JP2000273042A - Medicine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medicine having excellent inhibiting actions on emesis caused by a drug having emetic actions by including a compound having excellent antagonistic actions on tachykinin receptors and the drug in combination. SOLUTION: This medicine is obtained by including (A) a compound represented by the formula [ring M is a heterocyclic ring having N=C, CON or the like as a partial structure X=Y; Ra and Rb together are bound to form ring A, H or a substituent group in the ring M; rings A and B are each a (substituted)heterocyclic ring or the like; ring C is a (substituted)heterocyclic ring or the like; ring Z is a (substituted)nitrogen-containing heterocyclic ring; n is 1-6], e.g. (9S)-7-[3,5-bis(trifluoromethyl)benzyl]-6,7,8,9,10,12-hexahydro-9- methyl-6,12-dioxo-5-phenyl[1,4]diazepino[2,1-g][1,7]naphthyridine and (B) a drug having emetic actions (e.g. a carcinostatic agent, an antibiotic, morphine or apomorphine) in combination.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a medicament obtained by combining the following compound (I) having an excellent tachykinin receptor antagonistic activity or a salt thereof with a drug having an emetic effect.

[0002]

2. Description of the Related Art Nausea and vomiting caused by administration of drugs having an emetic effect such as anticancer drugs and opioid analgesics are the most painful side effects for patients. 5-HT ₃ antagonists have been found to have a significant effect on the vomiting of anticancer drugs and are currently widely used. However, in recent years, it has become clear that 5-HT ₃ antagonists have poor efficacy against delayed emesis that occurs over two to several days after administration of an anticancer drug, and this is a new problem. The analgesic morphine is commonly used for patients with cancer pain, etc.
Since the efficacy of any antiemetic drugs including 5-HT ₃ antagonists is not clear, it is a factor that lowers the quality of life (QOL) of patients. Also, since apomorphine has been reported to improve impotence or erectile dysfunction in male patients, it has been expected to develop but often has undesirable side effects such as vomiting. Various studies have also been made on combinations with known antiemetic agents (eg, nicotine, domperidone, etc.), but they have not been able to sufficiently suppress side effects such as vomiting. As described above, a drug having an emetic action as a side effect lowers the quality of life of a patient, and its application range is limited. Under such circumstances, it has recently been reported that tachykinin antagonists are useful for treating various types of vomiting (Japanese Patent Laid-Open No. 6-107).
No. 563). However, the formula as the basic skeleton

Embedded image [The symbols in the formula are as defined above. And the condensed heterocyclic compound having a partial chemical structure represented by the formula [1].

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a medicine which can be widely applied to vomiting caused by a drug having an emetic action.

[0004]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies in view of the above circumstances, and as a result, have found that Japanese Patent Application Laid-Open No. 9-263585.
The basic skeleton described in

Embedded image [The symbols in the formula are as defined above. That the fused heterocyclic compound having a partial chemical structure represented by And completed the present invention based on these.

[0005] That is, the present invention provides the following [1]

Embedded image A heterocyclic ring having -CS-N <; R ^a and R ^b are bonded together to form a ring A, or the same or different and a substituent on a hydrogen atom or an M ring; A homocyclic or heterocyclic ring optionally having a group, at least one of which is a heterocyclic ring optionally having a substituent; C
The ring is a homo- or heterocyclic ring which may have a substituent; the Z-ring is a nitrogen-containing heterocyclic ring which may be substituted; and n is an integer of 1 to 6. The compound represented by the compound (I) or a salt thereof and a drug having an emetic action,
[2] ^Ra and ^Rb are each a hydrogen atom or (1) a halogen atom; (2) (i) a hydroxyl group, (ii) a C _1-6 alkoxy group, (iii) a C _1-6 alkylthio group, (iv) ) Amino group, (v) C _1-7 acylamino group, (vi) carboxyl group, (vii) nitro group, (viii) mono- or di-C _1-6 alkylamino group, (ix) mono- or di- C _3-8 cycloalkylamino group, (x) C _6-10 arylamino group, (x
i) C _1-6 alkyl optionally substituted, an oxygen atom in addition to the nitrogen atom, a hetero atom selected from sulfur atom 1
A 5- to 9-membered cyclic amino group optionally containing three (xi
i) a 5- or 6-membered aromatic heterocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom; (xiii) a nitrogen atom and an oxygen other than a carbon atom A 5- to 9-membered non-aromatic heterocyclic group containing 1 to 3 heteroatoms selected from atoms and sulfur atoms,
(Xiv) C _1-4 alkylsulfonylamino group, (xv) C
_A C _1-6 alkyl group _optionally having 1 to 5 substituents selected from a _1-6 alkyl-carbonyloxy group and (xvi) a halogen atom, (3) an optionally halogenated C _1-6 alkoxy group, (4) optionally halogenated C _1-6 alkylthio group, (5) C _3-10 cycloalkyl group, (6) C _6-10 aryl group, (7) C _{1- 7} acylamino group, (8) C _1-3 acyloxy group, (9) hydroxyl group, (10) nitro group, (11) cyano group, (12) amino group, (13) mono- or di-C _1-6 Alkylamino group,
(14) a 5- to 9-membered cyclic amino group which may be substituted with C _1-6 alkyl and which may contain 1 to 3 heteroatoms selected from an oxygen atom and a sulfur atom in addition to a nitrogen atom; (15) C _1-6 alkyl-carbonylamino group, (1
6) C _1-6 alkyl-sulfonylamino group, (17) C _1-6
Alkoxy-carbonyl group, (18) carboxyl group,
(19) a substituent selected from the group consisting of C _1-6 alkyl-carbonyl group, (20) carbamoyl group, (21) mono- or di-C _1-6 alkylcarbamoyl group, and (22) C _1-6 alkylsulfonyl group. R ^a and R ^b are linked together to form a ring A, wherein the ring A is (1) a halogen atom, (2) (i)
Hydroxyl, (ii) amino, (iii) carboxyl, (iv) nitro, (v) mono- or di-C _1-6 alkylamino, (vi) C _1-6 alkyl-carbonyloxy and (Vii) a C _1-6 alkyl group optionally having 1 to 5 substituents selected from halogen atoms, (3) an optionally halogenated C _1-6 alkoxy group, (4)
An optionally halogenated C _1-6 alkylthio group,
(5) C _6-10 aryl group, (6) C _1-7 acylamino group, (7) C _1-3 acyloxy group, (8) hydroxyl group, (9) nitro group, (10) cyano group, (11) ) Amino group, (12) mono- or di-C _1-6 alkylamino group, (1
3) nitrogen heteroatoms selected from oxygen atom and sulfur atom in addition to atoms of 1 to 3 which may contain 5-9 membered cyclic amino group, (14) C _1-6 alkyl - carbonylamino group, ( 15) C _1-6 alkyl-sulfonylamino group, (1
6) C _1-6 alkoxy-carbonyl group, (17) carboxyl group, (18) C _1-6 alkylcarbonyl group, (19) carbamoyl group, (20) mono- or di-C _1-6 alkylcarbamoyl group, (21) In addition to a carbon atom which may be substituted with 1 to 4 substituents selected from a C _1-6 alkylsulfonyl group and (22) oxo group, other than a carbon atom selected from a nitrogen atom, a sulfur atom and an oxygen atom A 5- to 9-membered aromatic heterocyclic ring containing 1 to 3 heteroatoms or 1 to 3 heteroatoms, and one or two heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom; Represents a 5- to 9-membered non-aromatic heterocyclic ring or a 3- to 10-membered cyclic hydrocarbon containing 1 to 3 rings; wherein ring B is (1) a halogen atom, (2) (i) a hydroxyl group, or (ii) an amino group. , (I
ii) carboxyl group, (iv) nitro group, (v) mono- or di-C _1-6 alkylamino group, (vi) C _1-6 alkyl-
A C _1-6 alkyl group optionally having 1 to 5 substituents selected from a carbonyloxy group and (vii) a halogen atom, (3) an optionally halogenated C _1-6 alkoxy group , (4) optionally halogenated C _1-6 alkylthio group, (5) C _6-10 aryl group, (6) C _1-7
Acylamino group, (7) C _1-3 acyloxy group, (8)
Hydroxyl group, (9) nitro group, (10) cyano group,
(11) amino group, (12) mono- or di-C _1-6 alkylamino group, (13) other than nitrogen atom, may contain 1 to 3 hetero atoms selected from oxygen atom and sulfur atom 5-9 membered cyclic amino group, (14) C _1-6 alkyl - carbonylamino group, (15) C _1-6 alkyl - sulfonylamino group, (16) C _1-6 alkoxy - carbonyl group, (1
7) carboxyl group, (18) C _1-6 alkylcarbonyl group, (19) carbamoyl group, (20) mono- or di-C
_1-6 alkylcarbamoyl group, (21) C _1-6 alkylsulfonyl and (22) one to four substituents substituted by optionally nitrogen atoms in addition also good carbon atoms selected from oxo group, a sulfur atom and an oxygen A 5- to 9-membered aromatic heterocyclic ring containing 1 to 3 heteroatoms selected from the group consisting of one or two heteroatoms, one or two selected from nitrogen, sulfur and oxygen other than carbon A 5- to 9-membered non-aromatic heterocyclic ring containing 1 to 3 heteroatoms or a 3 to 10-membered cyclic hydrocarbon; wherein the ring C is (1) a halogen atom, (2) halogenated, C _1-10 alkyl group, C substituted with (3) amino group
_1-4 alkyl group, (4) mono - or di -C _1-4 C _1-4 alkyl group substituted with an alkylamino group, (5) C _1-4 alkyl group substituted with a carboxyl group, (6 ) C _1-4 alkoxy - C _1-4 alkyl group substituted by a carbonyl group,
(7) a C _1-4 alkyl group substituted with a hydroxyl group,
(8) C _3-10 cycloalkyl group, (9) nitro group, (1
0) cyano group, (11) hydroxyl group, (12) optionally halogenated C _1-10 alkoxy group, (13) optionally halogenated C _1-4 alkylthio group, (14) amino group , (15) a mono- or di-C _1-4 alkylamino group, (16) 5 to 9 which may contain 1 to 3 hetero atoms selected from an oxygen atom and a sulfur atom in addition to a nitrogen atom.
Membered cyclic amino group, (17) C _1-4 alkyl-carbonylamino group, (18) aminocarbonyloxy group, (19) mono- or di-C _1-4 alkylaminocarbonyloxy group, (20) C _{1 -4} alkylsulfonylamino group, (21)
C _1-4 alkoxy-carbonyl group, (22) aralkyloxycarbonyl group, (23) carboxyl group, (24) C
_1-6 alkyl-carbonyl group, (25) C _3-6 cycloalkyl-carbonyl group, (26) carbamoyl group, (27) mono- or di-C _1-4 alkylcarbamoyl group, (28) C _1-6
An alkylsulfonyl group or (29) one selected from a nitrogen atom, a sulfur atom and an oxygen atom, other than a carbon atom optionally substituted by 1 to 3 optionally halogenated C _1-4 alkyl groups Or a nitrogen atom other than a carbon atom, which may be substituted with 1 to 5 substituents selected from a 5- or 6-membered aromatic monocyclic heterocyclic ring containing 1 to 4 heteroatoms, A 5- to 9-membered heterocyclic ring containing 1 to 3 one or two heteroatoms selected from a sulfur atom and an oxygen atom; or (1) a halogen atom, (2) an optionally halogenated C _1-10 alkyl group, (3) C _1-4 alkyl group substituted with amino group,
(4) mono - or di -C _1-4 C _1-4 alkyl group substituted with an alkylamino group, (5) C _1-4 alkyl group substituted with a carboxyl group, (6) C _1-4 alkoxy A C _1-4 alkyl group substituted with a carbonyl group, (7) a C _1-4 alkyl group substituted with a hydroxyl group, (8) a C _3-10 cycloalkyl group, (9) a nitro group, (10) Cyano group,
(11) hydroxyl group, (12) optionally halogenated C _1-10 alkoxy group, (13) optionally halogenated C _1-4 alkylthio group, (14) amino group, (15)
A mono- or di-C _1-4 alkylamino group, (16) a 5- to 9-membered cyclic amino group which may contain 1 to 3 heteroatoms selected from an oxygen atom and a sulfur atom in addition to a nitrogen atom, (17) C _1-4 alkyl-carbonylamino group, (1
8) aminocarbonyloxy group, (19) mono- or di-
C _1-4 alkylaminocarbonyloxy group, (20) C _1-4
Alkylsulfonylamino group, (21) C _1-4 alkoxy - carbonyl group, (22) aralkyloxycarbonyl groups, (23) carboxyl group, (24) C _1-6 alkyl - carbonyl group, (25) C _3-6 Cycloalkyl-carbonyl group, (26) carbamoyl group, (27) mono- or di-C
_1-4 alkylcarbamoyl groups, in addition to (28) C _1-6 alkylsulfonyl group and (29) one to three optionally halogenated and C _1-4 carbon atoms which may be substituted by an alkyl group 1 to 5 substituents selected from a 5- or 6-membered aromatic monocyclic heterocyclic ring containing 1 to 4 one or two hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom 3 to 10 which may be substituted
The Z ring is (1) a C _1-6 alkyl group,
(2) C _2-6 alkenyl group, (3) C _2-6 alkynyl group,
(4) C _3-8 cycloalkyl group, (5) C _3-8 cycloalkyl-C _1-4 alkyl group, (6) C _6-14 aryl group,
(7) nitro group, (8) cyano group, (9) hydroxyl group, (10) C _1-4 alkoxy group, (11) C _1-4 alkylthio group (12) amino group, (13) mono- or di- -C _1-4 alkylamino group, (14) nitrogen heteroatoms selected from oxygen atom and sulfur atom in addition to atoms of 1 to 3 which may contain 5-9 membered cyclic amino group, (15) C _1-4 alkyl-
Carbonylamino group, (16) _C1-4 alkylsulfonylamino group, (17) _C1-4 alkoxy-carbonyl group, (1
8) carboxyl group, (19) C _1-6 alkyl-carbonyl group, (20) carbamoyl group, (21) mono- or di-C
_1-4 alkylcarbamoyl group, (22) C _1-6 alkylsulfonyl group, may be substituted with 1 to 5 substituents selected from (23) oxo group and (24) thioxo group, Y and carbon The drug according to the above [1], which is a 5- to 12-membered heterocyclic ring which may contain at least one hetero atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, in addition to the atom and the nitrogen atom, [3] R ^a and R ^b are bonded together to form ring A, and ring C is a benzene ring which may have a substituent, a hetero ring which may have a substituent, and a ring Z is oxo-modified. A nitrogen-containing heterocyclic ring which may be optionally selected, and the medicament according to the above-mentioned [1], wherein n is 1 or 2.
[4] the drug of the above-mentioned [1], wherein the Z ring is a nitrogen-containing heterocyclic ring which may be oxo-modified, [5] an aromatic ring in which one of the rings A and B may have a substituent Wherein the other is an aromatic heterocyclic ring which may have a substituent; the drug according to the above-mentioned (1), wherein the ring A is an aromatic heterocyclic ring which may have a substituent, The pharmaceutical according to the above-mentioned [1], wherein the ring B is a benzene ring which may have a substituent, [7] a heterocycle wherein the aromatic heterocyclic ring is selected from a nitrogen atom, a sulfur atom and an oxygen atom other than a carbon atom. The drug according to the above [5], which is a 5- or 6-membered aromatic heterocyclic ring containing one or two atoms, and [8] The above-mentioned [1], wherein the C ring is a benzene ring which may be substituted. Medicines,

[9] benzene having 1 to 3 substituents whose C ring is selected from a halogen atom, an optionally halogenated C _1-6 alkyl group and an optionally halogenated C _1-6 alkoxy group [10] The medicament according to [1], wherein the ring is a 5- to 10-membered ring wherein the Z ring may be substituted with one or two oxo groups. 11]

Embedded image The pharmaceutical according to the above-mentioned [1], wherein [12] the pharmaceutical according to the above [1], wherein n is 1; A benzene ring which may have a group, a benzene ring which may have a substituent on the C ring, and 5 to 10
Member ring,

Embedded image The pharmaceutical according to [1], wherein n is 1, [14] R ^a and R ^b are the same or different and each represents a hydrogen atom, a halogen atom,
Alkyl group which may have a substituent, alkoxy group which may be halogenated, alkylthio group which may be halogenated, cycloalkyl group, aryl group, acylamino group, acyloxy group, hydroxyl group, nitro Group, cyano group, amino group, mono- or di-alkylamino group, cyclic amino group, alkylcarbonylamino group, alkylsulfonylamino group, alkoxycarbonyl group, carboxyl group, alkylcarbonyl group, carbamoyl group, mono- or di- The drug according to the above [1], which is an alkylcarbamoyl group, an alkylsulfonyl group or an oxo group, [15] ^a hydrogen atom or a C _1-6 alkoxy group, a C _1-6 alkylthio group wherein R ^a and R ^b are the same or different. , An amino group, a C _1-7 acylamino group,
Mono - or di -C _1-6 alkylamino group, C _3-10 cyclic amino group, C _1-6 alkyl optionally substituted 5 or 6-membered cyclic amino group with a group, C _1-6 alkylsulfonylamino Or a C _1-6 alkyl group which may be substituted with a C _1-6 alkylcarbonyloxy group, or ^a C _1-6 alkyl group wherein R ^a and R ^b are bonded together and selected from a halogen atom and a C _1-4 alkyl group. 3 to form a pyridine ring optionally having a substituent, B ring is a halogen atom, an optionally halogenated C _1-4 alkyl group and a halogenated which may be C _1-4 alkoxy A benzene ring optionally having 1 to 3 substituents selected from a group, wherein the C ring is a halogen atom, an optionally halogenated C _1-4 alkyl group, good C _1-4 alkoxy group, substituted with a C _1-4 alkyl group There is also an amino group, a C _1-3 acyloxy group and one to three benzene ring which may have a substituent group selected from a hydroxyl group, Z ring is substituted by C _1-4 alkyl group or a hydroxyl group A 5- to 10-membered nitrogen-containing heterocyclic group which may be

Embedded image [16] The drug according to the above [1], wherein n is 1, [16] R ^a and R ^b are bonded together and have 1 to 3 substituents selected from a halogen atom and a C _1-4 alkyl group. Form a pyridine ring which may be

Embedded image The pharmaceutical according to the above-mentioned (15), wherein the (17) pyridine ring is an unsubstituted pyridine ring, the pharmaceutical according to the above-mentioned (16), and the (18) C _1-4 wherein the ring B may be halogenated.
The pharmaceutical according to the above-mentioned [15], which is a benzene ring optionally having 1 to 3 alkyl groups, [19] a halogen atom in the C-ring, a C _1-4 alkyl group which may be halogenated and halogen. The medicament according to the above-mentioned [15], which is a benzene ring which may have 1 to 3 substituents selected from optionally substituted C _1-4 alkoxy groups.
[20] ring Z is a formula

Embedded image [Wherein, m and p are the same or different and represent an integer of 1 to 5, Z ₁ and Z ₂ are the same or different and represent a hydrogen atom,
A C _1-4 alkyl group or a hydroxyl group, and Y is the above [15]
Wherein the compound (I) is (9S) -7- [3,5].
-Bis (trifluoromethyl) benzyl] -6,7,
8,9,10,12-hexahydro-9-methyl-6,6
The pharmaceutical of the above-mentioned [1], which is 12-dioxo-5-phenyl [1,4] diazepino [2,1-g] [1,7] naphthyridine, wherein [22] the compound (I) is (9S)-
7- [3,5-bis (trifluoromethyl) benzyl]
-6,7,8,9,10,12-Hexahydro-9-methyl-5- (4-methylphenyl) -6,12-dioxo- [1,4] diazepino [2,1-g] [1, 7] The medicament according to the above-mentioned [1], wherein the compound (I) is naphthyridine, wherein the compound (I) is (9R) -7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9, 10, 11-
Hexahydro-9-methyl-6,13-dioxo-5-
Phenyl-13H- [1,4] diazosino [2,1-
g] [1] The drug according to the above [1], which is [1,7] naphthyridine; [24] Compound (I) is (9R) -7- [3,5-
Bis (trifluoromethyl) benzyl] -6,7,8,
9,10,11-Hexahydro-9-methyl-5- (4
-Methylphenyl) -6,13-dioxo-13H-
[1] The pharmaceutical according to the above [1], which is [1,4] diazosino [2,1-g] [1,7] naphthyridine;
(I) is (9R) -7- (3,5-dimethoxybenzyl)
-5- (4-Fluorophenyl) -6,7,8,9,1
0,11-hexahydro-9-methyl-6,13-dioxo-13H- [1,4] diazosino [2,1-g]
The pharmaceutical according to the above-mentioned [1], which is [1,7] naphthyridine; [26] the compound (I) is (9R) -7- (3,5-dimethoxybenzyl) -6,7,8,9,10, 11-hexahydro-9-methyl-5- (4-methylphenyl)
The pharmaceutical of the above-mentioned [1], which is -6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine; The medicament according to the above [1], [28] the medicament according to the above [1], wherein the drug having an emetic action is morphine or a derivative or a salt thereof, and [29] the apomorphine or a salt thereof having the emetic action. [30] The pharmaceutical according to [28], [31] morphine or a derivative thereof or a salt thereof, wherein the pharmaceutical according to the above [1], [30] the compound (I) or a salt thereof is contained in a preparation for oral administration. The pharmaceutical according to [28], which is contained in a sustained-release preparation, the pharmaceutical according to [28], wherein [32] morphine or a derivative or salt thereof is contained in a preparation for oral administration, [33] oral administration The pharmaceutical preparation according to the above (32), wherein the preparation is a sublingual tablet or buccal; (34) the pharmaceutical preparation according to the above (32), wherein the preparation for oral administration is a rapid disintegrating agent in the oral cavity; (35) the compound (I) or The medicament according to the above [28], which is a combination of a preparation for oral administration containing a salt thereof and an injection or a preparation for oral administration containing morphine or a derivative thereof or a salt thereof, [36] The pharmaceutical of the above-mentioned [1], which is a combination of a serotonin antagonist and / or a carbohydrate steroid;

Embedded image A heterocyclic ring having -CS-N <; R ^a and R ^b are bonded together to form a ring A, or the same or different and a substituent on a hydrogen atom or an M ring; A homocyclic or heterocyclic ring optionally having a group, at least one of which is a heterocyclic ring optionally having a substituent; C
The ring is a homo- or heterocyclic ring which may have a substituent; the Z-ring is a nitrogen-containing heterocyclic ring which may be substituted; and n is an integer of 1 to 6. A compound comprising the compound (I) or a salt thereof represented by the formula
8] Formula for producing a drug that suppresses vomiting of a drug having an emetic action

Embedded image A heterocyclic ring having -CS-N <; R ^a and R ^b are bonded together to form a ring A, or the same or different and a substituent on a hydrogen atom or an M ring; A homocyclic or heterocyclic ring optionally having a group, at least one of which is a heterocyclic ring optionally having a substituent; C
The ring is a homo- or heterocyclic ring which may have a substituent; the Z-ring is a nitrogen-containing heterocyclic ring which may be substituted; and n is an integer of 1 to 6. And the use of compound (I) or a salt thereof represented by formula (39), and

Embedded image A heterocyclic ring having -CS-N <; R ^a and R ^b are bonded together to form a ring A, or the same or different and a substituent on a hydrogen atom or an M ring; A homocyclic or heterocyclic ring optionally having a group, at least one of which is a heterocyclic ring optionally having a substituent; C
The ring is a homo- or heterocyclic ring which may have a substituent; the Z-ring is a nitrogen-containing heterocyclic ring which may be substituted; and n is an integer of 1 to 6. Or a salt thereof, which comprises administering the compound (I) or a salt thereof. Compound (I)
Or a salt thereof, wherein R ^a and R ^b are bonded together to form ring A,

Embedded image [Wherein the symbols have the same meanings as described above], or a salt thereof.

Hereinafter, the present invention will be described in detail. And have "M ring, X and Y" Nitsu

Embedded image "R ^a and R ^b" Formula for in (I), R ^a and R ^b are either form a A ring bonded together, or the same or different and each represents a hydrogen atom or M
Shows a substituent in the ring. Examples of the substituents ^Ra and ^Rb in the M ring include a halogen atom, an alkyl group which may have a substituent, an alkoxy group which may be halogenated, and an alkylthio group which may be halogenated. , Cycloalkyl group, aryl group, acylamino group, acyloxy group, hydroxyl group, nitro group, cyano group, amino group, mono- or di-alkylamino group,
Cyclic amino group (for example, a cyclic amino group which may contain a hetero atom such as an oxygen atom or a sulfur atom in addition to a nitrogen atom), an alkylcarbonylamino group, an alkylsulfonylamino group, an alkoxycarbonyl group, a carboxyl group, an alkylcarbonyl group Carbamoyl group, mono- or di-alkylcarbamoyl group, alkylsulfonyl group, oxo group and the like.

The "halogen atom" includes, for example, fluorine, chlorine, bromine and iodine atoms. Preferred halogen atoms include, for example, fluorine, chlorine, and bromine atoms. Examples of the “optionally substituted alkyl group” include, for example, a hydroxyl group, a C _1-6 alkoxy group (C _1- such as methoxy, ethoxy, propoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, etc.) ₄ alkoxy group), C _1-6 alkylthio group (methylthio, ethylthio, propylthio, butylthio, isobutylthio,
a C _1-4 alkylthio group such as s-butylthio, t-butylthio, etc.), an amino group, a C _1-7 acylamino group (formylamino, acetylamino, propionylamino, butyrylamino, benzoylamino group, etc.), an N-alkylamino group Carboxyl group, nitro group, mono- or di-C _1-6 alkylamino group (for example, mono- or di-C _1-4 such as methylamino, ethylamino, propylamino, butylamino, dimethylamino, diethylamino group, etc.)
Alkylamino group), which may have a substituent,
N-substituted amino groups substituted by one or two homologous rings (for example, mono- or di-C _3-8 cycloalkylamino groups such as cyclopropylamino, cyclobutylamino, cyclohexylamino group; phenylamino group and the like) such as C _6-10 arylamino group), Hajime Tamaki which may have a substituent [for example, an oxygen atom in addition to the nitrogen atom, may contain 1 to 3 hetero atoms such as sulfur atom 5 A 9-membered cyclic amino group (e.g., piperidino, 4-methylpiperidino, morpholino, thiomorpholino, piperazinyl, 4-
5- or 6-membered non-aromatic cyclic amino group such as methylpiperazinyl, 4-ethylpiperazinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl; pyridyl, pyrazyl,
5- or 6-membered aromatic cyclic amino groups such as pyrimidinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, etc.), aromatic heterocyclic groups such as thiophenyl, furanyl, thiazole, isothiazole, oxazole and isoxazole groups, tetrahydropyridyl, dihydro Pyridyl, tetrahydropyrazyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl,
Dihydropyrrolyl, dihydroimidazolyl, dihydropyrazolyl, dihydrothiophenyl, dihydrofuranyl, dihydrothiazolyl, dihydroisothiazolyl, dihydrooxazolyl, dihydroisoxazolyl, hexahydropyrimidinyl, hexahydropyridazinyl, Non-aromatic heterocyclic groups such as tetrahydropyranyl, pyrazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, and tetrahydroisoxazolyl groups], alkylsulfonylamino group ( For example, C _1-4 alkylsulfonylamino groups such as methylsulfonylamino and ethylsulfonylamino groups), C
_1-6 alkyl-carbonyloxy group (for example, C _1-4 alkyl- such as acetoxy, ethylcarbonyloxy, propylcarbonyloxy, butylcarbonyloxy group)
A carbonyloxy group or the like and a halogen atom (eg, a fluorine, chlorine, bromine atom, etc.)
A C _1-6 alkyl group _optionally having up to 5 substituents (eg, methyl, ethyl, propyl, isopropyl,
Butyl, isobutyl, sec-butyl, tert-butyl and the like).

The preferred "alkyl group optionally having substituent (s)" includes a C _1-6 alkyl group which may be substituted by about 1 to 4 halogen atoms [particularly, a halogenated alkyl group] C _1-4 alkyl group (for example, methyl, chloromethyl, fluoromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoro Ethyl, pentafluoroethyl, propyl,
3,3,3-trifluoropropyl, isopropyl, 1
-(Trifluoromethyl) ethyl, butyl, 4,4,4
-Trifluorobutyl, isobutyl, sec-butyl, te
rt - C _1-4 alkyl groups and 1-5, such as butyl group C _1-4 (especially 1-3) about a halogen atom has been substituted
Alkyl group etc.]], C _1-6 alkoxy-C _1-6 alkyl group (for example, methoxymethyl, ethoxymethyl, isopropoxymethyl, butoxymethyl, methoxyethyl,
A C _1-4 alkoxy-C _1-4 alkyl group such as ethoxyethyl), a C _1-6 alkylthio-C _1-6 alkyl group (for example, methylthiomethyl, ethylthiomethyl, butylthiomethyl, methylthioethyl, ethylthioethyl _C1-4 alkylthio- _C1-4 alkyl group), amino-C
_1-6 alkyl group (for example, aminomethyl, 2-aminoethyl, 2-aminopropyl, 3-aminopropyl, 2-
Amino-C _1-4 alkyl groups such as aminobutyl, 3-aminobutyl and 4-aminobutyl groups; C _1-7 acylamino-C _1-6 alkyl groups (formylaminomethyl, acetylaminomethyl, propionylaminomethyl, A C _1-7 acylamino-C _1-4 alkyl group such as formylaminoethyl, acetylaminoethyl, propionylaminoethyl, butyrylaminoethyl, benzoylaminomethyl group), mono- or di-C _1-6 alkylamino-C _1-6 alkyl group (for example, methylaminomethyl, ethylaminomethyl, butylaminomethyl, dimethylaminomethyl,
Diethylaminomethyl, 2- (N-methylamino) ethyl, 2- (N-ethylamino) ethyl, 2- (N-methylamino) propyl, 3- (N-methylamino) propyl, 3- (N-methylamino) ) Butyl, 4- (N-methylamino) butyl, 2- (N-dimethylamino) ethyl, 2- (N-diethylamino) ethyl, etc.
Or di-C _1-4 alkylamino-C _1-4 alkyl group),
C _3-10 cycloalkylamino-C _1-6 alkyl group (for example, cyclopropylaminomethyl, cyclobutylaminomethyl, cyclohexylaminomethyl, cyclopropylaminoethyl, cyclobutylaminoethyl, cyclohexylaminoethyl group, phenylaminomethyl group Such as C
_3-10 cycloalkylamino-C _1-4 alkyl group),

A 5- or 6-membered cyclic amino-C _1-6 alkyl group which may contain 1 to 3 heteroatoms such as an oxygen atom and a sulfur atom in addition to the nitrogen atom (for example, piperidinomethyl, 4-methylpiperidyl Nomethyl, morpholinomethyl,
Non-aromatic cyclic amino-C _1-4 alkyl groups such as thiomorpholinomethyl, piperazinylmethyl, 4-methylpiperazinylmethyl, piperidinoethyl, morpholinoethyl, piperazinylethyl; pyridylmethyl, pyrimidinylmethyl, imidazolylmethyl, 5- or 6-membered aromatic cyclic amino-C _1-4 alkyl group such as pyridylethyl),
C _1-6 alkylsulfonylamino-C _1-6 alkyl group (for example, methylsulfonylaminomethyl, ethylsulfonylaminomethyl, methylsulfonylaminoethyl,
C _1-6 alkylsulfonylamino -C _1-6 alkyl group such as ethylsulfonyl aminoethyl group), C _1-6 alkyl - carbonyloxy -C _1-6 alkyl group (e.g., methyl carbonyloxy methyl, ethyl carbonyl oxymethyl , butylcarbonyloxy, methyl carbonyloxy ethyl, C _1-4 alkyl such as ethyl carbonyloxy ethyl - carbonyloxy -C _1-4 alkyl group).

The "optionally halogenated alkoxy group" is, for example, a C _1-6 alkoxy group or a 1 to ₆ alkoxy group.
And a C _1-6 alkoxy group substituted with about 5 halogen atoms. Such alkoxy groups or halogenated alkoxy groups include, for example, methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy,
Trichloromethoxy, ethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy Pentoxy, hexyloxy and the like. Preferred "optionally halogenated alkoxy groups" include C _1-4 alkoxy groups,
A C _1-4 alkoxy group substituted by about 3 halogen atoms, for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,
4,4-trifluorobutoxy, isobutoxy, sec −
Butoxy group and the like.

The "optionally halogenated alkylthio group" includes, for example, a C _1-6 alkylthio group and 1
And C _1-6 alkylthio groups having about 5 halogen atoms. Examples of such alkylthio groups and halogenated alkylthio groups include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, and isopropylthio groups. , Butylthio,
4,4,4-trifluorobutylthio, pentylthio,
Hexylthio group and the like. Preferred is the "even alkylthio group optionally halogenated", C _1-4 alkylthio, or one to three degree C _1-4 alkylthio group halogen atom is substituted, for example, methylthio, difluoromethylthio, trifluoromethyl Methylthio, ethylthio, propylthio, isopropylthio, butylthio,
It includes a 4,4,4-trifluorobutylthio group and the like.

Further, the “cycloalkyl group” includes C
_3-10 cycloalkyl groups (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl groups, etc.) and the like;
_{The 6-10} aryl group (eg, phenyl group, etc.) and the “acylamino group” include, for example, a C _1-7 acylamino group (eg, formylamino, acetylamino, propionylamino, butyrylamino, benzoylamino group, etc.). It is. The “acyloxy group” includes, for example, C _1-3
An acyloxy group (eg, formyloxy, acetoxy, propionyloxy group, etc.) and the like are included. As the “mono- or di-alkylamino group”, for example, a mono- or di-C _1-4 alkylamino group (for example, a methylamino, ethylamino, propylamino, dimethylamino, diethylamino group and the like) and the like can be mentioned. . Also,
The “cyclic amino group” includes, for example, a 5- to 9-membered cyclic amino group which may contain 1 to 3 hetero atoms such as an oxygen atom and a sulfur atom in addition to a nitrogen atom (for example, pyrrolidino, piperidino, morpholino, Thiomorpholino group) and the like. The “alkylcarbonylamino group” includes, for example, a C _1-4 alkyl-carbonylamino group (eg, acetylamino, propionylamino, butyrylamino group, etc.), and the “alkylsulfonylamino group” includes, for example, C _1-4 alkyl. A sulfonylamino group (eg, methylsulfonylamino, ethylsulfonylamino group, etc.) and “alkoxycarbonyl group” include, for example, C
_1-4 alkoxy-carbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
Such as butoxycarbonyl group), to the "alkylcarbonyl group", for example, C _1-6 alkyl - carbonyl group (e.g., formyl, methylcarbonyl, ethylcarbonyl, and propyl group), "mono - or di - alkylcarbamoyl group "Include, for example, mono- or di-
C _1-4 alkylcarbamoyl group (for example, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl,
The “alkylsulfonyl group” and the “alkylsulfonyl group” include, for example, a C _1-6 alkylsulfonyl group (eg, a methylsulfonyl, ethylsulfonyl, propylsulfonyl group and the like).

[0013] In the above formula with the "A ring and B ring" (I) and (Ia), ring A and ring B, respectively, is a good allotrope or heterocyclic ring which may have a substituent, the At least one is a heterocyclic ring which may have a substituent. The "homologous or heterocyclic" includes, for example,
(i) an aromatic heterocyclic ring or a non-aromatic heterocyclic ring preferably containing one to three heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom, or ii) Cyclic hydrocarbons (homocycles) composed of carbon atoms are included. As the "aromatic heterocycle", for example, a 5- or 6-membered aromatic heterocycle containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom (for example, pyridine , Pyrazine, pyrimidine, pyridazine, pyrrole, imidazole, pyrazole, triazole, thiophene, furan, thiazole, isothiazole, oxazole and isoxazole rings). Preferred aromatic heterocycles include, for example, pyridine, pyrazine, thiophene rings and the like, as well as, for example, pyrrole, thiazole rings and the like. In particular, (i) one or two nitrogen atoms other than carbon atoms
A 6-membered nitrogen-containing heterocyclic ring (for example, a pyridine or pyrazine ring) or (ii) a 5-membered aromatic heterocycle containing one sulfur atom in addition to a carbon atom (for example, a thiophene ring) is preferable.

The "non-aromatic heterocycle" includes, for example, a 5- to 9-membered non-aromatic heterocyclic ring containing one to three hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms. Heterocycles, preferably 5- or 6-membered non-aromatic heterocycles and the like are included. For example, for ring A, tetrahydropyridine, dihydropyridine, tetrahydropyrazine, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, dihydropyrrole, dihydroimidazole, dihydropyrazole, dihydrothiophene, dihydrofuran, dihydrothiazole, dihydroisothiazole, dihydrooxazole, dihydro Examples include isoxazole ring, and for ring B, in addition to those described above, piperidine, piperazine, hexahydropyrimidine, hexahydropyridazine, tetrahydropyran, morpholine, pyrrolidine, imidazolidine, pyrazolidine, tetrahydrothiophene, tetrahydrofuran, Tetrahydrothiazole, tetrahydroisothiazole, tetrahydrooxazole, And La tetrahydroisoquinoline isoxazole ring. As the ring A, for example, a 6-membered non-aromatic heterocyclic ring containing one or two nitrogen atoms in addition to a carbon atom (eg, a tetrahydropyridine, tetrahydropyrimidine, tetrahydropyridazine ring, etc.) is preferable, and a tetrahydropyridine ring is particularly preferable. Are commonly used. As the ring B, for example, a 6-membered non-aromatic heterocyclic ring containing one or two nitrogen atoms in addition to a carbon atom (eg, a piperidine or piperazine ring) is preferable, and a piperazine ring and the like are particularly used.

The "cyclic hydrocarbon (homocycle)" includes, for example, a 3- to 10-membered (for example, 5- to 9-membered) cyclic hydrocarbon, preferably a 5- or 6-membered cyclic hydrocarbon. It is. For example, for ring A, benzene, C
_3-10 cycloalkenes (for example, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, etc.) and the like.
Preferred are _5-6 cycloalkenes (eg, cyclopentene, cyclohexene, etc.). As for the ring B, in addition to the above, C _3-10 cycloalkanes (eg, cyclobutane, cyclopentane, cyclohexane,
Cycloheptane, cyclooctane, etc.)
As the cycloalkane, C _5-6 cycloalkane (eg, cyclohexane, cyclopentane, etc.) is preferable. With respect to the ring A, for example, a 6-membered homocyclic ring such as a benzene or cyclohexene ring is preferable, and a benzene ring or the like is particularly preferable. As the ring B, for example, a 6-membered homocyclic ring such as a benzene or cyclohexane ring is preferable, and a benzene ring is particularly preferable.

At least one of the ring A and the ring B is
The ring A and the ring B may be each composed of a heterocyclic ring which may have a substituent. One of ring A and ring B is composed of an aromatic ring which may have a substituent, and the other is composed of a heterocyclic ring which may have a substituent (particularly, an aromatic heterocyclic ring). Is preferred. The “aromatic ring” includes, for example, (i) the “aromatic heterocycle”, that is, one or two heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom in addition to a carbon atom; An optionally substituted 5- or 6-membered aromatic heterocycle containing 1 to 3 substituents (for example, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, imidazole, pyrazole, triazole, thiophene, furan, Thiazole,
(Such as isothiazole, oxazole and isoxazole rings) or (ii) a benzene ring which may have a substituent.

Examples of the substituent which the "aromatic ring" may have include, for example, the same substituents as those in the ring A and the ring B which will be described later. Examples of the “aromatic heterocycle” of the “good aromatic heterocycle” include the same aromatic heterocycles as the above “5- or 6-membered aromatic heterocycle”. Examples of the substituent which the “aromatic heterocyclic ring which may have a substituent (s)” may have include, for example, the same substituents as those in the ring A and the ring B described below. As the above “5- or 6-membered aromatic heterocycle”, the same heterocycle as described in the section of “Aromatic heterocycle” and the like are preferable. More preferably, one of the ring A and the ring B is an aromatic heterocyclic ring which may have a substituent (for example, a 5- or 6-membered aromatic heterocyclic ring), and the other has a substituent. Is a benzene ring which may be substituted.

"Homo- or heterocyclic ring", "aromatic heterocyclic ring", "non-aromatic heterocyclic ring", "cyclic hydrocarbon", "aromatic ring", and "benzene ring" represented by ring A and ring B Examples of the substituent which may be present include, for example, a halogen atom, an alkyl group which may have a substituent, an alkoxy group which may be halogenated, an alkylthio group which may be halogenated, and an aryl Group, acylamino group, acyloxy group, hydroxyl group, nitro group, cyano group, amino group, mono- or di-alkylamino group, cyclic amino group (for example, including a hetero atom such as an oxygen atom and a sulfur atom other than a nitrogen atom Cyclic amino group which may be substituted), alkylcarbonylamino group, alkylsulfonylamino group, alkoxycarbonyl group, carboxyl group, alkylcarbonyl group, carbamo Group, mono - or di - alkylcarbamoyl group, an alkylsulfonyl group, an oxo group. The “halogen atom” that the ring A and the ring B may have include, for example, fluorine, chlorine, bromine and iodine atoms. Preferred halogen atoms include, for example, fluorine, chlorine, and bromine atoms (particularly, fluorine, chlorine atoms, etc.).

Examples of the “optionally substituted alkyl group” which the ring A and the ring B may have include, for example,
Hydroxyl, amino, carboxyl, nitro, mono- or di-C _1-6 alkylamino group (for example,
From methylamino, ethylamino, dimethylamino, diethylamino groups, etc., C _1-6 alkyl-carbonyloxy groups (eg, acetoxy, ethylcarbonyloxy groups, etc.) and halogen atoms (eg, fluorine, chlorine, bromine atoms, etc.) A selected C _1-6 alkyl group _optionally having 1 to 5 substituents (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, se
c-butyl, tert-butyl group, etc.).
Particularly, an alkyl group which may be halogenated, for example, a C _1-6 alkyl group and a C _1-6 alkyl group substituted with about 1 to 4 halogen atoms are preferable. Such alkyl groups or halogenated alkyl groups include, for example, methyl, chloromethyl, fluoromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trichloroethyl, 2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, 1- (trifluoromethyl) ethyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec -Butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, 4-trifluoromethylbutyl, hexyl, 6,
6,6-trifluorohexyl, 5-trifluoromethylpentyl and the like.

Further preferred “optionally substituted alkyl group” includes an optionally halogenated C
_1-4 alkyl groups, for example, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,
C _1-4 alkyl groups such as 3,3-trifluoropropyl, isopropyl, 2-trifluoromethylethyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, It includes a C _1-4 alkyl group substituted by about three halogen atoms. Examples of the “optionally halogenated alkoxy group” that the ring A and the ring B may have include, for example, a C _1-6 alkoxy group or about 1 to 5 halogen atoms as described above are substituted. And a C _1-6 alkoxy group. Such alkoxy groups or halogenated alkoxy groups include
For example, methoxy, difluoromethoxy, trifluoromethoxy, trichloromethoxy, ethoxy, 2,2,2
-Trifluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentoxy, hexyloxy, etc. . Preferred "optionally halogenated alkoxy groups" include C _1-4 alkoxy groups and C _1-4 substituted with about 1 to 3 halogen atoms.
Alkoxy groups, for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy group, etc. Is included.

The "optionally halogenated alkylthio group" which the ring A and the ring B may have include, for example, a C _1-6 alkylthio group and about 1 to 5 halogen atoms as described above. C _1-6 alkylthio group having an atom and the like. Examples of such an alkylthio group and a halogenated alkylthio group include, for example, methylthio, difluoromethylthio, trifluoromethylthio, ethylthio,
Propylthio, isopropylthio, butylthio, 4,
4,4-trifluorobutylthio, pentylthio, hexylthio and the like. Preferred "optionally halogenated alkylthio groups" include a _C1-4 alkylthio group or a _C1-4 substituted with about 1 to 3 halogen atoms.
_1-4 alkylthio groups, for example, methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4
A 4-trifluorobutylthio group and the like are included. Further, the aryl group as a substituent includes a C _6-10 aryl group (eg, phenyl group), and the acylamino group includes, for example, a C _1-7 acylamino group (eg, formylamino, acetylamino, propionylamino, Butyrylamino, benzoylamino group, etc.). The acyloxy group includes, for example, a C _1-3 acyloxy group (eg, formyloxy, acetoxy, propionyloxy group, etc.). Examples of the mono- or di-alkylamino group include, for example, a mono- or di- _C1-4 alkylamino group (for example, a methylamino, ethylamino, propylamino, dimethylamino, diethylamino group and the like).
And the like. Further, in the cyclic amino group, for example,
Examples thereof include a 5- to 9-membered cyclic amino group (for example, pyrrolidino, piperidino, morpholino group and the like) which may contain 1 to 3 hetero atoms such as an oxygen atom and a sulfur atom in addition to the nitrogen atom. The alkylcarbonylamino group includes, for example, a C _1-4 alkyl-carbonylamino group (eg, acetylamino, propionylamino, butyrylamino group, etc.), and the alkylsulfonylamino group includes, for example, C
_1-4 alkylsulfonylamino group (for example, methylsulfonylamino, ethylsulfonylamino group, etc.) and alkoxycarbonyl group include, for example, C _1-4 alkoxy-
A carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl group, etc.) and an alkylcarbonyl group include, for example, C
_1-6 alkyl - carbonyl group (e.g., formyl, methylcarbonyl, ethylcarbonyl, and propyl group), mono - or di - The alkylcarbamoyl group, for example, mono- - or di -C _1-4 alkylcarbamoyl group ( For example, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, etc.) and alkylsulfonyl include, for example, C _1-6 alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, etc.). .

Hereinafter, when the term “optionally halogenated” is used in this specification, the number of halogen atoms is 1
-5, preferably about 1-3. Preferred substituents that ring A and ring B may have include a halogen atom and an optionally halogenated C
_1-4 alkyl group, optionally halogenated C _1-4 alkoxy group, optionally halogenated C _1-4 alkylthio group, C _1-3 acyloxy group, hydroxyl group, amino group, mono- or Examples include a di-C _1-4 alkylamino group, a carboxyl group, a C _1-4 alkoxy-carbonyl group and an oxo group. More preferred substituents that the ring A and the ring B may have include a halogen atom, an optionally halogenated C _1-4 alkyl group, an optionally halogenated C _1-4 alkoxy, and hydroxyl. Groups, amino groups, mono- or di-C _1-4 alkylamino groups, C _1-3 acyloxy groups, oxo groups and the like. Particularly, a halogen atom, an optionally halogenated C _1-4 alkyl group, an optionally halogenated C _1-4 alkoxy group, and the like are preferable.

The substituents on ring A and ring B may be substituted on any substitutable position of the ring, and the substituent may be 2
When the number is more than 3, the substituents may be the same or different, and the number may be about 1 to 4. The number of substituents is preferably about 1 to 3.
If ring A and / or B ring has a nitrogen atom, it may form a quaternary ammonium salt, for example, halogen ions ^{(e.g., Cl -, Br -, I} - , etc.), sulfate ion, hydroxy ion, etc. May form a salt with the anion.

As the preferred homocyclic ring in the ring A for the “ring A”, an homocyclic ring composed of an optionally substituted carbon atom, for example, a compound represented by the formula (A-
1)

Embedded image [Wherein A ¹ represents a halogen atom (eg, fluorine, chlorine atom, etc.), an optionally halogenated C _1-4 alkyl group (eg, methyl, isopropyl, trifluoromethyl, trichloromethyl, ethyl, , 2,2-trifluoroethyl, pentafluoroethyl and the like) or an optionally halogenated C _1-4 alkoxy group (for example, methoxy, trifluoromethoxy, trichloromethoxy, ethoxy, 2,2,2- Trifluoroethoxy,
Pentafluoroethoxy group) or the formula (A-
2)

[0025]

Embedded image [Wherein A ² and A ³ are the same or different and are each a halogen atom (for example, fluorine, chlorine atom, etc.), a C _1-4 alkyl group which may be halogenated (for example, methyl,
Isopropyl, trifluoromethyl, trichloromethyl, ethyl, 2,2,2-trifluoroethyl, pentafluoroethyl and the like, or optionally halogenated C _1-4 alkoxy group (for example, methoxy, trifluoromethoxy , Trichloromethoxy, ethoxy, 2,
2,2-trifluoroethoxy, pentafluoroethoxy, etc.). More preferred homocycles include, for example, compounds of the formula (A-3)

Embedded image Wherein A ⁴ and A ⁵ are the same or different and are each a halogen atom (eg, fluorine, chlorine atom, etc.) or a C _1-4 alkyl group which may be halogenated (eg,
Methyl, trifluoromethyl, trichloromethyl, ethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, isopropyl, etc.), and the like (e.g., a benzene ring).

As the homocyclic ring, for example, the following formula (A-4)

Embedded image [Each symbol in the formula is as defined above. And a benzene ring which may have a substituent represented by In the homocyclic ring represented by the above formula, particularly preferably, an homocyclic ring having the following substituent is included. (1) A ¹ is a halogen atom (eg, fluorine, chlorine atom, etc.) or a C _1-4 alkyl group which may be halogenated (eg, methyl, trifluoromethyl, ethyl,
(2) A ² and A ³ are the same or different and each may be a halogenated C _1-4 alkyl group (for example, methyl, trifluoromethyl, ethyl, isopropyl group), or a halogenated which may be C _1-4 alkoxy group (e.g., methoxy, trifluoromethoxy, homocyclic is an ethoxy group), is (3) a ⁴ and a ^5, the same or Differently, a homocyclic ring which is a C _1-4 alkyl group (eg, methyl, ethyl, isopropyl group, etc.), (4) A ¹ is a halogen atom (eg, fluorine, chlorine atom, etc.), (5) A ² And an homocycle wherein A ³ is the same or different and is a C _1-4 alkoxy group (eg, methoxy, ethoxy group, etc.).

The preferred aromatic or non-aromatic heterocyclic ring in the ring A is a 5- or 6-membered aromatic or non-aromatic heterocyclic ring, for example, pyridine, pyrazine, thiophene, tetrahydropyridine, pyrrole, thiazole And the like. Specifically, for example, a heterocyclic ring represented by the formula (A-5) is preferable.

Embedded image Preferred examples of the aromatic or non-aromatic heterocyclic ring which may have a substituent include, for example, an oxo group and an alkyl group which may have a substituent ( As defined for good substituents), C _6-10
Pyridine, pyrazine, thiophene, tetrahydropyridine, pyrrole optionally having one or two substituents selected from an aryl group (eg, phenyl group) and a halogen atom (eg, fluorine, chlorine, bromine atom, etc.) And a thiazole ring, and specifically, for example, an aromatic or non-aromatic heterocyclic ring represented by the following formula (A-6) is preferable.

Embedded image [Wherein, D ¹ represents a hydrogen atom, a halogen atom (eg, fluorine, chlorine, bromine atom, etc.), E ¹ represents a C _1-4 alkyl group (eg, methyl, ethyl, propyl, isopropyl group, etc.), compounds having a partial structure represented by (ii) a halogen ion ^{(e.g., Cl -, Br -, I} -
Quaternary ammonium salts with sulfate ions or hydroxy ions. G is a hydrogen atom or C
_1-4 alkyl groups (eg, methyl, ethyl, propyl,
J represents a hydrogen atom, a C _1-4 alkyl group (eg, methyl, ethyl, propyl, isopropyl group, etc.) or a C _6-10 aryl group (eg, phenyl group, etc.). Ring A is a 5- or 6-membered nitrogen-containing heterocyclic ring, for example, (i) a 6-membered aromatic nitrogen-containing heterocyclic ring containing one or two nitrogen atoms other than a carbon atom (eg, a pyridine, pyrazine ring, etc.) , (I
i) It is preferably a 6-membered non-aromatic heterocyclic ring containing one or two nitrogen atoms in addition to a carbon atom (for example, a tetrahydropyridine, tetrahydropyrimidine, tetrahydropyridazine ring and the like). Particularly preferred ring A includes an aromatic nitrogen-containing heterocycle, especially a pyridine ring.

As the preferred homocyclic ring in the ring B for the “ring B”, an homocyclic ring consisting of an optionally substituted carbon atom, for example, a compound represented by the formula (B-
1)

Embedded image [In the formula, B ¹ represents a halogen atom, a C _1-4 alkyl group optionally substituted or halogenated with hydroxy, a C _1-4 alkoxy group optionally halogenated, a C _1-6 alkyl-carbonyl group. Or a carboxyl group], formula (B-2)

Embedded image [Wherein B ² and B ³ are the same or different and each represent a halogen atom, an optionally halogenated C _1-4 alkyl group or an optionally halogenated C _1-4 alkoxy group] Or formula (B-3)

Embedded image [In the formula, B ⁴ , B ⁵ and B ⁶ are the same or different and each is a halogen atom, an optionally halogenated C _1-4
Alkyl group and C _1-4 alkoxy group which may be halogenated].

Further preferred homocyclic rings include those represented by the formula (B-4)

Embedded image [Wherein B ⁷ , B ⁸ and B ⁹ are the same or different,
A halogen atom, a C _1-4 alkyl group which may be halogenated or a C _1-4 alkoxy group which may be halogenated]. Particularly preferred homocyclic rings include the following formula (B-5)

Embedded image [In the formula, B ¹⁰ represents a halogen atom, a C _1-4 alkyl group optionally substituted or halogenated with hydroxy, an optionally halogenated C _1-4 alkoxy group, C _1-6 alkyl-carbonyl Or a carboxyl group].

In the above formula, the halogen atom in B ^{1 to} B ¹⁰ includes, for example, fluorine, chlorine, bromine atom and the like, and the optionally halogenated C _1-4 alkyl group includes, for example, methyl , Trifluoromethyl, trichloromethyl, ethyl, 2,2,2-trifluoroethyl,
2,2,2-trichloroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl, propyl,
C _1-4 containing 2,2,3,3-tetrafluoropropyl, isopropyl group, etc., which may be halogenated
The alkoxy group includes, for example, methoxy, trifluoromethoxy, trichloromethoxy, ethoxy, 2,2,2-
Includes trifluoroethoxy, 2,2,2-trichloroethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy, propoxy, 2,2,3,3-tetrafluoropropoxy, isopropoxy group, etc. . In the above formula, the C _1-6 alkyl-carbonyl group represented by B ¹ or B ¹⁰ includes formyl, acetyl and the like.

It is also preferred that ring B is a benzene ring which may have a substituent. Such a benzene ring has, for example, the formula (B-6)

Embedded image Is more preferable, and more preferably, formula (B-7)

Embedded image In particular, the formula (B-8)

Embedded image [The symbols in the formula are as defined above].

Among the substituents in the above formula, particularly preferred substituents are (1) B ¹ , B ² , B ³ , B ⁴ , B ⁵ and B ^{6, which} are the same or different and each have a halogen atom (For example, fluorine, chlorine atom, etc.), optionally halogenated C _1-4 alkyl group (for example, methyl, trifluoromethyl, ethyl, isopropyl group, etc.), (2) B ¹ ,
B ² , B ³ , B ⁴ , B ⁵ and B ⁶ are the same or different and each may be a halogenated C _1-4 alkoxy group (for example, methoxy, trifluoromethoxy, ethoxy group and the like), ( 3) B ⁷ , B ⁸ and B ⁹ are a halogen atom (eg, fluorine, chlorine atom, etc.), (4) B ¹⁰ is a fluorine atom, (5) B ¹⁰ is a C _1-4 alkyl group (eg, a methyl group) And (6) a C _1-6 alkyl group in which B ¹ or B ¹⁰ may be substituted with hydroxy (eg, hydroxymethyl), a C _1-6 alkyl-carbonyl (eg, formyl, acetyl, etc.), And a carboxyl group. As a benzene ring which may have a more preferable substituent, the following formula (B-9)

Embedded image And a phenyl group represented by

Preferred examples of the aromatic or non-aromatic hetero ring in the ring B include 5- or 6-membered aromatic or non-aromatic hetero rings such as pyridine, thiophene and piperidine rings. May have the same preferable substituents as those exemplified in the section of the ring A. When the ring B is an aromatic heterocyclic ring or a non-aromatic heterocyclic ring, a particularly preferred aromatic heterocyclic ring or non-aromatic heterocyclic ring includes, for example, a compound represented by the formula (B-10)

Embedded image And the like. When both or one of the ring A and the ring B is a heterocyclic ring, the heterocyclic ring is also preferably an unsubstituted heterocyclic ring.

[0034] Preferred combinations of A ring and B ring the combination of A ring and B ring (1) is as follows. (1) Any one of ring A and ring B: selected from a nitrogen atom and a sulfur atom other than a carbon atom which may be substituted with a C _1-4 alkyl group (eg, methyl, ethyl, isopropyl group, etc.) 5- or 6-membered heterocycle containing one or two heteroatoms (eg, pyridine, pyrazine,
Thiophene, tetrahydropyridine, piperidine, piperazine ring, etc.), the other of A ring and B ring: a halogen atom (eg, fluorine, chlorine, bromine atom, etc.), a C _1-4 alkyl group which may be halogenated (eg, Methyl, trifluoromethyl, trichloromethyl, ethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 2,2,2-trichloroethyl, propyl, isopropyl, etc.) and optionally halogenated C ₁ Selected from _-4 alkoxy groups (e.g., methoxy, trifluoromethoxy, trichloromethoxy, ethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 2,2,2-trichloroethoxy, propoxy, isopropoxy, etc.) A benzene ring which may be substituted with one to three substituents.

A more preferred combination (2) of the ring A and the ring B is as follows. (2) Any one of ring A and ring B: a 5- or 6-membered aromatic heterocyclic ring containing one or two hetero atoms selected from a nitrogen atom and a sulfur atom in addition to a carbon atom (for example,
Pyridine, pyrazine, thiophene ring, etc.), the other of the A ring and the B ring: a halogen atom (eg, fluorine, chlorine, bromine atom, etc.), an optionally halogenated C _1-4 alkyl group (eg, methyl, Trifluoromethyl, trichloromethyl, ethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 2,2,2-trichloroethyl, propyl, isopropyl, etc.) and optionally halogenated C _1-4. Selected from alkoxy groups (eg, methoxy, trifluoromethoxy, trichloromethoxy, ethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, 2,2,2-trichloroethoxy, propoxy, isopropoxy, etc.) A benzene ring optionally substituted with 1 to 3 substituents; In particular, the aromatic heterocycle (for example, a 5- or 6-membered aromatic heterocycle, particularly a pyridine ring or the like) in which the ring A may have a substituent, and the ring B may have a substituent. It is preferably a benzene ring.

“C ring” In the above formula, the C ring represents an homocyclic ring which may have a substituent or a heterocyclic ring which may have a substituent. The homocyclic ring or heterocyclic ring has about 1 to 5 identical or different substituents,
Preferably, about 1 to 3 may be provided. Further, those substituents may be substituted at any position of the homocyclic ring or the heterocyclic ring. The homocyclic ring includes the same “cyclic hydrocarbon (homocyclic ring)” as described in the section of “A ring and B ring”, for example,
3 such as benzene, C _3-10 cycloalkene (eg, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene), C _3-10 cycloalkane (eg, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, etc.); And a 10-membered cyclic hydrocarbon, preferably a 5- or 6-membered cyclic hydrocarbon. Preferred homocyclic rings include 6-membered homocyclic rings such as benzene, cyclohexene, and cyclohexane rings, and a benzene ring is particularly preferable.

