + R1 is as defined in the compound of formula I in item 1 of the patent application, where 'where X' and X 'are (C ^ _C6) alkoxy groups, and M forms a compound of formula V1_ (VII) where R1' R6 , R7, R8, and ^ 9 are as defined by Shen Fanli, and the compound is hydrogenolyzed to form a compound of formula VIII 5- _ .........-VI This paper uses the Chinese National Slope (CNS > A4 * yj · 010X297). A8 387890 cs. The scope of patent application is R1, R6, R7, R8 and R9 are as defined in item 1 of the scope of the patent application, followed by thermal cyclization and simultaneous deoxygenation to form a compound of formula I, where X 'and X〃 are (C i -C 6) alkoxy, or b Make the compound of formula IX (Please read the notes on the back before filling out this page) NH q (IX) where R6, R7, R8 and R9 are defined as bromine · gas, iodine as defined in item 1 of the patent application scope, and react with the compound of formula VI R 1- C 0 C 1 (VI) where R1 is as defined in the compound of formula I in item 1 of the Shenyang Patent Fanyuan, where X 'and X " are (Ci-Cs) alkane groups * M form a compound of formula XI Ministry of Economic Affairs wisdom Printed by the Property Bureau Shellfish Consumer Cooperatives 0 (XI) -6-This paper is based on China's national standard (CNS) Α4 size (210X297 mm) 387890 ~ ____, patent application scope A8 B8 C8 D8 Among which R1 * R 6. R 7, R 8 and R 9 as claimed谪 Patent Fanhua No. 1 In the definition of stomach, Q is bromine, nitrogen or iodine, and then cyclized and then hydrolyzed, or the compound is hydrolyzed and hydrolyzed with the stomach to form a compound of formula I, where X ′ and hydroxy are respectively, (Ci-Ce) an alkoxy group, or c) a substituted benzylamine substituted with a methoxy, dimethyl, or trimethoxy group (XII) Among them, R7, R8 and R9 are as defined in item i of the patent application, where 'Z is halogen or (Ct_C6) alkoxy group to form a compound of formula X ΓI I (Please read the precautions on the back before (Fill in this page) R9 printed by Shelley Consumer Cooperatives, Bureau of Intellectual Property, Ministry of Economic Affairs (XI of which R6 · R7, R8 and RS are as defined in the first patent application, V 'and 乂 # are respectively "or methoxy · make the hydrazone compound and ethyl grass« chlorine reaction · form the formula XIV Object-7- This paper is in the same size as the Chinese National Kneaded Half (CNS) A4 (210X297 mm) 387890 A8 B8 C8 D8 (XIV) where R6, R7, R8, and R9 are as defined in the application of the 専 Li Fan circle, V ′ and V 氲 are 氲 or methoxy, respectively, and then the hydration reaction is performed to form a cyclized N-hydroxy compound. Intermediate, followed by deoxygenation or cyclization by M hydrogenation reaction * to form a compound of formula XV ρ R (XV) (Please read the note ^ h on the back before filling in the basic education.) The Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs printed R6, R7, R8 and R9 as defined in item 1 of the Shenfan Patent Fanhua, V 'And V 为 are respectively a gas or a methyl group, and the compound thus prepared is reacted with hydrazine from a compound of formula XV, followed by the general formula VI 醸 group as defined in item 1 of the patent application. And then cyclized to form a compound of formula XVI '· -8. The paper ruler is used in the Chinese national kneading rate (〇 阳) person 4 wash grid (2 丨 0 > < 297 mm) 387890 B8 C8 Wherein R1, R6, R7, R8 and R9 are as defined in item 1 of the patent application, V ′ and V 〃 are hydrogen or methoxy, respectively, and hydrolyzed to form a compound of formula I, where X ′ and χ〃 are respectively Hydrogen or (Ci_C6) alkoxy, or d) M aqueous alkaline hydrolysis of a compound of formula I, where X 'and (Ci-C6) alkoxy form a compound of formula I, where X' is a hydroxyl group and X " is ( Ci—Ce) alkoxy * or e) M halotrimethylsilane reacts with formula I, where X * is a hydroxyl group or (Ci ™ Ce) alkoxy, and X " is (Ci—Cs) alkoxy, forming A compound of formula I, wherein X and X 'are hydroxy. ----: ------ Install-- (Please read the note on the back of the page before filling in this page) The paper ruler A printed by the employee consumer cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs uses the Chinese national gradient. CNS) A4 specifications (210x297 public envy) 2 4