WO2001046190A1 - Tricyclic compounds and addition salts thereof - Google Patents

Abstract

Compounds are provided, which exhibit antagonism against excitatory amino acid receptors, particularly AMPA receptor. Specifically, tricyclic compounds of general formula (1) and addition salts thereof; and drugs containing the compounds or salts as the active ingredient, wherein R is halogeno or a group represented by general formula (2), [wherein A is nitrogen or =CH-; and E is hydroxyl or a group of general formula (3), (wherein V is oxygen or -NH-; W is halogeno, carboxyl, or the like)]; Q is nitro or trifluoromethyl; X is oxygen or a group of general formula (4), [wherein T is hydrogen, lower alkyl, aralkyl, or the like]; Y is hydrogen, lower alkyl, or oxygen; and Z is -NH- or the like.

Description

 m Itoda β Tricyclic compounds and their addition salts

 The present invention relates to a tricyclic quinoline derivative which is effective as an excitatory amino acid receptor antagonist, in particular, a selective antagonist of η ο η-NMDA receptor for AMP 治療 receptor, for treating cerebral nerve cell disorders. It relates to an addition salt thereof and a pharmaceutical composition containing these compounds. Background art

 Glutamate, an excitatory amino acid, is a major excitatory transmitter in the vertebrate central nervous system and is known to be the most abundant amino acid in the brain. However, it is known that when released from the end of the axon beyond the physiological range, the glucanic acid receptor at the postsynapse is excessively excited, causing neuronal death. This is called excitatory neuronal death (exciototoxicity).

 In recent years, various types of cranial nerve diseases such as stroke, head trauma, status epilepticus, Huntington's chorea, Parkinson's disease, amyotrophic lateral sclerosis and Alzheimer's disease, have deep neuronal cell death caused by glutamate-minic acid. Involvement is being shown to effectively prevent such excitatory neuronal cell death, and if possible, the potential for treatment of these intractable diseases with almost no cure at present. It is thought that it opens.

Glutamate receptors are roughly divided into ion channel receptors and G protein-coupled receptors. These ion channel receptors are further divided into NMDA (N-methyl-D-aspartate) receptors, n 0 n — divided into NMD A receptors. The latter non-NMDA receptor is composed of AMPA (amino-3-hydroxy-15-methyl-14-isoxazolylpropionic acid) receptor and KA (kainic acid). Classified into receptors.

 Research on these excitatory amino acid receptors has been advanced. Among them, drugs that have antagonism of AMP A receptor of n 0 n-NMD A receptor include drugs that have NMD A receptor antagonism (MK-80 1) has no side effects (learning, memory impairment, schizophrenia-like symptoms, etc.) ^ Neurosci. Bioobeh e v. R ev., 1992, 16, 13-24 Exp. T her 1958, 245, 969—974), and that a cranial nerve protective effect can also be expected by administration after ischemia (Scice, 1990). , 2 47, 5 71 1-5 74). In addition, compounds having a quinoxalinedione AMP A receptor antagonist, such as NB QX (2,3-dihydroxy-16-nitro-17-sulfamoylbenzo [:] quinoxalin), are known as physicochemical compounds. Have been reported to cause renal damage which is considered to be based on the chemical properties (</ Cere W. B_Zood Fowlow Metab 1 994, 14, 25 1 1 1 26 1) There is a problem.

 By the way, as a compound having a similar structure to the tricyclic compound of the present invention, a) a compound having a bronchodilator effect and an antiviral effect represented by the general formula (5) described in JP-A-60-123348 )

[Wherein R ¹ is a hydrogen atom, an alkyl group having 1 to about 10 carbon atoms, a hydroxyalkyl group having 1 to about 6 carbon atoms, a benzyl group which may have one or more substituents, A phenyl) ethyl group which may have one or more substituents, Represents a phenyl group which may have one or more substituents, and R ² is a hydrogen atom, a trifluoromethyl group, a hydroxyalkyl group having 1 to about 6 carbon atoms, an aminoalkyl group having 1 to about 4 carbon atoms. Wherein each alkyl group represents an alkane amide alkyl group having 1 to about 4 carbon atoms, a benzylthio group, a mercapto group, an alkylthio group having 1 to about 4 carbon atoms, an alkyl group having 1 to about 8 carbon atoms, and each R Represents an alkoxy group having 1 to about 4 carbon atoms, an alkyl group having 1 to about 4 carbon atoms, a halogen atom, and n represents an integer of 0 to 2], b) a bronchodilator effect and As the compound having an antiallergic action, a compound represented by the general formula (6) described in JP-A No. 03-264685:

[Wherein, R ¹ represents a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, an aralkyl group, an aralkenyl group, a substituted or unsubstituted aryl group, and R ² represents an alkyl group, a cycloalkyl group, an alkoxy group. alkyl group, an alkenyl group, Ararukiru group, Ararukeniru group represents an _{(C Η 2) η -Η Θ} t ( also the H et where substitution properly is unsubstituted aromatic heterocyclic group, n represents the 1-3 Represents an integer), (CH ₂ ) _n C 0 ₂ R ⁵ (wherein n represents as described above, R ⁵ represents the same meaning as R ² ), and R ³ and R ⁴ are the same or different , Hydrogen atom, lower alkyl group, trifluoromethyl group, cycloalkyl group, halogen atom, hydroxy group, lower alkoxyl group, lower alkylthio group, nitro group, amino group, lower alkylamino group, lower alkanoylamino Group, Roiruamino group, a lower Arukanoiru group, the compound represented by represents a Aroiru group], c) JP 0 3 as a compound having a bone resorption inhibitory action -General formula (29)

(Wherein R ¹ represents a hydrogen atom or a lower alkyl group, R ² represents a hydrogen atom, a hydroxyl group, or a thiol group, and R ³ represents a lower alkyl group or a lower alkoxyalkyl group) D) a compound having an inhibitory action on the H + K + ATPase enzyme as represented by the general formula (8) described in JP-A-07-21593;

(Wherein R i to R ⁴ are the same or different and each represents a hydrogen atom, a C 1-4 alkyl group, a C 1-6 alkoxy group, a phenyl group, a C 1-6 alkylthio group, a C 1-4 alkanol group, an amino group Represents a C 1-6 alkylamino group, a di C 1-6 alkylamino group, a halogen atom, a trifluoromethyl group, or a nitro group, and R ^{5 to} R ⁹ are the same or different and each represents a hydrogen atom, a C 1— 6 alkyl group, C 1-6 alkoxy group, C 1-6 alkyl Compounds known as ruthio, halogen, cyano, amino, hydroxy, carbamoyl, carboxy, C1-6 alkanol, trifluoromethyl, and nitro) I have. However, none of the compounds represented by a) to d), which have different substituents at the 7th and 8th positions as in the compound of the present invention, are disclosed as examples, and the compounds of the excitatory amino acid receptor are not disclosed. Nor is it described that it has AMP A receptor antagonism.

 Further, as a compound having G ABA Aa activity, a general formula (9) described in U.S. Pat. No. 5,182,290,

[In the formula, R ¹ represents a phenyl group, a phenyl group, a phenyl group (which may have a substituent), and R ² and R ⁵ are the same or different and each represents a hydrogen atom, a halogen atom, 6 represents an alkyl group, and R ³ and R ⁴ are the same or different and each represents a hydrogen atom, a halogen atom, a hydroxy group, a C 16 alkyl group, an amino group, an alkylamino group, or a di C 1-6 alkylamino group. Are known. However, this compound also does not disclose a compound having a different substituent at the 7- or 8-position as an example, and has a structure different from that of the compound of the present invention. It is not described that it has any effect.

Compounds having an excitatory amino acid receptor AMP A receptor antagonistic activity e) General formulas (10a) and (10b) described in JP-A-07-501719 , (10a)

(10b)

[Wherein RR ² is the same or different and represents a hydrogen atom, a C 1-6 alkyl group, a halogen atom, a nitro group, an amino group, a cyano group, a trifluoromethyl group, a S 0 ₂ NR ⁴ R ⁵ (R ⁴ and R ⁵ are the same or different and represent a hydrogen atom, a C 1-6 alkyl group), C 0 R ⁶ (R ⁶ represents a C 1-6 alkyl), R ³ is a hydrogen atom, A C 1-6 alkyl group or a trifluoromethyl group), f) a compound represented by the general formula (11) described in WO93 / 20777;

(11)

End

(AN—

(In the formula, a 5-membered heterocyclic group containing 2 to 3 nitrogen atoms which may be substituted with a lower alkyl group or a lower alkanoylamino lower alkyl group is represented, and R ¹ is a nitro group or a trifluoromethyl group. Where X is the formula — N = C—

[Wherein R ² is a hydrogen atom, a lower alkyl group, a formula—T-R ³ (where T represents a single bond or a lower alkylene group; ³ represents a mono or di-lower alkylamino group imidazolyl group)] one ^{T- S (0) n- R 4} ( wherein T represents as mentioned above, n represents 0, 1, 2, R ⁴ is lower alk kill group, a cycloalkyl group)] , One G = N-

(Where R ² is as described above), — c = c—

[Wherein R ⁵ and R ⁶ are the same or different, and are a hydrogen atom, a lower alkyl group, a formula —T—R ³ (where T and R ³ are as described above), -Τ-S (0) _n -R ⁴ (where T, R4, and n represent as described above)],

(Wherein, R ⁷ and R ⁸ represent the same as R ⁵ and R ⁶ ), g) a compound represented by the general formula (12) described in JP-A-05-163131 ,

{Wherein A ¹ A ² and A ³ are the same or different and represent C or N (however, at least one of A ¹ , A ² and A ³ represents N), A ⁴ and A ⁵ One represents C, the other represents N, and RR ² is the same or different and is a hydrogen atom, a halogen atom, a cyano group, a nitro group, a C 1-4 alkyl group, a phenyl or fused benzo group, or an azide group. , Trifluoromethyl group, NH ₂ S ⁴ R ⁴ [R ⁴ represents a C 1-4 alkyl group, phenyl group, SO 2 NR ⁵ R ⁶ (R ⁵ and R ⁶ represent a hydrogen atom and a C 1-4 alkyl group, respectively. Wherein R ³ represents a hydrogen atom, an alkyl group, an aromatic group, or a trifluoromethyl group; h) a compound represented by the general formula (13) described in WO96 / 105572; ,

[Wherein, R ¹ represents a hydrogen atom, a C 1-5 alkyl group, a phenyl group, a pyridyl group, a phenyl group (these may have a substituent), and R ² represents a hydrogen atom, a C 1-5 Represents an alkyl group, a C 3-8 dialkylaminoalkyl group, and R ³ represents a chlorine atom, a bromine atom, a trifluoromethyl group, Represents a cyano group or a nitro group; ring A represents a 5-membered heterocyclic ring containing 1-4 nitrogen atoms or 1-2 nitrogen atoms and one oxygen atom or sulfur atom; R ⁴ and R ⁵ represent The same or different, and represents a hydrogen atom, a C15 alkyl group, a C1-5 hydroxyshetyl group, or a phenyl group which may have a substituent, and T is a single bond or a C15 alkylene chain A) a compound represented by the general formula (14a) and the general formula (14b) described in US Pat. No. 5,688,033.

[Wherein R ¹ R ² are the same or different and each represents a hydrogen atom, a lower alkyl group-a lower alkoxy group, a nitro group, a trifluoromethyl group, an amino group, a halogen atom, a cyano group, one S (0) ₂ NR ³ R ⁴ (R ³ and R ⁴ represent a lower alkyl group)], and all of e) to i) are tricyclic fused quinoxaline or tricyclic fused quinazoline And the compound of the present invention is a condensed quinoline represented by the general formula (1) and has a different structure. Also, the reported AMPA receptor antagonism is not sufficient.