Examples of the substituent on the homocyclic ring such as the benzene ring include a halogen atom (for example, fluorine, chlorine,
Bromine, iodine atom), optionally halogenated C
_1-10 alkyl group (for example, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, perfluoroethyl, propyl, isopropyl, 3,3 , 3-trifluoropropyl, butyl, isobutyl, t-butyl, perfluorobutyl, pentyl, hexyl, octyl, decyl group, etc.), and a C _1-4 alkyl group substituted with an amino group (for example, aminomethyl,
A 2-aminoethyl group), mono - or di -C _1-4 C _1-4 alkyl group substituted with an alkylamino group (e.g.,
Methylaminomethyl, dimethylaminomethyl, 2-methylaminoethyl, 2-dimethylaminoethyl, etc.),
A C _1-4 alkyl group substituted with a carboxyl group (for example, a carboxymethyl, carboxyethyl group, etc.);
A C _1-4 alkyl group substituted with a _1-4 alkoxy-carbonyl group (eg, methoxycarbonylethyl, ethoxycarbonylethyl group, etc.), a C _1-4 alkyl group substituted with a hydroxyl group (eg, hydroxymethyl, hydroxy Ethyl group), a C _1-4 alkyl group substituted with a C _1-4 alkoxy-carbonyl group (eg, methoxymethyl, methoxyethyl, ethoxyethyl group and the like), C
_3-10 cycloalkyl group (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl group, etc.), nitro group, cyano group, hydroxyl group, optionally halogenated C
_1-10 alkoxy group (for example, methoxy, difluoromethoxy, trichloromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, A fluorobutoxy, pentyloxy, hexyloxy, octyloxy, decyloxy group, etc., an optionally halogenated C _1-4 alkylthio group (eg, methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio) group, etc.), amino group, mono- - or di -C _1-4 alkylamino group (e.g., methylamino, ethylamino, propylamino, dimethylamino, diethylamino group), a cyclic amino group (e.g., nitrogen atom Outside oxygen atom, such as 1 to 3 which may contain 5-9 membered cyclic amino group a hetero atom such as sulfur atoms, specifically, for example, pyrrolidino, piperidino, morpholino group), C _{1- 4} alkyl-carbonylamino group (eg, acetylamino, propionylamino, butyrylamino, etc.), aminocarbonyloxy group, mono- or di-C _1-4 alkylaminocarbonyloxy group (eg, methylaminocarbonyloxy, ethylaminocarbonyloxy , Dimethylaminocarbonyloxy, diethylaminocarbonyloxy, etc.), C _1-4 alkylsulfonylamino group (eg, methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino group, etc.), C _1-4 alkoxy-carbonyl group (eg, methoxy Carbonyl, ethoxyca Boniru, propoxycarbonyl, butoxycarbonyl, etc. isobutoxycarbonyl group), an aralkyloxycarbonyl group (e.g., phenyl -C _1-4 alkyloxy - carbonyl (e.g., benzyloxycarbonyl group) C _7-19 aralkyloxycarbonyl such as A carboxyl group, a C _1-6 alkyl-carbonyl group (eg, methylcarbonyl, ethylcarbonyl, butylcarbonyl group, etc.), a C _3-6 cycloalkyl-carbonyl group (eg, cyclohexylcarbonyl group, etc.), a carbamoyl group, A mono- or di-C _1-4 alkylcarbamoyl group (eg, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl, etc.), C
_1-6 alkylsulfonyl group (for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl group and the like) and the like.

Further, the homocyclic ring as the ring C is, for example,
One 5- or 6-membered aromatic monocyclic heterocyclic group (for example, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl , 1,3,4-oxadiazolyl, furazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3
-Triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.), and these aromatic monocyclic heterocyclic groups are It may be substituted by about C _1-4 alkyl groups which may be halogenated (for example, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, isopropyl groups, etc.).

Preferred substituents for substitution on the homocyclic ring (benzene ring or the like) as the ring C include, for example, a halogen atom (for example, fluorine, chlorine, bromine atom and the like) and an optionally halogenated C _{1- 6} alkyl groups (for example, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl,
2,2,2-trifluoroethyl, perfluoroethyl, propyl, isopropyl, 3,3,3-trifluoropropyl, butyl, s-butyl, t-butyl, perfluorobutyl group, etc.), nitro group, hydroxyl group An optionally halogenated C _1-6 alkoxy group (for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy,
Perfluoroethoxy, propoxy, isopropoxy,
3,3,3-trifluoro propoxy and butoxy group), an amino group, a mono - or di -C _1-4 alkylamino C _1-4 alkyl group substituted by group (e.g., methylaminomethyl, dimethylaminomethyl , 2-methylaminoethyl, 2-dimethylaminoethyl, etc.), mono- or di-C _1-4 alkylamino (eg, methylamino,
Ethylamino, dimethylamino, diethylamino and the like), C _1-4 alkoxy-carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl and the like), carboxyl group and carbamoyl group.

Among them, a halogen atom (for example, fluorine, chlorine, bromine atom, etc.) and a C _1-4 alkyl group which may be halogenated (for example, methyl, chloromethyl,
Difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, perfluoroethyl, propyl, isopropyl, t-butyl group, etc.), And an optionally halogenated C _1-4 alkoxy group (for example, methoxy, trifluoromethoxy,
Ethoxy, 2,2,2-trichloroethoxy, 2,2
2-trifluoroethoxy, perfluoroethoxy, propoxy group, etc.), di-C _1-4 alkylamino group (eg, dimethylamino, diethylamino group, etc.), C _1-3
An acyloxy group (for example, an acetoxy group) and a hydroxyl group are preferred. The number of these substituents is
For example, the number is preferably about 1 to 3. In particular, a halogen atom (eg, fluorine, chlorine, bromine atom, etc.), an optionally halogenated C _1-4 alkyl group (eg,
Methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, perfluoroethyl, propyl, isopropyl, t- Butyl group, etc., optionally halogenated C _1-4 alkoxy group (for example, methoxy, trifluoromethoxy, ethoxy, 2,2,2-trichloroethoxy, 2,2,2-trifluoroethoxy, perfluoro Ethoxy, propoxy, etc.) are preferred.

The “heterocycle” of the “heterocycle optionally having substituent (s)” includes, for example, a nitrogen atom,
It includes a 5- to 10-membered heterocyclic ring containing 1 to 4 kinds of one or two kinds of hetero atoms such as an oxygen atom and a sulfur atom.
Specific examples of the heterocycle include (1) furyl,
Thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-
Oxadiazolyl, 1,3,4-oxadiazolyl, furazanil, 1,2,3-thiadiazolyl, 1,2,4-
Thiadiazolyl, 1,3,4-thiadiazolyl, 1,
2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl,
5- or 6-membered aromatic monocyclic heterocycle such as pyrazinyl and triazinyl;

(2) Benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl, 1,2- Benzoisothiazolyl, 1H-
Benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, prenyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothinyl, phenazinyl , Thianthrenyl, phenatridinyl, phenatrolinyl, indolizinyl, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-
b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3-a] pyridyl,
9- or 10-membered fused aromatic heterocycle such as 1,2,4-triazolo [4,3-b] pyridazinyl; or

(3) 5- to 10-membered non-aromatic heterocycles such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl and pyrazinyl. The heterocycle (1) to
Among (3), for example, a 5- or 6-membered heterocycle containing 1 to 3 hetero atoms such as a nitrogen atom, an oxygen atom, and a sulfur atom in addition to a carbon atom is widely used. Such heterocycles include, for example, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, quinolyl, isoquinolyl, thiazolyl, thiadiazolyl, thiophenyl, and the like. As the substituent which the heterocyclic ring may have,
Substituents similar to those described in the above section of “Homocycle optionally having substituent (s)” can be mentioned.

A more preferred ring C is a benzene ring which may have a substituent (particularly, a benzene ring substituted by a substituent), for example, a halogen atom or an optionally halogenated C _1-4. Substituted with 1 to 3 substituents selected from an alkyl group, an optionally halogenated C _1-4 alkoxy group, a di-C _1-4 alkylamino group, a C _1-3 acyloxy group and a hydroxyl group. Benzene ring (particularly, a benzene ring substituted with the substituent). Specifically, preferred C ring includes, for example, the following formula (C-1)

Embedded image [Wherein C ¹ , C ² and C ³ are the same or different and are each a hydrogen atom, a halogen atom, an optionally halogenated C _1-4 alkyl group, an optionally halogenated C
_1-4 alkoxy group, mono- or di-C _1-4 alkylamino group, C _1-3 acyloxy group or hydroxyl group], or the following formula (C-2)

Embedded image [Wherein C ⁴ and C ⁵ are the same or different and are each a hydrogen atom, a halogen atom, an optionally halogenated C
_1-4 alkyl group or optionally halogenated C
_1-4 represents an alkoxy group], which may be substituted.

Here, C ¹ , C ² , C ³ , C ⁴ or C ⁵
A halogen atom, an optionally halogenated C _1-4 alkyl group, an optionally halogenated C _1-4
The alkoxy group and the mono- or di-C _1-4 alkylamino group are the above-mentioned halogen atom, an optionally halogenated C _1-4 alkyl group, an optionally halogenated C _1-4 alkoxy group and The same ones as the mono- or di-C _1-4 alkylamino group are used. More preferred C
In the ring, for example, in the formulas (C-1) and (C-2),
A benzene ring in which C ^{1 to} C ⁵ are the following substituents is included. (1) When C ¹ , C ² and C ³ are the same or different,
A halogen atom, an optionally halogenated C _1-4 alkyl group or an optionally halogenated C _1-4 alkoxy group, (2) wherein C ¹ , C ² and C ³ are the same or different, A halogen atom or a C _1-4 alkyl group which may be halogenated, (3) C ¹ , C ² and C ³ are the same or different, and are halogen atoms, (4) C ¹ , C ² and C ³ Is the same or different and may be a halogenated C _1-4 alkyl group,

(5) C ¹ , C ² and C ³ are the same or different, and optionally a halogenated C _1-4 alkoxyl group; and (6) C ⁴ and C ⁵ are the same or different. And halogen atoms, (7) C ⁴ and C ⁵ are the same or different, and optionally a halogenated C _1-4 alkyl group, or (8) C ⁴ and C ⁵ are the same or different A C _1-4 alkoxy group which may be halogenated. In the embodiments (1) to (8), the “optionally halogenated C _1-4 alkyl group”, the “optionally halogenated C _1-4 alkoxy group” and the “halogen atom” The same groups or atoms as described above can be exemplified.

Further preferred ring C is, for example, a benzene ring in which C ⁴ and C ⁵ in the formula (C-2) are the following substituents. (A) one of C ⁴ and C ⁵ is a hydrogen atom, the other is a methoxy group, (b) C ⁴ and C ⁵ are chlorine atoms, (c) C 4
One is a methoxy group of ⁴ and C ^5, the other is an isopropyl group, (d) C one methoxy group of ⁴ and C ^5, the other is 1-methoxy-1-methylethyl or (e) C ⁴ and, C ⁵ is a trifluoromethyl group.

Regarding “Z ring” In the above formula, the Z ring represents a nitrogen-containing heterocyclic ring which may be substituted. As the substituent for the Z ring, various substituents, for example,
Alkyl groups (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-
A linear or branched alkyl group having 1 to 6 carbon atoms such as a butyl group, preferably a linear or branched alkyl group having 1 to 4 carbon atoms, an alkenyl group (for example, ethenyl, propenyl, isopropenyl) , Butenyl, isobutenyl, sec −
C2-C6 alkenyl groups such as butenyl groups, preferably C2-C4 alkenyl groups, alkynyl groups (e.g. ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, sec-butynyl, etc. ~
6 alkynyl groups, preferably alkynyl groups having 2 to 4 carbon atoms), cycloalkyl groups (for example, cyclopropyl,
Cyclobutyl, cyclopentyl, C _3-8 cycloalkyl groups such as cyclohexyl group, preferably a C _3-6 cycloalkyl group), a cycloalkyl - alkyl group (e.g., cyclopropylmethyl, cyclopropylethyl, C _3, such as a cyclohexylmethyl group _-6 cycloalkyl-C _1-4 alkyl group), aryl group (for example, aryl group having 6 to 14 carbon atoms such as phenyl, 1-naphthyl, 2-naphthyl, anthryl, phenanthryl group, and preferably 6 carbon atoms)
To 10 aryl groups, especially phenyl group), nitro group, cyano group, hydroxyl group, C _1-4 alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy group, etc.), C _1-4 alkylthio group ( For example, methylthio, ethylthio, propylthio groups, etc.),
An amino group, a mono- or di-C _1-4 alkylamino group (for example, methylamino, ethylamino, propylamino,
Specific examples include a dimethylamino, diethylamino group, and a cyclic amino group (for example, a 5- to 9-membered cyclic amino group which may contain 1 to 3 hetero atoms such as an oxygen atom and a sulfur atom in addition to a nitrogen atom). Is, for example, a pyrrolidino, piperidino, morpholino, thiomorpholino group, etc.), C _1-4
Alkyl-carbonylamino group (for example, acetylamino, propionylamino, butyrylamino group, etc.), C
_1-4 alkylsulfonylamino group (for example, methylsulfonylamino, ethylsulfonylamino group and the like), C
_1-4 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl group, etc.), carboxyl group, C _1-6 alkyl-carbonyl group (eg, methylcarbonyl, ethylcarbonyl, propylcarbonyl group, etc.), carbamoyl group A mono- or di-C _1-4 alkylcarbamoyl group (eg, methylcarbamoyl, ethylcarbamoyl group, etc.), a C _1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl group, etc.), an oxo group, And a thioxo group. The number of these substituents is, for example, about 1 to 5, preferably about 1 or 2, depending on the size of the Z ring.

The ring Z may be a heterocyclic ring which may contain at least one heteroatom selected from nitrogen, oxygen and sulfur atoms in addition to Y and nitrogen atom N. It is preferably an optionally substituted ring. In the Z ring, the following formula (Z-1)

Embedded image (Wherein, D and E each represent a group that forms the Z ring together with the nitrogen atom adjacent to E). Examples of D and E forming the Z ring include an alkylene group, an oxyalkylene group, and an iminoalkylene group, at least one of which may be oxo-modified. Desirable D and E are often an alkylene group or an oxyalkylene group which may be oxo-ized in many cases. The alkylene group, oxyalkylene group, and iminoalkylene group which may be oxo represented by D and E are such that the Z ring has a carbon number forming a 5- to 12-membered ring, preferably a 5- to 9-membered ring. Is preferred. D and E
The carbon number of the alkylene group represented by may be the same or different.

Preferred D includes, for example, a C _1-7 alkylene group which may be oxo-modified (particularly a C _1-5 alkylene group which may be oxo- _modified ) and a C _1-7 oxyalkylene group (particularly C _1-7 oxyalkylene group). _1-5 oxyalkylene group) and C _1-7 iminoalkylene group (especially C _1-5 iminoalkylene group). More preferred D, the formula - (CH _{2) m} - (wherein, m is 1-7) alkylene group represented by the formula -O-
An oxyalkylene group represented by (CH ₂ ) _p — (where p is an integer of 1 to 7), a formula —NH— (CH ₂ ) _q — (wherein
q is an integer of 1 to 7). In the above formula, m and p are each 1 to
5, particularly preferably 2 to 5. A preferred E is
For example, it includes a C _1-3 alkylene group which may be oxo-modified, particularly an alkylene group having 1 or 2 carbon atoms which may be oxo-modified, and among them, a methylene group which may be oxo-modified. The number of oxo groups that can be substituted on the Z ring is not particularly limited, and can be selected from a range of about 1 to 3 depending on the size of the Z ring. The number is about one or two. The oxo group may be substituted on at least one of D and / or E. In a preferred Z ring, the oxo group is substituted with E.

In a preferred Z ring, D is a group having 1 to 1 carbon atoms.
5, particularly an alkylene group or an oxyalkylene group having 2 to 5 carbon atoms, and E is an oxo-modified alkylene group having 1 or 2 carbon atoms, particularly> C = O. Preferred Z rings include
For example, the following formula (Z-2)

Embedded image (Wherein, m and p each represent an integer of 1 to 5).

“Regarding n” In the above formula, n represents an integer of 1 to 6, and is preferably an integer of 1 to 3, particularly 1 or 2. More preferably, n is 1. Compounds (I) and (Ia ) in the compounds represented by the general formula (I) and the general formula (Ia)

Embedded image The combination is not particularly limited, and the compounds (I) and (Ia) can be constructed by appropriately combining. Preferred compounds (I) and (Ia) are the “M ring” of the preferred embodiment.

Embedded image It is constructed by combining.

Among the compounds represented by the above general formula (I), particularly the general formula (Ia), preferred compounds (1) include the following compounds or pharmaceutically acceptable salts. One of the ring A and the ring B is a 5- or 6-membered heterocyclic ring containing one or two hetero atoms selected from a nitrogen atom and a sulfur atom in addition to a carbon atom, and the other is a benzene ring , A ring and B ring are each selected from a halogen atom and an optionally halogenated C _1-4 alkyl group.
Or ring C may have a halogen atom, an optionally halogenated C _1-6 alkyl group (preferably a C _1-4 alkyl group) and a halogenated ring. A benzene ring optionally having 1 to 3 substituents selected from a C _1-6 alkoxy group (preferably a C _1-4 alkoxy group); and D constituting the Z ring is-(CH ₂ ) _M
- (m is an integer of 1 to 7) or -O- (CH _{2) p} -
(P represents an integer of 1 to 7);

E constituting the Z ring is> C = O;

Embedded image A compound wherein n is 1 or a pharmaceutically acceptable salt thereof. Examples of the above “5- or 6-membered heterocyclic ring” include pyridine, pyrazine, pyrrole, thiophene, thiazole, tetrahydropyrazine, piperidine and the like. Specifically, as the A ring, the above formula (A-5) And the ring B is represented by the formula (B-7) (B-
8), especially the benzene ring represented by the formula (B-10). The “halogen atom” includes, for example, fluorine, chlorine, bromine atom and the like. As the “optionally halogenated C _1-4 alkyl group”, for example, methyl, chloromethyl, difluoromethyl, trichloro Methyl, trifluoromethyl, ethyl, 2-bromoethyl,
2,2,2-trifluoroethyl, perfluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, 2-trifluoromethylethyl, butyl,
4,4,4-trifluorobutyl, isobutyl, sec-
Examples thereof include butyl and tert-butyl groups, and the “optionally halogenated C _1-6 alkyl group” includes a pentyl, hexyl group and the like in addition to the above-mentioned alkyl group or halogenated alkyl group.

The “optionally halogenated C _1-4 alkoxy group” includes, for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2
-Trifluoroethoxy, perfluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, te
Examples of the rt-butoxy group include “optionally halogenated C _1-6 alkoxy group” which includes pentyloxy, hexyloxy group and the like in addition to the above-mentioned alkoxy group or halogenated alkoxy group. Among the compounds represented by the general formula (I), particularly the general formula (Ia), the preferable compound (2) includes the following compounds or pharmaceutically acceptable salts. A ring is, other than carbon atom, 1
5- or 6-membered heterocyclic ring containing one nitrogen atom or one sulfur atom, for example, a heterocyclic ring represented by the following formula (A-7);

Embedded image Ring B is a benzene ring which may have 1 to 3 substituents selected from a halogen atom and a C _1-4 alkyl group which may be halogenated; A benzene ring optionally substituted with 1 to 3 substituents selected from an optionally substituted C _1-4 alkyl group and an optionally halogenated C _1-4 alkoxy group; constituting a Z ring D to the - (CH _{2) m} - (indicating represents an integer of 1-7 p) - (m is an integer of 1 to 7) or -O- (CH _{2) p;}

E constituting the Z ring is> C = O;

Embedded image A compound wherein n is 1 or a pharmaceutically acceptable salt thereof.
"Halogen atom", "optionally halogenated C
" _1-4 alkyl group" and "optionally halogenated C
Examples of the “ _1-4 alkoxy group” include the same atoms or groups as described in the section of the compound (1). More preferably, R ^a and R ^b are the same or different and are a hydrogen atom or a C _1-6 alkoxy group, a C _1-6 alkylthio group, an amino group, a C _1-7 acylamino group, a mono- or di-C _1-6 alkylamino group, C _3-10 cyclic amino group, C _1-6 alkyl which may be substituted 5 or optionally 6-membered cyclic amino group with a group, C _1-6 alkylsulfonylamino group or a C _1-6 alkylcarbonyloxy C optionally substituted with a group
_1-6 alkyl group, or R ^a and R ^b are bonded together to form a pyridine ring which may have 1 to 3 substituents selected from a halogen atom or a C _1-4 alkyl group,
Ring B is a halogen atom, an optionally halogenated C _1-4 alkyl group or an optionally halogenated C
_A benzene ring optionally having 1 to 3 substituents selected from _1-4 alkoxy groups, wherein the C ring is a halogen atom, an optionally halogenated C _1-4 alkyl group, Having one to three substituents selected from an optionally substituted C _1-4 alkoxy group, an amino group optionally substituted with a C _1-4 alkyl group, a C _1-3 acyloxy group and a hydroxyl group. A 5- to 10-membered nitrogen-containing heterocyclic group, wherein the Z ring may be substituted with a C _1-4 alkyl group or a hydroxyl group or may be oxo-modified,

Embedded image A compound in which n is 1 or a salt thereof is included.

Preferred compounds among the compounds (I) and (Ia) include, for example, a compound represented by the following general formula or a salt thereof.

Embedded image (In the formula, D and E are an alkylene group which may be oxo-ized, and other symbols are as defined above.) D and E are each a C _1-3 which may be substituted with one oxo group. It is preferably an alkylene group. More preferred compounds among the compounds (I) and (Ia) include, for example, a compound represented by the following general formula or a salt thereof.

Embedded image (In the formula, m is an integer of 1 to 7, and other symbols are as defined above.) M is preferably an integer of 2 to 5. In the above formula, ^Ra and ^Rb are each a hydrogen atom or a (I) halogen atom, (I
(I) (i) hydroxy group, (ii) C _1-6 alkoxy group, (iii) C
_1-6 alkylthio group, (iv) amino group, (v) C _1-7 acylamino group, (vi) mono- or di-C _1-6 alkylamino group,
(vii) a mono- or di-C _3-8 cycloalkylamino group, (v
iii) may be substituted by C _1-6 alkyl, nitrogen oxygen atom in addition to atoms, 1 to 3 which may contain 5-9 membered cyclic amino group a hetero atom selected from the group consisting of sulfur atoms , (Ix) C _1-4 alkylsulfonylamino group, (x) C
_A C _1-6 alkyl group _optionally having 1 to 5 substituents selected from the group consisting of _1-6 alkyl-carbonyloxy group and (xi) halogen atom, and (III) C _1-6 alkyl 5 to 9 optionally containing 1 to 3 (preferably 1 or 2) hetero atoms selected from the group consisting of an oxygen atom and a sulfur atom in addition to the nitrogen atom
(Preferably 6-membered) cyclic amino group, (IV) carboxyl group, (V) carbamoyl group and (VI) mono- or di-
A substituent selected from the group consisting of a C _1-6 alkylcarbamoyl group; R ^a and R ^b are bonded together to form a ring A, and the ring A is substituted with a C _1-6 alkyl group; A 5- to 9-membered aromatic heterocyclic ring (preferably a pyridine ring) containing one to three of one or two hetero atoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom other than a carbon atom; ) indicates; B ring is (i) hydroxy group optionally substituted by a C _1-6 alkyl group, including (ii) C _1-6 alkylcarbonyl group (formyl) and (iii) the group consisting of carboxyl group A C _6-14 aryl group (preferably a benzene ring) which may be substituted with a substituent selected from the group _{consisting of} : a ring represented by (i) a halogen atom, and (ii) an optionally halogenated C _{1- group. 10} alkyl groups and (iii) C _1-10
A C _6-14 aryl group (preferably a benzene ring) optionally substituted with 1 to 3 substituents selected from the group consisting of an alkoxy group; wherein the Z ring is (i) a C _1-6 alkyl group; , (Ii) optionally substituted with one to three substituents selected from the group consisting of a hydroxy group and (iii) oxo group, in addition to Y and a nitrogen atom, comprises a nitrogen atom, an oxygen atom and a sulfur atom It is preferable to show a 5- to 12-membered heterocyclic ring which may contain at least one heteroatom selected from the group. The compounds represented by the formulas (I) and (Ia) may form a salt, and when it is used as a pharmaceutical, the salt is preferably a pharmaceutically acceptable salt. As pharmaceutically acceptable salts, for example, hydrochloric acid,
Salts with inorganic acids such as sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid and nitric acid, or acetic acid, malic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, citric acid, lactic acid, methanesulfonic acid, p -Salts with organic acids such as toluenesulfonic acid, palmitic acid, salicylic acid and stearic acid.

The compounds (I) and (Ia) or salts thereof used in the present invention include stereoisomers such as cis and trans isomers, racemic forms, and optically active forms such as R-form and S-form. . In addition, depending on the size of the ring such as the Z ring, an isomer due to conformation may be generated, and such an isomer is also included in the compounds (I) and (Ia) or a salt thereof.

Preferred compounds among the compounds (I) and (Ia) are shown below. (1) 7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9-tetrahydro-5- (4-methylphenyl) -6,11-dioxo-11H-pyrazino [2, 1-g] [1,7] naphthyridine (hereinafter sometimes abbreviated as compound No. 1) (2) 7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8, 9,10,12-hexahydro-
5- (4-methylphenyl) -6,12-dioxo [1,4] diazepino [2,1-g] [1,7] naphthyridine (hereinafter sometimes abbreviated as compound No. 2) (3) ) 7- [3,5-Bis (trifluoromethyl) benzyl] -6,7,8,9,10,11-hexahydro-
5- (4-methylphenyl) -6,13-dioxo-1
3H- [1,4] diazosino [2,1-g] [1,7]
Naphthyridine (4) 6,7,8,9,10,12-hexahydro-7
-(2-methoxybenzyl) -5- (4-methylphenyl) -6,12-dioxo [1,4] diazepino [2,
1-g] [1,7] naphthyridine (5) 6,7,8,9,10,11-hexahydro-7
-(2-methoxybenzyl) -5- (4-methylphenyl) -6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine (6) 7- [ 3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,10,11,12,14-octahydro-5- (4-methylphenyl) -6,14-
Dioxo [1,4] diazonino [2,1-g] [1,
7] Naphthyridine (7) 7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,10,12-hexahydro-
6,12-dioxo-5-phenyl [1,4] diazepino [2,1-g] [1,7] naphthyridine (8) 7- [3,5-bis (trifluoromethyl) benzyl] -6,7 , 8,9,10,11-Hexahydro-
6,13-dioxo-5-phenyl-13H- [1,
4] diazosino [2,1-g] [1,7] naphthyridine (9) 7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,10,11-hexahydro-
5- (4-methylphenyl) -6,13-dioxo-1
3H- [1,4] diazosino [1,2-b] [2,7]
Naphthyridine

(10) 7- [3,5-bis (trifluoromethyl) benzyl] -1,2,3,4,6,7,8,
9,10,11-Decahydro-2-methyl-5- (4-
Methylphenyl) -6,13-dioxo-13H-
[1,4] diazosino [1,2-b] [2,7] naphthyridine (11) 4- [3,5-bis (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-5- Oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine (12) (9R) -7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,10 , 12-Hexahydro-9-methyl-5- (4-methylphenyl)
-6,12-Dioxo [1,4] diazepino [2,1-
g] [1,7] naphthyridine (13) (9S) -7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,10,12-hexahydro-9-methyl-6 , 12-Dioxo-5-phenyl [1,4] diazepino [2,1-g] [1,7]
Naphthyridine (14) (9S) -7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,10,12-hexahydro-9-methyl-5- (4-methylphenyl)
-6,12-Dioxo [1,4] diazepino [2,1-
g] [1,7] naphthyridine (15) (±) -7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,10,11-hexahydro-9-methyl-6 , 13-Dioxo-5-phenyl-13H- [1,4] diazosino [2,1-g]
[1,7] naphthyridine (16) (±) -7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,10,11-hexahydro-9-methyl-5- ( 4-methylphenyl)-
6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine (17) (9R) -7- [3,5-bis (trifluoromethyl) benzyl]- 6,7,8,9,10,11-hexahydro-9-methyl-6,13-dioxo-5-phenyl-13H- [1,4] diazosino [2,1-g]
[1,7] Naphthyridine (18) (9R) -7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,10,11-hexahydro-9-methyl-5- ( 4-methylphenyl)
-6,13-Dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine (hereinafter sometimes abbreviated as compound No. 3) (19) (9S)- 7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,10,11-hexahydro-9-methyl-6,13-dioxo-5-phenyl-13H- [1,4 ] Diazosino [2,1-g]
[1,7] Naphthyridine

(20) (9S) -7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,
10,11-hexahydro-9-methyl-5- (4-methylphenyl) -6,13-dioxo-13H- [1,
4] diazosino [2,1-g] [1,7] naphthyridine (21) 4- [3,5-bis (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-5-oxo-6 -Phenyl-1H-pyrido [2,3-e] [1,
4] Diazepine (22) 5- [3,5-bis (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-6-oxo-7-phenyl-6H-pyrido [2,3-b] [1,
5] Oxazosin (23) 4- [3,5-bis (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-7-methyl-5-oxo-6-phenylpyrido [3,2-f]
[1,4] oxazepine (24) 5- [3,5-bis (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-8-methyl-6-oxo-7-phenyl-6H-pyrido [2,3-
b] [1,5] oxazosin (25) (±) -7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,10,12-hexahydro-9-hydroxy-5 -(4-Methylphenyl) -6,12-dioxo [1,4] diazepino [2,
1-g] [1,7] naphthyridine (26) 7-benzyl-6,7,8,9,10,12-
Hexahydro-6,12-dioxo-5-phenyl [1,4] diazepino [2,1-g] [1,7] naphthyridine (27) 7-benzyl-6,7,8,9,10,11-
Hexahydro-6,13-dioxo-5-phenyl-1
3H- [1,4] diazosino [2,1-g] [1,7]
Naphthyridine (28) 7-benzyl-6,7,8,9,10,11,
12,14-octahydro-6,14-dioxo-5-
Phenyl [1,4] diazonino [2,1-g] [1,
7] Naphthyridine (29) 7- (3,4-dichlorobenzyl) -6,7,
8,9,10,12-Hexahydro-6,12-dioxo-5-phenyl [1,4] diazepino [2,1-g]
[1,7] Naphthyridine

(30) 7- (3,4-dichlorobenzyl) -6,7,8,9,10,11-hexahydro-
6,13-dioxo-5-phenyl-13H- [1,
4] diazosino [2,1-g] [1,7] naphthyridine (31) (S) -5- [3,5-bis (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-
3,8-dimethyl-6-oxo-7-phenyl-6H-
Pyrido [2,3-b] [1,5] oxazosin (32) (R) -5- [3,5-bis (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-
3,8-dimethyl-6-oxo-7-phenyl-6H-
Pyrido [2,3-b] [1,5] oxazosin (33) 4- [3,5-bis (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-8-methyl-5-oxo -6-phenylpyrido [3,2-f]
[1,4] oxazepine (34) 5- [3,5-bis (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-9-methyl-6-oxo-7-phenyl-6H-pyrido [2,3-
b] [1,5] oxazosin (35) 4- [3,5-bis (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-8-methyl-5-oxo-6-phenylpyrido [3 , 2-f]
[1,4] oxazepine 9-oxide (36) 5- [3,5-bis (trifluoromethyl) benzyl] -2,3,4,5, -tetrahydro-9-methyl-6-oxo-7-phenyl -6H-pyrido [2,3
-B] [1,5] oxazosin 10-oxide (37) 8-acetoxymethyl-4- [3,5-bis (trifluoromethyl) benzyl] -2,3,4,5-
Tetrahydro-5-oxo-6-phenylpyrido-
[3,2-f] [1,4] oxazepine (38) 9-acetoxymethyl-5- [3,5-bis (trifluoromethyl) benzyl] -2,3,4,5-
Tetrahydro-6-oxo-7-phenyl-6H-pyrido [2,3-b] [1,5] oxazosin (39) 4- [3,5-bis (trifluoromethyl) benzyl] -8-chloromethyl- 2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido [3,2-
f] [1,4] oxazepine

(40) 4- [3,5-bis (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-8-methoxymethyl-5-oxo-6-phenylpyrido [3,2-f ] [1,4] oxazepine (41) 4- [3,5-bis (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-8- (2-
Methylethyl) -5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine (42) 4- [3,5-bis (trifluoromethyl) benzyl] -2,3,4,5 -Tetrahydro-8-methylthiomethyl-5-oxo-6-phenylpyrido [3,2
-F] [1,4] oxazepine (43) 8-aminomethyl-4- [3,5-bis (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido [3,2-
f] [1,4] oxazepine (44) 4- [3,5-bis (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-8-methylaminomethyl-5-oxo-6-phenylpyrido [3,
2-f] [1,4] oxazepine (45) 4- [3,5-bis (trifluoromethyl) benzyl] -8-dimethylaminomethyl-2,3,4,5
-Tetrahydro-5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine (46) 4- [3,5-bis (trifluoromethyl) benzyl] -8-cyclopropylaminomethyl-2 , 3,
4,5-tetrahydro-5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine (47) 4- [3,5-bis (trifluoromethyl) benzyl] -2,3,4 , 5-Tetrahydro-8- (N-
Methylpiperazinomethyl) -5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine (48) 8-acetylaminomethyl-4- [3,5-bis (trifluoromethyl) benzyl ] -2,3,4,5
-Tetrahydro-5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine (49) 4- [3,5-bis (trifluoromethyl) benzyl] -2,3,4,5- Tetrahydro-8-methanesulfonylaminomethyl-5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine

(50) 6- [3,5-bis (trifluoromethyl) benzyl] -5,6,7,8-hexahydro-3,9-dimethyl-5,10-dioxo-4-phenylpyrido [2 3-f] [1,4] diazocine (51) 6- [3,5-bis (trifluoromethyl) benzyl] -5,6,7,8,9,10-hexahydro-
9-methyl-5,10-dioxo-4-phenylpyrido [2,3-f] [1,4] diazosin (52) 6-benzyl-5,6,7,8,9,10-hexahydro-3,9 -Dimethyl-5,10-dioxo-
4-phenylpyrido [2,3-f] [1,4] diazocine (53) 6- [3,5-bis (trifluoromethyl) benzyl] -9-ethyl-5,6,7,8,9,10 -Hexahydro-3-methyl-5,10-dioxo-4-phenylpyrido [2,3-f] [1,4] diazosin (54) 6- [3,5-bis (trifluoromethyl) benzyl] -6 7,8,9,10,11-hexahydro-3,10-dimethyl-5,11-dioxo-4-phenyl-5H-pyrido [2,3-g] [1,5] diazonine (55) 4- [ 3,5-bis (trifluoromethyl) benzyl] -8-hydroxymethyl-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido [3,2
-F] [1,4] oxazepine (56) 4- [3,5-bis (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido [3,2- f] [1,4] oxazepine-8-carboxylic acid (57) 4- [3,5-bis (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido [ 3,2-f] [1,4] oxazepine-8-carboxamide (58) 4- [3,5-bis (trifluoromethyl) benzyl] -N-methyl-2,3,4,5-tetrahydro-5 -Oxo-6-phenylpyrido [3,2-f]
[1,4] oxazepine-8-carboxamide (59) 4- [3,5-bis (trifluoromethyl) benzyl] -N, N-dimethyl-2,3,4,5-tetrahydro-5-oxo-6 -Phenylpyrido [3,2-
f] [1,4] oxazepine-8-carboxamide

(60) 4- [3,5-bis (trifluoromethyl) benzyl] -Nn-butyl-2,3,4
5-tetrahydro-5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine-8-carboxamide (61) 4- [3,5-bis (trifluoromethyl) benzyl] -2,3 , 4,5-Tetrahydro-5-oxo-6-phenyl-8-piperidinocarbonylpyrido [3,2-f] [1,4] oxazepine (62) 4- [3,5-bis (trifluoro Methyl) benzyl] -2,3,4,5-tetrahydro-8-morpholinocarbonyl-5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine (63) 4- [3,5- Bis (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-8- [1-
(4-Methylpiperazinyl) carbonyl] -5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine (64) 2,3,4,5-tetrahydro-5-oxo-
6-phenyl-4- (3,4,5-trimethoxybenzyl) pyrido “3,2-f] [1,4] oxazepine (65) 4- (3,4-dichlorobenzyl) -2,3
4,5-tetrahydro-5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine (66) 4- (3,4-dimethoxybenzyl) -2,
3,4,5-tetrahydro-5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine (67) 4-benzyl-2,3,4,5-tetrahydro-5-oxo-6 -Phenylpyrido [3,2-f]
[1,4] oxazepine (68) 2,3,4,5-tetrahydro-6-oxo-
7-phenyl-5- (3,4,5-trimethoxybenzyl) -6H-pyrido [2,3-b] [1,5] oxazosin (69) (S) -5-benzyl-2,3,4 , 5-Tetrahydro-3-methyl-6-oxo-7-phenyl-6
H-pyrido [2,3-b] [1,5] oxazosin

(70) (R) -5-benzyl-2,3,
4,5-tetrahydro-3-methyl-6-oxo-7-
Phenyl-6H-pyrido [2,3-b] [1,5] oxazosin (71) (S) -5- [3,5-bis (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro -3
-Methyl-6-oxo-7-phenyl-6H-pyrido [2,3-b] [1,5] oxazosin (72) (R) -5- [3,5-bis (trifluoromethyl) benzyl]- 2,3,4,5-tetrahydro-3
-Methyl-6-oxo-7-phenyl-6H-pyrido [2,3-b] [1,5] oxazosin (73) 7-benzyl-6,7,8,9,10,11-
Hexahydro-5- (4-methylphenyl) -6,13
-Dioxo-13H- [1,4] diazosino [2,1-
g] [1,7] Naphthyridine (74) (9R) -7-benzyl-6,7,8,9,1
0,11-hexahydro-9-methyl-5- (4-methylphenyl) -6,13-dioxo-13H- [1,
4] diazosino [2,1-g] [1,7] naphthyridine (75) (9S) -7-benzyl-6,7,8,9,1
0,11-hexahydro-9-methyl-5- (4-methylphenyl) -6,13-dioxo-13H- [1,
4] diazosino [2,1-g] [1,7] naphthyridine (76) (9R) -6,7,8,9,10,11-hexahydro-9-methyl-5- (4-methylphenyl)-
6,13-dioxo-7- (3,4,5-trimethoxybenzyl) -13H- [1,4] diazosino [2,1-
g] [1,7] naphthyridine (77) (9S) -6,7,8,9,10,11-hexahydro-9-methyl-5- (4-methylphenyl)-
6,13-dioxo-7- (3,4,5-trimethoxybenzyl) -13H- [1,4] diazosino [2,1-
g] [1,7] Naphthyridine (78) (9R) -7- (3,5-dimethoxybenzyl) -6,7,8,9,10,11-hexahydro-9
-Methyl-5- (4-methylphenyl) -6,13-dioxo-13H- [1,4] diazosino [2,1-g]
[1,7] Naphthyridine (79) 4-benzyl-2,3,4,5-tetrahydro-5-oxo-6- (4-methylphenyl) pyrido [3,2-f] [1,4] oxazepine

(80) 4- [3,5-bis (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-5-oxo-6- (4-methylphenyl) pyrido [3,2- f] [1,4] oxazepine (81) (S) -5-benzyl-2,3,4,5-tetrahydro-3-methyl-7- (4-methylphenyl)-
6-oxo-6H-pyrido [2,3-b] [1,5] oxazosin (82) (S) -5- [3,5-bis (trifluoromethyl) benzyl-2,3,4,5- Tetrahydro-3-
Methyl-7- (4-methylphenyl) -6-oxo-6
H-pyrido [2,3-b] [1,5] oxazosin (83) (9R) -7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,10,11 -Hexahydro-5- (4-hydroxymethylphenyl) -9-methyl-
6,13-dioxo-13H- [1,4] diazosino [2,1
-G] [1,7] naphthyridine (84) (9R) -7- [3,5-bis (trifluoromethyl) benzyl] -5- (4-formylphenyl) -6,7,
8,9,10,11-hexahydro-9-methyl-6,13
-Dioxo-13H- [1,4] diazosino [2,1-g]
[1,7] Naphthyridine (85) (9R) -7- [3,5-bis (trifluoromethyl) benzyl] -5- (4-formylphenyl) -6,7,
8,9,10,11-hexahydro-9-methyl-6,13
-Dioxo-13H- [1,4] diazosino [2,1-g]
[1,7] Naphthyridine (86) (9R) -7- [3,5-bis (trifluoromethyl) benzyl] -5- (4-carboxyphenyl) -6,7,
8,9,10,11-hexahydro-9-methyl-6,13
-Dioxo-13H- [1,4] diazosino [2,1-g]
[1,7] Naphthyridine (87) (9R) -7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,10,11-hexahydro-9-methyl-5- ( 4-methylphenyl) -6,13-
Dioxo-13H- [1,4] diazosino [2,1-g] [1,
7] Naphthyridine N-oxide (88) (9R) -7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,10,11-hexahydro-5- (4-hydroxymethyl Phenyl) -9-methyl-
6,13-dioxo-13H- [1,4] diazosino [2,1
-G] [1,7] naphthyridine N-oxide (89) (9R) -7- [3,5-bis (trifluoromethyl) benzyl] -5- (4-carboxyphenyl) -6,7,
8,9,10,11-hexahydro-9-methyl-6,13
-Dioxo-13H- [1,4] diazosino [2,1-g]
[1,7] naphthyridine N-oxide

(90) (9S)-[10, 10, 11, 1
1- ² H _4] -7- [3,5- bis (trifluoromethyl) benzyl] -8,9,10,11- tetrahydro -5
-(4-hydroxymethylphenyl) -9-methyl-7
H- [1,4] diazosino [2,1-g] [1,7] naphthyridine-6,13-dione (d ₄ form of the compound of the above (83)) (91) (9S)-[10,10 , 11,11− ² H ₄ ] −
7- [3,5-bis (trifluoromethyl) benzyl]
-5- (4-formylphenyl) -8,9,10,11-
Tetrahydro-9-methyl-7H-[l, 4] diazocino [2,1-g] [1,7] (d 4 body of the compound of the above (84)) naphthyridine 6,13-dione (92) (9S _{^{) - [10,10,11,11- 2 H 4]}} -
7- [3,5-bis (trifluoromethyl) benzyl]
-5- (4-carboxyphenyl) -8,9,10,11
-Tetrahydro-9-methyl-7H- [1,4] diazosino [2,1-g] [1,7] naphthyridine-6,13-
Dione (d ₄ body of the compound of the above (86)) (93) ( 9R) -7- [3,5- di (benzyloxy) benzyl] -6,7,8,9,10,11- hexahydro -9 -Methyl-5- (4-methylphenyl)-
6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine (94) (9R) -7- (3,5-dihydroxybenzyl) -6,7,8 , 9,10,11-Hexahydro-9
-Methyl-5- (4-methylphenyl) -6,13-dioxo-13H- [1,4] diazosino [2,1-g]
[1,7] Naphthyridine (95) (9R) -7- (3,5-diethoxybenzyl) -6,7,8,9,10,11-hexahydro-9
-Methyl-5- (4-methylphenyl) -6,13-dioxo-13H- [1,4] diazosino [2,1-g]
[1,7] Naphthyridine (96) (9R) -7- [3,5-di (1-methylethyloxy) benzyl] -6,7,8,9,10,11-
Hexahydro-9-methyl-5- (4-methylphenyl) -6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine (97) (9R) -7 -(3,5-dimethoxybenzyl) -6,7,8,9,10,11-hexahydro-9
-Methyl-6,13-dioxo-5-phenyl-13H
-[1,4] diazosino [2,1-g] [1,7] naphthyridine (98) (9R) -7- [3,5-bis (trifluoromethyl) benzyl] -5- (4-chlorophenyl) −
6,7,8,9,10,11-Hexahydro-9-methyl-6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine (99) (9R ) -7- [3,5-Bis (trifluoromethyl) benzyl] -5- (3,4-dichlorophenyl) -6,7,8,9,10,11-hexahydro-9
-Methyl-6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine

(100) (9R) -7- (3,5-dimethoxybenzyl) -5- (3,4-dichlorophenyl)
-6,7,8,9,10,11-Hexahydro-9-methyl-6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine (101) ( 9R) -7- (3,5-dimethylbenzyl) -6,7,8,9,10,11-hexahydro-9
-Methyl-5- (4-methylphenyl) -6,13-dioxo-13H- [1,4] diazosino [2,1-g]
[1,7] Naphthyridine (102) (9R) -7- (3,5-dichlorobenzyl) -6,7,8,9,10,11-hexahydro-9
-Methyl-5- (4-methylphenyl) -6,13-dioxo-13H- [1,4] diazosino [2,1-g]
[1,7] Naphthyridine (103) (9R) -5- (3,4-dichlorophenyl) -7- (3,5-dimethylbenzyl) -6,7,
8,9,10,11-hexahydro-9-methyl-6,6
13-dioxo-13H- [1,4] diazosino [2,
1-g] [1,7] naphthyridine (104) (9R) -7- (3,5-dimethoxybenzyl) -5- (4-fluorophenyl) -6,7,8,
9,10,11-hexahydro-9-methyl-6,13
-Dioxo-13H- [1,4] diazosino [2,1-
g] [1,7] Naphthyridine (105) (9R) -5- (4-chlorophenyl) -7
-(3,5-dimethoxybenzyl) -6,7,8,9,
10,11-Hexahydro-9-methyl-6,13-dioxo-13H- [1,4] diazosino [2,1-g]
[1,7] Naphthyridine (106) (9R) -7- [3,5-bis (trifluoromethyl) benzyl] -5- (4-fluorophenyl)
-6,7,8,9,10,11-Hexahydro-9-methyl-6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine (107) ( ±) -7- [3,5-bis (trifluoromethyl) benzyl] -9-ethyl-6,7,8,9,1
0,11-hexahydro-5- (4-methylphenyl)
-6,13-Dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine (108) (±) -7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,10,11-Hexahydro-9- (1-methylethyl) -5- (4-methylphenyl) -6,13-dioxo-13H- [1,
4] diazosino [2,1-g] [1,7] naphthyridine (109) (±) -5- (3,4-dichlorophenyl)
-7- (3,5-dimethoxybenzyl) -9-ethyl-
6,7,8,9,10,11-Hexahydro-6,13
-Dioxo-13H- [1,4] diazosino [2,1-
g] [1,7] naphthyridine (110) (±) -5- (3,4-dichlorophenyl)
-7- (3,5-dimethoxybenzyl) -6,7,8,
9,10,11-Hexahydro-9- (1-methylethyl) -6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine

The compounds or manufacturing methods Compound (I) and (Ia) or a salt thereof salt, Hei 9-26
It can be produced according to the method described in JP-A No. 3585 or JP-A No. 10-109989. The above (1)
Compounds (82) to (82) can be produced based on the description in Examples of JP-A-9-263585. The above (8
Compounds 3) to (92) can be produced based on the description in Examples of JP-A-10-109989. The compounds of the above (93) to (110) were prepared in Reference Examples 1 to 18 below.
2 (especially, Reference Examples 165 to 182).

The compounds (I) and (Ia) or salts thereof have low toxicity and are safe. Therefore, the compounds (I) and (Ia) or a salt thereof are useful as an antiemetic agent for mammals (eg, hamster, cat, ferret, dog, cow, sheep, monkey, human, etc.). Vomiting includes nausea, nausea and vomiting. Vomiting also includes acute vomiting, delayed vomiting and precursor vomiting. Compounds (I) and (Ia) or salts thereof may be used in radiation therapy for the treatment of cancer, poisons, toxins, metabolic disorders (eg, gastritis), sickness due to pregnancy, vertigo, motion sickness (eg, motion sickness, etc.) , Postoperative disease, gastrointestinal disorders, gastrointestinal motility, visceral pain (eg,
It is useful for suppressing vomiting caused by myocardial infarction, peritonitis), migraine, increased intercranial pressure, decreased intercranial pressure such as altitude sickness. In particular, it is extremely useful for suppressing emesis caused by the following drugs having an emetic action.

[Examples of Drugs with Emetic Effect] (1) Anticancer agents (antitumor agents): for example, cyclophosphamide,
Carmustine, lomustine, chlorambucil, busulfan, melphalan, mechlorethamine, vinca alkaloids (eg, etoposide, vinblastine, vincristine, etc.), ergot alkaloids (eg, ergot alkaloid, bromocriptine, etc.), fumagillin derivatives (eg,
(3R, 4S, 5S, 6R) -5-methoxy-4-
[(2R, 3R) -2-methyl-3- (3-methyl-2
-Butenyl) oxiranyl] -1-oxaspiro [2.
5] oct-6-yl (chloroacetyl) carbamate, etc.), methotrexate, emetine, mucin, cisplatin, dacarbazine, procarbazine, dactinomycin, doxorubicin, mitomycin-C, bleomycin, asparaginase, daunorubicin, floxuridine, cytarabine, fluorouracil , Mercaptopurine, mitotene, procarbazine, streptozocin, tamoxifen, thioguanine, busulfan, etc. (2) Antibiotics: for example, erythromycin or a derivative thereof (eg, erythromycin such as erythromycin A, B, C or D or a derivative thereof (eg, N -Demethyl-
N-isopropyl-8,9-anhydroerythromycin A-6,9-hemiacetal, etc.), clarithromycin, etc.), aminoglycosides (eg, spreptomycin, neomycin, gentamicin, etc.), actinomycin, adriamycin, cycloheximide, etc. (3) Morphine or a derivative or salt thereof (eg, an opioid analgesic such as morphine or a salt thereof, a drug for treating male erectile dysfunction (impotence) such as apomorphine or a salt thereof, and a drug for treating Parkinson's disease (dopamine D)
₂ receptor agonists)), (4) Other anti-asthmatic drugs such as antidiarrheal drugs such as opiate receptor agonists (eg, loperamide), antineoplastic drugs (eg, hydroxyurea), phosphodiesterase IV inhibitors (Eg, rolipram), histamine, pilocarpine, protoveratrine, levodopa, theophylline, hydroxycarbamide, thiotepa, carboplatin, epirubicin, etc. Drugs having an emetic action are obtained by combining several (preferably 2 to 3) of the above substances. Including drugs. Compounds (I) and (Ia) or a salt thereof are preferably used for vomiting caused by morphine or a derivative thereof or a salt thereof. As described above, apomorphine or a salt thereof is used as a therapeutic drug for male erectile dysfunction.In addition to psychogenic erectile dysfunction, male erectile dysfunction, diabetes, cardiovascular diseases such as heart disease, arteriosclerosis, elderly, hormonal It may be erectile dysfunction due to drugs, castration, prostatectomy, and the like. Therefore, apomorphine or a salt thereof is a hormonal drug (eg, leuprorelin acetate, etc.)
May be used in combination. As salts of morphine or its derivatives, pharmacologically acceptable salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and tartaric acid, bitartrate, citric acid,
Pharmaceutically acceptable salts with organic acids such as succinic acid and maleic acid. As a salt of morphine or apomorphine, a pharmaceutically acceptable acid addition salt with hydrochloric acid and sulfuric acid is preferably used.

The medicament of the present invention includes (1) a pharmaceutical composition containing compounds (I) and (Ia) or a salt thereof and a drug having an emetic action, and (2) a compound (I) and (Ia) or a salt thereof. And those separately prepared from a drug having an emetic action. The medicament of the present invention is obtained by mixing the compounds (I) and (Ia) or a salt thereof and the active ingredients of a drug having an emetic action separately or simultaneously, as it is, or with a pharmaceutically acceptable carrier or the like. Solid preparations such as powders, granules, tablets and capsules, syrups, emulsions, liquid preparations such as injections (including subcutaneous injections, intravenous injections, intramuscular injections, and infusions), sublingual tablets, buccals, troches , Microcapsules and the like, sustained release preparations, oral rapid disintegrants, and suppositories can be administered orally or parenterally. As the above-mentioned pharmaceutically acceptable carrier, various organic or inorganic carrier substances commonly used as pharmaceutical materials are used, and excipients, lubricants, binders, disintegrants in solid preparations; solvents in liquid preparations, dissolution aids Agents, suspending agents, isotonic agents, buffers, soothing agents and the like. If necessary, pharmaceutical additives such as preservatives, antioxidants, coloring agents, sweeteners and the like can also be used.

Preferable examples of the above-mentioned excipients include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid, calcium carbonate, calcium phosphate and the like. Preferred examples of the lubricant include:
Examples include stearic acid, magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferred examples of the binder include, for example, crystalline cellulose, sucrose, D-mannitol, dextrin,
Examples include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, arabic gum, gelatin and the like. Preferable examples of the disintegrant include starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, sodium carboxymethyl starch and the like. Preferred examples of the above-mentioned solvent include water for injection, physiological saline, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like. Preferable examples of the solubilizer include, for example, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Preferable examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; Examples include hydrophilic polymers such as alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose. Suitable examples of the tonicity agent include, for example, sodium chloride, glycerin, D-mannitol and the like. Preferable examples of the buffer include buffers such as phosphate, acetate, carbonate, and citrate. Preferred examples of the soothing agent include benzyl alcohol and the like. Preferable examples of the above preservative include, for example, p-hydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
Suitable examples of the antioxidant include, for example, sulfite, ascorbic acid and the like. In addition to the above-mentioned components, the medicament of the present invention further comprises an autonomic nervous response inhibitor, an anti-dopamine agent, a serotonin antagonist [eg, ondansetron ( Ondansetron (Zofran)) or its sustained release formulation (Zofran Zydis), granisetron (gran
isetron (Kytril)), Azasetron (Seroton
e)), Ramosetron (Nasea), metoclopramide (Primperan) or its sustained-release preparation (Pramidin), tropisetron (tropis)
etron (Novoban)), Mosapride (Gasmoti
n)), and Dolasetron (Anemet).
In addition, palonosetron (RS-42358-19
7)), Itasetron (U-98079A), Indisetron (Indisetron (N-3389)), KAE-393, R-zacoprid
(SL-920241), Lelysetron (F-0930-RS), E-3620, Ro-9
3777 etc.), histamine antagonist, parasympathetic agent, antiemetic (eg, metopimazine, trimethbenzamide, benzquinamine hydrochloride, diphenidol hydrochloride, etc.), carbohydrate steroids [eg, cortisone acetate (Cortone), hydrocortisone (Cortril, Hydrocorton) ) Or its sodium phosphate salt (Hydrocortisone soluble), dexamethasone (Cors
on, decaderon, Decadron S) or its acetate (Decadron A aqueous suspension injection etc.), sodium phosphate (Decadron, Decadron injection, Decadron S) or sodium sulfate (Dexa-Sheroson injection, Dexaron)
Sheroson Note B), Betamethasone (Rinderon, Betonela)
n) or its sodium phosphate (Rinderon) or acetate (Rinderone suspension), prednisolone (Predozolone)
nine, prednisolone tablets) or its acetate (Pred
onine soluble) or sodium phosphate (dogilone injection), butyl acetate (cordelkoton) or sodium succinate (water-soluble prednin), methylprednisolone (Medrol) or its acetate (Depo-Med)
rol) or sodium succinate (Sol-Medrol),
Corticosteroids such as triamcinolone acetate (Kenacort) and other steroids having glucocorticoid activity or salts thereof), tranquilizers such as chlorpromazine, and tranquilizers. In particular, serotonin antagonists such as ondansetron and / or
Or the use of saccharide steroids such as dexamethasone or its acetate, sodium phosphate or sodium sulfate in combination may enhance the antiemetic effect of compounds (I) and (Ia) or its salts, and is preferably used. Is done. That is, the medicine of the present invention comprises (1) a compound
A medicine comprising a combination of (I) and (Ia) or a salt thereof, a drug having an emetic action and a serotonin antagonist, (2)
Compounds (I) and (Ia) or a salt thereof, a drug having a combination with a drug having an emetic action and a carbohydrate steroid,
(3) Drugs comprising a combination of compounds (I) and (Ia) or salts thereof, a drug having an emetic action, a serotonin antagonist and a carbohydrate steroid. Such a combination is preferably used when suppressing vomiting caused by an anticancer drug such as cisplatin. These preparations can be produced by a method known per se which is generally used in the preparation process.

Compounds (I) and (Ia) or salts thereof and a drug having an emetic effect used in the present invention may be a dispersant (eg, Tween 80 (manufactured by Atlas Powder Co., USA), HCO 6
0 (manufactured by Nikko Chemicals), polyethylene glycol, carboxymethylcellulose, sodium alginate, hydroxypropylmethylcellulose, dextrin, etc., stabilizers (eg, ascorbic acid, sodium pyrosulfite, etc.), surfactants (eg, polysorbate 80, macrogol) ), A solvent (eg, glycerin, ethanol, etc.), a buffer (eg, phosphoric acid and its alkali metal salt, citric acid and its alkali metal salt, etc.), a tonicity agent (eg, sodium chloride, potassium chloride, Mannitol, sorbitol, glucose, etc.), pH adjusters (eg, hydrochloric acid, sodium hydroxide, etc.), preservatives (eg, ethyl paraoxybenzoate, benzoic acid, methylparaben, propylparaben, benzyl alcohol, etc.), solubilizers (eg, Concentrated glycerin, meglumine, etc.), dissolution aid (Eg, propylene glycol, sucrose, etc.) and soothing agents (eg, glucose, benzyl alcohol, etc.) for aqueous injection, or olive oil, sesame oil, cottonseed oil, vegetable oils such as corn oil, solubilizing agents such as propylene glycol Into an oily injection by dissolving, suspending or emulsifying the mixture to give an injection. In order to prepare a preparation for oral administration, the compounds (I) and (Ia) used in the present invention or a salt thereof or a drug having an emetic action can be prepared according to a method known per se, for example, an excipient (eg, lactose, sucrose, starch, etc.) ), Disintegrants (eg, starch, calcium carbonate, etc.), binders (eg, starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, etc.) or lubricants (eg, talc, magnesium stearate, polyethylene) Glycol 6000 etc.) and the like, and then compression-molded, if necessary, and then coated by a method known per se for the purpose of taste masking, enteric coating or long-lasting, to give a preparation for oral administration. Examples of the coating agent include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (Rohm) Manufactured by Germany, methacrylic acid / acrylic acid copolymer) and coloring matter (eg, red iron oxide, titanium dioxide, etc.). Preparations for oral administration are immediate release preparations,
Any of sustained-release preparations may be used.

For example, in order to prepare a suppository, the compounds (I) and (Ia) or a salt thereof or a drug having an emetic effect used in the present invention may be oily or aqueous solid or semi-solid according to a method known per se. Alternatively, it can be a liquid suppository. Examples of the oily base used in the composition include glycerides of higher fatty acids (eg, cocoa butter, witepsols (manufactured by Dynamite Nobel, Germany), etc.) and intermediate fatty acids (eg, miglyols (manufactured by Dynamite Nobel, Germany)) Or vegetable oils (eg, sesame oil, soybean oil,
Cottonseed oil). Examples of the aqueous base include polyethylene glycols and propylene glycol, and examples of the aqueous gel base include natural gums, cellulose derivatives, vinyl polymers, and acrylic acid polymers. Examples of the sustained release preparation include sustained release microcapsules. A method known per se can be used to obtain sustained release microcapsules. For example, it is preferable to administer the composition by shaping it into a sustained release preparation shown in the following [2].

The compounds (I) and (Ia) or a salt thereof may be formed into a preparation for oral administration such as solid preparation (eg, powder, granule, tablet, capsule) or a preparation for rectal administration such as suppository. It is preferred to mold. In particular, preparations for oral administration are preferred. The drug having an emetic action can be in the above-mentioned dosage form according to the type of the drug. When the drug having an emetic action is morphine or its derivative or a salt thereof, it is used as an injection or an immediate release preparation. (Eg, powders, granules,
Tablets) or sustained-release preparations (eg, microcapsule sustained-release preparations), sublingual tablets, buccals, oral disintegrants, and lozenges are preferably used for oral administration. More specifically, when the drug having an emetic action is morphine or a salt thereof, it is used as an injection, or a sustained-release preparation such as an immediate-release preparation (eg, powder, granule, tablet) or a microcapsule. And the like. When the drug having an emetic action is apomorphine or a salt thereof, it is preferable to prepare a preparation for oral administration such as a sublingual tablet, buccal, and a quick disintegrating agent in the oral cavity. When the above-mentioned serotonin antagonist and / or glucosteroid is used in combination with the medicament of the present invention, the medicament of the present invention may be separately formulated with the serotonin antagonist or glucosteroid, and may be used in combination. You may use together as a pharmaceutical composition containing an antagonist and a carbohydrate steroid. You may use together as a pharmaceutical composition of the following. A pharmaceutical composition comprising Compounds (I) and (Ia) or a salt thereof, and a serotonin antagonist. A pharmaceutical composition comprising Compounds (I) and (Ia) or a salt thereof, and a carbohydrate steroid. A pharmaceutical composition comprising Compounds (I) and (Ia) or a salt thereof, a serotonin antagonist and a carbohydrate steroid. Each of the above-mentioned pharmaceutical compositions may further contain a compound having an emetic action. Serotonin antagonists and / or carbohydrate steroids are compounds (I) and
In the same manner as in the case of (Ia) or a salt thereof or a drug having an emetic action, preparations for oral administration such as tablets, powders, granules and capsules, injections (subcutaneous injection, intravenous injection, muscle It is preferable to use it by shaping it into preparations such as internal injection and infusion method, suppositories and patches.

The following are [1] Injection and its preparation when morphine or a salt thereof is used as a drug having an emetic action, and [2] Slow release of a drug having an emetic action (eg, morphine or a salt thereof). Formulations or immediate-release preparations and their preparation, [3] sublingual tablets, buccal or intraoral fast disintegrating agents and their preparation when apomorphine or a salt thereof is used as an emetic drug.

[1] Morphine solution for injection and preparation thereof Morphine solution for injection obtained by dissolving morphine or a salt thereof in water is preferable. The morphine solution for injection may contain benzoate and / or salicylate. The morphine solution for injection is obtained by dissolving both morphine or a salt thereof and, if desired, benzoate and / or salicylate in water. Examples of the salts of benzoic acid and salicylic acid include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, ammonium salts, meglumine salts, and organic acid salts such as tromethamol. The concentration of morphine or a salt thereof in the morphine solution for injection is 0.5-5.
0 w / v%, preferably about 3 to 20 w / v%.
The concentration of the benzoate and / or salicylate is 0.5 to 50 w / v%, preferably 3 to 20 w / v%.

The present agent also contains additives generally used in morphine solutions for injection, such as stabilizers (ascorbic acid,
Sodium pyrosulfite, etc.), surfactants (polysorbate 80, macrogol, etc.), solvents (glycerin, ethanol, etc.), buffers (phosphoric acid and its alkali metal salts,
Citric acid and its alkali metal salts), tonicity agent (sodium chloride, potassium chloride, etc.), dispersant (hydroxypropylmethylcellulose, dextrin), pH regulator (hydrochloric acid, sodium hydroxide, etc.), preservative (paraoxybenzoate) Ethyl acid, benzoic acid, etc.), dissolving agent (concentrated glycerin,
Meglumine, etc.), dissolution aids (propylene glycol,
White sugar, etc.), soothing agents (glucose, benzyl alcohol, etc.) and the like can be appropriately compounded. These additives are generally blended in a ratio usually used for an injection.

The morphine solution for injection is adjusted to 2 to 12, preferably 2.5 to 8.0, by adding a pH adjuster. The morphine solution for injection contains both morphine or a salt thereof and optionally benzoate and / or salicylate,
Further, it can be obtained by dissolving the above additives in water as required. These dissolutions may be performed in any order, and can be appropriately performed in the same manner as in the conventional method for producing an injection. The morphine solution for injection is preferably heated, and can be used as an injection by performing, for example, sterilization by filtration or high-pressure heat sterilization in the same manner as an ordinary injection. The aqueous morphine solution for injection is preferably subjected to high-pressure heat sterilization at 100 ° C. to 121 ° C. for 5 minutes to 30 minutes. Further, a formulation having antimicrobial properties of the solution may be used so that the formulation can be used as a multiple-dose formulation.

[2] Sustained-release preparation or immediate-release preparation and preparation thereof A core containing a drug (eg, morphine or a salt thereof) is coated with a coating agent such as a water-insoluble substance or a swellable polymer, if desired. Preferred are sustained release formulations. In particular, when the drug is morphine or a salt thereof, a once-daily sustained release preparation for oral administration is particularly preferable.

Examples of the water-insoluble substance used in the coating agent include cellulose ethers such as ethyl cellulose and butyl cellulose; cellulose esters such as cellulose acetate and cellulose propionate; polyvinyl esters such as polyvinyl acetate and polyvinyl butyrate; Acrylic acid / methacrylic acid copolymer,
Methyl methacrylate copolymer, ethoxyethyl methacrylate / cinnamoethyl methacrylate / aminoalkyl methacrylate copolymer, polyacrylic acid, polymethacrylic acid, methacrylic acid alkylamide copolymer, poly (methyl methacrylate), polymethacrylate, polymethacryl Amides, aminoalkyl methacrylate copolymers, poly (methacrylic anhydride), glycidyl methacrylate copolymers, especially Eudragit RS
-100, RL-100, RS-30D, RL-30
D, RL-PO, RS-PO (ethyl acrylate / methyl methacrylate / trimethyl methacrylate / ammonium ethyl copolymer), Eudragit NE-3
Acrylic polymers such as Eudragits (ROHM Pharma Co., Ltd.) such as OD (methyl methacrylate / ethyl acrylate copolymer), and hardened oils such as hardened castor oil (eg, Lovely Wax (Freund Corporation)). Examples include waxes such as carnauba wax, fatty acid glycerin ester, and paraffin, and polyglycerin fatty acid ester.

As the swellable polymer, a polymer having an acidic dissociating group and exhibiting pH-dependent swelling is preferable. The swelling polymer swells little in an acidic region such as the stomach and swells in a neutral region such as the small and large intestine. Is preferred. Having such an acidic dissociating group, pH
Examples of polymers exhibiting a dependent swelling include, for example, Carbomer 934P, 940, 941, 974P,
980, 1342, etc., polycarbophi
l), calcium polycarbophil (carcium polycarbo)
phil) (all manufactured by BF Goodrich), and Hibiswako 103, 104, 105, 304 (all manufactured by Wako Pure Chemical Industries, Ltd.).

The coating agent used in the sustained-release preparation may further contain a hydrophilic substance. As the hydrophilic substance,
For example, pullulan, dextrin, polysaccharides which may have a sulfate group such as alkali metal alginate, hydroxypropylcellulose, hydroxypropylmethylcellulose, polysaccharides having a hydroxyalkyl group or a carboxyalkyl group such as sodium carboxymethylcellulose, methylcellulose, Polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol and the like can be mentioned. The content of the water-insoluble substance in the coating agent of the sustained-release preparation is about 30 to about 90% (w / w), preferably about 35 to about 80% (w / w), and more preferably about 40 to 75% (w / w). w / w), the content of swellable polymer is about 3 to about 30% (w / w), preferably about 3 to about 15% (w / w). The coating agent may further comprise a hydrophilic substance, in which case the content of the hydrophilic substance in the coating agent is about 50% (w / w) or less, preferably about 5 to about 40%.
% (W / w), more preferably about 5 to about 35% (w / w). Here, the above% (w / w) is calculated from the coating solution to the solvent (eg,
%, Based on the coating composition excluding water, lower alcohols such as methanol and ethanol).

The sustained-release preparation is prepared by preparing a nucleus containing a drug as shown below and then dissolving the obtained nucleus by heating or dissolving or dispersing a water-insoluble substance or a swellable polymer in a solvent. It is manufactured by coating with a chemical solution. I. Preparation of core containing drug. The form of the nucleus containing the drug to be coated with the coating agent (hereinafter, may be simply referred to as the nucleus) is not particularly limited, but is preferably formed into particles such as granules or fine granules. When the core is granules or fine granules, the average particle size is preferably about 150 to 2,000 μm, more preferably about 50 to 2,000 μm.
0 to about 1,400 μm. The nucleus can be prepared by a usual production method. For example, a drug is mixed with an appropriate excipient, binder, disintegrant, lubricant, stabilizer and the like, and is prepared by a wet extrusion granulation method, a fluidized bed granulation method and the like. The drug content of the nucleus is about 0.5 to about 95% (w /
w), preferably from about 5.0 to about 80% (w / w), more preferably from about 30 to about 70% (w / w). As the excipient contained in the core, for example, sugars such as sucrose, lactose, mannitol and glucose, starch, crystalline cellulose, calcium phosphate, corn starch and the like are used. Among them, crystalline cellulose and corn starch are preferred. As the binder, for example, polyvinyl alcohol, hydroxypropyl cellulose, polyethylene glycol, polyvinyl pyrrolidone, Pluronic F68, gum arabic, gelatin, starch and the like are used. As a disintegrant, for example, carboxymethylcellulose calcium
(ECG505), croscarmellose sodium (Ac-Di-So
l), cross-linked polyvinyl pyrrolidone (crospovidone),
Low-substituted hydroxypropylcellulose (L-HPC) or the like is used. Among them, hydroxypropylcellulose, polyvinylpyrrolidone and low-substituted hydroxypropylcellulose are preferred. For example, talc, magnesium stearate and inorganic salts thereof are used as a lubricant and an anti-agglomeration agent, and polyethylene glycol is used as a lubricant. Acids such as tartaric acid, citric acid, succinic acid, fumaric acid and maleic acid are used as stabilizers.

The nucleus may be formed by spraying a binder dissolved in a suitable solvent such as water or a lower alcohol (eg, methanol, ethanol, etc.) on the inert carrier particles serving as the core of the nucleus, in addition to the above-mentioned production method. It can also be prepared by a tumbling granulation method, a pan coating method, a fluidized bed coating method or a melt granulation method in which a small amount of a drug or a mixture thereof with an excipient, a lubricant and the like is added. As the inert carrier particles, for example, those made of sucrose, lactose, starch, crystalline cellulose, and waxes can be used, and those having an average particle diameter of about 100 μm to about 1,500 μm are preferable. In order to separate the drug contained in the nucleus from the coating agent, the surface of the nucleus may be coated with a protective agent. As the protective agent, for example, the above-mentioned hydrophilic substance, water-insoluble substance and the like are used. As the protective agent, polyethylene glycol or a polysaccharide having a hydroxyalkyl group or a carboxyalkyl group is preferably used, and hydroxypropylmethylcellulose and hydroxypropylcellulose are more preferably used. The protective agent may contain, as a stabilizer, an acid such as tartaric acid, citric acid, succinic acid, fumaric acid, and maleic acid, and a lubricant such as talc. When a protective agent is used, its coverage is about 1 to about 15% (w /
w), preferably about 1 to about 10% (w / w), more preferably about 2 to about 8% (w / w). The protective agent can be coated by a usual coating method. Specifically, the protective agent can be coated by spray coating the nucleus by, for example, a fluidized bed coating method or a pan coating method.

II. Coating of nucleus with coating agent The nucleus obtained in I is coated with a coating agent solution in which the water-insoluble substance, the pH-dependent swellable polymer, and the hydrophilic substance are dissolved by heating or dissolved or dispersed in a solvent. Produces a sustained-release preparation. Examples of the method of coating the nucleus with a coating agent solution include a spray coating method. The composition ratio of the water-insoluble substance, the swellable polymer or the hydrophilic substance in the coating agent solution is appropriately selected so that the content of each component in the coating becomes the above-mentioned content. The coating amount of the coating agent is about 1 to about 90% (w / w), preferably about 5 to about 50% (w / w), more preferably, about the core (not including the protective agent). About 5 to 35% (w / w).

As the solvent for the coating solution, water or an organic solvent can be used alone or in a mixture of both. The mixing ratio of water and organic solvent (water / organic solvent: weight ratio) when using the mixed solution can be changed in the range of 1 to 100%, and is preferably 1 to about 30%. The organic solvent is not particularly limited as long as it dissolves a water-insoluble substance. Methylene chloride or the like is used. Of these, lower alcohols are preferred, and ethyl alcohol and isopropyl alcohol are particularly preferred. Water and a mixture of water and an organic solvent are preferably used as a solvent for the coating agent. At this time, if necessary, an acid such as tartaric acid, citric acid, succinic acid, fumaric acid, or maleic acid may be added to the coating agent solution for stabilizing the coating agent solution. The operation in the case of coating by spray coating can be carried out by a usual coating method. Specifically, the operation is carried out by spray-coating a coating agent solution onto a core by, for example, a fluidized bed coating method, a pan coating method or the like. Can be. At this time, if necessary, talc, titanium oxide, magnesium stearate, calcium stearate, light anhydrous silicic acid, etc. as a lubricant,
Glycerin fatty acid ester, hydrogenated castor oil, triethyl citrate, cetyl alcohol, stearyl alcohol and the like may be added as a plasticizer. After coating with a coating agent, an antistatic agent such as talc may be mixed as necessary.

The immediate-release preparations may be liquid (solutions, suspensions, emulsions, etc.) or solids (particles, pills, tablets, etc.).
It may be. Parenteral preparations such as oral preparations and injections are used, but oral preparations are preferred. The quick-release preparation may generally contain, in addition to the drug as the active ingredient, carriers, additives and excipients (hereinafter sometimes abbreviated as excipients) commonly used in the pharmaceutical field. . The formulation excipient used is not particularly limited as long as it is a commonly used excipient. For example, excipients for oral solid preparations include lactose, starch, corn starch, crystalline cellulose (Abicel PH101, manufactured by Asahi Kasei Corporation), powdered sugar,
Granular sugar, mannitol, light anhydrous silicic acid, magnesium carbonate, calcium carbonate, L-cysteine and the like are preferable, and corn starch and mannitol are preferable. These excipients can be used alone or in combination of two or more. The content of the excipient is, for example, about 4.5 to about 99.4 w / w based on the whole amount of the immediate release preparation.
%, Preferably from about 20 to about 98.5 w / w%, more preferably from about 30 to about 97 w / w%. The content of the drug in the immediate release preparation is about 0.
It can be appropriately selected from the range of 5 to about 95%, preferably about 1 to about 60%. When the immediate-release preparation is an oral solid preparation, it usually contains a disintegrant in addition to the above components. Examples of such disintegrants include carboxymethylcellulose calcium (Gotoku Yakuhin, ECG-505) and croscarmellose sodium (for example, Asahi Kasei Corporation)
Acdizol), crospovidone (eg, BASF Corp., Kollidon CL), low-substituted hydroxypropylcellulose (Shin-Etsu Chemical Co., Ltd.), carboxymethyl starch (Matsuya Chemical Co., Ltd.), carboxymethyl starch sodium (Kimura Sangyo, extract Protab), partially pregelatinized starch (PCS, manufactured by Asahi Kasei Corporation) and the like are used. The disintegrant can be used alone or in combination of two or more.The amount of the disintegrant is determined by the type and amount of the drug used, the release It is appropriately selected depending on the formulation design and the like, but is, for example, about 0.05 to about 30 w / w%, preferably about 0.5 to about 15 w / w, based on the total amount of the immediate-release preparation. It is.

When the immediate-release preparation is an oral solid preparation, in the case of an oral solid preparation, in addition to the above-mentioned composition, if necessary, conventional additives in the solid preparation may be further contained. Examples of such additives include binders (eg, sucrose, gelatin, gum arabic powder, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose,
Polyvinylpyrrolidone, pullulan, dextrin, etc.), lubricants (eg, polyethylene glycol, magnesium stearate, talc, light anhydrous silicic acid (eg, Aerosil (Nippon Aerosil)), surfactants (eg, anions such as sodium alkyl sulfate) Surfactants, non-ionic surfactants such as polyoxyethylene fatty acid esters and polyoxyethylene sorbitan fatty acid esters, and polyoxyethylene castor oil derivatives, etc.), coloring agents (for example, tar dyes, caramel, red iron oxide, titanium oxide) Riboflavins), if necessary, bridging agents (eg, sweeteners, flavors, etc.), adsorbents, preservatives,
Wetting agents, antistatic agents and the like are used. Further, an organic acid such as tartaric acid, citric acid, succinic acid and fumaric acid may be added as a stabilizer. As the binder, hydroxypropylcellulose, polyethylene glycol, polyvinylpyrrolidone and the like are preferably used. The immediate-release preparation can be prepared by mixing the above-mentioned components, kneading and molding as necessary, based on a usual preparation production technique. The mixing is performed by a generally used method such as mixing and kneading. Specifically, for example, when the rapid release preparation is formed into particles, a vertical granulator, a universal kneading machine (manufactured by Hata Iron Works), a fluid It can be prepared by mixing using a layer granulator FD-5S (manufactured by Powrex) or the like, and then granulating by wet extrusion granulation, fluidized bed granulation, or the like.

The thus obtained immediate-release preparation and sustained-release preparation can be prepared as they are or separately, or separately and appropriately, together with preparation excipients, etc. by a conventional method, and then simultaneously or at an arbitrary administration interval. It may be a formulation to be administered in combination,
In addition, both may be formulated into one oral administration preparation (eg, granules, fine granules, tablets, capsules, etc.) as they are or as appropriate together with excipients. Both preparations may be made into granules or fine granules and filled into the same capsule or the like to prepare a preparation for oral administration.

[3] Apomorphine sublingual tablet, buccal or buccal disintegrating agent and its preparation The sublingual tablet, buccal preparation, buccal disintegrating agent may be a solid preparation such as a tablet, or a tablet adhered to oral mucosa. (the film)
It may be. As the apomorphine sublingual tablet, buccal or intraoral quick disintegrant, a preparation containing apomorphine or a salt thereof and an excipient is preferable. Also, lubricants,
An auxiliary agent such as a tonicity agent, a hydrophilic carrier, a water-dispersible polymer, or a stabilizer may be contained. Further, β-cyclodextrin or a β-cyclodextrin derivative (eg, hydroxypropyl-β-cyclodextrin or the like) may be contained to facilitate absorption and increase the bioavailability. The excipients include lactose, sucrose, D-
Mannitol, starch, crystalline cellulose, light anhydrous silicic acid and the like can be mentioned. Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica, and the like. Particularly, magnesium stearate and colloidal silica are preferable. Examples of the tonicity agent include sodium chloride, glucose, fructose, mannitol, sorbitol, lactose, saccharose, glycerin, urea and the like, with mannitol being particularly preferred. Examples of the hydrophilic carrier include swellable hydrophilic carriers such as crystalline cellulose, ethyl cellulose, crosslinkable polyvinylpyrrolidone, light anhydrous silicic acid, silicic acid, dicalcium phosphate, and calcium carbonate. In particular, crystalline cellulose (eg, microcrystalline cellulose, etc.) Is preferred. Water-dispersible polymers include gums (eg, tragacanth gum, acacia gum, guar gum), alginates (eg, sodium alginate), cellulose derivatives (eg, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose), gelatin , Water-soluble starch, polyacrylic acid (eg, carbomer), polymethacrylic acid,
Examples thereof include polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone, polycarbophil, and ascorbic acid palmitate, and preferred are hydroxypropylmethylcellulose, polyacrylic acid, alginate, gelatin, carboxymethylcellulose, polyvinylpyrrolidone, and polyethylene glycol. Particularly, hydroxypropyl methylcellulose is preferable. Stabilizers include cysteine, thiosorbitol, tartaric acid,
Examples thereof include citric acid, sodium carbonate, ascorbic acid, glycine, and sodium sulfite, and citric acid and ascorbic acid are particularly preferable.

The apomorphine sublingual tablet, buccal or intraoral quick disintegrating agent can be produced by mixing apomorphine or a salt thereof and an excipient by a method known per se. Further, if necessary, the above-mentioned auxiliary agents such as a lubricant, a tonicity agent, a hydrophilic carrier, a water-dispersible polymer, a stabilizer, a coloring agent, a sweetening agent and a preservative may be mixed. The above components are mixed at the same time or with a time lag, and then press-molded to give sublingual tablets, buccal tablets or rapidly disintegrating tablets in the oral cavity. In order to obtain an appropriate hardness, it may be produced by humidifying / wetting a solvent such as water or alcohol as needed before and after the tableting process, molding, and then drying. When molded into a mucoadhesive tablet (film), it is obtained by dissolving apomorphine or a salt thereof and the above-mentioned water-dispersible polymer (preferably, hydroxypropylcellulose, hydroxypropylmethylcellulose), an excipient and the like in a solvent such as water. The solution is cast into a film. Further, additives such as a plasticizer, a stabilizer, an antioxidant, a preservative, a coloring agent, a buffer, and a sweetener may be added. Contains glycols such as polyethylene glycol and propylene glycol to provide appropriate elasticity to the film, and contains bioadhesive polymers (eg, polycarbophil, carbopol) to enhance the adhesion of the film to the mucosal lining of the oral cavity May be. The casting is carried out by pouring the solution on the non-adhesive surface, and applying a uniform thickness (preferably 10
This is accomplished by spreading it to about 1000 microns) and then drying the solution to form a film. The film thus formed may be dried at room temperature or under heating, and cut into a desired surface area. Preferred intraoral quick disintegrating agents include solid rapid diffusion administration agents comprising a network of apomorphine or a salt thereof and a water-soluble or water-diffusible carrier inactive with apomorphine or a salt thereof. The network can be obtained by sublimating the solvent from the solid composition comprising a solution of apomorphine or a salt thereof in a suitable solvent. It is preferable that the composition of the intraoral quick disintegrating agent contains a matrix forming agent and a secondary component in addition to apomorphine or a salt thereof. Examples of the matrix-forming agent include gelatins, dextrins, and animal or vegetable proteins such as soybean, wheat, and psyllium seed proteins; gums such as gum arabic, guar gum, agar and xanthan; polysaccharides Alginic acids; carboxymethyl celluloses; carrageenans; dextrans; pectins; synthetic polymers such as polyvinylpyrrolidone; and substances derived from gelatin-gum arabic complex. Furthermore, sugars such as mannitol, dextrose, lactose, galactose and trehalose; cyclic sugars such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride and aluminum silicate; glycine, L-alanine, L-aspartic acid, L- It includes amino acids having 2 to 12 carbon atoms such as glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine and L-phenylalanine. One or more of the matrix-forming agents can be introduced into a solution or suspension before solidification. Such a matrix-forming agent may be present in addition to the surfactant, or may be present without the surfactant. The matrix-forming agent, in addition to forming the matrix, can help maintain the apomorphine or salt thereof in a diffuse state in the solution or suspension. Preservative,
Secondary components such as antioxidants, surfactants, thickeners, colorants, pH adjusters, flavors, sweeteners or taste masking agents may be included in the composition. Suitable colorants include red, black and yellow iron oxides and FD & C dyes such as FD & C Blue 2 and FD & C Red 40 from Ellis & Everard. Suitable flavors include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, terry and grape flavors and combinations thereof. Suitable pH adjusters include citric, tartaric, phosphoric, hydrochloric and maleic acids. Suitable sweeteners include aspartame, acesulfame K and thaumatin. Suitable taste masking agents include sodium bicarbonate, ion exchange resins, cyclodextrin inclusion compounds, adsorbate materials, and microencapsulated apomorphine.
The formulation usually contains about 0.1 to about 50% by weight, preferably about 0.1 to about 30% by weight of apomorphine or a salt thereof, for about 1 minute to about 60 minutes, preferably about 1 minute to about 1
Formulation capable of dissolving 90% or more of apomorphine or its salt (in water) for 5 minutes, more preferably for about 2 minutes to about 5 minutes (see above, sublingual tablets, buccal, etc.)
Also, a rapid disintegrating agent in the oral cavity that disintegrates within 1 to 60 seconds, preferably within 1 to 30 seconds, and more preferably within 1 to 10 seconds after being placed in the oral cavity is preferable.

The content of the above-mentioned excipient in the whole preparation is as follows:
It is about 10 to about 99% by weight, preferably about 30 to about 90% by weight. The content of β-cyclodextrin or β-cyclodextrin derivative in the whole preparation is from 0 to about 30.
% By weight. The content of the lubricant in the whole preparation is about 0.01 to about 10% by weight, preferably about 1 to about 5% by weight.
It is. The content of the tonicity agent in the whole preparation is about 0.1.
1 to about 90% by weight, preferably about 10 to about 70% by weight
It is. The content of the hydrophilic carrier in the whole preparation is about 0.5.
It is 1 to about 50% by weight, preferably about 10 to about 30% by weight. The content of the water-dispersible polymer with respect to the whole preparation is
It is about 0.1 to about 30% by weight, preferably about 10 to about 25% by weight. The content of the stabilizer in the whole preparation is about 0.1 to about 10% by weight, preferably about 1 to about 5% by weight. The above preparations may further contain additives such as coloring agents, sweetening agents, preservatives and the like, if necessary. The apomorphine preparation may be used in combination with a phosphodiesterase V inhibitor such as sildenafil, a prostaglandin preparation such as bathomax, an α-blocker preparation such as zonagen, etc. for enhancing the therapeutic effect of apomorphine or a salt thereof on male erectile dysfunction. Also, if the patient's male erectile dysfunction is due to diabetes or the like, the apomorphine preparation is used in combination with a diabetic drug such as a sulfonylurea drug such as pioglitazone, troglitazone, rosiglitazone, insulin, metformin, or a biguanide drug. May be effective.

The daily dose of the medicament of the present invention includes the degree of symptoms, age, sex, body weight, sensitivity difference of administration subject, timing of administration, interval, nature of pharmaceutical preparation, preparation, kind, kind of active ingredient, etc. It differs depending on the type, and is not particularly limited. The dose of the compounds (I) and (Ia) or a salt thereof is not particularly limited within a range that does not cause a problem of side effects, and is usually about 0.005 per kg body weight of a mammal by oral administration.
The dose is about 100 to 100 mg, preferably about 0.05 to 50 mg, more preferably about 0.2 to 30 mg, which is usually administered once to three times a day.

The amount of the drug having an emetic effect can be set to any value as long as side effects do not become a problem. The daily dose as a drug having an emetic effect depends on the degree of symptoms, age, gender, weight, sensitivity difference of administration subject, timing of administration, interval, nature of pharmaceutical preparation, preparation, type, type of active ingredient, etc. Differently, although not particularly limited, the amount of the drug is usually, for example, about 0.001 to 2000 mg, preferably about 0.2 mg / kg body weight of a mammal by oral administration.
01-500 mg, more preferably about 0.1-10
The dose is about 0 mg, usually administered in 1 to 4 times a day. In the case where the drug having an emetic action is morphine or a salt thereof, for example, in the case of a once-a-day preparation, in the case of prevention and treatment of pain in cancer patients and the like, the daily (one-time) dose of morphine or a salt thereof per patient Is usually about 4-1000m
g, preferably about 20-600 mg, more preferably about 50-500 mg. However, as long as safety can be ensured, it is also possible to administer beyond the above range as needed. When the drug having an emetic effect is apomorphine or a salt thereof, for example, in the treatment of impotence or male erectile dysfunction, a single dose is usually about 0.01 mg to 300 mg per kg body weight of a mammal by oral administration, preferably About 0.01 mg to 100 mg, more preferably,
It is about 0.01 mg to 30 mg. Apomorphine or a salt thereof is preferably administered about 5 to 60 minutes, preferably about 15 to 20 minutes prior to sexual activity, to maintain predetermined apomorphine circulating serum and midbrain tissue levels during sexual activity (eg, intercourse). Oral administration (preferably sublingual administration) is preferred. When the medicament of the present invention is used in combination with a serotonin antagonist and / or a carbohydrate steroid, the amount of the serotonin antagonist and / or the carbohydrate steroid can be set to any value as long as side effects are not problematic. It is. Daily doses of serotonin antagonists and carbohydrate steroids are usually 1k for mammals, respectively.
about 0.005 to 50 mg, preferably about 0.01 to 30 mg, more preferably 0.01 to 10 m per g body weight
g, which is usually administered once to three times a day.

When the medicament of the present invention is administered, it may be administered at the same time, but a drug having an emetic effect is administered first, and before or after the onset of vomiting, Compounds (I) and (I)
a) or a salt thereof may be administered, or the compounds (I) and (Ia) or a salt thereof may be administered first, followed by administration of a drug having an emetic action. In the case of administration with a time lag, the time lag varies depending on the active ingredient to be administered, the dosage form, and the administration method. For example, when a drug having an emetic action is administered first, 1 minute after administration of the compound having an emetic action,
The method includes administering the compounds (I) and (Ia) or a salt thereof within 3 days, preferably within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour. When the compounds (I) and (Ia) or a salt thereof are administered first, the compound (I)
And after administration of (Ia) or a salt thereof, within 1 minute to 1 day, preferably within 10 minutes to 6 hours, more preferably 1 minute to 1 hour.
Examples include a method of administering a compound having an emetic effect within 5 minutes to 1 hour. When the medicament of the present invention is used in combination with a serotonin antagonist and / or a carbohydrate steroid, the serotonin antagonist and / or the carbohydrate steroid may be administered simultaneously with Compounds (I) and (Ia) or a salt thereof. Good, but may be administered at different times. When administered with a time lag, for example, when a drug having an emetic effect is administered first, after administration of a compound having an emetic effect, 1
For example, the administration method may be performed within minutes to 3 days, preferably within 10 minutes to 1 day, and more preferably within 15 minutes to 1 hour.

As a preferable administration method, for example, a drug having an emetic action formed into a preparation for oral administration having about 0.00
1 to 200 mg / kg is orally administered, and about 15 minutes later, about 0.005 to 100 mg / kg of the compounds (I) and (Ia) or a salt thereof formed into an oral administration preparation is orally administered as a daily dose.

In the medicament of the present invention, the content of compounds (I) and (Ia) or a salt thereof with respect to the whole preparation varies depending on the form of the preparation.
01 to 100% by weight, preferably 0.1 to 50% by weight,
More preferably, it is about 0.5 to 20% by weight. When the serotonin antagonist and / or glucosteroid is used in combination in the medicament of the present invention, the content of the serotonin antagonist and / or glucosteroid in the whole preparation is 0.001 to 100% by weight, preferably 0.01 to 100% by weight, respectively.
To 50% by weight, more preferably about 0.5 to 20% by weight.

The compounds (I) and (Ia) or salts thereof are useful as emetic suppressants, and can particularly quickly and safely suppress emesis induced by a drug having an emetic action at a low dose.

[0102]

DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, the present invention will be described in more detail with reference to Reference Examples and Examples. May be changed.

Elution by column chromatography in Reference Example was performed by TLC (Thin Layer C) unless otherwise specified.
hromatography, thin layer chromatography). In the TLC observation, using Merck (Merck) manufactured by 60F ₂₅₄ as TLC plate, was used as a developing solvent, the solvent used as an elution solvent in column chromatography. A UV detector was used for detection. As silica gel for column chromatography, silica gel 60 (70-230 manufactured by Merck & Co., Inc.) is used.
Mesh). Room temperature usually means a temperature of about 10 ° C to 35 ° C. Further, sodium sulfate or magnesium sulfate was used for drying the extract.

The meanings of the abbreviations in the reference examples are as follows. NMR: nuclear magnetic resonance spectrum EI-MS: electron impact mass spectrometry spectrum SI-MS: secondary electron ion mass spectrometry spectrum DMF: dimethylformamide, THF: tetrahydrofuran, DMSO: dimethyl sulfoxide, Hz: hertz, J: coupling constant, m: multiplet, q:
Quartet, t: triplet, d: doublet,
s: singlet, b: broad, like: approximation.

[0105]

Reference Example Reference Example 1 N- [3,5-bis (trifluoromethyl) benzyl]
-7,8-dihydro-7- (2-hydroxyethyl)-
5- (4-Methylphenyl) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide (Step 1) Magnesium (2.4 g) in THF (30 m
l) Iodine (catalytic amount) was added to the suspension while stirring at room temperature under a nitrogen atmosphere, and then a solution of 4-bromotoluene (17.1 g) in THF (20 ml) was added dropwise.
Stirred for hours. This mixture was added to a solution of 2,3-pyridinedicarboxylic anhydride (12.7 g) in THF (50 ml) with stirring while maintaining the temperature at 0 to 5 ° C.
Stirred for 0 minutes and then at room temperature for 1 hour. The solvent was distilled off from the reaction mixture, water (30 ml) was added to the residue, and the pH was adjusted to 1.0 using hydrochloric acid. The mixture was extracted with dichloromethane, washed with water and dried, and the solvent was distilled off. Dichloromethane (about 10 ml) is added to the residue,
Then isopropyl ether (about 70 ml) was added,
After stirring at room temperature for 16 hours, 3- (4-methylbenzoyl) -2-pyridinecarboxylic acid was obtained as colorless crystals (5.0.
g). Melting point: 168-170 ° C (recrystallized from dichloromethane-ethyl acetate) NMR (200 MHz, CDCl ₃ ) ppm: 2.41 (3H, s), 7.24 (2H, d, J =
8.4Hz), 7.62 (2H, d, J = 8.4Hz), 7.70 (1H, dd, J = 8.0,
4.8Hz), 7.85 (1H, dd, J = 8.0, 1.5Hz), 8.77 (1H, dd, J
= 4.8, 1.5Hz).

(Step 2) The compound obtained in Step 1 (6.
0g), DMF (catalytic amount), thionyl chloride (10m
l), THF (50 ml), dichloroethane (50 m
The mixture of 1) was refluxed for 3 hours. After evaporation of the solvent, the residue was dissolved in dichloromethane (100 ml). Iminodiacetonitrile (3.0 g) and triethylamine (10 ml) were added to this solution, and the mixture was stirred at room temperature for 16 hours.
The reaction mixture was washed sequentially with water, diluted hydrochloric acid, aqueous sodium hydrogen carbonate and water, dried, and evaporated to remove the solvent.
N, N-bis (cyanomethyl) -3- (4-methylbenzoyl) -2-pyridinecarboxamide was obtained as light brown crystals (4.3 g). Melting point: 166-168 ° C (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.44 (3H, s), 4.55 (2H, s),
4.69 (2H, s), 7.31 (2H, d, J = 8.1Hz), 7.56 (1H, dd, J =
7.9, 4.9Hz), 7.69 (2H, d, J = 8.1Hz), 7.94 (1H, dd, J
= 7.9, 1.6Hz), 8.78 (1H, dd, J = 4.9, 1.6Hz) Elemental analysis: C ₁₈ H ₁₄ N ₄ O ₂ Calculated (%): C 67.92, H 4.43, N 17.60 Actual measurement ( %): C 67.76, H 4.54, N 17.62.

(Step 3) The compound (0.
86g), 1,8-diazabicyclo [5.4.0] -7
-Undecene (DBU) (1 ml) and toluene (4
0 ml) was heated at reflux for 1 hour. The reaction mixture was diluted with ethyl acetate, washed successively with water, dilute acid, aqueous sodium hydrogen carbonate and water, dried, and evaporated to remove 7-cyanomethyl-7,8-dihydro-5-.
(4-Methylephenyl) -8-oxo-6-pyrido [3,4-b] pyridinecarbonitrile was obtained as pale brown crystals (765 mg). Melting point: 229-231 ° C. (recrystallized from ethyl acetate) NMR (200 MHz, CDCl ₃ ) ppm: 2.48 (3H, s), 5.28 (2H, s),
7.31 (2H, d, J = 8.2Hz), 7.40 (2H, d, J = 8.2Hz), 7.64 (1
H, dd, J = 8.2, 4.4Hz), 7.80 (1H, dd, J = 8.2, 1.4Hz),
9.06 (1H, dd, J = 4.4, 1.4Hz) Elemental analysis: C ₁₈ H ₁₂ N ₄ O · 0.2H ₂ O Calculated (%): C 71.14, H 4.11, N 18.43 Actual (%) : C 71.20, H 4.26, N 18.20.

(Step 4) The compound (2.
A mixture of 35 g), hydrochloric acid (25 ml) and acetic acid (25 ml) was heated under reflux for 1.5 hours. After evaporating the solvent, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried, and evaporated to remove 7-carboxymethyl-7,8-dihydro-5-.
(4-Methylphenyl) -8-oxo-6-pyrido [3,4-b] pyridinecarbonitrile was obtained as colorless crystals (1.62 g). Melting point: 253-254 ° C. (recrystallized from ethyl acetate) NMR (200 MHz, CDCl ₃ ) ppm: 2.46 (3H, s), 5.22 (2H, s),
6.64 (1H, bs, -CO ₂ H), 7.32 (2H, d, J = 8.2Hz), 7.37 (2H,
d, J = 8.2Hz), 7.62 (1H, dd, J = 8.4, 4.4Hz), 7.82 (1H,
d, J = 8.4 Hz), 9.09 (1H, d, J = 4.4 Hz) Elemental analysis: C ₁₈ H ₁₃ N ₃ O ₃ · 0.1 H ₂ O Calculated (%): C 67.33, H 4.14, N 13.09 Found (%): C 67.28, H 4.19, N 13.00.

(Step 5) The compound (1.
Hydroxybenzotriazole (770 mg) and 1,3-dicyclohexylcarbodiimide (1.23 g) were added to a solution of 54 g) in THF (50 ml).
Stirred for hours. Next, sodium borohydride (550 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and dried, and the solvent was distilled off. Dichloromethane was added to the residue, the insoluble portion was removed by filtration, and the solvent was distilled off. Hydrochloric acid (50 ml) was added to the residue, and the mixture was heated under reflux for 16 hours. The solvent was distilled off, ice water was added to the residue, the mixture was made alkaline with aqueous potassium carbonate, and extracted with ethyl acetate. The extract was washed with water, dried, and evaporated to remove the solvent.
8,9,11-tetrahydro-5- (4-methylphenyl) -6,11-dioxo [1,4] oxazino [3
4-g] [1,7] naphthyridine is a colorless crystal (0.86
g). Melting point: 247-249 ° C. (recrystallized from ethyl acetate) NMR (200 MHz, CDCl ₃ ) ppm: 2.45 (3H, s), 4.48-4.72 (4H,
m), 7.12 (2H, d, J = 8.0Hz), 7.32 (2H, d, J = 8.0Hz), 7.
55 (1H, dd, J = 8.4, 4.4Hz), 7.68 (1H, dd, J = 8.4, 1.6
Hz), 9.01 (1H, dd , J = 4.4, 1.6Hz) Elemental _{analysis: C 18 H 14 N 2 O} 3 · 0.2H 2 O Calculated (%): C 69.76, H 4.68, N 9.04 Found Value (%): C 69.64, H 4.86, N 8.95.

(Step 6) Compound (41) obtained in Step 5
0 mg) and 3,5-bis (trifluoromethyl) benzylamine (1.2 g) under argon atmosphere.
Heated at 50 ° C. for 2.5 hours. After cooling to room temperature, isopropyl ether was added to give the title compound as colorless crystals (441 mg). Melting point: 123-125 ° C. (recrystallized from ethyl acetate) NMR (200 MHz, CDCl ₃ ) ppm: 2.28 (3H, s), 3.71 (2H, m),
3.97 (2H, m), 4.46 (2H, d, J = 5.2Hz), 7.00-7.20 (4H,
m), 7.37 (1H, dd, J = 8.4, 4.2Hz), 7.52 (1H, dd, J = 8.4,
1.6Hz), 7.66 (2H, s), 7.76 (1H, s), 8.51 (1H, bs),
8.61 (1H, dd, J = 4.2, 1.6 Hz) Elemental analysis: C ₂₇ H ₂₁ N ₃ O ₃ F ₆ Calculated (%): C 59.02, H 3.85, N 7.65 Actual (%): C 58.95 , H 3.95, N 7.52.

Reference Example 2 N- [3,5-bis (trifluoromethyl) benzyl]
-7- (3-chloropropyl) -7,8-dihydro-5
-(4-Methylphenyl) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide (Step 1) 3- (4-methylbenzoyl) -2-pyridinecarboxylic acid (13.9 g), bromomalonic acid Diethyl ester (15.4 g), triethylamine (9.1 m
A mixture of 1) and THF (120 ml) was heated at reflux for 6 hours. The solvent was distilled off, ethyl acetate was added to the residue, and the mixture was washed with water, diluted hydrochloric acid and saturated saline in that order, dried, and the solvent was distilled off. Residue (oil) (20.5 g)
In a THF (120 ml) solution at −78 ° C. with DBU
(4.2 ml) was added. After the mixture was stirred at 0 ° C. for 15 minutes, the solvent was concentrated. The concentrated solution is 2N-HCl
And the pH is adjusted to about 10 with sodium bicarbonate.
And extracted with ethyl acetate. After the extract was washed with water and dried, the solvent was distilled off to give 5,6-dihydro-5-hydroxy-5- (4-methylphenyl) -8-.
Oxo-8H-pyrano [3,4-b] pyridine-6,6
-Dicarboxylic acid diethyl ester is a colorless crystal (14.
1g). Melting point: 148-149 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.06 (3H, t, J = 7.1 Hz), 1.21
(3H, t, J = 7.1Hz), 2.31 (3H, s), 3.95-4.30 (4H, m),
4.65 (1H, s), 7.15 (2H, d, J = 8.3Hz), 7.55 (1H, dd, J =
8.0, 4.8Hz), 7.65 (2H, d, J = 8.3Hz), 8.47 (1H, dd, J =
8.0, 1.4Hz), 8.86 (1H, dd, J = 4.8, 1.4Hz) Elemental analysis: C ₂₁ H ₂₁ NO ₇ Calculated (%): C 63.15, H 5.30, N 3.51 Actual (%): C 63.09, H 5.16, N 3.47. This compound was also obtained by the method described below. 3
-(4-Methylbenzoyl) -2-pyridinecarboxylic acid (3.0 g), DMF (1 drop), thionyl chloride (4.5 m
A mixture of l) and THF (30 ml) was heated at reflux for 2 hours. The solvent was distilled off, and the obtained crystalline residue was washed with THF.
(50 ml). While stirring this solution at -10 ° C, hydroxymalonic acid diethyl ester (4.1
g) and then sodium hydride (60% oil)
(646 mg) was added in small portions. This reaction mixture is
After stirring at 0 ° C. for 30 minutes, it was added to a mixture of ethyl acetate (100 ml) and water (100 ml). Separate the organic layer,
The aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with water and brine, dried and evaporated to give the compound as colorless crystals (4.0 g). The physicochemical data for this compound was consistent with the data for the above compound.

(Step 2) Compound (1) obtained in Step 1
4.1 g), acetic acid (100 ml) and hydrochloric acid (100 m
The mixture of 1) was heated at reflux for 3 hours. The solvent was distilled off, and water was added to the residue to give 5- (4-methylphenyl) -8-oxo-8H-pyrano [3,4-b] pyridine-6-carboxylic acid as colorless crystals (8. 45 g). Melting point: 274 to 277 ° C. (changed from around 240 ° C. to brown) (recrystallized from THF-isopropyl ether) NMR (200 MHz, CDCl ₃ -DMSO-d ₆ ) ppm: 2.43 (3H, s), 6.10 (1
H, bs, -CO ₂ H), 7.16 (2H, d, J = 8.0Hz), 7.29 (2H, d, J
= 8.0Hz), 7.50-7.70 (2H, m), 8.94 (1H, m) Elemental analysis: C ₁₆ H ₁₁ NO ₄ · 0.1H ₂ O Calculated (%): C 67.89, H 3.99, N 4.95 Found (%): C 67.70, H 4.06, N 4.83.

(Step 3) 3-bromopropylamine hydrobromide (1.5 g), triethylamine (2.0 m
l) and methanol (5 ml) in a mixture of 5- (4
-Methylphenyl) -8-oxo-8H-pyrano [3
4-b] pyridine-6-carboxylic acid (150 mg) T
An HF (5 ml) solution was added dropwise, and after stirring at room temperature for 2 hours, the solvent was distilled off. Hydrochloric acid (10 ml) was added to the residue, and the mixture was stirred at room temperature for 14 hours, concentrated, and concentrated with 1N-NaO.
The pH of the concentrate was adjusted to 1 using H. The precipitated crystals were collected by filtration and washed with water to give 7- (3-bromopropyl) -7,8-dihydro-5- (4-methylphenyl) -8-oxo-6-pyrido [3,4-b The pyridinecarboxylic acid was obtained as colorless crystals (131 mg). Melting point: 194 ° -196 ° C. (recrystallized from THF-isopropyl ether) NMR (200 MHz, CDCl ₃ -DMSO-d ₆ ) ppm: 2.30-2.60 (2H, m),
2.42 (3H, s), 3.54 (2H, t, J = 6.8Hz), 4.29 (2H, t, J = 7.
2Hz), 5.42 (1H, bs, -CO ₂ H), 7.20-7.40 (4H, m), 7.50
(1H, m), 7.64 (1H, d, J = 8.0 Hz), 8.88 (1H, m).

(Step 4) Compound (11) obtained in Step 3
0 mg), DMF (catalytic amount), thionyl chloride (0.3 m
l), 1,2-dichloromethane (3 ml) and THF
(3 ml) was heated under reflux for 40 minutes, and the solvent was distilled off. THF (5 ml), 3,5-bis (trifluoromethyl) benzylamine (82 mg) were added to the residue,
Triethylamine (0.12 ml) and THF (2 m
1) was added and stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, washed sequentially with water, diluted hydrochloric acid, aqueous sodium hydrogen carbonate and water, dried, and then the solvent was distilled off to give the title compound as colorless crystals (79 mg).
As obtained. Melting point: 227-229 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.10-2.40 (2H, m), 2.27 (3H,
s), 3.4-3.7 (4H, m), 4.49 (2H, d, J = 5.8Hz), 7.07 (2H,
d, J = 7.6Hz), 7.24 (2H, d, J = 7.6Hz), 7.40 (1H, dd, J =
8.4, 4.2Hz), 7.54 (1H, dd, J = 8.4, 1.4Hz), 7.67 (2H,
s), 7.78 (1H, s), 8.06 (1H, bt), 8.70 (1H, dd, J = 4.2,
1.4 Hz) Elemental analysis: C ₂₈ H ₂₂ N ₃ O ₂ ClF ₆ .0.2 H ₂ O Calculated (%): C 57.43, H 3.86, N 7.18 Actual (%): C 57.29, H 3.98, N 7.07.

Reference Example 3 N- [3,5-bis (trifluoromethyl) benzyl]
-5- (4-Methylphenyl) -8-oxo-8H-pyrano [3,4-b] pyridine-6-carboxamide The compound obtained in Step 2 of Reference Example 2 and 3,5-bis (trifluoro The reaction and treatment were carried out using methyl) benzylamine in the same manner as in Step 4 of Reference Example 2, whereby the title compound was obtained as colorless crystals. Melting point: 182-183 ° C. (recrystallized from ethyl acetate-ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.44 (3H, s), 4.63 (2H, d, J =
6.4Hz), 7.17 (2H, d, J = 8.1Hz), 7.34 (2H, d, J = 8.1Hz),
7.50-7.65 (3H, m), 7.73 (2H, s), 7.80 (1H, s), 8.96 (1
H, m) Elemental analysis: C ₂₅ H ₁₆ N ₂ O ₃ F ₆ Calculated (%): C 59.30, H 3.18, N 5.53 Found (%): C 59.42, H 3.30, N 5.45.

Reference Example 4 N- (2-methoxybenzyl) -5- (4-methylphenyl) -8-oxo-8H-pyrano [3,4-b] pyridine-6-carboxamide In Step 2 of Reference Example 2, The obtained compound was reacted with 2-methoxybenzylamine in the same manner as in Step 4 of Reference Example 2 and treated to give the title compound as colorless crystals. Melting point: 189-190 ° C (recrystallized from ethyl acetate) NMR (200 MHz, CDCl ₃ ) ppm: 2.44 (3H, s), 3.90 (3H, s),
4.48 (2H, d, J = 5.8Hz), 6.85-6.95 (2H, m), 7.10-7.35 (6
H, m), 7.43 (1H, bt), 7.50-7.63 (2H, m), 8.93 (1H,
m).

Reference Example 5 N- [3,5-bis (trifluoromethyl) benzyl]
-7,8-dihydro-7- (4-hydroxybutyl)-
5- (4-Methylphenyl) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide THF (5 m) of the compound (200 mg) obtained in Reference Example 3
l) To a solution of -methanol (10 ml) was added 4-amino-1-butanol (0.5 ml) at 0 ° C, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off from the reaction mixture, hydrochloric acid (15 ml) was added to the residue, and the mixture was stirred at room temperature for 14 hours. The reaction solution was poured into aqueous potassium carbonate-ice and extracted with ethyl acetate. The extract was washed with water, dried and the solvent was distilled off to give the title compound as colorless crystals (144 mg). Melting point: 187-188 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.3-1.5 (2H, m), 1.6-1.9 (2
H, m), 2.29 (3H, s), 2.82 (1H, bs), 3.55 (2H, t, J = 5.7
Hz), 3.69 (2H, m), 4.48 (2H, d, J = 5.8Hz), 7.08 (2H,
d, J = 8.1Hz), 7.21 (2H, d, J = 8.1Hz), 7.29 (1H, dd, J =
8.4, 4.2Hz), 7.52 (1H, dd, J = 8.4, 1.4Hz), 7.68 (2H,
s), 7.78 (1H, s), 8.39 (1H, bt), 8.61 (1H, dd, J = 4.2,
1.4Hz).

Reference Example 6 7,8-dihydro-7- (3-hydroxypropyl)-
N- (2-methoxybenzyl) -5- (4-methylphenyl) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide The compound obtained in Reference Example 4 and 3-amino-1-propanol were used. The reaction was carried out and treated in the same manner as in Reference Example 5 to give the title compound. This compound was used for the reaction of Reference Example 58 without purification.

Reference Example 7 7,8-dihydro-7- (4-hydroxybutyl) -N
-(2-Methoxybenzyl) -5- (4-methylphenyl) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide Using the compound obtained in Reference Example 4 and 4-amino-1-butanol Then, the reaction and treatment were carried out in the same manner as in Reference Example 5 to give the title compound as colorless crystals. Melting point: 205-206 ° C (recrystallized from methanol-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.57 (2H, m), 1.95 (2H, m),
2.33 (3H, s), 2.71 (1H, bs), 3.66 (2H, t, J = 6.0Hz),
3.75 (3H, s), 4.00-4.15 (2H, m), 4.29 (2H, d, J = 6.2H
z), 6.59 (1H, bt), 6.71-6.92 (3H, m), 7.04-7.30 (5H,
m), 7.41 (1H, dd, J = 8.4, 4.4Hz), 7.62 (1H, dd, J = 8.
4, 1.4Hz), 8.82 (1H, dd, J = 4.4, 1.4Hz).

Reference Example 8 N- [3,5-bis (trifluoromethyl) benzyl]
-7,8-dihydro-7- (5-hydroxypentyl)
-5- (4-methylphenyl) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide Using the compound obtained in Reference Example 3 and 5-amino-1-pentanol, The reaction and treatment were carried out in the same manner to give the title compound as colorless crystals. Melting point: 136-137 ° C (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.10-1.35 (2H, m), 1.35-1.
55 (2H, m), 1.6-1.9 (2H, m), 2.28 (3H, s), 3.50-3.70
(4H, m), 4.47 (2H, d, J = 5.8Hz), 7.06 (2H, d, J = 8.0H
z), 7.19 (2H, d, J = 8.0Hz), 7.35 (1H, dd, J = 8.3, 4.4H
z), 7.50 (1H, d, J = 8.3, 1.4Hz), 7.69 (2H, s), 7.78 (1
H, s), 8.29 (1H, bt), 8.64 (1H, dd, J = 4.4, 1.4Hz).

Reference Example 9 N- [3,5-bis (trifluoromethyl) benzyl]
-7,8-dihydro-7- (3-hydroxypropyl)
-8-oxo-5-phenyl-6-pyrido [3,4-
b) Pyridinecarboxamide (Step 1) The procedure of Reference Example 2 was repeated using 3-benzoyl-2-pyridinecarboxylic acid instead of 3- (4-methylbenzoyl) -2-pyridinecarboxylic acid in Step 1 of Reference Example 2. Reacts in the same manner as 1, and when treated, gives 5,6-dihydro-5
-Hydroxy-8-oxo-5-phenyl-8H-pyrano [3,4-b] pyridine-6,6-dicarboxylic acid diethyl ester was obtained as colorless crystals. Melting point: 146-147 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.07 (3H, t, J = 7.2 Hz), 1.1
8 (3H, t, J = 7.2Hz), 4.00-4.25 (4H, m), 4.70 (1H, s),
7.30-7.40 (3H, m), 7.56 (1H, dd, J = 8.0, 4.8Hz), 7.74
-7.85 (2H, m), 8.48 (1H, dd, J = 8.0, 1.5Hz), 8.87 (1H,
dd, J = 4.8, 1.5Hz). (Step 2) Using the compound obtained in Step 1, acetic acid and hydrochloric acid, reacting and treating in the same manner as in Step 2 of Reference Example 2, 8-
Oxo-5-phenyl-8H-pyrano [3,4-b] pyridine-6-carboxylic acid was obtained as colorless crystals. Melting point: 288-290 ° C (recrystallized from THF-methanol-ether) NMR (200 MHz, DMSO-d ₆ ) ppm: 7.28-7.60 (6H, m), 7.81
(1H, dd, J = 8.2, 4.4Hz), 8.95 (1H, dd, J = 4.4, 1.6Hz)
.

(Step 3) The compound obtained in Step 2 and 3,5-
Using bis (trifluoromethyl) benzylamine,
The reaction and treatment were carried out in the same manner as in Reference Example 3 to give N- [3,5-bis (trifluoromethyl) benzyl] -8-oxo-5.
-Phenyl-8H-pyrano [3,4-b] pyridine-6
-Carboxamide was obtained as colorless crystals. Melting point: 182-183 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 4.61 (2H, t, J = 6.2 Hz), 7.2
4-7.34 (2H, m), 7.49-7.67 (6H, m), 7.72 (2H, s), 7.79
(1H, s), 8.96 (1H, dd, J = 4.2, 1.6 Hz). (Step 4) The compound obtained in Step 3 was reacted with 3-amino-1-propanol in the same manner as in Reference Example 5 to give the title compound as colorless crystals. Melting point: 129-130 ° C (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.91 (2H, m), 3.45 (2H, t,
J = 5.4Hz), 3.70 (2H, m), 4.46 (2H, d, J = 6.0Hz), 7.2-
7.4 (5H, m), 7.44 (1H, dd, J = 8.4, 4.4Hz), 7.59 (1H, d
d, J = 8.4, 1.6Hz), 7.61 (2H, s), 7.78 (1H, s), 8.25 (1
H, bt), 8.70 (1H, dd, J = 4.4, 1.6Hz).

Reference Example 10 N- [3,5-bis (trifluoromethyl) benzyl]
-7,8-dihydro-7- (4-hydroxybutyl)-
8-oxo-5-phenyl-6-pyrido [3,4-b]
Pyridinecarboxamide When the compound obtained in Step 3 of Reference Example 9 and 4-amino-1-butanol were reacted and treated in the same manner as in Reference Example 5, the title compound was obtained as colorless crystals. Melting point: 155-157 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.45 (2H, m), 1.83 (2H, m),
3.58 (2H, t, J = 5.8Hz), 3.73 (2H, m), 4.44 (2H, d, J =
5.8Hz), 7.2-7.4 (6H, m), 7.54 (1H, dd, J = 8.1, 1.1H
z), 7.60 (2H, s), 7.77 (1H, s), 8.05 (1H, bt), 8.66 (1
H, dd, J = 4.1, 1.1 Hz).

Reference Example 11 N- [3,5-bis (trifluoromethyl) benzyl]
-1,2-dihydro-2- (4-hydroxybutyl)-
4- (4-methylphenyl) -1-oxo-3-pyrido [3,4-c] pyridinecarboxamide (Step 1) 3- (4-methylbenzoyl) -2-pyridinecarboxylic acid of Step 1 of Reference Example 2 In place of 4- (4-methylbenzoyl) -3-pyridinecarboxylic acid, the reaction was carried out in the same manner as in Step 1 of Reference Example 2 to give 3,4-dihydro-4-hydroxy-4- (4-methyl Phenyl)
-1-oxo-1H-pyrano [3,4-c] pyridine-
3,3-Dicarboxylic acid diethyl ester was obtained as a yellow oil. NMR (200 MHz, CDCl ₃ ) ppm: 1.08 (3H, t, J = 7.1 Hz), 1.2
1 (3H, t, J = 7.2Hz), 2.31 (3H, s), 4.00-4.40 (4H, m),
4.72 (1H, bs), 7.14 (2H, d, J = 8.4Hz), 7.64 (2H, d, J =
8.4Hz), 8.05 (1H, d, J = 5.3Hz), 8.85 (1H, d, J = 5.3H
z), 9.12 (1H, s). (Step 2) Using the compound obtained in Step 1, acetic acid and hydrochloric acid, reacting and treating in the same manner as in Step 2 of Reference Example 2, 4-
(4-Methylphenyl) -1-oxo-1H-pyrano [3,4-c] pyridine-3-carboxylic acid was obtained as colorless crystals. Melting point: 254-256 ° C. (recrystallized from THF-isopropyl ether) NMR (200 MHz, CDCl ₃ + d ₆ -DMSO) ppm: 2.43 (3H, s), 5.3
1 (1H, bs, COOH), 7.04 (1H, d, J = 5.5Hz), 7.16 (2H, d,
J = 7.8Hz), 7.29 (2H, d, J = 7.8Hz), 8.81 (1H, d, J = 5.5H
z), 9.54 (1H, s).

(Step 3) Compound obtained in step 2 and 3,5-
Using bis (trifluoromethyl) benzylamine,
Reaction and treatment were carried out in the same manner as in Reference Example 3, and N- [3,5-bis (trifluoromethyl) benzyl] -4- (4-methylphenyl) -1-oxo-1H-pyrano [3,4-
c] Pyridine-3-carboxamide was obtained as colorless crystals. Melting point: 188-189 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.44 (3H, s), 4.61 (2H, d,
J = 6.2Hz), 7.05 (1H, d, J = 5.3Hz), 7.15 (2H, d, J = 8.1H
z), 7.32 (2H, d, J = 8.1Hz), 7.43 (1H, bt), 7.7.0 (2H,
s), 7.80 (1H, s), 8.85 (1H, d, J = 5.3Hz), 9.56 (1H,
s). (Step 4) The compound obtained in Step 3 was reacted with 4-amino-1-butanol in the same manner as in Reference Example 5 to give the title compound as colorless crystals. Melting point: 128-131 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.45-1.70 (2H, m), 1.75-2.
05 (2H, m), 2.31 (3H, s), 3.65 (2H, t, J = 5.9Hz), 3.98
(2H, m), 4.36 (2H, d, J = 6.0Hz), 7.00 (1H, d, J = 5.7H
z), 7.12 (2H, d, J = 8.1Hz), 7.18 (2H, d, J = 8.1Hz), 7.
56 (2H, s), 7.80 (1H, s), 8.47 (1H, d, J = 5.7Hz), 9.41
(1H, s).