In addition, it has an excitatory amino acid receptor AMP A receptor antagonism, As a quinoline-fused tricyclic compound, j) a compound represented by the general formula (15) described in US Pat. No. 5,688,803,

[Wherein RR ² is the same or different and represents a hydrogen atom, a lower alkyl group. A lower alkoxy group, a nitro group, a trifluoromethyl group, an amino group, a halogen atom, a cyano group, — S (0) ₂ NR ³ R ⁴ ( R ³ and R ⁴ each represent a lower alkyl group), and X represents an oxygen atom, mono NH—, —CO—], a compound represented by the formula: k) a general formula described in GB2288800

(16),

[And RR ² are the same or different in the formula, a hydrogen atom, a hydrocarbon, heterocyclic group, halogen atom, Shiano group, preparative Rifuruoromechiru group, nitro group, one 0 R ^a, - SR ^a, one S 0R ^a, single S〇 ₂ R ^a , — S 0 ₂ NR ^a R ^b ,-NR ^a R — NR ^a C 0 R ^b , one NR ^a C〇 ₂ R ^b , one C0R ^a , one C 0 ₂ R ^a , one C〇NR ^a R ^b (where R ^a and R ^b are the same or different and represent a hydrogen atom, a hydrocarbon, a heterocyclic group) or And R ³ , R ⁴ , R ⁵ , and R ⁶ are the same or different, and represent a hydrogen atom, a hydrocarbon, a heterocyclic group, a halogen atom, a cyano group, a trifluoromethyl group, a nitro group, — 0R ^a , — SR ^a , — S 0R ^a , — S〇 ₂ R ^a , one S〇 ₂ NR ^a R ^b , one NR ^a R ^b , one NR ^a C〇R ^b , — NR ^a C〇 ₂ R ^b, one C 0R ^a, one ^{_{C0 2 R a, - C 0}} NR ab Although the compound represented by (wherein R ^a, R ^b represents a as described above) representing a] are known, they: i ) To k), those having different substituents at positions 7 and 8 are not disclosed as examples, and the structure of the 5-membered condensed ring is different from that of the compound of the present invention. However, the structure is different from that of the compound of the present invention. Also, the reported AMP A antagonism is not sufficient.

 The present invention is directed to a glutamate receptor antagonism, which is considered to be a cause of memory disorders and dementia caused by the above-mentioned diseases and selective cell death, and in particular, has a high affinity for non-NMD A receptor AMP A receptor. And a compound having a selectivity and a protective effect on brain nerve cells. Disclosure of the invention

 DISCLOSURE OF THE INVENTION The present inventors aimed at the development of a novel therapeutic agent for cerebral neuronal damage and selected an excitatory amino acid receptor antagonist effective for the treatment of cerebral neuronal damage, in particular, selection of n 0 n-NMDA receptor for AMP A receptor As a result of intensive studies in search of a potential antagonist, it was found that the tricyclic compound of the present invention and its addition salt have excellent AMP A receptor antagonistic activity.

That is, according to the present invention, the general formula (1)

(Where R is a halogen atom, or a general formula (2)

(Where A represents a nitrogen atom, = CH—, E represents a hydroxyl group, or general formula (3)

(Wherein V represents an oxygen atom, —NH—, W represents a halogen atom, a carboxyl group, a lower alkoxycarbonyl group, a phosphono group, or a di-lower alkylphosphoryl group).

Q represents a nitro group or a trifluoromethyl group,

X is an oxygen atom, or general formula (4) lo

(Wherein T represents a hydrogen atom, a lower alkyl group, or an aralkyl group which may have one or more substituents)

 When one of C-Y and C = Z represents a single bond, the other represents a double bond,

 Represents a hydrogen atom or a lower alkyl group when C = Y is a single bond,

 When C = Y is a double bond, it represents an oxygen atom,

Z represents one NH— when C = z is a single bond,

 When c = z is a double bond, it represents a nitrogen atom)

It has been found that the tricyclic compound represented by the formula (1) and its addition salt have excellent AMP A receptor antagonism, and have completed the present invention.

 In the general formula (1) of the compound of the present invention, preferably, a compound in which X is an oxygen atom or in the general formula (4), T is a methyl group is exemplified. More preferably, a compound in which R is represented by the general formula (2) and E in the general formula (2) is represented by the general formula (3) is exemplified.

 These preferred compounds include the following compounds: 8-bromo-17-nitrooxazolo [4,5-c] quinolin-2 ヽ 4 (3H ", 5H) -dione,

 8—Chloro—7—Nitro 1-year-old quinazoline [4,5—c] quinoline—1,4 (35H) —dione,

 8 — ((4-Hydroxymethyl) imidazole-1—yl) -1 7—Trifluoromethyloxazozo mouth [4,5—c] quinolin-1 2,4 (3H, 5H) — Zeon,

8— (4-(((2 —Fluorophenyl) Power rubamoyloxy) Methyl imidazole 1 —yl) 1 7— Trifluoromethylmethyl oxa Zoro [4,5-c] quinoline- 1,2,4 (35H) -dione, 8- (4-((((4-carboxyphenyl) potumbamoyloxy) methyl) imidazole-1 ) — 7— Trifluoromethyloxysazolo [4, 5 — c] quinolinine 2, 4 (3U, 5i) — dione, 8- (4-(((4-phosphonophenyl)) rubamoyloxy ) Methyl) imidazole-1 1-yl) 1 7-trifluoromethylloxazolo [4,5—c] quinoline 1-2,4 (35H) —dione, 8-(4-( ((4-diethoxyphosphorylphenyl) rubamoyloxy) methyl) imidazoyl 1-yl) 1 7-trifluorome tylooxazolo [4,5—c] quinoline 1,2,4 (35H) Geon,

 8— (4 — (((4-Di (2-propoxy) phosphorylphenyl) power rubamoyloxy) methyl) imidazole-1-yl) — 7—trifluormethylmethyloxazolo [4,5-c] quinoli 2, 4 (3H, 5H) -dione,

 8-(4-(((2-Fluorophenyl) carbamoyloxy) methyl) imidazole-1-1-yl) -1 7-Trifluoromethyl-1-oxazolo [4,5-c] quinolin-1 4 (5H) — ON,

 8— (4— (((4-Carboxyphenyl) Powerbamoyloxy) Methyl) Imidazole-1 —yl) — 7— Trifluoromethyloxysazolo [4,5—c] quinoline One four (5H) —on,

 8-Fluoro-1-methyl-1 7-nitro l fi-imidazo [4,5-1c] quinoline-1 4 (5H) one,

 8— (4 — (((2-Fluorophenyl) pothamamoyloxy) methyl) imidazole-1 1-yl) 1-1-methyl-7-trifluoromethyl-imidazo [4,5-c] quinolin-1 4 ( 5 H) — ON,

8- (4-(((4-carboxyphenyl) pothamamoyloxy) methyl) imidazole-1 1-yl) — 1—Methyl—7—Trifluoromethylimidazo [4,5—c] quinolin One four (5H) —on, And the like.

 The compound of the present invention is, for example, a compound represented by the general formula (1) produced by the following production method:

(Wherein R, Q, X, Y, Z, C = Y and C = Z represent as described above, and R ¹ represents an aralkyl group optionally having one or more substituents). The compound is used without solvent or in a suitable solvent such as toluene, anisol, tetrahydrofuran, acetic acid, etc., using a suitable acid such as hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid or a mixed acid thereof. At 0 to 120 ° C. for 2 to 72 hours.

 In the compounds represented by the general formula (17), X is an oxygen atom, C = Y is a double bond, Y is an oxygen atom, and C = Z is a single bond. Where Z is -NH-, a general formula (17a)

(Where R and R ¹ Q represent the same as described above) is represented by the general formula (18a) CONHNH ₂

 (18a)

 Q eight

R ¹

(Wherein R and R \ Q represent as described above) without solvent or an appropriate solvent such as water, diluted hydrochloric acid, acetic acid, ethanol, tetrahydrofuran, 1,4-dioxane, N, N— In dimethylformamide or a mixture thereof, a suitable nitrite such as sodium nitrite or potassium nitrite, or a suitable nitrite such as t-butyl nitrite or nitrite. — Can be synthesized by reacting with butyl or the like at 0 to 120 ° C. for 10 minutes to 24 hours.

 The compound represented by the general formula (18a) has the general formula (19a)

(Wherein R, R ¹ Q represents a as described above, R ² is a lower alkyl group, also optionally Ararukiru group substituted) without solvent or in an appropriate solvent a compound represented by, for example, water, It can be synthesized by reacting with hydrazine or a salt thereof in methanol, ethanol, tetrahydrofuran, N, N-dimethylformamide, etc. at 0 to 120 ° C for 1 to 12 hours. In the compound represented by 17), X is the general formula (4), C ^ .Y is a double bond, Y is an oxygen atom, and C2 z is General formula (17b) in which a single bond and Z is —NH—

(Where R, R ¹ , Q, and T represent the same as described above) is represented by the general formula (20)

(Wherein R, R ¹ Q and T represent the same as described above) in a suitable solvent such as benzene, tetrahydrofuran, 1,4-dioxane, Ν, Ν-dimethylformamide, etc. In the presence of a suitable organic base, such as triethylamine, Ν, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undesen 7-ene or a mixture thereof, It can be synthesized by reacting with nylphosphoryl azide at 20 to 120 ° C for 1 to 12 hours.

Further, the compound represented by the general formula (20) is represented by the general formula (21) 18

(Wherein R, ^ R ² , Q and T are as described above) in a suitable solvent such as ethanol, methanol, tetrahydrofuran, water or a mixture thereof. It can be synthesized by hydrolysis for 0.5 to 12 hours at 0 to 100 ° C. in the presence of an alkali, for example, sodium hydroxide, hydroxylating power or the like.

 Further, the compound represented by the general formula (21) can be prepared by converting the compound represented by the general formula (19a) into a suitable solvent such as benzene, chloroform, methylene chloride, 1,4-dioxane, N, N -In dimethylformamide, etc., in the presence of non-basic or suitable organic bases, such as triethylamine, pyridine, 1,3-collidine, etc., with methanesulfonic acid chloride or maleic sulfonic anhydride. After reacting for 1 to 12 hours at 20 to 120 ° C, the general formula (22)

T-NH ₂ (2 2)

 (T represents as described above), and is synthesized.

In the compound represented by the general formula (17), X is an oxygen atom, d is a single bond, Y is a lower alkyl group, and C =: Z is a double bond. , Where Z is a nitrogen atom (17c)

(Wherein R, R ¹ Q represents a as described above, Y ¹ represents a lower alkyl group), the general formula suitable solvent a compound represented by (1 7 a), For example water, died some evening In the presence of a suitable inorganic or organic base, such as sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, potassium t-butoxide, triethylamine, etc., in ethanol, methanol, methanol, etc. After reacting at 120 ° C for 2 to 10 hours, the general formula (23)

(Y ¹ -C 0) (2 3)

(Y ¹ represents the same as described above), and can be synthesized by reacting at 20 to 100 ° C. for 2 to 48 hours.

 In the compound represented by the general formula (1), X is an oxygen atom;

General formula (1a-1) where C = Y is a double bond, Y is an oxygen atom, c = z is a single bond, and Z is one NH—

Is the general formula (18b)

(Wherein R and Q represent the same as described above) in a suitable solvent such as water, diluted hydrochloric acid, acetic acid, ethanol, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide Alternatively, using a suitable nitrite, for example, sodium nitrite, nitrite rim, or a suitable nitrite, for example, t-butyl nitrite, n-butyl nitrite, etc. It can be synthesized by reacting at 0 to 120 ° C for 10 minutes to 24 hours.

 Further, the compound represented by the general formula (18b) has the general formula (19b)

(19b)

(Wherein R, R ² and Q are as described above) in a solvent-free or suitable solvent such as water, methanol, ethanol, tetrahydrofuran, N, N-dimethylformamide, etc. Can be synthesized by reacting with hydrazine or a salt thereof at 0 to 120 ° C. for 1 to 24 hours. Also, among the compounds represented by the general formula (1), R is a general formula (2), In the general formula (2), E is the general formula (3), and in the general formula (3), V is an oxygen atom.