Reference Example 12 N- [3,5-bis (trifluoromethyl) benzyl]
-2-Chloro-N- (2-hydroxyethyl) -4-phenyl-3-pyridinecarboxamide (Step 1) TH of 2-aminoethanol (3.6 ml)
3,5-Bis (trifluoromethyl) benzyl bromide (1.1 ml) was added to the F (30 ml) solution under ice cooling. After the mixture was stirred at room temperature for 1 hour, ethyl acetate (30 ml) was added, and the mixture was washed with water and saturated aqueous sodium chloride. After drying the organic layer, the solvent was distilled off to give N-
[3,5-bis (trifluoromethyl) benzyl] -N
-(2-Hydroxyethyl) amine is a colorless crystal (1.3
8g). Melting point: 107-108 ° C (recrystallized from ethanol-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.83 (2H, t, J = 5.4 Hz), 3.72
(2H, t, J = 5.4Hz), 3.96 (2H, s), 7.78 (1H, s), 7.82 (2
H, s). (Step 2) To a solution of 2-chloro-4-phenyl-3-pyridinecarboxylic acid (318 mg) in THF (10 ml),
Thionyl chloride (0.7 ml) and DMF (catalytic amount) were added, and the mixture was heated under reflux for 4 hours. The solvent was distilled off and the residue was
Dissolved in F (5 ml). This solution was cooled in ice under step 1
N- [3,5-bis (trifluoromethyl) obtained in
Benzyl] -N- (2-hydroxyethyl) amine (3
91 mg), triethylamine (0.57 ml) and T
It was added to a mixture of HF (10 ml) and stirred at room temperature for 2 hours. The solvent was distilled off, water was added to the residue, and the mixture was extracted with ethyl acetate. After the extract was washed with water and dried, the solvent was distilled off. The residue was separated and purified by column chromatography on silica gel (hexane: ethyl acetate = 1: 1) to give the title compound as an oil (551 mg) (about 2: 1 cis-trans isomer ratio for the amide bond). Obtained. NMR (200 MHz, CDCl ₃ ) ppm: 2.82-3.92 (4H, m), 4.16 (1H
× 1/3, d, J = 16.0Hz), 4.41 (1H × 1/3, d, J = 16.0Hz), 4.
73 (1H × 2/3, d, J = 15.0Hz), 4.87 (1H × 2/3, d, J = 15.0H
z), 7.20-8.85 (9H, m), 8.43 (1H, m).

Reference Example 13 (S) -N- [3,5-bis (trifluoromethyl) benzyl] -7,8-dihydro-7- (3-hydroxy-
2-methylpropyl) -5- (4-methylphenyl)-
8-oxo-6-pyrido [3,4-b] pyridinecarboxamide THF (10 m) of the compound (1.0 g) obtained in Reference Example 3
l) (S) -3-Amino-2-methyl-1-propanol (307 mg) was added to a solution of -methanol (7.5 ml), and the mixture was stirred at room temperature for 14 hours. After adding dilute hydrochloric acid to the reaction mixture, the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried, and the solvent was distilled off. Acetonitrile (3 ml), toluene (21 ml) and DB were added to the residue.
U (0.42 ml) was added, and the mixture was heated under reflux for 1 hour. After cooling, the reaction solution was diluted with ethyl acetate, and washed with water, diluted hydrochloric acid, and saturated saline in this order. After the organic layer was dried, the solvent was distilled off to obtain the title compound as colorless crystals. Melting point: 123-125 ° C (once melted and solidified again), 2
15-216 ° C (remelting) (recrystallized from ethyl acetate-isopropyl ether) [α] _D : + 11.1 ° (C = 0.350, CHC
l ₃ ) NMR (200 MHz, CDCl ₃ ) ppm: 0.79 (3H, d, J = 7.0 Hz), 2.1
3 (1H, m), 2.28 (3H, s), 3.10-3.70 (4H, m), 4.48 (2H,
d, J = 6.2Hz), 7.00-7.25 (4H, m), 7.43 (1H, dd, J = 8.4,
4.2Hz), 7.59 (1H, dd, J = 8.4, 1.6Hz), 7.69 (2H, s),
7.79 (1H, s), 8.38 (1H, bt), 8.70 (1H, dd, J = 4.2, 1.6
Hz) Elemental analysis: C ₂₉ H ₂₅ N ₃ O ₃ F ₆ .0.5H ₂ O Calculated (%): C 59.39, H 4.47, N 7.16 Actual (%): C 59.64, H 4.31, N 7.01.

Reference Example 14 (R) -N- [3,5-bis (trifluoromethyl) benzyl] -7,8-dihydro-7- (3-hydroxy-
2-methylpropyl) -8-oxo-5-phenyl-6
-Pyrido [3,4-b] pyridinecarboxamide The compound obtained in Step 3 of Reference Example 9 and (R) -3-amino-
The reaction and treatment were conducted in the same manner as in Reference Example 13 using 2-methyl-1-propanol, and the title compound was obtained as colorless crystals. Melting point: 101-103 ° C (recrystallized from ethyl ether-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.77 (3H, d, J = 6.6 Hz), 2.1
4 (1H, m), 3.10-3.70 (4H, m), 4.47 (2H, d, J = 5.8Hz),
7.1-7.4 (5H, m), 7.45 (1H, dd, J = 8.4, 4.2Hz), 7.60 (1
H, d, J = 8.4Hz), 7.65 (2H, s), 7.78 (1H, s), 8.60 (1H,
bt), 8.69 (1H, d, J = 4.2 Hz) [α] _D : -5.4 ° (C = 0.512, CHC
l ₃ ).

Reference Example 15 (R) -N- [3,5-bis (trifluoromethyl) benzyl] -7,8-dihydro-7- (3-hydroxy-
2-methylpropyl) -5- (4-methylphenyl)-
8-oxo-6-pyrido [3,4-b] pyridinecarboxamide Using the compound obtained in Reference Example 3 and (R) -3-amino-2-methyl-1-propanol, in the same manner as in Reference Example 13 After reaction and treatment, the title compound was obtained as colorless crystals. Melting point: 123-125 ° C (once melted and solidified again), 2
15-216 ° C. (remelting (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: same as the spectrum of the compound of Reference Example 13 [α] _D : -9.0 ° (C = 0. 346, CHCl
₃ ).

Reference Example 16 (±) -N- [3,5-bis (trifluoromethyl) benzyl] -7,8-dihydro-7- (4-hydroxy-
3-methylbutyl) -8-oxo-5-phenyl-6-
Pyrid [3,4-b] pyridinecarboxamide The compound obtained in Step 3 of Reference Example 9 was reacted with 4-amino-2-methyl-1-butanol in the same manner as in Reference Example 13 and treated. The title compound was obtained as colorless crystals. Melting point: 217-219 ° C (recrystallized from ethyl acetate-isopropyl ether).

Reference Example 17 (±) -N- [3,5-bis (trifluoromethyl) benzyl] -7,8-dihydro-7- (4-hydroxy-
3-methylbutyl) -5- (4-methylphenyl) -8
-Oxo-6-pyrido [3,4-b] pyridinecarboxamide The compound obtained in Reference Example 3 and 4-amino-2-methyl-1-
The reaction was carried out in the same manner as in Reference Example 13 using butanol,
Upon treatment, the title compound was obtained as colorless crystals. Melting point: 129-130 ° C (once melted and solidified again), 1
88-190 ° C (remelting) (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.79 (3H, d, J = 6.6 Hz), 1.4
-1.8 (3H, m), 2.28 (3H, s), 3.03 (1H, t, J = 6.6Hz, -O
H), 3.2-3.7 (4H, m), 4.49 (2H, d, J = 5.8Hz), 7.0-7.3
(4H, m), 7.30 (1H, dd, J = 8.4, 4.4Hz), 7.53 (1H, dd,
J = 8.4, 1.4Hz), 7.68 (2H, s), 7.78 (1H, s), 8.48 (1H,
t, J = 6.0Hz), 8.61 (1H, dd, J = 4.4, 1.4Hz).

Reference Example 18 (R) -N- [3,5-bis (trifluoromethyl) benzyl] -7,8-dihydro-7- (4-hydroxy-
3-methylbutyl) -8-oxo-5-phenyl-6-
Pyrido [3,4-b] pyridinecarboxamide The compound obtained in Step 3 of Reference Example 9 and (R) -4-amino-
The reaction was carried out using 2-methyl-1-butanol tetrahydropyranyl (THP) ether in the same manner as in Reference Example 13, and the title compound THP ether was obtained as a pale orange oil. This compound is reacted with p-toluenesulfonic acid in methanol at room temperature to give T
Removal of the HP group gave the title compound as colorless crystals. Melting point: 213-215 ° C. (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: same as the spectrum of the compound of Reference Example 16 [α] _D : + 1.0 ° (C = 0.519, CHCl
₃ ). In addition, (R) -4-amino-2-methyl-1-butanol THP ether was prepared by the following method. (S)-
Using (+)-3-hydroxy-2-methylpropionic acid methyl ester as a starting material, the method described in the literature [Kenji Mori, Tetrahedron 39, 31
07-3109 (1983): describes a synthesis method for enantiomers. Or etch. Mattes (H, Matte
s) et al., Journal of Medicinal Chemistry, 30, 194.
8-1951 (1987)].
(R) -4-hydroxy-3-methylbutanenitrile T
An HP ether was prepared. [Colorless oil, NMR (200 MHz, CDCl ₃ ) ppm:
1.09 (3H × 1/2, d, J = 6.8 Hz), 1.1
0 (3H × 1/2, d, J = 6.8 Hz), 1.5-1.9
(6H, m), 2.1-2.6 (3H, m), 3.17-3.
88 (4H, m), 4.60 (1H, b)]. Ethyl ether (100m) of this compound (22.7g)
l) Bring the solution to lithium aluminum hydride (3.7
g) was slowly added to a suspension of ethyl ether (200 ml) with vigorous stirring. Then, the reaction mixture was stirred at room temperature for 1 hour, cooled again with ice water, and water (3 ml), 15 ml
Aqueous sodium hydroxide solution (3 ml) and water (10 ml) were added with stirring. The precipitate was filtered off using Celite and washed with ethyl acetate. The filtrate and the washing solution were combined, washed with aqueous potassium carbonate and brine, dried, and the solvent was distilled off to give (R) -4-amino-2-methyl-1-butanol THP ether as a colorless oil (21.7 g). )
Was obtained as NMR (200 MHz, CDCl ₃ ) ppm: 0.94 (3
H × 1/2, d, J = 6.8 Hz), 0.95 (3H × 1 /
2, d, J = 6.8 Hz), 1.2-1.9 (11 H, m),
3.13-3.90 (6H, m), 4.57 (1H, b).

Reference Example 19 (R) -N- [3,5-bis (trifluoromethyl) benzyl] -7,8-dihydro-7- (4-hydroxy-
3-methylbutyl) -5- (4-methylphenyl) -8
-Oxo-6-pyrido [3,4-b] pyridinecarboxamide Using the compound obtained in Reference Example 3 and (R) -4-amino-2-methyl-1-butanol THP ether, Reference Example 1
Reaction and treatment in a manner similar to 3 gave the title compound THP ether as a pale orange oil. This compound was reacted with p-toluenesulfonic acid in methanol at room temperature to remove the THP group, and the title compound was obtained as colorless crystals. Melting point: 123-125 ° C (once melted and solidified again), 2
05-206 ° C (remelting) (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: same as the spectrum of the compound of Reference Example 17 [α] _D : + 1.2 ° (C = 0. 471, CHCl ₃ )
.

Reference Example 20 (S) -N- [3,5-bis (trifluoromethyl) benzyl] -7,8-dihydro-7- (4-hydroxy-
3-methylbutyl) -8-oxo-5-phenyl-6-
Pyrido [3,4-b] pyridinecarboxamide (R) -4-amino-2-methyl- in Reference Example 18
(S) -4 instead of 1-butanol THP ether
The reaction was carried out using -amino-2-methyl-1-butanol THP ether in the same manner as in Reference Example 18 to give the title compound as colorless crystals. Melting point: 213-214 ° C. (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: same as the spectrum of the compound of Reference Example 16 [α] _D : -1.5 ° (C = 0.492) , CHC
l ₃ ).

Reference Example 21 (S) -N- [3,5-bis (trifluoromethyl) benzyl] -7,8-dihydro-7- (4-hydroxy-
3-methylbutyl) -5- (4-methylphenyl) -8
-Oxo-6-pyrido [3,4-b] pyridinecarboxamide (R) -4-amino-2-methyl- in Reference Example 19
(S) -4 instead of 1-butanol THP ether
The reaction and treatment with -amino-2-methyl-1-butanol THP ether in the same manner as in Reference Example 19 were carried out, whereby the title compound was obtained as colorless crystals. Melting point: 213 to 215 ° C (once melted, then solidified again), 2
07-208 ° C (remelting) (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: same as the spectrum of the compound of Reference Example 17 [α] _D : -2.7 ° C (C = 0) .391, CHC
l ₃ ).

Reference Example 22 N- (2-aminoethyl) -N- [3,5-bis (trifluoromethyl) benzyl] -2-chloro-4-phenyl-3-pyridinecarboxamide (Step 1) 2-chloro To a solution of -4-phenyl-3-pyridinecarboxylic acid (145 mg) in THF (5 ml) was added thionyl chloride (0.15 ml) and DMF (catalytic amount).
The mixture was heated under reflux for 2 hours. The solvent was distilled off, and the residue was washed with THF.
(5 ml). This solution was cooled under ice-cooling with N- [3,
5-bis (trifluoromethyl) benzyl] -N'-te
rt-butoxycarbonylethylenediamine (240m
g), triethylamine (0.26 ml) and THF
(10 ml) and stirred at room temperature for 3 hours. In addition, N- [3,5-bis (trifluoromethyl)
[Benzyl] -N'-tert-butoxycarbonylethylenediamine is a mixture of ethylenediamine and methanesulfonic acid 3,
5-bis (trifluoromethyl) benzyl ester is converted to T
After reacting in HF to give N- [3,5-bis (trifluoromethyl) benzyl] ethylenediamine as an oil, this compound is reacted with di-tert-butyl dicarbonate in THF in the presence of triethylamine. To give an oil. The solvent was distilled off from the reaction mixture, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and evaporated to remove N- [3,5-bis (trifluoromethyl) benzyl] -N- [2- (tert.
-Butoxycarbonylamino) ethyl] -2-chloro-
4-Phenyl-3-pyridinecarboxamide was obtained as a pale yellow oil. NMR (200 MHz, CDCl ₃ ) ppm: 1.20-1.60 (total 9H, m), 2.7
0-4.90 (total 7H, m), 7.20-8.00 (total 9H, m), 8.46 (1
H, d, J = 5.2Hz). (Step 2) To the compound obtained in step 1 was added a 4N-HCl ethyl acetate solution (10 ml), and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off, aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and evaporated to give the title compound as a pale yellow oil (34
9 mg). NMR (200 MHz, CDCl ₃ ) ppm: 2.30-3.70 (4H, m), 4.15 (1H ×
2/5, d, J = 16.2Hz), 4.38 (1H × 2/5, d, J = 16.2Hz), 4.6
5 (1H × 3/5, d, J = 15.2Hz), 4.84 (1H × 3/5, d, J = 15.2H
z), 7.20-7.60 (6H, m), 7.65-7.80 (6H, m), 8.47 (1H,
m).

Reference Example 23 N- [3,5-bis (trifluoromethyl) benzyl]
-2-Chloro-N- (3-hydroxypropyl) -4-
Phenyl-3-pyridinecarboxamide (Step 1) Reaction and treatment were carried out in the same manner as in Step 1 of Reference Example 12 using 3-amino-1-propanol instead of 2-aminoethanol in Step 1 of Reference Example 12. However, N- [3,5-bis (trifluoromethyl) benzyl] -N- (3-hydroxypropyl) amine was obtained as colorless crystals. Melting point: 57-58 ° C (recrystallized from ethyl ether-hexane) NMR (200 MHz, CDCl ₃ ) ppm: 1.77 (2H, quintet, J = 5.8 Hz),
2.89 (2H, t, J = 5.8Hz), 3.82 (2H, t, J = 5.8Hz), 3.93
(2H, s), 7.89 (3H, s) Elemental analysis: C ₁₂ H ₁₃ NOF ₆ Calculated (%): C 47.85, H 4.35, N 4.65 Actual (%): C 47.76, H 4.32, N 4.65.

(Step 2) N in Step 2 of Reference Example 12
-[3,5-bis (trifluoromethyl) benzyl]-
Step 1 instead of N- (2-hydroxyethyl) amine
The reaction was carried out using the amine obtained in Step 2 in the same manner as in Step 2 of Reference Example 12, and the title compound was obtained as colorless crystals (cis-trans isomer ratio about amino bond: about 3: 1). . Melting point: 121-122 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.00-1.70 (2H, m), 2.75-3.20
(2H, m), 3.35-3.55 (3H, m), 4.06 (1H × 1/4, d, J = 16.2
Hz), 4.31 (1H × 1/4, d, J = 16.2Hz), 4.65 (1H × 3/4, d,
J = 15.2Hz), 4.76 (1H × 3/4, d, J = 15.2Hz), 7.20-7.55 (6
H, m), 7.72 (2H, s), 7.80 (1H, s), 8.47 (1H, d, J = 5.2
Hz) Elemental analysis: C ₂₄ H ₁₉ N ₂ O ₂ F ₆ Cl Calculated (%): C 55.77, H 3.71, N 5.42 Found (%): C 55.65, H 3.70, N 5.57.

Reference Example 24 N- [3,5-bis (trifluoromethyl) benzyl]
2-chloro-N- (2-hydroxyethyl) -5-methyl-4-phenyl-3-pyridinecarboxamide 2 in place of 2-chloro-4-phenyl-3-pyridinecarboxylic acid in Step 2 of Reference Example 12. -Chloro-5-
The reaction was carried out in the same manner as in Step 2 of Reference Example 12 using methyl-4-phenyl-3-pyridinecarboxylic acid, and the title compound was obtained as colorless crystals. Melting point: 146-148 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.09 (3H, s), 3.02 (1H, dt, J)
= 15.0, 5.6Hz), 3.25 (1H, dt, J = 15.0, 5.6Hz), 3.60 (2
H, m), 4.57 (1H, d, J = 15.2Hz), 4.79 (1H, d, J = 15.2H
z), 7.05-7.50 (5H, m), 7.62 (2H, s) 7.76 (1H, s), 8.3
3 (1H, s).

Reference Example 25 N- [3,5-bis (trifluoromethyl) benzyl]
-2-Chloro-N- (3-hydroxypropyl) -5
Methyl-4-phenyl-3-pyridinecarboxamide Instead of 2-chloro-4-phenyl-3-pyridinecarboxylic acid in Step 2 of Reference Example 12, 2-chloro-5-
Using methyl-4-phenyl-3-pyridinecarboxylic acid, obtained in Step 1 of Reference Example 23 instead of N- [3,5-bis (trifluoromethyl) benzyl] -N- (2-hydroxyethyl) amine. The reaction was carried out using N- [3,5-bis (trifluoromethyl) benzyl] -N- (3-hydroxypropyl) amine in the same manner as in Step 2 of Reference Example 12, and the title compound was obtained. Obtained as a pale yellow oil. NMR (200 MHz, CDCl ₃ ) ppm: 1.10-1.80 (2H, m), 2.06 (3H
× 1/2, s), 2.08 (3H × 1/2, s), 2.80-3.30 (3H, m), 3.3
5-3.70 (1H, m), 4.08 (1H × 1/2, d, J = 16.4Hz), 4.39 (1H
× 1/2, d, J = 15.0Hz), 4.47 (1H × 1/2, d, J = 16.4Hz),
4.70 (1H × 1/2, d, J = 15.0Hz), 6.90-7.62 (7H, m), 7.72
(1H × 1/2, s), 7.77 (1H × 1/2, s), 8.28 (1H × 1/2, s),
8.31 (1H x 1/2, s).

Reference Example 26 (±) -N- [3,5-bis (trifluoromethyl) benzyl] -7,8-dihydro-7- (2,3-dihydroxypropyl) -5- (4-methylphenyl ) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide The compound obtained in Reference Example 3 and (±) -3-amino-1,2-
The reaction and treatment were carried out using propanediol in the same manner as in Reference Example 13, and the title compound was obtained as a pale yellow foam. NMR (200 MHz, CDCl ₃ ) ppm: 2.20 (3H, s), 3.50 (2H, m),
4.02-4.30 (5H, m), 4.75 (1H, b), 5.35 (1H, b), 6.92-
7.46 (6H, m), 7.55 (2H, s), 7.70 (1H, s), 8.63 (1H,
m), 8.83 (1H, b).

Reference Example 27 N-benzyl-8-oxo-5-phenyl-8H-pyrano- [3,4-b] pyridine-6-carboxamide Using the compound obtained in Step 2 of Reference Example 9 and benzylamine Then, the reaction and treatment were carried out in the same manner as in Reference Example 3 to obtain the title compound as colorless crystals. Melting point: 188-189 ° C (recrystallized from acetone-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 4.48 (2H, d, J = 5.4 Hz), 7.2
-7.4 (8H, m), 7.49-7.65 (5H, m), 8.95 (1H, dd, J = 4.4,
2.0Hz).

Reference Example 28 N- (3,4-dichlorobenzyl) -8-oxo-5
Phenyl-8H-pyrano [3,4-b] pyridine-6-
Carboxamide When the compound obtained in Step 2 of Reference Example 9 and 3,4-dichlorobenzylamine were reacted and treated in the same manner as in Reference Example 3, the title compound was obtained as colorless crystals. Melting point: 198-200 ° C (recrystallized from acetone-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 4.44 (2H, d, J = 6.0 Hz), 7.1
0 (1H, dd, J = 8.2, 2.0Hz), 7.25-7.70 (10H, m), 8.96 (1
H, dd, J = 4.3, 1.7Hz).

Reference Example 29 N- [3,5-bis (trifluoromethyl) benzyl]
-2-chloro-N-[(S) -3-hydroxy-2-methylpropyl] -5-methyl-4-phenyl-3-pyridinecarboxamide 3,5-bis (trifluoromethyl) benzylmethanesulfonate and (S ) -3-Amino-2-methylpropanol is reacted in THF to give N- [3,5-bis (trifluoromethyl) benzyl] -N-[(S) -3-hydroxy-2-methylpropyl] amine Was obtained as a colorless oil. NMR (200 MHz, CDCl ₃ ) ppm: 0.86 (3H, d, J = 6.8 Hz), 1.9
8 (1H, m), 2.63 (1H, dd, J = 9.4, 11.8Hz), 2.70-2.90 (3
H, m), 3.56 (1H, dd, J = 8.6, 10.6Hz), 3.71 (1H, ddd,
J = 1.4, 4.0, 10.6Hz), 3.87 (1H, d, J = 13.8Hz), 3.98 (1
H, d, J = 13.8 Hz), 7.79 (3H, s) 2-chloro-4-phenyl-3-pyridinecarboxylic acid and N- [3,5-bis (trifluoromethyl) in Step 2 of Reference Example 12. In place of benzyl] -N- (2-hydroxyethyl) amine, 2-chloro-5-methyl-4-phenyl-3-pyridinecarboxylic acid and the above N-
[3,5-bis (trifluoromethyl) benzyl] -N
The reaction was carried out using-[(S) -3-hydroxy-2-methylpropyl] amine in the same manner as in Step 2 of Reference Example 12 to give the title compound as a colorless oil. NMR (200 MHz, CDCl ₃ ) ppm: 0.60-0.82 (3H, m), 1.50-2.
00 (1H, m), 2.00-2.15 (3H, m), 2.15-3.92 (4H, m), 4.05
-4.92 (2H, m), 7.00-7.85 (8H, m), 8.34 (1H, m).

Reference Example 30 N- [3,5-bis (trifluoromethyl) benzyl]
-2-Chloro-N-[(R) -3-hydroxy-2-methylpropyl] -5-methyl-4-phenyl-3-pyridinecarboxamide N- [3,5-bis (trifluoromethyl) of Reference Example 29 ) Benzyl] -N-[(S) -3-hydroxy-2-
N- [3,5-bis (trifluoromethyl) benzyl] -N-[(R) -3 instead of methylpropyl] amine
-Hydroxy-2-methylpropyl] amine was reacted and treated in the same manner as in Reference Example 29 to give the title compound as a colorless oil. NMR spectrum of this product (2
00MHz, CDCl ₃ ) was identical to the spectrum of the compound obtained in Reference Example 29.

Reference Example 31 N- [3,5-bis (trifluoromethyl) benzyl]
-2-Chloro-N- (2-hydroxyethyl) -6-methyl-4-phenyl-3-pyridinecarboxamide (Step 1) 2-Chloro-6-methyl-4-phenyl-3
-Pyridinecarboxylic acid ethyl ester (15.43
g), a mixture of ethanol (70 ml) and a 4N aqueous solution of sodium hydroxide (70 ml) was heated under reflux for 2.5 hours. The reaction solution was concentrated, the concentrated solution was made acidic (pH 3) using hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with saturated saline, dried, and the solvent was distilled off.
Chloro-6-methyl-4-phenyl-3-pyridinecarboxylic acid was obtained as colorless crystals (11.2 g). Melting point: 191-194 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200MHz, CDCl ₃ ) ppm: 2.59 (3H, s), 7.16 (1H, s),
7.45 (5H, s), 9.53 (1H, b). (Step 2) 2-chloro-4 in Step 2 of Reference Example 12
Instead of -phenyl-3-pyridinecarboxylic acid, 2-chloro-6-methyl-4-phenyl- obtained in step 1
Step 3 of Reference Example 12 using 3-pyridinecarboxylic acid
The title compound was obtained as a pale yellow oil. NMR (200 MHz, CDCl ₃ ) ppm: 1.95-3.80 (4H, m), 2.58 (3H,
s), 4.15 (1H × 2/5, d, J = 16.2Hz), 4.41 (1H × 2/5, d,
J = 16.2Hz), 4.75 (1H × 3/5, d, J = 15.0Hz), 4.85 (1H × 3 /
5, d, J = 15.0Hz), 7.15 (1H × 3/5, s), 7.17 (1H × 2/5,
d, J = 15.0Hz), 7.23-7.58 (5H, m), 7.74 (2H, s), 7.78
(1H, s).

Reference Example 32 N- [3,5-bis (trifluoromethyl) benzyl]
-2-chloro-N- (3-hydroxypropyl) -6
Methyl-4-phenyl-3-pyridinecarboxamide 2-chloro-4-phenyl-3-pyridinecarboxylic acid in Step 2 of Reference Example 12 and N- [3,5-bis (trifluoromethyl) benzyl] -N- ( 2-Chloro-6-methyl-4-phenyl-3-pyridinecarboxylic acid and N- [3,3
5-bis (trifluoromethyl) benzyl] -N- (3
The reaction was carried out using -hydroxypropyl) amine in the same manner as in Step 2 of Reference Example 12, and the title compound was obtained as a pale yellow oil. NMR (200 MHz, CDCl ₃ ) ppm: 1.15-1.65 (2H, m), 2.59 (3H,
s), 2.75-3.20 (2H, m), 4.06 (1H × 2/5, d, J = 15.4Hz),
4.31 (1H × 2/5, d, J = 15.4Hz), 4.65 (1H × 3/5, d, J = 15.
2Hz), 4.74 (1H × 3/5, d, J = 15.2Hz), 7.16 (1H, s), 7.2
0-7.60 (5H, m), 7.72 (2H, s), 7.78 (1H, s).

Reference Example 33 N- [3,5-bis (trifluoromethyl) benzyl]
-N- (2-hydroxyethyl) -5-methyl-2-methylaminocarbonyl-4-phenyl-3-pyridinecarboxamide (Step 1) 5 prepared according to the method described in JP-A-62-160881. -Methyl-4-phenyl-2,3
-Pyridinedicarboxylic acid diethyl ester [13.0
g, melting point 73-74 ° C (recrystallized from ethyl ether-isopropyl ether)], potassium hydroxide (20
g) and a 70% aqueous ethanol solution (200 ml) were heated to reflux for 3 hours. After evaporation of the solvent, the residue was diluted with water and washed with ethyl ether. 2N water layer
-The pH was adjusted to 2-3 using hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated saline solution, dried, and then the solvent was distilled off to obtain 5-methyl-4-phenyl-2,3-pyridinedicarboxylic acid as pale yellow crystals (3.06 g). Melting point: 187-188 ° C (recrystallized from THF-ethyl ether) NMR (200 MHz, DMSO-d ₆ ) ppm: 2.10 (3H, s), 7.20-7.30
(2H, m), 7.40-7.55 (3H, m), 8.65 (1H, s). (Step 2) The compound (2.9 g) obtained in Step 1 was heated and refluxed in acetic anhydride (50 ml) for 2 hours. After the solvent was distilled off, ethanol (50 ml) was added to the residue, and the mixture was stirred at room temperature for 4 hours. After evaporation of the solvent, the residue was dissolved in ethyl acetate. The solution was washed with saturated saline, dried, and the solvent was distilled off to give 5-methyl-4-phenyl-.
A mixture (about 3: 2) of 2-ethyl ester and 3-ethyl ester of 2,3-pyridinedicarboxylic acid was obtained as a light brown oil (3.39 g).

(Step 3) The oily substance obtained in Step 2 (1.
DMF (3 drops) in a solution of 94 g) in THF (30 ml)
And oxalyl chloride (2.0 ml).
Stirred for 0 minutes. After the solvent was distilled off, the residue was washed with THF.
(40 ml). N- [3,5-bis (trifluoromethyl) benzyl] -N- (2-hydroxyethyl) amine (2.2 g) and triethylamine (2.0 ml) were added to this solution, and the mixture was stirred at room temperature for 16 hours.
The reaction mixture was diluted with ethyl acetate, washed with water, diluted hydrochloric acid, aqueous potassium carbonate solution and saturated saline solution in that order, and dried. After the solvent was distilled off, the residue was subjected to column chromatography using silica gel (hexane-ethyl acetate =
1: 2), followed by purification, to give N- [3,5-bis (trifluoromethyl) benzyl] -2-ethoxycarbonyl-N- (2-hydroxyethyl) -5-methyl-4-phenyl -3-Pyridinecarboxamide was obtained as colorless crystals (1.31 g). Melting point: 138-139 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200MHz, CDCl ₃ ) ppm: 1.45 (3H × 1/4, t, J = 7.1Hz),
1.46 (3H × 3/4, t, J = 7.1Hz), 2.18 (3H × 3/4, s), 2.19
(3H x 1/4, s), 2.82 (1H, m), 3.2-3.7 (3H, m), 4.15-4.6
2 (4H, m), 7.05-7.80 (8H, m), 8.65 (1H × 3/4, s), 8.68
(1H × 1/4, s). (Step 4) T of the compound (377 mg) obtained in Step 3
A 40% methylamine-methanol solution (15 ml) was added to the HF (5 ml) solution, and the mixture was stirred at room temperature for 16 hours.
Evaporation of the solvent gave the title compound as a pale yellow oil (370
mg). NMR (200 MHz, CDCl ₃ ) ppm: 2.12 (3H × 2/3, s), 2.14 (3H
× 1/3, s), 2.83 (1H, m), 3.03 (3H × 1/3, d, J = 5.2Hz),
3.04 (3H × 2/3, d, J = 4.8Hz), 3.25-3.80 (3H, m), 4.30
(1H × 2/3, d, J = 15Hz), 4.36 (1H × 1/3, d, J = 15Hz), 4.
59 (1H × 1/3, d, J = 15Hz), 4.86 (1H × 2/3, d, J = 15Hz),
7.0-7.9 (8H, m), 8.02 (1H × 2/3, bd), 8.17 (1H × 1/3, b
d), 8.46 (1H, s).

Reference Example 34 N- [3,5-bis (trifluoromethyl) benzyl]
-N- (2-hydroxyethyl) -2-methylaminocarbonyl-4-phenyl-3-pyridinecarboxamide (Step 1) 5-methyl-4 in Step 1 of Reference Example 33
4-phenyl-2,3-pyridinedicarboxylic acid diethyl ester instead of -phenyl-2,3-pyridinedicarboxylic acid diethyl ester [Japanese Patent Laid-Open No. 62-1060]
No. 81], and the reaction was carried out in the same manner as in Step 1 of Reference Example 33 to give 4-phenyl-2,3-pyridinedicarboxylic acid as pale yellow crystals. Melting point: 146-148 ° C (recrystallized from THF-isopropyl ether) NMR (200 MHz, CDCl ₃ + DMSO-d ₆ ) ppm: 7.3-7.6 (6H, m),
8.69 (1H, d, J = 5.0Hz). (Step 2) Reference example 33 using the compound obtained in step 1
Reacting and treating in the same manner as in Step 2 of 4-phenyl-
A mixture of 2,3-pyridinedicarboxylic acid 2-ethyl ester and 3-ethyl ester (about 3: 2) was obtained as a light brown oil.

(Step 3) The oily substance obtained in step 2 was reacted in the same manner as in step 3 of Reference Example 33 to give N-
[3,5-bis (trifluoromethyl) benzyl] -2
-Ethoxycarbonyl-N- (2-hydroxyethyl)
-4-Phenyl-3-pyridinecarboxamide was obtained as a pale yellow oil. NMR (200 MHz, CDCl ₃ ) ppm: 1.48 (3H, t, J = 7.1 Hz), 2.71
(1H, m), 3.1-3.7 (3H, m), 4.1-4.9 (4H, m), 7.18-7.52
(6H, m), 7.65-7.82 (3H, m), 8.78 (1H × 3/4, d, J = 4.8H
z), 8.80 (1H × 1/4, d, J = 4.8Hz)). (Step 4) Reference example 33 using the compound obtained in step 3
The title compound was obtained as a pale-yellow oil upon treatment. NMR (200 MHz, CDCl ₃ ) ppm: 2.73 (1H, m), 3.05 (3H × 1/3,
d, J = 5.0Hz), 3.06 (3H × 2/3, d, J = 5.0Hz), 3.1-3.9 (3
H, m), 4.29 (1H × 1/3, d, J = 16Hz), 4.52 (1H × 2/3, d,
J = 15Hz), 4.54 (1H × 1/3, d, J = 16Hz), 4.93 (1H × 2/3,
d, J = 15Hz), 7.0-7.9 (9H, m), 7.95 (1H × 2/3, bd), 8.1
9 (1H × 1/3, bd), 8.59 (1H, d, J = 5.2Hz).

Reference Example 35 N-benzyl-2-ethoxycarbonyl-N- (2-hydroxyethyl) -5-methyl-4-phenyl-3-pyridinecarboxamide The oil obtained in Step 2 of Reference Example 33 and N -Benzyl-
Reference Example 3 using N- (2-hydroxyethyl) amine
Reaction and treatment as in step 3 of 3 gave the title compound as a pale yellow oil. NMR (200 MHz, CDCl ₃ ) ppm: 1.44 (3H × 1/4, t, J = 7.2 Hz),
1.46 (3H × 3/4, t, J = 7.1Hz), 2.15 (3H × 3/4, s), 2.19
(3H × 1/4, s), 2.6-3.7 (4H, m), 3.96 (1H × 3/4, d, J = 1
5Hz), 4.00 (1H × 1/4, d, J = 15Hz), 4.4-4.6 (2H + 1H × 1 /
4, m), 5.37 (1H × 3/4, d, J = 15Hz), 6.48 (2H × 3/4, m),
6.82 (2H x 1/4, m) 7.0-7.6 (8H, m), 8.65 (1H x 3/4,
s), 8.66 (1H x 1/4, s).

Reference Example 36 N- [3,5-bis (trifluoromethyl) benzyl]
-N- (3-hydroxypropyl) -5-methyl-2-
Methylaminocarbonyl-4-phenyl-3-pyridinecarboxamide (Step 1) The oil obtained in Step 2 of Reference Example 33 and N-
[3,5-bis (trifluoromethyl) benzyl] -N
Reference Example 3 using-(3-hydroxypropyl) amine
Reaction and treatment in the same manner as in Step 3 of Step 3 gave N- [3,5
-Bis (trifluoromethyl) benzyl] -2-ethoxycarbonyl-N- (3-hydroxypropyl) -5
Methyl-4-phenyl-3-pyridinecarboxamide was obtained as a pale yellow oil. NMR (200 MHz, CDCl ₃ ) ppm: 1.44 (3H × 1/4, t, J = 7.1 Hz),
1.45 (3H × 3/4, t, J = 7.1Hz), 1.60 (2H, m), 2.17 (3H ×
3/4, s), 2.18 (3H x 1/4, s), 2.7-3.7 (4H, m), 3.96 (1H
× 1/4, d, J = 16Hz), 4.35-4.60 (3H + 1H × 3/4, m), 7.10
-7.80 (8H, m), 8.64 (1H x 3/4, s), 8.68 (1H x 1/4, s). (Step 2) Reference example 33 using the compound obtained in step 1
The title compound was obtained as a pale-yellow oil upon treatment. NMR (200 MHz, CDCl ₃ ) ppm: 1.3-1.9 (2H, m), 2.11 (3H × 3
/ 5, s), 2.14 (3H × 2/5, s), 2.7-3.8 (4H, m), 3.02 (3H
× 3/5, d, J = 5.2Hz), 3.03 (3H × 2/5, d, J = 5.2Hz), 4.0
4 (1H × 2/5, d, J = 16Hz), 4.28 (1H × 3/5, d, J = 15Hz),
4.46 (1H × 2/5, d, J = 16Hz), 4.82 (1H × 3/5, d, J = 15Hz),
7.0-7.6 (5H, m), 7.63 (2H × 3/5, s), 7.67 (2H × 2/5,
s), 7.73 (1H, s), 7.96 (1H × 3/5, bd), 8.06 (1H × 2/5,
bd), 8.45 (1H × 3/5, s), 8.48 (1H × 2/5, s).

The compound of Reference Example 37-45 was 2-chloro-
4-phenyl-3-pyridinecarboxylic acid and N-substituted-N
-(Substituted) benzylamines, each of which is N- (2-hydroxyethyl) -N- (3,4,5-trimethoxybenzyl) amine, N- (3,4-dichlorobenzyl) -N
-(2-hydroxyethyl) amine, N- (3,4-
Dimethoxybenzyl) -N- (2-hydroxyethyl)
Amine, N-benzyl-N- (2-hydroxyethyl) amine, N- (2-hydroxypropyl) -N-
(3,4,5-trimethoxybenzyl) amine, N-
Benzyl-N-[(S) -3-hydroxy-2-methylpropyl] amine, N-benzyl-N-[(R) -3
-Hydroxy-2-methylpropyl] amine, N-
[3,5- (Bistrifluoromethyl) benzyl] -N
-[(S) -3-hydroxy-2-methylpropyl] amine and N- [3,5- (bistrifluoromethyl) benzyl] -N-[(R) -3-hydroxy-2-
Reference Example 12 Step 2 using [methylpropyl] amine}
The reaction was carried out in substantially the same manner as described above, and each was treated to give a pale yellow oil. The physicochemical data is described below.

Reference Example 37 2-Chloro-N- (2-hydroxyethyl) -4-phenyl-N- (3,4,5-trimethoxybenzyl) -3
- pyridinecarboxamide _{NMR (200MHz, CDCl 3) ppm} : 2.05-2.50 (2H, m), 2.80-4.0
0 (12H, m), 4.00-4.40 (1H × 3/2, m), 4.93 (1H × 1/2, d,
J = 14.2Hz), 6.22 (2H × 1/2, s), 6.55 (2H × 1/2, s), 7.
25-7.70 (6H, m), 8.42 (1H × 1/2, d, J = 6.2Hz), 8.48 (1H
× 1/2, d, J = 5.8Hz). (1: 1 mixture of amide rotamers).

Reference Example 38 2-Chloro-N- (3,4-dichlorobenzyl) -N-
(2-hydroxyethyl) -4-phenyl-3-pyridinecarboxamide _{NMR (200MHz, CDCl 3) ppm} : 1.80-3.85 (5H, m), 3.96 (1H
× 4/9, d, J = 16.0Hz), 4.24 (1H × 4/9, d, J = 16.0Hz), 4.
44 (1H × 5/9, d, J = 15.2Hz), 4.92 (1H × 5/9, d, J = 15.2H
z), 6.50-6.85 (2H, m), 7.10-7.70 (7H, m), 8.46 (1H,
m). (A mixture of amide rotamers 5: 4).

Reference Example 39 2-Chloro-N- (3,4-dimethoxybenzyl) -N
- (2-hydroxyethyl) -4-phenyl-3-pyridinecarboxamide _{NMR (200MHz, CDCl 3) ppm} : 2.70-4.30 (12H, m), 4.53 (1H
× 1/2, d, J = 14.8Hz), 4.74 (1H × 1/2, d, J = 14.8Hz), 6.
30-7.00 (3H, m), 7.20-7.65 (6H, m), 8.39 (1H × 1/2, d,
J = 5.0Hz), 8.46 (1H × 1/2, d, J = 5.2Hz). (1: 1 mixture of amide rotamers).

Reference Example 40 N-benzyl-2-chloro-N- (2-hydroxyethyl) -4-phenyl-3-pyridinecarboxamide NMR (200 MHz, CDCl ₃ ) ppm: 2.27 (1H × 1/2, b) , 2.60 (1H
× 1/2, b), 2.75-3.15 (1H, m), 3.25-3.65 (3H, m), 3.9
0 (1H × 1/2, d, J = 15.4Hz), 4.26 (1H × 1/2, d, J = 15.4H
z), 4.49 (1H × 1/2, d, J = 15.0Hz), 4.95 (1H × 1/2, d, J
= 15.0Hz), 6.74 (2H × 1/2, m), 6.92 (2H × 1/2, m), 7.10
-7.65 (9H, m), 8.42 (1H, m). (1: 1 mixture of amide rotamers).

Reference Example 41 2-chloro-N- (2-hydroxypropyl) -4-phenyl-N- (3,4,5-trimethoxybenzyl)-
3-pyridinecarboxamide _{NMR (200MHz, CDCl 3) ppm} : 1.10-2.30 (3H, m), 2.70-4.3
0 (14H + 1H × 3/7, m), 4.88 (1H × 4/7, d, J = 14.8Hz), 6.1
8 (2H × 4/7, s), 6.52 (2H × 3/7, s), 7.20-7.60 (6H, m),
8.47 (1H, m). (A mixture of amide rotamers 4: 3).

Reference Example 42 N-benzyl-2-chloro-N-[(S) -3-hydroxy-2-methylpropyl] -4-phenyl-3-pyridinecarboxamide NMR (200 MHz, CDCl ₃ ) ppm: 0.50- 0.85 (3H, m), 1.40-1.8
5 (1H, m), 2.20-3.75 (5H, m), 3.80-5.15 (2H, m), 6.60
-7.65 (11H, m), 8.42 (1H, m). (2: 1 mixture of amide rotamers).

Reference Example 43 N-benzyl-2-chloro-N-[(R) -3-hydroxy-2-methylpropyl] -4-phenyl-3-pyridinecarboxamide NMR (200 MHz, CDCl ₃ ) ppm: Reference Example Same as spectrum of compound 42.

Reference Example 44 N- [3,5- (bistrifluoromethyl) benzyl]
2-chloro -N - [(S) -3- hydroxy-2-methylpropyl] -4-phenyl-3-pyridinecarboxamide _{NMR (200MHz, CDCl 3) ppm} : 0.53 (3H × 1/4, d, J = 7.0Hz),
0.63 (3H × 1/4, d, J = 7.0Hz), 0.75 (3H × 1/4, d, J = 6.8
Hz), 0.81 (3H × 1/4, d, J = 6.8Hz), 1.50-1.90 (1H, m),
2.42-3.80 (5H, m), 4.00-4.95 (2H, m), 7.10-7.90 (9H,
m), 8.42 (1H, m). (1: 1 mixture of amide rotamers).

Reference Example 45 N- [3,5- (bistrifluoromethyl) benzyl]
2-chloro -N - [(R) -3- hydroxy-2-methylpropyl] -4-phenyl-3-pyridinecarboxamide _{NMR (200MHz, CDCl 3) ppm} : same as the spectrum of the compound of Reference Example 44.

Reference Example 46 N-benzyl-7,8-dihydro-7- (4-hydroxybutyl) -5- (4-methylphenyl) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide (Step 1) Reference Example 2 The compound obtained in Step 2 was reacted with benzylamine in substantially the same manner as in Step 4 of Reference Example 2 to give N-benzyl-5- (4-methylphenyl). ) -8-Oxo-8H-pyrano [3,4-b]
Pyridine-6-carboxamide was obtained as colorless crystals. Melting point: 208-209 ° C (recrystallized from acetone-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.45 (3H, s), 4.48 (2H, d, J)
= 5.6Hz), 7.10-7.40 (10H, m), 7.58 (2H, m), 8.94 (1H,
dd, J = 3.6, 2.2Hz). (Step 2) The compound obtained in Step 1 was reacted with 4-amino-1-butanol in substantially the same manner as in Reference Example 13 to give the title compound as colorless crystals. Melting point: 205-207 ° C (recrystallized from acetone-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.48 (2H, m), 1.83 (2H, m),
2.45 (3H, s), 2.86 (1H, b), 3.57 (2H, t, J = 5.9Hz), 3.
85 (2H, m), 4.34 (2H, d, J = 6.0Hz), 6.8-7.1 (2H, m),
7.10-7.35 (8H, m), 7.50 (1H, m), 7.55 (1H, dd, J = 8.4,
1.4Hz), 8.60 (1H, dd, J = 4.0, 1.4Hz).

Reference Example 47 (R) -N-benzyl-7,8-dihydro-7- (4-
(Hydroxy-3-methylbutyl) -5- (4-methylphenyl) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide Reference Example 46 The compound obtained in Step 1 and (R) -4-amino-
The reaction was carried out in substantially the same manner as in Reference Example 19 using THP ether of 2-methyl-1-butanol to give the title compound as colorless crystals. Melting point: 226-227 ° C. (recrystallized from acetone-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.81 (3H, d, J = 6.6 Hz), 1.5-
2.0 (3H, m), 2.44 (3H, s), 3.20-3.55 (3H, m), 3.93 (2H,
m), 4.31 (2H, d, J = 5.4Hz), 6.75-6.90 (2H, m), 7.1-7.
3 (8H, m), 7.39 (1H, dd, J = 8.2, 4.2Hz), 7.61 (1H, d,
J = 8.2Hz), 8.68 (1H, d, J = 4.2Hz).

Reference Example 48 (S) -N-benzyl-7,8-dihydro-7- (4-
(Hydroxy-3-methylbutyl) -5- (4-methylphenyl) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide The compound obtained in Reference Example 46 Step 1 and (S) -4-amino-
The reaction was carried out in substantially the same manner as in Reference Example 19 using THP ether of 2-methyl-1-butanol to give the title compound as colorless crystals. Melting point: 226-227 ° C. (recrystallized from acetone-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: Same as the spectrum of the compound of Reference Example 47.

Reference Example 49 (R) -7,8-dihydro-7- (4-hydroxy-3
-Methylbutyl) -5- (4-methylphenyl) -8-
Oxo-N- (3,4,5-trimethoxybenzyl)-
6-pyrido [3,4-b] pyridinecarboxamide (Step 1) Reference Example 2 The compound obtained in Step 2 and 3,4,5-
Reference Example 2 Step 4 using trimethoxybenzylamine
And treated in substantially the same manner as
(4-methylphenyl) -8-oxo-N- (3,4,
5-trimethoxybenzyl) -8H-pyrano [3,4-
b] Pyridine-6-carboxamide was obtained as colorless crystals. Melting point: 195-196 ° C (recrystallized from acetone-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.45 (3H, s), 3.84 (3H, s),
3.85 (6H, s), 4.40 (2H, d, J = 5.8Hz), 6.50 (2H, s), 7.
17 (2H, d, J = 8.0Hz), 7.27 (1H, b), 7.32 (2H, d, J = 8.0H
z), 7.58 (2H, m), 8.94 (1H, dd, J = 4.0, 2.2Hz). (Step 2) Compound obtained in Step 1 and (R) -4-amino-
The reaction was carried out in substantially the same manner as in Reference Example 19 using THP ether of 2-methyl-1-butanol to give the title compound as colorless crystals. Melting point: 194-195 ° C. (recrystallized from acetone-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.84 (3H, d, J = 6.8 Hz), 1.5-
2.0 (3H, m), 2.38 (3H, s), 3.2-3.6 (3H, m), 3.65-3.95
(2H, m), 3.80 (6H, s), 3.82 (3H, s), 4.23 (2H, d, J =
6.0Hz), 6.40 (2H, s), 7.05-7.40 (4H, m), 7.32 (1H, d
d, J = 8.2, 4.2Hz), 7.56 (1H, dd, J = 8.2, 1.6Hz), 7.80
(1H, m), 8.63 (1H, dd, J = 4.2, 1.6Hz).

Reference Example 50 (S) -7,8-dihydro-7- (4-hydroxy-3
-Methylbutyl) -5- (4-methylphenyl) -8-
Oxo-N- (3,4,5-trimethoxybenzyl)-
6-pyrido [3,4-b] pyridinecarboxamide Reference Example 49 The compound obtained in Step 1 and (S) -4-amino-
The reaction and treatment were carried out in substantially the same manner as in Reference Example 19 using THP ether of 2-methyl-1-butanol, whereby the title compound was obtained as colorless crystals. Mp: 194-195 ° C. (acetone - recrystallized from ethyl _{ether) NMR (200MHz, CDCl 3)} ppm: same as the spectrum of the compound of Reference Example 49.

Reference Example 51 (R) -N- (3,5-dimethoxybenzyl) -7,8
-Dihydro-7- (4-hydroxy-3-methylbutyl) -5- (4-methylphenyl) -8-oxo-6-
Pyrido [3,4-b] pyridinecarboxamide (Step 1) Reference Example 2 Using 3,5-dimethoxybenzylamine and the compound obtained in Step 2, substantially the same reaction as in Reference Example 2 Step 4 was carried out. After processing, N- (3,5
-Dimethoxybenzyl) -5- (4-methylphenyl)
-8-oxo-8H-pyrano [3,4-b] pyridine-
6-carboxamide was obtained as colorless crystals. Melting point: 154-155 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200MHz, CDCl ₃ ) ppm: 2.45 (3H, s), 3.78 (6H, s),
4.41 (2H, d, J = 5.4Hz), 6.41 (3H, m), 7.17 (2H, d, J =
8.0Hz), 7.23 (1H, b), 7.33 (2H, d, J = 8.0Hz), 7.58 (2H,
m), 8.94 (1H, dd, J = 4.0, 2.2Hz). (Step 2) Compound (R) -4-amino-2 obtained in Step 1
Using the THP ether of -methyl-1-butanol,
The reaction and treatment were conducted in substantially the same manner as in Reference Example 19 to give the title compound as colorless crystals. Melting point: 169-172 ° C (recrystallized from acetone-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.85 (3H, d, J = 6.8 Hz), 1.62
(1H, m), 1.79 (2H, m), 2.40 (3H, s), 3.11 (1H, b), 3.
25-3.60 (2H, m), 3.76 (6H, s), 3.86 (2H, m), 4.23 (2H,
d, J = 5.6Hz), 6.25 (2H, d, J = 2.2Hz), 6.35 (1H, t, J =
2.2Hz), 7.15-7.35 (4H, m), 7.30 (1H, dd, J = 8.4, 4.2H
z), 7.44 (1H, m), 7.56 (1H, dd, J = 8.4,1.6Hz), 8.65 (1
H, dd, J = 4.2, 1.6Hz).

The compounds of Reference Examples 52-54 and 144 were 2-chloro-4- (4-methylphenyl) -3-
Pyridine carboxylic acid [2-cyano-3-methyl-3-
(4-Methylphenyl) propenoic acid Ethyl ester is condensed with N, N-dimethylacetamide dimethylacetal, then cyclized with hydrogen chloride, and the ester group is alkali-hydrolyzed. Decomposition)] and N-substituted-N- (substituted) benzylamine {N-benzyl-N- (2-hydroxyethyl) amine, N- [3,5-bis (trifluoromethyl) benzyl] -N- (2-hydroxyethyl) amine, N-benzyl-N-[(S) -3-hydroxy-2-methylpropyl] amine, and N- [3,5-bis (trifluoromethyl) benzyl] -N- [ Reference Example 12 using (S) -3-hydroxy-2-methylpropyl] amine
The reaction was carried out in substantially the same manner as in Step 2, and each was obtained as a pale yellow oil upon treatment. The physicochemical data is described below.

Reference Example 52 N-benzyl-2-chloro-N- (2-hydroxyethyl) -4- (4-methylphenyl) -3-pyridinecarboxamide NMR (200 MHz, CDCl ₃ ) ppm: 2.43 (3H × 1) / 2, s), 2.46 (3H
× 1/2, s), 2.70-3.80 (total 4H, m), 3.90 (1H × 1/2,
d, J = 15.4Hz), 4.24 (1H × 1/2, d, J = 15.4Hz), 4.51 (1H
× 1/2, d, H = 15.2Hz), 4.94 (1H × 1/2, d, J = 15.2Hz),
6.74 (1H, m), 6.97 (1H, m), 7.10-7.55 (8H, m), 8.40 (1
H, m). (1: 1 mixture of amide rotamers).

Reference Example 53 N- [3,5-bis (trifluoromethyl) benzyl]
-2-Chloro-N- (2-hydroxyethyl) -4-
(4-Methylphenyl) -3-pyridinecarboxamide NMR (200 MHz, CDCl ₃ ) ppm: 2.36 (3H × 7/11, s), 2.44 (3H
× 4/11, s), 2.80-3.80 (total 4H, m), 4.16 (1H × 4/11,
d, J = 16.2Hz), 4.41 (1H × 4/11, d, J = 16.2Hz), 4.77 (1H
H × 7/11, d, H = 15.0Hz), 4.90 (1H × 7/11, d, J = 15.0H
z), 7.10-7.50 (6H, m), 7.76 (2H, m), 8.42 (1H, m). (A mixture of amide rotamers 7: 4).

Reference Example 54 N-benzyl-2-chloro-N-[(S) -3-hydroxy-2-methylpropyl] -4- (4-methylphenyl) -3-pyridinecarboxamide NMR (200 MHz, CDCl ₃ ) ppm: 0.59 (3H × 1/4, d, J = 7.0Hz),
0.66 (3H × 1/4, d, J = 7.0Hz), 0.77 (3H × 1/4, d, J = 3.8H
z), 0.80 (3H × 1/4, d, J = 3.8Hz), 1.40-1.90 (1H, m),
2.30-2.50 (3H, m), 2.50-3.80 (total 5H, m), 3.80-4.4
2 (2H × 3/4, m), 5.05 (2H × 1/4, m), 6.60-7.50 (total 10
H, m), 8.40 (1H, m). (1: 1 mixture of amide rotamers).

Reference Example 55 7- [3,5-bis (trifluoromethyl) benzyl]
-6,7,8,9-Tetrahydro-5- (4-methylphenyl) -6,11-dioxo-11H-pyrazino [2,1-g] [1,7] naphthyridine Compound obtained in Reference Example 1 ( 200 mg), triethylamine (0.20 ml), methanesulfonyl chloride (0.10
ml) and dichloromethane (10 ml) in 0 ml.
Stirred at C for 2 hours. Ethyl acetate was added to the reaction mixture,
After washing with water and drying and evaporating the solvent, N- [3,5-
Bis (trifluoromethyl) benzyl] -7,8-dihydro-7- (2-methanesulfonyloxyethyl) -5
-(4-Methylphenyl) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide was formed. After dissolving this compound in DMF (5 ml), sodium hydride (60% oil) (30 mg) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with ethyl acetate, washed sequentially with water, diluted hydrochloric acid, and water, dried, and evaporated to give the title compound as colorless crystals (109 mg). Melting point: 270-271 ° C (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.46 (3H, s), 3.67 (2H, tlik)
e, J = 5.4Hz), 4.51 (2H, t like, J = 5.4Hz), 4.81 (2H,
s), 7.13 (2H, d, J = 8.1Hz), 7.33 (2H, d, J = 8.1Hz), 7.
52 (1H, dd, J = 8.4, 4.4Hz), 7.64 (1H, dd, J = 8.4, 1.6H
z), 7.70 (2H, s), 7.84 (1H, s), 8.97 (1H, dd, J = 4.4,
1.6 Hz) Elemental analysis: C ₂₇ H ₁₉ N ₃ O ₂ F ₆ Calculated (%): C 61.02, H 3.60, N 7.91 Found (%): C 61.07, H 3.50, N 7.85.

Reference Example 56 7- [3,5-bis (trifluoromethyl) benzyl]
-6,7,8,9,10,12-Hexahydro-5-
(4-methylphenyl) -6,12-dioxo [1,
4] Diazepino [2,1-g] [1,7] naphthyridine N- [3,5-bis (trifluoromethyl) benzyl] -7- (3-chloropropyl) -7,8 obtained in Reference Example 2.
-Dihydro-5- (4-methylphenyl) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide (66 mg), sodium hydride (60% oil) (84
mg) and THF (3 ml) was stirred at room temperature for 14 hours. After adding 2N-HCl to the reaction mixture, it was made alkaline with aqueous potassium carbonate and extracted with ethyl acetate. The extract was washed with water, dried and the solvent was distilled off to give the title compound as colorless crystals (35 mg). Melting point: 194-195 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.16 (2H, m), 2.42 (3H, s),
3.25-3.70 (3H, m), 4.12 (1H, d, J = 15Hz), 5.34 (1H, d,
J = 15Hz), 5.52 (1H, m), 6.93 (1H, d, J = 8.2Hz), 7.20
(1H, d, J = 8.2Hz), 7.30-7.45 (2H, m), 7.51 (1H, dd, J
= 8.4, 4.4Hz), 7.62 (2H, s), 7.70 (1H, dd, J = 8.4, 1.6
Hz), 7.84 (1H, s), 8.93 (1H, dd, J = 4.4, 1.6 Hz) Elemental analysis: C ₂₈ H ₂₁ N ₃ O ₂ F ₆ Calculated (%): C 61.65, H 3.88, N 7.70 Found (%): C 61.29, H 4.06, N 7.61.

Reference Example 57 7- [3,5-bis (trifluoromethyl) benzyl]
-6,7,8,9,10,11-Hexahydro-5-
(4-methylphenyl) -6,13-dioxo-13H
-[1,4] diazosino [2,1-g] [1,7] naphthyridine The compound obtained in Reference Example 5 was reacted and treated in the same manner as in Reference Example 55 to give the title compound as colorless crystals Was obtained as Melting point: 192-193 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.7-2.5 (4H, m), 2.37 (3H,
s), 3.25 (1H, m), 3.40-3.72 (2H, m), 4.01 (1H, d, J = 1
5Hz), 5.13 (1H, dd, J = 14, 5.4Hz), 5.46 (1H, d, J = 15H
z), 6.85 (1H, d, J = 7.9Hz), 7.05 (1H, d, J = 7.9Hz), 7.
26 (1H, d, J = 7.8Hz), 7.34 (1H, d, J = 7.8Hz), 7.42-7.6
0 (2H, m), 7.47 (2H, s), 7.81 (1H, s), 8.92 (1H, m).

Reference Example 58 6,7,8,9,10,12-Hexahydro-7- (2
-Methoxybenzyl) -5- (4-methylphenyl)-
6,12-dioxo [1,4] diazepino [2,1-
g] [1,7] Naphthyridine The compound obtained in Reference Example 6 was reacted and treated in the same manner as in Reference Example 55, whereby the title compound was obtained as colorless crystals. Melting point: 264-266 ° C. (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.7-2.1 (2H, m), 2.43 (3H,
s), 3.25-3.52 (3H, m), 3.84 (3H, s), 4.67 (2H, s), 5.
39 (1H, dd, J = 14, 5.8Hz), 6.85-7.00 (3H, m), 7.10-7.2
2 (2H, m), 7.22-7.44 (3H, m), 7.48 (1H, dd, J = 8.4, 4.
4Hz), 7.72 (1H, dd, J = 8.4, 1.4Hz), 8.90 (1H, dd, J =
4.4, 1.4Hz).

Reference Example 59 6,7,8,9,10,11-Hexahydro-7- (2
-Methoxybenzyl) -5- (4-methylphenyl)-
6,13-Dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine The compound obtained in Reference Example 7 was reacted and treated in the same manner as in Reference Example 55. However, the title compound was obtained as colorless crystals. Melting point: 235-236 ° C. (recrystallized from ethyl acetate) NMR (200 MHz, CDCl ₃ ) ppm: 1.6-2.3 (4H, m), 2.46 (3H,
s), 3.15-3.30 (1H, m), 3.38-3.65 (2H, m), 3.80 (3H,
s), 4.24 (1H, d, J = 15Hz), 5.04 (1H, d, J = 15Hz), 5.13
(1H, dd, J = 15, 6.4Hz), 6.25 (1H, dd, J = 7.6, 1.4Hz),
6.63 (1H, dt, J _d = 0.5Hz, J _t = 7.6Hz), 6.82 (1H, d, J =
7.4Hz), 6.96 (1H, dd, J = 7.6, 2.0Hz), 7.11-7.34 (3H,
m), 7.38-7.47 (1H, m), 7.47 (1H, dd, J = 8.3, 4.3Hz),
7.62 (1H, dd, J = 8.3, 1.7Hz), 8.90 (1H, dd, J = 4.3, 1.
7Hz).

Reference Example 60 7- [3,5-bis (trifluoromethyl) benzyl]
-6,7,8,9,10,11,12,14-Octahydro-5- (4-methylphenyl) -6,14-dioxo [1,4] diazonino [2,1-g] [1,7 Naphthyridine The reaction was carried out using the compound obtained in Reference Example 8 in the same manner as in Reference Example 55, and the title compound was obtained as colorless crystals. Melting point: 177-179 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.45-1.95 (4H, m), 2.10 (2
H, m), 2.33 (3H, s), 3.06-3.24 (1H, m), 3.32-3.56 (2
H, m), 3.86 (1H, d, J = 15Hz), 4.95 (1H, dt, Jd = 15Hz,
Jt = 4.8Hz), 5.38 (1H, d, J = 15Hz), 6.86 (1H, dd, J = 8.
0, 1.5Hz), 7.00 (1H, d, J = 8.0Hz), 7.17 (1H, d, J = 8.2
Hz), 7.29 (1H, dd, J = 8.2, 1.5Hz), 7.40-7.54 (2H, m),
7.44 (2H, s), 7.79 (1H, s), 8.89 (1H, dd, J = 3.8, 2.0
Hz).

Reference Example 61 7- [3,5-bis (trifluoromethyl) benzyl]
-6,7,8,9,10,12-Hexahydro-6,1
2-Dioxo-5-phenyl [1,4] diazepino [2,1-g] [1,7] naphthyridine The compound obtained in Reference Example 9 was reacted and treated in the same manner as in Reference Example 55. The title compound was obtained as colorless crystals. Melting point: 244-245 ° C. (recrystallized from ethyl acetate-THF-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.00-2.25 (2H, m), 3.25-3.
70 (3H, m), 4.15 (1H, d, J = 15Hz), 5.30 (1H, d, J = 15H
z), 5.52 (1H, m), 7.05 (1H, d, J = 7.4Hz), 7.3-7.7 (6H,
m), 7.62 (2H, s), 7.84 (1H, s), 8.93 (1H, dd, J = 4.2,
1.6Hz).

Reference Example 62 7- [3,5-bis (trifluoromethyl) benzyl]
-6,7,8,9,10,11-Hexahydro-6,1
3-Dioxo-5-phenyl-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine Using the compound obtained in Reference Example 10, reacted in the same manner as in Reference Example 55, Upon treatment, the title compound was obtained as colorless crystals. Melting point: 205-206 ° C (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.70-2.35 (4H, m), 3.18-3.
36 (1H, m), 3.4-3.7 (2H, m), 3.98 (1H, d, J = 15Hz), 5.
14 (1H, dd, J = 14, 5.8Hz), 5.43 (1H, d, J = 15Hz), 6.94
(1H, d, J = 7.3Hz), 7.19 (1H, t, J = 7.3Hz), 7.3-7.6 (5
H, m), 7.44 (2H, s), 7.79 (1H, s), 8.91 (1H, dd, J = 4.
0, 1.8Hz).

Reference Example 63 7- [3,5-bis (trifluoromethyl) benzyl]
-6,7,8,9,10,11-Hexahydro-5-
(4-methylphenyl) -6,13-dioxo-13H
-[1,4] diazosino [1,2-b] [2,7] naphthyridine The compound obtained in Reference Example 11 was reacted and treated in the same manner as in Reference Example 55, and the title compound was found to be colorless crystals Was obtained as Melting point: 231-233 ° C. (recrystallized from THF-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.7-2.3 (4H, m), 2.37 (3H,
s), 3.2-3.7 (3H, m), 4.00 (1H, d, J = 15Hz), 5.05 (1H, d
d, J = 15, 6.2Hz), 5.44 (1H, d, J = 15Hz), 6.83 (1H, dd,
J = 7.8, 1.6Hz), 6.98 (1H, d, J = 5.4Hz), 7.04 (1H, d,
J = 7.8Hz), 7.25 (1H, d, J = 7.8Hz), 7.33 (1H, dd, J = 7.
8, 1.6Hz), 7.46 (2H, s), 7.81 (1H, s), 8.64 (1H, d, J =
5.4Hz), 9.68 (1H, s).

Reference Example 64 7- [3,5-bis (trifluoromethyl) benzyl]
-1,2,3,4,6,7,8,9,10,11-Decahydro-2-methyl-5- (4-methylphenyl)-
6,13-Dioxo-13H- [1,4] diazosino [1,2-b] [2,7] naphthyridine A mixture of the compound obtained in Reference Example 63 (250 mg), iodomethane (3 ml) and ethyl acetate (6 ml). 1.
The mixture was refluxed for 5 hours. After evaporating the solvent, the residue was dissolved in methanol (15 ml). To this solution was added sodium borohydride (50 mg) at 0 ° C with stirring, and the mixture was added at 0 ° C.
After stirring for 1 hour, the mixture was concentrated. Ethyl acetate was added to the concentrate, washed with water and dried, and the solvent was distilled off. The residue was dissolved in methanol (15 ml), and 10% palladium / carbon (50% water-containing) (100 mg) was added.
Stir at room temperature for 3 hours. The catalyst was filtered off, and the solvent was distilled off from the filtrate. The residue was subjected to column chromatography using silica gel (ethyl acetate → ethyl acetate: methanol =
4: 1) gave the title compound as pale yellow crystals (150 m
g). Melting point: 233-235 ° C. (recrystallized from THF-ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.7-2.6 (8H, m), 2.31 (3H,
s), 2.47 (3H, s), 3.1-3.8 (5H, m), 3.95 (1H, d, J = 15H
z), 4.93 (1H, dd, J = 14, 6.2Hz), 5.41 (1H, d, J = 15Hz),
6.72 (1H, d, J = 7.8Hz), 6.98 (1H, d, J = 7.8Hz), 7.19
(2H, s), 7.42 (2H, s), 7.78 (1H, s).

Reference Example 65 4- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine N- [3,5-bis (trifluoromethyl) benzyl]
-2-Chloro-N- (2-hydroxyethyl) -4-phenyl-3-pyridinecarboxamide (Reference Example 12)
To a solution of (348 mg) in THF (15 ml) was added sodium hydride (60% oil) (60 mg), and the mixture was stirred under reflux with heating for 2 hours. Ethyl acetate was added to the reaction mixture,
After washing with water and drying, the solvent was distilled off to give the title compound as colorless crystals (278 mg). Melting point: 200-201 ° C (recrystallized from ethanol-hexane) NMR (200MHz, CDCl ₃ ) ppm: 3.70 (2H, t, J = 5.8Hz), 4.4
7 (2H, t, J = 5.8Hz), 4.88 (2H, s), 7.24 (1H, d, J = 5.2H
z), 7.25-7.55 (5H, m), 7.80 (2H, s), 7.86 (1H, s), 8.
44 (1H, d, J = 5.2Hz) EI-MS m / z: 466 (M +) [(C 23 H 16 N 2 O 2 F 6) +].

Reference Example 66 (9R) -7- [3,5-bis (trifluoromethyl)
Benzyl] -6,7,8,9,10,12-hexahydro-9-methyl-5- (4-methylphenyl) -6,1
2-dioxo [1,4] diazepino [2,1-g]
[1,7] Naphthyridine The compound obtained in Reference Example 13 (700 mg), triethylamine (0.41 ml), methanesulfonyl chloride (0.2
A mixture of 24 ml) and THF (15 ml) was stirred at room temperature for 30 minutes, and then saturated aqueous sodium hydrogen carbonate (15 ml) was added.
ml) and stirred at room temperature for another 30 minutes. The reaction mixture was extracted with ethyl acetate, and the extract was washed with diluted hydrochloric acid and saturated saline, dried and evaporated. Residue in TH
F (15 ml) and then sodium hydride (60
% Oil) (76 mg) and stirred at room temperature for 1.5 hours. The reaction mixture was diluted with ethyl acetate, washed with dilute hydrochloric acid, aqueous sodium carbonate, and saturated saline, dried and evaporated. The residue was purified by column chromatography on silica gel (ethyl acetate: methanol = 9: 1) to give the title compound as colorless crystals (408 mg).
Was obtained as Melting point: 179-180 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.05 (3H × 2/3, d, J = 7.0 Hz),
1.22 (3H × 1/3, d, J = 7.0Hz), 2.39 (3H × 1/3, s), 2.42
(3H × 2/3, s), 2.52 (1H, m), 3.0-3.3 (2H, m), 3.48 (1H
× 2/3, dd, J = 14, 4.6Hz), 3.71 (1H × 1/3, dd, J = 16,
5.2Hz), 4.06 (1H × 1/3, d, J = 15Hz), 4.12 (1H × 2/3, d,
J = 15Hz), 5.28-5.65 (2H, m), 6.83 (1H × 1/3, d, J = 7.4
Hz), 6.96 (1H × 2/3, d, J = 7.6Hz), 7.09 (1H × 1/3, d, J
= 7.4Hz), 7.20 (1H × 2/3, d, J = 7.6Hz), 7.35 (2H, m), 7.
42-7.75 (4H, m), 7.83 (1H, s), 8.92 (1H, d, J = 3.6 Hz) Elemental analysis: C ₂₉ H ₂₃ N ₃ O ₂ F ₆ Calculated (%): C 62.25 , H 4.14, N 7.51 Actual value (%): C 62.00, H 4.08, N 7.24 [α] _D : -60.2 ° (C = 0.348, MeO
H).

Reference Example 67 (9S) -7- [3,5-bis (trifluoromethyl)
[Benzyl] -6,7,8,9,10,12-hexahydro-9-methyl-6,12-dioxo-5-phenyl [1,4] diazepino [2,1-g] [1,7] naphthyridine Reference When the compound obtained in Example 14 was reacted and treated in the same manner as in Reference Example 66, the title compound was obtained as colorless crystals. Melting point: 150-152 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.06 (3H × 2/3, d, J = 7.0 Hz),
1.21 (3H × 1/3, d, J = 7.0Hz), 2.50 (1H, m), 3.05-3.30
(2H, m), 3.49 (1H × 2/3, dd, J = 14, 4.6Hz), 3.72 (1H ×
1/3, dd, J = 16, 5.4Hz), 4.07 (1H × 1/3, d, J = 15Hz),
4.14 (1H × 2/3, d, J = 15Hz), 5.25-5.62 (2H, m), 6.94 (1H
× 1/3, d, J = 7.6Hz), 7.08 (1H × 2/3, d, J = 7.4Hz), 7.2-
7.7 (8H, m), 7.83 (1H, s), 8.93 (1H, dd, J = 4.3, 1.7H
z) Elemental analysis: C ₂₈ H ₂₁ N ₃ O ₂ F ₆ Calculated (%): C 61.65, H 3.88, N 7.70 Actual (%): C 61.33, H 3.89, N 7.51 [α] _D : + 69.8 ° (C = 0.353, MeO
H).

Reference Example 68 (9S) -7- [3,5-bis (trifluoromethyl)
Benzyl] -6,7,8,9,10,12-hexahydro-9-methyl-5- (4-methylphenyl) -6,1
2-dioxo [1,4] diazepino [2,1-g]
[1,7] Naphthyridine The compound obtained in Reference Example 15 was reacted and treated in the same manner as in Reference Example 66, whereby the title compound was obtained as colorless crystals. Melting point: 179-180 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: same as the spectrum of the compound of Reference Example 60 Elemental analysis: calculated as C ₂₉ H ₂₃ N ₃ O ₂ F ₆ Value (%): C 62.25, H 4.14, N 7.51 Actual value (%): C 61.94, H 4.16, N 7.24 [α] _D : + 58.2 ° (C = 0.353, MeO
H).

Reference Example 69 (±) -7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,10,11-hexahydro-9-methyl-6,13-dioxo- 5-phenyl-1
3H- [1,4] diazosino [2,1-g] [1,7]
Naphthyridine To a solution of the compound (830 mg) obtained in Reference Example 16 and triethylamine (0.56 ml) in THF (15 ml) was added methanesulfonyl chloride (0.29 m
l) was added. The mixture was stirred for 50 minutes under ice-cooling, then saturated aqueous sodium hydrogen carbonate (15 ml) was added, and the mixture was further stirred at room temperature for 40 minutes. The reaction mixture was extracted with ethyl acetate, and the extract was washed with diluted hydrochloric acid and saturated saline,
After drying, the solvent was distilled off. After the residue was dissolved in THF (25 ml), sodium hydride (60% oil) (90 m
g) was added, and the mixture was stirred for 1 hour while heating under reflux. The reaction mixture was diluted with ethyl acetate, washed with diluted hydrochloric acid, aqueous sodium carbonate, and saturated saline, dried, and evaporated to give the title compound as colorless crystals (460 mg). Melting point: 257-258 ° C (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.92 (3H, d, J = 6.6 Hz), 1.73
(1H, m), 1.95-2.40 (2H, m), 2.98 (1H, d, J = 15Hz), 3.
30-3.65 (2H, m), 3.97 (1H, d, J = 15Hz), 5.11 (1H, dd,
J = 14, 5.9Hz), 5.43 (1H, d, J = 15Hz), 6.93 (1H, d, J =
7.6Hz), 7.19 (1H, dd, J = 7.6, 7.0Hz), 7.3-7.6 (7H, m),
7.81 (1H, s), 8.91 (1H, dd, J = 4.0, 2.0 Hz) Elemental analysis: C ₂₉ H ₂₃ N ₃ O ₂ F ₆ Calculated (%): C 62.25, H 4.14, N 7.51 Value (%): C 61.93, H 4.05, N 7.57.

Reference Example 70 (±) -7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,10,11-hexahydro-9-methyl-5- (4-methyl Phenyl) -6,13
-Dioxo-13H- [1,4] diazosino [2,1-
g] [1,7] Naphthyridine The compound obtained in Reference Example 17 was reacted and treated in the same manner as in Reference Example 69, whereby the title compound was obtained as colorless crystals. Melting point: 280-281 ° C. (recrystallized from ethyl acetate-THF-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.91 (3H, d, J = 6.8 Hz), 1.73
(1H, m), 1.95-2.40 (2H, m), 2.37 (3H, s), 2.97 (1H,
d, J = 15Hz), 3.35-3.62 (2H, m), 3.99 (1H, d, J = 15Hz),
5.10 (1H, dd, J = 14, 5.3Hz), 5.46 (1H, d, J = 15Hz),
6.83 (1H, dd, J = 7.8, 1.6Hz), 7.05 (1H, d, J = 7.8Hz),
7.25 (1H, d, J = 7.8Hz), 7.34 (1H, dd, J = 7.8, 1.6Hz),
7.46 (1H, dd, J = 8.4, 4.2Hz), 7.47 (2H, s), 7.55 (1H,
dd, J = 8.4,1.8Hz), 7.81 (1H, s), 8.91 (1H, dd, J = 4.2,
1.8 Hz) Elemental analysis: Calculated _{C 30 H 25 N 3 O 2} F 6 (%): C 62.83, H 4.39, N 7.33 Found (%): C 62.61, H 4.21, N 7.12.

Reference Example 71 (9R) -7- [3,5-bis (trifluoromethyl)
[Benzyl] -6,7,8,9,10,11-hexahydro-9-methyl-6,13-dioxo-5-phenyl-
13H- [1,4] diazosino [2,1-g] [1,
7] Naphthyridine The compound obtained in Reference Example 18 was reacted and treated in the same manner as in Reference Example 69, and the title compound was obtained as colorless crystals. Melting point: 245-247 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: same as the spectrum of the compound of Reference Example 69 [α] _D : + 133.8 ° (C = 0.51) MeOH) Elemental analysis: C ₂₉ H ₂₃ N ₃ O ₂ F ₆ Calculated (%): C 62.25, H 4.14, N 7.51 Found (%): C 62.13, H 4.13, N 7.40.

Reference Example 72 (9R) -7- [3,5-bis (trifluoromethyl)
Benzyl] -6,7,8,9,10,11-hexahydro-9-methyl-5- (4-methylphenyl) -6,1
3-dioxo-13H- [1,4] diazosino [2,1
-G] [1,7] naphthyridine The compound obtained in Reference Example 19 was reacted and treated in the same manner as in Reference Example 69, and the title compound was obtained as colorless crystals. Melting point: 226-228 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: same as the spectrum of the compound of Reference Example 70 [α] _D : + 109.4 ° (C = 0.541, MeO
H) Elemental analysis: C ₃₀ H ₂₅ N ₃ O ₂ F ₆ Calculated (%): C 62.83, H 4.39, N 7.33 Actual (%): C 62.55, H 4.56, N 7.10.

Reference Example 73 (9S) -7- [3,5-bis (trifluoromethyl)
[Benzyl] -6,7,8,9,10,11-hexahydro-9-methyl-6,13-dioxo-5-phenyl-
13H- [1,4] diazosino [2,1-g] [1,
7] Naphthyridine The compound obtained in Reference Example 20 was reacted and treated in the same manner as in Reference Example 69, and the title compound was obtained as colorless crystals. Melting point: 242-244 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: same as the spectrum of the compound of Reference Example 69 [α] _D : -130.4 ° (C = 0.496) , MeO
H) Elemental analysis: C ₂₉ H ₂₃ N ₃ O ₂ F ₆ Calculated (%): C 62.25, H 4.14, N 7.51 Actual (%): C 62.07, H 4.15, N 7.36.

Reference Example 74 (9S) -7- [3,5-bis (trifluoromethyl)
Benzyl] -6,7,8,9,10,11-hexahydro-9-methyl-5- (4-methylphenyl) -6,1
3-dioxo-13H- [1,4] diazosino [2,1
-G] [1,7] naphthyridine The compound obtained in Reference Example 21 was reacted and treated in the same manner as in Reference Example 69, and the title compound was obtained as colorless crystals. Melting point: 227-228 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: same as the spectrum of the compound of Reference Example 70 [α] _D : -107.1 ° (C = 0.521) , MeO
H) Elemental analysis: C ₃₀ H ₂₅ N ₃ O ₂ F ₆ Calculated (%): C 62.83, H 4.39, N 7.33 Actual (%): C 62.55, H 4.40, N 7.13.

Reference Example 75 4- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-5-oxo-6-phenyl-1H-pyrido [2,3-e] [1,4] diazepine The compound obtained in Reference Example 22 (370 mg), anhydrous potassium carbonate ( A mixture of 200 mg) and xylene (10 ml) was stirred for 9 hours while heating under reflux. After cooling the reaction mixture, water was added and extracted with ethyl acetate. The extract was washed with water, dried and evaporated to give the title compound as colorless crystals. Melting point: 242-243 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 3.60-3.80 (4H, m), 4.81 (2H,
s), 4.86 (1H, s), 6.87 (1H, d, J = 5.2Hz), 7.30-7.50 (6
H, m), 7.79 (2H, s), 7.85 (1H, s), 8.21 (1H, d, J = 5.2H
z) Elemental analysis: C ₂₃ H ₁₇ N ₃ OF ₆ Calculated (%): C 59.36, H 3.68, N 9.03 Actual (%): C 59.24, H 3.66, N 9.06 EI-MS m / z: 465 (M ⁺ ) [(C ₂₃ H ₁₇ N ₃ OF
₆ ) ⁺ ].

Reference Example 76 5- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-6-oxo-7-phenyl-6H-pyrido [2,3-b] [1,5] oxazosin Using the compound obtained in Reference Example 23, The reaction and treatment were carried out in the same manner to give the title compound as colorless crystals. Melting point: 188-189 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.65-1.88 (1H, m), 2.18-2.
45 (1H, m), 3.36 (1H, dd, J = 15.2Hz), 3.73 (1H, m), 4.1
7 (1H, d, J = 15.2Hz), 4.32 (1H, dt, J = 12.6,3.6Hz), 4.
67 (1H, ddd, J = 12.6, 5.6, 2.4Hz), 5.50 (1H, d, J = 15.
2Hz), 7.16 (1H, d, J = 5.2Hz), 7.20-7.45 (5H, m), 7.71
(2H, s), 7.83 (1H, s), 8.41 (1H, d, J = 5.2 Hz) Elemental analysis: C ₂₄ H ₁₈ N ₂ O ₂ F ₆ Calculated (%): C 60.00, H 3.78 , N 5.83 Found (%): C 59.92, H 3.76, N 5.89.

Reference Example 77 4- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-7-methyl-5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine Using the compound obtained in Reference Example 24, Reference Example 65 The reaction and treatment were carried out in the same manner to give the title compound as colorless crystals. Melting point: 179-181 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.13 (3H, s), 3.57 (2H, t,
J = 5.8Hz), 4.42 (2H, t, J = 5.8Hz), 4.80 (2H, s), 7.16
(2H, m), 7.47 (3H, m), 7.65 (2H, s), 7.81 (1H, s), 8.3
2 (1H, s).

Reference Example 78 5- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-8-methyl-6-oxo-7-phenyl-6H-pyrido [2,3-b]
[1,5] oxazosin The compound obtained in Reference Example 25 was reacted and treated in the same manner as in Reference Example 65, and the title compound was obtained as colorless crystals. Melting point: 180-182 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.71 (1H, m), 2.07 (3H, m),
2.28 (1H, m), 3.24 (1H, dd, J = 15.2, 3.8Hz), 3.64 (1
H, dd, J = 15.2, 12.0Hz), 4.05 (1H, d, J = 15.6Hz), 4.2
7 (1H, dt, J = 12.6, 3.8Hz), 4.63 (1H, ddd, J = 12.6, 5.
4, 2.0Hz), 5.45 (1H, d, J = 15.6Hz), 7.38 (5H, m), 7.5
4 (2H, s), 7.78 (1H, s), 8.29 (1H, s)

Reference Example 79 (±) -7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,10,12-hexahydro-9-hydroxy-5- (4-methyl Phenyl) -6
12-dioxo [1,4] diazepino [2,1-g]
[1,7] Naphthyridine The compound obtained in Reference Example 26 was reacted and treated in the same manner as in Reference Example 56, and the title compound was obtained as colorless crystals. Melting point: 282-283 ° C. (recrystallized from acetone-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.43 (3H, s), 3.35-3.63 (3H,
m), 4.02 (1H × 3/8, d, J = 3.5Hz, -OH), 4.21 (1H × 3/8,
d, J = 15Hz), 4.30 (1H × 5/8, d, J = 3.5Hz, -OH), 4.38 (1
H × 5/8, d, J = 15Hz), 4.60 (1H, m), 5.24 (1H × 3/8, d,
J = 15Hz), 5.61 (1H × 5/8, d, J = 15Hz), 5.68 (1H, m), 6.
92 (1H, t-like, J = 3.8Hz), 7.19-7.86 (8H, m), 8.95 (1
(H, d, J = 4 Hz) Elemental analysis: C ₂₈ H ₂₁ N ₃ O ₃ F ₆ .1 / 4H ₂ O Calculated (%): C 59.42, H 3.83, N 7.42 Actual (%): C 59.45, H 3.74, N 7.39 EI-MS m / z: 561 (M ⁺ ) [(C ₂₈ H ₂₁ N ₃ O ₃ F)
₆ ) ⁺ ].

Reference Example 80 7-benzyl-6,7,8,9,10,12-hexahydro-6,12-dioxo-5-phenyl [1,4] diazepino [2,1-g] [1,7 Naphthyridine The compound obtained in Reference Example 27 was reacted with 3-amino-1-propanol in the same manner as in Reference Example 13 and treated to give 7-benzyl-7,8-dihydro-7-.
(3-Hydroxypropyl) -8-oxo-5-phenyl-6-pyrido [3,4-b] pyridinecarboxamide was prepared. When this compound was reacted and treated in the same manner as in Reference Example 12, the title compound was obtained as colorless crystals. Melting point: 210-212 ° C (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.7-2.2 (2H, m), 3.2-3.6 (3
H, m), 4.30 (1H, d, J = 14Hz), 4.89 (1H, d, J = 14Hz),
5.43 (1H, dd, J = 14, 5.7Hz), 7.0-7.7 (11H, m), 7.70 (1
H, dd, J = 8.4, 1.6Hz), 8.92 (1H, dd, J = 4.4, 1.6Hz).

Reference Example 81 7-benzyl-6,7,8,9,10,11-hexahydro-6,13-dioxo-5-phenyl-13H-
[1,4] diazosino [2,1-g] [1,7] naphthyridine Using the compound obtained in Reference Example 27 and 4-amino-1-butanol, reacting and treating in the same manner as in Reference Example 16. 7-
Benzyl-7,8-dihydro-7- (4-hydroxybutyl) -8-oxo-5-phenyl-6-pyrido [3,
4-b] Pyridinecarboxamide was prepared, reacted with this compound in the same manner as in Reference Example 69, and treated to give the title compound as colorless crystals. Melting point: 243-244 ° C. (recrystallized from acetone-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.6-2.3 (4H, m), 3.15 (1H,
m), 3.35-3.65 (2H, m), 3.76 (1H, d, J = 15Hz), 5.15 (1
H, dd, J = 14, 5.7Hz), 5.42 (1H, d, J = 15Hz), 6.64 (2H,
d, J = 6.2Hz), 7.0-7.3 (4H, m), 7.3-7.7 (6H, m), 8.91
(1H, dd, J = 4.2,1.8Hz).

Reference Example 82 7-benzyl-6,7,8,9,10,11,12,1
4-octahydro-6,14-dioxo-5-phenyl [1,4] diazonino [2,1-g] [1,7] naphthyridine Using the compound obtained in Reference Example 27 and 5-amino-1-pentanol Then, the reaction and treatment were carried out in the same manner as in Reference Example 16 to give 7
-Benzyl-7,8-dihydro-7- (5-hydroxypentyl) -8-oxo-5-phenyl-6-pyrido [3,4-b] pyridinecarboxamide was prepared, and this compound was used in Reference Example 69. The title compound was obtained as colorless crystals after treatment. Melting point: 224-226 ° C. (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.3-1.9 (4H, m), 2.09 (2H,
m), 2.85-3.05 (1H, m), 3.15-3.40 (1H, m), 3.50 (1H, d
t, Jd = 15Hz, Jt = 6.4Hz), 3.64 (1H, d, J = 15Hz), 4.97 (1
H, dt, Jd = 15Hz, Jt = 4.8Hz), 5.48 (1H, d, J = 15Hz), 6.
43 (2H, d, J = 7.2Hz), 7.05-7.25 (4H, m), 7.3-7.7 (6H,
m), 8.91 (1H, dd, J = 4.2, 1.8Hz).

Reference Example 83 7- (3,4-Dichlorobenzyl) -6,7,8,9,
10,12-hexahydro-6,12-dioxo-5-
Phenyl [1,4] diazepino [2,1-g] [1,
7] Naphthyridine Using the compound obtained in Reference Example 28 and 3-amino-1-propanol, reacting and treating in the same manner as in Reference Example 13
-(3,4-dichlorobenzyl) -7,8-dihydro-
7- (3-Hydroxypropyl) -8-oxo-5-phenyl-6-pyrido [3,4-b] pyridinecarboxamide was prepared, reacted with this compound and treated in the same manner as in Reference Example 66. The title compound was obtained as colorless crystals. Melting point: 224-226 ° C. (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.9-2.3 (2H, m), 3.2-3.6 (3
H, m), 4.01 (1H, d, J = 15Hz), 5.05 (1H, d, J = 15Hz),
5.49 (1H, dd, J = 13, 5.0Hz), 6.9-7.1 (2H, m), 7.25 (1H,
m), 7.38 (1H, d, J = 8.6Hz), 7.3-7.8 (6H, m), 8.93 (1
H, d, J = 4.0Hz).

Reference Example 84 7- (3,4-Dichlorobenzyl) -6,7,8,9,
10,11-hexahydro-6,13-dioxo-5-
Phenyl-13H- [1,4] diazosino [2,1-
g] [1,7] Naphthyridine The compound obtained in Reference Example 28 and 4-amino-1-butanol were reacted and treated in the same manner as in Reference Example 16 to give 7-.
(3,4-dichlorobenzyl) -7,8-dihydro-7
-(4-Hydroxybutyl) -8-oxo-5-phenyl-6-pyrido [3,4-b] pyridinecarboxamide was prepared, and reacted with this compound in the same manner as in Reference Example 15 to give the title compound. The compound was obtained as colorless crystals. Melting point: 236-238 ° C. (recrystallized from acetone-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.7-2.3 (4H, m), 3.14 (1H,
m), 3.39-3.60 (2H, m) 3.70 (1H, d, J = 15Hz), 5.14 (1H,
dd, J = 15, 5.9Hz), 5.35 (1H, d, J = 15Hz), 6.35 (1H, d
d, J = 8.4, 2.0Hz), 7.02 (2H, m), 7.18 (1H, d, J = 8.4H
z), 7.3-7.6 (6H, m), 8.91 (1H, dd, J = 4.0, 1.8Hz).

Reference Example 85 (S) -5- [3,5-bis (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-3,8-dimethyl-6-oxo-7-phenyl- 6H-pyrido [2,3-b] [1,5] oxazosin Using the compound obtained in Reference Example 29, reacted and treated in the same manner as in Reference Example 65, and the title compound was obtained as colorless crystals. . Melting point: 147-148 ° C (recrystallized from ethyl acetate-hexane) NMR (200 MHz, CDCl ₃ ) ppm: 0.83 (3H, d, J = 7.4 Hz), 2.0
7 (3H, s), 2.39 (1H, m), 2.97 (1H, d, J = 15.4Hz), 3.48
(1H, m), 3.87 (1H, dd, J = 10.4, 12.4Hz), 4.06 (1H, d,
J = 15.6Hz), 4.59 (1H, dd, J = 5.2, 12.4Hz), 5.44 (1H,
d, J = 15.4Hz), 7.37 (5H, s), 7.53 (2H, s), 7.78 (1H,
s), 8.29 (1H, s) Elemental analysis: C ₂₆ H ₂₂ N ₂ O ₂ F ₆ Calculated (%): C 61.42, H 4.36, N 5.51 Actual (%): C 61.30, H 4.52, N 5.70 [α] _D ²⁰ : -106.8 ° (C = 0.257, CHC
l ₃ ).

Reference Example 86 (R) -5- [3,5-bis (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-3,8-dimethyl-6-oxo-7-phenyl- 6H-pyrido [2,3-b] [1,5] oxazosin Using the compound obtained in Reference Example 30, reacted and treated in the same manner as in Reference Example 65, and the title compound was obtained as colorless crystals. . Melting point: 147-149 ° C. (recrystallized from ethyl acetate-hexane) NMR (200 MHz, CDCl ₃ ) ppm: same as the spectrum of Reference Example 85 Elemental analysis: C ₂₆ H ₂₂ N ₂ O ₆ Calculated (%): C 61.42, H 4.36, N 5.51 Actual measured value (%): C 61.26, H 4.33, N 5.69 [α] _D ²⁰ : + 102.5 ° (C = 0.573, CHC
l ₃ ).

Reference Example 87 4- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-8-methyl-5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine Using the compound obtained in Reference Example 31, Reference Example 65 The reaction and treatment were carried out in the same manner to give the title compound as colorless crystals. Melting point: 151-153 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.58 (3H, s), 3.69 (2H, t,
J = 5.4Hz), 4.47 (2H, t, J = 5.4Hz), 4.87 (2H, s), 7.11
(1H, s), 7.17-7.56 (5H, m), 7.80 (2H, s), 7.86 (1H,
s) Elemental analysis: C ₂₄ H ₁₈ N ₂ O ₂ F ₆ .1 / 4 H ₂ O Calculated (%): C 59.44, H 3.85, N 5.78 Actual (%): C 59.42, H 3.82, N 5.84.

Reference Example 88 5- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-9-methyl-6-oxo-7-phenyl-6H-pyrido [2,3-b]
[1,5] oxazosin Using the compound obtained in Reference Example 32, the reaction and treatment were carried out in the same manner as in Reference Example 65, whereby the title compound was obtained as colorless crystals. Melting point: 164-165 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200MHz, CDCl ₃ ) ppm: 1.79 (1H, m), 2.30 (1H, m),
2.56 (3H, s), 3.35 (1H, m), 3.77 (1H, m), 4.14 (1H,
d, J = 15.2Hz), 4.31 (1H, m), 4.65 (1H, m), 5.49 (1H,
d, J = 15.2Hz), 7.02 (1H, s), 7.20-7.50 (5H, m), 7.72
(2H, s), 7.83 (1H, s) Elemental analysis: C ₂₅ H ₂₀ N ₂ O ₂ F ₆ Calculated (%): C 60.73, H 4.08, N 5.67 Actual (%): C 60.43, H 4.04, N 5.74.

Reference Example 89 4- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-Tetrahydro-8-methyl-5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine 9-oxide Compound obtained in Reference Example 87 (1.20 g) M-chloroperbenzoic acid (870 m
g) was added and the mixture was stirred at room temperature for 20 hours. Evaporate the solvent,
Aqueous potassium carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous solution of potassium carbonate, dried, and the solvent was distilled off to give the title compound as colorless crystals (1.1
0 g). Melting point: 181-183 ° C. (recrystallized from THF-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.62 (3H, s), 3.72 (2H, m),
4.65 (2H, m), 4.89 (2H, s), 7.18 (1H, s), 7.20-7.50
(5H, m), 7.79 (2H, s), 7.87 (1H, s) Elemental analysis: C ₂₄ H ₁₈ N ₂ O ₃ F ₆ Calculated (%): C 57.03, H 3.79, N 5.54 (%): C 57.15, H 3.77, N 5.16

Reference Example 90 5- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-9-methyl-6-oxo-7-phenyl-6H-pyrido [2,3-b]
[1,5] oxazosin 10-oxide Using the compound obtained in Reference Example 88, the reaction was carried out in the same manner as in Reference Example 89, and the title compound was obtained as colorless crystals (727 mg). Melting point: 116-118 ° C (recrystallized from ethanol-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.60-1.82 (1H, m), 2.42 (1H,
m), 2.61 (3H, s), 3.43 (1H, dd, J = 6.0, 17.0Hz), 3.8
1 (1H, m), 4.18 (1H, d, J = 15.4Hz), 4.25 (1H, m), 4.78
(1H, dd, J = 5.2, 12.6Hz), 5.52 (1H, d, J = 15.4Hz), 7.
16 (1H, s), 7.18-7.50 (5H, m), 7.72 (2H, s), 7.84 (1H,
s) Elemental analysis: C ₂₅ H ₂₀ N ₂ O ₃ .1 / 4 H ₂ O Calculated (%): C 58.31, H 4.01, N 5.44 Actual (%): C 58.17, H 4.38, N 5.31 .

Reference Example 91 8-acetoxymethyl-4- [3,5-bis (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido- [3,2- f]
[1,4] oxazepine A mixture of the compound (939 mg) obtained in Reference Example 89 and acetic anhydride (25 ml) was heated under reflux for 20 minutes. The solvent was distilled off, an aqueous potassium carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and evaporated to give the title compound as colorless crystals (740 mg). Melting point: 122-124 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.18 (3H, s), 3.71 (2H, t, J
= 5.6Hz), 4.50 (2H, t, J = 5.6z), 4.88 (2H, s), 5.21 (2H,
s), 7.18-7.50 (6H, m), 7.79 (2H, s), 7.87 (1H, s) Elemental analysis: C ₂₆ H ₂₀ N ₂ O ₄ F ₆ Calculated (%): C 58.00, H 3.74, N 5.20 actual values (%): C 57.60, H 4.02, N 5.09.

Reference Example 92 9-acetoxymethyl-5- [3,5-bis (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-6-oxo-7-phenyl-6H-pyrido [2 , 3
-B] [1,5] oxazosin Using the compound obtained in Reference Example 90, the reaction was carried out in the same manner as in Reference Example 91, and the title compound was obtained as colorless crystals (479 mg). Melting point: 156-157 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.60-1.95 (1H, m), 2.00-2.2
0 (1H, m), 2.17 (3H, s), 3.36 (1H, m), 3.75 (1H, m),
4.14 (1H, d, J = 15.2Hz), 4.31 (1H, m), 4.61 (1H, m),
5.20 (2H, s), 5.48 (1H, d, J = 15.2Hz), 7.18 (1H, s),
7.20-7.50 (5H, m), 7.70 (2H, s), 7.83 (1H, s) Elemental analysis: C ₂₇ H ₂₂ N ₂ O ₄ F ₆ Calculated (%): C 58.70, H 4.01, N 5.07 Found (%): C 58.81, H 4.11, N 5.17.

Reference Example 93 4- [3,5-bis (trifluoromethyl) benzyl]
-8-Chloromethyl-2,3,4,5-tetrahydro-
5-oxo-6-phenylpyrido [3,2-f] [1,
4] Oxazepine Phosphorus oxychloride (1.24 ml) and triethylamine (1.85 m) were added to a solution of the compound (4.40 g) obtained in Reference Example 89 in dichloromethane (100 ml) at room temperature with stirring.
l) was added dropwise at the same time. After the mixture was refluxed for 1 hour, the solvent was distilled off. Aqueous potassium carbonate was added to the residue, and the mixture was extracted with ethyl acetate-THF. The extract was washed with water, dried and the solvent was distilled off to give the title compound as colorless crystals (1.
44g). Melting point: 183-184 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200MHz, CDCl ₃ ) ppm: 3.73 (2H, t, J = 5.4Hz), 4.51
(2H, t, J = 5.4Hz), 4.66 (2H, s), 4.89 (2H, s), 7.27 (1
H, s), 7.30-7.55 (5H, m), 7.81 (2H, s), 7.88 (1H, s) Elemental analysis: C ₂₄ H ₁₇ N ₂ O ₂ F ₆ Cl Calculated (%): C 55.99, H 3.33, N 5.44 Found (%): C 55.75, H 3.53, N 5.27.

Reference Example 94 4- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-8-methoxymethyl-5-oxo-6-phenylpyrido [3,2-f]
[1,4] oxazepine The compound (151 mg) obtained in Reference Example 93, THF (2 m
l), a mixture of methanol (1 ml) and a 28% sodium methoxide-methanol solution (1 ml) was stirred at room temperature for 2 hours. The solvent was distilled off, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and the solvent was distilled off to give the title compound as colorless crystals (118 mg). Melting point: 139-140 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200 MHz, CDCl ₃ ) ppm: 3.51 (3H, s), 3.71 (2H, t, J =
5.6Hz), 4.49 (2H, t, J = 5.6Hz), 4.58 (2H, s), 4.89 (2H,
s), 7.27 (1H, s), 7.30-7.52 (5H, m), 7.81 (2H, s),
7.87 (1H, s) Elemental _{analysis: C 25 H 20 N 2 O} 3 F 6 Calculated (%): C 58.83, H 3.95, N 5.49 Found (%): C 58.73, H 3.95, N 5.57.

Reference Example 95 4- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-8- (1-methylethyloxy) -5-oxo-6-phenylpyrido [3,
2-f] [1,4] oxazepine The compound obtained in Reference Example 93 (150 mg), THF (1 m
l), a mixture of isopropanol (10 ml) and sodium hydride (60% oil) (120 mg) was stirred at room temperature for 3 hours. The solvent was distilled off, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried, and the solvent was distilled off. The residue was subjected to column chromatography using silica gel (hexane-ethyl acetate = 1: 1).
Purification provided the title compound as colorless crystals (74 mg). Melting point: 134-136 ° C (recrystallized from ethyl acetate-hexane) NMR (200 MHz, CDCl ₃ ) ppm: 1.26 (6H, d, J = 6.0 Hz), 3.60-
3.90 (3H, m), 4.48 (2H, t, J = 5.4Hz), 4.63 (2H, s), 4.
89 (2H, s), 7.27 (1H, s), 7.30-7.55 (5H, m), 7.81 (2H,
s), 7.87 (1H, s) Elemental analysis: C ₂₇ H ₂₄ N ₂ O ₃ F ₆ Calculated (%): C 60.22, H 4.49, N 5.20 Actual (%): C 60.00, H 4.61, N 5.07.

Reference Example 96 4- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-8-methylthiomethyl-5-oxo-6-phenylpyrido [3,2-f]
[1,4] oxazepine A mixture of the compound obtained in Reference Example 93 (125 mg), methanol (5 ml), and a 15% aqueous solution of sodium methylmercaptan (1 ml) was stirred at room temperature for 10 minutes.
The solvent was distilled off, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and evaporated to give the title compound as colorless crystals (103 mg). Melting point: 165-166 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.14 (3H, s), 3.72 (2H, t, J =
5.4Hz), 3.79 (2H, s), 4.49 (2H, t, J = 5.4Hz), 4.89 (2H, s)
s), 7.30-7.50 (5H, m), 7.34 (1H, s), 7.81 (2H, s),
7.87 (1H, s) Elemental _{analysis: C 25 H 20 N 2 O} 2 SF 6 · 1/6 H 2 O Calculated (%): C 56.71, H 3.87, N 5.29 Found (%): C 56.67 , H 3.87, N 5.23.

Reference Example 97 8-Aminomethyl-4- [3,5-bis (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-
5-oxo-6-phenylpyrido [3,2-f] [1,
4] Oxazepine Compound (500 mg) obtained in Reference Example 93, THF (10
mixture) and 25% aqueous ammonia (10 ml) was heated in a sealed tube at 120 ° C. for 1 hour. After cooling, the solvent was distilled off, water was added to the residue, and the mixture was extracted with ethyl acetate.
The extract was washed with water, dried and the solvent was distilled off to give the title compound as colorless crystals (443 mg). Melting point: 188-191 ° C (recrystallized from THF-ethyl ether) NMR (200MHz, CDCl ₃ ) ppm: 3.71 (2H, t, J = 5.6Hz), 4.00
(2H, s), 4.50 (2H, t, J = 5.6Hz), 4.89 (2H, s), 7.20-7.
60 (6H, m), 7.81 (2H, s), 7.87 (1H, s) Elemental analysis: C ₂₄ H ₁₉ N ₃ O ₂ F ₆ Calculated (%): C 58.19, H 3.87, N 8.48 Value (%): C 58.36, H 3.81, N 8.00.

Reference Example 98 4- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-8-methylaminomethyl-5-oxo-6-phenylpyrido [3,2-f]
[1,4] oxazepine A mixture of the compound (150 mg) obtained in Reference Example 93 and a 40% methylamine-methanol solution (10 ml) was stirred at room temperature for 30 minutes. The solvent was distilled off, water was added to the residue, and the mixture was extracted with ethyl acetate. After washing the extract with water, dry it,
The solvent was distilled off to give the title compound as colorless crystals (115 m
g). Melting point: 152-154 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.50 (3H, s), 3.70 (2H, t, J =
5.6Hz), 3.89 (2H, s), 4.48 (2H, t, J = 5.6Hz), 4.88 (2H, s)
s), 7.22-7.50 (6H, m), 7.80 (2H, s), 7.86 (1H, s) Elemental analysis: C ₂₅ H ₂₁ N ₃ O ₂ F ₆ Calculated (%): C 58.94, H 4.15, N 8.25 Found (%): C 58.71, H 4.25, N 8.35.

Reference Example 99 4- [3,5-bis (trifluoromethyl) benzyl]
-8-dimethylaminomethyl-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido [3,2-
f] [1,4] oxazepine THF (3 m) of the compound (150 mg) obtained in Reference Example 93
l) Dimethylamine (1 ml) was added to the solution,
Stirred for 0 minutes. The solvent was distilled off, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and the solvent was distilled off to give the title compound as colorless crystals (128 mg). Melting point: 186-188 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.33 (6H, s), 3.60 (2H, s),
3.71 (2H, t, J = 5.6Hz), 4.49 (2H, t, J = 5.6Hz), 4.89 (2
H, s), 7.26 (1H, s), 7.30-7.50 (5H, m), 7.81 (2H, s),
7.86 (1H, s) Elemental analysis: C ₂₆ H ₂₃ N ₃ O ₂ F ₆ Calculated (%): C 59.66, H 4.43, N 8.03 Found (%): C 59.43, H 4.49, N 7.84.

Reference Example 100 4- [3,5-bis (trifluoromethyl) benzyl]
-8-Cyclopropylaminomethyl-2,3,4,5-
Tetrahydro-5-oxo-6-phenylpyrido [3,
2-f] [1,4] oxazepine THF (10 mg) of the compound (155 mg) obtained in Reference Example 93
ml) solution, cyclopropylamine (0.5 ml) was added, and the mixture was heated under reflux with stirring for 15 hours. The solvent was distilled off, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried, and the solvent was distilled off. The residue was subjected to column chromatography using silica gel (ethyl acetate: methanol = 9: 1), separated and purified to give the title compound as colorless crystals (127 mg). Melting point: 129-131 ° C (recrystallized from ethyl acetate-hexane) NMR (200 MHz, CDCl ₃ ) ppm: 0.44 (4H, m), 2.19 (1H, m),
3.69 (2H, t, J = 5.6Hz), 3.97 (2H, s), 4.48 (2H, t, J =
5.6Hz), 4.87 (2H, s), 7.25 (1H, s), 7.26-7.55 (5H,
m), 7.79 (2H, s), 7.86 (1H, s). Elemental _{analysis: C 27 H 23 N 3 O} 2 F 6 · 1/6 H 2 O Calculated (%): C 60.22, H 4.37, N 7.80 Found (%): C 59.98, H 4.40, N 7.85 .

Reference Example 101 4- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-Tetrahydro-8- (N-methylpiperazinomethyl) -5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine The compound obtained in Reference Example 93 (150 mg) THF (1 m
l) N-Methylpiperazine (1 ml) was added to the solution, and the mixture was stirred at room temperature for 15 hours. The solvent was distilled off, water was added to the residue, and the mixture was extracted with ethyl acetate. After washing the extract with water, dry it,
The solvent was distilled off to give the title compound as colorless crystals (105 m
g). Melting point: 181-182 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.30 (3H, s), 2.48 (4H, br),
2.59 (4H, br), 3.68 (2H, s), 3.71 (2H, t, J = 5.6Hz),
4.48 (2H, t, J = 5.6Hz), 4.89 (2H, s), 7.27 (1H, s), 7.
30-7.50 (5H, m), 7.81 (2H, m), 7.87 (1H, s) Elemental analysis: C ₂₆ H ₂₈ N ₄ O ₂ F ₆ Calculated (%): C 60.20, H 4.88, N 9.68 Found (%): C 59.96, H 5.00, N 9.51.

Reference Example 102 8-Acetylaminomethyl-4- [3,5-bis (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido [3,2-
f] [1,4] oxazepine Compound (150 mg) obtained in Reference Example 97 was treated with pyridine (3
Acetic anhydride (1 ml) was added to the solution, and the mixture was stirred at room temperature for 20 minutes. The solvent was distilled off, and ethyl acetate was added to the residue. The mixture was washed with 1N hydrochloric acid and water, and then dried,
The solvent was distilled off to give the title compound as colorless crystals (113 m
g). Melting point: 223-224 ° C. (recrystallized from THF-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.07 (3H, s), 3.72 (2H, t, J)
= 5.4Hz), 4.49 (2H, t, J = 5.4Hz), 4.56 (2H, d, J = 5.4H)
z), 4.88 (2H, s), 6.62 (1H, br), 7.21 (1H, s), 7.22-
7.55 (5H, m), 7.80 (2H, s), 7.87 (1H, s) Elemental analysis: C ₂₆ H ₂₁ N ₃ O ₃ F ₆ Calculated (%): C 58.10, H 3.94, N 7.82 Values (%): C 58.06, H 3.97, N 7.99.

Reference Example 103 4- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-8-methanesulfonylaminomethyl-5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine THF of the compound (150 mg) obtained in Reference Example 97 (5m
l) Triethylamine (0.085 ml) and methanesulfonyl chloride (0.050 ml) were added to the solution, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off, and ethyl acetate was added to the residue. The mixture was washed with aqueous potassium carbonate and water, dried and evaporated to give the title compound as colorless crystals (108 mg). Melting point: 194-195 ° C. (recrystallized from THF-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.99 (3H, s), 3.72 (2H, t, J)
= 5.4Hz), 4.44 (2H, d, J = 6.0Hz), 4.48 (2H, t, J = 5.4H)
z), 4.88 (2H, s), 5.55 (1H, t, J = 6.0Hz), 7.26 (1H,
s), 7.27-7.50 (5H, m), 7.80 (2H, s), 7.87 (1H, s) Elemental analysis: C ₂₅ H ₂₁ N ₃ O ₄ SF ₆ · 1/2 H ₂ O Calculated ( %): C 51.55, H 3.80, N 7.21 Actual values (%): C 51.43, H 3.78, N 7.07.

Reference Example 104 6- [3,5-bis (trifluoromethyl) benzyl]
-5,6,7,8,9,10-Hexahydro-3,9-
Dimethyl-5,10-dioxo-4-phenylpyrido [2,3-f] [1,4] diazosin THF (15 mg) of the compound (370 mg) obtained in Reference Example 33
ml) solution and triethylamine (0.42 m
l) and methanesulfonyl chloride (0.24 ml) were added, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate (15 ml) was added to the reaction solution, and the mixture was further stirred at room temperature for 40 minutes, and extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid and saturated saline, dried, and the solvent was distilled off. After the residue was dissolved in THF (30 ml), sodium hydride (60% oil) (84 mg) was added, and the mixture was heated under reflux for 40 minutes. The reaction mixture was diluted with ethyl acetate, diluted with hydrochloric acid,
The extract was washed with aqueous sodium carbonate and saturated saline, dried and evaporated to give the title compound as colorless crystals (213 mg). Melting point: 203-205 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200MHz, CDCl ₃ ) ppm: 1.72 (1H, dd, J = 15, 7.2Hz),
2.18 (3H, s), 2.75 (1H, m), 3.04 (3H, s), 3.54 (3H, s)
m), 4.09 (1H, dd, J = 14, 7.2Hz), 7.2-7.6 (5H, m), 7.48
(2H, s), 7.74 (1H, s), 8.69 (1H, s) Elemental analysis: C ₂₆ H ₂₁ N ₃ O ₂ F ₆ .0.2 H ₂ O Calculated (%): C 59.48, H 4.11 , N 8.00 Found (%): C 59.39, H 4.13, N 7.83 EI-MS m / s: 521 (M ⁺ ) [(C ₂₆ H ₂₁ N ₃
O ₂ F ₆₎ ^+].

Reference Example 105 6- [3,5-bis (trifluoromethyl) benzyl]
-5,6,7,8,9,10-Hexahydro-9-methyl-5,10-dioxo-4-phenylpyrido [2,3
-F] [1,4] diazocine Using the compound obtained in Reference Example 34, and reacting and treating in the same manner as in Reference Example 104, the title compound was obtained as colorless crystals. Melting point: 167-169 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200MHz, CDCl ₃ ) ppm: 2.05 (1H, m), 2.87 (1H, m),
3.10 (3H, s), 3.36 (1H, d, J = 14Hz), 3.48 (1H, d, J = 1
4Hz), 3.97 (1H, m), 4.26 (1H, dd, J = 15, 7.1Hz), 7.35
(3H, m), 7.53 (5H, m), 7.71 (1H, s), 8.81 (1H, d, J =
5.0 Hz) Elemental analysis: C ₂₅ H ₁₉ N ₃ O ₂ F ₆ Calculated (%): C 59.18, H 3.77, N 8.28 Actual (%): C 58.90, H 3.81, N 8.05.

Reference Example 106 6-benzyl-5,6,7,8,9,10-hexahydro-3,9-dimethyl-5,10-dioxo-4-phenylpyrido [2,3-f] [1,4 Diazosin Using the compound obtained in Reference Example 35 and methylamine, reacting and treating in the same manner as in Step 4 of Reference Example 33 to give N-benzyl-N- (2-hydroxyethyl) -5-methyl-2- Methylaminocarbonyl-4-phenyl-3-pyridinecarboxamide was prepared, and this compound was used to prepare Reference Example 10.
Reaction and treatment as in 4 gave the title compound as colorless crystals. Melting point: 183-184 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200MHz, CDCl ₃ ) ppm: 1.46 (1H, dd, J = 15, 8.1H)
z), 2.17 (3H, s), 2.69 (1H, m), 3.02 (3H, s), 3.27 (1
H, d, J = 13Hz), 3.44 (1H, d, J = 13Hz), 3.56 (1H, m), 4.
00 (1H, m), 7.01 (2H, m), 7.2-7.6 (8H, m), 8.68 (1H, m
s) Elemental analysis: calculated as C ₂₄ H ₂₃ N ₃ O ₂ Calculated (%): C 74.78, H 6.01, N 10.90 Found (%): C 74.52, H 6.13, N 10.82.

Reference Example 107 6- [3,5-bis (trifluoromethyl) benzyl]
-9-ethyl-5,6,7,8,9,10-hexahydro-3-methyl-5,10-dioxo-4-phenylpyrido [2,3-f] [1,4] diazocine Step of Reference Example 33 Using the compound obtained in Step 3 and ethylamine, the reaction was carried out in the same manner as in Step 4 of Reference Example 33, followed by treatment with N-
[3,5-bis (trifluoromethyl) benzyl] -2
-Ethylaminocarbonyl-N- (2-hydroxyethyl) -5-methyl-4-phenyl-3-pyridinecarboxamide was prepared, reacted with this compound in the same manner as in Reference Example 104, and treated to give the title compound. Obtained as colorless crystals. Melting point: 228-229 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200MHz, CDCl ₃ ) ppm: 1.33 (3H, t, J = 7.0Hz), 1.5
1 (1H, dd, J = 15, 7.6Hz), 2.18 (3H, s), 2.72 (1H, m),
3.39 (1H, m), 3.42 (1H, d, J = 14Hz), 3.57 (1H, d, J = 14H
z), 3.57 (1H, m), 3.77 (1H, m), 4.03 (1H, dd, J = 15,
7.6Hz), 7.2-7.6 (5H, m), 7.48 (2H, s), 7.74 (1H, s),
8.69 (1H, s) Elemental analysis: C ₂₇ H ₂₃ N ₃ O ₂ F ₆ Calculated (%): C 60.56, H 4.33, N 7.85 Found (%): C 60.28, H 4.51, N 7.65.

Reference Example 108 6- [3,5-bis (trifluoromethyl) benzyl]
-6,7,8,9,10,11-Hexahydro-3,1
0-dimethyl-5,11-dioxo-4-phenyl-5
H-pyrido [2,3-g] [1,5] diazonine The compound obtained in Reference Example 36 was reacted and treated in the same manner as in Reference Example 104, and the title compound was obtained as colorless crystals. Melting point: 247-249 ° C. (recrystallized from THF-ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.2-1.4 (1H, m), 1.8-2.3 (1
H, m), 2.15 (3H, s), 3.0-3.6 (4H, m), 3.04 (3H, s), 3.
91 (1H, d, J = 15Hz), 5.32 (1H, d, J = 15Hz), 7.0-7.5 (7
H, m), 7.75 (1H, s), 8.59 (1H, s) Elemental analysis: C ₂₇ H ₂₃ N ₃ O ₂ F ₆ Calculated (%): C 60.56, H 4.33, N 7.85 %): C 60.41, H 4.46, N 7.87 EI-MS m / s: 535 (M ⁺ ) [(C ₂₇ H ₂₃ N ₃
O ₂ F ₆₎ ^+].