(Where Q, X, Y, Ζ ヽ W, C = Y, represent as described above) is the general formula (I d)

(Wherein X, Y, Ζ, C-γ, and C = z represent the same as described above) in a suitable solvent such as chloroform, methylene chloride, ethyl acetate, acetonitrile, Benzene, toluene, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, N, In N-dimethylacetamide, dimethylsulfoxide, etc., in the presence of an abasic or a suitable organic base, for example, triethylamine, pyridine, etc., the general formula (24)

 (twenty four)

(Wherein W represents as described above) and is reacted at 20 to 150 ° C for 1 to 15 hours.

Also, instead of the general formula (24), the general formula (24a)

(Wherein W represents as described above, and D represents an amino group, a carboxyl group, an amide group, a lower alkoxycarbonyl group, and a carbonylazide group). It can also be synthesized by converting to ester or carbamic acid chloride and reacting in the same manner as in the general formula (24).

In the compound represented by the general formula (lc), W is a carboxyl group or a phosphono group.

(Wherein X, Y, Z, c-γ and c = z represent the same as above and W represents a carboxyl group or a phosphono group) is represented by the general formula (If)

(Wherein X, Y, Z, C = Y and c = z represent the same as described above, and W ² represents a lower alkoxycarbonyl group or a di-lower alkoxyphosphoryl group). In a solvent, for example, water, ethanol, 1,4-dioxane, etc., in the presence of a suitable alkali, for example, potassium hydroxide, sodium hydroxide, lithium hydroxide, etc., at 20 to 100 ° C. Hydrolyze for 5 to 10 hours or in a suitable solvent such as water, acetic acid, ethanol or a mixture thereof in the presence of a suitable acid such as hydrochloric acid, hydrobromic acid or a mixed acid thereof. 0 to 120 °. Can be synthesized by hydrolysis for 6 to 170 hours.

In the compound represented by the general formula (1), X is the general formula (4), and in the general formula (4), T is a hydrogen atom.

(Where R, Q, Y, Z, C2Y and C2z represent as described above) is represented by the general formula (1h)

(Wherein R, Q, Y, Z, CY, and C = z represent as described above, and T ¹ represents an aralkyl group which may have a substituent) without a solvent or a suitable solvent, for example, toluene, 0 to 120 ° 〇 in anisol, tetrahydrofuran, acetic acid, etc. in the presence of a suitable acid such as hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid, or a mixed acid thereof. It can be synthesized by reacting for 72 hours.

In the compound represented by the general formula (1), CY is a single bond, C = Z is a double bond, and Z is a nitrogen atom.

(Where R, Q, X, and Y represent as described above) is represented by the general formula (25)

(Wherein R, Q, X, and Y represent as described above, and R ⁴ represents a hydrogen atom or a lower alkyl group) without a solvent or a suitable solvent such as water, acetic acid, ethanol, or methanol. In the presence of a suitable acid, for example, hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid, or a mixed acid thereof in tetrahydrofuran, etc., at a temperature of 20 to 100 ° (2 to 72 hours). Can be synthesized.

 The compound represented by the general formula (19a) is represented by the general formula (26)

(Wherein R, R ¹ Q represents a as described above, R ⁵ is a lower alkyl group, an optionally Ararukiru group which may have a substituent) apply a compound represented by In a suitable solvent, for example, acetonitrile, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, etc., a suitable organic base, for example, triethylamine, diisopropylethylamine or these In the presence of a mixture of the general formula (27)

(Wherein R ² represents as described above, and hal. Represents a halogen atom). The compound represented by the general formula (26a) is reacted at 20 to 120 ° for 0.5 to 6 hours. )

(Wherein R, R \ R ² and Q represent the same as described above), and then a suitable solvent such as ethanol, methanol, tetrahydrofuran, N, N-dimethylformamide, N, N- In the presence of a suitable inorganic or organic base, such as sodium ethoxide, sodium methoxide, sodium hydride, or potassium butoxide, in dimethylacetamide, etc. It can be synthesized by cyclization at 70 ° (for 2 to 24 hours.

In addition, a compound represented by the general formula (26) is dissolved in a suitable solvent such as acetonitrile, tetrahydrofuran, Ν, Ν-dimethylformamide, Ν, Ν-dimethylacetamide, etc. In the presence of a base, for example, Ν, Ν-diisopropylethylamine, 1,8-diazabicyclo [54.0] indesene-7-ene or a mixture thereof, represented by the general formula (27) Compound at 20 to 120 ° (0.5 to 6 hours at 3) It can also be synthesized by reacting.

 Further, the compound represented by the general formula (19a) can be obtained by converting the compound represented by the general formula (26) into a suitable solvent such as ethanol, methanol, tetrahydrofuran, N, N-dimethylformamide, N, In the presence of a suitable inorganic or organic base, such as sodium methoxide, sodium methoxide, sodium hydride, potassium t-butoxide, etc. in N-dimethylacetamide, etc. Equation (28)

(Wherein R ² represents the same as described above), and can be synthesized by reacting with a dialkyl malonate at 20 to 170 ° C. for 2 to 24 hours.

The compound represented by the general formula (19a) is represented by the general formula (29)

(Wherein R, R ¹ Q represents a as described above) in anhydrous Isa bets acid suitable solvents represented by, for example ethanol, methanol, Te Torahi Dorofu run, N, N-dimethyl formamidine de, N, N- In the presence of a suitable inorganic or organic base such as sodium ethoxide, sodium methoxide, sodium hydride, or potassium t-butoxide in dimethylacetamide or the like, the general formula It can also be synthesized by reacting with a dialkyl malonate represented by (28) at 20 to 170 ° C for 2 to 24 hours.

In addition, the compound represented by the general formula (26) is prepared by the method of the following scheme 1. Can be combined.

 (30) (31) (26)

 Scheme 1

(Wherein R, RR ^5, Q represents as mentioned above)

 That is, the anthranilic acid represented by the general formula (30) is converted into a suitable solvent such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, etc.

^{R 1 - 0 H (3 2} )

(Wherein R ¹ represents as described above) at 50 to 200 ° C. to give a general formula (31), which is converted to a suitable solvent, for example, acetonitrile , Tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, etc., suitable inorganic or organic bases such as sodium carbonate, carbonated carbonate, sodium hydroxide. (33) 5-hal. (33) in the presence of sodium hydride, sodium hydride, triethylamine, etc.

(Wherein R ⁵ and hal. Represent as described above) at 0 to 120 ° C.

Further, among the compounds represented by the general formula (26), the general formula (26a) wherein R ¹ and R ⁵ are the same

(Wherein R ¹ represents as described above) can be synthesized by Scheme 2 below.

 Scheme, 2

(Where R and R \ Q are as described above)

 That is, the anthranilic acid represented by the general formula (30) is converted to a suitable carbonyl in a solvent-free or suitable solvent such as benzene, ether, dioxane, acetonitrile, N, N-dimethylformamide and the like. Using a phosgene, phosgene dimer, phosgene trimer, dimethyl carbonate, carberdiimidazole, etc. at 20 to 150 ° C for 1 to 12 hours to obtain the general formula (34), In a suitable solvent, for example, acetonitrile, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, etc., a suitable inorganic or organic base such as sodium carbonate, potassium carbonate In the presence of sodium, sodium hydroxide, sodium hydride, triethylamine, etc., the general formula (33a)

R ¹ -hal. (3 3 a) (Where R ha 1 represents the same as described above).

 The compound represented by the general formula (19b) is represented by the general formula (35)

(Wherein R and R ⁵ are as defined above) in a suitable solvent such as acetonitrile, tetrahydrofuran, N, N-dimethylformamide, dimethylacetamide, etc. In the presence of an organic base such as triethylamine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] indene-17-ene, etc., it is represented by the general formula (27). After reacting with the compound to be prepared, in a suitable solvent such as ethanol, methanol, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, etc., a suitable inorganic or organic base such as sodium The reaction is carried out at 20 to 170 ° C for 2 to 24 hours in the presence of rhodium ethoxide, sodium methoxide, sodium hydride, potassium hydroxide, etc. That.

 Further, the compound represented by the general formula (19b) can be obtained by converting the compound represented by the general formula (35) into a suitable solvent such as ethanol, methanol, tetrahydrofuran, N, N-dimethylformamide, N, In the presence of a suitable inorganic or organic base in N-dimethyl acetate, such as sodium methoxide, sodium methoxide, sodium hydride, potassium butoxide, etc. Can also be synthesized by reacting with a dialkyl malonate represented by the general formula (28) at 20 to 170 ° C for 2 to 24 hours.

Further, the compound represented by the general formula (19b) is represented by the general formula (36)

(Wherein R and Q represent as described above) in an appropriate solvent, for example, ethanol, methanol, tetrahydrofuran, N, N-dimethylformamide, N, N— In the presence of a suitable inorganic or organic base, such as sodium ethoxide, sodium methoxide, sodium hydride, or potassium monobutoxide, in dimethyl acetate amide or the like, the compound represented by the general formula (2 It can also be synthesized by reacting with dialkyl malonate represented by 8) at 20 to 170 ° 〇 for 2 to 24 hours.

 The compound represented by the general formula (35) can be synthesized by esterifying the anthranilic acid represented by the general formula (30) by a known method. For example, an anthranilic acid represented by the general formula (30) is dissolved in a solvent or in a suitable solvent such as benzene, tetrahydrofuran, 1,4-dioxane, or the like, and a suitable acid such as hydrochloric acid, sulfuric acid, ρ-toluene. In the presence of sulfonic acid, etc., using a suitable dehydrating agent, for example, molecular sieves 4Α, the general formula (37)

R 0 H (3 7)

(Wherein R ⁵ is as described above) and dehydration-condensed to 20 at 12 ° C. for 2 to 48 hours.

Further, among the compounds represented by the general formula (35), R is the general formula (2), and in the general formula (2), E is a hydroxyl group.

(Wherein R ⁵ and Q represent as described above) can be synthesized by the method of Scheme 3 below.

 Scheme 3

(Where R ⁵ and Q represent as described above)

 That is, a commercially available or synthesizable general formula (38) is converted into a suitable solvent such as ether, tetrahydrofuran or the like in a suitable inorganic or organic base, such as lithium t-butoxide, sodium hydride, or the like. In the presence of etc., react with ホ ル -form at -78 to 25 ° C for 1 to 5 hours to obtain the general formula

(39) without solvent or a suitable solvent such as tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone In bases, acetonitrile, benzene, toluene, etc. For example, in the presence of sodium hydride, sodium carbonate, potassium carbonate, sodium hydroxide, triethylamine, pyridine, etc., 4- (hydroxymethyl) imidazole and 20% The reaction is carried out at a temperature of 160 ° C. for 2 to 6 hours to obtain a general formula (40). This is dissolved in a suitable solvent, for example, water, diluted hydrochloric acid, acetic acid, tetrahydrofuran, or a mixture thereof, using a suitable reducing agent, for example, titanium trichloride, at 20 to 80 ° C for 10 minutes to 6 minutes. After reacting for a period of time, the mixture is made alkaline with a suitable alkali, such as potassium hydroxide, sodium hydroxide, lithium hydroxide, or the like, to give the general formula (41). In methylene, benzene, etc., in the presence of a suitable cyanate such as sodium cyanide or potassium cyanide, an alcohol represented by the general formula (37) using a suitable oxidizing agent such as manganese dioxide. For 0.5 to 8 hours at 0 to 80 ° C.

 Further, among the compounds represented by the general formula (30), the general formula (30a) wherein Q is a nitro group

(Wherein R represents as described above) can be synthesized by the method of Scheme 4 below.

 (43)

 (45) (30a) Scheme 4

(Where R represents as described above)

That is, the general formula (42) which can be obtained or synthesized can be obtained by converting a general formula (42) without a solvent or an appropriate solvent, for example, methylene chloride, chloroform, tetrahydrofuran, etc., in an abasic or an appropriate base such as pyridine or triethylamine. In the presence of acetic acid or acetyl chloride, acetylation is carried out at 10 to 120 ° C. for 1 to 24 hours to give a general formula (43), which is then converted into a suitable solvent such as nitromethane, acetic acid, or the like. Using a suitable nitrifying agent, such as concentrated nitric acid, fuming nitric acid, potassium nitrate, acetyl nitrate, etc., in sulfuric acid, sulfuric acid, etc. for 0.5 to 2 hours at 10 to 80 ° C. Let it be the general formula (44). This is mixed with a suitable solvent, for example, water, acetone, methylene chloride, benzene or a mixture thereof, using a suitable oxidizing agent, for example, potassium permanganate, periodate, etc. The reaction is carried out at 0 ° C. for 1 to 15 hours to obtain the general formula (45), which is then dissolved in a suitable solvent, for example, water, ethanol, methanol or a mixture thereof, in a suitable base, for example, sodium hydroxide. Hydrolyze at 20 to 100 ° C for 1 to 10 hours in the presence of a hydroxylating rim, or in a suitable solvent such as water, ethanol, methanol or a mixture thereof. It can be synthesized by hydrolysis at 20 to 100 ° C. for 1 to 10 hours in the presence of an acid such as hydrochloric acid, hydrobromic acid or a mixed acid thereof. _n _

 35 Further, the compound represented by the general formula (25) is a compound represented by the general formula (46)

(Wherein R and Q represent the same as described above, and R ⁶ and R ⁷ may be the same or different and represent a lower alkyl group, a lower alkoxyl group, or a ring formed by R ⁶ BR ⁷ ) The compound of formula (I) is converted into a suitable solvent, for example, chloroform, methylene chloride, ethyl acetate, acetonitril, benzene, toluene, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, etc. Medium, a suitable palladium catalyst, for example, tetraxtriphenylphosphine palladium (0), diphenylphosphinofluorophenyldichloropalladium (II), and a suitable inorganic or organic base such as sodium carbonate; In the presence of potassium carbonate, triethylamine, N, N-diisopropylethylamine, etc., the general formula (47)

(47)

O ゥ R ⁴

(Wherein R ⁴ , X, and Y represent the same as described above, and R ⁸ represents a bromine atom or an iodine atom) and can be synthesized by reacting at 20 to 140 ° for 1 to 24 hours. .

The compound represented by the general formula (46) is represented by the general formula (48)

(Wherein R and Q represent as described above, and R ⁹ represents a bromine atom or an iodine atom). A compound represented by the formula (I) is dissolved in a suitable solvent, for example, chloroform, methylene chloride, ethyl acetate, acetonitrile, In benzene, toluene, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, etc., a suitable palladium catalyst, such as tetraxtriphenylphosphine palladium (0), diphenylphosphinophenylenedichloro Palladium (II) and other suitable inorganic or organic bases, such as sodium carbonate, potassium carbonate, potassium acetate, triethylamine, N, N-diisopropylethylamine, etc. Below, general formula (4 9 a)

(Where R ⁶ and R ⁷ represent as described above) or a general formula (49 b).

(Wherein R ⁶ and R ⁷ represent the same as described above) by reacting with an organic boron compound at 20 to 140 ° C. for 1 to 24 hours.

In the compound represented by the general formula (48), Q is a nitro group. General formula (48a)

(Wherein R and R ⁹ represent as described above) can be synthesized by the method of Scheme 5 below.

Scheme 5

(Where R and R ⁹ represent as described above)

 That is, the available or synthesizable general formula (50) is converted into a suitable solvent such as nitromethane, acetic acid, sulfuric acid, etc., and a suitable nitrating agent such as concentrated nitric acid, fuming nitric acid, potassium nitrate, acetyl nitrate, etc. The reaction is carried out at —10 to 80 ° 〇 for 0.5 to 2 hours to obtain a general formula (51), which is free of a solvent or an appropriate solvent, for example, methylene chloride, chloroform, tetrahydrofuran. In acetic acid or in the presence of an appropriate base, for example, pyridin, triethylamine or the like, use acetic anhydride or acetyl chloride at —10 to 80 ° C for 0.5 to 6 hours. Can be synthesized

In the compound represented by the general formula (47), R ³ is an ethyl group, Y is a hydrogen atom, and X is the general formula (4).

(Wherein R ⁸ and T represent as described above) can be synthesized by the method of Scheme 6 below.

 (52) (53) (47a)

Scheme 6

(Where R ⁸ and T represent as described above)

That is, available or synthesizable ethylcyanoglyoxylate—2-oxime (52) is dissolved in a suitable solvent, for example, methanol, ethanol, tetrahydrofuran, etc., in a suitable palladium catalyst, for example, palladium. After reacting at 20 to 60 ° C for 1 to 6 hours in a hydrogen atmosphere under normal pressure or pressure in the presence of carbon, etc., this is reacted with an appropriate solvent such as acetonitrile, tetrahydrofuran, etc. The reaction is carried out with an appropriate trialkyl orthoformate, for example, triethyl orthoformate, at 20 to 100 ° C for 0.5 to 4 hours. This is reacted with an amide represented by the general formula (22) in an appropriate solvent, for example, acetonitril, tetrahydrofuran or the like, at a temperature of 20 to 100 ° C for 0.5 to 4 hours. To the general formula (53). In a suitable solvent such as water, diluted hydrochloric acid, acetic acid or a mixture thereof, a suitable nitrite such as sodium nitrite or potassium nitrite and a suitable metal halide such as Daiichi bromide are used. Using copper, calcium iodide, etc. And reacting at 0 to 80 ° C for 0.5 to 2 hours. BEST MODE FOR CARRYING OUT THE INVENTION

 Examples of the compound of the present invention will be described to explain the present invention in more detail.

(Example 1)

 8—Bromo 7—Nitrooxazolo [4, 5—c] Quinoline 24 (35H) —dione

8-Bromo-5- (2,4-dimethoxyphenyl) methyl-7-nitrooxazolo [4,5-c] quinolin-1 2,4 (35H) -dione (Reference Example 4) (12.0 mg) , 0.52 mmol) of trifluoroacetic acid (0.5 ml) was added to a solution of ethanol (0.5 ml), and the mixture was stirred at 80 ° C for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the residue was washed with diisopropyl ether and dried to obtain 4.90 mg of the title compound as a yellow powder. Yield 60%.

 Mp.: 2 8 7-2 89 ° C.

 H R F A B -M S: 3 2 4. 9 3 2 7 (—0.7 mmu).

(Example 2)

8-Chloro-7-2 Trooxazolo [4,5—c] quinoline 1 2,4 (35H) —dione

8—Chloro-5— (2,4 dimethoxyphenyl) Methyl-7—Nitrooxazolo [4,5—c] quinoline 1,4 (35H) —dione (Reference Example 7) (80.0) mg, 0.185 mmol) to obtain 29.0 mg of the title compound as a pale brown powder in the same manner as in Example 1. Yield 56%.

 M p.:> 300 ° C.

 H R F A B-M S: 2 79. 9 7 6 4 (+0.3 mmu).

(Example 3)

 8 —Black mouth— 7—Nitro 1 i—Imidazo [4,5-c] quinoline 1 2,4 (35H) dione

8-chloro-5- (2,4-dimethoxyphenyl) methyl-7-nitro-li-imidazo [4,5-c] quinolin-1,4 (35H) dione (Reference Example 1) 0) (12.0 mg, 0.0279 mmo1) in the same manner as in Example 1 to give the title compound of light brown powder. This gave 2.9 mg of product. Yield 37%.

 M p.:> 300 ° C.

 H R F A B -M S: 2 7.8.9 9 2 7 (+0.3 mmu).

(Example 4)

 8—Promo 7—Trooxazolo [4,5—c] Quinoline 1 2 4 (35H) —Dione

6-Bromo-1, 2-dihydroxy 4-hydroxy-7-nitro-2-oxoquinoline-3-carboxylic hydrazide (Reference Example 3) (180 mg, 0.474) mmo 1) in a suspension of acetic acid (5 ml), N, N-dimethylformamide (5 ml) and 1,4-dioxane (3 ml) at 10 ° C. A solution of 55.8 mg, 0.809 mmo 1) in water (2 m 1) was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was washed with water and dried to give the title compound as yellow powder (155 mg). Yield quantitative.

 M p.:> 300 ° C.

 H R F AB -M S: 3 2 4. 9 3 2 7 (-0.7 mmu).

(Example 5)

8 — [4- (Hydroxymethyl) imidazole-1-yl] -1 7 — Trifluoromethyloxazozo mouth [4,5-c] quinoline 1,2,4 (35H) —dione

1,2-Dihydroxy 4-Hydroxy-6— [4- (Hydroxymethyl) imidazole—1—yl] —2—Oxo-1 7—Trifluoromethylquinoline-1 3-Carboxylic hydrazide (Reference Example 25) A solution of (1.64 g, 4.28 mm 01) in acetic acid (45 ml) was added at 10 ° C to water (9 ml) and sodium nitrite. A solution of (399 mg, 5.78 mmo 1) in water (9 ml) was added sequentially, and the mixture was stirred for 4 hours. After standing overnight, the reaction solution was concentrated under reduced pressure, and the residue was washed with water and dried to obtain 1.74 g of the title compound as a light brown powder. Yield quantitative.

 M p.:> 300 ° C.

HRFAB ⁺ MS: 36.7.0661 (+0.7 mmu).

(Example 6)

8-[4-1 [[(2 -Fluorophenyl) Powerbamoyloxy] methyl] midazo 1 -yl]-7-Trifluoromethyloxazozo mouth [4, 5-c] Quinoline 1 2, 4 (35H) dione

A suspension of the compound of Example 5 (100 mg, 1.27 mmol) in tetrahydrofuran (5 ml) was added to a suspension of 2-fluorophenyl isocyanate (56.2 m: 0.41). 0 mm o 1) was added, and the mixture was heated and refluxed for 48 hours. After cooling, the precipitated crystals were collected by filtration, washed successively with tetrahydrofuran and ethyl acetate, and dried. The obtained crude crystals were subjected to silica gel column chromatography (hexane: ethyl acetate = 4: 1 to 10: 0 ethyl acetate: methanol = 30: 1) to give the title compound as a white powder. 0.0 mg was obtained. Yield 29%.

 M p.:> 300 ° C.

 H R F A B -M S: 50.204.04 (+3.0 mmu).

(Example 7)

8-[4-[[(4-ethoxycarbonyl) phenyl] -lvamoyloxy] methyl] imidazole- 1 -yl] — 7-Trifluoromethyloloxazolo [4, 5-c] Quinoline 1, 4 (3 5 H) — Zion

To a solution of the compound of Example 5 (200 mg, 0.546 mmol) in N, N-dimethylformamide (4 ml) was added ethyl 4-isocyanate benzoate (208 mg, 1.09). mmol) and triethylamine (55.2 mg, 0.546 mmo1) were added, and the mixture was stirred at 80 ° C for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 5: 1 to 10: 0 ethyl acetate: ethyl acetate = 20: 1) to give a white powder. 61.0 mg of the compound was obtained. Yield 16%.

 M p.:> 300. C.

 H R F A B-M S: 55.6.10 7 8 (—0.2 mmu).

(Example 8)

8-[4 — [[(4-Carboxyphosphoryloxy) methyl] -midazo- 1-yl]-7-Trifluoromethyloxazolo [4,5-c] quinoline 1-, 2- 4 3 5 H) —Zeon

Concentrated hydrochloric acid (2 ml) was added to a solution of the compound of Example I (61.0 mg, 0.109 mmo 1) in acetic acid (2 ml), and the mixture was stirred at 40 ° C for 4 days. Water was added to the reaction solution, and the precipitated crystals were collected by filtration, washed with water, and dried to give 44.3 mg of the title compound as a white powder. Yield 77%.