Reference Example 109 4- [3,5-bis (trifluoromethyl) benzyl]
-8-hydroxymethyl-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido [3,2-f]
[1,4] oxazepine 8-acetoxymethyl-4- [3,5-bis (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido [3,2-f ]
[1,4] oxazepine (Reference Example 91) (4.51)
g), ethanol (50 ml) and 4N-NaOH
(50 ml) was stirred at room temperature for 1.5 hours. The solvent was distilled off, and water was added to the residue. The pH of the mixture was adjusted to about 8 using dilute hydrochloric acid and extracted with ethyl acetate.
The extract was washed with water, dried and the solvent was distilled off to obtain the title compound as colorless crystals (4.10 g). Melting point: 199-201 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200 MHz, CDCl ₃ ) ppm: 3.10 (1H, b), 3.71 (2H, t, J
= 5.6Hz), 4.50 (2H, t, J = 5.6Hz), 4.78 (2H, s), 4.88 (2
H, .s), 7.20-7.50 (6H, m), 7.80 (2H, m), 7.87 (1H, s)

Reference Example 110 4- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine-
4-carboxylic acid 4- [3,5-bis (trifluoromethyl) benzyl]
-8-hydroxymethyl-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido [3,2-f]
[1,4] oxazepine (Reference Example 109) (3.49)
g) A mixture of 2N-NaOH (100 ml) and potassium permanganate (2.22 g) was stirred at room temperature for 45 hours. A saturated aqueous solution of sodium thiosulfate (10 ml) was added to the reaction mixture, and the pH was adjusted to about 3 using hydrochloric acid, followed by extraction with ethyl acetate-THF (1: 2). The extract was washed with brine, dried, and evaporated to give the title compound as colorless crystals (2.74 g). Mp: 199-123 ℃ (methanol - recrystallized from ethyl ether) NMR (200MHz, DMSO-d 6) ppm: 3.94 (2H, b), 4.46 (2H,
b), 4.91 (2H, s), 7.25-7.55 (5H, m), 7.90 (1H, s), 8.
06 (2H, s), 8.12 (1H, s)

Reference Example 111 4- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine-
8-carboxamide 4- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine-
8-carboxylic acid (Reference Example 110) (220 mg), TH
A mixture of F (15 ml), DMF (catalytic amount) and thionyl chloride (0.087 ml) was stirred under superheated reflux for 2.5 hours. The solvent was distilled off, and the residue was washed with THF (10 ml).
Was dissolved. Aqueous ammonia (2 ml) was added to the solution, the mixture was stirred at room temperature for 1 hour, and the solvent was concentrated. Water was added to the concentrate and extracted with ethyl acetate. The extract was washed with water, dried and the solvent was distilled off to give the title compound as colorless crystals (163 mg). Melting point: 221-222 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200 MHz, CDCl ₃ ) ppm: 3.74 (2H, t, J = 5.6 Hz), 4.50
(2H, t, J = 5.6Hz), 4.92 (2H, s), 5.80 (1H, b), 7.30-
7.55 (6H, m), 7.83 (2H, s), 7.89 (1H, s), 8.20 (1H, s)

The compound of Reference Example 112-117 was 4-
[3,5-bis (trifluoromethyl) benzyl]-
2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine-8
-Carboxylic acid (Reference Example 110) is converted to substituted amines (methylamine, dimethylamine, n
-Butylamine, piperidine, morpholine, 1-methylpiperazine) in the same manner as in Reference Example 111, and treated. The physicochemical data is described below. Reference Example 112 4- [3,5-bis (trifluoromethyl) benzyl]
-N-methyl-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine-8-carboxamide Melting point: 145 ° C (decomposition) (THF-ethyl Recrystallized from ether) NMR (200 MHz, CDCl ₃ ) ppm: 3.04 (3H, d, J = 5.2 Hz), 3.73
(2H, t, J = 5.4Hz), 4.48 (2H, t, J = 5.4Hz), 4.09 (2H,
s), 7.25-7.60 (5H, m), 7.65-7.95 (1H, b), 7.81 (2H,
s), 7.87 (1H, s), 8.17 (1H, s)

Reference Example 113 4- [3,5-bis (trifluoromethyl) benzyl]
-N, N-dimethyl-2,3,4,5-tetrahydro-
5-oxo-6-phenylpyrido [3,2-f] [1,
4] Oxazepine-8-carboxamide Melting point: 235-236 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200MHz, CDCl ₃ ) ppm: 3.11 (3H, s), 3.15 (3H, s),
3.72 (2H, t, J = 5.6Hz), 4.47 (2H, t, J = 5.6Hz), 4.90 (2
H, s), 7.25-7.50 (5H, m), 7.60 (1H, s), 7.82 (2H, s),
7.88 (1H, s)

Reference Example 114 4- [3,5-bis (trifluoromethyl) benzyl]
-N-n-butyl-2,3,4,5-tetrahydro-5
-Oxo-6-phenylpyrido [3,2-f] [1,
4] Oxazepine-8-carboxamide Melting point: 194-196 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200MHz, CDCl ₃ ) ppm: 0.96 (3H, t, J = 7.2Hz), 1.20
-1.80 (6H, m), 4.78 (2H, m), 3.73 (2H, t, J = 5.6Hz),
4.49 (2H, t, J = 5.6Hz), 4.91 (2H, s), 7.30-7.58 (5H,
m), 7.82 (2H, s), 7.88 (1H, s), 8.18 (1H, s)

Reference Example 115 4- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-5-oxo-6-phenyl-8-piperidinocarbonylpyrido [3,2-
f] [1,4] oxazepine Melting point: 218-220 ° C (recrystallized from THF-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.60 (2H, b), 1.69 (4H, b),
3.44 (2H, t, J = 5.6Hz), 3.72 (4H, m), 4.46 (2H, t, J =
5.6Hz), 4.89 (2H, s), 7.20-7.60 (6H, m), 7.81 (2H,
s), 7.87 (1H, s)

Reference Example 116 4- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-8-morpholinocarbonyl-5-oxo-6-phenylpyrido [3,2-
f] [1,4] oxazepine Melting point: 265-266 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200 MHz, CDCl ₃ ) ppm: 3.55-3.90 (10H, m), 4.46 (2
(H, t, J = 5.6Hz), 4.89 (2H, s), 7.25-7.52 (5H, m), 7.5
9 (1H, s), 7.81 (2H, s), 7.88 (1H, s)

Reference Example 117 4- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-8- [1- (4-methylpiperazinyl) carbonyl] -5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine Melting point: 196 -198 ° C (recrystallized from THF-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.35 (3H, s), 2.45 (2H, m),
2.54 (2H, m), 3.61 (2H, m), 3.72 (2H, t, J = 5.6Hz), 3.
84 (2H, m), 4.46 (2H, t, J = 5.6Hz), 4.89 (2H, s), 7.25-
7.50 (5H, m), 7.54 (1H, s), 7.81 (2H, s), 7.88 (1H, s)

The compounds of Reference Examples 118 to 126 were reacted with the compounds of Reference Examples 37 to 45 in substantially the same manner as in Reference Example 65 (in THF in the presence of sodium hydride). To give colorless crystals. The respective physicochemical data are shown below. Reference Example 118 2,3,4,5-tetrahydro-5-oxo-6-phenyl-4- (3,4,5-trimethoxybenzyl) pyrido "3,2-f] [1,4] oxazepine Melting point: 177-179 ° C (recrystallized from acetone-ethyl ether) NMR (200MHz, CDCl ₃ ) ppm: 3.70 (2H, t, J = 5.6Hz), 3.85
(6H, s), 3.87 (3H, s), 4.34 (2H, t, J = 5.6Hz), 4.72 (2H,
s), 6.60 (2H, s), 7.24 (1H, d, J = 5.2Hz), 7.30-7.55
(5H, m), 8.42 (1H, d, J = 5.2Hz)

Reference Example 119 4- (3,4-dichlorobenzyl) -2,3,4,5-
Tetrahydro-5-oxo-6-phenylpyrido [3,
2-f] [1,4] oxazepine Melting point: 189-192 ° C (recrystallized from THF-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 3.67 (2H, t, J = 5.4 Hz), 4.42
(2H, t, J = 5.4Hz), 4.71 (2H, s), 7.10-7.70 (9H, m),
8.43 (1H, d, J = 5.2Hz)

Reference Example 120 4- (3,4-dimethoxybenzyl) -2,3,4,5
-Tetrahydro-5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine Melting point: 175-176 ° C (recrystallized from THF-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 3.67 (2H , t, J = 5.4Hz), 3.85
(3H, s), 3.91 (3H, s), 4.29 (2H, t, J = 5.4Hz), 4.72 (2
H, s), 6.80-7.00 (3H, m), 7.22 (1H, d, J = 5.2Hz), 7.3
0-7.50 (5H, m), 8.40 (1H, d, J = 5.2Hz)

Reference Example 121 4-benzyl-2,3,4,5-tetrahydro-5-oxo-6-phenylpyrido [3,2-f] [1,4] oxazepine Melting point: 209-211 ° C. (methanol-ethyl Recrystallized from ether) NMR (200MHz, CDCl ₃ ) ppm: 3.64 (2H, t, J = 5.6Hz), 4.33
(2H, t, J = 5.6Hz), 4.77 (2H, s), 7.22 (1H, d, J = 5.2H
z), 7.30-7.55 (5H, m), 8.39 (1H, d, J = 5.2Hz)

Reference Example 122 2,3,4,5-tetrahydro-6-oxo-7-phenyl-5- (3,4,5-trimethoxybenzyl) -6
H-pyrido [2,3-b] [1,5] oxazosin Melting point: 155-156 ° C. (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.65-1.85 (1H, m), 2.29 (1H,
m), 3.40-3.75 (2H, m), 3.77 (6H, s), 3.87 (3H, s),
4.07 (1H, d, J = 14.2Hz), 4.27 (1H, m), 4.66 (1H, m),
5.22 (1H, d, J = 14.2Hz), 6.53 (2H, s), 7.15 (1H, d, J =
5.2Hz), 7.35 (5H, m), 8.40 (1H, d, J = 5.2Hz)

Reference Example 123 (S) -5-benzyl-2,3,4,5-tetrahydro-3-methyl-6-oxo-7-phenyl-6H-pyrido [2,3-b] [1,5 Oxazosin melting point: 139-141 ° C (ethyl acetate-isopropyl
Recrystallized from ether) NMR (200MHz, CDCl ₃ ) ppm: 0.84 (3H, d, J = 7.0Hz), 2.43
(1H, m), 3.12 (1H, d, J = 14.8Hz), 3.39 (1H, dd, J = 15.
4, 10.2Hz), 3.72-4.00 (2H, m), 4.60 (1H, dd, J = 12.4,
5.2Hz), 5.51 (1H, d, J = 14.8Hz), 7.16 (1H, d, J = 5.0H
z), 7.20-7.50 (10H, m), 8.39 (1H, dd, J = 5.0Hz)

Reference Example 124 (R) -5-benzyl-2,3,4,5-tetrahydro-3-methyl-6-oxo-7-phenyl-6H-pyrido [2,3-b] [1,5 Oxazosin melting point: 139-141 ° C (ethyl acetate-isopropyl
Recrystallized from ether) NMR (200 MHz, CDCl ₃ ) ppm: the same as the spectrum of the compound of Reference Example 123.

Reference Example 125 (S) -5- [3,5-bis (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-3-methyl-6-oxo-7-phenyl-6H- Pyrido [2,3-
b] [1,5] oxazosin Melting point: 142-143 ° C (ethyl acetate-isopropyl)
Recrystallization from ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.87 (3H, d, J = 7.0 Hz), 2.46
(1H, m), 3.10 (1H, d, J = 15.4Hz), 3.59 (1H, dd, J = 15.
0, 10.6Hz), 3.92 (1H, dd, .J = 12.6, 10.4Hz), 4.20 (1
H, d, J = 15.4Hz), 4.63 (1H, dd, J = 12.6, 5.2Hz), 5.50
(1H, d, J = 15.4Hz), 7.18 (1H, d, J = 5.0Hz), 7.20-7.50
(5H, m), 7.72 (2H, s), 7.84 (1H, s), 8.43 (1H, d, J =
5.0Hz)

Reference Example 126 (R) -5- [3,5-bis (trifluoromethyl) benzyl] -2,3,4,5-tetrahydro-3-methyl-6-oxo-7-phenyl-6H- Pyrido [2,3-
b] [1,5] oxazosin Melting point: 142-143 ° C (ethyl acetate-isopropyl)
Recrystallization from ether) NMR (200 MHz, CDCl ₃ ) ppm: the same as the spectrum of the compound of Reference Example 125.

Reference Example 127 7-Benzyl-6,7,8,9,10,11-hexahydro-5- (4-methylphenyl) -6,13-dioxo-13H- [1,4] diazosino [2,7 1-g]
[1,7] Naphthyridine Using the compound obtained in Reference Example 46, reacted in the same manner as in Reference Example 69, and treated to give the title compound as colorless crystals. Melting point: 239-241 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.6-2.1 (4H, m), 2.50 (3H,
s), 3.14 (1H, dd, J = 15, 3.8Hz), 3.3-3.7 (2H, m), 3.7
7 (1H, d, J = 15Hz), 5.14 (1H, dd, J = 14, 5.9Hz), 5.42
(1H, d, J = 15Hz), 6.67 (2H, d, J = 7.0Hz), 6.92 (1H, d
d, J = 7.6, 1.8Hz), 7.1-7.5 (6H, m), 7.46 (1H, dd, J =
8.4, 4.4Hz), 7.60 (1H, dd, J = 8.4, 1.8Hz), 8.90 (1H,
(dd, J = 4.4, 1.8Hz)

Reference Example 128 (9R) -7-benzyl-6,7,8,9,10,11
-Hexahydro-9-methyl-5- (4-methylphenyl) -6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine Compound obtained in Reference Example 47 And treated in the same manner as in Reference Example 69 to give the title compound as colorless crystals. Melting point: 218-220 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.85 (3H, d, J = 7.0 Hz), 1.5
0-1.75 (1H, m), 1.90-2.35 (2H, m), 2.50 (3H, s), 2.89
(1H, d, J = 15Hz), 3.26 (1H, dd, J = 14, 10Hz), 3.59 (1H,
dd, J = 14, 11Hz), 3.75 (1H, d, J = 15Hz), 5.10 (1H, d
d, J = 14, 6.1Hz), 5.42 (1H, d, J = 15hz), 6.69 (2H, d,
J = 6.8Hz), 6.91 (1H, dd, J = 7.8, 1.8Hz), 7.1-7.5 (6H,
m), 7.46 (1H, dd, J = 8.4, 4.2Hz), 7.60 (1H, dd, J = 8.
4, 1.8Hz), 8.90 (1H, dd, J = 4.2, 1.8Hz)

Reference Example 129 (9S) -7-benzyl-6,7,8,9,10,11
-Hexahydro-9-methyl-5- (4-methylphenyl) -6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine Compound obtained in Reference Example 47 And treated in the same manner as in Reference Example 69 to give the title compound as colorless crystals. Melting point: 218-220 ° C (ethyl acetate-isopropyl)
Recrystallized from ether) NMR (200 MHz, CDCl ₃ ) ppm: same as the spectrum of the compound of Reference Example 128.

Reference Example 130 (9R) -6,7,8,9,10,11-Hexahydro-9-methyl-5- (4-methylphenyl) -6,13
-Dioxo-7- (3,4,5-trimethoxybenzyl) -13H- [1,4] diazosino [2,1-g]
[1,7] Naphthyridine Using the compound obtained in Reference Example 49, reacted in the same manner as in Reference Example 69, and treated to give the title compound as colorless crystals. White powder NMR (200 MHz, CDCl ₃ ) ppm: 0.90 (3H, d, J = 6.6 Hz), 1.5
-1.8 (1H, m), 1.9-2.5 (2H, m), 2.41 (3H, s), 3.11 (1H,
d, J = 15Hz), 3.35 (1H, dd, J = 15, 11Hz), 3.56 (1H, d
d, J = 14, 11Hz), 3.7-3.9 (1H, m), 3.75 (6H, s), 3.87
(3H, s), 5.07 (1H, dd, J = 14, 5.9Hz), 5.19 (1H, d, J =
15Hz), 6.30 (2H, s), 6.77 (1H, d, J = 8.0Hz), 6.97 (1H,
d, J = 8.0Hz), 7.29 (1H, d, J = 8.2Hz), 7.37 (1H, d, J =
8.2Hz), 7.45 (1H, dd, J = 8.4, 4.0Hz), 7.58 (1H, dd, J
= 8.4, 1.4Hz), 8.89 (1H, dd, J = 4.0, 1.4Hz)

Reference Example 131 (9S) -6,7,8,9,10,11-Hexahydro-9-methyl-5- (4-methylphenyl) -6,13
-Dioxo-7- (3,4,5-trimethoxybenzyl) -13H- [1,4] diazosino [2,1-g]
[1,7] Naphthyridine The compound obtained in Reference Example 50 was reacted in the same manner as in Reference Example 69, and treated to give the title compound as colorless crystals. White powder NMR (200 MHz, CDCl ₃ ) ppm: Same as the spectrum of the compound of Reference Example 130.

Reference Example 132 (9R) -7- (3,5-dimethoxybenzyl) -6
7,8,9,10,11-hexahydro-9-methyl-
5- (4-methylphenyl) -6,13-dioxo-1
3H- [1,4] diazosino [2,1-g] [1,7]
Naphthyridine Using the compound obtained in Reference Example 51, reacted in the same manner as in Reference Example 69, and treated to give the title compound as colorless crystals. Melting point: 206-208 ° C (ethanol-isopropyl)
Recrystallized from ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.87 (3H, d,
J = 7.0 Hz), 1.67 (1H, m), 1.
9-2.4 (2H, m), 2.42 (3H,
s), 3.05 (1H, d, J = 15 Hz),
3.24-3.40 (1H, m), 3.45-3.
85 (2H, m), 3.74 (6H, s), 5.
08 (1H, dd, J = 14, 5.8 Hz),
5.26 (1H, d, J = 14 Hz), 6.12
(2H, d, J = 2.0 Hz), 6.38 (1
H, t, J = 2.0 Hz), 6.84 (1H,
d, J = 7.0 Hz), 7.09 (1H, d,
J = 7.0 Hz), 7.29 (1H, d, J =
9.2 Hz), 7.38 (1H, d, J = 9.2)
Hz), 7.46 (1H, dd, J = 8.2,
4.2 Hz), 7.62 (1H, dd, J = 8.
2, 1.6 Hz), 8.89 (1H, dd, J
= 4.2, 1.6 Hz)

The compounds of Reference Examples 133 to 136 were obtained from Reference Examples 52 to 54 and Reference Example 14, respectively.
The compound (4) was subjected to a reaction (cyclization reaction in THF in the presence of sodium hydride) and treatment substantially in the same manner as in Reference Example 65 to give colorless crystals. Each physicochemical data is described below. Reference Example 133 4-benzyl-2,3,4,5-tetrahydro-5-oxo-6- (4-methylphenyl) pyrido [3,2-
f] [1,4] oxazepine Melting point: 203-204 ° C (recrystallized from methanol-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.41 (3H, s), 3.64 (2H,
t, J = 5.4Hz), 4.32 (2H, t, J = 5.4Hz), 4.78 (2H, s), 7.
21 (1H, d, J = 5.2Hz), 7.25 (4H, s), 7.38 (5H, s), 8.37
(1H, d, J = 5.2Hz)

Reference Example 134 4- [3,5-bis (trifluoromethyl) benzyl]
-2,3,4,5-tetrahydro-5-oxo-6-
(4-methylphenyl) pyrido [3,2-f] [1,
4] Oxazepine Melting point: 212-213 ° C (recrystallized from acetone-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.40 (3H, s), 3.70 (2H, t,
J = 5.6Hz), 4.47 (2H, t, J = 5.6Hz), 4.89 (2H, s), 7.24
(total 5H, m), 7.81 (2H, s), 7.87 (1H, s), 8.41 (1H,
d, J-5.2Hz)

Reference Example 135 (S) -5-benzyl-2,3,4,5-tetrahydro-3-methyl-7- (4-methylphenyl) -6-oxo-6H-pyrido [2,3-b ] [1,5] oxazosin Melting point: 148-149 ° C (recrystallized from acetone-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.83 (3H, d, J = 7.4 Hz), 2.3
0-2.60 (1H, b), 2.42 (3H, s), 3.11 (1H, d, J = 15.4Hz),
3.40 (1H, dd, J = 15.4, 10.4Hz), 3.75-4.00 (2H, m),
4.59 (1H, dd, J = 12.4, 4.8Hz), 5.50 (1H, d, J = 15.0H
z), 7.15 (1H, d, J = 4.8Hz), 7.20-7.40 (total 9H, m),
8.37 (1H, d, J = 4.8Hz)

Reference Example 136 (S) -5- [3,5-bis (trifluoromethyl) benzyl-2,3,4,5-tetrahydro-3-methyl-
7- (4-Methylphenyl) -6-oxo-6H-pyrido [2,3-b] [1,5] oxazosin Melting point: 159-160 ° C. (recrystallized from acetone-isopropyl ether) NMR (200 MHz, CDCl ₃₎ ) Ppm: 0.86 (3H, d, J = 7.0Hz), 2.2
0-2.60 (1H, b), 2.37 (3H, s), 3.09 (1H, d, J = 15.4Hz),
3.58 (1H, dd, J = 15.4, 10.4Hz), 3.89 (1H, t, J = 11.6H
z), 4.18 (1H, d, J = 15.4Hz), 4.62 (1H, dd, J = 12.2, 5.
2Hz), 5.53 (1H, d, J = 15.4Hz), 7.17 (total 5H, m), 7.7
2 (2H, s), 7.84 (1H, s), 8.40 (1H, d, J = 5.2Hz)

Reference Example 137 (9R) -7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,10,11-hexahydro-5-
(4-hydroxymethylphenyl) -9-methyl-6,1
3-dioxo-13H- [1,4] diazosino [2,1-g]
[1,7] Naphthyridine yeast extract 0.4%, malt extract 1%, glucose 0.4
%, Agar 2% (ISP Medium No. 2), pH 7.
28 Streptomyces subrutilus IFO 13388 on agar slant 3
C. for 14 days. Separately, 0.5% glucose, 5% dextrin, 3.5% defatted soy bean meal,
Prepare a medium containing 0.7% calcium carbonate and add 200ml
40 ml was placed in a conical flask and steam sterilized at 120 ° C. for 20 minutes. One platinum loop of the above-mentioned cultured cells was inoculated into this medium, and cultured with shaking at 28 ° C. for 48 hours. The obtained culture solution was further transferred to 13 flasks each containing the same medium in an amount of 1 ml, and cultured at 28 ° C. for 48 hours with shaking. The (9R) -7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,10,11-hexahydro-9-methyl- obtained in Reference Example 72 was added to each culture. 5- (4-methylphenyl)-
6,13-dioxo-13H- [1,4] diazosino [2,1
-G] [1,7] Naphthyridine (104 mg) in DMSO
(5.2 ml) The solution was added in 0.4 ml portions and added at 28 ° C.
For 48 hours to react. After the reaction, p with 2N sulfuric acid
Adjusted to H4 and extracted with 500 ml of ethyl acetate. The extract was concentrated, and the concentrate was separated and purified by column chromatography using silica gel (ethyl acetate-methanol = 9: 1) to give the title compound as colorless crystals (30 mg).
Was obtained as 240-241 ° C (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.91 (3
H, d, J = 6.6 Hz), 1.5-1.9 (2H, m),
1.95-2.40 (2H, m), 2.98 (1H, d, J
= 15 Hz), 3.35-3.65 (2H, m), 4.02
(1H, d, J = 15Hz), 4.75 (2H, s), 5.
10 (1H, dd, J = 15, 5.5 Hz), 5.46 (1
H, d, J = 15 Hz), 6.97 (1 H, d, J = 8.0)
Hz), 7.26 (1H, d, J = 8.0Hz), 7.4-
7.6 (6H, m), 7.81 (1H, s), 8.93 (1
H, dd, J = 4.0, 1.8 Hz) Elemental analysis: calculated as C ₃₀ H ₂₅ N ₃ O ₃ F ₆ Calculated (%): C 61.12, H 4.27, N
7.13 Found (%): C 61.15, H 4.21, N
7.03 EI-MS m / z: 589 (M ⁺ ) [(C ₃₀ H ₂₅ N ₃ O
₃ F ₆₎ ^+].

Reference Example 138 (9R) -7- [3,5-bis (trifluoromethyl) benzyl] -5- (4-formylphenyl) -6,7,8,9,10,
11-hexahydro-9-methyl-6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine 0.4% yeast extract, 1% malt extract, 0.1% glucose. 4
%, Agar agar 2% (ISP Medium No. 2), pH 7.
Streptomyces tanaciensis subsp. Cephalomyceticas on agar slant 3
es tanashiensis subsp. cephalomyceticus) IFO 1
3929 was cultured at 28 ° C. for 14 days. Separately, glucose 0.5%, dextrin 5%, defatted soy flour (soy bean me
al) Prepare a medium containing 3.5% and 0.7% calcium carbonate, place 40 ml in a 200 ml Erlenmeyer flask,
For 20 minutes. One platinum loop of the above-mentioned cultured cells was inoculated into this medium, and cultured with shaking at 28 ° C. for 48 hours. The obtained culture solution was further transferred to 25 flasks each containing the same medium in an amount of 1 ml each, and cultured with shaking at 28 ° C. for 48 hours. The (9R) -7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,10, obtained in Reference Example 72 was added to each of the culture solutions.
D of 11-hexahydro-9-methyl-5- (4-methylphenyl) -6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine (200 mg)
MSO (10 ml) solution was added in 0.4 ml portions,
The mixture was shaken at 28 ° C. for 48 hours to be reacted. After the reaction, the pH was adjusted to 4 with 2N sulfuric acid and extracted with 1 L of ethyl acetate. The extract was concentrated, and the concentrate was separated and purified by column chromatography using silica gel (ethyl acetate-methanol = 9: 1) to give colorless crystals containing the title compound. The structure of this product was determined by comparing the NMR spectrum with the compound separately prepared in Reference Example 139.

Reference Example 139 (9R) -7- [3,5-bis (trifluoromethyl) benzyl] -5- (4-formylphenyl) -6,7,8,9,10,
11-hexahydro-9-methyl-6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine (9R) -7- [3 obtained in Reference Example 137 , 5-Bis (trifluoromethyl) benzyl] -6,7,8,9,10,11
-Hexahydro-5- (4-hydroxymethylphenyl)
-9-Methyl-6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine (109 m
g), manganese dioxide (1.3 g) and dichloromethane (13 ml) were stirred at room temperature for 2 hours and the precipitate was filtered off using Celite. The filtrate was concentrated to give the title compound as colorless crystals (70 mg). Mp 213-214 ° C (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.95 (3
H, d, J = 6.6 Hz), 1.60-1.85 (1H,
m), 1.95-2.40 (2H, m), 3.05 (1H,
d, J = 15 Hz), 3.35-3.65 (2H, m), 4.
00 (1H, d, J = 15 Hz), 5.11 (1H, dd,
J = 14,5.7 Hz), 5.38 (1H, d, J = 15H)
z), 7.12 (1H, d, J = 8.4Hz), 7.40-
7.55 (4H, m), 7.60-7.75 (2H, m),
7.78 (1H, s), 7.96 (1H, d, J = 8.0H)
z), 8.94 (1H, m ), 10.03 (1H, s) Elemental analysis: Calculated _{C 30 H 23 N 3 O 3} F 6 (%): C 61.33, H 3.95 , N
7.15 Found (%): C 61.25, H 4.04, N
7.11 EI-MS m / z: 587 (M +) [(C 30 H 23 N 3 O
₃ F ₆₎ ^+].

Reference Example 140 (9R) -7- [3,5-bis (trifluoromethyl) benzyl] -5- (4-carboxyphenyl) -6,7,8,9,1
0,11-hexahydro-9-methyl-6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine 0.4% yeast extract, 1% malt extract, glucose 0.4
%, Agar 2% (ISP Medium No. 2), pH 7.
Streptomyces lavenduligriseus IFO 13 on agar agar slant 3
405 was cultured at 28 ° C. for 14 days. Separately, glucose 0.5%, dextrin 5%, defatted soy flour (soy bean me
al) A medium containing 3.5% and 0.7% calcium carbonate was prepared, placed in a 200 ml Erlenmeyer flask, and sterilized with steam at 120 ° C. for 20 minutes. The above culture cells were added to this medium for 1 hour.
A platinum loop was inoculated and cultured with shaking at 28 ° C. for 48 hours. The obtained culture solution was further added to 25 flasks containing the same medium.
Each ml was transferred and shake-cultured at 28 ° C. for 48 hours. The (9R) -7- [3,5-bis) obtained in Reference Example 72 was added to each culture solution.
(Trifluoromethyl) benzyl] -6,7,8,9,10,1
DM of 1-hexahydro-9-methyl-5- (4-methylphenyl) -6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine (200 mg)
SO (10 ml) solution was added in 0.4 ml portions, and 2
The mixture was shaken at 8 ° C for 48 hours to react. After the reaction, the pH was adjusted to 4 with 2N sulfuric acid and extracted with 1 L of ethyl acetate. The extract was concentrated, and the concentrate was extracted with 1N aqueous sodium hydroxide. The extract was adjusted to pH 3-4 using 2N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated saline and dried, and the solvent was distilled off. The residue was separated and purified by column chromatography on silica gel (ethyl acetate-methanol = 9: 1) to give the title compound as colorless crystals (58 mg). 300-301 ° C (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.96 (3
H, d, J = 6.6 Hz), 1.76 (1H, m), 1.95
-2.40 (2H, m), 3.09 (1H, d, J = 15H
z), 3.40-3.65 (2H, m), 4.02 (1H,
d, J = 15 Hz), 5.12 (1H, dd, J = 14,5.
6 Hz), 5.36 (1 H, d, J = 15 Hz), 7.04
(1H, dd, J = 8.0, 1.6Hz), 7.45-7.6
5 (5H, m), 7.83 (1H, s), 7.91 (1
H, d, J = 8.4 Hz), 8.20 (1 H, dd, J = 8.
4,1.8 Hz), 8.97 (1H, dd, J = 3.6, 2.
2Hz) EI-MS m / z : 603 (M +) [(C 30 H 23 N 3 O
₄ F ₆₎ ^+].

Reference Example 141 (9R) -7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,10,11-hexahydro-9-methyl-5- (4-methyl (Phenyl) -6,13-dioxo-
13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine N-oxide (9R) -7- [3,5-bis (trifluoromethyl) benzyl] obtained in Reference Example 72 −6,7,8,9,10,11−
Hexahydro-9-methyl-5- (4-methylphenyl)
-6,13-Dioxo-13H- [1,4] diazosino [2,
1-g] [1,7] naphthyridine (1.60 g), m-chloroperbenzoic acid (1.2 g) and dichloromethane (20 m
After the mixture of l) was stirred at room temperature for 3 hours, the solvent was distilled off. The residue was dissolved in ethyl acetate, washed with aqueous potassium carbonate and saturated saline, and dried. Evaporation of the solvent gave the title compound as pale yellow crystals (0.73 g). 237-239 ° C (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.91 (3
H, d, J = 6.6 Hz), 1.73 (1H, m), 1.9−
2.4 (2H, m), 2.36 (3H, s), 2.97 (1
H, d, J = 15 Hz), 3.3-3.5 (2H, m), 3.
97 (1H, d, J = 15 Hz), 4.97 (1H, dd,
J = 14, 5.2Hz), 5.41 (1H, d, J = 15H)
z), 6.82 (2H, m), 7.04 (1H, d, J = 7.
4Hz), 7.15-7.35 (3H, m), 7.44 (2
H, s), 7.81 (1H, s), 8.31 (1H, dd, J
= 5.4, 0.8 Hz) Elemental analysis: calculated as C ₃₀ H ₂₅ N ₃ O ₃ F ₆ Calculated (%): C 61.12, H 4.27, N
7.13 Found (%): C 60.77, H 4.55, N
7.00

Reference Example 142 (9R) -7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,10,11-hexahydro-5- (4
-Hydroxymethylphenyl) -9-methyl-6,13-
Dioxo-13H- [1,4] diazosino [2,1-g] [1,
7] Naphthyridine N-oxide (9R) -7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,10,11 obtained in Reference Example 137
-Hexahydro-5- (4-hydroxymethylphenyl)
-9-Methyl-6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine (100 m
After stirring a mixture of g), 4-dimethylaminopyridine (catalytic amount), acetic anhydride (0.1 ml) and pyridine (3 ml) at room temperature for 16 hours, the solvent was distilled off. Ethyl acetate was added to the residue, washed with dilute hydrochloric acid and saturated saline, dried, and the solvent was distilled off. The residue was diluted with dichloromethane (10 ml).
Was dissolved. To this solution was added m-chloroperbenzoic acid (102
mg) and stirred at room temperature for 1 hour. The reaction solution was diluted with dichloromethane and washed with 0.1N aqueous sodium hydroxide.
It was dried and the solvent was distilled off. Methanol (10m
l) and 1N aqueous sodium hydroxide (2 ml) were added, the mixture was stirred at room temperature for 30 minutes, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried, and evaporated to give the title compound as pale yellow crystals (28 mg). 240-243 ° C (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.91 (3
H, d, J = 6.2 Hz), 1.5-2.4 (4H, m),
2.98 (1H, d, J = 15 Hz), 3.44 (2H,
m), 4.00 (1 H, d, J = 15 Hz), 4.74 (2
H, s), 4.98 (1H, m), 5.40 (1H, d, J
= 15 Hz), 6.88 (1H, m), 7.26 (1H,
d, J = 7.4 Hz), 7.45 (6H, m), 7.81 (1
H, s), 8.32 (1H, m)

Reference Example 143 (9R) -7- [3,5-bis (trifluoromethyl) benzyl] -5- (4-carboxyphenyl) -6,7,8,9,1
0,11-hexahydro-9-methyl-6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine N-oxide (9R) obtained in Reference Example 140 -7- [3,5-bis (trifluoromethyl) benzyl] -5- (4-carboxyphenyl) -6,7,8,9,10,11-hexahydro-9-
TH of methyl-6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine (200 mg)
Ethyl ether (10 ml) of diazomethane (adjusted with N-nitrosomethylurea and potassium hydroxide) was added to the F (20 ml) solution, and the mixture was stirred at room temperature for 30 minutes. After evaporation of the solvent, the residue was dissolved in dichloromethane (20 ml). To this solution, m-chloroperbenzoic acid (0.6 g) was added little by little, and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with dichloromethane, washed with 1N aqueous sodium hydroxide and water, dried, and the solvent was distilled off. Methanol (2
0 ml) and 1N aqueous sodium hydroxide (5 ml) were added,
The mixture was heated under reflux for 30 minutes. After the solvent was distilled off, water was added to the residue, and the mixture was adjusted to pH 2-3 with 2N hydrochloric acid. The solution was extracted with ethyl acetate, the extract was washed with saturated saline, dried, and the solvent was distilled off to obtain the title compound as pale yellow crystals (88 mg). NMR (200 MHz, CDCl ₃ ) ppm: 0.95 (3
H, d, J = 6.6 Hz), 1.75 (1H, m), 1.9−
2.4 (2H, m), 3.08 (1H, d, J = 15H
z), 3.47 (2H, m), 4.00 (1H, d, J = 1)
5Hz), 5.00 (1H, dd, J = 14, 6.0Hz),
5.29 (1H, d, J = 15 Hz), 6.80 (1H,
d, J = 8.4 Hz), 7.02 (1 H, d, J = 7.3 H)
z), 7.28 (1H, dd, J = 7.0, 6.6Hz), 7.
46 (2H, s), 7.54 (1H, d, J = 7.0H)
z), 7.81 (1H, s), 7.88 (1H, d, J = 7.
3 Hz), 8.16 (1 H, d, J = 8.4 Hz), 8.39
(1H, d, J = 6.6 Hz).

Reference Example 144 N- [3,5-bis (trifluoromethyl) benzyl]
2-chloro -N - [(S) -3-hydroxy-2-methylpropyl] -4- (4-methylphenyl) -3-pyridinecarboxamide _{NMR (200MHz, CDCl 3) ppm} : 0.54 (3H × 1 / 4, d, J = 7.0Hz),
0.63 (3H × 1/4, d, J = 7.0Hz), 0.79 (3H × 1/4, d, J = 7.0H
z), 0.84 (3H × 1/4, d, J = 7.0Hz), 1.50-1.90 (1H, m),
2.25-2.45 (3H, m), 2.45-3.90 (total 5H, m), 4.05-4.4
5 (1H, m), 4.50-4.95 (1H, m), 7.00-7.20 (1H, m), 7.20
-7.50 (total 5H, m), 7.70-7.85 (2H, m), 8.42 (1H, m). (1: 1 mixture of amide rotamers).

[0264] Reference Example ^{145 (9R) - [10,10,11,11- 2} H 4] -7- [3,
5-bis (trifluoromethyl) benzyl] -8,9.1
0,11-tetrahydro-9-methyl-5- (4-methylphenyl) -7H- [1,4] diazosino [2,1-
g] [1,7] Naphthyridine-6,13-dione (d ₄ form of the compound of Reference Example 72) (Step 1) (S)-(+)-3-hydroxy-2-methylpropionic acid methyl ester THP ether (3
9.5 g) (prepared according to the method described in the literature [Kenji Mori, Vol. 39, Tetrahedron 39, 3107-3109 (1983): Synthetic method is described for enantiomers)]. 60 ml) solution at 0 ° C. with lithium aluminum deuteride (5.80 g) in ethyl
It was slowly added to a suspension of ether (200 ml) with vigorous stirring. Then, the reaction mixture was stirred at room temperature for 1 hour, cooled again with ice water, and 1N aqueous sodium hydroxide (24%).
ml) and THF (24 ml) were added with stirring. After the precipitate was filtered off through celite, and the filtrate was dried and the solvent was evaporated ^{(S) - [1,1- 2 H} 2] -2
-Methyl-1,3-propanediol mono THP ether was obtained as a colorless oil (35.6 g). NMR (200 MHz, CDCl ₃ ) ppm: 0.90 (3
H × 1/2, d, J = 7.0 Hz), 0.91 (3H × 1 /
2, d, J = 7.0 Hz), 1.4-1.9 (6 H, m), 2.
01 (1H, m), 2.74 (1H, bs), 3.3-3.6
(3H, m), 3.89 (1H, m), 4.58 (1H,
b). (Step 2) While stirring under cooling with a solution of the compound (35.6 g) obtained in Step 1 in pyridine (150 ml), p-chloride was added.
Toluenesulfonyl (39 g) was added. The mixture was stirred overnight at room temperature, diluted with ethyl ether, washed with water, dilute hydrochloric acid and brine, dried, and evaporated. The residue was dissolved in DMSO (150 ml), sodium cyanide (13 g) was added, and the mixture was stirred at room temperature for 6 hours. After diluting with hexane, washing with water and drying, and evaporating the solvent, (R)
- [2,2- _² H ^2] -4- hydroxy-3-methyl butane nitrile THP ether pale yellow oil (19.1
g). NMR (200 MHz, CDCl ₃ ) ppm: 1.09 (3
H × 1/2, d, J = 6. Hz, 1.10 (3H × 1 /
2, d, J = 6.8 Hz), 1.5-1.9 (6 H, m),
2.16 (1H, m), 3.16-3.88 (4H, m),
4.60 (1H, b).

(Step 3) Compound (19.1) obtained in Step 2
A solution of g) in ethyl ether (80 ml) was added slowly at 0 ° C. to a suspension of lithium aluminum deuteride (4.85 g) in ethyl ether (200 ml) with vigorous stirring. The reaction mixture was then stirred at room temperature for 1 hour,
After cooling again with ice water, 1N aqueous sodium hydroxide solution (20 ml)
And a mixture of THF (20 ml) was added with stirring. After the precipitate was filtered off through celite, and the filtrate was dried and the solvent was evaporated ^{(R) - [3,3,4,4- 2 H} 4]
-4-Amino-2-methyl-1-butanol THP ether was obtained as a pale yellow oil (19.3 g). NMR (200 MHz, CDCl ₃ ) ppm: 0.93 (3
H × 1/2, d, J = 6.8 Hz), 0.94 (3H × 1 /
2, d, J = 6.8 Hz), 1.2-1.9 (9 H, m), 3.
13-3.27 (1H, m), 3.45-3.64 (2H,
m), 3.86 (1H, m), 4.57 (1H, b).

(Step 4) Compound obtained in Step 3 and Reference Example 3
The compound obtained in the above was reacted and treated in the same manner as in Reference Example 5 to obtain (R) -N- [3,5- (bistrifluoromethyl) benzyl] -7,8-dihydro-7-([ One,
1,2,2- ² H _4] -4- hydroxy-3-methylbutyl) -5- (4-methylphenyl) -8-oxo - 1,
7-Naphthyridine-6-carboxamide was obtained as colorless crystals. Melting point: 205-207 ° C (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.78 (3
H, d, J = 7.0 Hz), 1.55 (1H, m), 2.28
(3H, s), 3.14 (1H, b, OH), 3.2-3.
5 (2H, m), 4.50 (2H, d, J = 6.0 Hz),
7.0-7.3 (4H, m), 7.29 (1H, dd, J =
8.4, 4.4 Hz), 7.54 (1H, dd, J = 8.4,
1.6Hz), 7.69 (2H, s), 7.78 (1H,
s), 8.55 (1 H, t, J = 6.0 Hz), 8.61 (1
H, dd, J = 4.4, 1.6 Hz). Elemental analysis: C ₃₀ H ₂₃ D ₄ F ₆ N ₃ O ₃ .1 / 2H ₂ O Calculated (%): C, 59.60 H, 4.00 D, 1.
33 N, 6.95 found (%): C, 59.94 H, 3.82 D, 1.
29 N, 7.13.

(Step 5) The compound obtained in Step 4 was reacted and treated in the same manner as in Reference Example 69 to give the title compound as colorless crystals. Melting point: 227-229 ° C (recrystallized from ethyl acetate-methanol-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.91 (3
H, d, J = 7.0 Hz), 2.08 (1 H, m), 2.3
7 (3H, s), 2.97 (1H, dd, J = 15, 1.4
Hz), 3.45 (1H, dd, J = 15, 11 Hz), 3.
99 (1H, d, J = 15 Hz), 5.46 (1H, d, J
= 15Hz), 6.83 (1H, dd, J = 7.8, 1.8H)
z), 7.05 (1H, d, J = 7.8Hz), 7.26 (1
H, d, J = 7.8 Hz, 7.34 (1H, dd, J = 7.3)
8, 1.8 Hz), 7.47 (1H, dd, J = 8.6, 4.4)
Hz), 7.48 (2H, s), 7.56 (1H, dd, J =
8.6, 1.8 Hz), 7.82 (1H, s), 8.91 (1
H, dd, J = 4.1, 1.8 Hz). Elemental analysis: C ₃₀ H ₂₁ D ₄ F ₆ N ₃ O ₂ Calculated (%): C, 62.39 H, 3.66 D, 1.
39 N, 7.28 found (%): C, 62.41 H, 3.65 D, 1.
35 N, 7.21. EI-MS m / z: 577 (M ⁺ ), 558, 35
0, 313 [α] _D : + 116.6 ° (c = 0.541, MeOH).

[0268] Reference Example ^{146 (9R) - [10,10,11,11- 2} H 4] -7- [3,
5-bis (trifluoromethyl) benzyl] -8,9.1
0,11-tetrahydro-5- (4-hydroxymethylphenyl) -9-methyl-7H- [1,4] diazosino [2,1-g] [1,7] naphthyridine-6,13-dione (Reference Example) using the compound obtained in d ₄ body) reference example 145 compound 137, was treated by the same reaction as in reference example 137, the title compound was obtained as colorless crystals. Melting point: 241-242 ° C. (recrystallized from ethyl acetate-methanol-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.91 (3
H, d, J = 7.0 Hz), 1.85 (1H, m), 2.09
(1H, m), 2.98 (1H, dd, J = 15, 1.4H
z), 3.47 (1H, dd, J = 15, 11 Hz), 4.0
2 (1H, d, J = 15 Hz), 4.75 (2H, d, J
= 4.4 Hz), 5.45 (1 H, d, J = 15 Hz), 6.
97 (1H, d, J = 8.0 Hz), 7.25 (1H, d,
J = 8.0 Hz), 7.4-7.6 (6 H, m), 7.81
(1H, s), 8.91 (1H, dd, J = 4.0, 2.2H
z). Elemental analysis: C ₃₀ H ₂₁ D ₄ F ₆ N ₃ O ₃ .1 / 2H ₂ O Calculated (%): C, 59.80 H, 3.68 D, 1.
34 N, 6.97 Found (%): C, 59.76 H, 3.78 D, 1.
40 N, 6.73. EI-MS m / z: 593 (M ⁺ ), 554, 51
9,366,313 [α] _D : + 94.2 ° (c = 0.538, MeOH).

[0269] Reference Example ^{147 (9R) - [10,10,11,11- 2} H 4] -7- [3,
5-bis (trifluoromethyl) benzyl] -5- (4
-Formylphenyl) -8,9,10,11-tetrahydro-9-methyl-7H- [1,4] diazosino [2,1-
g] [1,7] Naphthyridine-6,13-dione (d ₄ form of the compound of Reference Example 138) The title compound was obtained as colorless crystals. Melting point: 215-216 ° C (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.95 (3
H, d, J = 7.0 Hz), 2.10 (1H, m), 3.05
(1H, dd, J = 15, 1.4 Hz), 3.47 (1H, d
d, J = 15, 11 Hz), 4.00 (1H, d, J = 15)
Hz), 5.39 (1H, d, J = 15Hz), 7.12
(1H, dd, J = 8.0, 1.8Hz), 7.40-7.5
5 (4H, m), 7.62-7.74 (2H, m), 7.7
9 (1H, s), 7.97 (1H, dd, J = 8.0, 1.8
Hz), 8.94 (1H, dd, J = 4.0, 1.8Hz),
10.04 (1H, s). Elemental analysis: C ₃₀ H ₁₉ D ₄ F ₆ N ₃ O ₃ Calculated (%): C, 60.91 H, 3.24 D, 1.
36 N, 7.10 found (%): C, 60.89 H, 3.31 D, 1.
36 N, 6.99. EI-MS m / z: 591 (M ⁺ ), 572, 51
7,364,313 [α] _D : + 106.1 ° (c = 0.510, MeOH).

[0270] Reference Example ^{148 (9S) - [10,10,11,11- 2} H 4] -7- [3,
5-bis (trifluoromethyl) benzyl] -5- (4
-Carboxyphenyl) -8,9,10,11-tetrahydro-9-methyl-7H- [1,4] diazosino [2,1
-G] [1,7] naphthyridine-6,13-dione compound obtained in Reference Example 146 (d ₄ body of the compound of Reference Example 140) (2.0g), t- butanol (80 ml), 0.3 N aqueous Aqueous sodium oxide (55 ml)
To this mixture was added potassium permanganate (1.7 g) in small portions while stirring at 0 ° C. After stirring at room temperature for 1 hour, ethanol (10 ml) was added, and the mixture was stirred at room temperature for 30 minutes. The precipitate was separated by filtration using Celite and washed with ethanol. The filtrate and the washing were combined, the solvent was distilled off, and the residue was dissolved in 1N aqueous sodium hydroxide. After washing this solution with a mixture of ethyl ether and THF,
The mixture was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried, and evaporated to give the title compound as colorless crystals (1.71 g). Melting point: 302-303 ° C (recrystallized from ethyl acetate-methanol-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.95 (3
H, d, J = 6.6 Hz), 2.09 (1H, m), 3.09
(1H, d, J = 14 Hz), 3.49 (1H, dd, J =
14, 9.4Hz), 4.02 (1H, d, J = 15Hz),
5.36 (1H, d, J = 15 Hz), 7.04 (1H, d,
J = 8.0 Hz), 7.50 (4H, m), 7.59 (1H,
d, J = 8.4 Hz), 7.82 (1H, s), 7.91 (1
H, d, J = 8.4 Hz, 8.20 (1H, d, J = 8.0)
Hz), 8.97 (1H, dd, J = 3.6, 2.2 Hz). Elemental analysis: C ₃₀ H ₁₉ D ₄ F ₆ N ₃ O ₄ .1 / 2H ₂ O Calculated (%): C, 58.44 H, 3.27 D, 1.
31 N, 6.82 found (%): C, 58.47 H, 3.21 D, 1.
32 N, 6.89. EI-MS m / z: 607 (M ⁺ ), 568, 53
3,380,313 [α] _D : + 123.2 ° (c = 0.545, MeOH).

Reference Example 149 (R) -N- [3,5-di (benzyloxy) benzyl] -7,8-dihydro-7- (4-hydroxy-3-
(Methylbutyl) -5- (4-methylphenyl) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide (Step 1) The compound obtained in Step 2 of Reference Example 2 and 3,5
-Di (benzyloxy) benzylamine was reacted and treated in the same manner as in Step 4 of Reference Example 2 to give N-
[3,5-di (benzyloxy) benzyl] -5- (4
-Methylphenyl) -8-oxo-8H-pyrano [3
4-b] pyridine-6-carboxamide was obtained as colorless crystals. Melting point: 177-179 ° C (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.43 (3H, s), 4.40 (2H,
d, J = 5.8 Hz), 5.01 (4H, s), 6.51 (3H, m), 7.1-7.5
(15H, m), 7.57 (2H, m), 8.94 (1H, dd, J = 3.6, 2.2
Hz) Elemental analysis: C ₃₇ H ₃₀ N ₂ O ₅ Calculated (%): C 76.27, H 5.19, N 4.81 Found (%): C 76.36, H 5.11, N 4.78. (Step 2) Compound obtained in Step 1 and (R) -4-amino-
The reaction and treatment were carried out in the same manner as in Reference Example 19 using THP ether of 2-methyl-1-butanol, and the title compound was obtained as colorless crystals. Melting point: 168-170 ° C (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.83 (3H, d, J = 6.6 H)
z), 1.5-1.9 (3H, m), 2.30 (3H, s), 2.99 (1H, m),
3.2-3.6 (2H, m), 3.75-3.95 (2H, m), 4.21 (2H, d, J
= 6.0 Hz), 4.98 (4H, s), 6.33 (2H, d, J = 1.8 Hz),
6.50 (1H, bt), 7.1-7.5 (16H, m), 7.58 (1H, d, J =
8.4 Hz), 8.67 (1H, dd, J = 4.4, 1.2 Hz) Elemental analysis: C ₄₂ H ₄₁ N ₃ O ₅ .0.3 H ₂ O Calculated (%): C 74.93, H 6.23, N 6.24 Found (%): C 74.80, H 6.25, N 6.28.

Reference Example 150 (R) -N- (3,5-dimethoxybenzyl) -7,8
-Dihydro-7- (4-hydroxy-3-methylbutyl) -8-oxo-5-phenyl-6-pyrido [3,4
-B] pyridinecarboxamide (Step 1) Compound obtained in Step 2 of Reference Example 9 and 3,5
Step 4 of Reference Example 2 using -dimethoxybenzylamine
The reaction and treatment were carried out in the same manner as described above.
Dimethoxybenzyl) -8-oxo-5-phenyl-8
H-Pyrano [3,4-b] pyridine-6-carboxamide was obtained as colorless crystals. Melting point: 126-127 ° C (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 3.78 (6H, s), 4.40 (2H,
d, J = 5.8 Hz), 6.41 (3H, m), 7.20-7.35 (3H, m), 7.
45-7.65 (5H, m), 8.95 (1H, dd, J = 4.0, 1.4 Hz) Elemental analysis: C ₂₄ H ₂₀ N ₂ O ₅ Calculated (%): C 69.22, H 4.84, N 6.73 Value (%): C 69.27, H 4.72, N 6.83. (Step 2) Compound obtained in Step 1 and (R) -4-amino-
The reaction and treatment were carried out in the same manner as in Reference Example 19 using THP ether of 2-methyl-1-butanol, and the title compound was obtained as colorless crystals. Melting point: 150-151 ° C. (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.83 (3H, d, J = 6.6 H)
z), 1.5-1.9 (3H, m), 3.09 (1H, m), 3.2-3.6 (2H,
m), 3.6-3.9 (2H, m), 3.76 (6H, s), 4.20 (2H, d, J
= 5.8 Hz), 6.27 (2H, d, J = 2.2 Hz), 6.35 (1H, t,
J = 2.2 Hz), 7.2-7.7 (8H, m), 8.61 (1H, dd, J = 4.
Elemental analysis: C ₂₉ H ₃₁ N ₃ O ₅ Calculated (%): C 69.44, H 6.23, N 8.38 Found (%): C 69.11, H 6.04, N 8.51.

Reference Example 151 (R) -N- [3,5-bis (trifluoromethyl) benzyl] -5- (4-chlorophenyl) -7,8-dihydro-7- (4-hydroxy-3-methylbutyl ) -8
-Oxo-6-pyrido [3,4-b] pyridinecarboxamide (Step 1) Instead of 3- (4-methylbenzoyl) -2-pyridinecarboxylic acid in Step 1 of Reference Example 2, 3- (4-
Using (chlorobenzoyl) -2-pyridinecarboxylic acid, the reaction was carried out in the same manner as in Steps 1 and 2 of Reference Example 2 to give 5- (4-chlorophenyl) -8-oxo-8H.
-Pyrano [3,4-b] pyridine-6-carboxylic acid was obtained as colorless crystals. NMR (200 MHz, CDCl ₃ + DMSO-d ₆ ) ppm: 7.24 (2H, d, J =
8.0 Hz), 7.47 (2H, d, J = 8.0 Hz), 7.50 (1H, d, J
= 8.0 Hz), 7.63 (1H, dd, J = 8.0, 4.4 Hz), 8.96 (1
H, d, J = 4.4 Hz). (Step 2) The compound obtained in Step 1 was reacted with 3,5-bis (trifluoromethyl) benzylamine in the same manner as in Step 4 of Reference Example 2 and treated to give N-
[3,5-bis (trifluoromethyl) benzyl] -5
-(4-Chlorophenyl) -8-oxo-8H-pyrano [3,4-b] pyridine-6-carboxamide was obtained as colorless crystals. Melting point: 217-219 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 4.63 (2H, d, J = 6.2 H)
z), 7.23 (2H, d, J = 8.2 Hz), 7.51 (2H, d, J = 8.2
Hz), 7.53 (1H, dd, J = 8.4, 1.6 Hz), 7.65 (1H, d
d, J = 8.4, 4.4 Hz), 7.6-7.8 (1H, m), 7.73 (2H,
s), 7.80 (1H, s), 8.98 (1H, dd, J = 4.4, 1.6 Hz). (Step 3) Compound obtained in step 2 and (R) -4-amino-
The reaction and treatment were carried out in the same manner as in Reference Example 19 using THP ether of 2-methyl-1-butanol, and the title compound was obtained as colorless crystals. Melting point: 259-261 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.78 (3H, d, J = 6.2 H)
z), 1.4-1.8 (3H, m), 3.02 (1H, m), 3.2-3.7 (4H,
m), 4.48 (2H, m), 7.1-7.4 (5H, m), 7.46 (1H, d, J
= 8.0 Hz), 7.72 (2H, s), 7.85 (1H, s), 8.60 (2H,
m).

Reference Example 152 (R) -N- [3,5-bis (trifluoromethyl) benzyl] -5- (3,4-dichlorophenyl) -7,8
-Dihydro-7- (4-hydroxy-3-methylbutyl) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide (Step 1) 3- (4-methylbenzoyl) of Step 1 of Reference Example 2 3- (3,3) instead of 2-pyridinecarboxylic acid
Using 4-dichlorobenzoyl) -2-pyridinecarboxylic acid, the reaction was carried out in the same manner as in Steps 1 and 2 of Reference Example 2 to give 5- (3,4-dichlorophenyl) -8-oxo-8H-pyrano [ [3,4-b] pyridine-6-carboxylic acid was obtained as colorless crystals. NMR (200MHz, DMSO-d ₆ ) ppm: 7.34 (1H, dd, J = 8.2,
1.8 Hz), 7.50 (1H, dd, J = 8.4, 1.4 Hz), 7.66 (1H,
d, J = 1.8 Hz), 7.72-7.85 (2H, m), 8.96 (1H, dd, J
= 4.4, 1.4 Hz). (Step 2) The compound obtained in Step 1 was reacted with 3,5-bis (trifluoromethyl) benzylamine in the same manner as in Step 4 of Reference Example 2 and treated to give N-
[3,5-bis (trifluoromethyl) benzyl] -5
-(3,4-dichlorophenyl) -8-oxo-8H-
Pyrano [3,4-b] pyridine-6-carboxamide was obtained as colorless crystals. Melting point: 220-221 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 4.64 (2H, d, J = 6.2 H)
z), 7.15 (1H, dd, J = 8.4, 1.8 Hz), 7.39 (1H, d, J
= 1.8 Hz), 7.5-7.8 (4H, m), 7.75 (2H, s), 7.81 (1
H, s), 8.99 (1H, dd, J = 4.4, 1.4 Hz). (Step 3) Compound obtained in step 2 and (R) -4-amino-
The reaction and treatment were carried out in the same manner as in Reference Example 19 using THP ether of 2-methyl-1-butanol to give the title compound. This compound was prepared in Example 7 without purification.
Was used for the reaction.

Reference Example 153 (R) -5- (3,4-dichlorophenyl) -N-
(3,5-dimethoxybenzyl) -7,8-dihydro-
7- (4-hydroxy-3-methylbutyl) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide (Step 1) The compound obtained in Step 1 of Reference Example 152 and 3,5-dimethoxybenzyl The reaction and treatment were carried out in the same manner as in Step 4 of Reference Example 2 using an amine.
(3,4-dichlorophenyl) -N- (3,5-dimethoxybenzyl) -8-oxo-8H-pyrano [3,4-
b] Pyridine-6-carboxamide was obtained as colorless crystals. Melting point: 220-221 ° C. (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 3.78 (6H, s), 4.41 (2H,
d, J = 6.0 Hz), 6.38-6.48 (3H, m), 7.15 (1H, dd, J
= 8.4, 1.8 Hz), 7.34-7.82 (5H, m), 8.96 (1H, dd,
J = 4.2, 1.6 Hz) Elemental analysis: C ₂₄ H ₁₈ N ₂ O ₅ Cl ₂ Calculated (%): C 59.40, H 3.74, N 5.77 Actual (%): C 59.13, H 3.81, N 5.77 . (Step 2) Compound obtained in Step 1 and (R) -4-amino-
The reaction and treatment were carried out in the same manner as in Reference Example 19 using THP ether of 2-methyl-1-butanol to give the title compound. This compound was prepared in Example 8 without purification.
Was used for the reaction.

Reference Example 154 (R) -N- (3,5-dimethylbenzyl) -7,8-
Dihydro-7- (4-hydroxy-3-methylbutyl)
-5- (4-Methylphenyl) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide (Step 1) The compound obtained in Step 2 of Reference Example 2 and 3,5
-Dimethylbenzylamine was reacted and treated in the same manner as in Step 4 of Reference Example 2 to give N- (3,5-dimethylbenzyl) -5- (4-methylphenyl) -8-
Oxo-8H-pyrano [3,4-b] pyridine-6-carboxamide was obtained as colorless crystals. Melting point: 201-202 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.30 (6H, s), 2.45 (3H,
s), 4.39 (2H, d, J = 5.8 Hz), 6.88 (2H, s), 6.93 (1
H, s), 7.17 (2H, d, J = 8.0 Hz), 7.19 (1H, m), 7.3
3 (2H, d, J = 8.0 Hz), 7.57 (2H, m), 8.93 (1H, dd,
J = 4.0, 2.2 Hz) Elemental analysis: C ₂₅ H ₂₂ N ₂ O ₃ Calculated (%): C 75.36, H 5.57, N 7.03 Found (%): C 74.93, H 5.58, N 7.00. (Step 2) Compound obtained in Step 1 and (R) -4-amino-
The reaction and treatment were carried out in the same manner as in Reference Example 19 using THP ether of 2-methyl-1-butanol, and the title compound was obtained as colorless crystals. Melting point: 193 ° -194 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.86 (3H, d, J = 6.6 H)
z), 1.5-2.0 (3H, m), 2.25 (6H, s), 2.42 (3H, s),
3.14 (1H, m), 3.2-3.4 (2H, m), 3.89 (2H, m), 4.20
(2H, d, J = 5.4 Hz), 6.61 (2H, s), 6.87 (1H, s),
7.1-7.4 (6H, m), 7.58 (1H, dd, J = 8.4, 1.4 Hz),
8.62 (1H, dd, J = 4.4, 1.4 Hz) Elemental analysis: C ₃₀ H ₃₃ N ₃ O ₃ · 0.3 H ₂ O Calculated (%): C 73.69, H 6.93, N 8.59 Actual measured (% ): C 73.85, H 6.95, N 8.52.