 M p.:> 300 ° C.

 HR FAB-MS: 5 2 8. 0 7 5 0 (-1.7 mmu).

(Example 9)

 8-Bromo-2-methyl-1 7-nitrooxazolo [4,5-c] quinolin-4 (5H) -one

To a solution of the compound of Example 1 (134 mg, 0.281 mmol) in potassium hydroxide (5 ml) was added potassium t-butoxide (63.2 mg, 0.563). mm 0 1), and the mixture was stirred at 80 ° C for 5 hours. After cooling, The reaction solution was acidified with acetic acid and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (methylene chloride). Acetic anhydride (5 ml) was added to the obtained green amorphous, and the mixture was heated under reflux for 3 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (methylene chloride: hexane = 2: 1). Anisole (1 ml) and trifluoroacetic acid (1 ml) were added to the obtained brown amorphous, and the mixture was stirred at 60 ° C for 1.5 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the residue was washed with methylene chloride and dried to obtain 10.0 mg of the title compound as a white powder. Yield 11%.

 Mp.:> 300 ° C.

 H R F A B-M S: 3 2 .9 5 4 7 (+0.5 mmu).

(Example 10)

 8-Fluoro-1-methyl-7-nitro-1H-imidazo [4,5-c] quinolin-4 (5H) -one

5- (2-acetamide-5-fluoro-4-nitrotrop-2--1-methylimidazole-4 monoethyl rubonate (Reference Example 33) (31.0 mg, 0.0882 mm 0 1 )) Was added to concentrated ethanol (6 ml) solution, concentrated hydrochloric acid (2 ml) was added, and the mixture was stirred at 50 ° C for 16 hours. After cooling, the precipitated crystals were collected by filtration, washed with water, and dried to give a light color. 23 O mg of the title compound were obtained as a brown powder, yield 89%.

M p.:> 300 ° C. HRFAB ⁺ MS: 26.3.006 (+2.6 mmu)

A nal.: Calcd. For C!! H ₇ FN ₄ 0 ₃ 4 5 H

0

 C45.34, H2.70, N19.2.33.

Foun d C 45.08, H2.62, N18.96.

(Example 11)

 8-Fluoro-1— (4-methoxyphenyl) methyl-1-7-nitone 1—Imidazo [4,5—c] quinoline-1 4 (5H) —one

5- (2-acetamide-5-fluoro-412-trofu-2--1- (4-methoxyphenyl) methylimidazole-41-carboxyethyl ester (Reference Example 34) (18.0 mg The title compound was obtained as brown powder in an amount of 12.0 mg in the same manner as in Example 10 by using 0.0394 Ramo 1) in a yield of 83%.

 M p.:> 300 ° C.

 H R F A B— M S: 36.7.065 (+2.3 mmu).

(Example 12)

8—Fluoro 7—Nitro li—Imidazo [4, 5—c] Quinoline 1 (5H) —On

Trifluoroacetic acid (0.5 ml) was added to a solution of the compound of Example 11 (8.0 mg, 0.0217 mmo 1) in anisol (0.5 ml), and the mixture was added at room temperature for 4 hours. Stirred. The reaction solution was concentrated under reduced pressure, diisopropyl ether was added to the residue, and the precipitated crystals were collected by filtration, washed with diisopropyl ether, and dried to give 6.30 mg of the title compound as a brown powder. Yield quantitative.

 M p.:> 300 ° C.

 H RMS: 2 48. 0 3 6 1 (+1.6 mmu).

(Example 13)

 8-[4-[[(4-ethoxyphosphorylphenyl) carbamoyloxy] methyl] imidazole-1-yl] _ 7-trifluoromethyloxazolo [4, 5-c] quinoline 1, 2, 4 ( 3 5 H) Zeon

To a solution of the compound of Example 5 (258 mg, 0.904 mmo 1) in dimethyl sulfoxide (10 ml) was added (4-diethoxyphosphoryl) benzoyl azide (93.0 mg, 0.3 69 mm 0 1) was added, and the mixture was stirred at 150 ° C for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the residue was washed successively with ethyl acetate, acetonitrile, and acetone, and dried to obtain 62.1 mg of the title compound as a yellow powder. Yield 14%.

 Mp.: 198-200 ° C.

 H R F A B— M S: 62.11.77 (+1.9 mmu).

(Example 14)

 8-[4-[[[4-di (2-propoxy) phosphorylphenyl] rubamoyloxy] methyl] imidazole-1-yl] 1 7-trifluoromethyloxazo [4, 5 -c] quinoline_2,4 (3H5H) —dione

Using the compound of Example 5 (500 mg, 1.37 mmol) and (4-di (2-propoxy) phosphoryl) benzoyl azide (2.13 g, 6.85 mmol) By a method similar to that in Example 13, 70 mg of the title compound was obtained as a pale yellow powder. Yield 7.9%. Mp.: 204-206 ° C.

 H R F A B + M S: 65.0.159 1 (one 3.7 mmu).

(Example 15)

 8-[4-[[(4-Phosphonophenyl rubamoyloxy) methyl] imidazole— 1 — yl] — 7-Trifluoromethyloxazolo [4, 5 — c] Quinoline 4 (3 5 H) dione

 Using the compound of Example 14 (15.0 mg, 0.0231 mm 01), 11.5 mg of the title compound as a white powder was obtained in the same manner as in Example 8. Yield 88%.

 M p.:> 300 ° C.

 H R F AB— M S: 56.6.0708 (+1.9 mmu). Reference example 1)

N— (2,4-Dimethoxyphenethyl-5-bromo-4-throanthranilic acid

5—Promo 4-Nitroanthranilic acid (2.44 g, 9.35 mm 01) in N, N-dimethylacetamide (15 ml)

4-Dimethoxybenzyl alcohol (1.58 g, 9.39 mm 01) was added, and the mixture was stirred at 170 ° C. for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the residue was washed with diisopropyl ether and dried to obtain 2.74 g of the title compound as a red powder. Yield 70%.

^{1 H-NMR (DM S O-} d 6, δ): 3. 8 0 (3 Η, s), 3. 8

5 (3H, s), 4.36 (2H, s), 6.44 (1H, dd, J2.4, 8.3), 6.48 (1H, d, J 2.4), 7.12 (1 H, d, J 8.3), 7.17 (1 H, s) _} 8.2 1 (1 H, s).

(Reference example 2)

 6—Promo 1,2—Dihydro 1 (2,4 dimethoxyphenyl) Methyl 1-4 Hydroxy 7—Thor 2—Oxoquinoline 13

To a solution of the compound of Reference Example 1 (1.61 g, 3.92 mmol) in 1,4-dioxane (20 ml) was added trichloromethyl chloroformate (0.923 ml, 7.71 mmol). 1) was added and the mixture was heated under reflux for 4 hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the solvent was distilled off. Thus, 1.72 g of yellow amorphous 6-bromo-1- (2,4-dimethoxyphenyl) methyl-7-nitroisatoic anhydride was obtained. Was. Yield quantitative.

 A solution of getyl malonate (0.27 ml, 1.79 mmol) in N, N-dimethylacetamide (3 ml) was dissolved in 60% sodium hydride (70.0 mg, 1.0 ml). 75 mm 0 1) was added, and the mixture was stirred at room temperature for 20 minutes. A solution of 6-promo 1- (2,4-dimethoxyphenyl) methyl-7-nitroisatoic anhydride (700 mg) obtained above in N, N-dimethylacetamide (3 ml) was added to the reaction mixture. Was added and the mixture was stirred at 120 ° C. for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was washed with getyl ether. The aqueous layer was made weakly acidic with 1 N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was dried over anhydrous magnesium sulfate, the solvent was distilled off. The residue was washed with diisopropyl ether and dried to give 250 mg of the title compound as a tan powder. Yield 32%.

^{1 H-NMR (DMS 0- d} e, δ):. 1 5 1 (. 3 Η, t, J7 3), 3. 7 6 (3 H, s), 3. 9 5 (3 H, s) , 4.56 (2H _; q, J7.3), 5.40 (2H, s), 6.37 (1H, dd, J2.0, 8.8), 6. 4 8 (1H, d, J2.0), 7.10 (1H, d, J8.8), 8.07 (1H, s), 8.45 (1H, s ), 14.37 (1H, s).

(Reference example 3)

6-Bromo-1,2-dihydroxy-1 (2,4-dimethoxyphenyl) methyl-4-hydroxy-1 7-toro-2-oxoquinoline-3-carboxylic hydrazide

To a solution of the compound of Reference Example 2 (248 mg, 0.489 mmol) in ethanol (10 ml) was added hydrazine monohydrate (160 mg, 4.99 mmol). o 1) was added and the mixture was heated under reflux for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was acidified with 1 mol / l hydrochloric acid. The precipitated crystals were collected by filtration, washed with water, and dried to give 221 mg of the title compound as a tan powder. Yield 92%.

^{1 H-NMR (DMS O- d} 6, δ):. 3. 7 7 (3 Η, s), 3. 9 5 (3 H, s), 5 4 1 (2 H, s), 6. 3 8 (1H, dd, J2.4, 8.3), 6.50 (1H, d, J2.4), 7.02 (1H, d, J8.3), 8 1 2 (1 H, s), 8.49 (1 H, s), 10.95 (1 H, s 16.6.8 (1 H, s).

(Reference example 4)

8—Bromo-5— (2,4 dimethoxyphenethyl-1 7—nitrooxazolo [4,5—c] quinolin-1 2,4 (35H) dione

A suspension of the compound of Reference Example 3 (210 mg, 0.426 mmol) in acetic acid (5 ml) and water (1 ml) was added to sodium nitrite (44.1 mg ヽ 0.6). A solution (39 mmol) of water (1 ml) and a solution of black-mouthed form (3 ml) were added at 10 ° C. The reaction solution was brought to room temperature and stirred for 2.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was washed with water and dried. The resulting crude crystals were subjected to silica gel column chromatography (methylene chloride) to obtain 126 mg of the title compound as a yellow powder. Yield 62%.

^{1 H-NMR (DM S O-} d 6, δ):.. 3. 7 2 (3 H, s), 3 9 0 (3 H, s), 5 4 2 (2 H, s), 6. 39 (1H, dd, J2.0, 8.3), 6.64 (1H, d, J2.0), 6.72 (1H, d, J8.3), 8.19 (1H, s), 8.24 (1H, s), 12.81 (1H, s). Reference example 5)

6—Cross mouth 1,2—Dihydro 1 (2,4-Dimethoxyphenyl) Methyl-4-hydroxy 1 7—Toro 2-oxoquinoline 3-Ethyl carboxylate

To a solution of 5-chloro-412throanthranilic acid (1.65 g, 7.62 mmol) in N, N-dimethylacetamide (17 ml) was added 2,4-dimethoxybenzyl alcohol (1.2 8 g, 7.6 mm0 1) were added, and the mixture was stirred at 170 ° C for 3 hours. After cooling, the reaction solution was concentrated under reduced pressure, the residue was dissolved in N, N-dimethylformamide (17 ml), benzyl chloride (0.90 ml, 7.82 mmo1), carbonate A force beam (1.65 g, 11.9 mm 01) was sequentially added, and the mixture was stirred at 80 ° C for 3 hours. After cooling, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue, washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting powder was dissolved in N, N-dimethylformamide (17 ml), and 3-chloro-3-ethoxypropionate (1.86 ml, 14.5 mmo1) and N, N-Diisopropylethylamine (3.32 ml, 19. lmmol) was added, and the mixture was stirred at 70 ° C for 3 hours. Again, 3-chloro-ethyl 3-ethoxypropionate (0.93 ml, 7.25 mmol) and N, N-diisopropylethylamine (1.16 ml, 9.55 mm) 0 1) was added and the mixture was stirred at 70 ° C. for 1 hour. Again, ethyl 3-ethyl-3-chloro-3-oxypropionate (0.993 ml, 7.25 mmol) and N, N-diisopropylethylamine (1.16 ml, 9. Then, the mixture was stirred at 80 ° C for 30 minutes. After cooling, the reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. Ethyl acetate The layer was washed sequentially with dilute hydrochloric acid, water, and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was washed with a mixed solution of disopropyl ether: methylene chloride (10: 1) and dried to give the title compound as a yellow-brown powder. The washed solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (methylene chloride: hexane = 2: 1) to further obtain the title compound. Total yield 2.0 2 g. Yield 57%.

1 H-NMR (DM SO - d 6, δ):.. 1 5 1 (. 3 Η, t} J1 2), 3 7 6 (3 H, s), 3. 9 5 (3 H, s) , 4.56 (2H _; q, J7.2), 5.41 (2H, s), 6.37 (1H, dd, J2.4, 8.4), 6. 4 9 (1H, d, J2.4), 7.12 (1H, d, J8.4), 8.10 (1H, s), 8.2.8 (1H, s ).

(Reference example 6)

 6-Chloro-1,2-dihydroxy (2,4 dimethoxyphenyl) Methyl 4-hydroxy 7 Nitro-1-oxoquinoline-3-3-Hydronic acid hydrazide

Using the compound of Reference Example 5 (150 mg, 0.324 mmol), 98.0 mg of the title compound was obtained as a tan powder in the same manner as in Reference Example 3. Yield 67%.

¹ H-NMR (DMS 0-de _> δ): 3.77 (3 Η, s), 3.96 (3 H, s), 5.41 (2 H, s), 6. 3 9 (1 H, dd, J 2.4, 8.4), 6.50 (1H, d, J2.4), 7.02 (1H, d, J8.4), 8.16 (1H, s ), 8.32 (1H, s), 16.6.6 (1H, brs).

(Reference example 7)

 8—Black mouth 5 — (2,4 dimethoxyphenethyl-1 7-nitroxazolo [4,5-c] quinoline 1 2,4 (3,5Η) dione

Using the compound of Reference Example 6 (95.0 mg, 0.212 mmol), 83.3 mg of the title compound was obtained as a tan powder in the same manner as in Reference Example 4. Yield 91%.

¹ H-NMR (DMS 0-d ₆ , δ): 3.72 (3 layers, s), 3.91 (3H, s), 5.43 (2H, s), 6.3 9 (1H, dd, J2.4, 8.3), 6.64 (1H, d, J2.4), 6.75 (1H, d, J8.3), 8 1 5 (1H, s), 8.23 (1H, s), 12.2.82 (1H, s).

(Reference Example 8)

4-Amino-6-chloro-1,2-dihydroxy-1- (2,4-dimethoxyphenyl) methyl-7-nitro-2-oxoquinoline-3 Echiru rubonate

To a solution of the compound of Reference Example 5 (500 mg, 1.08 mmo1) in pyridine (4 ml) was added methanesulfonyl chloride (0.0836 ml, 1.08 mm01). The mixture was stirred at room temperature for 2 hours. Again, mainsulfonyl chloride (0.0836 ml, 1.08 mmol) was added and stirred at room temperature for 30 minutes. Once again, methanesulfonyl chloride (0.0836 ml, 1.08 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Further, 2.0 ml / l methylamine tetrahydrofuran solution (5 ml) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, methylene chloride was added to the residue, and the mixture was washed with water. The methylene chloride layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (methylene chloride), and the obtained crude crystals were washed with diisopropyl ether and dried to give 297 mg of the title compound as a brown powder. Yield 60%.

^{1 H-NMR (DMS O- d} 6, δ):. 1 4 6 (. 3 Η, t, J 6 8), 3. 7 5 (3 H, s 3. 9 5 (3 H, s), 4.46 (2H _: q, J6.8), 5.41 (2H, s), 6.37 (1H, dd, J2.4,8.8), 6.4 8 (1H, d, J2.4), 7.11 (1H, d, J8.8), 7.42 (2H, brs7.73 (1H, s), 8 . 1 1 (1 H, s). (Reference Example 9)

 4-Amino-6c π-law 1 2—Dihydroxy 1 — (2,4 Dimethoxyphenethyl 1 7 Nitro 1 2 —Oxoquinoline 1 3

A solution of the compound of Reference Example 8 (290 mg, 0.628 mmol) in ethanol (10 ml) was added to tetrahydrofuran (2 ml) and potassium hydroxide (145). mg, 2.22 mm 01) in water (2 ml) was added, and the mixture was stirred at 50 ° C for 1 hour. After cooling, the reaction solution was concentrated under reduced pressure, water was added to the residue, the mixture was adjusted to pH 4 with lmol / 1 hydrochloric acid, and the precipitated crystals were collected by filtration, washed with water and dried to give the title compound as a brown powder. 0 mg was obtained. Yield 92%.

¹ H-NMR (DMS 0-d ₆ , δ): 3.78 (triple, s), 3.97 (3 H, s), 5.47 (2 H, s), 6.4 2 (1H, dd, J2.4, 8.3), 6.51 (1H, d, J2.4)), 7.12 (1H, d, J8.3), 7.86 (1H, s), 8.34 (1H, s), 15.5.55 (1H, s).

(Reference Example 10)

8-chloro-5— (2,4-dimethoxyphenyl) methyl-17—nitro1 ^^ imidazo “4,5—c] quinolin-1 2,4 (3 5 H) — Zeon

To a solution of the compound of Reference Example 9 (50.0 mg, 0.115 mmol) in 1,4-dioxane (1.5 ml) was added triethylamine (0.024.1 ml, 0.1 ml). 7.3 mm 01) and diphenylphosphoryl azide (0.03000 ml, 0.140 mm 01) were added, and the mixture was stirred at 80 ° 1 for 1 hour, and then N, N-diisopropyl ester was added. Add thiamine (0.0500 ml, 0.287 mmol) and diphenylphosphoryl azide (0.3000 ml, 0.140 mmol) and heat to reflux for 2 hours. did. Further, 1,8-diazabicyclo [4,5,0] indene 7-ene (0.03000 ml, 0.210 mmol) was added, and the mixture was heated under reflux for 1 hour. After cooling, the reaction solution was dried under reduced pressure, IN hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was washed successively with a mixed solution of disopropyl ether: methylene chloride (10: 1) and getyl ether, and dried to obtain 15.0 mg of the title compound as a brown powder. Yield 30%.

¹ H-NM (DMS 0-d ₆ , δ): 3.71 (3H, s), 3.92 (3H, s), 5.42 (2H, s), 6.3 9 (1H, dd, J2.4, 8.3), 6.64 (1H, d, J2.4), 6.71 (1H, d, J8.3), 8 .1 5 (1H, s), 8.19 (1H, s). (Reference Example 11)

 5—Bromo-4-412throan ethyl ester tolanylate

5-Broth 4-Nitroanthranilic acid (20. lg, 77.0 mmo1) in ethanol (200 ml) was added to concentrated sulfuric acid (10 ml), and heated under reflux for 72 hours. did. After cooling, water was added to the reaction solution, and the precipitated crystals were collected by filtration, washed with water, and dried. The resulting crude crystals were subjected to silica gel column chromatography (ethyl acetate) to give 20.7 g of the title compound as an orange powder. Yield 93%.

^{1 H-NMR (DMS O- d} 6, δ):. 1 3 3 (. 3 H, t, J 6 8), 4. 3 0 (. 2 Η, q} J 6 8), 7. 2 0 (2H, s), 7.38 (1H, s), 8.00 (1H, s).

(Reference Example 1 2)

 6—Promo 1, 2-Dihydroxy 4-Hydroxy 7—2 Toro 2 —Oxoquinoline 1—3-Ethyl rubonate

Reference Example 11 A solution of the compound of Example 1 (2.89 g, 10.0 mmol) in N, N dimethylformamide (30 ml) was added to a solution of 3-chloro-1,3-oxo. Ethyl cypropionate (1.41 ml, 11.10 mmol) and triethylamine (1.53 ml) were added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, extracted with ethyl acetate, the ethyl acetate layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain 2.92 g of a tan powder. This powder was dissolved in ethanol (36 ml), and sodium metal (499 mg, 21.7 mmo1) was added to ethanol (2 O ml) to prepare sodium. An ethanol solution of ethoxide was added, and the mixture was stirred at room temperature for 1 hour. Acetic acid was added to the reaction solution to make it acidic, and concentrated under reduced pressure. The residue was recrystallized from a mixed solution of N, N-dimethylformamide and ethanol to obtain 2.42 g of the title compound as a pale yellow powder. Yield 94%.

^{1 H-NMR (DM S 0-} d G, δ):. 1 2 9 (. 3 H, t, Jl 3), 4. 3 1 (3 Η, t, J 7 - 3), 7. 8 2 (1H, s), 8.29 (1H, s), 11.97 (1H, brs).

(Reference Example 13)

 6—Bromo 1,2—Dihydro 4-hydroxy 7 Nitro 2-oxoquinoline 3-Hydroxyhydrazine

Using the compound of Example 12 (200 mg, 0.489 mmo 1), in the same manner as in Reference Example 3, 18.5 mg of the title compound was obtained as a yellow powder. Yield 98%.

¹ H-NMR (DMS O-de, δ) 7.89 (1 H, s), 8.3 0 (1Hs), 10.0.94 (1H, brs), 12.30 (1Hbrs).

(Reference example 14)

 4-Mouth 2-methyl-5-nitroacetanilide

4-Methylacetanilide (1.84 g, 10.0 mm 01) in a solution of acetic acid (10 ml) in acetic acid (10 ml) was mixed with potassium nitrate (1.21 g, 12.0 mm). A solution of 01) in sulfuric acid (10 ml) was added over 10 minutes, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into ice water, extracted with ethyl acetate, the ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 1.86 g of the title compound as a light brown powder.

¹ H-NMR (CDC 13, δ): 2.24 (triple, s), 2.31 (3H, s), 7.25 (1H, s), 7.31 (1 H, s), 8.55 (1H, brs).

(Reference example 15)

 N-Acetyl-5-Chloro-1-nitroanthranilic acid

REFERENCE EXAMPLE 14 The water (1) of the compound (9.◦0: 39.4 mm 0 1) of 4 To this suspension was added potassium permanganate (12.4 g, 78.7 mm 01), and the mixture was heated under reflux for 8 hours. The reaction solution was filtered while hot using celite, and the residue was washed with hot water. After cooling, the filtrate and the washings are combined, adjusted to pH 1 with 6 ml of 1/1 hydrochloric acid, and the precipitated crystals are collected by filtration, washed with water and dried to give 5.0 g of the title compound as a pale brown powder. 9 g were obtained. Yield 50%.

^{1 H-NMR (DMS O- d} 6, δ):.. 2 1 7 (3 Η, s), 8. 1 5 (1 H, s), 9 0 0 (1 H, s).

(Reference Example 16)

 5—Cross mouth 4-Nitroanthranilic acid

Reference Example 15 A water (200 ml) solution of the compound (33.2 g, 128 mm 01) and sodium hydroxide (15.4 g, 3885 mmol) was prepared. The mixture was heated under reflux for 4 hours. After cooling, the pH was adjusted to pH 4 with 6 ml of 1/1 hydrochloric acid, and the precipitated crystals were collected by filtration and dried to give 20.5 g of the title compound as a dark brown powder. Yield 74%.

¹ H-NMR (DMS 0- d ₆ ,: 7.39 (1 H, s), 7.86 (1 H, s).

(Reference Example 17)

4-bromo-1-methyl-5-nitroacetanilide

Using 4-promo 2-methylacetanilide (120 g, 526 mmol), 128 g of the title compound as a light brown powder was obtained in the same manner as in Reference Example 14. Yield 89%.

¹ H-NMR (CDC 1 a, (Π: 2.12 (3 H, s), 2.3 1 (3 H, s)) _7.79 (1 H, s), 8.33 ( 1 H, s), 9.56 (1 H, s).