Reference Example 155 (R) -N- (3,5-dichlorobenzyl) -7,8-
Dihydro-7- (4-hydroxy-3-methylbutyl)
-5- (4-Methylphenyl) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide (Step 1) The compound obtained in Step 2 of Reference Example 2 and 3,5
-Dichlorobenzylamine was reacted and treated in the same manner as in Step 4 of Reference Example 2 to give N- (3,5-dichlorobenzyl) -5- (4-methylphenyl) -8-
Oxo-8H-pyrano [3,4-b] pyridine-6-carboxamide was obtained as colorless crystals. Melting point: 232-233 ° C. (recrystallized from THF-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.45 (3H, s), 4.44 (2H,
d, J = 6.4 Hz), 7.1-7.3 (5H, m), 7.34 (2H, d, J =
7.6 Hz), 7.43 (1H, bt), 7.59 (2H, m), 8.95 (1H, dd,
J = 4.0, 2.2 Hz) Elemental analysis: C ₂₃ H ₁₆ N ₂ O ₃ Cl ₂ Calculated (%): C 62.89, H 3.67, N 6.38 Actual (%): C 62.62, H 3.70, N 6.36 . (Step 2) Compound obtained in Step 1 and (R) -4-amino-
The reaction and treatment were carried out in the same manner as in Reference Example 19 using THP ether of 2-methyl-1-butanol, and the title compound was obtained as colorless crystals. Melting point: 123-125 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.81 (3H, d, J = 7.0 H)
z), 1.5-2.0 (3H, m), 2.39 (3H, s), 3.17 (1H, m),
3.2-3.8 (4H, m), 4.34 (2H, d, J = 6.2 Hz), 6.95 (2
H, d, J = 2.0 Hz), 7.1-7.4 (5H, m), 7.31 (1H, dd,
J = 8.2, 4.4 Hz), 7.56 (1H, dd, J = 8.2, 1.6 Hz),
8.31 (1H, bt), 8.62 (1H, dd, J = 4.4, 1.6 Hz) Elemental analysis: C ₂₈ H ₂₇ N ₃ O ₃ Cl ₂ Calculated (%): C 64.13, H 5.19, N 8.01 Value (%): C 63.82, H 5.01, N 7.96.

Reference Example 156 (R) -5- (3,4-dichlorophenyl) -N-
(3,5-dimethylbenzyl) -7,8-dihydro-7
-(4-hydroxy-3-methylbutyl) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide (Step 1) The compound obtained in Step 1 of Reference Example 152 and 3,5-dimethylbenzylamine Was reacted and treated in the same manner as in Step 4 of Reference Example 2 to give 5- (3,
4-Dichlorophenyl) -N- (3,5-dimethylbenzyl) -8-oxo-8H-pyrano [3,4-b] pyridine-6-carboxamide was obtained as colorless crystals. Melting point: 210-211 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.30 (6H, s), 4.40 (2H,
d, J = 5.6 Hz), 6.89 (2H, s), 6.94 (1H, s), 7.16 (1
H, dd, J = 8.2, 2.2 Hz), 7.30 (1H, bt), 7.39 (1H,
d, J = 2.2 Hz), 7.50 (1H, dd, J = 8.4, 1.6 Hz), 7.
60 (1H, d, J = 8.2 Hz), 7.65 (1H, dd, J = 8.4, 4.4
Hz), 8.97 (1H, dd, J = 4.4, 1.6 Hz) Elemental analysis: C ₂₄ H ₁₈ N ₂ O ₃ Cl ₂ .0.2 H ₂ O Calculated (%): C 63.09, H 4.06, N 6.13 Found (%): C 63.13, H 3.94, N 6.14. (Step 2) Compound obtained in Step 1 and (R) -4-amino-
The reaction was carried out in the same manner as in Reference Example 19 using THP ether of 2-methyl-1-butanol to give the title compound as a colorless foam. NMR (200MHz, CDCl ₃ ) ppm: 0.86 (3H, d, J = 5.8 H
z), 1.4-1.9 (3H, m), 2.29 (6H, s), 2.90 (1H, m),
3.25-3.85 (4H, m), 4.29 (2H, d, J = 5.6 Hz), 6.72
(2H, s), 6.93 (1H, s), 7.25-7.55 (5H, m), 7.75 (1
H, m), 8.60 (1H, m).

Reference Example 157 (R) -N- (3,5-dimethoxybenzyl) -5-
(4-Fluorophenyl) -7,8-dihydro-7-
(4-hydroxy-3-methylbutyl) -8-oxo-
6-pyrido [3,4-b] pyridinecarboxamide (Step 1) In place of 3- (4-methylbenzoyl) -2-pyridinecarboxylic acid in Step 1 of Reference Example 2, 3- (4-
Using (fluorobenzoyl) -2-pyridinecarboxylic acid, the reaction was carried out in the same manner as in Steps 1 and 2 of Reference Example 2 to give 5- (4-fluorophenyl) -8-oxo-8.
H-Pyrano [3,4-b] pyridine-6-carboxylic acid was obtained as colorless crystals. NMR (200MHz, DMSO-d ₆ ) ppm: 7.25-7.50 (5H, m), 7.8
1 (1H, dd, J = 8.4,4.4 Hz), 8.95 (1H, dd, J = 4.4,
1.4 Hz). (Step 2) The compound obtained in Step 1 was reacted with 3,5-dimethoxybenzylamine in the same manner as in Step 4 of Reference Example 2 and treated to give N- (3,5-dimethoxybenzyl)- 5- (4-Fluorophenyl) -8-oxo-8H-pyrano [3,4-b] pyridine-6-carboxamide was obtained as colorless crystals. Melting point: 193-194 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200MHz, CDCl ₃ ) ppm: 3.78 (6H, s), 4.41 (2H,
d, J = 6.0 Hz), 6.42 (3H, m), 7.2-7.4 (5H, m), 7.52
(1H, dd, J = 8.4, 1.6 Hz), 7.64 (1H, dd, J = 8.4,
4.497), 8.97 (1H, dd, J = 4.4, 1.6 Hz) Elemental analysis: C ₂₄ H ₁₉ N ₂ O ₅ F Calculated (%): C 66.36, H 4.41, N 6.45 Actual (%) : C 66.07, H 4.55, N 6.27. (Step 3) Compound obtained in step 2 and (R) -4-amino-
The reaction and treatment were carried out in the same manner as in Reference Example 19 using THP ether of 2-methyl-1-butanol, and the title compound was obtained as colorless crystals. Melting point: 170-171 ° C. (recrystallized from ethyl acetate-ethyl ether-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.82 (3H, d, J = 6.6 H)
z), 1.5-1.9 (3H, m), 3.06 (1H, m), 3.2-3.6 (2H,
m), 3.65-3.85 (2H, m), 3.78 (6H, s), 4.27 (2H, d, J
= 6.2 Hz), 6.26 (2H, d, J = 2.2 Hz), 6.36 (1H, t,
J = 2.2 Hz), 7.07 (2H, t, J = 8.6 Hz), 7.28 (1H,
dd, J = 8.4, 4.0 Hz), 7.35-7.50 (2H, m), 7.46 (1H,
dd, J = 8.4, 1.4 Hz), 7.91 (1H, bt), 8.59 (1H, d
d, J = 4.0, 1.4 Hz) Elemental analysis: C ₂₉ H ₃₀ N ₃ O ₅ F Calculated (%): C 67.04, H 5.82, N 8.09 Actual (%): C 66.87, H 5.73, N 8.04.

Reference Example 158 (R) -5- (4-Chlorophenyl) -N- (3,5-
Dimethoxybenzyl) -7,8-dihydro-7- (4-
(Hydroxy-3-methylbutyl) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide (Step 1) Using the compound obtained in Step 1 of Reference Example 151 and 3,5-dimethoxybenzylamine, The reaction and treatment were carried out in the same manner as in Step 4 of Example 2.
-Chlorophenyl) -N- (3,5-dimethoxybenzyl) -8-oxo-8H-pyrano [3,4-b] pyridine-6-carboxamide was obtained as colorless crystals. Melting point: 179-180 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 3.78 (6H, s), 4.41 (2H,
d, J = 5.8 Hz), 6.42 (3H, m), 7.23 (2H, d, J = 8.4
Hz), 7.34 (1H, bt), 7.51 (2H, d, J = 8.4Hz), 7.52
(1H, dd, J = 8.2, 1.6 Hz), 7.63 (1H, dd, J = 8.2,
4.4 Hz), 8.97 (1H, dd, J = 4.4, 1.6 Hz) Elemental analysis: C ₂₄ H ₁₉ N ₂ O ₅ Cl Calculated (%): C 63.93, H 4.25, N 6.21 Actual measured (%) : C 63.70, H 4.37, N 6.11. (Step 2) Compound obtained in Step 1 and (R) -4-amino-
The reaction and treatment were carried out in the same manner as in Reference Example 19 using THP ether of 2-methyl-1-butanol, and the title compound was obtained as colorless crystals. Melting point: 181-182 ° C (recrystallized from ethyl acetate-ethyl ether-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.83 (3H, d, J = 6.6 H)
z), 1.4-1.8 (3H, m), 2.98 (1H, m), 3.2-3.4 (2H, m),
3.60-3.85 (2H, m), 3.78 (6H, s), 4.27 (2H, d, J =
5.8 Hz), 6.29 (2H, d, J = 2.2 Hz), 6.38 (1H, t, J
= 2.2 Hz), 7.22-7.45 (5H, m), 7.45 (1H, dd, J = 8.
4, 1.8 Hz), 7.82 (1H, bt), 8.60 (1H, dd, J = 4.0,
1.8 Hz) Elemental analysis: C ₂₉ H ₃₀ N ₃ O ₅ Cl Calculated (%): C 64.98, H 5.64, N 7.84 Found (%): C 64.79, H 5.58, N 7.73.

Reference Example 159 (R) -N- [3,5-bis (trifluoromethyl) benzyl] -5- (4-fluorophenyl) -7,8-dihydro-7- (4-hydroxy-3- Methylbutyl)-
8-oxo-6-pyrido [3,4-b] pyridinecarboxamide (Step 1) Using the compound obtained in Step 1 of Reference Example 157 and 3,5-bis (trifluoromethyl) benzylamine, Reference Example 2 The reaction and treatment were carried out in the same manner as in step 4 of the above, and N- [3,5-bis (trifluoromethyl) benzyl] -5- (4-fluorophenyl) -8-oxo-8H-pyrano [3,4 -B] Pyridine-6-carboxamide was obtained as colorless crystals. Melting point: 166-167 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200MHz, CDCl ₃ ) ppm: 4.63 (2H, d, J = 6.2H)
z), 7.1-7.3 (4H, m), 7.54 (1H, dd, J = 8.4, 1.6 H
z), 7.6-7.8 (1H, m), 7.65 (1H, dd, J = 8.4, 4.4 H
z), 7.73 (2H, s), 7.80 (1H, s), 8.98 (1H, dd, J =
(4.4, 1.6 Hz) Elemental analysis: C ₂₄ H ₁₃ N ₂ O ₃ F ₇ Calculated (%): C 56.48, H 2.57, N 5.49 Found (%): C 56.52, H 2.68, N 5.47. (Step 2) Compound obtained in Step 1 and (R) -4-amino-
The reaction and treatment were carried out in the same manner as in Reference Example 19 using THP ether of 2-methyl-1-butanol, and the title compound was obtained as colorless crystals. Melting point: 212-213 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.77 (3H, d, J = 7.0 H)
z), 1.4-1.8 (3H, m), 3.1-3.7 (5H, m), 4.51 (2H,
m), 6.84-7.00 (2H, m), 7.25-7.48 (3H, m), 7.48 (1H,
dd, J = 8.4, 1.8 Hz), 7.69 (2H, s), 7.82 (1H, s),
8.60 (1H, dd, J = 4.2, 1.8 Hz), 8.76 (1H, bt) Elemental analysis: C ₂₉ H ₂₄ N ₃ O ₃ F ₇ Calculated (%): C 58.49, H 4.06, N 7.06 Value (%): C 58.28, H 4.06, N 7.02.

Reference Example 160 (±) -N- [3,5-bis (trifluoromethyl) benzyl] -7,8-dihydro-7- (4-hydroxy-
3-ethylbutyl) -5- (4-methylphenyl) -8
-Oxo-6-pyrido [3,4-b] pyridinecarboxamide Using the compound obtained in Reference Example 3 and (±) -4-amino-2-ethyl-1-butanol, reacting in the same manner as in Reference Example 5. After treatment, the title compound was obtained as a colorless oil. NMR (200MHz, CDCl ₃ ) ppm: 0.86 (3H, t, J = 7.0 H
z), 1.0-1.4 (3H, m), 1.5-1.9 (2H, m), 2.28 (3H,
s), 3.0-3.6 (5H, m), 4.50 (2H, d, J = 6.2 Hz), 7.07
(2H, d, J = 8.6 Hz), 7.1-7.3 (2H, m), 7.31 (1H, d
d, J = 8.0, 4.2 Hz), 7.55 (1H, dd, J = 8.0, 1.4 H
z), 7.68 (2H, s), 7.78 (1H, s), 8.43 (1H, bt), 8.6
5 (1H, m).

Reference Example 161 (±) -N- [3,5-bis (trifluoromethyl) benzyl] -7,8-dihydro-7- [4-hydroxy-
3- (1-Methylethyl) butyl] -5- (4-methylphenyl) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide The compound obtained in Reference Example 3 and (±) -4- Amino-2- (1
Reference Example 5 using -methylethyl) -1-butanol
The title compound was obtained as a colorless oil upon treatment. NMR (200MHz, CDCl ₃ ) ppm: 0.82 (6H, d, J = 6.6 H
z), 1.3-2.0 (4H, m), 2.27 (3H, s), 3.30 (1H, m),
3.52 (4H, m), 4.50 (2H, d, J = 5.8 Hz), 7.07 (2H,
d, J = 8.6 Hz), 7.20-7.35 (3H, m), 7.54 (1H, dd, J
= 8.4, 1.6 Hz), 7.67 (2H, s), 7.78 (1H, s), 8.51
(1H, bt), 8.63 (1H, dd, J = 4.4, 1.6 Hz).

Reference Example 162 (±) -5- (3,4-dichlorophenyl) -N-
(3,5-dimethoxybenzyl) -7,8-dihydro-
7- (4-Hydroxy-3-ethylbutyl) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide The compound obtained in Step 1 of Reference Example 153 and (±) -4-amino-2-ethyl The reaction was carried out in the same manner as in Reference Example 5 using -1-butanol to give the title compound.
This compound was used for the reaction of Example 17 without purification.

Reference Example 163 (±) -5- (3,4-dichlorophenyl) -N-
(3,5-dimethoxybenzyl) -7,8-dihydro-
7- [4-hydroxy-3- (1-methylethyl) butyl] -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide The compound obtained in Step 1 of Reference Example 153 and (±) -4 The reaction was carried out using -amino-2- (1-methylethyl) -1-butanol in the same manner as in Reference Example 5, and the title compound was obtained as a colorless oil upon treatment. This compound was used for the reaction of Example 18 without purification.

Reference Example 164 (±) -7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,10,11-hexahydro-10-methyl-5- (4-methyl Phenyl) -6,1
3-dioxo-13H- [1,4] diazosino [2,1
-G] [1,7] naphthyridine (Step 1) Using the compound obtained in Reference Example 3 and (±) -4-amino-3-methyl-1-butanol, reacted in the same manner as in Reference Example 5, Upon treatment, (±) -N- [3,5-bis (trifluoromethyl) benzyl] -7,8-dihydro-7- (4-hydroxy-2-methylbutyl) -5
(4-Methylphenyl) -8-oxo-6-pyrido [3,4-b] pyridinecarboxamide was obtained as a colorless foam. NMR (200MHz, CDCl ₃ ) ppm: 0.81 (3H, d, J = 7.0 H
z), 1.3-2.4 (3H, m), 2.30 (3H, s), 2.95 (1H, m),
3.4-3.9 (4H, m), 4.46 (2H, m), 7.0-7.4 (5H, m), 7.
52 (1H, d, J = 7.0 Hz), 7.71 (2H, s), 7.78 (1H,
s), 8.56 (1H, bt), 8.64 (1H, d, J = 3.0 Hz). (Step 2) The compound obtained in Step 1 was reacted and treated in the same manner as in Reference Example 69 to give the title compound as a colorless powder. NMR (200MHz, CDCl ₃ ) ppm: 1.18 (3H, d, J = 7.0 H
z), 1.4-2.5 (3H, m), 2.37 (3H, s), 3.1-3.8 (3H,
m), 4.02 (1H, d, J = 15 Hz), 4.81 (1H, d, J = 14 H
z), 5.46 (1H, d, J = 15 Hz), 6.84 (1H, d, J = 7.2
Hz), 7.06 (1H, d, J = 7.2 Hz), 7.2-7.6 (4H, m), 7.4
8 (2H, s), 7.81 (1H, s), 8.90 (1H, m).

Reference Example 165 (9R) -7- [3,5-di (benzyloxy) benzyl] -6,7,8,9,10,11-hexahydro-9
-Methyl-5- (4-methylphenyl) -6,13-dioxo-13H- [1,4] diazosino [2,1-g]
[1,7] Naphthyridine The compound obtained in Reference Example 149 was reacted and treated in the same manner as in Reference Example 69, and the title compound was obtained as a colorless powder. NMR (200MHz, CDCl ₃ ) ppm: 0.82 (3H, d, J = 6.6 H
z), 1.65 (1H, m), 1.8-2.4 (2H, m), 2.15 (3H, s),
3.02 (1H, d, J = 15 Hz), 3.32 (1H, dd, J = 15, 10
Hz), 3.52 (1H, dd, J = 14, 10 Hz), 3.81 (1H, d, J
= 14 Hz), 4.97 (4H, s), 5.04 (1H, dd, J = 14, 5.6
Hz), 5.24 (1H, d, J = 14 Hz), 6.28 (2H, d, J = 2.2
Hz), 6.55 (1H, bt), 6.86 (1H, d, J = 8.0 Hz), 7.03
(1H, d, J = 8.0 Hz), 7.2-7.5 (13H, m), 7.60 (1H, d
d, J = 8.4, 1.2 Hz), 8.88 (1H, dd, J = 4.4, 1.2 Hz) Elemental analysis: C ₄₂ H ₃₉ N ₃ O ₄ .0.5H ₂ O Calculated value (%): C 76.57 , H 6.12, N 6.38 Found (%): C 76.19, H 6.33, N 6.25.

Reference Example 166 (9R) -7- (3,5-dihydroxybenzyl)-
6,7,8,9,10,11-hexahydro-9-methyl-5- (4-methylphenyl) -6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1 ,
7] Naphthyridine A mixture of the compound obtained in Reference Example 165 (2.3 g), 10% palladium-carbon (50% water content) (3.0 g) and methanol (70 ml) was heated under reflux in a hydrogen atmosphere for 15 hours. After the catalyst was removed by filtration using Celite, the filtrate was concentrated to give the title compound as a colorless powder (1.08 g). NMR (200MHz, DMSO-d ₆ ) ppm: 0.78 (3H, d, J = 6.2 H
z), 1.1-1.6 (1H, m), 1.9-2.5 (2H, m), 2.38 (3H, s),
2.90 (1H, d, J = 15 Hz), 3.0-3.6 (2H, m), 3.87 (1
H, d, J = 14 Hz), 4.7-4.9 (1H, m), 4.84 (1H, d, J
= 14 Hz), 5.88 (2H, d, J = 1.8 Hz), 6.17 (1H, bt),
6.9-7.3 (4H, m), 7.5-7.7 (2H, m), 8.84 (1H, m), 9.
21 (2H, s).

Reference Example 167 (9R) -7- (3,5-diethoxybenzyl) -6
7,8,9,10,11-hexahydro-9-methyl-
5- (4-methylphenyl) -6,13-dioxo-1
3H- [1,4] diazosino [2,1-g] [1,7]
Naphthyridine The compound obtained in Reference Example 166 (200 mg), sodium hydride (60% oil) (70 mg) and DMF (7 m
After the mixture of 1) was stirred at room temperature for 30 minutes, ethyl iodide was added thereto under ice cooling, and the mixture was stirred at room temperature for 1 hour. After the reaction solution was diluted with ethyl acetate, it was washed successively with water, diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline. After drying the organic layer, the solvent was distilled off, and the residue was purified by silica gel column chromatography (ethyl acetate: methanol = 9: 1) to give the title compound as a colorless powder (66.5 m
g). NMR (200MHz, CDCl ₃ ) ppm: 0.86 (3H, d, J = 6.6 H
z), 1.43 (6H, t, J = 6.9 Hz), 1.66 (1H, m), 1.9-2.
4 (2H, m), 2.42 (3H, s), 3.06 (1H, d, J = 15Hz),
3.33 (1H, dd, J = 15, 11 Hz), 3.56 (1H, dd, J = 1
4, 11 Hz), 3.81 (1H, d, J = 14 Hz), 3.95 (4H, q, J
= 6.9 Hz), 5.06 (1H, dd, J = 14, 5.6 Hz), 5.23 (1
H, d, J = 14 Hz), 6.17 (2H, d, J = 2.2 Hz), 6.38
(1H, t, J = 2.2 Hz), 6.88 (1H, dd, J = 7.8, 1.6 H
z), 7.15 (1H, d, J = 7.8 Hz), 7.29 (1H, d, J = 7.8
Hz), 7.36 (1H, dd, J = 7.8, 1.6 Hz), 7.46 (1H, dd,
J = 8.4, 4.4 Hz), 7.63 (1H, dd, J = 8.4, 1.4 Hz),
8.90 (1H, dd, J = 4.4, 1.4Hz).

Reference Example 168 (9R) -7- [3,5-di (1-methylethyloxy) benzyl] -6,7,8,9,10,11-hexahydro-9-methyl-5- (4 -Methylphenyl)-
6,13-Dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine Reacted in the same manner as in Reference Example 167 using the compound obtained in Reference Example 166 and 2-iodopropane. Upon treatment, the title compound was obtained as a colorless powder. NMR (200MHz, CDCl ₃ ) ppm: 0.84 (3H, d, J = 7.0 Hz),
1.34 (12H, d, J = 6.0 Hz), 1.65 (1H, m), 1.9-2.4
(2H, m), 2.44 (3H, s), 3.06 (1H, d, J = 15Hz), 3.3
5 (1H, dd, J = 15, 10 Hz), 3.55 (1H, dd, J = 14, 1
1 Hz), 3.88 (1H, d, J = 14 Hz), 4,48 (2H, m), 5.05
(1H, dd, J = 14, 5.7 Hz), 5.19 (1H, d, J = 14 H
z), 6.18 (2H, d, J = 2.2 Hz), 6.37 (1H, t, J = 2.2
Hz), 6.95 (1H, d, J = 7.4 Hz), 7.23 (1H, d, J =
7.6 Hz), 7.29 (1H, d, J = 7.6 Hz), 7.36 (1H, d, J
= 7.4 Hz), 7.47 (1H, dd, J = 8.4, 4.2 Hz), 7.65 (1
H, dd, J = 8.4, 1.6 Hz), 8.90 (1H, dd, J = 4.2, 1.
6 Hz).

Reference Example 169 (9R) -7- (3,5-dimethoxybenzyl) -6
7,8,9,10,11-hexahydro-9-methyl-
6,13-dioxo-5-phenyl-13H- [1,
4] diazosino [2,1-g] [1,7] naphthyridine The compound obtained in Reference Example 150 was reacted and treated in the same manner as in Reference Example 69, and the title compound was obtained as colorless crystals. Melting point: 199-201 ° C (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.87 (3H, d, J = 7.0 H)
z), 1.70 (1H, m), 1.90-2.29 (2H, m), 3.05 (1H, d,
J = 15 Hz), 3.33 (1H, dd, J = 15, 10 Hz), 3.56 (1
H, dd, J = 14, 11 Hz), 3.73 (6H, s), 3.80 (1H, d,
J = 14 Hz), 5.08 (1H, dd, J = 14, 5.7 Hz), 5.23 (1
H, d, J = 14 Hz), 6.12 (2H, d, J = 2.2 Hz), 6.37 (1
H, t, J = 2.2 Hz), 6.97 (1H, d, J = 7.2 Hz), 7.23-
7.55 (5H, m), 7.59 (1H, dd, J = 8.2, 1.4 Hz), 8.90
(1H, dd, J = 4.2, 1.4 Hz) Elemental analysis: C ₂₉ H ₂₉ N ₃ O ₄ Calculated (%): C 72.03, H 6.04, N 8.69 Actual (%): C 71.94, H 6.09 , N 8.93.

Reference Example 170 (9R) -7- [3,5-bis (trifluoromethyl)
Benzyl] -5- (4-chlorophenyl) -6,7,
8,9,10,11-hexahydro-9-methyl-6,6
13-dioxo-13H- [1,4] diazosino [2,
1-g] [1,7] naphthyridine The compound obtained in Reference Example 151 was reacted and treated in the same manner as in Reference Example 69, and the title compound was obtained as colorless crystals. Melting point: 226-227 ° C. (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.92 (3H, d, J = 6.6 H)
z), 1.73 (1H, m), 1.9-2.4 (2H, m), 3.02 (1H, d, J
= 16 Hz), 3.35-3.65 (2H, m), 4.01 (1H, d, J = 15 H
z), 5.10 (1H, dd, J = 14, 5.2 Hz), 5.39 (1H, d, J
= 15 Hz), 6.88 (1H, d, J = 8.4 Hz), 7.19 (1H, d, J
= 8.4 Hz), 7.4-7.6 (6H, m), 7.85 (1H, s), 8.93 (1
H, t, J = 3.0 Hz).

Reference Example 171 (9R) -7- [3,5-bis (trifluoromethyl)
Benzyl] -5- (3,4-dichlorophenyl) -6
7,8,9,10,11-hexahydro-9-methyl-
6,13-Dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine The compound obtained in Reference Example 152 was reacted and treated in the same manner as in Reference Example 69. However, the title compound was obtained as colorless crystals. Melting point: 280-282 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.93 (3H × 5/9, d, J = 6)
6 Hz), 0.96 (3H × 4/9, d, J = 6.2 Hz), 1.67 (1H,
m), 1.9-2.4 (2H, m), 3.02 (1H × 5/9, d, J = 15 Hz),
3.13 (1H × 4/9, d, J = 15 Hz), 3.35-3.65 (2H, m),
4.04 (1H × 5/9, d, J = 15 Hz), 4.05 (1H × 4/9, d, J
= 15 Hz), 5.00-5.18 (1H, m), 5.26 (1H × 4/9, d, J =
15 Hz), 5.41 (1H × 5/9, d, J = 15 Hz), 6.79 (1H × 5
/ 9, dd, J = 8.2, 2.0 Hz), 6.98 (1H × 4/9, d, J = 2.0
Hz), 7.25-7.65 (6H, m), 7.85 (1H, s), 8.94 (1H,
m).

Reference Example 172 (9R) -7- (3,5-dimethoxybenzyl) -5
(3,4-dichlorophenyl) -6,7,8,9,1
0,11-hexahydro-9-methyl-6,13-dioxo-13H- [1,4] diazosino [2,1-g]
[1,7] Naphthyridine The compound obtained in Reference Example 153 was reacted and treated in the same manner as in Reference Example 69, and the title compound was obtained as colorless crystals. Melting point: 207-208 ° C (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.88 (3H × 1/2, d, J = 6)
8 Hz), 0.89 (3H × 1/2, d, J = 6.8 Hz), 1.65 (1H,
m), 1.9-2.4 (2H, m), 3.00-3.38 (2H, m), 3.44-3.90
(2H, m), 3.75 (3H, s), 3.77 (3H, s), 5.07 (1H, dd,
J = 14, 6.2 Hz), 5.25 (1H, dd, J = 15, 7.4 Hz),
5.99 (1H, d, J = 2.2 Hz), 6.12 (1H, d, J = 2.2 Hz),
6.36 (1H × 1/2, t, J = 2.2 Hz), 6.40 (1H × 1/2, t,
J = 2.2 Hz), 6.79 (1H × 1/2, dd, J = 8.0, 2.2 Hz),
7.11 (1H × 1/2, d, J = 1.8 Hz), 7.25-7.65 (4H, m),
8.91 (1H, m) Elemental analysis: C ₂₉ H ₂₇ N ₃ O ₄ Cl ₂ Calculated (%): C 63.05, H 4.93, N 7.61 Found (%): C 62.73, H 5.07, N 7.64.

Reference Example 173 (9R) -7- (3,5-dimethylbenzyl) -6
7,8,9,10,11-hexahydro-9-methyl-
5- (4-methylphenyl) -6,13-dioxo-1
3H- [1,4] diazosino [2,1-g] [1,7]
Naphthyridine The reaction was carried out using the compound obtained in Reference Example 154 in the same manner as in Reference Example 69, and the title compound was obtained as colorless crystals. Melting point: 200-202 ° C. (recrystallized from THF-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.85 (3H, d, J = 6.6 H)
z), 1.67 (1H, m), 1.9-2.4 (2H, m), 2.25 (6H, s),
2.44 (3H, s), 2.97 (1H, d, J = 15 Hz), 3.27 (1H, d
d, J = 15, 10 Hz), 3.58 (1H, dd, J = 14, 11 Hz),
3.73 (1H, d, J = 15 Hz), 5.08 (1H, dd, J = 14, 5.7
Hz), 5.38 (1H, d, J = 15 Hz), 6.50 (2H, s), 6.92
(2H, m), 7.15 (1H, d, J = 8.0 Hz), 7.35 (1H, d, J
= 7.6 Hz), 7.45 (1H, d, J = 7.6 Hz), 7.46 (1H, dd,
J = 8.2, 4.2 Hz), 7.58 (1H, dd, J = 8.2, 1.6 Hz),
8.90 (1H, dd, J = 4.2, 1.6 Hz) Elemental _{analysis: C 30 H 31 N 3 O} 2 Calculated (%): C 77.39, H 6.71, N 9.03 Found (%): C 77.01, H 6.75, N 8.95.

Reference Example 174 (9R) -7- (3,5-dichlorobenzyl) -6
7,8,9,10,11-hexahydro-9-methyl-
5- (4-methylphenyl) -6,13-dioxo-1
3H- [1,4] diazosino [2,1-g] [1,7]
Naphthyridine The reaction was carried out using the compound obtained in Reference Example 155 in the same manner as in Reference Example 69, and the title compound was obtained as colorless crystals. Melting point: 139-141 ° C. (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.90 (3H, d, J = 6.6 H)
z), 1.70 (1H, m), 1.9-2.4 (2H, m), 2.43 (3H, s),
2.95 (1H, d, J = 15 Hz), 3.38 (1H, dd, J = 15, 11
Hz), 3.52 (1H, dd, J = 15, 11 Hz), 3.74 (1H, d, J
= 15 Hz), 5.08 (1H, dd, J = 15, 5.6 Hz), 5.39 (1H,
d, J = 15 Hz), 6.79 (2H, d, J = 1.8 Hz), 6.88 (1
H, dd, J = 7.6, 1.8 Hz), 7.21 (1H, d, J = 7.6 Hz),
7.29 (1H, s), 7.31 (1H, d, J = 7.6 Hz), 7.38 (1H, s)
dd, J = 7.6, 1.8 Hz), 7.47 (1H, dd, J = 8.4, 4.4
Hz), 7.59 (1H, dd, J = 8.4, 1.8 Hz), 8.90 (1H, dd,
J = 4.4, 1.8 Hz) Elemental analysis: C ₂₈ H ₂₅ N ₃ O ₂ Cl ₂ · 0.3 H ₂ O Calculated (%): C 65.71, H 5.04, N 8.21 Actual (%): C 65.40 , H 4.90, N 8.17.

Reference Example 175 (9R) -5- (3,4-dichlorophenyl) -7-
(3,5-dimethylbenzyl) -6,7,8,9,1
0,11-hexahydro-9-methyl-6,13-dioxo-13H- [1,4] diazosino [2,1-g]
[1,7] Naphthyridine The compound obtained in Reference Example 156 was reacted and treated in the same manner as in Reference Example 69, and the title compound was obtained as a colorless powder. Melting point: 137-139 ° C NMR (200 MHz, CDCl ₃ ) ppm: 0.86 (3H × 1/2, d, J = 6.
2 Hz), 0.89 (3H × 1/2, d, J = 6.0 Hz), 1.5-2.3 (3H,
m), 2.25 (3H, s), 2.28 (3H, s), 2.90-3.84 (4H, m),
5.07 (1H, dd, J = 14, 5.8 Hz), 5.31 (1H, dd, J =
14, 9.2 Hz), 6.50 (1H, s), 6.57 (1H, s), 6.78 (1H ×
1/2, dd, J = 8.0, 1.8 Hz), 6.93 (1H, d, J = 6.0 H
z), 7.12 (1H × 1/2, d, J = 1.8 Hz), 7.30 (1H, d, J
= 8.8 Hz), 7.4-7.7 (3H, m), 8.92 (1H, m) Elemental analysis: C ₂₉ H ₂₇ N ₃ O ₂ Cl ₂ .0.3 H ₂ O Calculated (%): C 66.24, H 5.29, N 7.99 Found (%): C 66.21, H 5.49, N 7.70.

Reference Example 176 (9R) -7- (3,5-dimethoxybenzyl) -5-
(4-fluorophenyl) -6,7,8,9,10,1
1-hexahydro-9-methyl-6,13-dioxo-
13H- [1,4] diazosino [2,1-g] [1,
7] Naphthyridine The compound obtained in Reference Example 157 was reacted and treated in the same manner as in Reference Example 69, and the title compound was obtained as colorless crystals. Melting point: 192-193 ° C. (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.88 (3H, d, J = 6.8 H)
z), 1.5-1.8 (1H, m), 1.9-2.4 (2H, m), 3.03 (1H, d,
J = 15 Hz), 3.36 (1H, dd, J = 15, 10 Hz), 3.56 (1
H, dd, J = 14, 11 Hz), 3.75 (1H, d, J = 15 Hz), 3.
76 (6H, s), 5.08 (1H, dd, J = 14, 5.6 Hz), 5.27 (1
H, d, J = 15 Hz), 6.03 (2H, d, J = 2.2 Hz), 6.37 (1
H, t, J = 2.2 Hz), 6.9-7.1 (2H, m), 7.19 (1H, m),
7.45-7.60 (3H, m), 8.91 (1H, dd, J = 4.2, 2.0 Hz) [a] _D = + 109.4 ° (c = 0.497%, methanol) Elemental analysis: C ₂₉ H ₂₈ N Calculated for ₃ O ₄ F (%): C 69.45, H 5.63, N 8.38 Found (%): C 69.32, H 5.57, N 8.31.

Reference Example 177 (9R) -5- (4-chlorophenyl) -7- (3,5
-Dimethoxybenzyl) -6,7,8,9,10,11
-Hexahydro-9-methyl-6,13-dioxo-1
3H- [1,4] diazosino [2,1-g] [1,7]
Naphthyridine The reaction was carried out using the compound obtained in Reference Example 158 in the same manner as in Reference Example 69, and the title compound was obtained as colorless crystals. Melting point: 229-230 ° C (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.88 (3H, d, J = 7.0 H)
z), 1.5-1.8 (1H, m), 1.9-2.4 (2H, m), 3.06 (1H, d,
J = 15 Hz), 3.29 (1H, dd, J = 15, 9.8 Hz), 3.56 (1
H, dd, J = 14, 11 Hz), 3.76 (1H, d, J = 15 Hz), 3.
77 (6H, s), 5.07 (1H, dd, J = 14, 5.6 Hz), 5.27 (1
H, d, J = 15 Hz), 6.08 (2H, d, J = 2.2 Hz), 6.39
(1H, t, J = 2.2 Hz), 6.91 (1H, d, J = 8.4 Hz), 7.2
8 (1H, d, J = 8.4 Hz), 7.46 (2H, m), 7.48 (1H, dd,
J = 8.4, 4.0 Hz), 7.55 (1H, dd, J = 8.4, 1.8 Hz),
8.91 (1H, dd, J = 4.0, 1.8 Hz) Elemental analysis: C ₂₉ H ₂₈ N ₃ O ₄ Cl.0.2 H ₂ O Calculated (%): C 66.78, H 5.49, N 7.99 Actual measurement ( %): C 66.78, H 5.54, N 7.88.

Reference Example 178 (9R) -7- [3,5-bis (trifluoromethyl)
Benzyl] -5- (4-fluorophenyl) -6,7,
8,9,10,11-hexahydro-9-methyl-6,6
13-dioxo-13H- [1,4] diazosino [2,
1-g] [1,7] naphthyridine The compound obtained in Reference Example 159 was reacted and treated in the same manner as in Reference Example 69, and the title compound was obtained as colorless crystals. Melting point: 234-236 ° C. (recrystallized from ethyl acetate-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.93 (3H, d, J = 6.8 H)
z), 1.73 (1H, m), 2.0-2.4 (2H, m), 3.00 (1H, d, J
= 15 Hz), 3.34-3.62 (2H, m), 3.97 (1H, d, J = 15 H
z), 5.10 (1H, dd, J = 15, 5.2 Hz), 5.42 (1H, d, J
= 15 Hz), 6.85-6.95 (2H, m), 7.13 (1H, dt, J _d = 2.
2, J _t = 9.0 Hz), 7.40-7.52 (3H, m), 7.45 (2H, s),
7.83 (1H, s), 8.92 (1H, t, J = 2.9 Hz) Elemental analysis: C ₂₉ H ₂₂ N ₃ O ₂ F Calculated (%): C 60.31, H 3.84, N 7.28 Actual (% ): C 60.43, H 3.98, N 7.13.

Reference Example 179 (±) -7- [3,5-bis (trifluoromethyl) benzyl] -9-ethyl-6,7,8,9,10,11-
Hexahydro-5- (4-methylphenyl) -6,13
-Dioxo-13H- [1,4] diazosino [2,1-
g] [1,7] Naphthyridine The compound obtained in Reference Example 160 was reacted and treated in the same manner as in Reference Example 69, and the title compound was obtained as colorless crystals. Melting point: 258-260 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200MHz, CDCl ₃ ) ppm: 0.90 (3H, t, J = 7.1H)
z), 1.0-1.4 (2H, m), 1.5-1.9 (2H, m), 2.28 (1H,
m), 2.39 (3H, s), 3.04 (1H, d, J = 15 Hz), 3.39 (1
H, dd, J = 15, 9.6 Hz), 3.52 (1H, dd, J = 15, 11 H
z), 3.97 (1H, d, J = 15 Hz), 5.11 (1H, dd, J = 15,
6.6 Hz), 5.48 (1H, d, J = 15 Hz), 6.82 (1H, d, J =
7.6 Hz), 7.06 (1H, d, J = 7.6 Hz), 7.2-7.6 (4H,
m), 7.48 (2H, s), 7.82 (1H, s), 8.91 (1H, dd, J =
4.0, 1.8 Hz) Elemental analysis: C ₃₁ H ₂₇ N ₃ O ₂ F ₆ Calculated (%): C 63.37, H 4.63, N 7.15 Found (%): C 63.24, H 4.67, N 7.29.

Reference Example 180 (±) -7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,10,11-hexahydro-9- (1-methylethyl) -5 -(4-methylphenyl) -6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine Using the compound obtained in Reference Example 161, reference Example 69 was carried out. The reaction and treatment were carried out in the same manner to give the title compound as colorless crystals. Melting point: 228-229 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.82 (3H, d, J = 6.6 H)
z), 0.87 (3H, d, J = 7.0 Hz), 1.5-2.4 (4H, m), 2.
39 (3H, s), 3.06 (1H, d, J = 15 Hz), 3.38 (1H, dd,
J = 15, 9.0 Hz), 3.50 (1H, dd, J = 14, 10 Hz), 3.
95 (1H, d, J = 15 Hz), 5.14 (1H, dd, J = 14, 5.6 H
z), 5.49 (1H, d, J = 15 Hz), 6.83 (1H, dd, J = 7.8,
1.4 Hz), 7.07 (1H, d, J = 7.8 Hz), 7.28 (1H, d, J
= 8.0 Hz), 7.35 (1H, dd, J = 8.0, 1.4 Hz), 7.47
(1H, dd, J = 8.4, 4.4 Hz), 7.48 (2H, s), 7.56 (1H,
dd, J = 8.4, 1.8 Hz), 7.82 (1H, s), 8.91 (1H, dd,
J = 4.4, 1.8 Hz) Elemental analysis: Calculated _{C 32 H 29 N 3 O 2} F 6 (%): C 63.89, H 4.86, N 6.98 Found (%): C 63.82, H 4.70, N 7.13 .

Reference Example 181 (±) -5- (3,4-dichlorophenyl) -7-
(3,5-dimethoxybenzyl) -9-ethyl-6,
7,8,9,10,11-Hexahydro-6,13-dioxo-13H- [1,4] diazosino [2,1-g]
[1,7] Naphthyridine The compound obtained in Reference Example 162 was reacted and treated in the same manner as in Reference Example 69, and the title compound was obtained as colorless crystals. Melting point: 260-262 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200MHz, CDCl ₃ ) ppm: 0.85-1.00 (3H, m), 1.0-
1.4 (2H, m), 1.5-1.9 (2H, m), 2.23 (1H, m), 3.19 (2
H, m), 3.47-3.80 (2H, m), 3.75 (3H, s), 3.77 (3H,
s), 5.09 (1H, dd, J = 14, 6.2 Hz), 5.28 (1H, dd, J
= 14, 7.6 Hz), 5.99 (1H, d, J = 2.2 Hz), 6.13 (1
H, d, J = 2.2 Hz), 6.36 (1H × 1/2, t, J = 2.2 Hz),
6.40 (1H × 1/2, t, J = 2.2 Hz), 6.76 (1H × 1/2, dd,
J = 8.2, 2.2 Hz), 7.09 (1H × 1/2, d, J = 2.2 Hz), 7.
25-7.62 (4H, m), 8.91 (1H, m) Elemental analysis: C ₃₀ H ₂₉ N ₃ O ₄ Cl ₂ Calculated (%): C 63.61, H 5.16, N 7.42 Actual (%): C 63.20, H 5.15, N 7.58.

Reference Example 182 (±) -5- (3,4-dichlorophenyl) -7-
(3,5-dimethoxybenzyl) -6,7,8,9,1
0,11-hexahydro-9- (1-methylethyl)-
6,13-Dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine The compound obtained in Reference Example 163 was reacted and treated in the same manner as in Reference Example 69. However, the title compound was obtained as colorless crystals. Melting point: 202-205 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.85 (6H, m), 1.4-2.0 (3
H, m), 2.15 (1H, m), 3.18 (2H, m), 3.4-3.8 (2H, m),
3.75 (3H, s), 3.77 (3H, s), 5.11 (1H, dd, J = 14,
6.4 Hz), 5.28 (1H, dd, J = 14, 6.2 Hz), 5.9-6.8
(3.5H, m), 7.0-7.6 (4.5H, m), 8.91 (1H, m).

Reference Example 183 (1) Compound of Reference Example 72 10.0 mg (2) Lactose 60.0 mg (3) Corn starch 35.0 mg (4) Hydroxypropylmethylcellulose 3.0 mg (5) Magnesium stearate 2.0 mg Reference 10.0 mg of the compound obtained in Example 72 and lactose
A mixture of 0 mg and 35.0 mg of corn starch was granulated using 0.03 ml of a 10% by weight aqueous solution of hydroxypropylmethylcellulose (3.0 mg as hydroxypropylmethylcellulose), dried at 40 ° C. and sieved. The resulting granules were mixed with 2.0 mg of magnesium stearate and compressed. The obtained uncoated tablet,
It was coated with sugar coating with an aqueous suspension of sucrose, titanium dioxide, talc and gum arabic. The coated tablets were polished with beeswax to obtain coated tablets.

Reference Example 184 (1) Compound of Reference Example 72 10.0 mg (2) Lactose 70.0 mg (3) Corn starch 50.0 mg (4) Soluble starch 7.0 mg (5) Magnesium stearate 3.0 mg Reference Example After granulating 10.0 mg of the compound obtained in 72 and 3.0 mg of magnesium stearate with 0.07 ml of an aqueous solution of soluble starch (7.0 mg as soluble starch), drying, 70.0 mg of lactose and 50.0 mg of corn starch And mixed. The mixture was compressed to give tablets.

Reference Example 185 (1) Compound of Reference Example 176 10.0 mg (2) Lactose 60.0 mg (3) Corn starch 35.0 mg (4) Hydroxypropyl methylcellulose 3.0 mg (5) Magnesium stearate 2.0 mg Reference 10.0 mg of the compound obtained in Example 176 and lactose 6
A mixture of 0.0 mg and 35.0 mg of corn starch was granulated using 0.03 ml of a 10% by weight aqueous solution of hydroxypropylmethylcellulose (3.0 mg as hydroxypropylmethylcellulose), and then granulated at 40 ° C.
And sieved. The resulting granules were mixed with 2.0 mg of magnesium stearate and compressed. The resulting uncoated tablets were coated with a sugar coating of an aqueous suspension of sucrose, titanium dioxide, talc and acacia. The coated tablets were polished with beeswax to obtain coated tablets.

Reference Example 186 (1) Compound of Reference Example 176 10.0 mg (2) Lactose 70.0 mg (3) Corn starch 50.0 mg (4) Soluble starch 7.0 mg (5) Magnesium stearate 3.0 mg Reference Example After granulating 10.0 mg of the compound obtained in 176 and 3.0 mg of magnesium stearate with 0.07 ml of an aqueous solution of soluble starch (7.0 mg as soluble starch), drying, 70.0 mg of lactose and 50.0 mg of corn starch And mixed. The mixture was compressed to give tablets.

Reference Example 187 (1) Compound No. 2 10.0 mg (2) Lactose 60.0 mg (3) Corn starch 35.0 mg (4) Hydroxypropyl methylcellulose 3.0 mg (5) Magnesium stearate 2.0 mg Compound No. 2 A mixture of 10.0 mg, lactose 60.0 mg and corn starch 35.0 mg was added to a 10% by weight aqueous solution of hydroxypropyl methylcellulose 0.03.
ml (3.
0 mg), dried at 40 ° C. and sieved. The obtained granules were treated with 2.0 m of magnesium stearate.
g and compressed. The resulting uncoated tablets were coated with a sugar coating of an aqueous suspension of sucrose, titanium dioxide, talc and acacia. The coated tablets were polished with beeswax to obtain coated tablets.

Reference Example 188 (1) Compound No. 1 10.0 mg (2) Lactose 70.0 mg (3) Corn starch 50.0 mg (4) Soluble starch 7.0 mg (5) Magnesium stearate 3.0 mg Compound No. 1 10.0 mg and 3.0 mg of magnesium stearate in 0.07 ml of aqueous solution of soluble starch
(7.0 mg as soluble starch)
Dry, lactose 70.0 mg and corn starch 50.
0 mg. The mixture was compressed to give tablets.

Reference Example 189 Morphine Hydrochloride 200 mg Sodium Benzoate 200 mg Distilled Water for Injection Total 2 ml Morphine hydrochloride and sodium benzoate were dissolved in distilled water for injection and aseptically produced.

Reference Example 190 Morphine Hydrochloride 200 mg Sodium Benzoate 500 mg Distilled Water for Injection Total 2 ml Morphine hydrochloride and sodium benzoate were dissolved in distilled water for injection and made aseptically.

Reference Example 191 Morphine hydrochloride 300 mg Sodium benzoate 700 mg Hydrochloric acid Appropriate amount Distilled water for injection Total amount 2 ml Morphine hydrochloride and sodium benzoate were dissolved in distilled water for injection, adjusted to pH 6 with hydrochloric acid, and then sterilized. After that, high-pressure heat sterilization was performed.

Reference Example 192 Morphine hydrochloride 400 mg Sodium benzoate 500 mg Glucose 400 mg Distilled water for injection Total 2 ml Morphine hydrochloride, sodium benzoate and glucose were dissolved in distilled water for injection, sterilized, and then sterilized under high pressure under high pressure.

Reference Example 193 Morphine Hydrochloride 400 mg Sodium Salicylate 400 mg Benzyl Alcohol 20 mg Distilled Water for Injection Total 2 ml Morphine hydrochloride, sodium salicylate and benzyl alcohol were dissolved in distilled water for injection, sterilized, and then subjected to high-pressure heat sterilization.

Reference Example 194 Morphine hydrochloride 500 mg Sodium benzoate 300 mg Sodium salicylate 300 mg Distilled water for injection A total of 2 ml Morphine hydrochloride, sodium benzoate and sodium salicylate were dissolved in distilled water for injection and made aseptically.
It was heat-sterilized under high pressure.

Reference Example 195 Preparation of Morphine Immediate Release Granules Formulation examples of the immediate release granules are shown below. Ingredients Formulation 1 Formulation 2 Formulation 3 Recipe 4 Formulation 5 Morphine hydrochloride 24 mg 48 mg 48 mg 24 mg 48 mg D- mannitol 14 20 20 - - crystalline cellulose - - - 14.2 20 Corn starch 6.7 6.5 6.5 4.5 4.5 low-substituted human Bu proxy Cellulose 1.5 1.5 1.5 1.5 1.5 Human cellulose cellulose 1.5 1.5 1.5 1.0 1.0 Polyvinyl cellulose---3.0 3.0 Polyethylene glycol 6000---0.5 0.5 Tartaric acid 2.0 2.0-1.0 1.0 Citric acid--2.0--Magnesium stearate 0.3 0.5 0.5 0.3 0.5 total 50 mg 80 mg 80 mg 50 mg 80 mg

[0318] After mixing, 3 g of human hydroxypropyl cellulose and 4 g of tartaric acid
Was added and the mixture was kneaded in a mortar. The obtained kneaded product was dried under reduced pressure (40 ° C., 16 hours), and then sized with a 16-mesh sieve. To 89.5 g of this sized powder, add 0.54 g of magnesium stearate,
Immediate release granules 1 were obtained.

[0319] After mixing, 1.5 g of human hydroxypropyl cellulose and tartaric acid 2
Then, 15 g of an aqueous solution containing g was added and kneaded in a mortar. The obtained kneaded product was dried under reduced pressure (40 ° C., 16 hours), and then sized using a 16 mesh sieve. To 71.5 g of the sized powder, 0.45 g of magnesium magnesium stearate was added to obtain immediate-release granules 2.

[0320] After mixing, 2 g of human hydroxypropyl cellulose, polyhydroxypropyl cellulose
25 g of an aqueous solution containing 6 g and 2 g of tartaric acid was added and kneaded in a mortar. The obtained kneaded product was dried under reduced pressure (40 ° C., 16 hours), and then sized using a 16 mesh sieve. To 89.5 g of the sized powder, 0.54 g of magnesium magnesium stearate was added to obtain immediate-release granules 3.

[0321] After mixing, 1 g of human hydroxy cellulose and polyhydroxy cellulose
14 g of an aqueous solution containing 3 g and 1 g of tartaric acid was added and kneaded in a mortar. The obtained kneaded product was dried under reduced pressure (40 ° C., 16 hours), and then sized using a 16 mesh sieve. To 71.5 g of the sized powder, 0.45 g of magnesium magnesium stearate was added to obtain immediate-release granules 4.

Reference Example 196 Preparation of morphine sustained release (controlled release) granules After mixing, 12 g of polyethylene glycol 6000 and tartaric acid 2
Add 290 g of an aqueous solution containing 4 g, and add a vertical granulator (FM-VG-10).
(Hauleck). The obtained kneaded material is used for tomato couran (DG-
(L1 type, Fujibattle) and granulated with Malmerizer (QJ-230). Dry the obtained granules under reduced pressure (40 ° C, 16 hours)
After that, it is sieved and classified.
1050 g was obtained.

(2) Production of underlay granules 22.5 g of human peroxyfluoromethylcellulose 0.45 g of tartaric acid in aqueous ethanol
After dissolving in 340 ml (80% ethanol (W / W)), a suspension solution in which 4.05 g of talc was dispersed was prepared. Element obtained in (1)
450 g of (core) granules were placed in a Wurster-type fluidized granulator (FD-3, Powellec), and the undercoat liquid was sprayed to obtain about 470 g of undercoated granules.

[0324] (3) a controlled release membrane solution (coating agent solution) of Formulation Example Ingredient Formulation 1 Formulation 2 Formulation 3 ethylcellulose (45cps) 11.6 mg 12.2 mg 12.6 mg crosslinked port Riakuriru acid polymer (Haihi Bu Suwako 103) 1.6 1.6 1.6 Human peroxypropyl cellulose 4 4 4 Polyethylene glycol 6000 2.4 1.8 1.4 Tartaric acid 0.4 0.4 0.4 Cetyl alcohol 0.7 0.7 0.7 Talc 6 6 6 Ethanol / water (90/10 w / w) 480 480 480 Total 506.7 mg 506.7 mg 506.7 mg

(I) Production Example 1 of Morphine Sustained-Release Granules 200 g of the underlay granules obtained in (2) was placed in a Wurster-type fluidized-granulator (FD-3, Powellec), and a controlled-release membrane liquid formulation was prepared. Was sprayed to obtain sustained-release granules. The coating amount was 25% by weight as a solid based on the underlay granules. After sieving and classification, about 250 g of sustained-release granules having a particle size of 600 to 1600 μm were obtained. This granule
0.25 g of talc was mixed with 250 g to obtain sustained-release granules 1

(Ii) Production Example 2 of Morphine Sustained Release Granules 200 g of the underlay granules obtained in (2) was placed in a Wurster-type fluidized granulator (FD-3, Powellec), and a controlled release membrane liquid formulation was prepared. And sustained release granules 2 were prepared in the same manner as in (i).
0 g was obtained.

Reference Example 197 Formulation Example of Morphine Capsule Preparation 150 mg of the immediate release granules obtained in Reference Example 195 (1) and 2184 mg of sustained release granules obtained in Reference Example 196 (3) (ii) were prepared as described in No. 2 The capsules were filled into capsules of a size to obtain capsules containing 120 mg of morphine hydrochloride.

Reference Example 198 Formulation Example of Morphine Capsule Preparation The 440 mg of the immediate-release granules obtained in Reference Example 195 (4) and the 169 mg of the sustained-release granules obtained in Reference Example 196 (3) (i) were prepared as described in No. 3 The capsules were filled into a capsule having a size, and a capsule containing 60 mg of morphine hydrochloride was obtained.

REFERENCE EXAMPLE 199 Formulation Example of Morphine Capsule Preparation 20 mg of the immediate release granules obtained in Reference Example 195 (4) and 235 mg of sustained release granules obtained in Reference Example 196 (3) (ii) The capsules were sized to give capsules containing 30 mg of morphine hydrochloride.

Reference Example 200 Formulation examples of an immediate release preparation are shown below. Ingredients Formulation 1 Formulation 2 Formulation 3 Morphine hydrochloride 5 mg 10 mg 10 mg D-mannitol 33 28 38 Corn starch 6.7 6.7 6.65 Low-substituted human hydroxypropyl cellulose 1.5 1.5 1.5 Human hydroxypropyl cellulose 1.5 1.5 1.5 Tartaric acid 2.0-2.0 Citric acid-2.0- Magnesium stearate 0.3 0.3 0.35 Total 50 mg 50 mg 60 mg

[0331] After mixing, 15 g of human hydroxypropyl cellulose and 20 g of tartaric acid
g of an aqueous solution containing 150 g of water, and added to a vertical granulator (FM-VG-10).
(Hauleck). Dry the resulting kneaded product under reduced pressure (40
After 16 hours), the mixture was sieved with a power mill (Model P-3, Showa Kagaku Kikai Seisakusho) through a 1.0 mm punching screen to obtain sized powder.
To 447 g of the sized powder, 2.7 g of magnesium magnesium stearate was added to obtain granules for filling. Using a capsule filling machine (6F type, Sanashini), 50 mg of the granules for filling are filled into a capsule of size 5 and morphine hydrochloride is filled with 5 m
About 3,000 capsules containing g were obtained.

[0332] After mixing, 15 g of human hydroxypropyl cellulose and 20 g of tartaric acid
g of an aqueous solution containing 150 g of water, and added to a vertical granulator (FM-VG-10).
(Hauleck). Dry the resulting kneaded product under reduced pressure (40
After 16 hours), the mixture was sieved with a power mill (Model P-3, Showa Kagaku Kikai Seisakusho) through a 1.0 mm punching screen to obtain sized powder.
3.2 g of magnesium stearate was added to 536 g of the sized powder to prepare a filling granule. Using a capsule filling machine (6F type, Sanashini), fill 60 mg of granules for filling into a capsule of size 5, and add 10 mg of morphine hydrochloride.
Approximately 1,500 capsules were obtained. Also, 30 mg of the filled granules were similarly filled into a capsule of size 5 to obtain about 2,000 capsules containing 5 mg of morphine hydrochloride.