(Reference Example 18)

 N-Acetyl-5-bromo-41-2throanthranilic acid

Using the compound of Reference Example 17 (32.0 g, 117 mmol), 20.6 g of the title compound as a pale yellow powder was obtained in the same manner as in Reference Example 15. Yield 58%.

¹ H-NMR (DMS 0-d ₆ , δ) 2.14 (3 Η, s), 8.29 (1 H, s), 9.01 (1 ,, s), 12.6 0-1 2.80 (1 H, brs). Reference example 19)

5-Promo 4-Nitroanthranilic acid

To the compound of Reference Example 18 (35.9 g, 118 mmol) was added 4 mol / 1 hydrochloric acid (600 ml), and the mixture was heated under reflux for 3 hours. After cooling, the precipitated crystals were collected by filtration and dried to give the title compound as an orange powder (27.7 g). Yield 90%.

¹ H-NMR (DMS 0-d _e> δ): Ί. 35 (1 H, s), 7.99 (1 H, s).

(Reference Example 20)

 4-dichloromethyl 2-fluoro-5-nitrobenzotrifluoride

A solution of potassium t-butoxide (36.5 g, 325 mm 01) in tetrahydrofuran (400 ml) was stirred at 178 ° C for 2-fluoro-5- A solution of trobenzotrifluoride (20.0 g, 95. 6 mm 01) and cloform (17. lg, 144 mm o 1) in tetrahydrofuran (40 ml) Was slowly dripped. After completion of the dropwise addition, the mixture was stirred at the same temperature for 3 minutes, and then a mixture of acetic acid (25 ml) and methanol (25 ml) was added. Pour the reaction solution into ice-cooled diluted hydrochloric acid. And extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1100: 0 to 100: 1) to obtain 10.3 g of the title compound as a pale yellow liquid. Yield 41%.

^{1 H-NMR (DMS 0- d} 6 3 δ):.. 7. 7 3 (1 H, s), 8 3 7 (. 1 H, d, J 1 1 2), 8 5 0 (1 H, d, J 6.3).

41- (Hydroxymethyl) i Midazo Benzo Trifluoride

To a solution of the compound of Reference Example 20 (38.5 g, 0.148 mol) in tetrahydrofuran (250 ml) was added 41- (hydroxymethyl) imidazole hydrochloride (29.9 g). , 0.222 mol) and triethylamine (44.9 g, 0.444 mo 1) were added, and the mixture was heated under reflux for 2 hours. After cooling, ethyl acetate was added to the reaction solution, and the mixture was washed with saturated saline. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from methylene chloride to obtain 22.4 g of the title compound as a pale brown powder. Yield 41%.

_{^{1 H-NMR (DMS 0- 6}} 3 δ):. 4. 4 4 (. 2 H, d, J 4 4), 5 0 8 (. 1 H, t, J4 4), 7. 3 8 (l H, s), 7.78 (1H, s), 7.91 (1H, s), 8.19 (1H, s), 859 (1H, s). (Reference Example 2 2)

 5 [41- (Hydroxymethyl) imidazole-1 1-yl] 1-4-Trifluoromethylanthranilaldehyde

Reference Example 21 Water (20 ml) was added to a solution of the compound of Example 1 (10.0 g, 30.5 mm 01) in acetic acid (200 ml), and the mixture was vigorously stirred to give 24% titanium trichloride. (18.0 g 18.3 mm o 1) was slowly dropped at room temperature. After the addition, the mixture was stirred at the same temperature for 1 hour. The reaction solution was ice-cooled, adjusted to pH 14 with a 20% aqueous sodium hydroxide solution, and stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction solution, insolubles were removed by filtration using celite, and the filtrate was concentrated under reduced pressure. The residue was washed with ethyl acetate and dried to give 5.26 g of the title compound as a yellow powder. Yield 62%.

¹ H-NMR (DMSO-d ₆ , δ): 4.40 (2 H, d, J 5.4), 4.95 (1 H, t, J 5.4), 7.1 0 (1H, s), 7.30 (1H, s), 7.64 (1H, s), 7.67 (1H, s), 779 (1H, s) , 9.9.1 (1H, s).

(Reference Example 23)

5 — [4-(Hydroxymethyl) imidazole-1 1 -yl] 1 4 1 Methyl trifluoromethylanthranilate

Reference Example 22 To a solution of the compound of Example 2 (500 mg, 1.75 mmol) in methanol (15 ml) was added sodium cyanide (429 mg, 8.75 mmol). The mixture was stirred at room temperature for 15 minutes. Mangan dioxide (1.52 g, 17.5 mmol) was added to the reaction solution in small portions, and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was filtered using celite, a small amount of a saturated aqueous solution of sodium hydrogen carbonate was added to the filtrate, and the mixture was concentrated under reduced pressure. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from a mixed solution of methanol and diisopropyl ether to obtain 214 mg of the title compound as a pale yellow powder. Yield 39%.

¹ H-NMR (DMS 0-d ₆ , δ): 3.82 (3 H, s), 4.38 (2 H, d, J 5.9), 4.93 (1 H, t, J5.9), 7.08 (1H, s), 7.27 (2H, s), 7.33 (1H, s), 7, 61 (1H, s) ), 7.66 (1 H, s).

(Reference Example 24)

1, 2-dihydroxy 4-hydroxy-1 6 — [4- (hydroxymethyl) imidazole 1 —yl] 1-2-oxo-1 7-trifluoromethylquinoline 1-3 carboxylate

1M sodium ethoxide (11.4 ml) was added to getyl malonate (1.83 g, 11.4 mmol), and the mixture was stirred at room temperature for 15 minutes. The reaction solution was added to a solution of the compound of Reference Example 23 (1.79 g, 5.68 mm 01) in ethanol (80 ml), and the mixture was heated under reflux for 2 days. After cooling, the precipitated crystals were collected by filtration and washed with ethanol. The obtained powder was dissolved in water and adjusted to pH 4 with 3 m 0 1 1 hydrochloric acid. The precipitated crystals were collected by filtration, washed with water, and dried to give 1.32 g of the title compound as a pale brown powder. Yield 38%.

¹ H-NMR (DMS O—d ₆ , δ): 1.29 (3Η, t, J 6.8), 4.29 (2H, q, J 6.8), 4.44 ( 2H, s), 5.12 (1H, brs), 7.28 (1H, s), 7.75 (1H, s) .. 7.93 (1H, s) , 7.98 (1 H, s), 1 1.87 (1 H, brs).

(Reference Example 25)

 1,2-Dihydro 4-Hydroxy 6- [4- (Hydroxymethyl) imidazole 1-yl] — 2-Oxo 1 7—Trifluoromethylquinoline 1-3 Carboxylic hydrazide

Reference Example 24 Hydrazine monohydrate (2.36 g, 4.72 mm) was added to a solution of the compound of Example 4 (1.98 g, 4.72 mmol) in ethanol (40 ml). 0 1) was added and the mixture was heated under reflux for 2 hours. After cooling, the reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was acidified with 3m0 / 1 hydrochloric acid. The precipitated crystals were collected by filtration, washed with water, and dried to give 1.2 g of the title compound as a pale brown powder. Yield 68%.

^{1 H-NMR (DMS 0-} d 6 3 δ): 4. 4 2 (. 2 Η, d, J5 3), 5. 0 0 (1 H, t, J 5. 3), 5. 0 5 ( 1H, brs), 7.23 (1H, s), 7.76 (1H, s), 7.84 (1H, s) 7.95 (1H, s), 1 0.93 (1H, brs), 12.3 2 (1H, brs).

(Reference Example 26)

 2-bromo-4 monofluoro-5-2 troaniline

To a solution of 2-bromo-4-fluoroaniline (10.0 g, 52.6 mmo 1) in concentrated sulfuric acid (65 ml) at 0 ° C was fuming nitric acid (4.97 g, 7 8.9 mm o 1) was added dropwise. After the addition, the mixture was stirred at the same temperature for 15 minutes. The reaction solution was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 50: 1 to 10: 1) to obtain 8.50 g of the title compound as a pale brown liquid. Yield 63%. ¹ H-NMR (DMS O-d ₆ , δ): β.82 (2 H, s), 7.50 (1H, d, J 6.8), 7.75 (1 H, d , J 1 0.7).

(Reference Example 27)

 2-bromo-4-fluoro-5-nitroacetanilide

Acetic anhydride (70 ml) was added to the compound of Reference Example 26 (8.50 g, 36.2 mm 01), and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was washed with disoprole ether and dried to obtain 11.5 g of the title compound as a white powder. Yield quantitative.

¹ H-NMR (DMS 0- d ₆₎ δ): 2.13 (3 Η, s), 8.1 1 (1 H, d, J 10.7), 8.43 (1 H, d, J7.8), 9.80 (1H, s).

(Reference Example 28)

 2 —acetamide 5 monofluoro-4--2-binacol trophenyl borate

Reference Example 27 1,4 of compound (1.00 g, 4.26 mmol) —Dioxane (50 ml) solution, bispinacol borane (1.19 g, 4.69 mmol), diphenylphosphine phenolic sencyclochloropalladium: methylene chloride (1: 1) complex (1774) mg, 0.213 mm 01) and lithium acetate (1.26 g, 12.8 mm o 1) were added, and the mixture was stirred at 100 ° C for 6 hours. After cooling, the reaction solution was added to a hot-water form, heated in a warm bath, filtered while hot, and insoluble materials were removed by filtration. The filtrate was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (dichloromethane: methanol = 50: 1 to L0: 1) to give 283 mg of the title compound as a white powder. Yield 21%.

^{1 H-NMR (DMS O- d} 6, δ):.. 1 1 7 (1 2 H, s), 2 3 2 (3 H, s), 7. 3 2 (1 H, d, J 1 1 2), 7.73 (1H, d, J5.9), 12.47 (1H, brs).

(Reference Example 2 9)

 5-Amino 1-Methylimidazolo 4-Ethyl carboxylate

10% platinum carbon (500 mg) was added to a solution of ethyl cyanoglyoxylate mono-oxime (5.0 g, 35.2 mm 01) in ethanol (50 ml), and hydrogen atmosphere was added. ^{(3. 9 2 xl 0 5} P a) below, and stirred at room temperature for 4 hours. The reaction solution was filtered using celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in acetonitril (50 ml), triethyl orthoformate (5.48 g, 37.0 mm 01) was added, and the mixture was heated under reflux for 35 minutes. After cooling, the reaction mixture is concentrated and the residue is washed with acetonitril. (50 ml), 2.0 M methylamine tetrahydrofuran solution (18.5 ml) was added, and the mixture was heated under reflux for 30 minutes. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was added with chloroform. Concentrated. The residue was washed with ethyl acetate and dried to give 1.73 g of the title compound as a white powder. Yield 29%.

^{1 H-NMR (DMS O- d} 6, δ):. 1 2 3 (. 3 H, t, Jl 3), 3. 3 9 (3 Η, s), 4. 1 5 (2 H, q, Jl. 3), 5.96 (2H, s), 7.08 (1H, s).

(Reference Example 30)

 5-amino-1 — [(4-methoxyphenyl) methyl] imidazole—4-ethyl carboxylate

Using ethyl cyanoglyoxylate 2-oxoxime (25.0 g, 176 mmol) and 4-methoxybenzylamine (25.4 g, 185 mm01), reference By a method similar to that in Example 29, 24.7 g of the title compound was obtained as a white powder. Yield 51%.