Reference Example 201 A formulation example of an apomorphine hydrochloride sublingual tablet is shown below. (1) Apomorphine hydrochloride 2.00% by weight Mannitol 66.67 Ascorbic acid 3.33 Citric acid 2.00 Avicel PH102 (crystalline cellulose) 15.00 Methocel E4M (human peroxyfluoromethyl cellulose) 10.00 Aspartame 0.67 Magnesium stearate 0.33

(2) Apomorphine hydrochloride 2.66% by weight Mannitol 66.00 Ascorbic acid 3.33 Citric acid 2.00 Avicel PH102 (crystalline cellulose) 15.00 Methocel E4M (human peroxyfluoromethyl methylcellulose) 10.00 Aspartame 0.67 Magnesium stearate 0.33

(3) Apomorphine hydrochloride 3.33% by weight Mannitol 65.34 Ascorbic acid 3.33 Citric acid 2.00 Avicel PH102 (crystalline cellulose) 15.00 Methocel E4M (human peroxyfluoromethyl cellulose) 10.00 Aspartame 0.67 Magnesium stearate 0.33

Reference Example 202 (3R, 4S, 5S, 6
R) -5-methoxy-4-[(2R, 3R) -2-methyl-3- (3-methyl-2-butenyl) oxiranyl]
Preparation of -1-oxaspiro [2.5] oct-6-yl (chloroacetyl) carbamate (1) Preparation of fumagillol from fumagillin dicyclohexylammonium
The mixture was added to 2133 ml of a sodium hydroxide solution and stirred at about 25 ° C. for 24 hours. 1600 ml of ethyl acetate and 288 g of sodium chloride were added to the mixed solution, and the mixture was stirred for about 10 minutes. The precipitated crystals were filtered, washed with ethyl acetate, and the filtrate was separated to obtain an organic layer. next,
After the organic layer was washed with water, it was washed with an aqueous solution of ammonium sulfate dissolved in 0.4N sulfuric acid and a 5% aqueous solution of ammonium sulfate. Magnesium sulfate (anhydrous) was added to the organic layer for dehydration. The magnesium sulfate was filtered, and the organic layer was concentrated under reduced pressure to obtain a yellow-brown oil. Next, this oily substance was dissolved in a mixed solution of methylene chloride and ethyl acetate (3: 1 (v / v)), adsorbed on a silica gel chromatography column, and eluted with a mixed solution of methylene chloride and ethyl acetate. It was collected and concentrated under reduced pressure to obtain a pale yellow oil. N-Hexane is added to this oily substance to add about 40
C., and the solution was crystallized by stirring for about 4 hours while gradually cooling the solution to about 3 ° C. After filtering the crystals, the crystals were washed with cooled n-hexane and dried under vacuum at about 30 ° C. for about 12 hours to obtain 198 g of fumagillol crystals. (Yield: 70%) (2) From fumagillol (3R, 4S, 5S, 6R)-
5-methoxy-4-[(2R, 3R) -2-methyl-3
-(3-methyl-2-butenyl) oxiranyl] -1-
Production of oxaspiro [2.5] oct-6-yl (chloroacetyl) carbamate 198 g of fumagillol obtained in the above (1) was mixed with 3260 ml of methylene chloride.
And dissolved. The solution was cooled to about −3 ° C. under a nitrogen atmosphere, and 92 g of α-chloroacetyl isocyanate was added dropwise over about 10 minutes while maintaining the internal temperature at 4 ° C. or less. Then, -5
Stirred at 4 ° C. for about 20 minutes. To the reaction solution, 1160 ml of water cooled to 5 ° C. or lower was added, and after standing for about 15 minutes, the organic layer obtained by separation and the aqueous layer were extracted twice with methylene chloride. The extract was washed with water (20% (w / v). Magnesium sulfate (anhydrous) was added to the organic layer for dehydration, and the magnesium sulfate was filtered. The organic layer was concentrated under reduced pressure to obtain an oily substance. The oily substance was dissolved in n-hexane-ethyl acetate (3: 1 (v /
v)) dissolved in the mixture, adsorbed on a silica gel chromatography column, and eluted with a mixture of n-hexane and ethyl acetate, and the effective fraction was collected.
Concentrate under reduced pressure to give a pale yellow crude (3R, 4S, 5S, 6
R) -5-methoxy-4-[(2R, 3R) -2-methyl-3- (3-methyl-2-butenyl) oxiranyl]
A dried product of -1-oxaspiro [2.5] oct-6-yl (chloroacetyl) carbamate was obtained. Next, crude (3R, 4S, 5S, 6R) -5-methoxy-4-
[(2R, 3R) -2-methyl-3- (3-methyl-2
-Butenyl) oxiranyl] -1-oxaspiro [2.
5] Isopropyl ether was added to the dried product of oct-6-yl (chloroacetyl) carbamate, dissolved at about 40 ° C, and activated carbon was added. After stirring for about 10 minutes, the activated carbon was filtered, the filtrate was cooled to about 15 ° C., and seed crystals were added for crystallization. After filtering the obtained crystals, the crystals were washed with cooled isopropyl ether and dried in vacuum at about 30 ° C. to obtain dried crystals. The dried crystals were added to n-hexane cooled to about 10 ° C. with stirring, then a small amount of distilled water was added dropwise with stirring, and the crystals were filtered after stirring for about 4 hours. The crystals are vacuum dried at about 30 ° C. for about 15 hours,
(3R, 4S, 5S, 6R) -5-methoxy-4-
[(2R, 3R) -2-methyl-3- (3-methyl-2
-Butenyl) oxiranyl] -1-oxaspiro [2.
5] 192 g of white crystals of oct-6-yl (chloroacetyl) carbamate were obtained. (Yield: 68%)

Reference Example 203 (1) Ondansetron 10.0 mg (2) Lactose 70.0 mg (3) Corn starch 50.0 mg (4) Soluble starch 7.0 mg (5) Magnesium stearate 3.0 mg Ondansetron 10 0.07 ml of an aqueous solution of soluble starch containing 3.0 mg and 3.0 mg of magnesium stearate
(7.0 mg as soluble starch)
Dry, lactose 70.0 mg and corn starch 50.
0 mg. The mixture is compressed to give tablets.

Reference Example 204 (1) Dexamethasone 10.0 mg (2) Lactose 70.0 mg (3) Corn starch 50.0 mg (4) Soluble starch 7.0 mg (5) Magnesium stearate 3.0 mg Dexamethasone 10.0 mg and stearin Magnesium acid salt 3.0mg in soluble starch aqueous solution 0.07ml
(7.0 mg as soluble starch)
Dry, lactose 70.0 mg and corn starch 50.
0 mg. The mixture is compressed to give tablets.

Reference Example 205 Rapid disintegration of apomorphine in oral cavity (rapid diffusion dosage form)
Preparation of (a) Preparation of 20% Apomorphine Hydrochloride Diffusion Gelatin (792 g) and mannitol (594 g) were thoroughly mixed in a bowl of a vacuum mixer and dispersed in one part of purified water (16 kg). Next, the resulting mixture was heated to 40 ° C. ± 2 ° C. and homogenized for 10 minutes. Thereafter, the mixture was cooled to room temperature (20-24 ° C). Upon cooling, apomorphine hydrochloride (3
60 g) was added. Homogenize this mixture,
Dissolution of the drug was ensured. Citric acid (166.32 g) was slowly added with stirring to adjust the pH of the solution to 3.0. The remaining water (87.68 g) was added to the mixer and the bulk mixture was homogenized to ensure dissolution, yielding the diffusing agent. (B) Preparation of apomorphine hydrochloride 10 mg unit Apomorphine hydrochloride 2.0% produced in (a) above
500 mg of diffused material with a 16 mm pocket inside diameter
Packaged in each of the blister pockets in a row. Blister laminate is 4 per square meter of PVdC
It consisted of 200 μm of PVC coated at a rate of 0 g. The product was immediately frozen in a liquid nitrogen freeze tunnel and frozen. The frozen product was then stored at −20 ° C. for a minimum of 12 hours before lyophilization in a freeze dryer using a drying temperature of + 10 ° C. and a tower pressure of 0.5 hPa. The lyophilized unit was then inspected for fatal defects and the rest of the batch was sealed with a lid foil made of paper / foil laminate (20 μm aluminum). Each blister is then coded with a batch number, the blister is placed in a sachet, and the open end of the sachet is completely sealed.
Packaged in sachets. Each sachet was then labeled with the product name, batch number, date of manufacture and supplier name. Ingredient Weight (mg) vs. Composition Wt% Purified Water USP / EP * 446.880 89.4 Apomorphine HCl EP / EP 10.000 2.0 Gelatin EP / USNF 22.000 4.4 Mannitol EP / USP 16.500 3.3 citric acid EP / USP 4.620 0.9 total 500.000 100.0 *) means removed during lyophilization process. The following Reference Examples further illustrate prescription examples that can be produced using the above method. Ingredient Weight (mg) vs. Composition Wt% Purified Water EP / USP * 438.500 87.70 Apomorphine HCl BP / EP 10.000 2.00 Gelatin EP / USNF 25.00 5.00 Mannitol EP / USP 20.000 4.00 Citric acid EP / USP 1.500 0.30 Aspartame EP / USNF 2.500 0.50 Peppermint flavor 2.500 0.50 Total 500.000 100.0 *) Removed during freeze drying process Means Component weight (mg) vs. composition weight% purified water EP / USP * 215,000 86.00 Apomorphine HCl BP / EP 10.000 4.00 Gelatin EP / USNF 11.500 4.60 Mannitol EP / USP 10.000 4.00 citric acid EP / USP 1.500 0.60 aspartame EP / USNF 2.000 0.80 total 250.000 100.0 *) means removed during lyophilization process. Component weight (mg) versus composition weight% purified water EP / USP * 441.000 88.20 Apomorphine HCl BP / EP 10.000 2.00 Gelatin EP / USNF 25,000 5.00 Mannitol EP / USP 20.000 4.00 citric acid EP / USP 1.500 0.30 aspartame EP / USNF 2.500 0.50 total 500.000 100.0 *) means removed during lyophilization process.

[0340]

Examples Example 1 Orally administered (9R) -7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8, for the anticancer drug cisplatin-induced acute emesis
9,10,11-Hexahydro-9-methyl-5- (4
-Methylphenyl) -6,13-dioxo-13H-
Effects of [1,4] diazosino [2,1-g] [1,7] naphthyridine (compound No. 3) (1) Compound No. 1 administered orally to cisplatin acute emesis in ferrets. Action of 3 [Method] Five to six male ferrets (1.2 to 2.3 kg) were used per group. Cisplatin was administered intraperitoneally at 10 mg / 10 ml / kg. One hour before the administration of cisplatin, the animals were ingested a small amount of food, and 30 minutes before the administration of cisplatin, Compound No. 3 was orally administered in a predetermined amount. Similarly, control animals were orally administered a 0.5% methylcellulose (MC) solution under non-fasting conditions. Vomiting was counted up to 5 hours after cisplatin administration. Compound N
o. 3 was suspended at a predetermined concentration in a 0.5% methylcellulose solution and orally administered at a rate of 1 ml per kg of body weight. Also,
The 0.5% methylcellulose solution was orally administered at a rate of 1 ml per kg of body weight. Data on the number of times of vomiting, the time to first vomiting (latency), and the time from the onset of vomiting to the end thereof were statistically analyzed by the Dunnett test to determine the difference from the control group. [Results] The acute vomiting pattern of cisplatin in ferrets is shown in FIG. In control animals, vomiting and vomiting began at 1.5 ± 0.1 hours (mean ± standard error) after cisplatin administration, and frequently occurred 1.5 to 2.5 hours after administration,
It has been seen continuously since then. Vomiting and vomiting induced within the 5-hour observation period were 126.7 ± 19.4 and 10.7 ± 1.2, respectively.
It was times. This vomiting was compound no. Oral administration of 3 mg / kg of 3 significantly suppressed the dose, and markedly suppressed at 10 mg / kg. The results are shown in FIG. 2 and Table 1.

[0341]

[Table 1]

Cisplatin-induced acute vomiting in ferrets was compound no. It was clarified that oral administration of No. 3 suppressed the activity.

(2) Compound No. administered orally for acute cisplatin vomiting in dogs. Action of 3 [Method] A group of 3 or 4 beagle dogs (7.9 to 13.3 kg)
Was used regardless of gender. Cisplatin 3 mg / 3 ml / kg
Was administered intravenously. One hour before the administration of cisplatin, the animals were ingested a small amount of food, and 30 minutes before the administration of cisplatin, Compound No. 3 was orally administered in a predetermined amount. Similarly, control animals were orally administered a 0.5% methylcellulose solution under non-fasting conditions. Vomiting was counted up to 5 hours after cisplatin administration. Compound No. 3 was suspended at a predetermined concentration in a 0.5% methylcellulose solution, and orally administered at a rate of 1 ml per kg of body weight. The 0.5% methylcellulose solution was orally administered at a rate of 1 ml per kg of body weight. Number of vomiting, time to first vomiting
For the data on (latency) and the time from the onset of vomiting to the end thereof, the difference from the control group was statistically analyzed by Dunnett's test. [Results] The vomiting pattern of cisplatin in dogs is shown in FIG. In control animals after cisplatin administration 1.
Vomiting started at 3 ± 0.2 hours (mean ± standard error) and administration
Frequent after 2 to 3 hours, it gradually decreased.
Vomiting evoked within 5 hours of observation was 13.7 ± 0.3 times. Compound No. 3 significantly suppressed cisplatin vomiting at 3 mg / kg or more. Compound No. 10 mg / kg of 3
Reduced the vomiting almost completely and prolonged the latency. The results are shown in FIG. 4 and Table 2.

[0344]

[Table 2]

Cisplatin-induced acute emesis in dogs was compound no. It was clarified that oral administration of No. 3 suppressed the activity.

(3) Compound No. administered orally. 3. Cisplatin-induced acute vomiting inhibition rate The acute emptying vomiting inhibition rate and the acute vomiting inhibition rate were calculated by the following formulas, and the results are shown in [Table 3] and [Table 4].

(Equation 1)

[0347]

[Table 3]

[0348]

[Table 4]

Example 2 Compound N administered intraperitoneally or intravenously for the anticancer drug cisplatin-induced acute emesis
o. Effect of Compound No. 3 (1) Compound No. 3 administered intraperitoneally to acute cisplatin vomiting in ferrets. Action of 3 [Method] Six to nine male ferrets (1.2 to 1.7 kg) were used per group. Cisplatin was administered intraperitoneally at 10 mg / 10 ml / kg. Compound No. 3 was administered intraperitoneally in a predetermined amount under fasting 30 minutes before cisplatin administration. Control animals are similarly fasted
PEG400 was administered intraperitoneally. Vomiting was counted up to 5 hours after cisplatin administration. Compound No. 3 was dissolved in PEG400 and administered intraperitoneally at a rate of 1 ml per kg of body weight. PEG400 was administered intraperitoneally at a rate of 1 ml per kg of body weight. The data on the number of vomits, the latency and the time from the onset of vomiting to the end of the vomiting were statistically analyzed for differences from the control group by t test. [Results] 1.3 ± 0.2 hours after cisplatin administration in control animals
Vomiting started from (mean ± standard error), and vomiting and vomiting that occurred within the 5-hour observation period were 123.3 ± 12.7, respectively.
Times and 11.2 ± 1.6 times. Compound No. 3 is 1 mg / kg
, Significantly suppressed cisplatin vomiting and vomiting [Table 5].

[0350]

[Table 5]

Cisplatin-induced acute vomiting in ferrets was compound no. It was clarified that intraperitoneal administration of No. 3 suppressed the activity.

(2) Compound No. administered intravenously to acute cisplatin vomiting in dogs. 3. Effect of [Method] Three beagle dogs (7.3 to 12.0 kg) in one group were used regardless of gender. Cisplatin was administered intravenously at 3 mg / 3 ml / kg. Compound No. 3 was administered intravenously in a predetermined amount under fasting 30 minutes before the administration of cisplatin. Control animals were similarly administered a predetermined amount of PEG400 intravenously under fasting conditions. Compound No. 3
Was dissolved in PEG400 and administered intravenously at a rate of 1 ml / kg body weight. PEG400 was intravenously administered at a rate of 1 ml per kg of body weight. Data on the number of vomits, latency and the time between the onset and termination of vomiting are available from Dunnettte
The difference from the control group was statistically analyzed by st. [Results] 0.9 ± 0.1 hours after administration of cisplatin in control animals
Vomiting started from (mean ± standard error), and the number of vomiting induced within the observation time of 5 hours was 18.3 ± 1.9. Compound N
o. No. 3 significantly suppressed cisplatin vomiting at 0.3 mg / kg or more. Compound No. A dose of 3 mg / kg almost completely suppressed this vomiting and prolonged the latency. The results are shown in FIG. 5 and Table 6.

[0353]

[Table 6]

(3) Compound No. administered intraperitoneally or intravenously. Example 3 Inhibition rate of cisplatin-induced acute vomiting Example 1
It was determined in the same manner as (3). The results are shown in [Table 7] and [Table 8].

[0355]

[Table 7]

[0356]

[Table 8]

Example 3 Compound No. 1 administered orally for delayed emesis due to the anticancer drug cisplatin. Effects of Compound No. 3 (1) Compound No. 3 administered orally on acute and delayed emesis due to cisplatin in ferrets. Action of 3 [Method] Four to six male ferrets (1.1 to 2.2 kg) were used per group. Cisplatin was administered intraperitoneally at 5 mg / 5 ml / kg. Compound No. 3 is 30 minutes before administration of cisplatin and 24 and 48 hours after administration for once-daily administration, 30 minutes before administration of cisplatin for twice-daily administration, and 12, 24, 36, 48 and 60
After a certain time, a predetermined amount of oral administration was performed. All doses of Compound N
o. 3 minutes 30 minutes before administration, the animals were ingested a small amount of food. Similarly, control animals were orally administered a predetermined amount of a 0.5% methylcellulose solution under non-fasting conditions. Ondansetron was orally administered in a predetermined amount under fasting. Ondansetron control animals were orally administered a predetermined amount of physiological saline under fasting conditions. Vomiting was counted up to 72 hours after cisplatin administration. Compound No. 3 is
Suspend in 0.5% methylcellulose solution, 1 / kg body weight
A predetermined amount was orally administered at a rate of ml. Ondansetron is 0.
A predetermined amount of a 2% (w / v) injection was orally administered. Also, 0.5
The% methylcellulose solution was orally administered at a rate of 1 ml per kg of body weight, and the physiological saline was orally administered at a rate of 0.5 to 1.5 ml per kg of body weight. Number of vomiting, time to first vomiting (latency)
Data on the time from the onset of vomiting to the end thereof were statistically analyzed by the Dunnett test to determine the difference from the control group. [Results] When vomiting of cisplatin 5 mg / kg intraperitoneally to ferrets, vomiting and vomiting occurred up to 24 hours after administration.
The average number of (acute vomiting) was 109.8 times, 72 hours after administration 24 hours
The average number of vomiting and vomiting (late vomiting) that occurred by the time was 347.8 times, and the average total number of vomiting observed in 3 days was 457.5 times. These vomiting and vomiting were caused by Compound No. Administration of 3 mg / kg of 3 once a day resulted in significant suppression (suppression rate: 42%). Compound No. 10 mg of 3
/ kg once daily significantly reduced acute and delayed vomiting, with a suppression rate of 83% for acute vomiting and 6% for delayed vomiting.
It was 5% ([FIG. 8], [FIG. 9] and [Table 11]).
Compound No. If 1 mg / kg of 3 is administered twice a day,
Delayed vomiting was reduced by 70%, and the average number of acute and delayed vomiting in 3 days was reduced by 54%. Further, compound N
o. Administration of 3 mg / kg twice a day markedly suppressed acute and delayed vomiting, with a suppression rate of 82% for acute vomiting,
Late vomiting was 59%. The results are shown in [FIG. 6], [FIG. 7], [Table 9] and [Table 10].

[0358]

[Table 9]

[0359]

[Table 10]

[0360]

[Table 11]

Compound No. Oral administration of 3 or more at 0.1 mg / kg twice a day significantly suppressed the delayed vomiting of ferrets due to cisplatin. Also, 10 mg / kg
By oral administration once daily, acute and delayed vomiting of ferrets by cisplatin was significantly suppressed.

(2) Compound No. Cisplatin-induced acute and delayed vomiting suppression rate in ferret No. 3 The acute vomiting suppression rate, delayed vomiting suppression rate, and total vomiting suppression rate were calculated by the following formulas, and the results were shown in [Table 12] and [Table 13]. Shown in

(Equation 2)

[0363]

[Table 12]

[0364]

[Table 13]

Example 4 An anticancer drug methotrexate (M
TX) Compound N administered orally for delayed emesis
o. Effect of 3 (1) Compound No. 3 administered orally on delayed emesis due to methotrexate in dogs. Action of 3 [Method] 3 or 4 beagle dogs per group (8.3 to 12.6 kg)
Was used regardless of gender. 2.5 mg / m for methotrexate
l / kg was administered intravenously. Compound No. 3. Ondansetron and 0.5% methylcellulose solution were orally administered in predetermined amounts at 8, 24 and 48 hours after the administration of methotrexate. Compound No. Animals were given a small amount of food 30 minutes before administration of 3 and 0.5% methylcellulose, and then ondansetron was administered under fasting. Vomiting was counted up to 72 hours after methotrexate administration. Compound No. 3 is 0.5%
Suspended in methylcellulose solution, 0.25-
Oral administration was performed at a rate of 1 ml. Ondansetron is 0.2% (w
/ v) Oral administration of a predetermined amount of the injection at a concentration. The 0.5% methylcellulose solution was orally administered at a rate of 1 ml per kg of body weight. Data on the number of vomits, latency, and the time from the onset of vomiting to the end thereof were statistically analyzed by Dunnett's test for differences from the control group. [Results] The vomiting pattern of methotrexate in the animals to which the solvent was administered is shown in FIG. In control animals, vomiting began 25.3 ± 1.5 hours (mean ± standard error) after administration of methotrexate, and was continuously observed until about 70 hours after administration. Vomiting evoked within 72 hours of observation was 12.3 ±
0.7 times. Vomiting of methotrexate is compound N
o. 3, which was significantly suppressed at 0.01 mg / kg or more, and the time from the onset of vomiting to the end was significantly shortened. Also,
This vomiting was compound no. 3 was almost completely suppressed by 10 mg / kg. The results are shown in FIG. 11 and Table 14.

[0366]

[Table 14]

Delayed vomiting of dogs induced by methotrexate was compound no. It was clarified that oral administration of No. 3 once a day suppressed it. (2) Compound No. Inhibition rate of methotrexate-induced late emesis in dog No. 3 The late emesis suppression rate and the total emesis suppression rate were calculated by the following formula, and the results are shown in [Table 15].

[0368]

[Table 15]

Example 5 Compound No. 5 administered orally for vomiting due to the analgesic morphine. Effects of Compound No. 3 (1) Compound No. 3 administered orally on vomiting by morphine in ferrets. Action of 3 [Method] Six to seven male ferrets (1.6 to 2.0 kg) were used per group. Morphine was administered subcutaneously at 0.3 mg / 0.3 ml / kg.
2.5 hours before morphine administration, feed the animals with a small amount of food,
Thirty minutes later, Compound No. 3 was orally administered in a predetermined amount. Similarly, control animals were orally administered a predetermined amount of a 0.5% methylcellulose solution under non-fasting conditions. Ondansetron was orally administered in a predetermined amount under fasting. Ondansetron control animals were orally administered a predetermined amount of physiological saline under fasting conditions. Vomiting was counted up to 30 minutes after morphine administration. Compound No. 3 is 0.5%
It was suspended in a methylcellulose solution and orally administered at a rate of 1 ml per kg of body weight. Ondansetron was orally administered by injection at a concentration of 0.2% (w / v). The 0.5% methylcellulose solution was orally administered at a rate of 1 ml per kg of body weight, and the physiological saline was orally administered at a rate of 1.5 ml per kg of body weight. The data on the number of times of vomiting, the time until the first vomiting (latency), and the time from the onset of vomiting to the end thereof were statistically analyzed by the Dunnett test or the t test from the control group. [Results] In control animals, vomiting or vomiting started at 3.3 to 3.6 minutes (average value) after morphine administration, and continued for about 10 minutes thereafter. Vomiting and vomiting induced within the 30 minute observation period were 31.9 ± 5.2 and 3.6 ± 0.7, respectively. This empty vomiting and vomiting was caused by Compound No. Oral administration of 3 at 1 mg / kg showed a tendency of suppression, and was significantly suppressed at 3 mg / kg. On the other hand, oral administration of 3 mg / kg of ondansetron did not suppress this vomiting. The measurement results are shown in FIG.
2], [FIG. 13], [Table 16] and [Table 17].

[0370]

[Table 16]

[0371]

[Table 17] Morphine-induced emesis in ferrets was compound no.
It was clarified that oral administration of No. 3 suppressed the activity.

(2) Compound No. administered orally for vomiting by morphine in dogs. [3] Action [Method] Three to five beagle dogs (8.8 to 14.5 kg) in each group were used regardless of gender. Morphine was administered subcutaneously at 0.3 mg / 0.03 ml / kg. The animals were ingested a small amount of food 2.5 hours before morphine administration, and 30 minutes later, Compound No. 3 was orally administered in a predetermined amount. Similarly, control animals were orally administered a predetermined amount of a 0.5% methylcellulose solution under non-fasting conditions. Ondansetron was orally administered in a predetermined amount under fasting. Ondansetron control animals were orally administered a predetermined amount of physiological saline under fasting conditions.
Vomiting was counted up to 30 minutes after morphine administration. Compound N
o. 3 is suspended in 0.5% methylcellulose solution and weighs 1 kg
Oral administration was carried out at a rate of 1 ml per mouse. Ondansetron
A 0.2% (w / v) injection was orally administered. The 0.5% methylcellulose solution was orally administered at a rate of 1 ml per kg of body weight, and the physiological saline was orally administered at a rate of 0.5 ml per kg of body weight. Data on the number of vomits, the time to first vomiting (latency) and the time between the onset and termination of vomiting
The difference from the control group was statistically analyzed by nnett test or t test. [Results] In the control animals, vomiting started 5.6 ± 0.5 minutes after morphine administration (mean ± standard error) and continued for about 2 minutes thereafter. 2.2 vomiting evoked within the 30 minute observation period
± 0.5 times. This vomiting was compound no. 0.3 of 0.3 mg /
The dose was significantly suppressed by oral administration of kg and completely suppressed by 1 mg / kg. On the other hand, oral administration of 1 mg / kg of ondansetron did not suppress this vomiting. The results are shown in Table 18
And [Table 19].

[0373]

[Table 18]

[0374]

[Table 19]

The morphine-induced vomiting in dogs was compound no. It was clarified that oral administration of No. 3 suppressed the activity. Compound No. administered orally. The morphine-induced vomiting inhibition rate of No. 3 is shown below. The idling suppression rate and the vomiting suppression rate were calculated by the following equations, and the results are shown in [Table 20] and [Table 21].

(Equation 3)

[0376]

[Table 20]

[0377]

[Table 21]

Example 6 Orally Administered Compound No. 1 for Central Emetic Loperamide-Induced Vomiting in Dogs 3
[Method] Three beagle dogs (7.7 to 12.7 kg) in each group were used regardless of gender. Loperamide was administered subcutaneously at 1 mg / ml / kg. The animals were ingested a small amount of food 2.5 hours before administration of loperamide, and 30 minutes later, Compound No. 3 was orally administered in a predetermined amount. Similarly, control animals were orally administered a predetermined amount of a 0.5% methylcellulose solution under non-fasting conditions. Naloxone and ondansetron were administered intravenously and orally in a prescribed amount, respectively, under fasting 30 minutes before administration of loperamide. Vomiting was counted up to 3 hours after loperamide administration. Compound No. 3 is suspended in a 0.5% methylcellulose solution, and 0.25-1 ml per kg of body weight
Orally administered at a rate of Naloxone was administered as a 0.05% (w / v) solution intravenously. Ondansetron was orally administered by injection at a concentration of 0.2% (w / v). The 0.5% methylcellulose solution was orally administered at a rate of 1 ml per kg of body weight. Data on the number of vomits, latency, and the time from the onset of vomiting to the end thereof were statistically analyzed by Dunnett's test for differences from the control group. [Results] 0.73 ± 0.04 hours after loperamide administration in control animals
Vomiting started at (mean ± standard error) and continued for about 1.5 hours thereafter. Vomiting evoked within the 3-hour observation period was 10.0 ± 0.6. This vomiting was compound no. 3
Is significantly suppressed by oral administration of 0.03 mg / kg or more, and 10 mg / kg
It was completely suppressed in kg. Also, 0.5 mg / kg of naloxone
By intravenous administration of, this vomiting was almost completely suppressed. On the other hand, oral administration of ondansetron at 10 mg / kg did not suppress this vomiting. The measurement results are shown in [FIG. 14], [FIG. 15] and [Table 22].

[0379]

[Table 22]

Loperamide-induced vomiting in dogs was compound no. It was clarified that oral administration of No. 3 suppressed the activity. Compound No. The rate of inhibition of loperamide-induced emesis in 3 dogs is shown below. The vomiting suppression rate was calculated by the following formula, and the results are shown in [Table 23].

(Equation 4)

[0381]

[Table 23]

Example 7 Compound No. 3 against central emetic apomorphine-induced emesis in dogs 3. Effect of 3 [Method] Three beagle dogs (7.8 to 15.9 kg) in one group were used regardless of gender. Apomorphine was administered subcutaneously at 0.1 mg / ml / kg. The animals were ingested a small amount of food 2.5 hours before administration of apomorphine, and 30 minutes later, Compound No. 3 was orally administered in a predetermined amount. Similarly, control animals were orally administered a predetermined amount of a 0.5% methylcellulose solution under non-fasting conditions. Ondansetron was orally administered in a predetermined amount under fasting. Vomiting was counted up to 1 hour after apomorphine administration. Compound No. 3
Suspended in 0.5% methylcellulose solution,
Oral administration was performed at a rate of 1 ml. Ondansetron is 0.2% (w
/ v) Oral injection of the concentration of the injection. The 0.5% methylcellulose solution was orally administered at a rate of 1 ml per kg of body weight. Data on the number of vomits, latency, and the time from the onset of vomiting to the end thereof were statistically analyzed by Dunnett's test for differences from the control group. [Results] 4.2 ± 0.0 minutes after administration of apomorphine in control animals
Vomiting began at (mean ± standard error) and continued for about 30 minutes thereafter. Vomiting evoked within 1 hour of observation was 12.0 ± 3.6 times. This vomiting was compound no. 3 of 3
The inhibitory tendency was shown at mg / kg, and was significantly suppressed at 10 mg / kg. Further, Compound No. 3 at 10 mg / kg markedly reduced the time from the onset of vomiting to the end. On the other hand, oral administration of ondansetron at 10 mg / kg did not suppress this vomiting. The results are shown in [FIG. 16], [FIG. 17] and [Table 24].

[0383]

[Table 24]

Apomorphine-induced vomiting in dogs was compound no. It was clarified that oral administration of No. 3 suppressed the activity. Compound No. The inhibition rate of apomorphine-induced emesis in 3 dogs is shown below. The vomiting suppression rate was calculated by the following equation, and the results are shown in [Table 25].

(Equation 5)

[0385]

[Table 25]

Example 8 Compound No. 10 against the anticancer drug cisplatin-induced acute emesis Effect of Combination of No.3 and Ondansetron [Method] Male ferrets (0.8 to 1.6 kg) were used. Cisplatin was administered intraperitoneally at 10 mg / 10 ml / kg. Compound No. 30 minutes before cisplatin administration. 3 (3 mg / kg) and ondansetron (0.03 mg / kg) were administered orally. Control animals were similarly orally administered a 0.5% (W / V) methylcellulose (MC) solution. Vomiting and vomiting were counted up to 180 minutes after cisplatin administration. Animal behavior was recorded on a closed-circuit video recording system and analyzed after the experiment. Data on the number of times of vomiting and vomiting were statistically analyzed by the Dunnett test to determine the difference from the control group. [Results] In the control animals, empty vomiting and vomiting induced within the observation time of 180 minutes after administration of cisplatin were 116.5 ± 22.5 times. The number of times of emptying and vomiting was determined according to Compound No. 3
(3 mg / kg) and ondansetron (0.03 mg / kg) were significantly suppressed [FIG. 18]. from this result,
Cisplatin-induced acute emesis in ferrets was compound no. 3 and ondansetron were found to be significantly suppressed.

Example 9 Compound No. 3 against delayed emesis due to the anticancer drug cisplatin Effect of Combination of 3 and Dexamethasone [Method] Male ferrets (1.2 to 1.9 kg) were used. Cisplatin was administered intraperitoneally at 5 mg / 5 ml / kg. Compound N
o. 3 (3 mg / kg) and dexamethasone (1 mg / kg) were orally administered 30 minutes after cisplatin administration. Control animals were similarly orally administered a 0.5% (W / V) methylcellulose (MC) solution. The number of empty vomiting and vomiting during the 13 hours from 31 to 44 hours after cisplatin administration was counted. If a ferret vomited within one hour after oral administration, the data for that ferret was not used. Animal behavior is closed-circuit
Recordings were made on a video recording system and analyzed after the experiment was completed.
The data on the number of vomiting and vomiting were statistically analyzed by the Dunnett test to determine the difference from the control group. [Results] In the control animals, the number of idling and vomiting 31 to 44 hours after the administration of cisplatin was 74.0 ± 20.7. Compound No. The combination of 3 (3 mg / kg) and dexamethasone (1 mg / kg) significantly reduced the number of empty vomiting and vomiting [FIG. 19]. The results show that cisplatin-induced delayed emesis in ferrets was compound no. 3 and dexamethasone were found to be significantly suppressed by the combined use.

Example 10 Compound No. 10 against acute emesis by anticancer drug cisplatin 3. Combined effect of ondansetron and dexamethasone [Method] Male ferrets (1.7 to 2.0 kg) were used. Cisplatin was administered intraperitoneally at 10 mg / 10 ml / kg. Compound N
o. 3 (3 mg / kg), ondansetron (0.03 mg / kg) and dexamethasone (1 mg / kg) were orally administered 30 minutes before cisplatin administration. Control animals were similarly orally administered a 0.5% (W / V) methylcellulose (MC) solution. The number of vomiting and vomiting 180 minutes after cisplatin administration was counted. Animal behavior is recorded by a closed-circuit video recording system
Analysis was performed after the end of the experiment. Data on the number of empty vomiting and vomiting were statistically analyzed by Student's t test to determine the difference from the control group. [Results] In the control animals, the number of idling and vomiting was 227 ± 52. Compound No. 3. The combination of ondansetron and dexamethasone significantly reduced the number of vomiting and vomiting. The results are shown in FIG. 20 and Table 26.

[0389]

[Table 26]

The results indicate that cisplatin-induced acute emesis in ferrets was compound No. 3. It was revealed that the combination was significantly suppressed by the combined use of ondansetron and dexamethasone.

Example 11 Compound No. 10 against delayed emesis by anticancer drug cisplatin 3. Combined effect of ondansetron and dexamethasone [Method] Male ferrets (1.7 to 1.9 kg) were used. Cisplatin was administered intraperitoneally at 5 mg / 5 ml / kg. Compound N
o. 3 (3 mg / kg), ondansetron (0.03 mg / kg) and dexamethasone (1 mg / kg) were orally administered 30 minutes after cisplatin administration. Control animals were similarly orally administered a 0.5% (W / V) methylcellulose (MC) solution. The number of empty vomiting and vomiting during the 13 hours from 31 to 44 hours after cisplatin administration was counted. Animal behavior was recorded on a closed-circuit video recording system and analyzed after the experiment. Data on the number of empty vomiting and vomiting were statistically analyzed by Student's t test to determine the difference from the control group. (Results) In the control animals, the number of idling and vomiting was 63.0 ± 9.1.
It was times. Compound No. 3. The combined use of ondansetron and dexamethasone significantly reduced the number of vomiting and vomiting [FIG. 21]. The results show that cisplatin-induced delayed emesis in ferrets was compound no. 3,
It was clarified that the combination of ondansetron and dexamethasone significantly suppressed.

[0392]

EFFECTS OF THE INVENTION The compound (I) or a salt thereof can suppress vomiting caused by a drug having an emetic action quickly and safely at a low dose, and widen the application range of a drug having an emetic action as a side effect. In addition, the patient's QOL can be improved.

[0393]

[Brief description of the drawings]

FIG. 1 shows patterns of acute emptying and vomiting when cisplatin was administered at 10 mg / kg, ip to ferrets. As a result, the number of empty vomiting and the number of vomiting every 20 minutes of the total observation time were shown by an average value ± standard error.

FIG. 2. Compound No. on cisplatin-induced vomiting in ferrets. 3 shows the effect of oral administration. As a result, the number of empty vomiting and the number of vomiting for the entire observation time were shown as mean ± standard error.

FIG. 3 shows the pattern of vomiting when cisplatin was intravenously administered at 3 mg / kg to dogs. The results are shown as the mean ± standard error of the number of vomiting every 10 minutes during the entire observation time.

FIG. 4. Compound No. on cisplatin-induced emesis in dogs. 3 shows the effect of oral administration. As a result, the number of vomiting at all observation time was shown by an average value ± standard error.

FIG. 5. Compound No. on cisplatin-induced emesis in dogs. 3 shows the effect of intravenous administration. As a result, the number of vomiting at all observation time was shown by an average value ± standard error.

FIG. 6 shows the pattern of vomiting and vomiting when cisplatin was administered to ferrets at 5 mg / kg, ip. Also,
Compound no. 3 shows the effect of twice daily administration.

FIG. 7. Compound No. on cisplatin-induced acute and delayed emesis in ferrets. 3 shows the effect of oral administration of 3 and ondansetron twice daily.

FIG. 8 shows the patterns of vomiting and vomiting when cisplatin was administered at 5 mg / kg, ip to ferrets. Also,
Compound no. 3 shows the effect of once-a-day administration.

FIG. 9. Compound No. on cisplatin-induced acute and delayed emesis in ferrets. 3 shows the effect of oral administration once a day.

FIG. 10. Compound No. on MTX-induced delayed emesis in dogs. 3 shows the effect of oral administration of 3 and ondansetron. As a result, the number of vomiting every 4 hours of the total observation time (72 hours) was shown by an average value ± standard error.

FIG. 11. Compound No. on MTX-induced delayed emesis in dogs. 3 shows the effect of oral administration of 3 and ondansetron. As a result, the number of vomits during the entire observation time (72 hours) was shown as an average value ± standard error.

FIG. 12 shows the patterns of vomiting and vomiting when morphine was administered to ferrets. The results were expressed as the mean ± standard error of the number of vomiting every 10 minutes during the entire observation time.

FIG. 13. Morphine (0.3 mg / kg, s.
c.) Compound no. 3 shows the effect of oral administration of 3 and ondansetron. As a result, the number of vomiting at all observation time was shown by an average value ± standard error.

FIG. 14. Compound No. on loperamide-induced vomiting in dogs. 3 shows the effect of oral administration of 3 and ondansetron. The results were expressed as the mean ± standard error of the number of vomiting every 10 minutes during the entire observation time.

FIG. 15. Compound No. on loperamide-induced vomiting in dogs. 3 shows the effect of oral administration of 3 and ondansetron and the effect of intravenous administration of naloxone. As a result, the number of vomiting at all observation time was shown by an average value ± standard error.

FIG. 16. Compound No. on apomorphine-induced emesis in dogs. 3 shows the effect of oral administration of 3 and ondansetron. The results were expressed as the mean ± standard error of the number of vomiting every 10 minutes during the entire observation time.

FIG. 17. Compound No. on apomorphine-induced emesis in dogs. 3 shows the effect of oral administration of 3 and ondansetron. As a result, the number of vomiting at all observation time was shown by an average value ± standard error.

FIG. 18. Compound No. on cisplatin-induced acute emesis in ferrets. 3 shows the effect of ondansetron combined administration (Cpd. No. 3 + Ond). As a result, the number of empty vomiting and the number of vomiting in the total observation time (180 minutes after cisplatin administration) of the six animals were shown as mean ± standard error (* p <0.05).

FIG. 19. Compound No. on cisplatin-induced delayed emesis in ferrets. 3 shows the effect of combined administration of dexamethasone (Cpd. No. 3 + Dex). As a result, the number of empty vomiting and the number of vomiting in the total observation time (31 to 44 hours after cisplatin administration) of the six animals were shown as mean ± standard error (* p <0.05).

FIG. 20. Compound No. on cisplatin-induced acute emesis in ferrets. 3 shows the effect of ondansetron / dexamethasone combination administration (Drugs). As a result, the number of empty vomiting and the number of vomiting of all four animals during the entire observation time (180 minutes after the administration of cisplatin) were shown as mean ± standard error (* p <0.05).

FIG. 21. Compound No. on cisplatin-induced delayed emesis in ferrets. 3 shows the effect of ondansetron / dexamethasone combination administration (Drugs). The results were based on the total observation time of 4 animals (31-44 after cisplatin administration).
The number of empty vomiting and the number of vomiting at (time) were shown as the mean ± standard error (* p <0.05).

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/551 A61K 31/551 A61P 1/08 A61P 1/08 25/04 25/04 35/00 35 / 00 C07D 471/14 102 C07D 471/14 102 498/04 116 498/04 116 F term (reference) 4C065 AA01 AA04 BB09 CC08 DD03 EE03 HH01 JJ01 KK02 LL01 PP03 4C072 AA01 BB02 CC02 CC11 EE05 A02A01 001 CB22 MA02 MA04 MA35 MA52 MA57 MA66 NA12 NA14 ZA71 ZC42 ZC75

Claims (39)

[Claims] (1) Formula (1) A heterocyclic ring having -CS-N <; R ^a and R ^b are bonded together to form a ring A, or the same or different and a substituent on a hydrogen atom or an M ring; A homocyclic or heterocyclic ring optionally having a group, at least one of which is a heterocyclic ring optionally having a substituent; C
The ring is a homo- or heterocyclic ring which may have a substituent; the Z-ring is a nitrogen-containing heterocyclic ring which may be substituted; and n is an integer of 1 to 6. Or a salt thereof, and a drug having an emetic action. 2. R ^a and R ^b are each a hydrogen atom or (1) a halogen atom; (2) (i) a hydroxyl group, (ii)
C _1-6 alkoxy group, (iii) C _1-6 alkylthio group, (i
v) amino group, (v) C _1-7 acylamino group, (vi) carboxyl group, (vii) nitro group, (viii) mono- or di-C _1-6 alkylamino group, (ix) mono- or di- −C _3-8
Cycloalkylamino group, (x) C _6-10 arylamino group, (xi) C _1-6 alkyl optionally substituted, an oxygen atom in addition to the nitrogen atom, 1 to heteroatoms selected from sulfur atom A 5- or 6-membered 5- or 9-membered cyclic amino group which may contain 3 or 5 or 6-membered heteroatoms selected from nitrogen, oxygen and sulfur atoms in addition to (xii) carbon atoms An aromatic heterocyclic group, (xiii) a 5- to 9-membered non-aromatic heterocyclic group containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms, (xiv) C _1-4 alkylsulfonylamino group,
(Xv) a C _1-6 alkyl-carbonyloxy group and (xv
i) C _1-6 alkyl group optionally having 1 to 5 substituents selected from halogen atoms, (3) C _1-6 alkoxy group optionally halogenated, (4) halogen _Optionally substituted C _1-6 alkylthio group, (5) C _3-10 cycloalkyl group, (6) C _6-10 aryl group, (7) C
_1-7 acylamino group, (8) C _1-3 acyloxy group,
(9) hydroxyl group, (10) nitro group, (11) cyano group, (12) amino group, (13) mono- or di-C _1-6 alkylamino group, (14) C _1-6 alkyl which may also be a nitrogen atom other than the oxygen atom and the cyclic amino group a hetero atom selected from sulfur atom 1 to 3 which may contain 5-9 membered, (15) C _1-6 alkyl - carbonyl Amino group, (16) C _1-6 alkyl-sulfonylamino group,
(17) C _1-6 alkoxy-carbonyl group, (18) carboxyl group, (19) C _1-6 alkyl-carbonyl group, (2
0) a substituent selected from a carbamoyl group, (21) a mono- or di-C _1-6 alkylcarbamoyl group, and (22) a C _1-6 alkylsulfonyl group; R ^a and R ^b are bonded together Ring A to form ring A, wherein (1) halogen atom, (2) (i) hydroxyl group, (ii) amino group, (iii) carboxyl group, (iv) nitro group, (v) mono- or di- —C _1-6 alkylamino group,
(Vi) a C _1-6 alkyl-carbonyloxy group and (vi)
i) C _1-6 alkyl group optionally having 1 to 5 substituents selected from halogen atoms, (3) C _1-6 alkoxy group optionally halogenated, (4) halogen _Optionally substituted C _1-6 alkylthio group, (5) C _6-10 aryl group, (6) C _1-7 acylamino group, (7) C _1-3 acyloxy group, (8) hydroxyl group, ( 9) nitro group, (10) cyano group, (11) amino group, (12) mono- or di-C _1-6 alkylamino group, (13) heteroatom selected from oxygen atom and sulfur atom other than nitrogen atom Atom 1 to
A 5- to 9-membered cyclic amino group optionally containing three, (14)
C _1-6 alkyl-carbonylamino group, (15) C _1-6 alkyl-sulfonylamino group, (16) C _1-6 alkoxy-
Carbonyl group, (17) carboxyl group, (18) C _1-6 alkylcarbonyl group, (19) carbamoyl group, (20) mono- or di-C _1-6 alkylcarbamoyl group, (21) C
One or two selected from a nitrogen atom, a sulfur atom and an oxygen atom, in addition to a carbon atom which may be substituted with 1 to 4 substituents selected from _1-6 alkylsulfonyl groups and (22) oxo groups A 5- to 9-membered aromatic heterocyclic ring containing 1 to 3 heteroatoms, 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms A 5- to 9-membered non-aromatic heterocyclic ring or a 3- to 10-membered cyclic hydrocarbon, wherein ring B is (1) a halogen atom, (2) (i) a hydroxyl group, (ii) an amino group, (iii) Carboxyl group,
1 to 5 substitutions selected from (iv) a nitro group, (v) a mono- or di-C _1-6 alkylamino group, (vi) a C _1-6 alkyl-carbonyloxy group and (vii) a halogen atom. A C _1-6 alkyl group which may have a group, (3) a C _1-6 alkoxy group which may be halogenated, (4) a C _1-6 alkylthio group which may be halogenated, ( 5)
C _6-10 aryl group, (6) C _1-7 acylamino group,
(7) C _1-3 acyloxy group, (8) hydroxyl group,
(9) nitro group, (10) cyano group, (11) amino group,
(12) mono- or di-C _1-6 alkylamino group, (13)
Nitrogen atom except the oxygen atom and the cyclic amino group 1-3 which may contain also 5-9 membered sulfur atom from selected heteroatom, (14) C _1-6 alkyl - carbonyl amino group,
(15) C _1-6 alkyl-sulfonylamino group, (16) C
_1-6 alkoxy - carbonyl group, (17) carboxyl group, (18) C _1-6 alkylcarbonyl group, (19) carbamoyl group, (20) mono- - or di -C _1-6 alkylcarbamoyl group, (21) C _1-6 alkylsulfonyl and (2
2) One or two or more hetero atoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms which may be substituted with 1 to 4 substituents selected from oxo groups. A 5- to 9-membered aromatic heterocyclic ring,
One to three hetero atoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms;
A 5- to 9-membered non-aromatic heterocyclic ring or a 3- to 10-membered cyclic hydrocarbon; and wherein the ring C is (1) a halogen atom, (2) an optionally halogenated C _1-10 alkyl group, (3) a C _1-4 alkyl group substituted with an amino group,
(4) mono - or di -C _1-4 C _1-4 alkyl group substituted with an alkylamino group, (5) C _1-4 alkyl group substituted with a carboxyl group, (6) C _1-4 alkoxy A C _1-4 alkyl group substituted with a carbonyl group, (7) a C _1-4 alkyl group substituted with a hydroxyl group, (8) a C _3-10 cycloalkyl group, (9) a nitro group, (10) Cyano group,
(11) hydroxyl group, (12) optionally halogenated C _1-10 alkoxy group, (13) optionally halogenated C _1-4 alkylthio group, (14) amino group, (15)
A mono- or di-C _1-4 alkylamino group, (16) a 5- to 9-membered cyclic amino group which may contain 1 to 3 heteroatoms selected from an oxygen atom and a sulfur atom in addition to a nitrogen atom, (17) C _1-4 alkyl-carbonylamino group, (1
8) aminocarbonyloxy group, (19) mono- or di-
C _1-4 alkylaminocarbonyloxy group, (20) C _1-4
Alkylsulfonylamino group, (21) C _1-4 alkoxy - carbonyl group, (22) aralkyloxycarbonyl groups, (23) carboxyl group, (24) C _1-6 alkyl - carbonyl group, (25) C _3-6 Cycloalkyl-carbonyl group, (26) carbamoyl group, (27) mono- or di-C
_1-4 alkylcarbamoyl groups, in addition to (28) C _1-6 alkylsulfonyl group, or (29) one to three optionally halogenated and C _1-4 carbon atoms which may be substituted by an alkyl group 1 to 5 substituents selected from a 5- or 6-membered aromatic monocyclic heterocyclic ring containing 1 to 4 one or two hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom One selected from a nitrogen atom, a sulfur atom and an oxygen atom other than a carbon atom which may be substituted;
A 5- to 9-membered heterocyclic ring containing 1 to 3 kinds or 2 kinds of hetero atoms; or (1) a halogen atom, (2) an optionally halogenated C _1-10 alkyl group, (3) amino C _1-4 alkyl group substituted with a group, (4) mono - or C _1-4 alkyl group substituted with a di -C _1-4 alkylamino groups, C substituted with (5) a carboxyl group _{1- 4} alkyl group, (6) C _1-4 alkoxy - C _1-4 alkyl group substituted by a carbonyl group, (7) C _1-4 alkyl group substituted by a hydroxyl group, (8) C _3-10 cycloalkyl Alkyl group, (9) nitro group, (10) cyano group, (11) hydroxyl group, (12) optionally halogenated C _1-10 alkoxy group, (13) optionally halogenated C _{1 -4} alkylthio group, (14) amino group, (15) mono- or di-
A C _1-4 alkylamino group, (16) a 5- to 9-membered cyclic amino group which may contain 1 to 3 heteroatoms selected from an oxygen atom and a sulfur atom in addition to a nitrogen atom, (17) C _{1 -Four}
Alkyl-carbonylamino group, (18) aminocarbonyloxy group, (19) mono- or di-C _1-4 alkylaminocarbonyloxy group, (20) C _1-4 alkylsulfonylamino group, (21) C _{1- 4} alkoxy-carbonyl group,
(22) aralkyloxycarbonyl group, (23) carboxyl group, (24) C _1-6 alkyl-carbonyl group, (25)
C _3-6 cycloalkyl-carbonyl group, (26) carbamoyl group, (27) mono- or di-C _1-4 alkylcarbamoyl group, (28) C _1-6 alkylsulfonyl group and (2)
9) one or two selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom which may be substituted by 1 to 3 optionally halogenated C _1-4 alkyl groups;
A 3- to 10-membered homocyclic ring which may be substituted with 1 to 5 substituents selected from a 5- or 6-membered aromatic monocyclic heterocycle containing 1 to 4 heteroatoms. ;
The Z ring is composed of (1) a C _1-6 alkyl group, (2) a C _2-6 alkenyl group, (3) a C _2-6 alkynyl group, (4) a C _3-8 cycloalkyl group, and (5) a C _{3- 8} cycloalkyl-C _1-4 alkyl group, (6) C _6-14 aryl group, (7) nitro group, (8)
Cyano group, (9) hydroxyl group, (10) C _1-4 alkoxy group, (11) C _1-4 alkylthio group (12) amino group,
(13) mono- or di-C _1-4 alkylamino group, (14)
A 5- to 9-membered cyclic amino group which may contain 1 to 3 heteroatoms selected from an oxygen atom and a sulfur atom in addition to the nitrogen atom, (15) _C1-4 alkyl-carbonylamino group,
(16) C _1-4 alkylsulfonylamino group, (17) C _1-4
Alkoxy-carbonyl group, (18) carboxyl group,
(19) C _1-6 alkyl-carbonyl group, (20) carbamoyl group, (21) mono- or di-C _1-4 alkylcarbamoyl group, (22) C _1-6 alkylsulfonyl group, (23) oxo group And 1 to 5 selected from (24) thioxo groups
A 5- to 12-membered group which may contain at least one heteroatom selected from nitrogen, oxygen and sulfur, in addition to Y and carbon and nitrogen, which may be substituted by The medicament according to claim 1, which is a heterocyclic ring. 3. R ^a and R ^b are bonded together to form a ring A, and a ring C is a benzene ring which may have a substituent, a hetero ring which may have a substituent, and a ring Z. Is a nitrogen-containing heterocyclic ring which may be oxo-modified, and n is 1 or 2. 4. The medicament according to claim 1, wherein the ring Z is a nitrogen-containing heterocyclic ring which may be oxo-modified. 5. The medicament according to claim 1, wherein one of the rings A and B is an aromatic ring which may have a substituent, and the other is an aromatic hetero ring which may have a substituent. 6. The medicament according to claim 1, wherein ring A is an aromatic heterocyclic ring which may have a substituent, and ring B is a benzene ring which may have a substituent. 7. The aromatic heterocyclic ring is a nitrogen atom other than a carbon atom,
The medicament according to claim 5, which is a 5- or 6-membered aromatic heterocycle containing one or two hetero atoms selected from a sulfur atom and an oxygen atom. 8. The medicament according to claim 1, wherein the ring C is an optionally substituted benzene ring. 9. The ring C has 1 to 3 substituents selected from a halogen atom, an optionally halogenated C _1-6 alkyl group and an optionally halogenated C _1-6 alkoxy group. The medicament according to claim 1, which has a benzene ring. 10. The medicament according to claim 1, wherein the ring Z is a 5- to 10-membered ring which may be substituted with one or two oxo groups. (11) The medicament according to claim 1, which is: 12. The medicament according to claim 1, wherein n is 1. 13. A ring in which ring A may have a substituent, a benzene ring in which ring B may have a substituent, C
A benzene ring in which the ring may have a substituent, a 5- to 10-membered ring in which the Z ring may be oxo-modified, 2. The medicament according to claim 1, wherein n is 1. 14. R ^a and R ^b are the same or different and each represents a hydrogen atom, a halogen atom, an optionally substituted alkyl group, an alkoxy group which may be halogenated, optionally halogenated Good alkylthio, cycloalkyl, aryl, acylamino, acyloxy, hydroxyl, nitro, cyano, amino,
Mono- or di-alkylamino group, cyclic amino group, alkylcarbonylamino group, alkylsulfonylamino group, alkoxycarbonyl group, carboxyl group, alkylcarbonyl group, carbamoyl group, mono- or di-alkylcarbamoyl group, alkylsulfonyl group or The medicament according to claim 1, which is an oxo group. (15) R ^a and R ^b are the same or different and each is a hydrogen atom or a C _1-6 alkoxy group, a C _1-6 alkylthio group,
An amino group, a C _1-7 acylamino group, a mono- or di-C _1-6 alkylamino group, a C _3-10 cyclic amino group,
C _1-6 alkyl may also be 5 or be substituted with group 6-membered cyclic amino group, C _1-6 alkylsulfonylamino group or a C _1-6 alkylcarbonyloxy optionally substituted by a group C _1-6 An alkyl group or R ^a and R ^b are bonded together to form a pyridine ring optionally having 1 to 3 substituents selected from a halogen atom and a C _1-4 alkyl group, _1-3 selected from a halogen atom, a C _1-4 alkyl group which may be halogenated and a C _1-4 alkoxy group which may be halogenated
A benzene ring which may have one or more substituents, wherein the ring C is a halogen atom,
_1-4 alkyl groups, optionally halogenated C _1-4 alkoxy groups, amino groups optionally substituted by C _1-4 alkyl groups, C _1-3 acyloxy groups and hydroxyl groups selected from 1 to A 5- to 10-membered nitrogen-containing heterocyclic group which may be substituted with a C _1-4 alkyl group or a hydroxyl group or may be oxo-modified, which is a benzene ring optionally having three substituents; A cyclic group, 2. The medicament according to claim 1, wherein n is 1. 16. R ^a and R ^b are bonded together to form a pyridine ring which may have 1 to 3 substituents selected from a halogen atom and a C _1-4 alkyl group, 5] The medicament according to claim 15, which is: 17. The medicament according to claim 16, wherein the pyridine ring is an unsubstituted pyridine ring. (18) C wherein ring B may be halogenated;
The medicament according to claim 15, which is a benzene ring optionally having 1 to 3 _1-4 alkyl groups. 19. The ring C has one to three substituents selected from a halogen atom, an optionally halogenated C _1-4 alkyl group and an optionally halogenated C _1-4 alkoxy group. The medicament according to claim 15, which is a benzene ring that may be possessed. (20) the ring Z is a compound of the formula: [Wherein, m and p are the same or different and represent an integer of 1 to 5, Z ₁ and Z ₂ are the same or different and represent a hydrogen atom,
A C _1-4 alkyl group or a hydroxyl group, and Y has the same meaning as described in claim 15]. 21. Compound (I) is (9S) -7- [3,5-
Bis (trifluoromethyl) benzyl] -6,7,8,
9,10,12-Hexahydro-9-methyl-6,12
-Dioxo-5-phenyl [1,4] diazepino [2,
1-g] [1,7] naphthyridine. (22) the compound (I) is (9S) -7- [3,5-
Bis (trifluoromethyl) benzyl] -6,7,8,
9,10,12-Hexahydro-9-methyl-5- (4
-Methylphenyl) -6,12-dioxo- [1,4]
The medicament according to claim 1, which is diazepino [2,1-g] [1,7] naphthyridine. (23) The compound (I) is (9R) -7- [3,5-
Bis (trifluoromethyl) benzyl] -6,7,8,
9,10,11-hexahydro-9-methyl-6,13
The medicament according to claim 1, which is -dioxo-5-phenyl-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine. (24) The compound (I) is (9R) -7- [3,5-
Bis (trifluoromethyl) benzyl] -6,7,8,
9,10,11-Hexahydro-9-methyl-5- (4
-Methylphenyl) -6,13-dioxo-13H-
The medicament according to claim 1, which is [1,4] diazosino [2,1-g] [1,7] naphthyridine. (25) The compound (I) is (9R) -7- (3,5-
Dimethoxybenzyl) -5- (4-fluorophenyl)
-6,7,8,9,10,11-Hexahydro-9-methyl-6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine. The medicament according to 1. (26) the compound (I) is (9R) -7- (3,5-
Dimethoxybenzyl) -6,7,8,9,10,11-
The medicament according to claim 1, which is hexahydro-9-methyl-5- (4-methylphenyl) -6,13-dioxo-13H- [1,4] diazosino [2,1-g] [1,7] naphthyridine. . 27. The medicament according to claim 1, wherein the drug having an emetic action is an anticancer drug. 28. The medicament according to claim 1, wherein the drug having an emetic action is morphine or a derivative or salt thereof. 29. The medicament according to claim 1, wherein the drug having an emetic action is apomorphine or a salt thereof. (30) the medicament according to the above (28), wherein the compound (I) or a salt thereof is contained in a preparation for oral administration; 31. The medicament according to claim 28, wherein morphine or a derivative thereof or a salt thereof is contained in a sustained-release preparation. 32. The medicament according to claim 28, wherein morphine or a derivative thereof or a salt thereof is contained in a preparation for oral administration. 33. The medicament according to claim 32, wherein the preparation for oral administration is a sublingual tablet or buccal. 34. The medicament according to claim 32, wherein the preparation for oral administration is an intraoral quick disintegrating agent. 35. A combination of a preparation for oral administration containing the compound (I) or a salt thereof and an injection or a preparation for oral administration containing morphine or a derivative thereof or a salt thereof. The medicament according to claim. 36. The medicament according to claim 1, further comprising a serotonin antagonist and / or a carbohydrate steroid. 37. The formula: A heterocyclic ring having -CS-N <; R ^a and R ^b are bonded together to form a ring A, or the same or different and a substituent on a hydrogen atom or an M ring; A homocyclic or heterocyclic ring optionally having a group, at least one of which is a heterocyclic ring optionally having a substituent; C
The ring is a homo- or heterocyclic ring which may have a substituent; the Z-ring is a nitrogen-containing heterocyclic ring which may be substituted; and n is an integer of 1 to 6. Or a salt thereof and a drug having an emetic action. 38. A formula for producing a medicament for suppressing emesis of a drug having an emetic action. A heterocyclic ring having -CS-N <; R ^a and R ^b are bonded together to form a ring A, or the same or different and a substituent on a hydrogen atom or an M ring; A homocyclic or heterocyclic ring optionally having a group, at least one of which is a heterocyclic ring optionally having a substituent; C
The ring is a homo- or heterocyclic ring which may have a substituent; the Z-ring is a nitrogen-containing heterocyclic ring which may be substituted; and n is an integer of 1 to 6. Use of the compound (I) or a salt thereof represented by the formula: 39. A mammal to which a drug having an emetic action is administered or to which a drug having the effect is administered. A heterocyclic ring having -CS-N <; R ^a and R ^b are bonded together to form a ring A, or the same or different and a substituent on a hydrogen atom or an M ring; A homocyclic or heterocyclic ring optionally having a group, at least one of which is a heterocyclic ring optionally having a substituent; C
The ring is a homo- or heterocyclic ring which may have a substituent; the Z-ring is a nitrogen-containing heterocyclic ring which may be substituted; and n is an integer of 1 to 6. Or a salt thereof, which comprises administering the compound (I) or a salt thereof.