¹ H-NMR (DMS 0-d _e> δ): 1.23 (3Η, t, J6.8), 3.73 (3H, s), 4.15 (2H, d , J6.8), 5.00 (2H, s), 6.04 (2H, s), 6.91 (2H, d, J8.8), 7.183 (1 H, s), 7.184 (2 H, d, J 8. 8). Reference example 3 1)

 5-node 1-methylimidazole 4-ethyl carboxylate

Reference Example 29 A solution of the compound of Example 9 (1.00 g, 5.91 mmol) in 6 N hydrochloric acid (10 ml) was added at −20 ° C. to sodium nitrite (2.04 g). g, 29.6 mmol) in water (10 ml) was added dropwise and stirred at the same temperature for 15 minutes. The reaction solution was heated to 0 ° C., and a solution of potassium iodide (9.8 lg, 59.lmmol) in water (20 ml) was added dropwise. After the addition, the mixture was stirred at the same temperature for 5 hours. The reaction solution was heated to room temperature, neutralized with a 10% aqueous sodium hydroxide solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from a mixed solution of ethyl propyl isopropyl ether to give 883 mg of the title compound as a white powder. Yield 53%.

¹ H-NMR (DMS 0-d ₆ , δ): 1.29 (3Η, t, Jl.3), 3.64 (3H, s), 4.23 (2H, q, Jl. 3), 8.13 (1H, s).

(Reference Example 3 2)

5—1 — [(4-Methoxyphenyl) methyl] imidazole—4

Using the compound of Reference Example 30 (1.00 g, 3.63 mmol), 1.15 g of the title compound as a white powder was obtained in the same manner as in Reference Example 31. Yield 82%.

¹ H-NMR (DMS O-d ₆ , δ): 1.28 (3 Η, t, J 7.3), 3.73 (3 H, s 4.22 (2 H, q, Jl 3), 5.21 (2H, s), 6.92 (2H, d, J8.8), 7.12 (2H, d, J8.8), 8.1 7 (1H, s).

(Reference Example 3 3)

 5- (2-acetamide 5-fluoro-4-nitro-1-1-methylimidazo-l-4-ethyl carboxylate

Reference Example 31 To a solution of the compound of Example 1 (283 mg, 1.14 mmo 1) in 1,4-dioxane (7 ml) was added the compound of Reference Example 28 (133 mg, 0.571). mm o 1), diphenylphosphine phenolic dichloropalladium: methylene chloride (1: 1) complex (46.6 mg, 0.0 571 mmo1) and 2 mo1 / 1 aqueous sodium carbonate solution (857 ml) were added, and the mixture was stirred at 100 ° C for 6 hours. After cooling, the reaction mixture was added with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 5-0: 10) to obtain 31. O mg of the title compound as a pale yellow powder. Yield 15%.

¹ H-NMR (DMS O-d ₆ , δ): 1.03 (3 ,, t, J 6.8), 1.91 (3 H, s), 3.43 (3 H, s) ), 3.96-4.07 (2H, m), 7.70 (1H, d, J11.7), 7.93 (1H, s), 8.55 (1 H, d, J7.3), 9.5 1 (1 H, s).

(Reference example 3 4)

 5- (2-acetamide-5-fluoro-412) mouth-one-([4-methoxyethoxymethyl] imidazolu-l 4- 4-ethyl carboxylate

Using the compound of Reference Example 32 (420 mg, 1.29 mmo 1) and a method similar to that of Reference Example 33, 22 O mg of the title compound was obtained as a pale yellow powder. Yield 3.%.

^{1 H-NMR (DM SO- d} 6, δ):. 1 0 2 (3 Η, t, J 7 3), 1.92 (3 H, s), 3.70 (3 H, s), 3.97-4.06 (2 H,), 4.76 (1 H, d, J15.1), 5.02 (1H, d, J15.1), 6.80 (2H, d, J8.8), 6.92 (2H, d, J 8.8), 7.32 (1H, d, J11.7), 8.01 (1H, s), 8.64 (1H, d, Jl.3), 9. 2 5 (1 H, s).

(Reference example 3 5)

 (4-diethoxyphosphoryl benzoinazide

 To a solution of (4-diethoxyphosphoryl) benzoic acid (100 mg, 0.387 mmo1) in tetrahydrofuran (5 ml) was added diphenylphosphoryl azide (128 mg, 0.46 4 mmo1) and triethylamine (47.0 mg, 0.464 mmo1) were added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 3-1: 5) to give 93.0 mg of the title compound as a colorless liquid. Yield 85%.

¹ H-NMR (DMS 0-d ₆ , d): 1.24 (3 H, t, J7.3) 4.0 1-4.10 (4 H, m), 7.90 (2 H, dd, Jl. 8 1 2. 7), 8. 1 0 (2 H 3 dd} J3. 9, 7. 8).

(Reference Example 36)

[4-di (2-propoxy) phosphoryl] benzoyl azide

[4-Di (2-propoxy) phosphoryl] Using benzoic acid (2.72 g, 9.50 mmo 1), the title compound was obtained as a white powder in the same manner as in Reference Example 35. 5 g were obtained. Yield 96%.

^{1 H-NMR (DMS 0-} d 63 d): 1. 1 8 (6 H, d, J 6. 3) 1. 2 9 (6 H, d, J 6. 3), 4. 5 6 - 4 64 (2H, m), 7.89 (2H, dd, J8.3, 12.7), 8.09 (2H, dd, J3.9, 8.3).

[Biological activity]

 Binding experiments for AMP A receptor

Rats selectively bind to adjust crude Shinaputoso Ichimu membrane preparation from cerebral cortex AMP A receptor ^[3 H] - AMP A (final concentration: 5 nm o 1/1), Chioshian oxide Li um ( (Final concentration: 100 mmol / l) and the test compound were added, and the mixture was incubated at 0 ° C for 30 minutes. After terminating the reaction by suction filtration, the radioactivity on the filter was measured with a liquid scintillation counter. The specific binding of [ ³ H] -AMPA was determined by subtracting the non-specific binding in the presence of glutamate (1 mm 0 1/1) from the total binding. [ ³ H] —AMP A binding in the absence of the test compound was set at 100, the concentration (IC ₅ .value) of the compound that reduced 50% was determined, and this was converted to a Ki value. Eur.J.Pharmacol., 1993, 246, 195—204—Eur. J. Pharmacol. Activity Table A

Test compound [ ³ H] -AMP A (K i: nmol / 1) Example 1 300

 Example 5 4 8

 Example 6 1 8

 Example 8 0 1 5

 Example 1 0 2 8 0

 Example 1 3 2 6 0

 Example 1 4 2 1 0

 Example 1 5 2 0

Industrial applicability

 From the above results, it has been clarified that the tricyclic compound of the present invention is a novel compound having an excellent antagonism of the excitatory amino acid receptor, particularly the non-NMDA receptor against the AMP A receptor.

 These compounds of the present invention inhibit the binding of excitatory amino acids that cause neuronal cell death to AMP A receptors, and are therefore effective for treating excitatory amino acids-induced cerebral nerve cell damage and the like.

Claims

Range of mouth blue general formula (1)

(Where R is a halogen atom, or a general formula (2)

(Where A represents a nitrogen atom, = CH—, E represents a hydroxyl group, or general formula (3)

(Wherein V represents an oxygen atom, —NH—, W represents a halogen atom, a carboxyl group, a lower alkoxycarbonyl group, a phosphono group, or a di-lower alkylphosphoryl group).

Q represents a nitro group or a trifluoromethyl group,

X is an oxygen atom or a general formula (4)

(Wherein T represents a hydrogen atom, a lower alkyl group, or an aralkyl group which may have one or more substituents)

 When either C = Y or c = z represents a single bond, the other represents a double bond,

 Y represents a hydrogen atom or a lower alkyl group when d is a single bond, and represents an oxygen atom when C = Y is a double bond,

 Z represents —NH— when c = z is a single bond, and represents a nitrogen atom when c = z is a double bond.

And the addition salt thereof.

2. General formula (l a)

(Where R is a halogen atom, or a general formula (2)

(2)

(Where A represents a nitrogen atom, = CH—, E represents a hydroxyl group, or a general formula (3)

(Wherein V represents an oxygen atom, —NH—, W represents a halogen atom, a carboxyl group, a lower alkoxycarbonyl group, a phosphono group, or a di-lower alkylphosphoryl group).

Q represents a nitro group or a trifluoromethyl group,

 X is an oxygen atom or a general formula (4)

(Wherein T represents a hydrogen atom, a lower alkyl group, or an aralkyl group which may have one or more substituents)

γ represents an oxygen atom,

Z represents one NH—)

3. The tricyclic compound according to claim 1, wherein C Y is a double bond, and C = Z is a single bond, and an addition salt thereof.

3. General formula (lb)

(Where R is a halogen atom, or a general formula (2)

(Where A represents a nitrogen atom, two CH—, E represents a hydroxyl group, or a general formula (3)

(Wherein V represents an oxygen atom, one NH—, W represents a halogen atom, a carboxyl group, a lower alkoxycarbonyl group, a phosphono group, or a di-lower alkylphosphoryl group).

Q represents a nitro group or a trifluoromethyl group,

X is an oxygen atom, or general formula (4)

(Wherein T represents a hydrogen atom, a lower alkyl group, or an aralkyl group which may have one or more substituents)

Y represents a hydrogen atom or a lower alkyl group,

z represents a nitrogen atom)

Wherein c 2 Y according to claim 1 is a single bond, c = z

Is a double bond, and an addition salt thereof.

4. 'General formula (1

(Where R is a halogen atom, or a general formula (2)

(Where A is a nitrogen atom. = CH—, E is a hydroxyl group, or a general formula (3)

(Wherein V represents an oxygen atom, —NH—, and W represents a halogen atom, a carboxyl group, a lower alkoxycarbonyl group, a phosphono group, or a di-lower alkylphosphoryl group).

Q represents a nitro group or a trifluoromethyl group,

 X is an oxygen atom, or general formula (4)

(Wherein T represents a hydrogen atom, a lower alkyl group, or an aralkyl group which may have one or more substituents)

And one of c: z represents a single bond, the other represents a double bond,

 Y represents a hydrogen atom or a lower alkyl group when C = Y is a single bond,

When C = Y is a double bond, it represents an oxygen atom,

Z represents —NH— when c 二 z is a single bond, and represents a nitrogen atom when C = z is a double bond.

An excitatory amino acid antagonist having AMPA receptor antagonistic activity, which comprises, as an active ingredient, at least one of a tricyclic compound represented by the formula: and an addition salt thereof.

5. General formula (la)

(Where R is a halogen atom, or a general formula (2)

(Where A represents a nitrogen atom, two CH—, E represents a hydroxyl group, or a general formula (3)

(Wherein V represents an oxygen atom, —NH—, W represents a halogen atom, a carboxyl group, a lower alkoxycarbonyl group, a phosphono group, or a di-lower alkylphosphoryl group).

Q represents a nitro group or a trifluoromethyl group,

X is an oxygen atom, or general formula (4)

(Wherein T represents a hydrogen atom, a lower alkyl group, or an aralkyl group which may have one or more substituents)

Y represents an oxygen atom,

Z stands for —NH—)

5. The method according to claim 4, wherein C = Y is a double bond, and C = Z is a single bond. An excitatory amino acid antagonist having AMP A receptor antagonism.

6. General formula (Ib)

(Where R is a halogen atom, or a general formula (2)

(2)

(Where A represents a nitrogen atom, = CH—, E represents a hydroxyl group, or a general formula (3)

(Wherein V represents an oxygen atom, —NH—, W represents a halogen atom, a carboxyl group, a lower alkoxycarbonyl group, a phosphono group, or a di-lower alkylphosphoryl group).

Q represents a nitro group or a trifluoromethyl group,

X is an oxygen atom, or general formula (4)

(Wherein T represents a hydrogen atom, a lower alkyl group, or an aralkyl group which may have one or more substituents)

 Y represents a hydrogen atom or a lower alkyl group,

Z represents a nitrogen atom)

The method according to claim 4, wherein the compound comprises one or more of a tricyclic compound in which C = Y is a single bond and C = Z is a double bond and one or more addition salts thereof as an active ingredient. An excitatory amino acid antagonist having AMP A receptor antagonism.